Melissa C. Austin, Christina Smith, Colin C. Pritchard, Jonathan F. Tait, (2015) DNA Yield From Tissue Samples in Surgical Pathology and Minimum Tissue Requirements for Molecular Testing. Archives of Pathology & Laboratory Medicine In-Press.

Early Online Release

DNA Yield From Tissue Samples in Surgical Pathology and Minimum Tissue Requirements for Molecular Testing

Melissa C. Austin, MD, MBS; Christina Smith, BS; Colin C. Pritchard, MD, PhD; Jonathan F. Tait, MD, PhD

Reprints: Melissa C. Austin, MD, MBS, Department of Pathology, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889 (e-mail: melissa.c.austin6.mil@mail.mil).

Context.— Complex molecular assays are increasingly used to direct therapy and provide diagnostic and prognostic information but can require relatively large amounts of DNA.

Objectives.— To provide data to pathologists to help them assess tissue adequacy and provide prospective guidance on the amount of tissue that should be procured.

Design.— We used slide-based measurements to establish a relationship between processed tissue volume and DNA yield by A₂₆₀ from 366 formalin-fixed, paraffin-embedded tissue samples submitted for the 3 most common molecular assays performed in our laboratory (EGFR, KRAS, and BRAF). We determined the average DNA yield per unit of tissue volume, and we used the distribution of DNA yields to calculate the minimum volume of tissue that should yield sufficient DNA 99% of the time.

Results.— All samples with a volume greater than 8 mm³ yielded at least 1 μg of DNA, and more than 80% of samples producing less than 1 μg were extracted from less than 4 mm³ of tissue. Nine square millimeters of tissue should produce more than 1 μg of DNA 99% of the time.

Conclusions.— We conclude that 2 tissue cores, each 1 cm long and obtained with an 18-gauge needle, will almost always provide enough DNA for complex multigene assays, and our methodology may be readily extrapolated to individual institutional practice.

JAMA. 2015 Nov 17;314(19):2088. doi: 10.1001/jama.2014.12098.

Women Physicians and the War.

"In the medical profession especially the demands of the military service have produced a deficiency in the supply of civilian practitioners which can be remedied only by utilizing the services of women physicians."

Doctors could be penalized for ordering prostate tests

"Medicare officials are considering a measure that would penalize doctors who order routine prostate-cancer screening tests for their patients, as part of a federal effort to define and reward quality in health-care services.

The proposal, which hasn’t been widely publicized, has prompted a flurry of last-minute comments to the Centers for Medicare and Medicaid Services, including more than 200 in the past two days, virtually all in opposition. The official comment period began Oct. 26 and ends Friday."

Am J Respir Crit Care Med. 2015 Nov 19. [Epub ahead of print]

Macrophages, Inflammation, and Lung Cancer.

Conway EM1, Pikor LA2, Kung SH3, Hamilton MJ4, Lam S5, Lam WL6, Bennewith KL7.

Author information

• 1British Columbia Cancer Research Centre, Integrative Oncology, Vancouver, British Columbia, Canada ; econway@bccrc.ca.
• 2British Columbia Cancer Research Centre, Integrative Oncology, Vancouver, British Columbia, Canada ; lpikor@bccrc.ca.
• 3British Columbia Cancer Research Centre, Integrative Oncology, Vancouver, British Columbia, Canada ; skung@bccrc.ca.
• 4British Columbia Cancer Research Centre, Integrative Oncology, Vancouver, British Columbia, Canada ; mhamilto@bccrc.ca.
• 5British Columbia Cancer Research Centre, Integrative Oncology, Vancouver, British Columbia, Canada ; slam@bccrc.ca.
• 6British Columbia Cancer Research Centre, Integrative Oncology , 675 West 10th Avenue , 10th floor , Vancouver, British Columbia, Canada , V5Z1L3 , 6046758000 ext 7716 , 6046758232 ; wanlam@bccrc.ca.
• 7British Columbia Cancer Research Centre, Integrative Oncology, Vancouver, British Columbia, Canada ; kbennewi@bccrc.ca.

