Feeds:
Posts
Comments

Archive for the ‘Childhood cancer’ Category


Double Mutant PI3KA Found to Lead to Higher Oncogenic Signaling in Cancer Cells

Curator: Stephen J. Williams, PhD

PIK3CA (Phosphatidylinsitol 4,5-bisphosphate (PIP2) 3-kinase catalytic subunit α) is one of the most frequently mutated oncogenes in various tumor types ([1] and http://www.sanger.ac.uk/genetics/CGP/cosmic). Oncogenic mutations leading to the overactivation of PIK3CA, especially in context in of inactivating PTEN mutations, result in overtly high signaling activity and associated with the malignant phenotype.

In a Perspective article (Double trouble for cancer gene: Double mutations in an oncogene enhance tumor growth) in the journal Science[2], Dr. Alex Toker discusses the recent results of Vasan et al. in the same issue of Science[3] on the finding that double mutations in the same allele of PIK3CA are more frequent in cancer genomes than previously identified and these double mutations lead to increased PI3K pathway activation, increased tumor growth, and increased sensitivity to PI3K inhibitors in human breast cancer.

 

 

From Dr. Melvin Crasto blog NewDrugApprovals.org

Alpelisib: PIK3CA inhibitor:

Alpelisib: New PIK3CA inhibitor approved for HER2 negative metastatic breast cancer

 

FDA approves first PI3K inhibitor for breast cancer

syn https://newdrugapprovals.org/2018/06/25/alpelisib-byl-719/

Today, the U.S. Food and Drug Administration approved Piqray (alpelisib) tablets, to be used in combination with the FDA-approved endocrine therapy fulvestrant, to treat postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test) following progression on or after an endocrine-based regimen.

The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by

May 24, 2019

Today, the U.S. Food and Drug Administration approved Piqray (alpelisib) tablets, to be used in combination with the FDA-approved endocrine therapy fulvestrant, to treat postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test) following progression on or after an endocrine-based regimen.

The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by the therascreen test using the liquid biopsy should undergo tumor biopsy for PIK3CA mutation testing.

“Piqray is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating patients with this type of breast cancer. The ability to target treatment to a patient’s specific genetic mutation or biomarker is becoming increasingly common in cancer treatment, and companion diagnostic tests assist oncologists in selecting patients who may benefit from these targeted treatments,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For this approval, we employed some of our newer regulatory tools to streamline reviews without compromising the quality of our assessment. This drug is the first novel drug approved under the Real-Time Oncology Review pilot program. We also used the updated Assessment Aid, a multidisciplinary review template that helps focus our written review on critical thinking and consistency and reduces time spent on administrative tasks.”

Metastatic breast cancer is breast cancer that has spread beyond the breast to other organs in the body (most often the bones, lungs, liver or brain). When breast cancer is hormone-receptor positive, patients may be treated with anti-hormonal treatment (also called endocrine therapy), alone or in combination with other medicines, or chemotherapy.

The efficacy of Piqray was studied in the SOLAR-1 trial, a randomized trial of 572 postmenopausal women and men with HR-positive, HER2-negative, advanced or metastatic breast cancer whose cancer had progressed while on or after receiving an aromatase inhibitor. Results from the trial showed the addition of Piqray to fulvestrant significantly prolonged progression- free survival (median of 11 months vs. 5.7 months) in patients whose tumors had a PIK3CA mutation.

Common side effects of Piqray are high blood sugar levels, increase in creatinine, diarrhea, rash, decrease in lymphocyte count in the blood, elevated liver enzymes, nausea, fatigue, low red blood cell count, increase in lipase (enzymes released by the pancreas), decreased appetite, stomatitis, vomiting, weight loss, low calcium levels, aPTT prolonged (blood clotting taking longer to occur than it should), and hair loss.

Health care professionals are advised to monitor patients taking Piqray for severe hypersensitivity reactions (intolerance). Patients are warned of potentially severe skin reactions (rashes that may result in peeling and blistering of skin or mucous membranes like the lips and gums). Health care professionals are advised not to initiate treatment in patients with a history of severe skin reactions such as Stevens-Johnson Syndrome, erythema multiforme, or toxic epidermal necrolysis. Patients on Piqray have reported severe hyperglycemia (high blood sugar), and the safety of Piqray in patients with Type 1 or uncontrolled Type 2 diabetes has not been established. Before initiating treatment with Piqray, health care professionals are advised to check fasting glucose and HbA1c, and to optimize glycemic control. Patients should be monitored for pneumonitis/interstitial lung disease (inflammation of lung tissue) and diarrhea during treatment. Piqray must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Piqray is the first new drug application (NDA) for a new molecular entity approved under the Real-Time Oncology Review (RTOR) pilot program, which permits the FDA to begin analyzing key efficacy and safety datasets prior to the official submission of an application, allowing the review team to begin their review and communicate with the applicant earlier. Piqray also used the updated Assessment Aid (AAid), a multidisciplinary review template intended to focus the FDA’s written review on critical thinking and consistency and reduce time spent on administrative tasks. With these two pilot programs, today’s approval of Piqray comes approximately three months ahead of the Prescription Drug User Fee Act (PDUFA) VI deadline of August 18, 2019.

The FDA granted this application Priority Review designation. The FDA granted approval of Piqray to Novartis. The FDA granted approval of the therascreen PIK3CA RGQ PCR Kit to QIAGEN Manchester, Ltd.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-pi3k-inhibitor-breast-cancer?utm_campaign=052419_PR_FDA%20approves%20first%20PI3K%20inhibitor%20for%20breast%20cancer&utm_medium=email&utm_source=Eloqua

 

Alpelisib

(2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide

PDT PAT WO 2010/029082

CHEMICAL NAMES: Alpelisib; CAS 1217486-61-7; BYL-719; BYL719; UNII-08W5N2C97Q; BYL 719
MOLECULAR FORMULA: C19H22F3N5O2S
MOLECULAR WEIGHT: 441.473 g/mol
  1. alpelisib
  2. 1217486-61-7
  3. BYL-719
  4. BYL719
  5. UNII-08W5N2C97Q
  6. BYL 719
  7. Alpelisib (BYL719)
  8. (S)-N1-(4-Methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide
  9. NVP-BYL719

Alpelisib is an orally bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity. Alpelisib specifically inhibits PI3K in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

Alpelisib has been used in trials studying the treatment and basic science of Neoplasms, Solid Tumors, BREAST CANCER, 3rd Line GIST, and Rectal Cancer, among others.

 

SYN 2

POLYMORPHS

https://patents.google.com/patent/WO2012175522A1/en

(S)-pyrrolidine-l,2-dicarboxylic acid 2-amide l-(4-methyl-5-[2-(2,2,2-trifluoro-l,l- dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl)-amidei hereafter referred to as compound I,

is an alpha-selective phosphatidylinositol 3 -kinase (PI3K) inhibitor. Compound I was originally described in WO 2010/029082, wherein the synthesis of its free base form was described. There is a need for additional solid forms of compound I, for use in drug substance and drug product development. It has been found that new solid forms of compound I can be prepared as one or more polymorph forms, including solvate forms. These polymorph forms exhibit new physical properties that may be exploited in order to obtain new pharmacological properties, and that may be utilized in drug substance and drug product development. Summary of the Invention

In one aspect, provided herein is a crystalline form of the compound of formula I, or a solvate of the crystalline form of the compound of formula I, or a salt of the crystalline form of the compound of formula I, or a solvate of a salt of the crystalline form of the compound of formula I. In one embodiment, the crystalline form of the compound of formula I has the polymorph form SA, SB, Sc, or SD.

