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Reporter: Gail S. Thornton, M.A.

By USHA LEE MCFARLING

JULY 21, 2020

When dermatologist Jenna Lester learned that rashes on skin and toes were a symptom of Covid-19, she started searching the medical literature for images of what the rashes looked like on Black skin so she’d recognize it in her Black patients. She couldn’t find a single picture.

“I was frustrated because we know Covid-19 is disproportionately impacting communities of color,” said Lester, an assistant professor of dermatology at the University of California, San Francisco who recently published her analysis. “I felt like I was seeing a disparity being built right before my eyes.”

The dearth of images in the Covid-19 literature is just the newest example of the glaring lack of representation of Black and brown skin that has persisted in dermatology research journals and textbooks for decades. The issue is coming under closer scrutiny now as dermatologists, like many physicians, grapple more openly with systemic racism and the health disparities it is causing in their field.

 

“Black Lives Matter is forcing a lot of people to look inward and say, ‘Where are our shortcomings?’” said Nada Elbuluk, an associate professor of clinical dermatology at the University of Southern California and the founder of a diversity and inclusion program in her department. “Dermatology is no different.”

 

 

The discrimination in her specialty extends beyond images and gaps in training, to restrictive insurance coverage for skin conditions that affect people with heavily pigmented skin, and to the many dermatologists who don’t accept patients with Medicaid.

 

It may be no surprise that a field that focuses on skin is now reckoning with skin color. In dermatology, where images are critical for diagnoses, the lack of images of darker skin poses a roadblock to proper treatment and medical education. Skin conditions that involve redness or pinkness in light skin can be subtler or harder to see in dark skin, and physicians who haven’t been adequately trained with such images are prone to misdiagnose people of color. “We absolutely need a diversity of images,” said Elbuluk.

An analysis of textbooks by Jules Lipoff, an assistant professor of clinical dermatology at the University of Pennsylvania, showed the percentage of images of dark skin ranged from 4% to 18%. “We are not teaching (and possibly not learning) skin of color,” Lester wrote in a separate analysis she conducted. Many worry the field’s shift toward using artificial intelligence to aid diagnosis of disease will further deepen the divide, because the machine learning algorithms are trained with datasets consisting primarily of fair-skinned images.

Dr. Jenna Lester w/ patient
Dermatologist Jenna Lester treats Geoffry Blair Hutto at the UCSF skin of color clinic.COURTESY BARBARA RIES, UCSF

It gets worse. While many textbooks depict the vast majority of skin diseases using light skin, there is one notable exception: Black skin is more often used to depict sexually transmitted diseases, a glaring example of stereotyping that is all the more painful given the U.S. government’s complicity in the notorious Tuskegee experiments that left syphilis untreated for decades in a group of poor, Black men.

Lipoff’s analysis, published this year, showed many dermatology textbooks had zero images of dark skin with acne, psoriasis, or dermatitis. When it came to syphilis, however, many books relied heavily on images of dark skin. Lester’s analysis found that while 28% of images of infectious diseases used images of darker skin, the number of depictions of dark skin was twice as high for infections that were sexually transmitted.

“In the textbooks I used in medical school, every penis was a Black penis showing an STD. We’ve got to stop that,” said Susan Taylor, a pioneer in the push for better dermatologic care for patients with dark skin and the Sandra Lazarus professor of dermatology at the Perelman School of Medicine at the University of Pennsylvania.

Considered a trailblazer in the field of dermatology, Taylor established the nation’s first “Skin of Color” dermatology clinic at Mount Sinai in New York in the late 1990s. In 2004, she founded the Skin of Color Society to help educate fellow dermatologists about how to treat patients of color, push for research and clinical trials to include people with darker skin, and mentor and encourage medical students of color to enter dermatology, where only 3% of practitioners are Black and 4% are Hispanic. “These are really abysmal numbers,” Taylor said. “That’s got to change.”

Taylor is also the lead author of the textbook Dermatology for Skin of Color, a guide considered invaluable by many dermatologists. But even those who rely on the book say it’s frustrating that a separate book on dark skin is still required — when as a nation we are just a few decades away from a majority of residents having skin of color.

“This is the white patient treated as the default and the Black patient as the asterisk,” said Lipoff. “You can’t make skin of color a lecture that students get once a year. It can’t be ‘otherized’ or put in a separate textbook.”

Taylor agrees. “Nothing would make me happier than to not have to publish another edition of that book,” she said.

 

Dermatologists say the lack of images is one reason why many conditions, including Lyme disease, spider bites, and cancers can go misdiagnosed or underdiagnosed in darker skinned patients, sometimes with dangerous results. The five-year melanoma survival rate for Black patients is just 70% compared with 94% for white patients.

The mother of a mixed-race 13-year-old from Connecticut said she was told by her child’s pediatrician when she was 8 that the white patches on her skin were pityriasis alba, a skin rash that’s usually not considered a serious condition. She was given a lotion, but the skin patches never went away. “I kept going online and looking at things but I couldn’t see anyone with issues that looked like hers,” said the mother, who didn’t want her name used to protect the girl’s privacy. “And the doctor was casual about it.”

Partly because of insurance issues, and partly because the mother thought there was nothing to worry about, it took five years before her daughter’s white patches were properly diagnosed: She had T-cell lymphoma, a cancer. While she will require maintenance light therapy for life, her overall prognosis is good. But her case highlights the difficult and sometimes frightening challenge many patients of color face to get a proper dermatologic diagnosis.

“Black Lives Matter is forcing a lot of people to look inward and say, ‘Where are our shortcomings?’ Dermatology is no different.”

 

When Ellen Buchanan Weiss noticed patches on the dark brown skin of her toddler son, she wondered if it was eczema, or something more serious. “I Googled it and noticed immediately the pictures were all of white skin,” she said. “I Googled other conditions and it was the same. No matter what I searched, there were almost no images of dark skin.”

The patches did turn out to be eczema and were easily treated. Still, the disparity bothered her for months. About a year ago, Weiss, a stay-at-home mom in Raleigh, N.C., decided to create an Instagram account called “Brown Skin Matters.” She posted images of skin conditions in darker skin next to images of the same condition in white skin and asked followers to send in more photos. The account exploded almost immediately.

“I’ve had tons of medical schools, physicians, nurses, and pharmacists all contact me saying this was useful,” she said. “I never thought this was going to become a diagnostic tool.”

