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IsomicroRNA

Posted in Curation, Cytokines, Developmental biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Metabolism, Metabolomics, Molecular Genetics & Pharmaceutical, RNA Biology, Uncategorized, tagged , , , , , , , , , on February 18, 2016| Leave a Comment »

IsomicroRNA

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

GEN Feb 15, 2016 (Vol. 36, No. 4)

MicroRNAs Rise from Trash to Treasure  

MicroRNAs Are More Plentiful and More Subtle In Action Than Was Once Suspected

Richard A. Stein, M.D., Ph.D.

 

One of the unexpected findings of the Human Genome Project was that over 98% of the human genome does not encode for proteins. Once dismissed as “junk” genomic material, non-protein-coding DNA is now appraised more highly.

Or to be more precise, at least some portions of non-protein-coding DNA are thought to serve important biological functions.

For example, some stretches of DNA give rise to a noncoding but still functional kind of RNA called microRNA. MicroRNAs have increasingly emerged in recent years as key regulators of biological processes and pathways.

During the years since their discovery, a key question in the biology of microRNAs has focused on the number of microRNAs encoded in the genome. Between 1993 and 2015, approximately 1,900 human genome loci were discovered to produce microRNAs and were added to miRBbase, the public database that catalogues and annotates microRNA molecules.

The cataloguing of microRNAs work has been pursued with extra urgency since 2004, the year the connection between microRNAs and human disease was first demonstrated. “When this connection was made, it launched a whole new field,” says Isidore Rigoutsos, Ph.D., professor of pathology, anatomy, and cell biology and director of the Computational Medicine Center at Thomas Jefferson University.

 

 

 

Another Set of MicroRNAs Emerge

“We wanted to know how many microRNA-producing loci really exist in humans,” recalls Dr. Rigoutsos. In a study published in 2015, Dr. Rigoutsos and colleagues analyzed datasets from 1,323 individuals that represented 13 different tissues and identified an additional 3,356 such genomic loci that produce (at least) 3,707 novel microRNs

“We basically tripled the number of locations in the human genome that are now known to encode microRNAs,” asserts Dr. Rigoutsos. Considering that each microRNA regulates up to hundreds of different mRNAs, and that each mRNA is regulated by tens of microRNAs, this finding adds a new layer of complexity to the regulatory dynamics of the human transcriptome.

The newly unveiled microRNAs and previously characterized microRNAs have distinct expression patterns. While 50–60% of the microRNAs previously deposited into the miRBase are expressed in multiple tissues, only about 10% of the newly discovered microRNAs are shared across multiple tissue types. Also, most of the newly found microRNAs show tissue-specific expression.

Using Argonaute CLIP-seq data, Dr. Rigoutsos and colleagues showed that similar percentages of the two sets of microRNAs were in complex with Argonaute proteins. “This shows that these novel microRNAs participate in RNA interference just as frequently as the miRBase microRNAs,” contends Dr. Rigoutsos.

In a comparative analysis between the human microRNA datasets and the chimpanzee, gorilla, orangutan, macaque, mouse, fruit fly, and mouse genomes, Dr. Rigoutsos and colleagues discovered that almost 95% of the newly unveiled microRNAs were primate-specific, and over 56% of them were found only in humans.

“We are seeing many human microRNAs that do not exist in the mouse,” states Dr. Rigoutsos. “This means that the mouse models engineered to capture human disease cannot recapitulate the interactions mediated by these microRNAs.

 

  • Interest in IsomiRs Grows

  • In the years since the biology of microRNAs started receiving increasing attention, the conventional view has been that one microRNA locus generates one microRNA. However, once deep sequencing became widely available, microRNA variants that showed differences at their 5′- or 3′-termini have been described.

    “It was initially presumed that these variants were likely the result of the enzyme Dicer not being sufficiently accurate when processing microRNA precursors,” notes Dr. Rigoutsos. Subsequent research revealed that microRNAs are more dynamic than previously thought, with each precursor being able to generate multiple mature microRNA species known as isomiRs.

    To gain insight into the biology of isomiRs, Dr. Rigoutsos and colleagues analyzed genomic datasets from 452 individuals participating in the 1000 Genomes Project. The datasets comprised five different populations and two races. In addition, each population was represented by an even number of men and women.

    This collection allowed the abundance of microRNA isoforms to be examined with respect to population, gender, and race. “We found that isomiRs have expression profiles that are population-, race-, and gender-dependent,” informs Dr. Rigoutsos.

    All the transcriptome data that this analysis was based on came from immortalized B cells. “These are cells that normally are not associated with gender differences, but molecularly we found, in these cells, differences between men and women of the same population and race,” explains Dr. Rigoutsos.

  • Expanding these observations to disease states, Dr. Rigoutsos and colleagues collected isomiR profiles from tissue affected by breast cancer, and compared them with isomiR profiles from control breast tissue. The investigators found that the isomiR profiles also depend on tissue state (healthy vs. diseased), on disease subtype, and on the patient’s race.

    For example, their analysis identified several miR-183-5p isoforms that were upregulated in white triple-negative breast cancer patients compared to control breast samples, but not in black/African-American triple-negative breast cancer patients. In an in vitro phase of this study, three isoforms of this microRNA species were overexpressed in human breast cancer cell lines.

    “We found very little overlap in the gene sets that were affected by each of these isoforms,” emphasizes Dr. Rigoutsos. Despite being generated simultaneously by the same locus, each of the three isoforms affected distinct groups of genes, thus exerting different effects on the transcriptome.

    “As the relative abundance of these isoforms changes ever so slightly from patient to patient, it will affect the corresponding gene groups slightly differently,” concludes Dr. Rigoutsos. “In the process, it creates a new molecular background in each patient.”

    MicroRNAs Point to Therapeutic Strategies against Colorectal Cancer

  • “We are using microRNAs as modulators to overcome chemotherapy resistance in colorectal cancer,” says Jingfang Ju, Ph.D., associate professor of pathology and co-director of translational research at Stony Brook University School of Medicine. Resistance to chemotherapy is one of the major challenges in the clinical management of malignancies, including colorectal cancer. Chemotherapy is usually unable to eliminate cancer stem cells, which may become even more resistant over time, and several microRNAs have been implicated in this process.  “We reasoned that we could provide new modulatory approaches to target this small cell population and allow chemotherapy, radiotherapy, or immunotherapy to eliminate resistant populations or at least prolong long-term survival,”  Dr. Ju said.

  • http://www.genengnews.com/Media/images/Article/StonyBrookUniv_JingfangJu5310853233.jpg

    This image shows how miR-129 may function as a tumor suppressor in colorectal cancer. In this model, which has been proposed by researchers at Stony Brook University’s Translational Research Laboratory, miR-129 suppresses the protein expression of three critical targets—BCL2, TS, and E2F3. Downregulation of BCL2 activates the intrinsic apoptosis pathway by cleaving caspase-9 and caspase-3. Downregulation of TS and E2F3 inhibits cell proliferation by impacting the cell cycle. Consequently, miR-129 exerts a strong antitumor phenotype by induction of apoptosis and impairment of proliferation in tumor cells. [Mihriban Karaayvaz, Haiyan Zhai, Jingfang Ju]

     

    In a retrospective study in which colorectal patient samples were used, Dr. Ju and colleagues revealed that hsa-miR-140-5p expression progressively decreases from normal tissues to primary colorectal cancer tissue, and that it shows a further decrease in liver and lymph node metastases. The experimental overexpression of hsa-miR-140-5p inhibited colorectal cancer stem cell growth by disrupting autophagy, and in a mouse model of disease it abolished tumor formation and metastasis.

    In addition to hsa-miR-140-5p, Dr. Ju and colleagues recently identified hsa-miR-129 and found that it, too, has therapeutic potential. Specifically, they showed that hsa-miR-129 enhanced the sensitivity of colorectal cancer cells to 5-fluorouracil, pointing toward its ability to function as a tumor suppressor.

    One of the mechanisms implicated in this process was the ability of miR-192 to inhibit protein translation of several important targets. These include Bcl-2 (B-cell lymphoma 2), a key anti-apoptotic protein; E2F3, a major cell cycle regulator; and thymidylate synthase, an enzyme that is inhibited by 5-fluorouracil.

    The NIH recently awarded a $3 million grant to establish the Long Island Bioscience Hub (LIBH), which is part of the NIH’s Research Evaluation and Commercialization Hub (REACH) program and represents a partnership between the Center for Biotechnology, Stony Brook University, Cold Spring Harbor Laboratory, and Brookhaven National Laboratory. One of the technology development grants, as part of the first funding cycle of this initiative, will support a feasibility investigation of hsa-miR-129-based therapeutics in colon cancer, an effort led by Dr. Ju. “We are further exploring this novel mechanism,” states Dr. Ju. “We anticipate conducting pharmacokinetic studies and moving to a clinical trial in the future.”

    MicroRNA Insights Gleaned from Host-Virus Interactions

    http://www.genengnews.com/Media/images/Article/MtSinaiHosp_Benjamin_tenOever1664523413.jpg

    At Mount Sinai Hospital’s Icahn School of Medicine, researchers used a codon-optimized version of VP55 produced from an adenovirus-based vector to study the impact of microRNA deletion on the response to virus infection. This image shows RNA in situ hybridization of fibroblasts expressing VP55 (top left), and that of mock-treated fibroblasts (bottom right). Ribosomal RNA, DNA, and microRNAs (miR-26) are depicted by red, blue (DAPI), and green fluorophores, respectively.

    “We observed that when a poxvirus is artificially engineered to encode a microRNA, the microRNA is destroyed along with all the microRNAs from the host cell,” says Benjamin R. tenOever, Ph.D., professor of microbiology at the Icahn School of Medicine, Mount Sinai Hospital. Previously, Dr. tenOever’s group reported that a single vaccinia virus-encoded gene product, VP55, is sufficient to achieve this effect. The group also found that the protein adds nontemplate adenosines to the 3′-end of microRNAs associated with the RNA-induced silencing complex.

    biology,” asserts Dr. tenOever.

    In a recent study, Dr. tenOever and colleagues used a codon-optimized version of VP55 produced from an adenovirus-based vector to study the impact microRNA deletion would have on our normal response to virus infection. “We found that after administration of the vector and rapid ablation of microRNA expression, there is very little that happens over the first one to two days,” informs Dr. tenOever. During the first 24–48 hours after VP55 delivery, the elimination of cellular microRNAs impacted less than 0.35% of the over 11,000 genes expressed in the cell. After 9 days, however, almost 20% of the genes showed significant changes in expression.

    “MicroRNAs are very powerful and influential in controlling the biology of the cell but they do so over the long term,” declares Dr. tenOever. These findings are in agreement with knowledge that has accumulated over the years about microRNA biology, which established that microRNAs play a central role in determining how cells differentiate during development.

    “While microRNAs can act on hundreds of mRNAs, their action requires several days of fine-tuning to have long-term consequences,” adds Dr. tenOever. This finding suggests miRNAs are unable to significantly contribute to the acute response to virus infection.

    The one exception to this observation was that, even though very few genes were affected in the first 48 hours after VP55 delivery, several genes encoding chemokines were impacted. These included chemokines responsible for recruiting antigen-presenting cells, neutrophils, and other immune cells.

    An in vivo analysis of mouse lung tissue 48 hours after vector administration confirmed that several cytokines were specifically upregulated, resulting in immune cell infiltration following the degradation of all microRNAs. These results indicate that the acute viral infection is largely independent of microRNAs, and that microRNAs are primarily involved in the adaptive response to infection and other longer term processes.

    • MicroRNA Biomarkers Reveal Molecular Pathways of Kidney Damage

      “Our approach involves looking at microRNAs from the perspective of biomarkers as a readout for kidney damage,” says Vishal S. Vaidya, Ph.D., associate professor of medicine and environmental health at Brigham and Women’s Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health. “At the same time, we are exploring their utility as therapeutics.”

      A large number of medications and occupational toxins cause kidney damage, but many tests to assess kidney function and damage are not sufficiently sensitive or specific, opening the need for novel diagnostic strategies. MicroRNAs, which are differentially expressed between healthy and diseased states, are promising as early biomarkers for impaired renal function.

      “MicroRNAs can also provide information about which pathways are active and which targets can be druggable,” points out Dr. Vaidya.

      In a study that used microRNAs and proteins to provide a combined biomarker signature, Dr. Vaidya and colleagues examined two patient cohorts, one presenting with acetaminophen-induced kidney injury and the other one with cisplatin-induced kidney damage. “Protein biomarkers provide sensitivity, and microRNAs offer mechanistic insight,” explains Dr. Vaidya.

      This approach helped visualize metabolic pathways that are altered in the kidney during toxic injury. “The biggest challenge, from a therapeutic perspective, is that microRNAs regulate many mRNAs and, therefore, impact many proteins,” concludes Dr. Vaidya.

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Kurzweill Reports in Medical Science I

Posted in Alzheimer's Disease, Bacterial Resistance, Behavioral Genetics, Cardiac and Cardiovascular Surgical Procedures, Clinical & Translational, Clinical Genomics, Curation, Developmental biology, Embryology, Genetics & Pharmaceutical, Genome Biology, Human aging, Infectious Disease & New Antibiotic Targets, Innovations in Neurophysiology & Neuropsychology, Investment in Technological Breakthrough, Medical Imaging Technology, Microbiologial genetics, Microbiology, Molecular Genetics & Pharmaceutical, Myocardial Ischemia, Neurodegenerative Diseases, Neurological Diseases, Neuroscience, PCI, Pharmacotherapy and Cell Activity, tagged , , , , , , on November 21, 2015| Leave a Comment »

Kurzweill Reports in Medical Science I

Curator: Larry H. Bernstein, MD, FCAP

 

 

 

E-coli bacteria found in some China farms and patients cannot be killed with antiobiotic drug of last resort

“One of the most serious global threats to human health in the 21st century” — could spread around the world, requiring “urgent coordinated global action”
November 20, 2015

http://www.kurzweilai.net/e-coli-bacteria-found-in-some-china-farms-and-patients-cannot-be-killed-with-antiobiotic-drug-of-last-resort

Colistin antibiotic overused in farm animals in China apparently caused E-coli bacteria to become completely resistant to treatment; E-coli strain has already spread to Laos and Malaysia (credit: Yi-Yun Liu et al./Lancet Infect Dis)

Widespread E-coli bacteria that cannot be killed with the antiobiotic drug of last resort — colistin — have been found in samples taken from farm pigs, meat products, and a small number of patients in south China, including bacterial strains with epidemic potential, an international team of scientists revealed in a paper published Thursday Nov. 19 in the journal The Lancet Infectious Diseases.