In another aspect, provided herein is a pharmaceutical composition comprising a crystalline compound of formula I. In one embodiment of the pharmaceutical composition, the crystalline compound of formula I has the polymorph form SA, SB,Sc, or So.

In another aspect, provided herein is a method for the treatment of disorders mediated by PI3K, comprising administering to a patient in need of such treatment an effective amount of a crystalline compound of formula I, particularly SA, SB, SC,or SD .

In yet another aspect, provided herein is the use of a crystalline compound of formula I, particularly SA, SB, SC, or SD, for the preparation of a medicament for the treatment of disorders mediated by PI3K.

 

Source: https://newdrugapprovals.org/?s=alpelisib&submit=

 

Pharmacology and Toxicology from drugbank.ca

Indication

Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer.Label This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA­ mutated.Label The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen.Label

Associated Conditions

Contraindications & Blackbox Warnings

Learn about our commercial Contraindications & Blackbox Warnings data.

LEARN MORE

 

Pharmacodynamics

Alpelisib does not prolong the QTcF interval.Label Patients taking alpelisib experience a dose dependent benefit from treatment with a 51% advantage of a 200mg daily dose over a 100mg dose and a 22% advantage of 300mg once daily over 150mg twice daily.6 This suggests patients requiring a lower dose may benefit from twice daily dosing.6

Mechanism of action

Phosphatidylinositol-3-kinase-α (PI3Kα) is responsible for cell proliferation in response to growth factor-tyrosine kinase pathway activation.3 In some cancers PI3Kα’s p110α catalytic subunit is mutated making it hyperactive.3 Alpelisib inhibits (PI3K), with the highest specificity for PI3Kα.Label

TARGET ACTIONS ORGANISM
APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform inhibitor Humans

Absorption

Alpelisib reached a peak concentration in plasma of 1320±912ng/mL after 2 hours.4 Alpelisib has an AUClast of 11,100±3760h ng/mL and an AUCINF of 11,100±3770h ng/mL.4 A large, high fat meal increases the AUC by 73% and Cmax by 84% while a small, low fat meal increases the AUC by 77% and Cmax by 145%.Label

Volume of distribution

The apparent volume of distribution at steady state is 114L.Label

Protein binding

Alpelisib is 89% protein bound.Label

Metabolism

Alpelisib is metabolized by hydrolysis reactions to form the primary metabolite.Label It is also metabolized by CYP3A4.Label The full metabolism of Alpelisib has yet to be determined but a series of reactions have been proposed.4,5 The main metabolic reaction is the substitution of an amine group on alpelisib for a hydroxyl group to form a metabolite known as M44,5 or BZG791.Label Alpelisib can also be glucuronidated to form the M1 and M12 metabolites.4,5

Hover over products below to view reaction partners

Route of elimination

36% of an oral dose is eliminated as unchanged drug in the feces and 32% as the primary metabolite BZG791 in the feces.Label 2% of an oral dose is eliminated in the urine as unchanged drug and 7.1% as the primary metabolite BZG791.Label In total 81% of an oral dose is eliminated in the feces and 14% is eliminated in the urine.Label

Half-life

The mean half life of alprelisib is 8 to 9 hours.Label

Clearance

The mean apparent oral clearance was 39.0L/h.4 The predicted clearance is 9.2L/hr under fed conditions.Label

Adverse Effects

Learn about our commercial Adverse Effects data.

LEARN MORE

 

Toxicity

LD50 and Overdose

Patients experiencing an overdose may present with hyperglycemia, nausea, asthenia, and rash.Label There is no antidote for an overdose of alpelisib so patients should be treated symptomatically.Label Data regarding an LD50 is not readily available.MSDS In clinical trials, patients were given doses of up to 450mg once daily.Label

Pregnancy, Lactation, and Fertility

Following administration in rats and rabbits during organogenesis, adverse effects on the reproductive system, such as embryo-fetal mortality, reduced fetal weights, and increased incidences of fetal malformations, were observed.Label Based on these findings of animals studies and its mechanism of action, it is proposed that alpelisib may cause embryo-fetal toxicity when administered to pregnant patients.Label There is no data available regarding the presence of alpelisib in breast milk so breast feeding mothers are advised not to breastfeed while taking this medication and for 1 week after their last dose.Label Based on animal studies, alpelisib may impair fertility of humans.Label

Carcinogenicity and Mutagenicity

Studies of carcinogenicity have yet to be performed.Label Alpelisib has not been found to be mutagenic in the Ames test.Label It is not aneugenic, clastogenic, or genotoxic in further assays.Label

Affected organisms

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs 

 

Not Available

 

Source: https://www.drugbank.ca/drugs/DB12015

References

  1. Yuan TL, Cantley LC: PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008, 27(41):5497-5510.
  2. Toker A: Double trouble for cancer gene. Science 2019, 366(6466):685-686.
  3. Vasan N, Razavi P, Johnson JL, Shao H, Shah H, Antoine A, Ladewig E, Gorelick A, Lin TY, Toska E et al: Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kalpha inhibitors. Science 2019, 366(6466):714-723.

 

 

Read Full Post »


Live Conference Coverage of AACR 2020 Annual Virtual Meeting; April 27-28, 2020

Reporter: Stephen J. Williams, Ph.D.

The American Association for Cancer Research (AACR) will hold its Annual Meeting as a Virtual Online Format.  Registration is free and open to all, including non members.  Please go to

https://www.aacr.org/meeting/aacr-annual-meeting-2020/aacr-virtual-annual-meeting-i/?utm_source=Salesforce%20Marketing%20Cloud&utm_medium=Email&utm_campaign=&sfmc_s=0031I00000WsBJxQAN

to register for this two day meeting.  Another two day session will be held in June 2020 and will focus more on basic cancer research.

Please follow @pharma_BI who will be live Tweeting Real Time Notes from this meeting using the hashtag

#AACR20

And @StephenJWillia2

The following is a brief summary of the schedule.  Please register and go to AACR for detailed information on individual sessions.