Instagram is not exactly the best platform for making medical diagnoses, so Weiss is now working with medical experts to help create a more rigorous and searchable web-based tool for diagnosis of skin diseases in darker skin. It still floors Weiss that she, a person with no medical background, is at the center of it. “It’s curious to me, and troubling, that this is 2020 and this gap is still here,” she said. “Some large medical institution should have been taking care of this, not me.”

atopic dermatitis in infants
Comparison of atopic dermatitis in infants with darkly pigmented versus lightly pigmented skin, from the widely used textbook, Dermatology.COURTESY BOLOGNIA JL, SCHAFFER JV, AND CERRONI L, EDS. DERMATOLOGY. 4TH ED. ELSEVIER

Bolognia said she is extremely sensitive about not stigmatizing people of color by using only images of darkly pigmented skin to illustrate sexually transmitted diseases or drug users. “I noticed this as a student, the images of STDs were nearly all of patients with darkly pigmented skin, but the people I saw with syphilis were often fair-skinned,” she said. “I wondered about the possibility that pictures were being taken of individuals who were less likely to say no.”

The issue of textbooks failing to adequately represent skin of color is not a new one. Yet Lipoff’s study compared today’s textbooks with those of 15 years ago and found little has changed. Jean Bolognia, a professor of dermatology at the Yale School of Medicine, has spent more than two decades editing the widely used textbook, Dermatology; she said providing a wide spectrum of skin tones is critical and something she’s worked hard to include, though she acknowledged there’s more work to do.

“I’m not saying it’s perfect, but we’ve been working really hard for over 15 years to show the whole spectrum,” said Bolognia, who is now working on the fifth edition of the textbook. “I feel you can always do better and I realize I don’t have enough images of Asian skin, so that is something I’m addressing.”Related: 

The field’s other widely used textbook is Andrews’ Diseases of the Skin. That book’s lead author, William James, is a longtime champion of diversity in dermatology, according to his colleagues at Penn, who include Taylor and Lipoff. James said representing a variety of skin tones was an important issue, but said authors were challenged by limits placed on the number of photos by textbook publishers and because findings of redness or pinkness can be hard to see in images of darker skin. “Deciding if an entity is represented at all, or more than once, is always difficult,” he said in an email.

James said his textbook includes more photos of Black skin than white skin in conditions that are more common in Black patients, and noted that eight of 14 photos of syphilis are in lighter skin.

Agrowing number of dermatologists are following Taylor’s lead and opening skin of color clinics that provide care for darker-skinned patients. Lester opened one at UCSF last year. Elbuluk has worked at or founded three skin of color clinics throughout her training and early career, including at Penn, NYU Medical School, and, in 2018, at USC, where she hopes to also spur much-needed clinical research on darker skin. “It’s surprising to me when large cities don’t have these,” Elbuluk said.

There are many reasons why people of color, particularly those who do not have private health insurance, lack access to dermatologists. Lipoff, who has examined the issue, said many dermatologists do not take Medicaid. Racial bias that discourages the treatment of Black patients, he said, is literally built into the physician reimbursement system. Many conditions that affect darker skin are often not covered by insurance because they are considered cosmetic.

Meanwhile, the highest revenue procedures, Lipoff said, include those for the diagnosis and treatment of skin cancer, which is more likely to occur in white patients. This difference in how procedures are valued and reimbursed, he said, is a perfect example of structural racism that drives practices to directly and indirectly focus on white patients and marginalize Black patients. “If Black patients earned practices three times the revenue,” he said, “the disparity would disappear overnight.”

“It’s curious to me, and troubling, that this is 2020 and this gap is still here. Some large medical institution should have been taking care of this, not me.”

 

Until it does, physicians who run skin of color clinics are hoping to address the lack of care, and poor care, Black and brown patients have received. The clinics are a welcome addition to people like Dar Bray, a 45-year-old behavioral therapist and darker-skinned Black man from Los Angeles.

Bray had dealt for years with deep and persistent scars caused by acne, trying bleaching creams and expensive cosmetic products, all with no success. “I went to so many doctors who didn’t know what to do with my skin. All the pictures they had on their wall were fair-skinned people,” Bray said. “It didn’t feel like racism, it felt like just plain ignorance.”

Seeing Elbuluk, he said, was immediately different. Bray is now undergoing chemical peels to remove scarring and using simple (and inexpensive) cleansers and moisturizers, and says he sees a huge improvement in his skin. He’s also wearing sunscreen, something no physician had ever told him was necessary; like many, he had believed the myth “Black don’t crack.” “When I went to the beach, I never wore sunscreen,” he said. “Now I have years of sun damage.”

Mistrust of white physicians led Gregory Hines, a 63-year-old longshoreman who lives in Oakland, to go years without seeing a doctor about growths under his arm, on his back, and on his neck, even as they puffed up and became, in his words “kind of weird and ugly.”

“I experience it a lot, going to doctors — especially white, male doctors — they assume they know more than you. They assume they already know what your problem is the minute you walk through the door,” he said.

When he heard UCSF’s Skin of Color clinic had opened, he was willing to give it a try. “When Dr. Lester walked in, I said, ‘Whoa, this is great,’” he said. “I wanted a Black doctor who understands Black skin.”

Lester ended up removing the masses, one of which was nearly as large as a golf ball, and sent them for tests to see if they were cancerous. Fortunately, they were not.

Lester is the only Black dermatologist in San Francisco. She’s hoping that will change after her current crop of residents decides where they will establish their practices. Her Black patients, she said, are often shocked when she walks in the door.

“I’ve had patients ask if they can take a picture with me to show their grandkids,” she said. “They want to talk all about me and how I got here, and I have to say, ‘No, this time is for you.’”

SOURCE

:https://www.statnews.com/2020/07/21/dermatology-faces-reckoning-lack-of-darker-skin-in-textbooks-journals-harms-patients-of-color/?utm_source=STAT+Newsletters

 

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The Inequality and Health Disparity seen with the COVID-19 Pandemic Is Similar to Past Pandemics

Curator: Stephen J. Williams, PhD

2019-nCoV-CDC-23311

It has become very evident, at least in during this pandemic within the United States, that African Americans and poorer communities have been disproportionately affected by the SARS-CoV2 outbreak . However, there are many other diseases such as diabetes, heart disease, and cancer in which these specific health disparities are evident as well :

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

Personalized Medicine, Omics, and Health Disparities in Cancer:  Can Personalized Medicine Help Reduce the Disparity Problem?

Disease like cancer have been shown to have wide disparities based on socioeconomic status, with higher incidence rates seen in poorer and less educated sub-populations, not just here but underdeveloped countries as well (see Opinion Articles from the Lancet: COVID-19 and Cancer Care in China and Africa) and graphics below)

 

 

 

 

 

 

 

 

 

 

In an article in Science by Lizzie Wade, these disparities separated on socioeconomic status, have occurred in many other pandemics throughout history, and is not unique to the current COVID19 outbreak.  The article, entitled “An Unequal Blow”, reveal how

in past pandemics, people on the margins suffered the most.