The scientists in China, England, and the U.S. found a new gene, MCR-1, carried in E-coli bacteria strain SHP45. MCR-1 enables bacteria to be highly resistant to colistin and other polymyxins drugs.

“The emergence of the MCR-1 gene in China heralds a disturbing breach of the last group of antibiotics — polymixins — and an end to our last line of defense against infection,” said Professor Timothy Walsh, from the Cardiff University School of Medicine, who collaborated on this research with scientists from South China Agricultural University.

Walsh, an expert in antibiotic resistance, is best known for his discovery in 2011 of the NDM-1 disease-causing antibiotic-resistant superbug in New Delhi’s drinking water supply. “The rapid spread of similar antibiotic-resistant genes such as NDM-1 suggests that all antibiotics will soon be futile in the face of previously treatable gram-negative bacterial infections such as E.coli and salmonella,” he said.

Likely to spread worldwide; already found in Laos and Malaysia

The MCR-1 gene was found on plasmids — mobile DNA that can be easily copied and transferred between different bacteria, suggesting an alarming potential to spread and diversify between different bacterial populations.

Structure of plasmid pHNSHP45 carrying MCR-1 from Escherichia coli strain SHP45 (credit: Yi-Yun Liu et al./Lancet Infect Dis)

“We now have evidence to suggest that MCR-1-positive E.coli has spread beyond China, to Laos and Malaysia, which is deeply concerning,” said Walsh.  “The potential for MCR-1 to become a global issue will depend on the continued use of polymixin antibiotics, such as colistin, on animals, both in and outside China; the ability of MCR-1 to spread through human strains of E.coli; and the movement of people across China’s borders.”

“MCR-1 is likely to spread to the rest of the world at an alarming rate unless we take a globally coordinated approach to combat it. In the absence of new antibiotics against resistant gram-negative pathogens, the effect on human health posed by this new gene cannot be underestimated.”

“Of the top ten largest producers of colistin for veterinary use, one is Indian, one is Danish, and eight are Chinese,” The Lancet Infectious Diseases notes. “Asia (including China) makes up 73·1% of colistin production with 28·7% for export including to Europe.29 In 2015, the European Union and North America imported 480 tonnes and 700 tonnes, respectively, of colistin from China.”

Urgent need for coordinated global action

“Our findings highlight the urgent need for coordinated global action in the fight against extensively resistant and pan-resistant gram-negative bacteria,” the journal paper concludes.

“The implications of this finding are enormous,” an associated editorial comment to the The Lancet Infectious Diseases paper stated. “We must all reiterate these appeals and take them to the highest levels of government or face increasing numbers of patients for whom we will need to say, ‘Sorry, there is nothing I can do to cure your infection.’”

Margaret Chan, MD, Director-General of the World Health Organization, warned in 2011 that “the world is heading towards a post-antibiotic era, in which many common infections will no longer have a cure and, once again, kill unabated.”

“Although in its 2012 World Health Organization Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) report the WHO concluded that colistin should be listed under those antibiotics of critical importance, it is regrettable that in the 2014 Global Report on Surveillance, the WHO did not to list any colistin-resistant bacteria as part of their ‘selected bacteria of international concern,’” The Lancet Infectious Diseases paper says, reflecting WHO’s inaction in Ebola-stricken African countries, as noted last September by the international medical humanitarian organization Médecins Sans Frontières.

Funding for the E-coli bacteria study was provided by the Ministry of Science and Technology of China and National Natural Science Foundation of China.

Abstract of Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study

Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via
horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae.

The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model.

Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection.

The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria.

references:

 

Researchers discover signaling molecule that helps neurons find their way in the developing brain

November 20, 2015

http://www.kurzweilai.net/researchers-discover-signaling-molecule-that-helps-neurons-find-their-way-in-the-developing-brain

This image shows a section of the spinal cord of a mouse embryo. Neurons appear green. Commissural axons (which connect the two sides of the brain) appear as long, u-shaped threads, and the bottom, yellow segment of the structure represents the midline (between brain hemispheres). (credit: Laboratory of Brain Development and Repair/ The Rockefeller University)

Rockefeller University researchers have discovered a molecule secreted by cells in the spinal cord that helps guide axons (neuron extensions) during a critical stage of central nervous system development in the embryo. The finding helps solve the mystery: how do the billions of neurons in the embryo nimbly reposition themselves within the brain and spinal cord, and connect branches to form neural circuits?

Working in mice, the researchers identified an axon guidance factor, NELL2, and explained how it makes commissural axons (which connect the two sides of the brain).

The findings could help scientists understand what goes wrong in a rare disease called horizontal gaze palsy with progressive scoliosis. People affected by the condition often suffer from abnormal spine curvature, and are unable to move their eyes horizontally from side to side. The study was published Thursday Nov. 19 in the journal Science.

Abstract of Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2

Axon pathfinding is orchestrated by numerous guidance cues, including Slits and their Robo receptors, but it remains unclear how information from multiple cues is integrated or filtered. Robo3, a Robo family member, allows commissural axons to reach and cross the spinal cord midline by antagonizing Robo1/2–mediated repulsion from midline-expressed Slits and potentiating deleted in colorectal cancer (DCC)–mediated midline attraction to Netrin-1, but without binding either Slits or Netrins. We identified a secreted Robo3 ligand, neural epidermal growth factor-like-like 2 (NELL2), which repels mouse commissural axons through Robo3 and helps steer them to the midline. These findings identify NELL2 as an axon guidance cue and establish Robo3 as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits Slit repulsion, and facilitates Netrin attraction to achieve a common guidance purpose.

references:

Topics: Cognitive Science/Neuroscience

A sensory illusion that makes yeast cells self-destruct

A possible tactic for cancer therapeutics
November 20, 2015

http://www.kurzweilai.net/a-sensory-illusion-that-makes-yeast-cells-self-destruct

 

Effects of osmotic changes on yeast cell growth. (A) Schematic of the flow chamber used to create osmotic level oscillations for different periods of time. (B) Cell growth for these periods. The graphs show the average number of progeny cells (blue) before and after applying stress for different periods (gray shows orginal “no stress” line). The inset shows representative images of cells for two periods. (credit: Amir Mitchell et al./Science)

UC San Francisco researchers have discovered that even brainless single-celled yeast have “sensory biases” that can be hacked by a carefully engineered illusion — a finding that could be used to develop new approaches to fighting diseases such as cancer.

In the new study, published online Thursday November 19 in Science Express, Wendell Lim, PhD, the study’s senior author*, and his team discovered that yeast cells falsely perceive a pattern of osmotic levels (by applying potassium chloride) that alternate in eight minute intervals as massive, continuously increasing stress. In response, the microbes over-respond and kill themselves. (In their natural environment, salt stress normally gradually increases.)

The results, Lim says, suggest a whole new way of looking at the perceptual abilities of simple cells and this power of illusion could even be used to develop new approaches to fighting cancer and other diseases.

“Our results may also be relevant for cellular signaling in disease, as mutations affecting cellular signaling are common in cancer, autoimmune disease, and diabetes,” the researchers conclude in the paper. “These mutations may rewire the native network, and thus could modify its activation and adaptation dynamics. Such network rewiring in disease may lead to changes that can be most clearly revealed by simulation with oscillatory inputs or other ‘non-natural’ patterns.

“The changes in network response behaviors could be exploited for diagnosis and functional profiling of disease cells, or potentially taken advantage of as an Achilles’ heel to selectively target cells bearing the diseased network.”

https://youtu.be/CuDjZrM8xtA
UC San Francisco (UCSF) | Sensory Illusion Causes Cells to Self-Destruct

* Chair of the Department of Cellular and Molecular Pharmacology at UCSF, director of the UCSF Center for Systems and Synthetic Biology, and a Howard Hughes Medical Institute (HHMI) investigator.

** Normally, sensor molecules in a yeast cell detect changes in salt concentration and instruct the cell to respond by producing a protective chemical. The researchers found that the cells were perfectly capable of adapting when they flipped the salt stress on and off every minute or every 32 minutes. But to their surprise, when they tried an eight-minute oscillation of precisely the same salt level the cells quickly stopped growing and began to die off.

Abstract of Oscillatory stress stimulation uncovers an Achilles’ heel of the yeast MAPK signaling network

Cells must interpret environmental information that often changes over time. We systematically monitored growth of yeast cells under various frequencies of oscillating osmotic stress. Growth was severely inhibited at a particular resonance frequency, at which cells show hyperactivated transcriptional stress responses. This behavior represents a sensory misperception—the cells incorrectly interpret oscillations as a staircase of ever-increasing osmolarity. The misperception results from the capacity of the osmolarity-sensing kinase network to retrigger with sequential osmotic stresses. Although this feature is critical for coping with natural challenges—like continually increasing osmolarity—it results in a tradeoff of fragility to non-natural oscillatory inputs that match the retriggering time. These findings demonstrate the value of non-natural dynamic perturbations in exposing hidden sensitivities of cellular regulatory networks.

references:

Topics: Biotech

Google Glass helps cardiologists complete difficult coronary artery blockage surgery

November 20, 2015

http://www.kurzweilai.net/google-glass-helps-cardiologists-in-challenging-coronary-artery-blockage-surgery

 

Google Glass allowed the surgeons to clearly visualize the distal coronary vessel and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. (credit: Maksymilian P. Opolski et al./Canadian Journal of Cardiology

Cardiologists from the Institute of Cardiology, Warsaw, Poland have used Google Glass in a challenging surgical procedure, successfully clearing a blockage in the right coronary artery of a 49-year-old male patient and restoring blood flow, reports the Canadian Journal of Cardiology.

Chronic total occlusion, a complete blockage of the coronary artery, sometimes referred to as the “final frontier in interventional cardiology,” represents a major challenge for catheter-based percutaneous coronary intervention (PCI), according to the cardiologists.

That’s because of the difficulty of recanalizing (forming new blood vessels through an obstruction) combined with poor visualization of the occluded coronary arteries.

Coronary computed tomography angiography (CTA) is increasingly used to provide physicians with guidance when performing PCI for this procedure. The 3-D CTA data can be projected on monitors, but this technique is expensive and technically difficult, the cardiologists say.

So a team of physicists from the Interdisciplinary Centre for Mathematical and Computational Modelling of theUniversity of Warsaw developed a way to use Google Glass to clearly visualize the distal coronary vessel and verify the direction of the guide-wire advancement relative to the course of the blocked vessel segment.

Three-dimensional reconstructions displayed on Google Glass revealed the exact trajectory of the distal right coronary artery (credit: Maksymilian P. Opolski et al./Canadian Journal of Cardiology)

The procedure was completed successfully, including implantation of two drug-eluting stents.

“This case demonstrates the novel application of wearable devices for display of CTA data sets in the catheterization laboratory that can be used for better planning and guidance of interventional procedures, and provides proof of concept that wearable devices can improve operator comfort and procedure efficiency in interventional cardiology,” said lead investigatorMaksymilian P. Opolski, MD, PhD, of the Department of Interventional Cardiology and Angiology at the Institute of Cardiology, Warsaw, Poland.

“We believe wearable computers have a great potential to optimize percutaneous revascularization, and thus favorably affect interventional cardiologists in their daily clinical activities,” he said. He also advised that “wearable devices might be potentially equipped with filter lenses that provide protection against X-radiation.

Abstract of First-in-Man Computed Tomography-Guided Percutaneous Revascularization of Coronary Chronic Total Occlusion Using a Wearable Computer: Proof of Concept

We report a case of successful computed tomography-guided percutaneous revascularization of a chronically occluded right coronary artery using a wearable, hands-free computer with a head-mounted display worn by interventional cardiologists in the catheterization laboratory. The projection of 3-dimensional computed tomographic reconstructions onto the screen of virtual reality glass allowed the operators to clearly visualize the distal coronary vessel, and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. This case provides proof of concept that wearable computers can improve operator comfort and procedure efficiency in interventional cardiology.

references:

Topics: Biomed/Longevity | VR/Augmented Reality/Computer Graphics

Modulating brain’s stress circuity might prevent Alzheimer’s disease

Drug significantly prevented onset of cognitive and cellular effects in mice
November 17, 2015

http://www.kurzweilai.net/modulating-brains-stress-circuity-might-prevent-alzheimers-disease

 

Effect of drug treatment on AD mice in control group (left) or drug (right) on Ab plaque load. (credit: Cheng Zhang et al./Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association)

In a novel animal study design that mimicked human clinical trials, researchers at University of California, San Diego School of Medicine report that long-term treatment using a small-molecule drug that reduces activity of  the brain’s stress circuitry significantly reduces Alzheimer’s disease (AD) neuropathology and prevents onset of cognitive impairment in a mouse model of the neurodegenerative condition.

The findings are described in the current online issue of the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Previous research has shown a link between the brain’s stress signaling pathways and AD. Specifically, the release of a stress-coping hormone called corticotropin-releasing factor (CRF), which is widely found in the brain and acts as a neurotransmitter/neuromodulator, is dysregulated in AD and is associated with impaired cognition and with detrimental changes in tau protein and increased production of amyloid-beta protein fragments that clump together and trigger the neurodegeneration characteristic of AD.

“Our work and that of our colleagues on stress and CRF have been mechanistically implicated in Alzheimer’s disease, but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models,” said the study’s principal investigator and corresponding author Robert Rissman, PhD, assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer’s Disease Cooperative Study (ADCS).

The researchers determined that modulating the mouse brain’s stress circuitry mitigated generation and accumulation of amyloid plaques widely attributed with causing neuronal damage and death. As a consequence, behavioral indicators of AD were prevented and cellular damage was reduced.  The mice began treatment at 30-days-old — before any pathological or cognitive signs of AD were present — and continued until six months of age.

One particular challenge, Rissman noted, is limiting exposure of the drug to the brain so that it does not impact the body’s ability to respond to stress. “This can be accomplished because one advantage of these types of small molecule drugs is that they readily cross the blood-brain barrier and actually prefer to act in the brain,” Rissman said.

“Rissman’s prior work demonstrated that CRF and its receptors are integrally involved in changes in another AD hallmark, tau phosphorylation,” said William Mobley, MD, PhD, chair of the Department of Neurosciences and interim co-director of the Alzheimer’s Disease Cooperative Study at UC San Diego. “This new study extends those original mechanistic findings to the amyloid pathway and preservation of cellular and synaptic connections.  Work like this is an excellent example of UC San Diego’s bench-to-bedside legacy, whereby we can quickly move our basic science findings into the clinic for testing,” said Mobley.