 

AACR VIRTUAL ANNUAL MEETING I: SCHEDULE AT A GLANCE

AACR Virtual Annual Meeting I is available free Register Now

VIRTUAL MEETING I: BROWSER REQUIREMENTS AND ACCESSVIRTUAL MEETING I: FAQVIRTUAL MEETING I: MEETING PLANNER (ABSTRACT TITLES)

Presentation titles are available through the online meeting planner. The program also includes six virtual poster sessions consisting of brief slide videos. Poster sessions will not be presented live but will be available for viewing on demand. Poster session topics are as follows:

  • Phase I Clinical Trials
  • Phase II Clinical Trials
  • Phase III Clinical Trials
  • Phase I Trials in Progress
  • Phase II Trials in Progress
  • Phase III Trials in Progress

Schedule updated April 24, 2020

MONDAY, APRIL 27

Channel 1 Channel 2 Channel 3
9:00 a.m.-9:30 a.m.
Opening Session
_______________________
9:30 a.m.-11:40 a.m.
Opening Clinical Plenary
_______________________
11:40 a.m.-2:00 p.m.
Clinical Plenary: Immunotherapy Clinical Trials 1
_______________________
___ 11:45 a.m.-1:30 p.m.
Minisymposium: Emerging Signaling Vulnerabilities in Cancer
_______________________
___ 11:45 a.m.-1:15 p.m.
Minisymposium: Advances in Cancer Drug Design and Discovery
__________________________
2:00 p.m.-4:50 p.m.
Clinical Plenary: Lung Cancer Targeted Therapy
_______________________
___ 1:55 p.m.-4:15 p.m.
Clinical Plenary: Breast Cancer Therapy
_______________________
___ 1:30 p.m.-3:30 p.m.
Minisymposium: Drugging Undrugged Cancer Targets
__________________________
4:50 p.m.-6:05 p.m.
Symposium: New Drugs on the Horizon 1_______________________
___ 4:50 p.m.-5:50 p.m.
Minisymposium: Therapeutic Modification of the Tumor Microenvironment or Microbiome
_______________________
___ 4:00 p.m.-6:00 p.m.
Minisymposium: Advancing Cancer Research Through An International Cancer Registry: AACR Project GENIE Use Cases__________________________

All session times are EDT.

TUESDAY, APRIL 28

Channel 1 Channel 2 Channel 3
9:00 a.m.-101:00 a.m.
Clinical Plenary: COVID-19 and Cancer
__________________________
11:00 a.m.-1:35 p.m.
Clinical Plenary: Adoptive Cell Transfer Therapy__________________________
___ 10:45 a.m.-12:30 p.m.
Symposium: New Drugs on the Horizon 2_________________________
___ 10:45 a.m.-12:30 p.m.
Minisymposium: Translational Prevention Studies
______________________
___ 12:30 p.m.-1:25 p.m.
Symposium: New Drugs on the Horizon 3
_________________________
___ 12:30 p.m.-2:15 p.m.
Minisymposium: Non-coding RNAs in Cancer
______________________
1:35 p.m.-3:35 p.m.
Clinical Plenary: Early Detection and ctDNA__________________________
___ 1:30 p.m.-3:50 p.m.
Clinical Plenary: Immunotherapy Clinical
Trials 2
_________________________
___ 2:15 p.m.-3:45 p.m.
Minisymposium: Novel Targets and Therapies______________________
3:35 p.m.-5:50 p.m.
Minisymposium: Predictive Biomarkers for Immunotherapeutics__________________________
___ 3:50 p.m.-5:35 p.m.
Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease
_________________________
___ 4:00 p.m.-4:55 p.m.
Clinical Plenary: Targeted Therapy______________________
5:00 p.m.-5:45 p.m.
Symposium: NCI Activities– COVID-19 and Cancer Research
Dinah Singer, NCI
______________________
5:45 p.m.-6:00 p.m.
Closing Session
______________________

All session times are EDT.

 

 

 

Day

 

Session Type

Topic Tracks

For more on @pharma_BI and LPBI Group Conference Coverage in Real Time please go to

https://pharmaceuticalintelligence.com/press-coverage/

and

 

 

Read Full Post »


Diversity and Health Disparity Issues Need to be Addressed for GWAS and Precision Medicine Studies

Curator: Stephen J. Williams, PhD

 

 

From the POLICY FORUM ETHICS AND DIVERSITY Section of Science

Ethics of inclusion: Cultivate trust in precision medicine

 See all authors and affiliations

Science  07 Jun 2019:
Vol. 364, Issue 6444, pp. 941-942
DOI: 10.1126/science.aaw8299

Precision medicine is at a crossroads. Progress toward its central goal, to address persistent health inequities, will depend on enrolling populations in research that have been historically underrepresented, thus eliminating longstanding exclusions from such research (1). Yet the history of ethical violations related to protocols for inclusion in biomedical research, as well as the continued misuse of research results (such as white nationalists looking to genetic ancestry to support claims of racial superiority), continue to engender mistrust among these populations (2). For precision medicine research (PMR) to achieve its goal, all people must believe that there is value in providing information about themselves and their families, and that their participation will translate into equitable distribution of benefits. This requires an ethics of inclusion that considers what constitutes inclusive practices in PMR, what goals and values are being furthered through efforts to enhance diversity, and who participates in adjudicating these questions. The early stages of PMR offer a critical window in which to intervene before research practices and their consequences become locked in (3).

Initiatives such as the All of Us program have set out to collect and analyze health information and biological samples from millions of people (1). At the same time, questions of trust in biomedical research persist. For example, although the recent assertions of white nationalists were eventually denounced by the American Society of Human Genetics (4), the misuse of ancestry testing may have already undermined public trust in genetic research.

There are also infamous failures in research that included historically underrepresented groups, including practices of deceit, as in the Tuskegee Syphilis Study, or the misuse of samples, as with the Havasupai tribe (5). Many people who are being asked to give their data and samples for PMR must not only reconcile such past research abuses, but also weigh future risks of potential misuse of their data.

To help assuage these concerns, ongoing PMR studies should open themselves up to research, conducted by social scientists and ethicists, that examines how their approaches enhance diversity and inclusion. Empirical studies are needed to account for how diversity is conceptualized and how goals of inclusion are operationalized throughout the life course of PMR studies. This is not limited to selection and recruitment of populations but extends to efforts to engage participants and communities, through data collection and measurement, and interpretations and applications of study findings. A commitment to transparency is an important step toward cultivating public trust in PMR’s mission and practices.

From Inclusion to Inclusive

The lack of diverse representation in precision medicine and other biomedical research is a well-known problem. For example, rare genetic variants may be overlooked—or their association with common, complex diseases can be misinterpreted—as a result of sampling bias in genetics research (6). Concentrating research efforts on samples with largely European ancestry has limited the ability of scientists to make generalizable inferences about the relationships among genes, lifestyle, environmental exposures, and disease risks, and thereby threatens the equitable translation of PMR for broad public health benefit (7).

However, recruiting for diverse research participation alone is not enough. As with any push for “diversity,” related questions arise about how to describe, define, measure, compare, and explain inferred similarities and differences among individuals and groups (8). In the face of ambivalence about how to represent population variation, there is ample evidence that researchers resort to using definitions of diversity that are heterogeneous, inconsistent, and sometimes competing (9). Varying approaches are not inherently problematic; depending on the scientific question, some measures may be more theoretically justified than others and, in many cases, a combination of measures can be leveraged to offer greater insight (10). For example, studies have shown that American adults who do not self-identify as white report better mental and physical health if they think others perceive them as white (1112).

The benefit of using multiple measures of race and ancestry also extends to genetic studies. In a study of hypertension in Puerto Rico, not only did classifications based on skin color and socioeconomic status better predict blood pressure than genetic ancestry, the inclusion of these sociocultural measures also revealed an association between a genetic polymorphism and hypertension that was otherwise hidden (13). Thus, practices that allow for a diversity of measurement approaches, when accompanied by a commitment to transparency about the rationales for chosen approaches, are likely to benefit PMR research more than striving for a single gold standard that would apply across all studies. These definitional and measurement issues are not merely semantic. They also are socially consequential to broader perceptions of PMR research and the potential to achieve its goals of inclusion.

