3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

The Patient-Physician Relationship: Medical Students' Perceptions in a Novel Course.

The patient-physician relationship, especially in the case of severely ill patients, is often fraught with anxiety, grief, and guilt in the physician who may come to feel that he or she has failed the patient and thereby becomes a "second victim." This notion was first explored in a 1973 publication (Artiss and Levine N Engl J Med 288(23):1210-4, 1973) that described a novel interactive seminar series for oncology fellows that had been designed to address and possibly remedy the frequent disquiet experienced by young physicians in this setting. Fifty years later, the medical student co-authors of this Perspective enrolled in an elective course that comprised a similar series of interactive seminars, now addressing the contemporary patient-physician relationship. The earlier paper was employed as a historical background, and the framework of the course then broadened such that the students considered the current environmental changes in medical practice (social, cultural, financial, legal, policy) that may be linked to the character of individual patient-physician relationships. This essay reports on the students' perception of such relationships, and on the environmental elements that may be helpful or harmful to the well-being of both patients and physicians.

Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions.

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS, but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of the analyzed PanINs contained multiple KRAS mutations, suggesting a polyclonal origin even in PanINs that are contiguous by rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe, for the first time, the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia.

Common Patient-Reported Outcomes Within the Food and Drug Administration Voice of the Patient Reports.

OBJECTIVES: Proponents of disease-specific patient-reported outcome measurements (PROMs) often argue disease-agnostic measures do not adequately capture their patient population's experience. Patient-Reported Outcomes Measurement Information System (PROMIS) provides a disease-agnostic domain set that may adequately cover many diseases. This study seeks to investigate whether PROMIS's quality of life domain coverage can span patient-reported outcomes (PROs) elicited from patients across unrelated diseases. METHODS: The Food and Drug Administration Voice of the Patient reports were an initiative to elevate patient voices regarding their condition and associated treatments. Two reviewers extracted patient-reported health-related (quality of life) domains from the reports and categorized them into PROMIS domains or non-PROMIS domains. Domain coverage was summarized for each report. Any extracted PROs not covered by PROMIS domains were placed in an "other" category and analyzed for common themes. RESULTS: Across 26 reports, PROMIS covered 216 of 374 (70%) of the reports' PRO domains. The heritable bleeding disorders report had the highest coverage (82%). Human immunodeficiency virus had the lowest coverage (50%). The most common PROMIS domain, "ability to participate in social roles," appeared in 25 reports (96%). The most common domains not included in PROMIS were stigma, sensitivities, and sensory deficits as evident in 19 (73%), 18 (69%), and 18 reports (69%), respectively. If the top 3 unincluded domains were amended into PROMIS, the total domain coverage would increase to 84%. CONCLUSIONS: PRO domains elicited in the Food and Drug Administration Voice of the Patient reports were widely captured by PROMIS, suggesting domains patients experience contain enough overlap to be recorded by appropriate PROMIS domains. PROMIS could increase its coverage by adding domains.