Rissman said R121919 was well-tolerated by AD mice (no significant adverse effects) and deemed safe, suggesting CRF-antagonism is a viable, disease-modifying therapy for AD. Drugs like R121919 were originally designed to treat generalized anxiety disorder, irritable bowel syndrome and other diseases, but failed to be effective in treating those disorders.

Rissman noted that repurposing R121919 for human use was likely not possible at this point. He and colleagues are collaborating with the Sanford Burnham Prebys Medical Discovery Institute to design new assays to discover the next generation of CRF receptor-1 antagonists for testing in early phase human safety trials.

“More work remains to be done, but this is the kind of basic research that is fundamental to ultimately finding a way to cure — or even prevent —Alzheimer’s disease,” said David Brenner, MD, vice chancellor, UC San Diego Health Sciences and dean of UC San Diego School of Medicine. “These findings by Dr. Rissman and his colleagues at UC San Diego and at collaborating institutions on the Mesa suggest we are on the cusp of creating truly effective therapies.”

Abstract of Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer’s disease

Introduction: Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer’s disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models.

Methods: To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points.

Results: R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919.

Discussion: CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.

references:

Topics: Cognitive Science/Neuroscience

Allen Institute researchers decode patterns that make our brains human
Conserved gene patterning across human brains provide insights into health and disease
November 17, 2015

http://www.kurzweilai.net/allen-institute-researchers-decode-patterns-that-make-our-brains-human

 

Percentage of known neuron-, astrocyte- and oligodendrocyte-enriched genes in 32 modules, ordered by proportion of neuron-enriched gene membership. (credit: Michael Hawrylycz et al./Nature Neuroscience)

Allen Institute researchers have identified a surprisingly small set of just 32 gene-expression patterns for all 20,000 genes across 132 functionally distinct human brain regions, and these patterns appear to be common to all individuals.

In research published this month in Nature Neuroscience, the researchers used data for six brains from the publicly available Allen Human Brain Atlas. They believe the study is important because it could provide a baseline from which deviations in individuals may be measured and associated with diseases, and could also provide key insights into the core of the genetic code that makes our brains distinctly human.

While many of these patterns were similar in human and mouse, many genes showed different patterns in human. Surprisingly, genes associated with neurons were most conserved (consistent) across species, while those for the supporting glial cells showed larger differences. The most highly stable genes (the genes that were most consistent across all brains) include those associated with diseases and disorders like autism and Alzheimer’s, and these genes include many existing drug targets.

These patterns provide insights into what makes the human brain distinct and raise new opportunities to target therapeutics for treating disease.

The researchers also found that the pattern of gene expression in cerebral cortex is correlated with “functional connectivity” as revealed by neuroimaging data from the Human Connectome Project.

“The human brain is phenomenally complex, so it is quite surprising that a small number of patterns can explain most of the gene variability across the brain,” says Christof Koch, Ph.D., President and Chief Scientific Officer at the Allen Institute for Brain Science. “There could easily have been thousands of patterns, or none at all. This gives us an exciting way to look further at the functional activity that underlies the uniquely human brain.”

Abstract of Canonical genetic signatures of the adult human brain

The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure and function. We applied a correlation-based metric called differential stability to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization. The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations. Using genes with high differential stability, we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely patterned genes displayed marked shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry.

references:

Topics: Biotech

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Pharmacy International Conference

Posted in Clinical & Translational, Conference Coverage with Social Media, Curation, FDA Regulatory Affairs, Genetics & Pharmaceutical, Immunotherapy, Infectious Disease & New Antibiotic Targets, Innovations, Innovations in Neurophysiology & Neuropsychology, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Monoclonal antibody therapy, Nanotechnology for Drug Delivery, Neurodegenerative Diseases, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics, Pharmacologic toxicities, tagged , , on November 21, 2015| Leave a Comment »

Pharmacy International Conference

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

3rd Nirma Institute of Pharmacy International Conference
NIPiCON – 2016
January 21 – 23, 2016 ………….http://www.nipicon.org/.

Anthony Melvin Crasto   https://www.facebook.com/groups/worlddrugtracker/permalink/1170816792946389/

The pharmaceutical sciences is a dynamic and interdisciplinary field that combines a broad range of scientific disciplines that are critical to the discovery and development of new drugs and therapies. Over the years, pharmaceutical scientists have been instrumental in discovering and developing innovative drugs that save people’s lives and improve the quality of life.

NIPiCON was initiated in a year 2013 to offer a common platform for academicians, researchers, industrialists, clinical practitioners and young budding pharmacists to share their ideas and research work and finally emerge with new concepts, innovations and novel strategies for various challenges in the pharmaceutical field.

The 3 International Conference, NIPiCON 2016 aims to provide a knowledge sharing experience in the area of “Global Challenges in Drug Discovery, Development and Regulatory Affairs”.

Pharmaceutical innovation is a complex creative process that harnesses the application of knowledge and creativity for discovering, developing and bringing to clinical use, new medicinal products that extend or improve the lives of patients.A successful pharmaceutical R&D process is one that minimizes the time and cost needed to bring a compound from the scientific ‘idea’, through discovery and clinical development, to final regulatory approval and delivery to the patient. This conference will provide an open forum for the academicians, researchers, clinicians and professionals of pharmaceutical industry to enrich their knowledge in the area of drug discovery, development and its regulatory requirements.

The conference features plenary sessions which will be delivered by eminent national and international speakers from different disciplines of pharmaceutical field. In addition, there will be invited lectures and sessions delivered by distinguished and young researchers in their respective fields during parallel technical sessions. The conference willalso provide the opportunity to scientists and research scholars from various organizations to put forth their innovative ideas and research findings by means of deliberations, discussions and poster presentations.

 

NIPiCON was initiated in a year 2013 to offer a common platform for academicians, researchers, industrialists, clinical practitioners and young budding pharmacists to share their ideas and research work and finally emerge with new concepts, innovations and novel strategies for various challenges in the pharmaceutical field.

The 3 International Conference, NIPiCON 2016 aims to provide a knowledge sharing experience in the area of “Global Challenges in Drug Discovery, Development and Regulatory Affairs”.

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Antibiotic Resistance

Posted in Bacterial Resistance, Biological Networks, Gene Regulation and Evolution, Cell Biology, Chemical Genetics, Clinical & Translational, Clinical Genomics, Curation, Disease Biology, Gene Regulation and Evolution, Genetics & Pharmaceutical, Microbiologial genetics, Microbiology, Molecular Genetics & Pharmaceutical, tagged on November 19, 2015| Leave a Comment »

Antibiotic Resistance

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Resistance Gene to Last Line of Antibiotic Defense Has Emerged

http://www.genengnews.com/gen-news-highlights/resistance-gene-to-last-line-of-antibiotic-defense-has-emerged/81252000/

Drug resistance can often emerge due to the selective pressure of antibiotic use on a microbial population. [NIAID]

 

Until recently, resistance to the polymyxin class of antibiotics—the last line of microbial defense—was thought to be highly improbable. However now, Chinese scientists have discovered a new gene, called mcr-1 that is widespread among Enterobacteriaceae, a large family of Gram-negative bacteria that include a variety of human pathogens, after taking samples from pigs and patients in South China.

“These are extremely worrying results. The polymyxins (colistin and polymyxin B) were the last class of antibiotics in which resistance was incapable of spreading from cell to cell. Until now, colistin resistance resulted from chromosomal mutations, making the resistance mechanism unstable and incapable of spreading to other bacteria,” explained co-author Jian-Hua Liu, Ph.D., a professor at the South China Agricultural University in Guangzhou, China. “Our results reveal the emergence of the first polymyxin resistance gene that is readily passed between common bacteria such as Escherichia coli and Klebsiella pneumoniae, suggesting that the progression from extensive drug resistance to pandrug resistance is inevitable.”

The investigators found the mcr-1 gene on plasmids within various bacterial strains, suggesting an alarming potential to spread and differentiate between diverse microbial populations.

The findings from this study were published recently in The Lancet Infectious Diseases through an article entitled “Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.”

The researchers stumbled across the mcr-1 gene while performing routine testing of livestock for antimicrobial resistance on a pig farm in Shanghai. This prompted the researchers to collect bacteria samples from pigs at slaughter across four provinces, and from pork and chicken sold in 30 open markets and 27 supermarkets across Guangzhou between 2011 and 2014. Additionally, the scientists analyzed bacteria samples from patients presenting with infections at two hospitals in Guangdong and Zhejiang provinces.

What they found was troubling to say the least, as a high prevalence of the mcr-1 gene in E. coli was observed in isolates from animal (166 of 804) and raw meat samples (78 of 523). Moreover, the proportion of positive samples has been observed to be increasing from year to year.

The scientists also found that the transfer rate of the mcr-1 gene was very high between E. coli strains and that it has a strong potential to spread into other epidemic pathogenic bacterial species such asK. pneumoniae and Pseudomonas aeruginosa—making the rapid dissemination into humans very likely.

“Because of the relatively low proportion of positive samples taken from humans compared with animals, it is likely that mcr-1 mediated colistin resistance originated in animals and subsequently spread to humans,” noted senior author Jianzhong Shen, Ph.D., professor at the China Agricultural University in Beijing, China. “The selective pressure imposed by increasingly heavy use of colistin in agriculture in China could have led to the acquisition of mcr-1 by E. coli.”

The importance of selective pressure on this resistance gene becomes even more evident when considering the fact that China is one of the world’s largest users and producers of colistin for agriculture and veterinary use. Worldwide, the demand for colistin in agriculture is expected to reach almost 12,000 tons per year by the end of 2015, rising to 16,500 tons by 2021.

“The emergence of mcr-1 heralds the breach of the last group of antibiotics,” the authors stated. “Although currently confined to China, mcr-1 is likely to emulate other resistance genes such as blaNDM-1 and spread worldwide. There is a critical need to re-evaluate the use of polymyxins in animals and for very close international monitoring and surveillance of mcr-1 in human and veterinary medicine.”

 

Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study  

Yi-Yun Liu, Yang Wang, Timothy R Walsh, Ling-Xian Yi, Rong Zhang, James Spencer, et al.

DOI: http://dx.doi.org/10.1016/S1473-3099(15)00424-7      http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00424-7/abstract

Background

Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae.

Methods

The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli andKlebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model.

Findings

Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection.

Interpretation

The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as
NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria.

 

Colistin resistance: a major breach in our last line of defence

David L Paterson, Patrick N A Harris
DOI: http://dx.doi.org/10.1016/S1473-3099(15)00463-6http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00463-6/abstract
In hospital practice, clinicians have been buoyed by the recent development of new antibiotics active against multidrug resistant Gram-negative bacilli. However, recently approved antibiotics like ceftazidime-avibactam or ceftolozane-tazobactam do not provide activity against all Gram-negative bacilli, with notable gaps in their coverage, including the notorious New Delhi metallo-β-lactamase 1-producing organisms and many strains of carbapenem resistant Acinetobacter baumannii. For this reason, the polymyxins (colistin and polymyxin B) remain the last line of defence against many Gram-negative bacilli.
References
  1. The White House Office of the Press Secretary. FACT SHEET: Obama Administration Releases National Action Plan to Combat Antibiotic-Resistant Bacteria. https://www.whitehouse.gov/the-press-office/2015/03/27/fact-sheet-obama-administration-releases-national-action-plan-combat-ant. ((accessed Oct 20, 2015).)
  2. Walsh, F. Antibiotic resistance: Cameron warns of medical ‘dark ages’.http://www.bbc.co.uk/news/health-28098838. ((accessed Oct 20, 2015).)
  3. WHO. Antimicrobial resistance: global report on surveillance 2014. Wolrd Health Organization,Geneva; 2014http://www.who.int/drugresistance/documents/surveillancereport/en/. ((accessed Oct 20, 2015).)
  4. McKenna, M. CDC Threat Report: We will soon be in a post-antibiotic era. Wired. Sept 16, 2013;http://www.wired.com/2013/09/cdc-amr-rpt1/. ((accessed Oct 20, 2015).)
  5. Kumarasamy, KK, Toleman, MA, Walsh, TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study.Lancet Infect Dis. 2010; 10: 597–602
  6. Munoz-Price, LS, Poirel, L, Bonomo, RA et al. Clinical epidemiology of the global expansion ofKlebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013; 13: 785–796
  7. Falagas, ME, Karageorgopoulos, DE, and Nordmann, P. Therapeutic options for infections with Enterobacteriaceae producing carbapenem-hydrolyzing enzymes. Future Microbiol. 2011; 6: 653–666
  8. Halaby, T, Al Naiemi, N, Kluytmans, J, van der Palen, J, and Vandenbroucke-Grauls, CM.Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimicrob Agents Chemother. 2013; 57: 3224–3229

 

https://www.reddit.com/r/science/comments/3tdyaz/emergence_of_plasmidmediated_colistin_resistance/

This is my second attempt at my first time contributing a link so hopefully this is the correct subreddit. This really highlights why research focused on discovery of novel antibiotics and resistance modifying agents is so important.  The article is summarized in the BBC: http://www.bbc.com/news/health-34857015

 

What a shame this isn’t getting any more attention in the news, antibiotic resistance is becoming more and more of a problem, and nobody is giving a fuck it seems. Colistin is used as a last defense against extensive resistant Gram-negative bacteria, and if resistance against it now also comes in a plasmid flavor, implications could be big.

 

Yes, the gene has been known for a fair amount of time but the fact it is now in plasmids that can easily transfect other bacteria is a bit disconcerting. Hopefully some of the new soil cultured classes of antibiotics make it into clinical settings soon.