Study Practices, Improve Outcomes

Given the uncertainty and complexities of the current, early phase of PMR, the time is ripe for empirical studies that enable assessment and modulation of research practices and scientific priorities in light of their social and ethical implications. Studying ongoing scientific practices in real time can help to anticipate unintended consequences that would limit researchers’ ability to meet diversity recruitment goals, address both social and biological causes of health disparities, and distribute the benefits of PMR equitably. We suggest at least two areas for empirical attention and potential intervention.

First, we need to understand how “upstream” decisions about how to characterize study populations and exposures influence “downstream” research findings of what are deemed causal factors. For example, when precision medicine researchers rely on self-identification with U.S. Census categories to characterize race and ethnicity, this tends to circumscribe their investigation of potential gene-environment interactions that may affect health. The convenience and routine nature of Census categories seemed to lead scientists to infer that the reasons for differences among groups were self-evident and required no additional exploration (9). The ripple effects of initial study design decisions go beyond issues of recruitment to shape other facets of research across the life course of a project, from community engagement and the return of results to the interpretation of study findings for human health.

Second, PMR studies are situated within an ecosystem of funding agencies, regulatory bodies, disciplines, and other scholars. This partly explains the use of varied terminology, different conceptual understandings and interpretations of research questions, and heterogeneous goals for inclusion. It also makes it important to explore how expectations related to funding and regulation influence research definitions of diversity and benchmarks for inclusion.

For example, who defines a diverse study population, and how might those definitions vary across different institutional actors? Who determines the metrics that constitute successful inclusion, and why? Within a research consortium, how are expectations for data sharing and harmonization reconciled with individual studies’ goals for recruitment and analysis? In complex research fields that include multiple investigators, organizations, and agendas, how are heterogeneous, perhaps even competing, priorities negotiated? To date, no studies have addressed these questions or investigated how decisions facilitate, or compromise, goals of diversity and inclusion.

The life course of individual studies and the ecosystems in which they reside cannot be easily separated and therefore must be studied in parallel to understand how meanings of diversity are shaped and how goals of inclusion are pursued. Empirically “studying the studies” will also be instrumental in creating mechanisms for transparency about how PMR is conducted and how trade-offs among competing goals are resolved. Establishing open lines of inquiry that study upstream practices may allow researchers to anticipate and address downstream decisions about how results can be interpreted and should be communicated, with a particular eye toward the consequences for communities recruited to augment diversity. Understanding how scientists negotiate the challenges and barriers to achieving diversity that go beyond fulfilling recruitment numbers is a critical step toward promoting meaningful inclusion in PMR.

Transparent Reflection, Cultivation of Trust

Emerging research on public perceptions of PMR suggests that although there is general support, questions of trust loom large. What we learn from studies that examine on-the-ground approaches aimed at enhancing diversity and inclusion, and how the research community reflects and responds with improvements in practices as needed, will play a key role in building a culture of openness that is critical for cultivating public trust.

Cultivating long-term, trusting relationships with participants underrepresented in biomedical research has been linked to a broad range of research practices. Some of these include the willingness of researchers to (i) address the effect of history and experience on marginalized groups’ trust in researchers and clinicians; (ii) engage concerns about potential group harms and risks of stigmatization and discrimination; (iii) develop relationships with participants and communities that are characterized by transparency, clear communication, and mutual commitment; and (iv) integrate participants’ values and expectations of responsible oversight beyond initial informed consent (14). These findings underscore the importance of multidisciplinary teams that include social scientists, ethicists, and policy-makers, who can identify and help to implement practices that respect the histories and concerns of diverse publics.

A commitment to an ethics of inclusion begins with a recognition that risks from the misuse of genetic and biomedical research are unevenly distributed. History makes plain that a multitude of research practices ranging from unnecessarily limited study populations and taken-for-granted data collection procedures to analytic and interpretive missteps can unintentionally bolster claims of racial superiority or inferiority and provoke group harm (15). Sustained commitment to transparency about the goals, limits, and potential uses of research is key to further cultivating trust and building long-term research relationships with populations underrepresented in biomedical studies.

As calls for increasing diversity and inclusion in PMR grow, funding and organizational pathways must be developed that integrate empirical studies of scientific practices and their rationales to determine how goals of inclusion and equity are being addressed and to identify where reform is required. In-depth, multidisciplinary empirical investigations of how diversity is defined, operationalized, and implemented can provide important insights and lessons learned for guiding emerging science, and in so doing, meet our ethical obligations to ensure transparency and meaningful inclusion.

References and Notes

  1. C. P. Jones et al Ethn. Dis. 18496 (2008).
  2. C. C. GravleeA. L. NonC. J. Mulligan
  3. S. A. Kraft et al Am. J. Bioeth. 183 (2018).
  4. A. E. Shields et al Am. Psychol. 6077 (2005).

Read Full Post »


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. These enzymes are crucial for a number of cellular activities, including cell survival, proliferation and migration — functions that must be carefully controlled if cells get out of control and form a tumor. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Researchers at University of California San Diego School of Medicine found that another enzyme, called PHLPP1, acts as a “proofreader” to keep careful tabs on PKC.

 

The researchers discovered that in pancreatic cancer high PHLPP1 levels lead to low PKC levels, which is associated with poor patient survival. They reported that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. They discovered that any time an over-active PKC is inadvertently produced, the PHLPP1 “proofreader” tags it for destruction. That means the amount of PHLPP1 in patient’s cells determines his amount of PKC and it turns out those enzyme levels are especially important in pancreatic cancer.

 

This team of researchers reversed a 30-year paradigm when they reported evidence that PKC actually suppresses, rather than promotes, tumors. For decades before this revelation, many researchers had attempted to develop drugs that inhibit PKC as a means to treat cancer. Their study implied that anti-cancer drugs would actually need to do the opposite — boost PKC activity. This study sets the stage for clinicians to one day use a pancreatic cancer patient’s PHLPP1/PKC levels as a predictor for prognosis, and for researchers to develop new therapeutic drugs that inhibit PHLPP1 and boost PKC as a means to treat the disease.

 

The ratio — high PHLPP1/low PKC — correlated with poor prognoses: no pancreatic patient with low PKC in the database survived longer than five-and-a-half years. On the flip side, 50 percent of the patients with low PHLPP1/high PKC survived longer than that. While still in the earliest stages, the researchers hope that this information might one day aid pancreatic diagnostics and treatment. The researchers are next planning to screen chemical compounds to find those that inhibit PHLPP1 and restore PKC levels in low-PKC-pancreatic cancer cells in the lab. These might form the basis of a new therapeutic drug for pancreatic cancer.