Source: https://science.sciencemag.org/content/368/6492/700.summary

Health Disparities during the Black Death Bubonic Plague Pandemic in the 14th Century (1347-1351)

During the mid 14th century, all of Europe was affected by a plague induced by the bacterium Yersinia pestis, and killed anywhere between 30 – 60% of the European population.  According to reports by the time the Black Death had reached London by January 1349 there had already been horrendous reports coming out of Florence Italy where the deadly disease ravished the population there in the summer of 1348 (more than half of the city’s population died). And by mid 1349 the Black Death had killed more than half of Londoners.  It appeared that no one was safe from the deadly pandemic, affecting the rich, the poor, the young, the old.

However, after careful and meticulous archaeological and historical analysis in England and other sites, revealed a distinct social and economic inequalities that predominated and most likely guided the pandemics course throughout Europe.   According to Dr. Gwen Robbins Schug, a bio-archaeologist at Appalachian State University,

Bio-archaeology and other social sciences have repeatedly demonstrated that these kinds of crises play out along the preexisting fault lines of each society.  The people at greatest risk were often those already marginalized- the poor and minorities who faced discrimination in ways that damaged their health or limited their access to medical care even in pandemic times.

At the start of the Black Death, Europe had already gone under a climactic change with erratic weather.  As a result, a Great Famine struck Europe between 1315-17.  Wages fell and more people fell into poverty while the wealthiest expanded their riches, leading to an increased gap in wealth and social disparity.  In fact according to recordkeeping most of Englanders were living below the poverty line.

Author Lizzie Wade also interviewed Dr. Sharon, DeWitte, a biological anthropologist at University of South Carolina, who looks at skeletal remains of Black Death victims to get evidence on their health status, like evidence of malnutrition, osteoporosis, etc.   And it appears that most of the victims may have had preexisting health conditions indicative of poorer status.  And other evidence show that wealthy landowners had a lower mortality rate than poorer inner city dwellers.

1918 Spanish Flu

Socioeconomic and demographic studies have shown that both Native American Indians and African Americans on the lower end of the socioeconomic status were disproportionately affected by the 1918 Spanish flu pandemic.  According to census records, the poorest had a 50% higher mortality rate than wealthy areas in the city of Oslo.  In the US, minors and factory workers died at the highest rates.  In the US African Americans had already had bouts with preexisting issues like tuberculosis and may have contributed to the higher mortality.  In addition Jim Crow laws in the South, responsible for widespread discrimination, also impacted the ability of African Americans to seek proper medical care.

From the Atlantic

Source: https://www.theatlantic.com/politics/archive/2016/05/americas-health-segregation-problem/483219/

America’s Health Segregation Problem

Has the country done enough to overcome its Jim Crow health care history?

VANN R. NEWKIRK II

MAY 18, 2016

Like other forms of segregation, health-care segregation was originally a function of explicitly racist black codes and Jim Crow laws. Many hospitals, clinics, and doctor’s offices were totally segregated by race, and many more maintained separate wings or staff that could never intermingle under threat of law. The deficit of trained black medical professionals (itself caused by a number of factors including education segregation) meant that no matter where black people received health-care services, they would find their care to be subpar compared to that of whites. While there were some deaths that were directly attributable to being denied emergency service, most of the damage was done in establishing the same cumulative health disparities that plague black people today as a societal fate. The descendants of enslaved people lived much more dangerous and unhealthy lives than white counterparts, on disease-ridden and degraded environments. Within the confines of a segregated health-care system, these factors became poor health outcomes that shaped black America as if they were its genetic material.

 

https://twitter.com/time4equity/status/1175080469425266688?s=20

 

R.A.HahnaB.I.TrumanbD.R.Williamsc.Civil rights as determinants of public health and racial and ethnic health equity: Health care, education, employment, and housing in the United States.

SSM – Population Health: Volume 4, April 2018, Pages 17-24

Highlights

  • Civil rights are characterized as social determinants of health.
  • Four domains in civil rights history since 1950 are explored in—health care, education, employment, and housing.
  • Health care, education, employment show substantial benefits when civil rights are enforced.
  • Housing shows an overall failure to enforce existing civil rights and persistent discrimination.
  • Civil rights and their enforcement may be considered a powerful arena for public health theorizing, research, policy, and action.

 

For more articles on COVID-19 Please go to our Coronovirus Portal

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

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Live Notes, Real Time Conference Coverage AACR 2020 #AACR20: Tuesday June 23, 2020 Noon-2:45 Educational Sessions


Live Notes, Real Time Conference Coverage AACR 2020: Tuesday June 23, 2020 Noon-2:45 Educational Sessions

Reporter: Stephen J. Williams, PhD

Follow Live in Real Time using

#AACR20

@pharma_BI

@AACR

Register for FREE at https://www.aacr.org/

 

Presidential Address

Elaine R Mardis, William N Hait

DETAILS

Welcome and introduction

William N Hait

 

Improving diagnostic yield in pediatric cancer precision medicine

Elaine R Mardis
  • Advent of genomics have revolutionized how we diagnose and treat lung cancer
  • We are currently needing to understand the driver mutations and variants where we can personalize therapy
  • PD-L1 and other checkpoint therapy have not really been used in pediatric cancers even though CAR-T have been successful
  • The incidence rates and mortality rates of pediatric cancers are rising
  • Large scale study of over 700 pediatric cancers show cancers driven by epigenetic drivers or fusion proteins. Need for transcriptomics.  Also study demonstrated that we have underestimated germ line mutations and hereditary factors.
  • They put together a database to nominate patients on their IGM Cancer protocol. Involves genetic counseling and obtaining germ line samples to determine hereditary factors.  RNA and protein are evaluated as well as exome sequencing. RNASeq and Archer Dx test to identify driver fusions
  • PECAN curated database from St. Jude used to determine driver mutations. They use multiple databases and overlap within these databases and knowledge base to determine or weed out false positives
  • They have used these studies to understand the immune infiltrate into recurrent cancers (CytoCure)
  • They found 40 germline cancer predisposition genes, 47 driver somatic fusion proteins, 81 potential actionable targets, 106 CNV, 196 meaningful somatic driver mutations

 

 

Tuesday, June 23

12:00 PM – 12:30 PM EDT

Awards and Lectures

NCI Director’s Address

Norman E Sharpless, Elaine R Mardis

DETAILS

Introduction: Elaine Mardis

 

NCI Director Address: Norman E Sharpless
  • They are functioning well at NCI with respect to grant reviews, research, and general functions in spite of the COVID pandemic and the massive demonstrations on also focusing on the disparities which occur in cancer research field and cancer care
  • There are ongoing efforts at NCI to make a positive difference in racial injustice, diversity in the cancer workforce, and for patients as well
  • Need a diverse workforce across the cancer research and care spectrum
  • Data show that areas where the clinicians are successful in putting African Americans on clinical trials are areas (geographic and site specific) where health disparities are narrowing
  • Grants through NCI new SeroNet for COVID-19 serologic testing funded by two RFAs through NIAD (RFA-CA-30-038 and RFA-CA-20-039) and will close on July 22, 2020

 

Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Immunology, Tumor Biology, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Tumor Immunology and Immunotherapy for Nonimmunologists: Innovation and Discovery in Immune-Oncology

This educational session will update cancer researchers and clinicians about the latest developments in the detailed understanding of the types and roles of immune cells in tumors. It will summarize current knowledge about the types of T cells, natural killer cells, B cells, and myeloid cells in tumors and discuss current knowledge about the roles these cells play in the antitumor immune response. The session will feature some of the most promising up-and-coming cancer immunologists who will inform about their latest strategies to harness the immune system to promote more effective therapies.

