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Background: Histological response to treatment is an important outcome in patients with ulcerative colitis (UC). The accuracy of biopsy-based measurements of inflammation may be limited by error imposed by natural microscopic heterogeneity on the scale of individual biopsies. We determined the magnitude of this error, its histological correlates, and the density of biopsy sampling within mucosal regions of interest required to meet specified benchmarks for accuracy., Methods: A total of 994 sequential 1-mm digital microscopic images (virtual biopsies) from consecutive colectomies from patients with clinically severe UC were scored by 2 pathologists. Agreement statistics for Geboes subscores and Nancy (NHI) and Robarts Histological Indices (RHI) between random samples from 1 to 10 biopsies and a reference mean score across a 2-cm region of mucosa were calculated using bootstrapping with 2500 iterations., Results: The agreement statistics improved across all indices as the biopsy density increased, with the largest proportional gains occurring with addition of the second and third biopsies. One biopsy achieved moderate to good agreement with 95% confidence for NHI and RHI corresponding to scale-specific errors of 0.40 (0.25-0.66) and 3.02 (2.08-5.36), respectively; and 3 biopsies achieved good agreement with 95% confidence corresponding to scale-specific errors of 0.22 (0.14-0.39) and 1.87 (1.19-3.25), respectively. Of the individual histological features, erosions and ulcers had the greatest impact on the agreement statistics., Conclusions: In the setting of active colitis, up to 3 biopsy samples per region of interest may be required to overcome microscopic heterogeneity and ensure accurate histological grading., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The oncologic outcomes for atypical meningiomas can be poor. Generally, patients that have had a prior recurrence have a substantially elevated risk of a future recurrence. Additionally, certain tumor genomic profiles have been shown as markers of poor prognosis. We sought to characterize the genomic differences between primary and recurrent tumors as well as assess if those differences had implications on recurrence., Methods: We identified primary and recurrent gross totally resected WHO grade II meningiomas with > 30 days of post-surgical follow-up at our institution. For genes with a prevalence of > 5% in the cohort, we compared the mutational prevalence in primary and recurrent tumors. For a gene of interest, we assessed the time to radiographic recurrence using adjusted cox-regression., Results: We identified 88 meningiomas (77 primary, 16 recurrent) with a median follow-up of 5.33 years. Mutations in ARID1A found in association with recurrent tumors (7/16 recurrent tumors vs 5/72 primary tumors, p < 0.001). In the whole cohort, mutations in ARID1A were not associated with alterations in time to recurrence after adjusting for recurrence status (p = 0.713). When restricted to primary tumors, ARID1A is associated with a 625% increase in the hazard of recurrence (HR = 7.26 [1.42-37.0]; p = 0.017)., Conclusion: We demonstrate mutations in ARID1A, a chromatin remodeling gene, in a higher prevalence in recurrent tumors. We further demonstrate that when mutations in ARID1A are present in primary atypical meningiomas, these tumors tend to have worse prognosis. Further prospective study may validate ARID1A as a prognostic marker., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Meningiomas occur more frequently in older adults, with the incidence rates increasing from 5.8/100,000 for adults 35-44 years old to 55.2/100,000 for those 85+. Due to the increased risk of surgical management in older adults, there is a need to characterize the risk factors for aggressive disease course to inform management decisions in this population. We therefore sought to determine age-stratified relationships between tumour genomics and recurrence after resection of atypical meningiomas., Methods: We identified 137 primary and recurrent Grade 2 meningiomas from our existing meningioma genomic sequencing database. We examined the differential distribution of genomic alterations in those older than 65 compared to younger. We then performed an age stratified survival analysis to model recurrence for a mutation identified as differentially present., Results: In our cohort of 137 patients with grade 2 meningiomas, alterations in NF2 were present at a higher rate in older adults compared to younger (37.8% in < 65 vs. 55.3% in > 65; recurrence adjusted p-value =0.04). There was no association between the presence of NF2 and recurrence in the whole cohort. In the age-stratified model for those less than 65 years old, there was again no relationship. For patients in the older age stratum, there is a relationship between NF2 and worsened recurrence outcomes (HR = 3.64 (1.125 - 11.811); p  = 0.031)., Conclusions: We found that mutations in NF2 were more common in older adults. Further, the presence of mutant NF2 was associated with an increased risk of recurrence in older adults.