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Biomarker Development

Posted in Artificial Intelligence - Breakthroughs in Theories and Technologies, Big Data, Biochemical pathways, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biomarkers & Medical Diagnostics, Cancer Informatics, Clinical & Translational, Clinical Diagnostics, Clinical Genomics, Computational Biology/Systems and Bioinformatics, Curation, Diagnostics and Lab Tests, Digital HealthCare – biotech & internet joint ventures, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Electronic Health Record, Enzymes and isoenzymes, Epigenetics and Cardiovascular Risks, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Genomic Testing: Methodology for Diagnosis, Image Processing/Computing, Innovations, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Intelligent Information Systems, International Global Work in Pharmaceutical, Medical and Population Genetics, Metabolism, Microbiologial genetics, Microbiology, Micronutrients, Molecular Genetics & Pharmaceutical, Nutrigenomics, Nutrition and Phytochemistry, Personal Health Applications: Tech Innovations serves HealhCare, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Discovery, tagged , , , on November 16, 2015| Leave a Comment »

Biomarker Development, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Biomarker Development

Curator: Larry H. Bernstein, MD, FCAP

 

 

NBDA’s Biomarker R&D Modules

http://nbdabiomarkers.org/

“collaboratively creating the NBDA Standards* required for end-to-end, evidence – based biomarker development to advance precision (personalized) medicine”

http://nbdabiomarkers.org/sites/all/themes/nbda/images/nbda_logo.jpg

http://nbdabiomarkers.org/about/what-we-do/pipeline-overview/assay-development

 

Successful biomarkers should move systematically and seamlessly through specific R&D “modules” – from early discovery to clinical validation. NBDA’s end-to-end systems approach is based on working with experts from all affected multi-sector stakeholder communities to build an in-depth understanding of the existing barriers in each of these “modules” to support decision making at each juncture.  Following extensive “due diligence” the NBDA works with all stakeholders to assemble and/or create the enabling standards (guidelines, best practices, SOPs) needed to support clinically relevant and robust biomarker development.

Mission: Collaboratively creating the NBDA Standards* required for end-to-end, evidence – based biomarker development to advance precision (personalized) medicine.
NBDA Standards include but are not limited to: “official existing standards”, guidelines, principles, standard operating procedures (SOP), and best practices.

https://vimeo.com/83266065

 

“The NBDA’s vision is not to just relegate the current biomarker development processes to history, but also to serve as a working example of what convergence of purpose, scientific knowledge and collaboration can accomplish.”

NBDA Workshop VII – “COLLABORATIVELY BUILDING A FOUNDATION FOR FDA BIOMARKER QUALIFICATION”
NBDA Workshop VII   December 14-15, 2015   Washington Court Hotel, Washington, DC

The upcoming meeting was preceded by an NBDA workshop held on December 1-2, 2014, “The Promising but Elusive Surrogate Endpoint:  What Will It Take?” where we explored in-depth with FDA leadership and experts in the field the current status and future vison for achieving success in surrogate endpoint development.  Through panels and workgroups, the attendees extended their efforts to pursue the FDA’s biomarker qualification pathway through the creation of sequential contexts of use models to support qualification of drug development tools – and ultimately surrogate endpoints.

Although the biomarker (drug development tools) qualification pathway (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentTools…) represents an opportunity to increase the value of predictive biomarkers, animal models, and clinical outcomes across the drug (and biologics) development continuum, there are myriad challenges.  In that regard, the lack of evidentiary standards to support contexts of use-specific biomarkers emerged from the prior NBDA workshop as the major barrier to achieving the promise of biomarker qualification.  It also became clear that overall, the communities do not understand the biomarker qualification process; nor do they fully appreciate that it is up to the stakeholders in the field (academia, non-profit foundations, pharmaceutical and biotechnology companies, and patient advocate organizations) to develop these evidentiary standards.

This NBDA workshop will feature a unique approach to address these problems.  Over the past two years, the NBDA has worked with experts in selected disease areas to develop specific case studies that feature a systematic approach to identifying the evidentiary standards needed for sequential contexts of use for specific biomarkers to drive biomarker qualification.   These constructs, and accompanying whitepapers are now the focus of collaborative discussions with FDA experts.

The upcoming meeting will feature in-depth panel discussions of 3-4 of these cases, including the case leader, additional technical contributors, and a number of FDA experts.  Each of the panels will analyze their respective case for strengths and weaknesses – including suggestions for making the biomarker qualification path for the specific biomarker more transparent and efficient. In addition, the discussions will highlight the problem of poor reproducibility of biomarker discovery results, and its impact on the qualification process.

 

Health Care in the Digital Age

Mobile, big data, the Internet of Things and social media are leading a revolution that is transforming opportunities in health care and research. Extraordinary advancements in mobile technology and connectivity have provided the foundation needed to dramatically change the way health care is practiced today and research is done tomorrow. While we are still in the early innings of using mobile technology in the delivery of health care, evidence supporting its potential to impact the delivery of better health care, lower costs and improve patient outcomes is apparent. Mobile technology for health care, or mHealth, can empower doctors to more effectively engage their patients and provide secure information on demand, anytime and anywhere. Patients demand safety, speed and security from their providers. What are the technologies that are allowing this transformation to take place?

 

https://youtu.be/WeXEa2cL3oA    Monday, April 27, 2015  Milken Institute

Moderator

Michael Milken, Chairman, Milken Institute

 

Speakers

Anna Barker, Fellow, FasterCures, a Center of the Milken Institute; Professor and Director, Transformative Healthcare Networks, and Co-Director, Complex Adaptive Systems Network, Arizona State University
Atul Butte, Director, Institute of Computational Health Sciences, University of California, San Francisco
John Chen, Executive Chairman and CEO, BlackBerry
Victor Dzau, President, Institute of Medicine, National Academy of Sciences; Chancellor Emeritus, Duke University
Patrick Soon-Shiong, Chairman and CEO, NantWorks, LLC

 

Mobile, big data, the Internet of Things and social media are leading a revolution that is transforming opportunities in health care and research. Extraordinary advancements in mobile technology and connectivity have provided the foundation needed to dramatically change the way health care is practiced today and research is done tomorrow. While we are still in the early innings of using mobile technology in the delivery of health care, evidence supporting its potential to impact the delivery of better health care, lower costs and improve patient outcomes is apparent. Mobile technology for health care, or mHealth, can empower doctors to more effectively engage their patients and provide secure information on demand, anytime and anywhere. Patients demand safety, speed and security from their providers. What are the technologies that are allowing this transformation to take place?

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palivizumab prophylaxis for children with bronchiolitis

Posted in Human Immune System in Health and in Disease, Immunology, Immunotherapy, Innovations, Lung and pulmonology, Microbiologial genetics, Microbiology, Molecular Genetics & Pharmaceutical, Monoclonal antibody therapy, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, tagged , , , on November 10, 2015| Leave a Comment »

palivizumab prophylaxis for children with bronchiolitis

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Eligibility for palivizumab prophylaxis in a cohort of children with severe bronchiolitis
Kohei Hasegawa,1 Jonathan M. Mansbach,2 Pedro A. Piedra,3 Michelle B. Dunn,4 Sunday Clark,5 Ashley F. Sullivan1 and Carlos A. Camargo Jr1

Pediatrics International (2015) 57, 1031–1034          http://dx.doi.org:/10.1111/ped.12760

 

In 2014, the American Academy of Pediatrics (AAP) updated their recommendations for palivizumab prophylaxis for children who are at high risk for severe respiratory syncytial virus (RSV) infection. To investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis, we applied the 2012 and 2014 AAP recommendations for palivizumab prophylaxis to a multicenter cohort of 2207 US children hospitalized for bronchiolitis. According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis, while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations (34.9% relative decrease; 95% CI: 28.5–41.7%).  The  decrease was largely driven by the restriction of eligibility to preterm infants with gestational age < 29weeks. Further development of and refinement of cost-effective approaches for the prevention of severe RSV infection are needed.

 

Bronchiolitis remains an important public health problem in the USA. It is the leading cause of hospitalization in infants, accounting for 18% of all infant hospitalizations, with a total direct cost of $545m in 2009.1 Although many viruses are known to cause bronchiolitis, respiratory syncytial virus (RSV) is the most common etiology among children requiring hospitalization.2 Palivizumab, a humanized monoclonal antibody against the RSV Fglycoprotein, is licensed for the prevention of serious lower respiratory infection caused by RSV in high-risk children. Since palivizumab was first licensed, professional organizations have sought more precise guidance for determining who is at high risk.3

In 2014, the American Academy of Pediatrics (AAP) updated and replaced their recommendations for palivizumab prophylaxis from 2012.4  The updated guidelines support a more restrictive use of palivizumab:3 for example, they recommend against the use in infants born ≥ 29 weeks’ gestation who have no additional risk factors for severe RSV disease. Despite these substantial changes to the guideline recommendations, there are no publications that assess the potential impact on the eligibility for palivizumab prophylaxis in US children.

To address the knowledge gap in the literature, we investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis in a well-characterized national cohort of children hospitalized for bronchiolitis.

 

Over the 3year study period, we enrolled 2207 children hospitalized for bronchiolitis to one of the 16 sites. Demographic characteristics, medical history, and clinical course are summarized in Table 1. Overall, the median age was 4months (IQR, 2–9 months) and 1311 (59.4%) were male. Additionally, 285 children (12.9%) were born at gestational age <35 weeks; 460 (20.8%) had one or more major comorbid medical disorders.

Table 1 Bronchiolitis patient characteristics vs AAP palivizumab recommendations

Table 2 Eligibility for palivizumab prophylaxis vs 2012 and 2014 AAP recommendations

According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis (Table 2), while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations. Applying the more restrictive 2014 criteria would have led to 75 fewer children (34.9% relative decrease; 95%CI: 28.5–41.7%) being eligible for palivizumab prophylaxis. The most frequent reason for the loss of eligibility was the 2014 criterion for prematurity that restricts eligibility to infantswithgestationalage<29weeks;thischangeledto45fewer children being eligible (40.9% relative decrease; 95%CI: 31.6–50.7%). The next most frequent reason was the 2014 criteria that limit eligibility to infants with chronic lung disease or congenital heart disease in the first year of life;this change led to 22 fewer children being eligible for palivizumab prophylaxis (22.9%relative decrease; 95%CI: 15.0–32.6%).

Among the 2207 children in the cohort, 207 children (9.4%) had received palivizumab prophylaxis prior to the index hospitalization. Among 215 children eligible for prophylaxis based on the 2012 recommendations, 117 (54.4%) had received palivizumab prophylaxis. Among 140 children eligible for prophylaxis based on the 2014 recommendations, 72 (51.4%) had received palivizumab prophylaxis (Table 1).

 

In this analysis of a large multicenter cohort of children hospitalized for bronchiolitis, we found that approximately 10% of children were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When applying the more restrictive criteria of the 2014 updated recommendations, one-third of these children would have become ineligible for palivizumab prophylaxis. To thebestofourknowledge,thisisthe firststudytoreportthepotential impact of the change in the AAP recommendations on the eligibility for palivizumab prophylaxis in young children, a finding of public health and research importance.

In 1998, palivizumab was licensed by the US Food and Drug Administration (FDA) for prevention of severe RSV diseases in children at high risk, but the FDA did not issue more specific recommendations, nor define high risk.This absence of a specific definition has led several groups to attempt to identify children at high risk who would be eligible for palivizumab prophylaxis.3,6 The AAP published the first policy statement on the use of palivizumab in 1998.7 On the basis of the availability of additional data, the AAP has updated the guidelines in 2003, 2006, 2009, 2012,4 and 2014.3 Since the last update of the AAP recommendations, some studies have reported a high cost but limited benefit from palivizumab prophylaxis.8 In this context, the 2014 AAP guidelines recommended a more restrictive use.3 In particular, preterm infants with gestational age ≥29 weeks without additional risk factors became ineligible for palivizumab.

In parallel with this change in recommendations, within the present high risk population, the most frequent reason for the loss of eligibility was the use of the restrictive criterion for prematurity: that is, preterm infants born from 29t o35 weeks’ gestation with no additional risk factors became ineligible. This specific group of preterm infants accounts fo ra large number of births in the US:approximately 10% of US births in 2012.9 Thus, one may argue that the use of this restrictive criterion would result in an increase in the number of preventable severe RSV infections,10 even considering the potentially limited efficacy of palivizumab in this population. As described in the technical report of the 2014 AAP recommendations, however, it is challenging to define an optimal threshold of gestational age in preterm infants for which palivizumab prophylaxis may be indicated. The present observations should facilitate further investigations that seek high-quality and cost-effective preventive strategies for a large number of vulnerable children.

This study has several potential limitations. First, the analysis was not designed to examine the efficacy or effectiveness of palivizumabprophylaxis. Rather, we sought to examinethe potential impact of the updated recommendations on the eligibility for palivizumab in a well-characterized national cohort of children hospitalized for bronchiolitis. Second, the present study investigated only children hospitalized for bronchiolitis; thus, those with other types of severe respiratory infection (e.g. pneumonia) were not examined. Inclusion of these populations may yield different inferences. Nevertheless, the present findings are directly relevant to >120 000 US children hospitalized for bronchiolitis (and their families) each year.1 Finally, the study participants were those who were hospitalized in academic centers. Therefore, the present inferences may not be generalizable to the US population as a whole. Children hospitalized at academic centers, however, have disproportionately high morbidity; it is in precisely this population for which targeted preventive measures are needed.

In conclusion, we found that 10% of children hospitalized for bronchiolitis were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When we applied the more restrictive 2014criteria,one-third of these children were ineligible. The decrease was largely driven by the restriction of eligibility to preterminfantswithgestationalage <29weeks.Forpolicymakers and researchers, because bronchiolitis continues to be a substantial societal burden in an already-stressed health-care system,1 the present findings support further development and refinement of cost effective approaches for the prevention of severe RSV infection.

 

References

1 Hasegawa K,Tsugawa Y,Brown DF,Mansbach JM,Camargo CA Jr. Trends in bronchiolitis hospitalizations in the United States, 2000–2009. Pediatrics 2013; 132: 28 –36.

2 Hasegawa K, Mansbach JM,Camargo CAJr.Infectious pathogens and bronchiolitis outcomes. Expert Rev. Anti Infect. Ther. 2014; 12: 817 –28.

3 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Policy statement. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134: 415 –20.

4 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS (eds). Red Book: 2012. Report of the Committee on Infectious Diseases. American Academy of Pediatrics, Elk Grove Village, IL, 2012; 609–18.

5 Hasegawa K, Jartti T, Mansbach JM etal.Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: Multicenter cohort studies in the United States and Finland. J. Infect. Dis. 2015; 211: 1550 –9.

6 NHS Commissioning Board. Clinical Commissioning Policy: Palivizumab to reduce the risk of RSV in high risk infants. 2012. Accessed 13 May 2015. Available from URL: http://www.england.nhs.uk/.

7 American Academy of P

ediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Prevention of respiratory syncytial virus infections: Indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics 1998; 102: 1211 –6.

8 Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD,  Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst. Rev. 2013; 4 CD 006602.

9 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Technical report. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134 (2): e620–38.