Judith A Varner, Yuliya Pylayeva-Gupta

 

Introduction

Judith A Varner
New techniques reveal critical roles of myeloid cells in tumor development and progression
  • Different type of cells are becoming targets for immune checkpoint like myeloid cells
  • In T cell excluded or desert tumors T cells are held at periphery so myeloid cells can infiltrate though so macrophages might be effective in these immune t cell naïve tumors, macrophages are most abundant types of immune cells in tumors
  • CXCLs are potential targets
  • PI3K delta inhibitors,
  • Reduce the infiltrate of myeloid tumor suppressor cells like macrophages
  • When should we give myeloid or T cell therapy is the issue
Judith A Varner
Novel strategies to harness T-cell biology for cancer therapy
Positive and negative roles of B cells in cancer
Yuliya Pylayeva-Gupta
New approaches in cancer immunotherapy: Programming bacteria to induce systemic antitumor immunity

 

 

Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Cancer Chemistry

Chemistry to the Clinic: Part 2: Irreversible Inhibitors as Potential Anticancer Agents

There are numerous examples of highly successful covalent drugs such as aspirin and penicillin that have been in use for a long period of time. Despite historical success, there was a period of reluctance among many to purse covalent drugs based on concerns about toxicity. With advances in understanding features of a well-designed covalent drug, new techniques to discover and characterize covalent inhibitors, and clinical success of new covalent cancer drugs in recent years, there is renewed interest in covalent compounds. This session will provide a broad look at covalent probe compounds and drug development, including a historical perspective, examination of warheads and electrophilic amino acids, the role of chemoproteomics, and case studies.

Benjamin F Cravatt, Richard A. Ward, Sara J Buhrlage

 

Discovering and optimizing covalent small-molecule ligands by chemical proteomics

Benjamin F Cravatt
  • Multiple approaches are being investigated to find new covalent inhibitors such as: 1) cysteine reactivity mapping, 2) mapping cysteine ligandability, 3) and functional screening in phenotypic assays for electrophilic compounds
  • Using fluorescent activity probes in proteomic screens; have broad useability in the proteome but can be specific
  • They screened quiescent versus stimulated T cells to determine reactive cysteines in a phenotypic screen and analyzed by MS proteomics (cysteine reactivity profiling); can quantitate 15000 to 20,000 reactive cysteines
  • Isocitrate dehydrogenase 1 and adapter protein LCP-1 are two examples of changes in reactive cysteines they have seen using this method
  • They use scout molecules to target ligands or proteins with reactive cysteines
  • For phenotypic screens they first use a cytotoxic assay to screen out toxic compounds which just kill cells without causing T cell activation (like IL10 secretion)
  • INTERESTINGLY coupling these MS reactive cysteine screens with phenotypic screens you can find NONCANONICAL mechanisms of many of these target proteins (many of the compounds found targets which were not predicted or known)

Electrophilic warheads and nucleophilic amino acids: A chemical and computational perspective on covalent modifier

The covalent targeting of cysteine residues in drug discovery and its application to the discovery of Osimertinib

Richard A. Ward
  • Cysteine activation: thiolate form of cysteine is a strong nucleophile
  • Thiolate form preferred in polar environment
  • Activation can be assisted by neighboring residues; pKA will have an effect on deprotonation
  • pKas of cysteine vary in EGFR
  • cysteine that are too reactive give toxicity while not reactive enough are ineffective

 

Accelerating drug discovery with lysine-targeted covalent probes

 

Tuesday, June 23

12:45 PM – 2:15 PM EDT

Virtual Educational Session

Molecular and Cellular Biology/Genetics

Virtual Educational Session

Tumor Biology, Immunology

Metabolism and Tumor Microenvironment

This Educational Session aims to guide discussion on the heterogeneous cells and metabolism in the tumor microenvironment. It is now clear that the diversity of cells in tumors each require distinct metabolic programs to survive and proliferate. Tumors, however, are genetically programmed for high rates of metabolism and can present a metabolically hostile environment in which nutrient competition and hypoxia can limit antitumor immunity.

Jeffrey C Rathmell, Lydia Lynch, Mara H Sherman, Greg M Delgoffe

 

T-cell metabolism and metabolic reprogramming antitumor immunity

Jeffrey C Rathmell

Introduction

Jeffrey C Rathmell

Metabolic functions of cancer-associated fibroblasts

Mara H Sherman

Tumor microenvironment metabolism and its effects on antitumor immunity and immunotherapeutic response

Greg M Delgoffe
  • Multiple metabolites, reactive oxygen species within the tumor microenvironment; is there heterogeneity within the TME metabolome which can predict their ability to be immunosensitive
  • Took melanoma cells and looked at metabolism using Seahorse (glycolysis): and there was vast heterogeneity in melanoma tumor cells; some just do oxphos and no glycolytic metabolism (inverse Warburg)
  • As they profiled whole tumors they could separate out the metabolism of each cell type within the tumor and could look at T cells versus stromal CAFs or tumor cells and characterized cells as indolent or metabolic
  • T cells from hyerglycolytic tumors were fine but from high glycolysis the T cells were more indolent
  • When knock down glucose transporter the cells become more glycolytic
  • If patient had high oxidative metabolism had low PDL1 sensitivity
  • Showed this result in head and neck cancer as well
  • Metformin a complex 1 inhibitor which is not as toxic as most mito oxphos inhibitors the T cells have less hypoxia and can remodel the TME and stimulate the immune response
  • Metformin now in clinical trials
  • T cells though seem metabolically restricted; T cells that infiltrate tumors are low mitochondrial phosph cells
  • T cells from tumors have defective mitochondria or little respiratory capacity
  • They have some preliminary findings that metabolic inhibitors may help with CAR-T therapy

