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Pancreatic ductal adenocarcinoma (PDAC) is a lethal aggressive cancer, in part due to elements of the microenvironment (hypoxia, hypoglycemia) that cause metabolic network alterations. The FDA-approved antihelminthic pyrvinium pamoate (PP) has previously been shown to cause PDAC cell death, although the mechanism has not been fully determined. We demonstrated that PP effectively inhibited PDAC cell viability with nanomolar IC50 values (9-93 nmol/L) against a panel of PDAC, patient-derived, and murine organoid cell lines. In vivo , we demonstrated that PP inhibited PDAC xenograft tumor growth with both intraperitoneal (IP; P < 0.0001) and oral administration (PO; P = 0.0023) of human-grade drug. Metabolomic and phosphoproteomic data identified that PP potently inhibited PDAC mitochondrial pathways including oxidative phosphorylation and fatty acid metabolism. As PP treatment reduced oxidative phosphorylation ( P < 0.001), leading to an increase in glycolysis ( P < 0.001), PP was 16.2-fold more effective in hypoglycemic conditions similar to those seen in PDAC tumors. RNA sequencing demonstrated that PP caused a decrease in mitochondrial RNA expression, an effect that was not observed with established mitochondrial inhibitors rotenone and oligomycin. Mechanistically, we determined that PP selectively bound mitochondrial G-quadruplexes and inhibited mitochondrial RNA transcription in a G-quadruplex-dependent manner. This subsequently led to a 90% reduction in mitochondrial encoded gene expression. We are preparing to evaluate the efficacy of PP in PDAC in an IRB-approved window-of-opportunity trial (IND:144822)., (©2021 American Association for Cancer Research.)

Purpose: Neutropenia is a serious complication of chemotherapy in patients with solid tumors. The influence of hospital volume on outcomes in patients with neutropenia has been little investigated. We hypothesized that large-volume hospitals would have reduced mortality rates for neutropenic patients compared with small-volume institutions., Methods: We used the Nationwide Inpatient Sample database of the Healthcare Cost and Utilization Project, for the years 2007-2011. All adult inpatient episodes with a diagnosis of both neutropenia and solid-tumor malignancy were included. Hospital volume was defined as the number of neutropenic cancer episodes per institution per year. Mortality was defined as death during admission. A multilevel mixed-effects logistic regression model was applied., Results: Twenty thousand three hundred and ten hospitalizations were included in the study, from 1,869 different institutions. Median age was 62 years. The overall inpatient mortality was 2.3%, and was dependent on age (age 50-59 years-1.6% and age 80-89 years-5.3%). The median number of neutropenic inpatient episodes in each institution per year was 14 (range, 1-168). Mortality was 3.3%, 2.7%, 2.2%, 2.2%, and 1.2% for each quintile of hospital volume (from lowest to highest volume, P < .001). Likewise, the proportion discharged home was 85.7%, 90.3%, 91.5%, 92.7%, and 95.4% ( P < .001). The association between hospital volume and mortality remained significant after adjustment for patient-level and hospital-level variables., Discussion: Patients with neutropenia hospitalized in large-volume institutions have a substantially lower mortality compared with those hospitalized at low-volume institutions. Further study is required to validate our findings or overcome potential biases, understand mechanism, and investigate how smaller institutions can improve outcomes., Competing Interests: Damien UrbanHonoraria: Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, Takeda, AstraZenecaConsulting or Advisory Role: Merck Sharp & Dohme, Takeda, Teva, Roche IsraelTravel, Accommodations, Expenses: Boehringer Ingelheim, Takeda, Merck Sharp & Dohme Ofer MargalitEmployment: RocheResearch Funding: Checkmate PharmaceuticalsTravel, Accommodations, Expenses: Merck Serono Talia GolanHonoraria: MSD, Rafael PharmaceuticalsConsulting or Advisory Role: AbbVie, AstraZeneca, Bayer, MSD, TevaSpeakers' Bureau: AbbVie, AstraZenecaResearch Funding: AstraZeneca, MSDTravel, Accommodations, Expenses: AstraZeneca, MSD Yaacov Richard LawrenceHonoraria: Bristol-Myers SquibbConsulting or Advisory Role: Clinigen Group, Roche/GenentechResearch Funding: Karyopharm Therapeutics, Checkmate Pharmaceuticals, Bristol-Myers Squibb, Merck SeronoTravel, Accommodations, Expenses: PfizerNo other potential conflicts of interest were reported.