Abstract

Lung cancer is the leading cause of cancer mortality worldwide, and at only 18%, has one of the lowest 5-year survival rates of all malignancies. With its highly complex mutational landscape, treatment strategies against lung cancer have proved largely ineffective. However with the recent success of immunotherapy trials in lung cancer, there is renewed enthusiasm in targeting the immune component of tumors. Macrophages make up the majority of the immune infiltrate in tumors and are a key cell type linking inflammation and cancer. Although the mechanisms through which inflammation promotes cancer are not fully understood, two connected hypotheses have emerged: an intrinsic pathway, driven by genetic alterations that lead to neoplasia and inflammation, and an extrinsic pathway, driven by inflammatory conditions that increase cancerrisk. Here, we discuss the contribution of macrophages to these pathways and subsequently their roles in established tumors. We highlight studies investigating the association of macrophages with lung cancer prognosis, and discuss emerging therapeutic strategies for targeting macrophages in the tumor microenvironment.

Byron York: Obamacare death spiral a gift to 2016 GOP candidates

By BYRON YORK (@BYRONYORK) • 11/19/15 5:35 PM

"The problem is pretty simple: Not enough Americans, and certainly not enough healthy Americans, are signing up for coverage through Obamacare. And they're not doing it because it's not a good deal for them."

"Even in his mid-eighties, Pavlov had not lost the capacity to expand his intellectual horizons..."

Pavlov’s parables

STEPHEN LOVELL

"Even in his mid-eighties, Pavlov had not lost the capacity to expand his intellectual horizons and to question his own assumptions, although he still exploded at others who dared to challenge him. If he had lived to be a hundred, as both he and the Soviet propaganda industry hoped, perhaps he would have become a Marxist, or at least the dialectical materialist that Pravda had claimed him to be on his eightieth birthday. It is certainly arguable that there was influence in the other direction: the Bolshevik ideal of remaking man through a variety of stimuli – from excitation (inspiration and incentives) to inhibition (terror) – was more than a little Pavlovian."

Psychol Sci. 2015 Nov 18. pii: 0956797615611922. [Epub ahead of print]

Virtues, Vices, and Political Influence in the U.S. Senate.

Ten Brinke L1, Liu CC2, Keltner D3, Srivastava SB4.

Author information

• 1Haas School of Business, University of California, Berkeley leannetenbrinke@berkeley.edu.
• 2Rotman School of Management, University of Toronto.
• 3Department of Psychology, University of California, Berkeley.
• 4Haas School of Business, University of California, Berkeley.

Abstract

What qualities make a political leader more influential or less influential? Philosophers, political scientists, and psychologists have puzzled over this question, positing two opposing routes to political power-one driven by human virtues, such as courage and wisdom, and the other driven by vices, such as Machiavellianism and psychopathy. By coding nonverbal behaviors displayed in political speeches, we assessed the virtues and vices of 151 U.S. senators. We found that virtuous senators became more influential after they assumed leadership roles, whereas senators who displayed behaviors consistent with vices-particularly psychopathy-became no more influential or even less influential after they assumed leadership roles. Our results inform a long-standing debate about the role of morality and ethics in leadership and have important implications for electing effective government officials. Citizens would be wise to consider a candidate's virtue in casting their votes, which might increase the likelihood that elected officials will have genuine concern for their constituents and simultaneously promote cooperation and progress in government.

Curr Opin Clin Nutr Metab Care. 2015 Nov 10. [Epub ahead of print]

The biology of the metabolic syndrome and aging.

Dominguez LJ1, Barbagallo M.

Author information

• 1Geriatric Unit, Department of Internal Medicine and Geriatrics, University of Palermo, Palermo, Italy.

Abstract

PURPOSE OF REVIEW:

Aging of the world population is a major contributor to the growing prevalence of the metabolic syndrome, as older persons are frequently affected by the constellation of cardiovascular and metabolic risk factors that constitute the syndrome. The metabolic syndrome has been related to the increasing prevalence of obesity, which is escalating even among older age groups. The present review covers data on the novel proposed biological mediators of the metabolic syndrome, which are as well linked to the aging process.

RECENT FINDINGS:

Relevant biological mediators of metabolic syndrome and unhealthy aging include sarcopenic obesity, insulin resistance with ectopic fat accumulation, magnesium metabolism alterations, systemic and hypothalamic inflammation, shortening of telomeres length, epigenetics, and circadian rhythm disturbances.