 

References:

 

https://health.ucsd.edu/news/releases/Pages/2019-03-20-two-enzymes-linked-to-pancreatic-cancer-survival.aspx?elqTrackId=b6864b278958402787f61dd7b7624666

 

https://www.ncbi.nlm.nih.gov/pubmed/30904392

 

https://www.ncbi.nlm.nih.gov/pubmed/29513138

 

https://www.ncbi.nlm.nih.gov/pubmed/18511290

 

https://www.ncbi.nlm.nih.gov/pubmed/28476658

 

https://www.ncbi.nlm.nih.gov/pubmed/28283201

 

https://www.ncbi.nlm.nih.gov/pubmed/24231509

 

https://www.ncbi.nlm.nih.gov/pubmed/28112438

 

Read Full Post »

Immunoediting can be a constant defense in the cancer landscape


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

Read Full Post »

Immunotherapy may help in glioblastoma survival


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. But, in a glimmer of hope, a recent study found that a drug designed to unleash the immune system helped some patients live longer. Glioblastoma powerfully suppresses the immune system, both at the site of the cancer and throughout the body, which has made it difficult to find effective treatments. Such tumors are complex and differ widely in their behavior and characteristics.

 

A small randomized, multi-institution clinical trial was conducted and led by researchers at the University of California at Los Angeles involved patients who had a recurrence of glioblastoma, the most common central nervous system cancer. The aim was to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab (checkpoint inhibitor) in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone.

 

Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhanced both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

 

Immunotherapy has not proved to be effective against glioblastoma. This small clinical trial explored the effect of PD-1 blockade on recurrent glioblastoma in relation to the timing of administration. A total of 35 patients undergoing resection of recurrent disease were randomized to either neoadjuvant or adjuvant pembrolizumab, and surgical specimens were compared between the two groups. Interestingly, the tumoral gene expression signature varied between the two groups, such that those who received neoadjuvant pembrolizumab displayed an INF-γ gene signature suggestive of T-cell activation as well as suppression of cell-cycle signaling, possibly consistent with growth arrest. Although the study was not powered for efficacy, the group found an increase in overall survival in patients receiving neoadjuvant pembrolizumab compared with adjuvant pembrolizumab of 13.7 months versus 7.5 months, respectively.

 

In this small pilot study, neoadjuvant PD-1 blockade followed by surgical resection was associated with intratumoral T-cell activation and inhibition of tumor growth as well as longer survival. How the drug works in glioblastoma has not been totally established. The researchers speculated that giving the drug before surgery prompted T-cells within the tumor, which had been impaired, to attack the cancer and extend lives. The drug didn’t spur such anti-cancer activity after the surgery because those T-cells were removed along with the tumor. The results are very important and very promising but would need to be validated in much larger trials.

 

References:

 

https://www.washingtonpost.com/health/2019/02/11/immunotherapy-may-help-patients-with-kind-cancer-that-killed-john-mccain/?noredirect=on&utm_term=.e1b2e6fffccc

 

https://www.ncbi.nlm.nih.gov/pubmed/30742122

 

https://www.practiceupdate.com/content/neoadjuvant-anti-pd-1-immunotherapy-promotes-immune-responses-in-recurrent-gbm/79742/37/12/1

 

https://www.esmo.org/Oncology-News/Neoadjuvant-PD-1-Blockade-in-Glioblastoma

 

https://neurosciencenews.com/immunotherapy-glioblastoma-cancer-10722/

 

Read Full Post »


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Over the past 20 years, studies have shown that girls and possibly boys have been experiencing puberty at progressively younger ages. This is troubling news, as earlier age at puberty has been linked with increased risk of mental illness, breast and ovarian cancer in girls and testicular cancer in boys. Researchers found that daughters of mothers who had higher levels of diethyl phthalate and triclosan in their bodies during pregnancy experienced puberty at younger ages. The same trend was not observed in boys. So, researchers suspected that girls exposed to chemicals commonly found in toothpaste, makeup, soap and other personal care products before birth may hit puberty earlier.

 

Diethyl phthalate is often used as a stabilizer in fragrances and cosmetics. The antimicrobial agent triclosan — which the FDA banned from use in hand soap in 2017 because it was shown to be ineffective — is still used in some toothpastes. Researchers suspected that many chemicals in personal care products can interfere with natural hormones in human bodies, and studies have shown that exposure to these chemicals can alter reproductive development in rats. Chemicals that have been implicated include phthalates, which are often found in scented products like perfumes, soaps and shampoos; parabens, which are used as preservatives in cosmetics; and phenols, which include triclosan.

 

However, few studies have looked at how these chemicals might affect the growth of human children. This present study at UC Berkeley, USA recruited pregnant women living in the farm-working, primarily Latino communities of Central California’s Salinas Valley between 1999 and 2000. While the primary aim of the study was to examine the impact of pesticide exposure on childhood development, the researchers used the opportunity to examine the effects of other chemicals as well. The scientists measured concentrations of phthalates, parabens and phenols in urine samples taken from mothers twice during pregnancy, and from children at the age of 9. They then followed the growth of the children — 159 boys and 179 girls — between the ages of 9 and 13 to track the timing of developmental milestones marking different stages of puberty.

 

The vast majority — more than 90 percent — of urine samples of both mothers and children showed detectable concentrations of all three classes of chemicals, with the exception of triclosan which was present in approximately 70 percent of samples. The researchers found that every time the concentrations of diethyl phthalate and triclosan in the mother’s urine doubled, the timing of developmental milestones in girls shifted approximately one month earlier. Girls who had higher concentrations of parabens in their urine at age 9 also experienced puberty at younger ages. However, it is unclear if the chemicals were causing the shift, or if girls who reached puberty earlier were more likely to start using personal care products at younger ages.

 

The limitations are that these chemicals are quickly metabolized and one to two urinary measurements per developmental point may not accurately reflect usual exposure. The study population was limited to Latino children of low socioeconomic status living in a farmworker community and may not be widely generalizable. But, this study contributes to a growing literature that suggests that exposure to certain endocrine disrupting chemicals may impact timing of puberty in children.

 

References:

 

https://www.universityofcalifornia.edu/news/prenatal-exposure-chemicals-personal-care-products-may-speed-puberty-girls?utm_source=fiat-lux

 

https://www.ncbi.nlm.nih.gov/pubmed/30517665

 

https://www.ncbi.nlm.nih.gov/pubmed/24781428

 

https://www.ncbi.nlm.nih.gov/pubmed/30203993

 

https://www.ncbi.nlm.nih.gov/pubmed/25173057

 

Read Full Post »


Stem Cells Used as Delivery Truck for Brain Cancer Drugs

Reporter: Irina Robu, PhD

Medulloblastoma, common brain cancer in children has been very difficult to treat therapeutically with traditional interventions which relies on surgical techniques to remove the bulk of the cancerous tissue. The researchers seen the need for novel treatments of medulloblastomas that have recurred, as well as for treatments that are less toxic overall. For this reason, data from University of North Carolina (UNC) Lineberger Comprehensive Cancer Center and  Eshelman School of Pharmacy published a study in PLOS named “Intra-cavity stem cell therapy inhibits tumor progression in a novel murine model of medulloblastoma surgical resection”, validates how cancer-hunting stem cells can track down and deliver a drug to terminate medulloblastoma cells hiding after surgery.

The technology in the research is an extension of a discovery that won researchers a Nobel Prize in 2012 and showed they could transform skin cells into stem cells. The research team started by reprogramming skin cells into stem cells and genetically engineered them to manufacture a substance that becomes toxic to other cells when exposed to another drug. Inserting the drug carries the stem cells into the brain of laboratory models after surgery decreased the size of tumors by 15 times and extended median survival in mice by 133%.