Appendix I. Principal Investigators at the 16 participating sites in MARC-30
Besh Barcega, MD Loma Linda University Children’s Hospital, Loma Linda, CA, USA

John Cheng, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Carlos Delgado, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Haitham Haddad, MD Rainbow Babies and Children’s Hospital, Cleveland, OH, USA

Frank LoVecchio, MD Maricopa Medical Center, Phoenix, AZ, USA

Eugene Mowad, MD Akron Children’s Hospital, Akron, OH, USA

Brian Pate, MD Children’s Mercy Hospital and Clinics, Kansas City, MO, USA

Mark Riederer, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA

Paul Hain, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA M

Jason Sanders, MD Children’s Memorial Hermann Hospital, Houston, TX, USA

Nikhil Shah, MD New York Presbyterian Hospital, New York, NY, USA

Dorothy Damore, MD New York Presbyterian Hospital, New York, NY, USA

Michelle Stevenson, MD Kosair Children’s Hospital, Louisville, KY, USA

Erin Stucky Fisher, MD Rady Children’s Hospital, San Diego, CA, USA

Stephen Teach, MD, MPH Children’s National Medical Center, Washington, DC, USA

Lisa Zaoutis, MD Children’s Hospital of Philadelphia, Philadelphia, PA, USA

 

 

 

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Transparency in Clinical Trials

Posted in BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Clinical & Translational, Computational Biology/Systems and Bioinformatics, Curation, Diagnostics and Lab Tests, Digital HealthCare – biotech & internet joint ventures, Disease Biology, FDA Regulatory Affairs, Global Partnering & Biotech Investment, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, tagged , on November 9, 2015| Leave a Comment »

Transparency in Clinical Trials, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Transparency in Clinical Trials

Curator: Larry H. Bernstein, MD, FCAP

 

 

Does Pharma Really Want Transparency In Clinical Trials?

Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @outsourcedpharm
http://www.clinicalleader.com/doc/does-pharma-really-want-transparency-in-clinical-trials-0001

 

My recent article on transparency in clinical trials, featuring Dr. Brad Thompson, CEO of Oncolytics, solicited a good number of comments and emails from readers. While most readers agree that more transparency would be good for patients and the industry, there seems to be a lot of disagreement over how it can be achieved, and if it can actually be achieved at all.

To recap, Thompson believes we still have a long way to go, and questioned whether true transparency would ever be achieved. His primary argument noted researchers who want to be published will not put much focus on neutral or negative trials, and even the press releases put out by sponsors include a limited amount of information.

One reader that works for a CRO made the following comment: “Dr. Thompson from Oncolytics made some very interesting comments about investigators holding back information. An investigator will enter patient data into an EDC system that is then verified by monitors. And that is just one of a number of sites. These investigators will generally know when a drug is working and when it is not. As a CRO, I often saw statistical outputs on blinded studies where you could see where the data was trending. Even data guys can tell if a drug is working by the data results and improvements in patients.”

If physicians and researchers are able to see clear results even when the data is still in the process of being collected, then what is the problem with being more transparent? One possible explanation is that once physicians know a drug will not work, they will no longer continue to place patients at risk by having them participate in the trial. This could be done for purely ethical reasons.

But there may also be reluctance to greater transparency on the part of the pharma company. “No drug company truly wants transparency because it leaves the results and outcomes more open to interpretation, mainly by Kaiser, Blue Cross and other groups,” noted another reader.  “Pharma companies could cost themselves a lot of money in sales if they do not have the time to target and position.”

Investors Are A Consideration

There is still another consideration at play. If a study is not going well, would it be to the benefit of the executives of a company to share those results? Let’s play devil’s advocate for a moment and assume you are the CEO of a biotech company. You’re making $500,000 a year with good benefits. You have several investors who have dumped millions of dollars into your company and your product. The study is targeted for four years, but within the first year you see results that indicate your drug is not going to produce the intended results.

“In that scenario, how prone would you be to ending the trial, saving the investors their remaining money, and losing your job?” notes one reader. “Are companies prone or pressured to locate new targets for therapy or identifying reasons to extend the trials, sometimes for a few years or longer?”

All of us have heard discussions about the possibility of electronic medical records (EMRs) someday replacing electronic data capture (EDC). According to one email I received, this will never happen because of the physician issue mentioned above. After all, if patient results were posted in the EMR and every doctor on the network has access to the information, everyone would know if I drug was not having the desired effect. As soon as that happens, promises of riches being delivered to investors will fall by the wayside, and executives will be out of jobs.

“Within big pharma, this is called job preservation,” noted another reader. “If funding for the trial is cut, I am out of a job. At the same time, trial results are not getting any better for patients. Years ago about one in three trials resulted in a successful outcome. Then it went to one in four. Today that success rate is around 15 percent with R&D commitment at about 12% (down from approximately 28%). It appears that the industry is run by money and managed by guys who know how to play the system.  If patients are the primary concern, the industry would target physicians who have the right patients, get enrollment done faster, and quickly identify if the product works as advertised.”

Limit Procedures And Additional Fields

Going back to Thompson’s comments, the problem is not always investigators wanting to get published. One reader noted oftentimes it is the in-house pharma and biotech doctors as well as researchers in academia who are anxious to get their names into publications. “Unfortunately, these are often the same people who include numerous unnecessary procedures in protocols. They will also ask for additional data fields to be included in EDC systems after study launch, which can delay database activity for two months. The reason is they see a hint of something and decide they want to dig deeper, even if the activity has nothing to do with the study results and the overall goal of the trial.”

The obvious fix to this would be executive leadership and study teams standing up and challenging the reason for inclusion of the additional data fields, which cost the industry both time and money. A large number of procedures should be challenged as well, especially if they are not standard of care.

“If a researcher sees a hint of something that seems to be interesting but has nothing to do with the study, they should engage one of the thought leaders to conduct an IIR program to see if the hypothesis is valid,” notes the reader. “They can do this while keeping the clinical program on track to closure without delay, and still appease their interests.”

Clearly, there are no easy solutions. Many pharma companies are certainly making a concerted effort to put the patient first, and I believe those efforts are sincere. But there is no question they must also be focused on funding and trial results – the industry has gone from one focused on a patient to one driven by investors, and that trend is unfortunate. Physicians and researchers will always have their own goals and aspirations, and placing additional burdens upon them could have the unintended consequence of driving them away from trial participation – poor sponsor/CRO pay practices and poorly written/detailed protocols have already moved many physician practices away from clinical trial participation. Coming up with a solution will likely involve bringing together all stakeholders for a more in-depth discussion on the topic, which unfortunately I don’t see happening anytime soon.

 

Transparency In Clinical Trials: Will It Ever Be Achieved?
Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @outsourcedpharm

 

A lot has been made recently about transparency in clinical trials. In the EU a new regulation is about to address the issue, and CISCRPrecently sent a petition letter to the FDA asking it to pass a similar regulation in this country. The petition, signed by hundreds of patients, hopes to make trials results more accessible to patients.

It’s also not hard to understand why a patient participating in a trial would want to know the results of the study, and whether or not they received the active drug or a placebo. But while changes might help companies with patient recruitment and retention issues, will true trial transparency ever be possible?

Dr. Brad Thompson, CEO of biotech firm Oncolytics, believes we still have a very long way to go, and that perhaps pharma companies are not the ones that should be blamed. “I think a lot of people, patients especially, believe that companies are the roadblock in keeping the results of clinical studies from becoming public,” he says. “But personally, I believe it is a much wider issue than that, especially when it comes to finding out the results of unsuccessful trials.”

For example, Thompson looks at clinical investigators. He notes many of these individuals would like for their academic careers to progress. For these folks, the reporting of trial results, especially those that are negative or neutral, does nothing to advance their goals. It is not a deliberate action to conceal information, but the lack of an incentive to do so can often result in delays, provided the results are reported at all.

“If you are conducting a trial at 50 or 60 locations, it doesn’t take too many of them not reporting information to significantly slow down the ability of a sponsor to report on what is going on with the study,” notes Thompson. “And the more time that goes by, the more people will lose interest in doing so. Add to that the fact that there are no journals or annual meetings that are focused on reporting negative results. This is due to space and time limitations. If there are 100 speaking opportunities at the ASCO show in June, those spots will be given to people reporting exciting new results in cancer therapies. There is no time for, nor interest in, anyone reporting on therapies that didn’t work.”

From the standpoint of a public sponsor company, they will typically report negative trial results, but that will generally be via a press release, where there is very little detail. It’s also unlikely that a patient participating in a trial will be on the company’s PR distribution list. As a result, there is an entire system set up with no positive incentives to go into more detail about trials that did not go as planned.  That in itself is unfortunate, since we often learn as much from things that don’t work as we do from things that do.

“In many ways, knowing what didn’t work, or what caused a safety problem, can be more important than knowing what did work and knowing there were no safety problems,” adds Thompson. “Knowing of negative results will allow you to improve your own trials and continue to work to try and find something that does work. I think this is a bigger issue than people realize and it is not something that will be easy to address.”

All Requirements Fall On Sponsors

Of course in this entire daisy-chain of events, there is only one party involved that has a legal obligation to disclose positive or negative information on the trial. That is the sponsor company, which by law is required to disclose information about the trial. Failure to report something could result in a criminal offense. If an investigator doesn’t disclose something, they do not face the same negative repercussions.

“If you talk to an attorney from any sponsor company, they will tell you how important it is to disclose, disclose, disclose,” says Thompson. “They fully understand the importance of doing that. The situation might be slightly different in privately-held companies, because public companies have an obligation to their investors. But even then they have a duty of disclosure under the investment terms. More often than not the investors are sitting on your board of directors and would be privy to the information anyway.”

On a positive note, Thompson is quick to note that most companies, investigators, and researchers he knows want to disclose as much as they possibly can.  There are just a number of soft reasons that might end up keeping them from getting into more detail than they do. For example, there is generally the same amount of content going into a press release regardless of whether or not the trial was successful. He notes no one on the planet is going to put out a 30-page press release covering the detail of a clinical study, whether it was good or bad.

For that reason, most of the press releases that go out are seldom more than two pages, with just a few sentences on the results and the safety aspects. While that will meet the disclosure standards, it certainly does not disclose much detail to the investigators or others who wish to know the details.

“When you look closely at this situation, what you see is a system that is almost accidentally set up to inhibit full disclosure,” states Thompson. “The industry might feel it is good to publish negative results, but where would we publish them? Who is going to pay for it? Who is going to read it? It’s a difficult issue. You can try to induce people to do things, but if an investigator has a failed study, his academic career will not be helped by spending the weeks it would take to write a paper to be published. Especially if they can spend that time writing a paper on a study that did work. There is not a conspiracy of silence. It is just natural for people to want to focus on things that will help them out with their careers.”

More Information Benefits Patients

There are other reasons for reporting as much information as possible. Patients appreciate the information, but from the sponsor perspective, more information might mean coming up with better versions of existing medicines. Thompson likes to use bone marrow studies as an example of how more information can be helpful to patients. When physicians first started using radiation to kill off bone marrow for certain types of leukemia patients, that marrow had to be replaced. It was discovered that bone marrow transferred from people who did not match the patient’s tissue type caused them to perform better…but only for a period of time. After that, the patients began to die quicker. Still, researches published the complete findings.

“They could have reported that non-matching bone marrow works really well for six months and left it at that,” says Thompson. “But they opted to include the downside of the study as well. That led physicians to decide it would be used for emergency use only until a better match could be found. That knowledge ended up making these transplants better for the patients and better for the industry. I think in that case we were lucky that there was a positive effect to report along with the negative. If there was only the negative effect, I don’t know that it would have ever been published.”

Is There A Fix?

I wish I could report that there is an easy fix to this transparency issue. Unfortunately, there is not. According to Thompson, there are not a couple of adjustments that can be made to correct the problem.  After all, you cannot force a researcher to publish an article on a failed study if they have more important needs to attend to. You can’t force a company to produce or publish a 30-page press release or, if they did, force anyone to read it. Unfortunately, that is a reality of the industry.

“We need to come up with a mechanism where the end result is of benefit to the industry, such as people having access to needed information and disseminating it without the process being burdensome,” notes Thompson. “I honestly don’t know how you do that.”

There are so many pieces to this problem…the sponsor companies, the FDA, the investigators, the research sites. It is difficult to fix a problem when the players involved in it are so varied. Still, if this is an issue that is too complicated to tackle with all players at once, perhaps the best approach would be to take it one step at a time. If we put sponsors, patients, and investigators in a room together, all would likely be clamoring for the same end result.

“We would not see pockets of stakeholders fighting this,” adds Thompson. “A solution to this transparency problem would make everyone better off. It’s frustrating because everyone knows this is an issue, and that we have to do better. People who are a lot smarter than I am have spent time on this and were not able to come up with an answer.  But the fact that this is a complicated issue doesn’t mean we should throw our hands in the air and give up. Eventually we will have to produce a solution.”

 

Taking The “Risk” Out Of Risk-Based Monitoring

http://www.clinicalleader.com/doc/taking-the-risk-out-of-risk-based-monitoring-0002

The clinical trial landscape is continually evolving and with it, efforts in the improvement of participant safety and data integrity. CROs are beginning to transition from on-site monitoring, with 100% point-to-point source data verification, toward a risk-based monitoring (RBM) approach that utilizes source data review and more centralized monitoring techniques better adapted for mitigating risk.

While RBM has gained considerable attention in recent years, reluctance still remains around the approach—from uncertainty arising from the use of “risk” employed in its name to sponsors being wary of potential implications on data quality and regulatory inspection outcomes.

Despite these concerns, there is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% source data verification to ensure subject protection, data integrity, and overall study quality.

 

Improve the Inclusion & Exclusion Criteria for Your Next Clinical Trial

http://www.clinicalleader.com/doc/improve-the-inclusion-exclusion-criteria-for-your-next-clinical-trial-0001

 

 

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Huge Data Network Bites into Cancer Genomics

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Informatics, Clinical & Translational, Clinical Diagnostics, Clinical Genomics, Curation, Disease Biology, Gastroenterology, Gene Regulation, Genetics & Innovations in Treatment, Genome Biology, Genomic Expression, Global Partnering & Biotech Investment, Metabolomics, Microbiologial genetics, Microbiology, Molecular Genetics & Pharmaceutical, Population Health Management, Genetics & Pharmaceutical, Signaling & Cell Circuits, Statistical Methods for Research Evaluation, tagged , , on November 9, 2015| Leave a Comment »

Huge Data Network Bites into Cancer Genomics

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Closer to a Cure for Gastrointestinal Cancer

Suzanne Tracy, Editor-in-Chief, Scientific Computing and HPC Source
http://www.scientificcomputing.com/news/2015/11/closer-cure-gastrointestinal-cancer

In order to streamline workflows and keep pace with data-intensive discovery demands, CCS integrated its HPC environment with data capture and analytics capabilities, allowing data to move transparently between research steps, and driving discoveries such as a link between certain viruses and gastrointestinal cancers.