SUMMARY:

Metabolic syndrome is related to increased accumulation of central adiposity and ectopic fat infiltration in the skeletal muscle and the liver, linked to overeating and sedentarism with deleterious consequences in late life. Obesity may be complicated with sarcopenia, which refers to loss of muscle mass, strength, and quality in older populations. Prevention of obesity and metabolic syndrome is a priority through the promotion of healthier lifestyles and policies for sugar and saturated fats, which might be widely implemented.

J Health Polit Policy Law. 2015 Nov 13. pii: 3445601. [Epub ahead of print]

The Politics of Native American Health Care and the Affordable Care Act.

Skinner D1.

Author information

• 1Ohio University.

Abstract

This article examines an important but largely overlooked dimension of the Patient Protection and Affordable Care Act (ACA), namely its significance for Native American health care. The author maintains that reading the ACA against the politics of Native American health care policy shows that, depending on their regional needs and particular contexts, many Native Americans are well-placed to benefit from recent Obama-era reforms. At the same time, the kind of options made available by the ACA constitute a departure from the service-based (as opposed to insurance-based) Indian Health Service (IHS). Accordingly, the author argues that ACA reforms - private marketplaces, Medicaid expansion, as well as accommodations for Native Americans - are best read as potential "supplements" to an underfunded IHS. Whether or not Native Americans opt to explore options under the ACA will depend in the long run on the quality of the IHS in the post-ACA era. Beyond understanding the ACA in relation to IHS funding, the author explores how Native American politics interacts with the key tenets of Obama-era health care reform - especially "affordability" - which is critical for understanding what is required from and appropriate to future Native American health care policy making.

Public Health Genomics. 2015 Nov 20;18(6). [Epub ahead of print]

Charting the Course for a New Cancer Clinical Research Culture.

Tejpar S, Salgado R; Working Groups ‘Biomarker'' and ‘Clinical Trial Framework'' of the European Alliance for Personalised Medicine (EAPM).

Abstract

The convergence of new biological insights from sequencing, digital technologies and advanced bioinformatics tools are creating new opportunities to advance cancer care for individual patients. Fully realising this potential will require the integration and alignment of multiple stakeholders across the healthcare system. To increase the speed in which personalised medicine discoveries are translated into clinical practice and accessible to patients requires appropriately conducted clinical research with input and usage by patients, healthcare providers, regulatory authorities and policy makers. These stakeholders need to align in establishing the right evidence to facilitate clinical research and access to personalised treatments addressing the needs of targeted populations.

Health and wellness efforts: Stuck in neutral?

Nov 20, 2015by Sean Kilcarr in Trucks at Work

"That doesn’t bode well for trucking, where truck driver health issues can affect a whole host of operational metrics –especially safety.

Driven by ongoing concerns over worker stress (75%), obesity (70%) and sedentary lifestyles (61%), employer commitment to health and productivity remains strong, according to Towers Watson’s Staying@Work Survey, which polled 1,699 companies in North America, Latin America, Europe, the Middle East and Asia back in May and June this year."

Transpl Int. 2015 Nov 19. doi: 10.1111/tri.12720. [Epub ahead of print]

Ethical, legal and societal issues and recommendations for controlled and uncontrolled DCD.

Haase B1, Bos M2, Boffa C3, Lewis P4, Rudge C5, Valero R6, Wind T7, Wright L8.

Author information

• 1Dutch Transplant Foundation, the Netherlands.
• 2Health Council of the Netherlands.
• 3Oxford Transplant Center, Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom.
• 4King's College London, United Kingdom.
• 5Former Clinical Director for transplantation DoH, United Kingdom.
• 6Hospital Clinic de Barcelona, Spain.
• 7Maastricht University Medical Centre, the Netherlands.
• 8Toronto General Hospital, Canada.

Abstract

This report deals with organ retrieval procedures in both controlled and uncontrolled DCD, looking at the ethical, legal and psychosocial aspects during the different phases of the process. A recently published report by the UK Donation Ethics Committee (UKDEC) has served as an important reference document to outline the steps in the controlled DCD patient-donor pathway (1). For uncontrolled DCD the UKDEC pathway description was adapted. At the 6th International Conference in Organ Donation held in Paris in 2013 an established expert European Working Group reviewed the UKDEC reports, which were then considered along with the available published literature. Along this pathway the crucialethical, legal and psychosocial aspects have been flagged, and relevant recommendations have been formulated based on a consensus of the working group. 