In this study, the scientists indicated they could shrink tumors in murine models of medulloblastoma, hence extending the rodents life. The approach holds promise for reducing side effects and helping more children with medulloblastoma. Amazingly the researchers also developed a laboratory model of medulloblastoma that allowed them to simulate the way standard care is currently delivered—surgery followed by drug therapy. Using this model, they discovered that after surgically removing a tumor, the cancer cells that remained grew faster.

According to the study investigator, Shawn Hingtgen, PhD, the cells are like a FedEx truck that will deliver cytotoxic agents directly into the tumor to a particular location. In earlier studies, Dr. Hingtgen and his colleagues showed that they could flip skin cells into stem cells that hunt and transport cancer-killing drugs to glioblastoma, the deadliest malignant brain tumor in adults.

Medulloblastoma is cancer that happens mostly in kids between ages of three and eight, and while current therapy has changed survival pretty dramatically, it can still be pretty toxic. The ability to use a patient’s own cells to target the tumor directly would be “the holy grail” of therapy, the investigators trust it could hold capacity for other rare, and sometimes fatal, brain cancer types that occur in children as well.

Source

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198596

Read Full Post »


Knowing the genetic vulnerability of bladder cancer for therapeutic intervention

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

 

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

 

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

 

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

 

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

 

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

 

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

 

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

 

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

 

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

 

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29117162

 

https://www.ncbi.nlm.nih.gov/pubmed/27321955

 

https://www.ncbi.nlm.nih.gov/pubmed/28583312

 

https://www.ncbi.nlm.nih.gov/pubmed/24476821

 

https://www.ncbi.nlm.nih.gov/pubmed/28988769

 

https://www.ncbi.nlm.nih.gov/pubmed/28753430

 

Read Full Post »


University Children’s Hospital Zurich (Universitäts-Kinderspital Zürich), Switzerland – A Prominent Center of Pediatric Research and Medicine

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

 

University Children’s Hospital Zurich (Universitäts-Kinderspital Zürich —  http://www.kispi.uzh.ch), in Switzerland, is the largest specialized, child and adolescent hospital in the country and one of the leading research centers for pediatric and youth medicine in Europe. The hospital, which has about 220 beds, numerous outpatient clinics, a day clinic, an interdisciplinary emergency room, and a specialized rehabilitation center, is a non-profit private institution that offers a comprehensive range of more than 40 medical sub-specializations, including heart conditions, bone marrow transplantation and burns. There are approximately 2,200 physicians, nurses, and other allied health care and administrative personnel employed at the hospital.

Just as important, the hospital houses the Children’s Research Center (CRC), the first research center in Switzerland that is solely dedicated to pediatric research, and is on par with the largest children’s clinics in the world. The research center provides a strong link between research and clinical experience to ensure that the latest scientific findings are made available to patients and implemented in life-saving therapies. By developing highly precise early diagnoses, innovative therapeutic approaches and effective new drugs, the researchers aim to provide a breakthrough in prevention, treatment and cure of common and, especially, rare diseases in children.

Several significant milestones have been reached over the past year. One important project under way is approval by the hospital management board and Zurich city council to construct a new building, projected to be completed in 2021. The new Children’s Hospital will constitute two main buildings; one building will house the hospital with around 200 beds, and the other building will house university research and teaching facilities.

In the ongoing quest for growing demands for quality, safety and efficiency that better serve patients and their families, the hospital management established a new role of Chief Operating Officer. This new position is responsible for the daily operation of the hospital, focusing on safety and clinical results, building a service culture and producing strong financial results. Greater emphasis on clinical outcomes, patient satisfaction and partnering with physicians, nurses, and other medical and administrative staff is all part of developing a thriving and lasting hospital culture.

Recently, the hospital’s Neurodermatitis Unit in cooperation with Christine Kuehne – Center for Allergy Research and Education (CK-Care), one of Europe’s largest private initiatives in the field of allergology, has won the “Interprofessionality Award” from the Swiss Academy of Medical Sciences.  This award highlights best practices among doctors, nurses and medical staff in organizations who work together to diagnose and treat the health and well-being of patients, especially children with atopic dermatitis and their families.

At the northern end of Lake Zurich and between the mountain summit of the Uetliberg and Zurichberg, Children’s Hospital is located in the center of the residential district of Hottingen.

 

childrens-hospital4childrens-hospital3childrens-hospital2childrens-hospital1

Image SOURCE: Photograph courtesy of Children’s Hospital Zurich (Universitäts-Kinderspital Zürich), Switzerland. Interior and exterior photographs of the hospital.

 

Below is my interview with Hospital Director and Chief Executive Officer Markus Malagoli, Ph.D., which occurred in December, 2016.

How do you keep the spirit of innovation alive? 

Dr. Malagoli: Innovation in an organization, such as the University Children’s Hospital, correlates to a large extent on the power to attract the best and most innovative medical team and administrative people. It is our hope that by providing our employees with the time and financial resources to undertake needed research projects, they will be opened to further academic perspectives. At first sight, this may seem to be an expensive opportunity. However, in the long run, we have significant research under way in key areas which benefits children ultimately. It also gives our hospital the competitive edge in providing quality care and helps us recruit the best physicians, nurses, therapists, social workers and administrative staff.

The Children’s Hospital Zurich is nationally and internationally positioned as highly specialized in the following areas:

  • Cardiology and cardiac surgery: pediatric cardiac center,
  • Neonatal and malformation surgery as well as fetal surgery,
  • Neurology and neurosurgery as well as neurorehabilitation,
  • Oncology, hematology and immunology as well as oncology and stem cell transplants,
  • Metabolic disorders and endocrinology as well as newborn screening, and
  • Combustion surgery and plastic reconstructive surgery.

We provide patients with our special medical expertise, as well as an expanded  knowledge and new insights into the causes, diagnosis, treatment and prophylaxis of diseases, accidents or deformities. We have more than 40 medical disciplines that cover the entire spectrum of pediatrics as well as child and youth surgery.

As an example, for many years, we have treated all congenital and acquired heart disease in children. Since 2004, specialized heart surgery and post-operative care in our cardiac intensive care unit have been carried out exclusively in our child-friendly hospital. A separate heart operation area was set up for this purpose. The children’s heart center also has a modern cardiac catheter laboratory for children and adolescents with all diagnostic and catheter-interventional therapeutic options. Heart-specific non-invasive diagnostic possibilities using MRI are available as well as a large cardiology clinic with approximately 4,500 outpatient consultations per year. In April 2013, a special ward only for cardiac patients was opened and our nursing staff is highly specialized in the care of children with heart problems.

In addition to the advanced medical diagnostics and treatment of children, we also believe in the importance of caring and supporting families of sick children with a focus on their psychosocial well-being. For this purpose, a team of specialized nurses, psychiatrists, psychologists, and social workers are available. Occasionally, the children and their families need rehabilitation and we work with a team of specialists to plan and organize the best in-house or out-patient rehabilitation for the children and their families.