Obesity, lipids and suppression of anti-tumor immunity

Lydia Lynch
  • Hypothesis: obesity causes issues with anti tumor immunity
  • Less NK cells in obese people; also produce less IFN gamma
  • RNASeq on NOD mice; granzymes and perforins at top of list of obese downregulated
  • Upregulated genes that were upregulated involved in lipid metabolism
  • All were PPAR target genes
  • NK cells from obese patients takes up palmitate and this reduces their glycolysis but OXPHOS also reduced; they think increased FFA basically overloads mitochondria
  • PPAR alpha gamma activation mimics obesity

 

 

Tuesday, June 23

12:45 PM – 2:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials

The Evolving Role of the Pathologist in Cancer Research

Long recognized for their role in cancer diagnosis and prognostication, pathologists are beginning to leverage a variety of digital imaging technologies and computational tools to improve both clinical practice and cancer research. Remarkably, the emergence of artificial intelligence (AI) and machine learning algorithms for analyzing pathology specimens is poised to not only augment the resolution and accuracy of clinical diagnosis, but also fundamentally transform the role of the pathologist in cancer science and precision oncology. This session will discuss what pathologists are currently able to achieve with these new technologies, present their challenges and barriers, and overview their future possibilities in cancer diagnosis and research. The session will also include discussions of what is practical and doable in the clinic for diagnostic and clinical oncology in comparison to technologies and approaches primarily utilized to accelerate cancer research.

 

Jorge S Reis-Filho, Thomas J Fuchs, David L Rimm, Jayanta Debnath

DETAILS

Tuesday, June 23

12:45 PM – 2:45 PM EDT

 

High-dimensional imaging technologies in cancer research

David L Rimm

  • Using old methods and new methods; so cell counting you use to find the cells then phenotype; with quantification like with Aqua use densitometry of positive signal to determine a threshold to determine presence of a cell for counting
  • Hiplex versus multiplex imaging where you have ten channels to measure by cycling of flour on antibody (can get up to 20plex)
  • Hiplex can be coupled with Mass spectrometry (Imaging Mass spectrometry, based on heavy metal tags on mAbs)
  • However it will still take a trained pathologist to define regions of interest or field of desired view

 

Introduction

Jayanta Debnath

Challenges and barriers of implementing AI tools for cancer diagnostics

Jorge S Reis-Filho

Implementing robust digital pathology workflows into clinical practice and cancer research

Jayanta Debnath

Invited Speaker

Thomas J Fuchs
  • Founder of spinout of Memorial Sloan Kettering
  • Separates AI from computational algothimic
  • Dealing with not just machines but integrating human intelligence
  • Making decision for the patients must involve human decision making as well
  • How do we get experts to do these decisions faster
  • AI in pathology: what is difficult? =è sandbox scenarios where machines are great,; curated datasets; human decision support systems or maps; or try to predict nature
  • 1) learn rules made by humans; human to human scenario 2)constrained nature 3)unconstrained nature like images and or behavior 4) predict nature response to nature response to itself
  • In sandbox scenario the rules are set in stone and machines are great like chess playing
  • In second scenario can train computer to predict what a human would predict
  • So third scenario is like driving cars
  • System on constrained nature or constrained dataset will take a long time for commuter to get to decision
  • Fourth category is long term data collection project
  • He is finding it is still finding it is still is difficult to predict nature so going from clinical finding to prognosis still does not have good predictability with AI alone; need for human involvement
  • End to end partnering (EPL) is a new way where humans can get more involved with the algorithm and assist with the problem of constrained data
  • An example of a workflow for pathology would be as follows from Campanella et al 2019 Nature Medicine: obtain digital images (they digitized a million slides), train a massive data set with highthroughput computing (needed a lot of time and big software developing effort), and then train it using input be the best expert pathologists (nature to human and unconstrained because no data curation done)
  • Led to first clinically grade machine learning system (Camelyon16 was the challenge for detecting metastatic cells in lymph tissue; tested on 12,000 patients from 45 countries)
  • The first big hurdle was moving from manually annotated slides (which was a big bottleneck) to automatically extracted data from path reports).
  • Now problem is in prediction: How can we bridge the gap from predicting humans to predicting nature?
  • With an AI system pathologist drastically improved the ability to detect very small lesions

 

Virtual Educational Session

Epidemiology

Cancer Increases in Younger Populations: Where Are They Coming from?

Incidence rates of several cancers (e.g., colorectal, pancreatic, and breast cancers) are rising in younger populations, which contrasts with either declining or more slowly rising incidence in older populations. Early-onset cancers are also more aggressive and have different tumor characteristics than those in older populations. Evidence on risk factors and contributors to early-onset cancers is emerging. In this Educational Session, the trends and burden, potential causes, risk factors, and tumor characteristics of early-onset cancers will be covered. Presenters will focus on colorectal and breast cancer, which are among the most common causes of cancer deaths in younger people. Potential mechanisms of early-onset cancers and racial/ethnic differences will also be discussed.

Stacey A. Fedewa, Xavier Llor, Pepper Jo Schedin, Yin Cao

Cancers that are and are not increasing in younger populations

Stacey A. Fedewa

 

  • Early onset cancers, pediatric cancers and colon cancers are increasing in younger adults
  • Younger people are more likely to be uninsured and these are there most productive years so it is a horrible life event for a young adult to be diagnosed with cancer. They will have more financial hardship and most (70%) of the young adults with cancer have had financial difficulties.  It is very hard for women as they are on their childbearing years so additional stress
  • Types of early onset cancer varies by age as well as geographic locations. For example in 20s thyroid cancer is more common but in 30s it is breast cancer.  Colorectal and testicular most common in US.
  • SCC is decreasing by adenocarcinoma of the cervix is increasing in women’s 40s, potentially due to changing sexual behaviors
  • Breast cancer is increasing in younger women: maybe etiologic distinct like triple negative and larger racial disparities in younger African American women
  • Increased obesity among younger people is becoming a factor in this increasing incidence of early onset cancers

 

 

Other Articles on this Open Access  Online Journal on Cancer Conferences and Conference Coverage in Real Time Include

Press Coverage

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

 

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Opinion Articles from the Lancet: COVID-19 and Cancer Care in China and Africa

Reporter: Stephen J. Williams, PhD

Cancer Patients in SARS-CoV-2 infection: a nationwide analysis in China

Wenhua Liang, Weijie Guan, Ruchong Chen, Wei Wang, Jianfu Li, Ke Xu, Caichen Li, Qing Ai, Weixiang Lu, Hengrui Liang, Shiyue Li, Jianxing He

Lancet Oncol. 2020 Mar; 21(3): 335–337. Published online 2020 Feb 14. doi: 10.1016/S1470-2045(20)30096-6

PMCID: PMC7159000

 

The National Clinical Research Center for Respiratory Disease and the National Health Commission of the People’s Republic of China collaborated to establish a prospective cohort to monitor COVID-19 cases in China.  As on Jan31, 20202007 cases have been collected and analyzed with confirmed COVID-19 infection in these cohorts.