Anja Roden and colleagues: Transbronchial Cryobiopsies in the Evaluation of Lung Allografts: Do the Benefits Outweigh the Risks?

Anja C. Roden, Ryan M. Kern, Marie Christine Aubry, Sarah M. Jenkins, Eunhee S. Yi, John P. Scott, and Fabien Maldonado (2015) Transbronchial Cryobiopsies in the Evaluation of Lung Allografts: Do the Benefits Outweigh the Risks?. Archives of Pathology & Laboratory Medicine In-Press.

Early Online Release

Transbronchial Cryobiopsies in the Evaluation of Lung Allografts: Do the Benefits Outweigh the Risks?

Anja C. Roden, MD; Ryan M. Kern, MD; Marie Christine Aubry, MD; Sarah M. Jenkins, MS; Eunhee S. Yi, MD; John P. Scott, MD;Fabien Maldonado, MD

Reprints: Anja C. Roden, MD, Division of Anatomic Pathology, Mayo Clinic Rochester, Hilton 11, 200 First St SW, Rochester, MN 55905 (e-mail: Roden.anja@mayo.edu).

Context.— Transbronchial cryobiopsy technique yields larger biopsies with enhanced quality. The benefits and safety of cryobiopsies have not been thoroughly studied in lung allografts.

Objective. —To compare size, quality, reproducibility of interpretation of rejection and complications of cryobiopsies with those of conventional biopsies from lung allografts.

Design.— All cryobiopsies (March 2014–January 2015) of lung allografts performed at Mayo Clinic, Rochester, and medical records were reviewed. For comparison, conventional biopsies from the same patient or, if unavailable, from a random patient, were selected. Two pathologists blinded to outcome reviewed all biopsies. Specimen volume, number of alveoli, small airways, and pulmonary vessels were counted and statistically compared.

Results. —Fifty-four biopsies (27 cryobiopsies) from 18 patients (11 men) were reviewed. A median of 3 (range, 2–5) and 10 (range, 6–12) specimens were obtained with cryobiopsies and conventional biopsies, respectively. Cryobiopsies were larger and contained more alveoli (P < .001, both) and small airways (P = .04). Conventional biopsies showed more fresh alveolar hemorrhage (procedural) and crush artifact/atelectasis (P < .001, both). Cryobiopsies contained more pulmonary veins and venules (P < .001). There was no significant difference between the types of biopsies with respect to the reviewers' agreement on grades of rejection. Complications were more frequent in the cryobiopsy group, though the difference was not statistically significant.

Conclusions.— Cryobiopsies of lung allografts are larger and have less artifact. However, complications occur and should be considered. Three cryobiopsy specimens appear sufficient for histopathologic evaluation of lung allografts.

Probably too good to be true

The Scientific Case for Eating All the Pizza You Damn Well Please

http://www.maxim.com/maxim-man/article/scientific-case-pizza-2015-11

If not all, at least more than you think. 

"Stop the burpees, put down the kettlebell, spit out that paleo-approved bison jerky —s cience is here to piss you off with contrary news yes again. Research published by scientists tackling issues surrounding weight gain have come to the irritating possibility that having a little extra padding might actually protect your health, and that eating too much on a date might actually help you look a little more attractive to your would-be lover. While obviously morbid obesity is horrific, occaisionally pigging out on pizza might be just fine, and even good for you to boot."

Bryan Liang and me: Pathologists and Liability: An Old Medical Story Needing a New Ending

Am J Clin Pathol. 2015 Dec;144(6):828-9. doi: 10.1309/AJCP7R6XVXOEPFAH.

Pathologists and Liability: An Old Medical Story Needing a New Ending.

Allen TC1, Liang BA2.

Author information

• 1From the Department of Pathology, The University of Texas Medical Branch, Galveston; and.
• 2Global Health Policy Institute, University of California-San Diego, La Jolla.

Key molecular players in obesity-associated type 2 diabetes identified

"The researchers quantified inflammatory proteins from blood immune system cells and combined the measurements mathematically to identify dominant inflammatory proteins. Specifically, they identified Th17 cells, known to be involved in autoimmune diseases, as a dominant cell type in Type 2 diabetes.