 

SANTA CLARA, CA — At the University of Miami’s Center for Computational Science (CCS), more than 2,000 internal researchers and a dozen expert collaborators across academic and industry sectors worldwide are working together in workflow management, data management, data mining, decision support, visualization and cloud computing. CCS maintains one of the largest centralized academic cyberinfrastructures in the country, which fuels vital and critical discoveries in Alzheimer’s, Parkinson’s, gastrointestinal cancer, paralysis and climate modeling, as well as marine and atmospheric science research.

In order to streamline workflows and keep pace with data-intensive discovery demands, CCS integrated its high performance computing (HPC) environment with data capture and analytics capabilities, allowing data to move transparently between research steps. To speed scientific discoveries and boost collaboration with researchers around the world, the center deployed high-performance DataDirect Networks (DDN) GS12K scale-out file storage. CCS now relies on GS12K storage to handle bandwidth-driven workloads while serving very high IOPS demand resulting from intense user interaction, which simplifies data capture and analysis. As a result, the center is able to capture, store and distribute massive amounts of data generated from multiple scientific models running different simulations on 15 Illumina HiSeq sequencers simultaneously on DDN storage. Moreover, number-crunching time for genome mapping and SNP calling has been reduced from 72 to 17 hours.

“DDN enabled us to analyze thousands of samples for the Cancer Genome Atlas, which amounts to nearly a petabyte of data,” explained Dr. Nicholas Tsinoremas, director of the Center for Computational Sciences at the University of Miami. “Having a robust storage platform like DDN is essential to driving discoveries, such as our recent study that revealed a link between certain viruses and gastrointestinal cancers. Previously, we couldn’t have done that level of computation.”

In addition to providing significant storage processing power to meet both high I/O and interactive processing requirements, CCS needed a flexible file system that could support large parallel and short serial jobs. The center also needed to address “data in flight” challenges that result from major data surges during analysis, and which often cause a 10x spike in storage. The system’s performance for genomics assembly, alignment and mapping is enabling CCS to support all its application needs, including the use of BWA and Bowtie for initial mapping, as well as SamTools and GATK for variant analysis and SNP calling.

“Our arrangement is to share data or make it available to anyone asking, anywhere in the world,” added Tsinoremas. “Now, we have the storage versatility to attract researchers from both within and outside the HPC community … we’re well-positioned to generate, analyze and integrate all types of research data to drive major scientific discoveries and breakthroughs.”

About DDN

DataDirect Networks is a big data storage supplier to data-intensive, global organizations. For more than 15 years, the company has designed, developed, deployed and optimized systems, software and solutions that enable enterprises, service providers, universities and government agencies to generate more value and to accelerate time to insight from their data and information, on premise and in the cloud. Organizations leverage DDN technology and the technical expertise of its team to capture, store, process, analyze, collaborate and distribute data, information and content at largest scale in the most efficient, reliable and cost effective manner. DDN customers include financial services firms and banks, healthcare and life science organizations, manufacturing and energy companies, government and research facilities, and web and cloud service providers.

 

“Where DDN really stood out is in the ability to adapt to whatever we would need. We have both IOPS-centric storage and the deep, slower I/O pool at full bandwidth. No one else could do that.”

Joel P. Zysman

Director of High Performance Computing

Center for Computational Science at the University of Miami

The University of Miami maintains one of the largest centralized, academic, cyber infrastructures in the US, which is integral to addressing and solving major scientific challenges. At its Center for Computational Science (CCS), more than 2,000 researchers, faculty, staff and students across multiple disciplines collaborate on diverse and interdisciplinary projects requiring HPC resources.

With 50% of the center’s users come from University of Miami’s Miller School of Medicine with ongoing projects at the Hussman Institute for Human Genomics, the explosion of next-generation sequencing has had a major impact on compute and storage demands. At CCS, the heavy I/O required to create four billion reads from one genome in a couple of days only intensifies when the data from the reads needs to be managed and analyzed

Aside from providing sufficient storage power to meet both high I/O and interactive processing demands, CCS needed a powerful file system that was flexible enough to handle very large parallel jobs as well as smaller, shorter serial jobs. CCS also needed to address as much as 10X spikes in storage, so it was critical to scale and support petabytes of machine-generated data without adding a layer of complexity or creating inefficiencies.

Read their success story to learn how high-performance DDN® Storage I/O has helped the University of Miami:

  • Establish links between certain viruses and gastrointestinal cancers discovered with computation that were not possible before
  • Reduce genomics compute and analysis time from 72 to 17 hours
CHALLENGES

  • Diverse, interdisciplinary research projects required massive compute and storage power as well as integrated data lifecycle movement and management
  • Highly demanding I/O and heavy interactivity requirements from next-gen sequencing intensified data generation, analysis and management
  • Handle large parallel jobs and smaller, shorter serial jobs
  • Data surges during analysis created “data-in-flight” challenges

SOLUTION

An end-to-end, high performance DDN GRIDScaler® solution featuring a GS12K™ scale-out appliance with an embedded IBM® GPFS™ parallel file system

TECHNICAL BENEFITS

  • Centralized storage with an embedded file system makes it easy to add storage where needed—in the high-performance, high-transaction or slower storage pools—and then manage it all through a single pane of glass
  • DDN’s transparent data movement enables using one platform for data capture, download, analysis and retention
  • The ability to maintain an active archive of storage lets the center accommodate different types of analytics with varied I/O needs

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Dense Breast Mammogram

Posted in Biomedical Measurement Science, Cancer and Current Therapeutics, Cancer Screening, Clinical & Translational, Clinical Diagnostics, Curation, Diagnostics and Lab Tests, Genome Biology, History and physical exam, Human Immune System in Health and in Disease, Image Processing/Computing, Imaging-based Cancer Patient Management, Immunodiagnostics, Methods, Molecular Genetics & Pharmaceutical, MRI, Personalized and Precision Medicine & Genomic Research, Population Health Management, tagged , , on November 8, 2015| Leave a Comment »

Dense Breast Mammogram

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

The Problem With Mammograms

Madison MargolinNovember 7, 2015

http://forward.com/culture/324003/the-problem-with-mammograms/#ixzz3queBnx00

 

Hallie Leighton had dense breasts — a fact she discovered only in her late 30s, via a mammogram. She grew up in an Ashkenazi family in New York, pursued a career in writing and worked with organizations promoting peace between Israelis and Arabs. By 2013 she was making a documentary on her father Jan Leighton, an actor who set the record as an actor for appearing in the most roles (2,407 according to the 1985 Guinness Book of World Records). She was never able to complete it. She died that year, at the age of 42.

Every woman in Leighton’s family had breast cancer, so she began getting annual mammograms at 35 — five years earlier than the recommended age. In 2009 the results of Leighton’s mammogram came in as “negative” or “normal”; by 2013 she was bedridden, undergoing her final days of chemotherapy.

When Leighton was first diagnosed in 2010, her doctor told her, “You have breast cancer, and it was there in 2009.” The tumor in Leighton’s breast went undiscovered until it was palpable — and at that point, the cancer was already in stage 4.

“Happygram,” a documentary which exposes some of the shortcomings in mammography, chronicles Leighton’s struggle with cancer and the implications of having dense breasts.

“Most women simply aren’t informed that they have dense breast tissue,” said Leighton’s best friend Julie Marron. She wrote and directed the documentary, which is currently screening at film festivals around the country.

Breast density is defined by the relative amount of fat in relation to the amount of connective and epithelial tissue (tissue that lines blood vessels and cavities). When more than 50% of breast tissue is connective and epithelial tissue, instead of fatty tissue, the breasts are considered dense. Mammography is the only way to determine breast density.

“If you have dense breasts, what looks dense on a mammogram looks the same as a cancer would look. It tends to confuse or confound the physician, and reduces the sensitivity of the mammogram,” said Gerald Kolb, founder and president of The Breast Group, which counsels clients on different technologies in breast care. “Hallie Leighton’s breasts looked like snowballs; there was no chance they were going to find anything with the mammogram.”

Forty percent of women who are screened for breast cancer have dense breast tissue. These women also account for more than 70% of all invasive cancers. “Mammograms are not very effective screening tools for these women, as they miss between 50% and 75% of all invasive cancers in dense breast tissue,” Marron said. “This is obviously a very critical issue when you are dealing with a population that is more likely to develop cancer.”

Ashkenazi women are even more at risk. They are 1.6 times more likely than the general population to have dense breast tissue, according to Kolb. Moreover, one in 40 Ashkenazi women will test positive for one or both of BRCA gene mutations responsible for breast cancer. For the general population, that number is between one in 350 and one in 800.The BRCA 1 or 2 genes don’t cause cancer, they fight cancer, Kolb says. But if the gene is mutated, the body is not as well equipped to fight the cancer.

“A woman with a BRCA mutation has a lifetime risk of around 33% to 87%, depending on the gene and mutation,” Marron said. “Compare this to a lifetime risk of 12% for developing breast cancer for the overall population.” BRCA gene mutations can be inherited from either or both parents, and therefore they can be present in men as well as in women.

Breast density and BRCA gene mutations are not directly related, but both independently present an increased susceptibility to breast cancer.

“The biggest risk is that a doctor is not going to find the cancer when it’s really small,” Kolb said. When a tumor is detected at a centimeter or smaller, there’s a 95% cure rate. But if the cancer is the size of a golf ball by the time it’s detected, Kolb says, the woman has a 60% chance of living for five years, and then her mortality increases dramatically.

The good news is that mammography isn’t the only method of detecting breast cancer; the bad news is that very few people know this. “What we’re trying to do in the density movement is give women enough information so they can ask appropriate questions of a doctor,” Kolb said.

Kolb advises high-risk women to get a genetic risk analysis, which can be performed by a genetic counselor or a radiologist. He advises getting the risk analysis as early as age 25, but doing so is a personal decision. Not every woman is emotionally prepared to know the results.

“Mammography is a starting point,” said Dr. Dennis McDonald, a California-based women’s imager. Additionally, doctors recommend that women with dense breasts get an MRI, which McDonald says is reserved for high-risk women. It’s an expensive, invasive and time-consuming procedure that requires the injection of fluid in order to read the MRI. As of yet, doctors do not know the side effects of getting an annual MRI.

“A doctor should have started [Leighton] on an MRI right away. She was high risk and they chose to just monitor with a mammogram,” Kolb said. “That’s insufficient.”

Breast ultrasound is another alternative for women with dense breast tissue. “Most of the time, breast density doesn’t present a problem [with ultrasounds],” McDonald said. Though the ultrasound is effective in detecting cancer, he says the downside is that radiologists are often not that comfortable with the technology, simply because they have little experience with it. There are also a lot of false positives, he adds, which result in unnecessary exams or biopsies.

As “Happygram” documents, informing women of their breast density and of alternatives to mammography is a highly charged political issue.

“The whole breast cancer industry has grown up around mammograms,” Marron said. “Physicians weren’t educated on [breast density], deliberately so to a certain extent, and refused to inform patients on this issue, which is really outrageous if you think about it.” Marron says that doctors are required by law and ethical guidelines to inform patients of “material” medical information. “There is no legitimate reason that women have not been informed of this information,” she noted.

After Leighton’s diagnosis, she wanted to ensure that other women didn’t suffer the same misfortune of all-too-late tumor discovery on account of dense breast tissue. She gave media interviews, lobbied in Albany and starred in “Happygram,” all the while undergoing chemotherapy. She died four months after the Breast Density Information Bill passed in New York.

The law requires that every mammography report given to a patient with dense breasts inform the patient in plain language that she has dense breast tissue and that she should talk to her physician about the possible benefits of additional screenings. In New York, the first state in the nation to pass this kind of law, at least 2,500 women with dense breasts and invasive breast cancer received “normal” or “negative” results on their mammograms.

Similar legislation has been passed in more than 20 states throughout the country, but not without objection. Many well-intentioned radiologists, poorly informed about alternative screening options, feared that telling women the limitations of mammography would cause them to lose faith in it altogether and not get tested. Others argued that the information would make women anxious, and that it wouldn’t be fair for those who couldn’t afford additional testing. And still further arguments against informing women were possibly impacted by financial considerations, Marron added.

“Women aren’t getting the benefit of full notification across the board yet,” Marron said. “I think that has to change through education. That’s the primary reason we made this movie. There’s been so much resistance within the medical community to telling women. Change isn’t going to come from the medical community, it has to come from the patients.”

Ashkenazi women shouldn’t panic, Kolb says, but they need to carefully examine their breast density and alternative screening options: “Anytime you have a preventative tragedy like that, you have to do everything in your power to stop it from happening.”

Madison Margolin is a freelance writer based in New York. She writes frequently for the Village Voice.

Read more: http://forward.com/culture/324003/the-problem-with-mammograms/#ixzz3qufQOSmn

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Management of Follicular Lymphoma

Posted in Acute lymphocytic leukemia, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Hematology, Human Immune System in Health and in Disease, Immuno-Oncology & Genomics, Immunotherapy, Interviews with Scientific Leaders, Lymphoma, Molecular Genetics & Pharmaceutical, tagged , on November 5, 2015| Leave a Comment »

Management of Follicular Lymphoma

Curator: Larry H. Bernstein, MD, FCAP

Article ID #193: Management of Follicular Lymphoma. Published on 11/5/2015

WordCloud Image Produced by Adam Tubman

 

Targeted Approaches to the Management of Follicular Lymphoma  

By Chaitra Ujjani, MD

http://www.cancernetwork.com/oncology-journal/targeted-approaches-management-follicular-lymphoma

 

Despite high rates of response to initial chemoimmunotherapy, patients with follicular lymphoma experience frequent relapses, and better treatment options are needed. Several novel biologic agents have been developed based on a greater understanding of the intrinsic factors driving the development of this heterogeneous disease. Such therapies target extracellular surface proteins and intracellular signaling pathways, as well as manipulate and engage the tumor microenvironment. Many of these agents have shown great promise in early-phase studies and are the focus of ongoing clinical investigations.