Results: 18 or 1% of COVID-19 cases had a history of cancer (the overall average cancer incidence in the overall China population is 0.29%) {2015 statistics}.  It appeared that cancer patients had an observable higher risk of COVID related complications upon hospitalization. However, this was a higher risk compared with the general population.  There was no comparison between cancer patients not diagnosed with COVID-19 and an assessment of their risk of infection.  Interestingly those who were also cancer survivors showed an increased incidence of COVID related severe complications compared to the no cancer group.

Although this study could have compared the risk within a cancer group, the authors still felt the results warranted precautions when dealing with cancer patients and issued recommendations including:

  1. Postponing of adjuvant chemotherapy or elective surgery for stable cancer should be considered
  2. Stronger personal protection for cancer patients
  3. More intensive surveillance or treatment should be considered when patients with cancer are infected, especially in older patients

Further studies will need to address the risk added by specific types of chemotherapy: cytolytic versus immunotherapy e.g.

 

Preparedness for COVID-19 in the oncology community in Africa

Lancet Oncology, Verna Vanderpuye, Moawia Mohammed,Ali Elhassan

Hannah Simonds: Published:April 03, 2020DOI:https://doi.org/10.1016/S1470-2045(20)30220-5

Africa has a heterogeneity of cultures, economies and disease patterns however fortunately it is one of the last countries to be hit by the COVID-19 pandemic, which allows some time for preparation by the African nations.  The authors note that with Africa’s previous experiences with epidemics, namely ebola and cholera, Africa should be prepared for this pandemic.

However, as a result of poor economic discipline, weak health systems, and poor health-seeking behaviors across the continent, outcomes could be dismal. Poverty, low health literacy rates, and cultural practices that negatively affect cancer outcomes will result in poor assimilation of COVID-19 containment strategies in Africa.”

In general African oncologists are following COVID-19 guidelines from other high-income countries, but as this writer acknowledges in previous posts, there was a significant lag from first cases in the United States to the concrete formulation of guidelines for both oncologists and patients with regard to this pandemic.  African oncologist are delaying the start of adjuvant therapies and switching more to oral therapies and rethink palliative care.

However the authors still have many more questions than answers, however even among countries that have dealt with this pandemic before Africa (like Italy and US), oncologists across the globe still have not been able to answer questions like: what if my patient develops a fever, what do I do during a period of neutropenia, to their satisfaction or the satisfaction of the patient.  These are questions even oncologists who are dealing in COVID hotspots are still trying to answer including what constitutes a necessary surgical procedure? As I have highlighted in recent posts, oncologists in New York have all but shut down all surgical procedures and relying on liquid biopsies taken in the at-home setting. But does Africa have this capability of access to at home liquid biopsy procedures?

In addition, as I had just highlighted in a recent posting, there exists extreme cancer health disparities across the African continent, as well as the COVID responses. In West Africa, COVID-19 protocols are defined at individual institutions.  This is more like the American system where even NCI designated centers were left to fashion some of their own guidelines initially, although individual oncologists had banded together to do impromptu meetings to discuss best practices. However this is fine for big institutions, but as in the US, there is a large rural population on the African continent with geographical barriers to these big centers. Elective procedures have been cancelled and small number of patients are seen by day.  This remote strategy actually may be well suited for African versus more developed nations, as highlighted in a post I did about mobile health app use in oncology, as this telemedicine strategy is rather new among US oncologists (reference my posts with the Town Hall meetings).

The situation is more complicated in South Africa where they are dealing with an HIV epidemic, where about 8 million are infected with HIV. Oncology services here are still expecting to run at full capacity as the local hospitals deal with the first signs of the COVID outbreak. In Sudan, despite low COVID numbers, cancer centers have developed contingency plans. and are deferring new referrals except for emergency cases.  Training sessions for staff have been developed.

For more articles in this online open access journal on Cancer and COVID-19 please see our

Coronovirus Portal
Responses to the #COVID-19 outbreak from Oncologists, Cancer Societies and the NCI: Important information for cancer patients

 

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Personalized Medicine, Omics, and Health Disparities in Cancer:  Can Personalized Medicine Help Reduce the Disparity Problem?

Curator: Stephen J. Williams, PhD

In a Science Perspectives article by Timothy Rebbeck, health disparities, specifically cancer disparities existing in the sub-Saharan African (SSA) nations, highlighting the cancer incidence disparities which exist compared with cancer incidence in high income areas of the world [1].  The sub-Saharan African nations display a much higher incidence of prostate, breast, and cervix cancer and these cancers are predicted to double within the next twenty years, according to IARC[2].  Most importantly,

 the histopathologic and demographic features of these tumors differ from those in high-income countries

meaning that the differences seen in incidence may reflect a true health disparity as increases rates in these cancers are not seen in high income countries (HIC).

Most frequent male cancers in SSA include prostate, lung, liver, leukemia, non-Hodgkin’s lymphoma, and Kaposi’s sarcoma (a cancer frequently seen in HIV infected patients [3]).  In SSA women, breast and cervical cancer are the most common and these display higher rates than seen in high income countries.  In fact, liver cancer is seen in SSA females at twice the rate, and in SSA males almost three times the rate as in high income countries.

 

 

 

 

 

 

Reasons for cancer disparity in SSA

Patients with cancer are often diagnosed at a late stage in SSA countries.  This contrasts with patients from high income countries, which have their cancers usually diagnosed at an earlier stage, and with many cancers, like breast[4], ovarian[5, 6], and colon, detecting the tumor in the early stages is critical for a favorable outcome and prognosis[7-10].  In addition, late diagnosis also limits many therapeutic options for the cancer patient and diseases at later stages are much harder to manage, especially with respect to unresponsiveness and/or resistance of many therapies.  In addition, treatments have to be performed in low-resource settings in SSA, and availability of clinical lab work and imaging technologies may be limited.

Molecular differences in SSA versus HIC cancers which may account for disparities

Emerging evidence suggests that there are distinct molecular signatures with SSA tumors with respect to histotype and pathology.  For example Dr. Rebbeck mentions that Nigerian breast cancers were defined by increased mutational signatures associated with deficiency of the homologous recombination DNA repair pathway, pervasive mutations in the tumor suppressor gene TP53, mutations in GATA binding protein 3 (GATA3), and greater mutational burden, compared with breast tumors from African Americans or Caucasians[11].  However more research will be required to understand the etiology and causal factors related to this molecular distinction in mutational spectra.

It is believed that there is a higher rate of hereditary cancers in SSA. And many SSA cancers exhibit the more aggressive phenotype than in other parts of the world.  For example breast tumors in SSA black cases are twice as likely than SSA Caucasian cases to be of the triple negative phenotype, which is generally more aggressive and tougher to detect and treat, as triple negative cancers are HER2 negative and therefore are not a candidate for Herceptin.  Also BRCA1/2 mutations are more frequent in black SSA cases than in Caucasian SSA cases [12, 13].