The researchers also demonstrated that another important immune cell, Th1, may be involved in the glycemic control aspect of Type 2 diabetes. "This newly identified fingerprint of inflammation relative to different traits of Type 2 diabetes may be an important new biomarker to predict the 75 percent of people with obesity who will become Type 2 diabetic, versus the 25 percent of people with obesity who remain metabolically healthy," explained Barbara Nikolajczyk, PhD, associate professor of microbiology at BUSM."

Miao Crystal Yu, R. Marshall Austin, Jeff Lin, Tiffany Beck, Sushil Beriwal, John T. Comerci, Robert P. Edwards, Paniti Sukumvanich, Joseph Kelley, and Alexander B. Olawaiye (2015) The Role of High-Risk Human Papilloma Virus Testing in the Surveillance of Cervical Cancer After Treatment. Archives of Pathology & Laboratory Medicine: November 2015, Vol. 139, No. 11, pp. 1437-1440.

ORIGINAL ARTICLES

The Role of High-Risk Human Papilloma Virus Testing in the Surveillance of Cervical Cancer After Treatment

Miao Crystal Yu, MD; R. Marshall Austin, MD, PhD; Jeff Lin, MD; Tiffany Beck, MD; Sushil Beriwal, MD; John T. Comerci, MD; Robert P. Edwards, MD; Paniti Sukumvanich, MD; Joseph Kelley, MD; Alexander B. Olawaiye, MD

From the Departments of Gynecology Oncology (Drs Yu, Lin, Comerci, Edwards, Sukumvanich, Kelley, and Olawaiye), Pathology (Dr Austin), and Radiation Oncology (Dr Beriwal), Magee-Women's Hospital, Pittsburgh, Pennsylvania; and the Department of Gynecology Oncology, University of Washington, Seattle (Dr Beck).

Reprints: Alexander B. Olawaiye, MD, Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Magee-Women's Hospital of UPMC, 300 Halket St, Pittsburgh, PA 15213 (e-mail: olawaiyea@mail.magee.edu).

The authors have no relevant financial interest in the products or companies described in this article.

Context.— Cervical cancer affects 12 000 women in the United States annually. However, despite its prevalence, there remains no good methodology to detect its recurrence.

Objective.— To identify the role of cervicovaginal high-risk human papilloma virus (hr-HPV) testing in predicting cervical cancer recurrence.

Design.— This is a retrospective study of patients who underwent hr-HPV testing as part of their routine surveillance for cervical cancer. Standard statistical analyses, including χ² test and multivariable logistic regression, were performed with IBM SPSS 19.0.

Results.— A total of 133 patients were identified, of whom 107 (80%) had squamous cell carcinoma. Ninety patients (68%) had bulky disease and were treated primarily with chemoradiation and brachytherapy. Of patients whose disease recurred, 5 patients (42%) had tested positive for hr-HPV during their surveillance period, compared to 13 patients (11%) for whom disease did not recur (relative risk: 3.88, P = .002). On multivariate logistic regression, hr-HPV status remained significantly predictive of disease recurrence (odds ratio: 12.3, P = .02, 95% confidence interval: 1.5–99.6). Using 2 × 2 table analysis, we found that while cervicovaginal cytology has limited specificity (5.7%) in predicting recurrence, the combination of cytology with hr-HPV testing increases the specificity of testing to 89.3%.

Conclusions.— Persistence of hr-HPV is a risk factor for disease recurrence. High-risk–HPV testing is not routinely used during surveillance for cervical cancer, but this study suggests that large, prospective trials investigating the role of hr-HPV testing in cervical cancer surveillance are needed.

Debra Leonard and colleagues: Standards for Clinical Grade Genomic Databases

Sophia L. Yohe, Alexis B. Carter, John D. Pfeifer, James M. Crawford, Allison Cushman-Vokoun, Samuel Caughron, and Debra G. B. Leonard (2015) Standards for Clinical Grade Genomic Databases. Archives of Pathology & Laboratory Medicine: November 2015, Vol. 139, No. 11, pp. 1400-1412.