 

Introduction As the second most common form of non-Hodgkin lymphoma (NHL), follicular lymphoma affects thousands of new patients in the United States each year. Although follicular lymphoma is considered an indolent disease, its clinical course is highly variable. Asymptomatic patients with low tumor burden can be monitored closely with the “watch and wait” strategy, given that the early intervention of chemotherapy or immunotherapy has not demonstrated a survival benefit.[1,2] The most widely accepted indications for treatment are one or more of the following criteria from the Groupe d’Etude des Lymphomes Folliculaires (GELF): a single lesion > 7 cm, three nodal sites > 3 cm, splenomegaly, effusions, threat or evidence of organ compression, or constitutional symptoms.[3] Whereas patients with limited-stage disease have several treatment options—including single-agent rituximab, radiation, and chemoimmunotherapy, those with advanced-stage disease typically receive chemoimmunotherapy.[4,5] Both the German Study Group Indolent Lymphomas (StiL) NHL-2 study and the pharmaceutical company–sponsored Bendamustine Rituximab Investigational Non-Hodgkin’s Trial (BRIGHT) have established the front-line role of combination therapy with bendamustine and rituximab in the treatment of follicular lymphoma, based on comparable efficacy and better tolerability than standard regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).[6,7] Despite high response rates with initial therapy, follicular lymphoma is characterized by frequent relapses, and patients need improved treatment options.

Oncology (Williston Park). 29(10):760-768.

 

http://www.cancernetwork.com/sites/default/files/styles/figures_diagrams/public/figures_diagrams/1510ujjaniTable.png

Table: Targeted Therapies in Development and FDA-Approved for the Treatment of Follicular Lymphomas

 

Since the discovery of rituximab, there has been significant innovation in drug development, based on a greater understanding of the pathogenesis of the disease. The multistep process leading to follicular lymphoma is theorized to begin with an initial genetic insult, the hallmark t(14;18) translocation, which results in overexpression of the anti-apoptotic B-cell lymphoma protein, BCL-2.[8] This translocation is not the sole factor in malignant transformation, as it is a naturally occurring anomaly, often identified in healthy individuals. Furthermore, preclinical studies have indicated a positive correlation between increasing numbers of genetic alterations and the progression from follicular lymphoma in situ to grade 3A follicular lymphoma.[9] The B-cell receptor is a critical cellular factor in the development of the disease. Its active tonic signaling leads to recruitment of the spleen tyrosine kinase (SYK) and activation of multiple downstream pathways, including phosphatidylinositol 3-kinase (PI3K), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein kinase (MAPK). Activation of these pathways ultimately results in the maturation, proliferation, and survival of malignant lymphocytes.[10] Other key components include immune cells such as T cells, dendritic cells, and reticular cells, which infiltrate among the centrocytes.[11] In addition to stimulating the B-cell receptor, these immune cells induce exhaustion of cytotoxic T cells and allow for T-cell evasion via disruption of synapses and secretion of interleukin-12.[12] Expression of the inhibitory receptor programmed cell death 1 (PD-1) is another contributing factor, as its presence is believed to affect the ability of T cells to mount appropriate antitumor responses.[13] Several novel therapies have been developed to target these various aspects of the disease in the hope of identifying more effective, yet tolerable, treatment options for patients with follicular lymphoma. (See the Table for a summary of therapies approved and in development for treatment of follicular lymphoma.)

 

Since the approval of rituximab, there has been significant investigation into the development of a superior anti-CD20 monoclonal antibody. Second- and third-generation versions vary in their structures and mechanisms of action. Two anti-CD20 antibodies, ofatumumab and obinutuzumab, have been approved by the US Food and Drug Administration (FDA) for indications in chronic lymphocytic leukemia (CLL). Ofatumumab, a type I human monoclonal antibody, was initially approved for patients whose disease is refractory to fludarabine and alemtuzumab.[14] Obinutuzumab was approved in combination with chlorambucil for patients with preexisting comorbidities that preclude conventional chemoimmunotherapy.[15] Although designed to induce stronger complement-dependent cytotoxicity than rituximab, ofatumumab demonstrated minimal activity in rituximab-refractory follicular lymphoma (overall response rate [ORR], 10% to 13%; median progression-free survival [PFS], 5.8 months).[16] In phase II trials of ofatumumab in combination with chemotherapy, including bendamustine and CHOP, results appeared comparable to those achieved with rituximab-based regimens, although no direct comparisons have been made.[17,18]

Obinutuzumab, a type II glycoengineered humanized antibody, is further in development for use in NHL. This agent, which works primarily by triggering antibody-dependent cellular cytotoxicity (ADCC) and apoptosis, has demonstrated superiority to rituximab in preclinical studies, including those employing whole blood B cell–depletion assays, human lymphoma xenograft mice models, and nonhuman primates.[19] When compared with rituximab in patients with indolent B-cell NHL, obinutuzumab produced a higher ORR by independent radiology review (45% vs 27%; P = .01); however, complete response (CR) and PFS rates were similar.[20] Like ofatumumab, treatment with obinutuzumab is associated with a higher rate of infusion-related reactions than rituximab (grade 1–4, 72% vs 49%; and grade 3/4, 11% vs 5%, respectively). In contrast to ofatumumab, it has efficacy in rituximab-refractory indolent NHL, producing an ORR of 50% and median PFS of 12 months among 10 patients.[21] The phase III GADOLIN study evaluated obinutuzumab in combination with bendamustine followed by maintenance obinutuzumab in the same disease setting (N = 413).[22] While the response rates by independent review were similar to those observed in the comparative arm of patients randomized to single-agent bendamustine (bendamustine-obinutuzumab ORR, 69% [CR, 11%] vs bendamustine alone ORR, 63% [CR, 12%]), the median PFS was significantly higher with the combination (not reached vs 14.9 months; P = .00011). Treatment with the combination of bendamustine and obinutuzumab was associated with a similar incidence of grade ≥ 3 adverse events compared with bendamustine monotherapy (68% vs 62%), which included neutropenia (33% vs 26.3%) and infusion-related reactions (9% vs 3.5%). While there was no difference in overall survival (OS) noted, the study did demonstrate the clinical benefit of obinutuzumab in rituximab-refractory disease. The role of the drug in this setting is becoming less clear, as more patients now receive bendamustine-rituximab as front-line therapy. In the phase Ib GAUDI study, bendamustine-obinutuzumab and obinutuzumab-CHOP produced similar response rates in patients with previously untreated follicular lymphoma, with ORRs of 93% (CR, 39%) and 95% (CR, 35%), respectively.[23] The incidences of grade 3/4 neutropenia and infection were similar to historical data on rituximab chemotherapy. These data prompted the front-line phase III GALLIUM study of chemotherapy (CHOP, CVP [cyclophosphamide, vincristine, and prednisone], or bendamustine) with obinutuzumab or rituximab followed by maintenance obinutuzumab or rituximab in advanced-stage indolent B-cell NHL (ClinicalTrials.gov identifier: NCT01332968). Newer monoclonal antibodies directed against CD20, such as ublituximab, and rituximab biosimilars are also in development.

Monoclonal antibodies to alternative targets

Monoclonal antibodies directed against other B-cell antigens have also been developed. Galiximab, a chimeric human-macaque anti-CD80 antibody, and epratuzumab, a humanized anti-CD22 antibody, were two of the first antibodies directed against these targets to be explored in follicular lymphoma. Both antibodies have shown activity as single agents and in combination with rituximab in follicular lymphoma. However, neither is being studied further due to the availability of newer, more promising therapies.[24-28] MEDI-551, an afucosylated humanized anti-CD19 antibody, induces cell death via ADCC and cytotoxic T-cell response. The lack of a fucose moiety on the Fc portion of the antibody is believed to enhance the activity of ADCC. Phase I studies of MEDI-551 in heavily pretreated follicular lymphoma have reported ORRs ranging from 31% to 82%.[29,30] The median PFS from the earlier study was nearly 10 months. MEDI-551 is currently being evaluated in aggressive lymphomas in combination with rituximab and salvage chemoimmunotherapy (ClinicalTrials.gov identifiers: NCT00983619 and NCT01453205). Also targeting CD19 is MOR208, a humanized monoclonal antibody that has been engineered to have a higher affinity to FcγRIIIa and FcγRIIa, resulting in stronger ADCC. In a phase II study of patients with relapsed and refractory B-cell NHL who had received a median of two prior therapies, the ORR was 26% among those with follicular lymphoma (n = 31).[31] The median duration of response (DOR) was 2.6 months; however, the longest DOR was 15.4 months. Upcoming trials with MOR208 include combination studies with lenalidomide in diffuse large B-cell lymphoma (DLBCL) and CLL (ClinicalTrials.gov identifiers: NCT02399085 and NCT02005289).

Radioimmunotherapy

One of the first attempts to improve upon the efficacy of the naked monoclonal antibody was radioimmunotherapy, which produced ORRs of 65% to 74% in patients with relapsed and refractory indolent B-cell lymphomas.[32,33] 90Y-ibritumomab tiuxetan, the first radioimmunotherapy to receive FDA approval, was approved in February 2002 for relapsed or refractory low-grade, follicular, or transformed B-cell NHL. In 2009, it was granted expanded approval as consolidation therapy in previously untreated follicular lymphoma patients with a partial or complete response to first-line chemotherapy. 131I-tositumomab was approved in June 2003 (along with tositumomab) for CD20-positive follicular NHL, with and without transformation, in relapsed rituximab-refractory patients with relapse following chemotherapy. The use of 131I-tositumomab and 90Y-ibritumomab tiuxetan has declined significantly over the past several years; the manufacture and sale of 131I-tositumomab (marketed in the United States and Canada as Bexxar) was stopped in February 2014. Radioimmunotherapy can be difficult; there are strict hematologic criteria (< 25% lymphomatous marrow involvement, platelet count > 100 × 109, leukocyte count > 1.5 × 109), and its administration requires a certified nuclear medicine physician. In addition, the patient must not have had prior radiation to > 25% of the bone marrow nor undergone stem cell transplantation.[34]

Antibody-drug conjugates (ADCs)

Recent efforts in augmenting antibody-based therapy include the use of ADCs. Once bound to its target antigen, the ADC is engulfed via endocytosis, trafficked to the lysosome for degradation, and ultimately released, whereupon it causes damage to tubulin and DNA. The calicheamicin-bound anti-CD22, inotuzumab ozogamicin, was one of the first to be studied in patients with follicular lymphoma who were refractory to CD20-targeted therapy, yielding an ORR of 66%.[35] The ORR increased to 87% when inotuzumab ozogamicin was combined with rituximab in patients with relapsed and refractory follicular lymphoma, prompting a trial in which it was compared with combination treatment with rituximab plus chemotherapy.[36] The trial was closed early due to poor accrual. Inotuzumab ozogamicin is currently being studied in combination with the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in relapsed and refractory CD22-expressing NHL (ClinicalTrials.gov identifier: NCT01535989). Pinatuzumab vedotin and polatuzumab vedotin, which target CD22 and CD79b, respectively, are ADCs linked to the anti-tubulin molecule monomethyl auristatin E. While both agents have demonstrated activity in indolent NHL (with reported ORRs of 50% and 47%, respectively), polatuzumab vedotin is being taken further in development.[37,38] When polatuzumab vedotin was administered at a higher dose (2.4 mg/kg) with rituximab in patients with relapsed and refractory follicular lymphoma (n = 25), the ORR was 76% (CR, 44%) and median PFS was 15 months.[39] The cohort of 20 patients treated at the lower rituximab dose (1.8 mg/kg) had a similar response rate (ORR, 70%; CR, 40%), and median PFS and DOR were not reached. Peripheral neuropathy, a common toxicity with ADCs, occurred less frequently with the lower dose of polatuzumab vedotin and was ameliorated in some patients by dose delay and reduction. Ongoing studies with polatuzumab vedotin include phase I/II combinations with bendamustine-rituximab or obinutuzumab-bendamustine in relapsed and refractory follicular lymphoma (ClinicalTrials.gov identifier: NCT02257567) and R-CHOP in B-cell NHL patients who have received less than one prior therapy (ClinicalTrials.gov identifier: NCT01992653). Coltuximab ravtansine (formerly SAR3419) is an anti-CD19 ADC that has also been associated with neurologic complications, primarily dose-limiting ocular toxicity.[40] IMGN529, which targets the overexpressed CD37 protein, is another B-cell–directed ADC in development.[41]

Despite high rates of response to initial chemoimmunotherapy, patients with follicular lymphoma experience frequent relapses, and better treatment options are needed. Several novel biologic agents have been developed based on a greater understanding of the intrinsic factors driving the development of this heterogeneous disease. Such therapies target extracellular surface proteins and intracellular signaling pathways, as well as manipulate and engage the tumor microenvironment. Many of these agents have shown great promise in early-phase studies and are the focus of ongoing clinical investigations.

Small-Molecule Inhibitors – PI3K inhibitors

In contrast to the various antibody-based therapies under investigation for treatment of follicular lymphoma, several small molecules have been designed to inhibit key intracellular pathways of the malignant B cell. The majority of these agents are directed against kinases downstream of the B-cell receptor, and many have been combined with bendamustine-rituximab, given this combination’s efficacy and tolerability. Idelalisib, a potent PI3K-δ inhibitor, was the first PI3K inhibitor to be approved by the FDA for follicular lymphoma. It received an indication for patients who have received at least two prior systemic therapies, based on results of a phase II study in rituximab-refractory indolent NHL[42] As reported at the 2015 American Society of Clinical Oncology Annual Meeting, of the 72 patients in the study who had follicular lymphoma, 54% were considered high-risk by the Follicular Lymphoma International Prognostic Index.[43] The patients had received a median of four prior therapies, and 86% had disease that was refractory to the last regimen they received. The ORR was 56% and the median PFS was 11 months. The median PFS for the 10 patients who achieved a CR was 27 months. Notable grade 3/4 adverse events included neutropenia (27% of all patients), diarrhea/colitis (16%), elevations in hepatic transaminases (13%), and pneumonia (7%).
Idelalisib was subsequently administered with rituximab, bendamustine, and bendamustine-rituximab in a phase I study of patients with relapsed (n = 79) and refractory (n = 59) indolent NHL, the majority of whom had follicular lymphoma.[44] The ORRs were similar between the arms (75% to 88%); however, treatment with bendamustine-rituximab-idelalisib was associated with the highest CR (43%) and longest median PFS (37.1 months). A phase III trial of bendamustine-rituximab with or without idelalisib in relapsed and refractory indolent B-cell NHL is ongoing (ClinicalTrials.gov identifier: NCT01732926). In phase I investigations, combined treatment with idelalisib and lenalidomide plus the second-generation SYK inhibitor entospletinib has demonstrated considerable toxicity, including hepatic transaminitis, sepsis, and refractory pneumonitis.[45,46] Second-generation PI3K inhibitors, including duvelisib (IPI-145), TGR-1202, and INCB040093, are in development. Duvelisib, a dual inhibitor of the delta and gamma isoforms of PI3K, has demonstrated an ORR of 69% (CR, 38%) in a heavily pretreated follicular lymphoma cohort (n = 13).[47] Based on these encouraging data, duvelisib is being administered with rituximab or obinutuzumab in patients with previously untreated follicular lymphoma (ClinicalTrials.gov identifier: NCT02391545) and with bendamustine and/or rituximab in those with relapsed B-cell malignancies (ClinicalTrials.gov identifier: NCT01871675).