Initiatives to Combat Health Disparities in SSA

Multiple initiatives are being proposed or in action to bring personalized medicine to the sub-Saharan African nations.  These include:

H3Africa empowers African researchers to be competitive in genomic sciences, establishes and nurtures effective collaborations among African researchers on the African continent, and generates unique data that could be used to improve both African and global health.

There is currently a global effort to apply genomic science and associated technologies to further the understanding of health and disease in diverse populations. These efforts work to identify individuals and populations who are at risk for developing specific diseases, and to better understand underlying genetic and environmental contributions to that risk. Given the large amount of genetic diversity on the African continent, there exists an enormous opportunity to utilize such approaches to benefit African populations and to inform global health.

The Human Heredity and Health in Africa (H3Africa) consortium facilitates fundamental research into diseases on the African continent while also developing infrastructure, resources, training, and ethical guidelines to support a sustainable African research enterprise – led by African scientists, for the African people. The initiative consists of 51 African projects that include population-based genomic studies of common, non-communicable disorders such as heart and renal disease, as well as communicable diseases such as tuberculosis. These studies are led by African scientists and use genetic, clinical, and epidemiologic methods to identify hereditary and environmental contributions to health and disease. To establish a foundation for African scientists to continue this essential work into the future work, the consortium also supports many crucial capacity building elements, such as: ethical, legal, and social implications research; training and capacity building for bioinformatics; capacity for biobanking; and coordination and networking.

The World Economic Forum’s Leapfrogging with Precision Medicine project 

This project is part of the World Economic Forum’s Shaping the Future of Health and Healthcare Platform

The Challenge

Advancing precision medicine in a way that is equitable and beneficial to society means ensuring that healthcare systems can adopt the most scientifically and technologically appropriate approaches to a more targeted and personalized way of diagnosing and treating disease. In certain instances, countries or institutions may be able to bypass, or “leapfrog”, legacy systems or approaches that prevail in developed country contexts.

The World Economic Forum’s Leapfrogging with Precision Medicine project will develop a set of tools and case studies demonstrating how a precision medicine approach in countries with greenfield policy spaces can potentially transform their healthcare delivery and outcomes. Policies and governance mechanisms that enable leapfrogging will be iterated and scaled up to other projects.

Successes in personalized genomic research in SSA

As Dr. Rebbeck states:

 Because of the underlying genetic and genomic relationships between Africans and members of the African diaspora (primarily in North America and Europe), knowledge gained from research in SSA can be used to address health disparities that are prevalent in members of the African diaspora.

For example members of the West African heritage and genomic ancestry has been reported to confer the highest genomic risk for prostate cancer in any worldwide population [14].

 

PERSPECTIVEGLOBAL HEALTH

Cancer in sub-Saharan Africa

  1. Timothy R. Rebbeck

See all authors and affiliations

Science  03 Jan 2020:
Vol. 367, Issue 6473, pp. 27-28
DOI: 10.1126/science.aay474

Summary/Abstract

Cancer is an increasing global public health burden. This is especially the case in sub-Saharan Africa (SSA); high rates of cancer—particularly of the prostate, breast, and cervix—characterize cancer in most countries in SSA. The number of these cancers in SSA is predicted to more than double in the next 20 years (1). Both the explanations for these increasing rates and the solutions to address this cancer epidemic require SSA-specific data and approaches. The histopathologic and demographic features of these tumors differ from those in high-income countries (HICs). Basic knowledge of the epidemiology, clinical features, and molecular characteristics of cancers in SSA is needed to build prevention and treatment tools that will address the future cancer burden. The distinct distribution and determinants of cancer in SSA provide an opportunity to generate knowledge about cancer risk factors, genomics, and opportunities for prevention and treatment globally, not only in Africa.

 

References

  1. Rebbeck TR: Cancer in sub-Saharan Africa. Science 2020, 367(6473):27-28.
  2. Parkin DM, Ferlay J, Jemal A, Borok M, Manraj S, N’Da G, Ogunbiyi F, Liu B, Bray F: Cancer in Sub-Saharan Africa: International Agency for Research on Cancer; 2018.
  3. Chinula L, Moses A, Gopal S: HIV-associated malignancies in sub-Saharan Africa: progress, challenges, and opportunities. Current opinion in HIV and AIDS 2017, 12(1):89-95.
  4. Colditz GA: Epidemiology of breast cancer. Findings from the nurses’ health study. Cancer 1993, 71(4 Suppl):1480-1489.
  5. Hamilton TC, Penault-Llorca F, Dauplat J: [Natural history of ovarian adenocarcinomas: from epidemiology to experimentation]. Contracept Fertil Sex 1998, 26(11):800-804.
  6. Garner EI: Advances in the early detection of ovarian carcinoma. J Reprod Med 2005, 50(6):447-453.
  7. Brockbank EC, Harry V, Kolomainen D, Mukhopadhyay D, Sohaib A, Bridges JE, Nobbenhuis MA, Shepherd JH, Ind TE, Barton DP: Laparoscopic staging for apparent early stage ovarian or fallopian tube cancer. First case series from a UK cancer centre and systematic literature review. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2013, 39(8):912-917.
  8. Kolligs FT: Diagnostics and Epidemiology of Colorectal Cancer. Visceral medicine 2016, 32(3):158-164.
  9. Rocken C, Neumann U, Ebert MP: [New approaches to early detection, estimation of prognosis and therapy for malignant tumours of the gastrointestinal tract]. Zeitschrift fur Gastroenterologie 2008, 46(2):216-222.
  10. Srivastava S, Verma M, Henson DE: Biomarkers for early detection of colon cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2001, 7(5):1118-1126.
  11. Pitt JJ, Riester M, Zheng Y, Yoshimatsu TF, Sanni A, Oluwasola O, Veloso A, Labrot E, Wang S, Odetunde A et al: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features. Nature communications 2018, 9(1):4181.
  12. Zheng Y, Walsh T, Gulsuner S, Casadei S, Lee MK, Ogundiran TO, Ademola A, Falusi AG, Adebamowo CA, Oluwasola AO et al: Inherited Breast Cancer in Nigerian Women. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018, 36(28):2820-2825.
  13. Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH et al: Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Human mutation 2018, 39(5):593-620.
  14. Lachance J, Berens AJ, Hansen MEB, Teng AK, Tishkoff SA, Rebbeck TR: Genetic Hitchhiking and Population Bottlenecks Contribute to Prostate Cancer Disparities in Men of African Descent. Cancer research 2018, 78(9):2432-2443.