CAP LABORATORY IMPROVEMENT PROGRAMS

Standards for Clinical Grade Genomic Databases

Sophia L. Yohe, MD; Alexis B. Carter, MD; John D. Pfeifer, MD, PhD; James M. Crawford, MD, PhD; Allison Cushman-Vokoun, MD, PhD; Samuel Caughron, MD; Debra G. B. Leonard, MD, PhD

From the Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis (Dr Yohe); the Department of Pathology and Laboratory Medicine and the Department of Biomedical Informatics, Emory University, Atlanta, Georgia (Dr Carter); the Department of Pathology, Washington University School of Medicine, St. Louis, Missouri (Dr Pfeifer); the Department of Pathology and Laboratory Medicine, Hofstra North Shore–Long Island Jewish School of Medicine, Hempstead, New York (Dr Crawford); the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha (Dr Cushman-Vokoun); the MAWD Pathology Group, North Kansas City, Missouri (Dr Caughron); and the Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington (Dr Leonard).

Reprints: Sophia L. Yohe, MD, Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, MMC 609 Mayo Bldg, 420 Delaware St SE, Minneapolis, MN 55455 (e-mail: yohe0001@umn.edu).

The authors have no relevant financial interest in the products or companies described in this article.

Supplemental digital content is available for this article at www.archivesofpathology.org in the November 2015 table of contents.

Context.— Next-generation sequencing performed in a clinical environment must meet clinical standards, which requires reproducibility of all aspects of the testing. Clinical-grade genomic databases (CGGDs) are required to classify a variant and to assist in the professional interpretation of clinical next-generation sequencing. Applying quality laboratory standards to the reference databases used for sequence-variant interpretation presents a new challenge for validation and curation.

Objectives.— To define CGGD and the categories of information contained in CGGDs and to frame recommendations for the structure and use of these databases in clinical patient care.

Design.— Members of the College of American Pathologists Personalized Health Care Committee reviewed the literature and existing state of genomic databases and developed a framework for guiding CGGD development in the future.

Results.— Clinical-grade genomic databases may provide different types of information. This work group defined 3 layers of information in CGGDs: clinical genomic variant repositories, genomic medical data repositories, and genomic medicine evidence databases. The layers are differentiated by the types of genomic and medical information contained and the utility in assisting with clinical interpretation of genomic variants. Clinical-grade genomic databases must meet specific standards regarding submission, curation, and retrieval of data, as well as the maintenance of privacy and security.

Conclusion.— These organizing principles for CGGDs should serve as a foundation for future development of specific standards that support the use of such databases for patient care.

Patricia Kandalaft and Allen Gown: Practical Applications in Immunohistochemistry: Carcinomas of Unknown Primary Site

Patricia L. Kandalaft and Allen M. Gown (2015) Practical Applications in Immunohistochemistry: Carcinomas of Unknown Primary Site. Archives of Pathology & Laboratory Medicine In-Press.

doi: http://dx.doi.org/10.5858/arpa.2015-0173-CP

Early Online Release

Practical Applications in Immunohistochemistry: Carcinomas of Unknown Primary Site

Patricia L. Kandalaft, MD; Allen M. Gown, MD

Reprints: Patricia L. Kandalaft, MD, Department of Immunohistochemistry and Anatomic Services, Pacific Pathology Partners, 550 17th Ave, Ste 300, Seattle, WA 98122 (e-mail: pkandalaft@pacificpathologypartners.com).

Context.— Identification of the site of origin of carcinoma of unknown primary using immunohistochemistry is a frequent requirement of anatomic pathologists. Diagnostic accuracy is crucial, particularly in the current era of targeted therapies and smaller sample sizes.

Objectives.— To provide practical guidance and suggestions for classifying carcinoma of unknown primary using both proven and new antibodies, as well as targeting panels based on integration of morphologic and clinical features.

Data Sources.— Literature review, the authors' practice experience, and authors' research.

Conclusions.— With well-performed and interpreted immunohistochemistry panels, anatomic pathologists can successfully identify the site of origin of carcinoma of unknown primary. It is crucial to understand not only the diagnostic uses of the many available antibodies but also the potential limits and pitfalls.

"An effective core would produce an adaptable, resilient pathologist and allow the resident more time to develop advanced diagnostic skills in particular areas of pathology, thereby reducing the impression that multiple fellowships are needed."

Michael B. Prystowsky (2015) The People Have Spoken—Are Pathologists Listening?. Archives of Pathology & Laboratory Medicine In-Press.

Early Online Release

The People Have Spoken—Are Pathologists Listening?

Michael B. Prystowsky, MD, PhD

From the Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.