Purpose: Germline BRCA1 and/or BRCA2 mutations (gBRCAms) are risk factors for pancreatic cancer. The extent to which demographic and geographic factors affect the uptake of gBRCAm testing in pancreatic cancer (PC) is unknown., Methods: We conducted a retrospective, descriptive analysis of demographic/geographic data from the first 2,206 patients with metastatic PC (mPC) screened for eligibility to enter the phase III POLO trial of maintenance olaparib. No formal statistical tests were performed., Results: Of 2,167 patients with previously unknown gBRCAm status, 128 (5.9%) had a newly identified gBRCAm; rates were highest in the United States, France, and Israel (9.5%, 7.6%, and 7.4%, respectively). When including patients with a previously known gBRCAm, prevalence rose to 7.2% (or 5.8% after excluding populations enriched in Ashkenazi Jews, who are known to have a high rate of BRCA1 and BRCA2 founder mutations). Patients with a gBRCAm were slightly younger (57.9 v 61.1 years) and more likely to have early-onset mPC than those without. Higher newly identified gBRCAm prevalence was observed among African American (n = 28) versus white (n = 1,808), Asian (n = 218), and other (n = 61) patients (10.7% v 6.1%, 5.0%, and 1.6%, respectively). Of 139 white patients with a gBRCAm, 110 were newly identified during screening; the majority of gBRCAms in African American, Asian, and Hispanic patients (n = 3, n = 11, and n = 5, respectively) were newly identified., Conclusion: We identified substantial geographic and some racial variability in gBRCAm prevalence among patients with mPC, an important consideration given the increased use of familial screening and possible future use of targeted therapies in this setting. Although our study included small numbers of nonwhite patients, prior knowledge of their gBRCAm status was limited compared with their white counterparts, which suggests disparities in genetic testing uptake.

Background: Over the past 2 decades, significant progress has been made in the field of metastatic colorectal cancer (mCRC) regarding new imaging techniques, surgical interventions, and systemic therapy. It is not known whether the benefit from these interventions has extended overall survival (OS) within the general mCRC population. A population-based survival analysis of newly diagnosed patients who presented with mCRC was therefore performed., Methods: Survival statistics were extracted from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with mCRC between 1988 and 2008. Demographic variables collected included age, race, and tumor grade. Survival was analyzed using the Kaplan-Meier method and extended Cox proportional hazard model as appropriate., Results: The study population consisted of 42,347 patients diagnosed with mCRC between 1988 and 2008 (52% women; mean age, 67 years). The 1- and 2-year estimated OS rates were 44% and 22%, respectively. Prognostic variables included race, sex, age, tumor location, and year of diagnosis. Median OS improved from 8 months to 14 months between 1988 and 2008. Significant improvements in OS were seen for all disease sites, but especially for descending colon cancers. Whereas the median OS increased by 13 months in patients ≤50 years of age and by 7 months in patients 51-70 years of age, the median OS of patients >70 years of age increased by only 1 month between 1988 and 2008., Conclusions: There has been a continuous improvement in OS of patients diagnosed with mCRC between 1988 and 2008, especially for left-sided tumors. Little improvement has been seen in patients over 70 years of age., (Copyright © 2013 American Cancer Society.)

The late 19th-century discovery of X-rays befuddled not only the scientific world but also the medical and legal worlds. The possibility of looking into the human body as if through an open window challenged the time-honored medical monopoly over the inner cavities of the human body. Likewise, the possibility of visualizing objects unavailable to the naked eye challenged the established legal theories and practices of illustration and proof. This paper describes the reactions to those challenges by the medical and the legal professions in the USA. The two professions are treated as connected social institutions, producing ongoing negotiations through which legal doctrines affect medicine no less than scientific discoveries and medical applications affect the law. This joint analysis rewards us with a rich story about an early and overlooked chapter in X-ray history on the professionalization of radiology, the origins of defensive medicine, and the evolution of the legal theory and practice of visual evidence.