Other articles on Cancer Health Disparities and Genomics on this Online Open Access Journal Include:

Gender affects the prevalence of the cancer type
The Rutgers Global Health Institute, part of Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, New Jersey – A New Venture Designed to Improve Health and Wellness Globally
Breast Cancer Disparities to be Sponsored by NIH: NIH Launches Largest-ever Study of Breast Cancer Genetics in Black Women
War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert
Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk
Ethics Behind Genetic Testing in Breast Cancer: A Webinar by Laura Carfang of survivingbreastcancer.org
Live Notes from @HarvardMed Bioethics: Authors Jerome Groopman, MD & Pamela Hartzband, MD, discuss Your Medical Mind
Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test
Study Finds that Both Women and their Primary Care Physicians Confusion over Ovarian Cancer Symptoms May Lead to Misdiagnosis

 

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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).

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Lesson 10 on Cancer, Oncogenes, and Aberrant Cell Signal Termination in Disease for #TUBiol3373

Curator: Stephen J. Williams

Please click on the following file to get the Powerpoint Presentation for this lecture

cell signaling 10 lesson_SJW 2019

There is a good reference to read on The Hallmarks of Cancer published first in 2000 and then updated with 2 new hallmarks in 2011 (namely the ability of cancer cells to reprogram their metabolism and 2. the ability of cancer cells to evade the immune system)

a link to the PDF is given here:

hallmarks2000

hallmarks2011

Please also go to other articles on this site which are relevant to this lecture.  You can use the search box in the upper right hand corner of the Home Page or these are few links you might find interesting

Development of Chemoresistance to Targeted Therapies: Alterations of Cell Signaling & the Kinome

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

Feeling the Heat – the Link between Inflammation and Cancer

Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Immunotherapy Resistance Rears Its Ugly Head: PD-1 Resistant Metastatic Melanoma and More

Novel Mechanisms of Resistance to Novel Agents

 

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NIMHD welcomes nine new members to the National Advisory Council on Minority Health and Health Disparities

Reporter: Stephen J. Williams, Ph.D.

The National Institute on Minority Health and Health Disparities (NIMHD) has announced the appointment of nine new members to the National Advisory Council on Minority Health and Health Disparities (NACMHD), NIMHD’s principal advisory board. Members of the council are drawn from the scientific, medical, and lay communities, so they offer diverse perspectives on minority health and health disparities.

The NACMHD, which meets three times a year on the National Institutes of Health campus, Bethesda, Maryland, advises the secretary of Health and Human Services and the directors of NIH and NIMHD on matters related to NIMHD’s mission. The council also conducts the second level of review of grant applications and cooperative agreements for research and training and recommends approval for projects that show promise of making valuable contributions to human knowledge.

The next meeting of the NACMHD will be held on Thursday, Sept. 10, 8:30 a.m.-5:00 p.m. on the NIH campus. The meeting will be available on videocast at http://www.videocast.nih.gov.

NIMHD Director Eliseo J. Pérez-Stable, M.D., is pleased to welcome the following new members

Margarita Alegría, Ph.D., is the director of the Center for Multicultural Mental Health Research at Cambridge Health Alliance and a professor in the department of psychiatry at Harvard Medical School, Boston. She has devoted her career to researching disparities in mental health and substance abuse services, with the goal of improving access to and equity and quality of these services for disadvantaged and minority populations.

Maria Araneta, Ph.D., a perinatal epidemiologist, is a professor in the Department of Family and Preventive Medicine at the University of California, San Diego. Her research interests include maternal/pediatric HIV/AIDS, birth defects, and ethnic health disparities in type 2 diabetes, regional fat distribution, cardiovascular disease, and metabolic abnormalities.

Judith Bradford, Ph.D., is director of the Center for Population Research in LGBT Health and she co-chairs The Fenway Institute, Boston. Dr. Bradford has participated in health research since 1984, working with public health programs and community-based organizations to conduct studies on lesbian, gay, bisexual, and transgender people and racial minority communities and to translate the results into programs to reduce health disparities.

Linda Burhansstipanov, Dr.P.H., has worked in public health since 1971, primarily with Native American issues. She is a nationally recognized educator on cancer prevention, community-based participatory research, navigation programs, cultural competency, evaluation, and other topics. Dr. Burhansstipanov worked with the Anschutz Medical Center Cancer Research Center — now the University of Colorado Cancer Research Center — in Denver for five years before founding Native American Cancer Initiatives, Inc., and the Native American Cancer Research Corporation.

Sandro Galea, M.D., a physician and epidemiologist, is the dean and a professor at the Boston University School of Public Health. Prior to his appointment at Boston University, Dr. Galea served as the Anna Cheskis Gelman and Murray Charles Gelman Professor and chair of the Department of Epidemiology at the Columbia University Mailman School of Public Health, New York City. His research focuses on the causes of brain disorders, particularly common mood and anxiety disorders, and substance abuse.

Linda Greene, J.D., is Evjue Bascom Professor of Law at the University of Wisconsin–Madison Law School. Her teaching and academic scholarship include constitutional law, civil procedure, legislation, civil rights, and sports law. Most recently, she was the vice chancellor for equity, diversity, and inclusion at the University of California, San Diego.

Ross A. Hammond, Ph.D., a senior fellow in the Economic Studies Program at the Brookings Institution, Washington, D.C., is also director of the Center on Social Dynamics and Policy. His primary area of expertise is using mathematical and computational methods from complex systems science to model complex dynamics in economic, social, and public health systems. His current research topics include obesity etiology and prevention, tobacco control, and behavioral epidemiology.

Hilton Hudson, II, M.D., is chief of cardiothoracic surgery at Franciscan Healthcare, Munster, Indiana and a national ambassador for the American Heart Association. He also is the founder of Hilton Publishing, Inc., a national publisher dedicated to producing content on solutions related to health, wellness, and education for people in underserved communities. Dr. Hilton’s book, “The Heart of the Matter: The African American Guide to Heart Disease, Heart Treatment and Heart Wellness” has impacted at-risk patients nationwide.

Brian M. Rivers, Ph.D., M.P.H., currently serves on the research faculty at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. He is also an assistant professor in the Department of Oncologic Sciences at the University of South Florida College of Medicine, Tampa. Dr. Rivers’ research efforts include examination of unmet educational and psychosocial needs and the development of communication tools, couple-centered interventions, and evidence-based methods to convey complex information to at-risk populations across the cancer continuum.

NIMHD is one of NIH’s 27 Institutes and Centers. It leads scientific research to improve minority health and eliminate health disparities by conducting and supporting research; planning, reviewing, coordinating, and evaluating all minority health and health disparities research at NIH; promoting and supporting the training of a diverse research workforce; translating and disseminating research information; and fostering collaborations and partnerships. For more information about NIMHD, visit http://www.nimhd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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