"Currently, we are afforded moderate flexibility by the ABP to redesign our training programs. In concept, the elements of a core (described above) will give a strong foundation for diagnostic skills together with the much needed skills to practice in an interdisciplinary health care team. An effective core would produce an adaptable, resilient17 pathologist and allow the resident more time to develop advanced diagnostic skills in particular areas of pathology, thereby reducing the impression that multiple fellowships are needed. Certainly we would need to develop new metrics to assess the effectiveness of any new training programs. In addition, as such programs take hold, the ABP might need to adapt its requirements for certification."

Ann Oncol. 2015 Nov 16. pii: mdv550. [Epub ahead of print]

Challenges of Phase 1 Clinical Trials evaluating Immune Checkpoint Targeted Antibodies.

Postel-Vinay S1, Aspeslagh S2, Lanoy E3, Robert C4, Soria JC5, Marabelle A6.

Author information

• 1DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif, France Faculty of Medicine, Université Paris Saclay, Université Paris-Sud, Paris, France Inserm Unit U981, Gustave Roussy, Villejuif, France sophie.postel-vinay@gustaveroussy.fr.
• 2DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif, France.
• 3Biostatistics and Epidemiology unit, Gustave-Roussy, Villejuif, France; Inserm Unit U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
• 4Faculty of Medicine, Université Paris Saclay, Université Paris-Sud, Paris, France Inserm Unit U981, Gustave Roussy, Villejuif, France Department of Medical Oncology, Gustave Roussy, Villejuif, France.
• 5DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif, France Faculty of Medicine, Université Paris Saclay, Université Paris-Sud, Paris, France Inserm Unit U981, Gustave Roussy, Villejuif, France.
• 6DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif, France Inserm Unit U1015, Gustave Roussy, Villejuif, France.

Abstract

BACKGROUND:

Immunostimulatory monoclonal antibodies (imAbs) targeting immune checkpoint molecules are revolutionizing oncology not only regarding cancer therapeutics and clinical care, but also from a drug development point of view. A handful of first-generation molecules have been approved so far based on their tremendous efficacy, after an expedited development phase that has challenged most paradigms established in the era of conventional cytotoxic therapy and to some extent molecularly targeted agents. A huge wave of second-generation imAbs is just entering into phase 1 trials now, in monotherapy or in combination. In order to maximize their chances of success in early phase trials, and eventually for patients' benefit. their clinical development has to benefit from lessons learnt from previous imAbs phase 1 trials.

METHODS:

We reviewed the early clinical development of anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and anti-Programmed Death-1 Receptor (PD-1)/ligand (PD-L1). Particularities of each agent, including safety, dose-toxicity and dose-efficacy relationships, scheduling, pharmacokinetics, pharmacodynamics, trial design, biomarkers, response assessment and overall drug development strategies are described and challenged.

RESULTS:

As opposed to conventional cytotoxic agents, dose of imAbs is not linearly associated with efficacy and toxicity. Therefore, the definition of a minimal immunologically active dose (MIAD) could be proposed. Traditional patient eligibility criteria might also be revisited, as the toxicity profile and mechanism of toxicity - immune-related adverse events - are mostly known and somehow less unexpected than with molecularly targeted small molecules. Most challenging are the comprehensive investigation of complex pharmacokinetics and pharmacodynamics characteristics as well as the definition of patient selection biomarkers. Finally, the early focus on efficacy (and not only dose-confirmation) in expansion cohorts challenges the traditional phase 1 / 2 / 3 drug development process.

CONCLUSION:

Several drug development paradigms have been challenged by imAbs. Here we discuss novel approaches for an efficient and successful drug development of these agents.

"When students leave my classroom, any classroom, they have to and should face the real world, the best and worst of it."

The Seduction of Safety, on Campus and Beyond

Roxane Gay NOV. 13, 2015

"Rather than use trigger warnings, I try to provide students with the context they will need to engage productively in complicated discussions. I consider my classroom a safe space in that students can come as they are, regardless of their identities or sociopolitical affiliations. They can trust that they might become uncomfortable but they won’t be persecuted or judged. They can trust that they will be challenged but they won’t be tormented.

When students leave my classroom, any classroom, they have to and should face the real world, the best and worst of it. I can only hope they are adequately prepared to navigate the world as it is rather than how we wish it could be. But I also hope they are both realistic and idealistic. I hope that, like me, they search for safety, or work to create a world where some measure of safety, not to be confused with anything as infantile as coddling, is an inalienable right."