We also provide therapeutic, rehabilitation and social services that encompass nutritional advice, art and expression therapy, speech therapy, physical therapy, psychomotor therapy, a helpline for rare diseases, pastoral care, social counseling, and even hospital clowns. Our hospital teams work together to provide our patients with the best care so they are on the road to recovery in the fastest possible way.

What draws patients to Children’s Hospital?

Dr. Malagoli: Our hospital depends heavily on complex, interdisciplinary cases. For many diagnosis and treatments, our hospital is the last resort for children and adolescents in Switzerland and even across other countries. Our team is fully committed to the welfare of the patients they treat in order to deal with complex medical cases, such as diseases and disorders of the musculo-skeletal system and connective tissue, nervous system, respiratory system, digestive system, and ear, nose and throat, for example.

Most of our patients come from Switzerland and other cantons within the country, yet other patients come from as far away as Russia and the Middle East. Our hospital sees about 80,000 patients each year in the outpatient clinic for conditions, such as allergic pulmonary diseases, endocrinology and diabetology, hepatology, and gastroenterology; about 7,000 patients a year are seen for surgery; and about 37,000 patients a year are treated in the emergency ward.

We believe that parents are not visitors; they belong to the sick child’s healing, growth, and development. This guiding principle is a challenge for us, because we care not only for sick children, but also for their families, who may need personal or financial resources. Many of our services for parents, for example, are not paid by the Swiss health insurance and we depend strongly on funds from private institutions. We want to convey the feeling of security to children and adolescents of all ages and we involve the family in the recovery process.

What are the hospital’s strengths?

Dr. Malagoli: A special strength of our hospital is the interdisciplinary thinking of our teams. In addition to the interdisciplinary emergency and intensive care units, there are several internal institutionalized meetings, such as the uro-nephro-radiological conference on Mondays, the oncological conference and the gastroenterological meeting on Tuesdays,  and the pneumological case discussion on Wednesdays, where complex cases are discussed among our doctors. Foreign doctors are welcome to these meetings, and cases are also discussed at the appropriate external medical conferences.

Can you discuss some of the research projects under way at the Children’s Research Center (CRC)?

Dr. Malagoli: Our Children’s Research Center, the first research center in Switzerland focused on pediatric research, works closely with our hospital team. From basic research to clinical application, the hospital’s tasks in research and teaching is at the core of the Children’s Research Center for many young and established researchers and, ultimately, also for patients.

Our research projects focus on:

  • Behavior of the nervous, metabolic, cardiovascular and immune system in all stages of growth and development of the child’s condition,
  • Etiology (causes of disease) and treatment of genetic diseases,
  • Tissue engineering of the skin and skin care research: from a few cells of a child,  complex two-layered skin is produced in the laboratory for life-saving measures after severe burns and treatment of congenital anomalies of the skin,
  • Potential treatment approaches of the most severe infectious diseases, and
  • Cancer diseases of children and adolescents.

You are making great strides in diagnostic work in the areas of Hematology, Immumology, Infectiology and Oncology. Would you elaborate on this particular work that is taking place at the hospital?

Dr. Malagoli: The Department of Image Diagnostics handles radiological and ultrasonographic examinations, and the numerous specialist labs offer a complete  range of laboratory diagnostics.

The laboratory center makes an important contribution to the clarification and treatment of disorders of immune defense, blood and cancer, as well as infections of all kinds and severity. Our highly specialized laboratories offer a large number of analyzes which are necessary in the assessment of normal and pathological cell functions and take into account the specifics and requirements of growth and development in children and infants.

The lab center also participates in various clinical trials and research projects. This allows on-going validation and finally introducing the latest test methods.

The laboratory has been certified as ISO 9001 by the Swiss Government since 2002 and has met the quality management system requirements on meeting patient expectations and delivering customer satisfaction. The interdisciplinary cooperation and careful communication of the laboratory results are at the center of our activities. Within the scope of our quality assurance measures, we conduct internal quality controls on a regular basis and participate in external tests. Among other things, the work of the laboratory center is supervised by the cantonal medicine committee and Swissmedic organization.

Additionally, the Metabolism Laboratory  offers a wide variety of biochemical and molecular diagnostic analysis, including those for the following areas:

  • Disorders in glycogen and fructose metabolism,
  • Lysosomal disorders,
  • Disorders of biotin and vitamin B12 metabolism,
  • Urea cycle disorders and Maple Syrup Urine Disease (MSUD),
  • Congenital disorders of protein glycosylation, and
  • Hereditary disorders of connective tissue, such as Ehlers-Danlos Syndrome and Marfan Syndrome.

Screening for newborn conditions is equally important. The Newborn Screening Laboratory examines all newborn children in Switzerland for congenital metabolic and hormonal diseases. Untreated, the diseases detected in the screening lead in most cases to serious damage to different organs, but especially to the development of the brain. Thanks to the newborn screening, the metabolic and hormonal diseases that are being sought can be investigated by means of modern methods shortly after birth. For this, only a few drops of blood are necessary, which are taken from the heel on the third or fourth day after birth. On a filter paper strip, these blood drops are sent to the laboratory of the Children’s Hospital Zurich, where they are examined for the following diseases:

  • Phenylketonuria (PKU),
  • Hypothyroidism,
  • MCAD deficiency,
  • Adrenogenital Syndrome (AGS),
  • Galactosemia,
  • Biotinide deficiency,
  • Cystic Fibrosis (CF),
  • Glutaraziduria Type 1 (GA-1), and
  • Maple Syrup Urine Disease (MSUD).

Ongoing physician medical education and executive training is important for the overall well-being of the hospital. Would you describe the program and the courses?

Dr. Malagoli:  We place a high priority on medical education and training with a focus on children, youth, and their families. The various departments of the hospital offer regular specialist training courses for interested physicians at regular intervals. Training is available in the following areas:

  • Anesthesiology,
  • Surgery,
  • Developmental Pediatrics,
  • Cardiology,
  • Clinical Chemistry and Biochemistry,
  • Neuropediatrics,
  • Oncology,
  • Pediatrics, and
  • Rehabilitation.

As a training hospital, we have built an extensive network or relationships with physicians in Switzerland as well as other parts of the world, who take part in our ongoing medical education opportunities that focus on specialized pediatrics and  pediatric surgery. Also, newly trained, young physicians who are in private practice or affiliated with other children’s hospitals often take part in our courses.

We also offer our hospital management and leaders from other organizations professional development in the areas of leadership or specialized competence training. We believe that all executives in leadership or management roles contribute significantly to our success and to a positive working climate. That is why we have developed crucial training in specific, work-related courses, including planning and communications skills, professional competence, and entrepreneurial development.

How is Children’s Hospital transforming health care? 

Dr. Malagoli: The close cooperation between doctors, nurses, therapists and social workers is a key success factor in transforming health care. We strive for comprehensive child care that does not only focus on somatic issues but also on psychological support for patients and their families and social re-integration. However, it becomes more and more difficult to finance all the necessary support services.

Many supportive services, for example, for parents and families of sick children are not paid by health insurance in Switzerland and we do not receive financial support from the Swiss Government. Since 2012, we have the Swiss Diagnosis Related Groups (DRG) guidelines, a new tariff system for inpatient hospital services, that regulates costs for treatment in hospitals all over the country and those costs do not consider the amount of extra services we provide for parents and families as a children’s hospital. Those DRG principles mostly are for hospitals who treat adult patients.