Bruton tyrosine kinase (BTK) inhibitors

Ibrutinib, a selective and irreversible inhibitor of BTK, may also have some impact on the tumor microenvironment via cytokine and chemokine inhibition.[48] Approved in CLL, mantle cell lymphoma, and Waldenström macroglobulinemia, it has demonstrated activity in a number of B-cell malignancies.[49-53] In a phase II study of relapsed and refractory follicular lymphoma, ibrutinib yielded an ORR of 30% (with one CR) and a median PFS of 9.9 months. The 40 enrolled patients had received a median of three prior therapies, and 36% were considered refractory to treatment. Common adverse events included mild diarrhea, rash, and fatigue; rare events included atrial fibrillation and bleeding.[54] Like idelalisib, ibrutinib has been combined with bendamustine-rituximab in the treatment of B-cell NHL.[55] This triplet produced an ORR of 90% (CR, 50%) in a cohort of 10 patients with previously treated follicular lymphoma. At the time these results were reported, the median PFS had not been reached. Notable grade 3/4 adverse events included neutropenia (33%), rash (25%), and thrombocytopenia (19%). Results from SELENE, a randomized phase III trial of ibrutinib with bendamustine-rituximab or R-CHOP in previously treated follicular lymphoma and marginal zone lymphoma, will provide more insight into the role of ibrutinib in the management of indolent NHL (ClinicalTrials.gov identifier: NCT01974440). Phase I trials of combinations with targeted agents include the Alliance for Clinical Trials in Oncology study of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma[56] and the pharmaceutical-sponsored trial of combination therapy with ublituximab, TGR-1202, and ibrutinib in relapsed and refractory B-cell malignancies.[57] Second-generation BTK inhibitors, including ACP-196 and ONO-4059, are also in development.

B-cell lymphoma–2 (BCL-2) inhibitors

The chromosomal translocation t(14;18) allows for dysregulation of the BCL-2 oncogene and overexpression of the anti-apoptotic BCL-2 family of proteins, contributing to development of follicular lymphoma. Venetoclax, formerly known as ABT-199, is a second-generation selective BCL-2 inhibitor in the early stages of clinical investigation. When this agent was administered at a dose greater than 600 mg daily to six patients with relapsed and refractory follicular lymphoma, three patients achieved a response.[58] Common toxicities reported included mild nausea (34%) and diarrhea (25%), and grade 3/4 myelosuppression occurred in less than 15% of patients. Two patients (one with DLBCL and one with mantle cell lymphoma) in the entire NHL cohort (of 44 patients then enrolled in the study) developed laboratory evidence of grade 3 tumor lysis syndrome. When venetoclax was combined with bendamustine-rituximab in 21 patients with relapsed and refractory follicular lymphoma, the ORR was 71% (CR, 29%).[59] While a maximum tolerated dose was not reached, dose-limiting toxicities included thrombocytopenia, neutropenia, and Stevens-Johnson syndrome. Venetoclax is being evaluated in relapsed and refractory follicular lymphoma, in a three-arm phase II study of bendamustine-rituximab vs rituximab-venetoclax vs bendamustine-rituximab-venetoclax (ClinicalTrials.gov identifier: NCT02187861). It will be studied with ibrutinib in a phase I/II trial of relapsed follicular and marginal zone lymphoma (Ujjani C, principal investigator). Small-molecule inhibitors aimed at less well known targets are also under investigation, including selinexor (a selective inhibitor of nuclear export), MK-2206 (an AKT inhibitor), alisertib (an Aurora-A kinase inhibitor), and cerdulatinib (a dual SYK/Janus tyrosine kinase [JAK] inhibitor).

TO PUT THAT INTO CONTEXT

Loretta J. Nastoupil, MD
Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Houston, Texas

What Are the Challenges of Treating Follicular Lymphoma?

Follicular lymphoma, the most common indolent lymphoma, is characterized by high rates of initial response to chemoimmunotherapy, but it is not curable with standard therapy. The clinical course of the disease is highly variable and somewhat unpredictable. As a result, the optimal management of follicular lymphoma, including the most effective sequencing of therapy, is undefined. Identifying the subsets of patients at risk for early failure and those with indolent disease that remains quiescent would assist clinicians in tailoring therapy for individual patients. Given the heterogeneity of treatment options and possible clinical outcomes, improvement in risk stratification and personalization in follicular lymphoma is needed, particularly given the expanding treatment options outlined by Dr. Ujjani.

What Can We Expect in the Future?

Historically, prognostication for patients with follicular lymphoma has relied primarily on clinical characteristics. The Follicular Lymphoma International Prognostic Index (FLIPI) can distinguish patients with low or intermediate risk from those at high risk, but it is not routinely used to guide risk-adapted therapy. More recently, the development of m7-FLIPI, a multivariable risk model incorporating the mutation status of seven genes with established clinical relevance in follicular lymphoma, improved the ability to predict early treatment failure in patients receiving front-line chemoimmunotherapy. Identifying the follicular lymphoma patients at highest risk for early treatment failure with standard therapy allows for their prioritization to a clinical trial assessing some of the novel therapies outlined by Dr. Ujjani.

Given the number of therapeutic agents under investigation in follicular lymphoma, and the vast combinatorial possibilities, consideration of toxicity is as imperative as the need to conduct correlational studies to unravel the complexity of this disease.

Tumor Microenvironment
Immunomodulatory agents

As stated previously, the tumor microenvironment plays a critical role in the pathogenesis of follicular lymphoma. Approaches to promoting a functional immune system have allowed for effective treatment of the disease. The second-generation immunomodulatory agent lenalidomide has been the most extensively studied of these therapies. Its mechanisms of action include activation of natural killer cells and T cells, stimulation of apoptosis, and inhibition of tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF).[60] In follicular lymphoma cell lines, lenalidomide has been shown to restore immunologic synapses between malignant lymphocytes and T cells and augment rituximab-mediated ADCC.[61] Lenalidomide has demonstrated modest activity as a single agent in relapsed or refractory follicular lymphoma (with ORRs ranging from 27% to 49%); however, when lenalidomide was added to rituximab the ORR improved to 76% and the median event-free survival time was 2 years.[62,63] The doublet (dubbed “R2,” for Revlimid [lenalidomide] plus rituximab) was evaluated by the Alliance study as a front-line regimen, producing an ORR of 93% (CR, 72%) and 2-year PFS of 89% (n = 65).[64] Minimal toxicity was noted with the regimen; common grade 3/4 adverse events included neutropenia (in 19% of patients), rash (8%), and infection (8%). In a similar study from the University of Texas MD Anderson Cancer Center, 35 of the 50 patients with follicular lymphoma achieved a CR (70%) and 5 had an unconfirmed CR.[65] The Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group reported an ORR of 78% (CR, 61%) with the R2 combination (n = 77).[66] The impressive activity noted in the Alliance and MD Anderson studies prompted the pharmaceutical-sponsored phase III RELEVANCE trial of R2 vs rituximab with chemotherapy (CVP, CHOP, or bendamustine) in previously untreated advanced-stage follicular lymphoma (ClinicalTrials.gov identifier: NCT01650701). R2 has been studied in combination with other regimens such as CHOP, producing an ORR of 94% (CR/unconfirmed CR, 74%) in patients with previously untreated follicular lymphoma.[67] These data are relatively comparable to previously reported results with R2 and call into question the need for CHOP. The Alliance has conducted subsequent studies of R2 with targeted agents including ibrutinib and idelalisib. Results with ibrutinib are pending; however, the trial of idelalisib was closed owing to considerable toxicity.[45,56] Lenalidomide has also been combined with obinutuzumab in the treatment of relapsed and refractory disease, yielding an ORR of 68% (CR, 35%) among the 20 patients enrolled in the phase I portion of a phase I/II study.[68]

Immune checkpoint modulators

In patients with follicular lymphoma, the overexpression of PD-1 in the intratumoral T cells results in an impairment in antitumor immune surveillance. Inhibition of PD-1 or its ligands, PD-L1 and PD-L2, has shown promise in the treatment of follicular lymphoma. Pidilizumab, a humanized PD-1 monoclonal antibody, was the first PD-1 inhibitor to be explored. Although minimally active as a single agent, when pidilizumab was administered in conjunction with rituximab in the setting of relapsed follicular lymphoma, the ORR was 66% and median PFS was 18.8 months (n = 29).[69,70] The majority of the responses were complete (52%), and the median PFS had not been reached for those who achieved a response. Nivolumab, a fully human monoclonal antibody approved for the treatment of melanoma and squamous non–small-cell lung cancer, has also demonstrated activity in relapsed and refractory follicular lymphoma. A phase I evaluation has reported an ORR of 40% (CR, 10%) in 10 patients.[71] Nivolumab is currently being studied in combination with ibrutinib in patients with relapsed B-cell malignancies (ClinicalTrials.gov identifier: NCT02329847). Pembrolizumab and MEDI-0680 are humanized PD-1 antibodies also under clinical investigation in CLL and other low-grade B-cell NHLs, as well as in relapsed and refractory aggressive B-cell lymphomas (ClinicalTrials.gov identifiers: NCT02332980 and NCT02271945, respectively). MEDI4736, a human anti–PD-L1 antibody, is also being studied with ibrutinib in patients with relapsed lymphoma (ClinicalTrials.gov identifier: NCT02401048). Similar to PD-1, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T-cell function. Inhibition of CTLA-4 with ipilimumab, also approved in melanoma, has demonstrated some activity in lymphoid malignancies, including in one patient with follicular lymphoma.[72]

Bispecific T-cell engager (BiTE)

The BiTE is a unique form of immunotherapy that stimulates T-cell function via binding simultaneously to CD3 on the surface of the T cell and a specific marker on the malignant B cell, resulting in caspase-mediated apoptosis. Blinatumomab, a CD19-specific BiTE approved for treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (ALL), has demonstrated activity in other CD19-positive lymphoid diseases.[73] It produced an ORR of 100% in a phase I study of 13 patients with relapsed indolent NHL, the majority of whom had a follicular or mantle cell histology.[74] Four patients achieved a CR, and eight remained in remission at 13 months. A single cycle of blinatumomab requires a 4-week continuous IV infusion and is associated with significant, yet reversible, neurologic toxicity. The current focus of clinical investigations with this agent is ALL, and its role in follicular lymphoma is unclear.

Chimeric antigen receptor (CAR)-modified T cells

CAR-modified T cells are one of the newest, most intriguing, forms of immunotherapy. These autologous T cells have been genetically transduced using lentiviral vectors to express tumor cell–specific antigen receptors. Having demonstrated activity in CLL and ALL, CAR-modified T cells are now being explored in CD19-positive NHL. A phase II study at the University of Pennsylvania demonstrated an ORR of 100% among seven patients with relapsed and refractory follicular lymphoma who lacked curative treatment options.[75] Six patients achieved a CR by 6 months, and responses appeared to be durable. In all seven patients there was evidence of severe cytokine release syndrome (cytokine storm); in two of the patients this was a grade 3/4 toxicity. One patient developed grade 5 encephalopathy 2 months after completing therapy. Although quite promising, further investigation is necessary to fully understand this new method.

Conclusion
The treatment of follicular lymphoma has changed dramatically over the past several years. The availability of newer, novel forms of therapy has enabled the field to continue to evolve. In addition to having tumor-specific activity, these newer agents provide the possibility of a more favorable toxicity profile than conventional chemotherapy. Although chemoimmunotherapy has been the traditional front-line induction for patients with advanced-stage disease, this concept is being challenged by the remarkable efficacy of the R2 regimen (with ORR > 90%; CR, 61% to 72%).[64,66] If the phase III RELEVANCE trial demonstrates results with R2 that are even equivalent to those achieved with standard regimens such as R-CHOP or bendamustine-rituximab, a major paradigm shift will occur; R2 would then be the first chemotherapy-free option for the initial treatment of follicular lymphoma. Given that the attainment of a CR has been associated with a survival benefit in this setting, there is still room for improvement.[76] Although approved as a single agent, idelalisib is being studied in combination with rituximab in previously untreated and relapsed patients (ClinicalTrials.gov identifiers: NCT02258529 and NCT01732913). Ongoing clinical investigations, such as the Alliance phase I trial of R2 plus ibrutinib in previously untreated patients, are exploring the benefit of multitargeted agents in this population. Studies such as the phase II trial of bendamustine-rituximab vs rituximab-venetoclax vs bendamustine-rituximab-venetoclax are exploring the utility of other targeted agents in comparison to standard chemoimmunotherapy.

While the concept of multitargeted therapy is quite appealing, these regimens must be explored with caution. Early-phase investigations of idelalisib with R2 and entospletinib produced significant adverse events, requiring study closures.[45,46] In addition to understanding how to combine treatment with these agents safely and efficaciously, research efforts must incorporate sound correlative science. Through whole-exome sequencing, Woyach et al have already discovered mutations associated with resistance to ibrutinib in CLL.[77] The identification of other predictive biomarkers is imperative to tailor therapy effectively and to develop superior regimens for individual patients. Furthermore, this information may enable us to provide appropriate treatment options that are also financially prudent. Given the lengthy follow-up period required to achieve the traditional objectives of clinical trials, it is important to explore earlier, yet meaningful, surrogate endpoints. Residual positron emission tomography activity on post-induction imaging, the presence of minimal residual disease, and relapse within 2 years of chemoimmunotherapy have been associated with an inferior PFS and OS outcome; in contrast, the presence of a CR at 30 months has been correlated with a significantly reduced risk of progression in patients with follicular lymphoma.[78-81] By incorporating novel therapies into innovative clinical investigations, we may achieve significantly better outcomes and improve the outlook for patients with this incurable disease.

Financial Disclosure: Dr. Ujjani has served on advisory boards for Genentech, Inc., and Pharmacyclics, Inc.

 

 

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