Since you stepped into your role as CEO, how have you changed the way that you deliver health care?

Dr. Malagoli: I have definitely not reinvented health care! Giving my staff the space for individual development and the chance to realize their ideas is probably my main contribution to our success. Working with children is for many people motivating and enriching. We benefit from that, too. Moreover, we have managed to build up a culture of confidence and mutual respect – we call it the “Kispi-spirit”. “Kispi” as abbreviation of “Kinderspital.” Please visit our special recruiting site, which is www.kispi-spirit.ch.

I can think of a few examples where our doctors and medical teams have made a difference in the lives of our patients. Two of our physicians – PD (Privatdozent, a private university teacher) Dr. med. Alexander Moller and Dr. med. Florian Singer, Ph.D. – are involved in the development of new pulmonary functions tests which allow us to diagnose chronic lung diseases at an early stage in young children.

  • Often times, newly born babies have a lung disease but do not show any specific symptoms, such as coughing. One of these new tests measures lung function based on inhaling and exhaling pure oxygen, rather than using the standard spirometry test used in children and adults to assess how well an infant’s lungs work by measuring how much air they inhale, how much they exhale and how quickly they exhale. The new test is currently part of a clinical routine in children with cystic fibrosis as well as in clinical trials in Europe. The test is so successful that the European Respiratory Society presented Dr. med. Singer, Ph.D., with the ‘Pediatric Research Award’ in 2015.
  • Another significant research question among the pediatric pulmonary disease community is how asthma can be diagnosed reliably and at an earlier stage. PD Dr. med. Moller, chief physician of Pneumology at the hospital, has high hopes in a new way to measure exhaled air via mass spectrometry. If it succeeds, it will be able to evaluate changes in the lungs of asthmatics or help with more specific diagnoses of pneumonia.

In what ways have you built greater transparency, accountability and quality improvement for the benefit of patients?

Dr. Malagoli: Apart from the quality measures which are prescribed by Swiss law, we have decided not to strive for quality certifications and accreditations. We focus on outcome quality, record our results in quality registers and compare our outcome internationally with the best in class.

Our team of approximately 2,200 specialized physicians largely comes from Switzerland, although we have attracted a number of doctors from countries such as Germany, Portugal, Italy, Austria, and even Serbia, Turkey, Macedonia, Slovakia, and Croatia.

We recently conducted an employee satisfaction survey, which showed about 88 percent of employees were very satisfied or satisfied with their working conditions at the hospital and the job we are doing with patients and their families. This ranking is particularly gratifying for us as a service provider for the children and families we serve.

How does your volunteer program help families better deal with hospitalized children?

Dr. Malagoli: We have an enormous commitment from volunteers to care for hospitalized children and we are grateful to them. We offer our patients and their families child care, dog therapy, and even parenting by the Aladdin Foundation, a volunteer visiting service for hospitalized children to relieve parents and relatives and help young patients stay in hospital to recover quickly. The volunteers visit the child in the absence of the parents and are fully briefed on the child’s condition and care plan. The handling of care request usually takes no more than 24 hours and is free of charge. The assignments range from one-off visits to daily care for several weeks.

malagoli_m_905

Image SOURCE: Photograph of Hospital Director and Chief Executive Officer Markus Malagoli, Ph.D., courtesy of Children’s Hospital Zurich (Universitäts-Kinderspital Zürich), Switzerland.  

Markus Malagoli, Ph.D.
Director and Chief Executive Officer

Markus Malagoli, Ph.D., has been Hospital Director and Chief Executive Officer of the University Children’s Hospital Zurich (Universitäts-Kinderspital Zürich), since 2007.

Prior to his current role, Dr. Malagoli served as Chairman of Hospital Management and Head of Geriatrics of the Schaffhausen-Akutspital, the only public hospital in the Canton of Schaffhausen, from 2003 through 2007, where he was responsible for 10 departments, including surgery, internal medicine, obstetrics/gynecology, rheumatology/rehabilitation, throat and nose, eyes, radiology, anesthesia, hospital pharmacy and administration. The hospital employs approximately 1,000 physicians, nursing staff, other medical personal, as well as administration and operational services employees. On average, around 9,000 individuals are treated in the hospital yearly. Previously, he was Administrative Director at the Hospital from 1996 through 2003.

Dr. Malagoli began his career at Ciba-Geigy in 1985, spending 11 years in the company. He worked in Business Accounting in Basel, and a few years later, became Head of the Production Information System department in Basel. He then was transferred to Ciba-Geigy in South Africa as Controller/Treasurer and returned to Basel as Project Manager for the SAP Migration Project in Accounting.

Dr. Malagoli received his B.A. degree in Finance and Accounting and a Ph.D. in Business Administration at the University of St. Gallen.

He is a member of the Supervisory Board of Schaffhausen-Akutspital and President of the Ungarbühl in Schaffhausen, a dormitory for individuals with developmental impairments.

Editor’s note:

We would like to thank Manuela Frey, communications manager, University Children’s Hospital Zurich, for the help and support she provided during this interview.

 

REFERENCE/SOURCE

University Children’s Hospital Zurich (Universitäts-Kinderspital Zürich —  http://www.kispi.uzh.ch)

Other related articles

Retrieved from http://www.swisshealth.ch/en/patienten/spitaeler/Kispi.php

Retrieved from http://hospitals.webometrics.info/en/europe/switzerland%20

Retrieved from http://www.gruner.ch/en/projects/university-childrens-hospital-zurich

Retrieved from http://www.ebmt-swiss-ng.org/university-childrens-hospital-zurich.html

Other related articles were published in this Open Access Online Scientific Journal include the following: 

2016

Healthcare conglomeration to access Big Data and lower costs

https://pharmaceuticalintelligence.com/2016/01/13/healthcare-conglomeration-to-access-big-data-and-lower-costs/

A New Standard in Health Care – Farrer Park Hospital, Singapore’s First Fully Integrated Healthcare/Hospitality Complex

https://pharmaceuticalintelligence.com/2016/06/22/a-new-standard-in-health-care-farrer-park-hospital-singapores-first-fully-integrated-healthcarehospitality-complex/

A Rich Tradition of Patient-Focused Care — Richmond University Medical Center, New York’s Leader in Health Care and Medical Education

https://pharmaceuticalintelligence.com/2016/10/17/a-rich-tradition-of-patient-focused-care-richmond-university-medical-center-new-yorks-leader-in-health-care-and-medical-education/

2013

Risk Factor for Health Systems: High Turnover of Hospital CEOs and Visionary’s Role of Hospitals In 10 Years

https://pharmaceuticalintelligence.com/2013/08/08/risk-factor-for-health-systems-high-turnover-of-hospital-ceos-and-visionarys-role-of-hospitals-in-10-years/

Nation’s Biobanks: Academic institutions, Research institutes and Hospitals – vary by Collections Size, Types of Specimens and Applications: Regulations are Needed

https://pharmaceuticalintelligence.com/2013/01/26/nations-biobanks-academic-institutions-research-institutes-and-hospitals-vary-by-collections-size-types-of-specimens-and-applications-regulations-are-needed/

 

 

 

 

Read Full Post »

Older Posts »