Purpose: High grade meningiomas have a prognosis characterized by elevated recurrence rates and radiation resistance. Recent work has highlighted the importance of genomics in meningioma prognostication. This study aimed to assess the relationship between the most common meningioma genomic alteration (NF2) and response to postoperative radiation therapy (RT)., Methods: From an institutional tissue bank, grade 2 and 3 recurrent meningiomas with both > 30 days of post-surgical follow-up and linked targeted next-generation sequencing were identified. Time to radiographic recurrence was determined with retrospective review. The adjusted hazard of recurrence was estimated using Cox-regression for patients treated with postoperative RT stratified by NF2 mutational status., Results: Of 53 atypical and anaplastic meningiomas (29 NF2 wild-type, 24 NF2 mutant), 19 patients underwent postoperative RT. When stratified by NF2 wild-type, postoperative RT in NF2 wild-type patients was associated with a 78% reduction in the risk of recurrence (HR 0.216; 95%CI 0.068-0.682; p = 0.009). When stratified by NF2 mutation, there was a non-significant increase in the risk of recurrence for NF2 mutant patients who received postoperative RT compared to those who did not (HR 2.43; 95%CI 0.88-6.73, p = 0.087)., Conclusion: This study demonstrated a protective effect of postoperative RT in NF2 wild-type patients with recurrent high grade meningiomas. Further, postoperative RT may be associated with no improvement and perhaps an accelerated time to recurrence in NF2 mutant tumors. These differences in recurrence rates provide evidence that NF2 may be a valuable prognostic marker in treatment decisions regarding postoperative RT. Further prospective studies are needed to validate this relationship., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Meningiomas are common intracranial tumors with variable prognoses not entirely captured by commonly used classification schemes. We sought to determine the relationship between meningioma mutations and oncologic outcomes using a targeted next-generation sequencing panel., Materials and Methods: We identified 184 grade I and II meningiomas with both >90 days of post-surgical follow-up and linked targeted next-generation sequencing. For mutated genes in greater than 5% of the sample, we computed progression-free survival Cox-regression models stratified by gene. We then built a multi-gene model by including all gene predictors with a p -value of less than 0.20. Starting with that model, we performed backward selection to identify the most predictive factors., Results: ATM (HR = 4.448; 95% CI: 1.517-13.046), CREBBP (HR = 2.727; 95% CI = 1.163-6.396), and POLE (HR = 0.544; HR = 0.311-0.952) were significantly associated with alterations in disease progression after adjusting for clinical and pathologic factors. In the multi-gene model, only POLE remained a significant predictor of recurrence after adjusting for the same clinical covariates. Backwards selection identified recurrence status, resection extent, and mutations in ATM (HR = 7.333; 95% CI = 2.318-23.195) and POLE (HR = 0.413; 95% CI = 0.229-0.743) as predictive of recurrence., Conclusions: Mutations in ATM and CREBBP were associated with accelerated meningioma recurrence, and mutations in POLE were protective of recurrence. Each mutation has potential implications for treatment. The effect of these mutations on oncologic outcomes and as potential targets for intervention warrants future study., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare.

Background: Among patients with limited ulcerative colitis (UC), 30% ultimately extend to pancolitis and are at increased risk of adverse clinical outcomes. Risk of endoscopic extension has been found to correlate with clinical features such as early age of onset., Aims: We sought to determine whether histologic features correlate with disease extension., Methods: The study population consisted of 40 patients with UC from two large academic centers diagnosed between 2006 and 2017. Eligible cases had a diagnosis of endoscopically limited UC (Montreal E1 or E2) at baseline and ≥ 2 subsequent endoscopic examinations with biopsies. Severity of inflammation was scored using both the Mount Sinai Activity Index and Nancy Histological Index., Results: Patients were divided into two cohorts: those who progressed to pancolitis (Montreal E3) were defined as "Extenders" (n = 21), whereas "Non-extenders" (n = 19) were cases without progression in the follow-up period. The median follow-up time was 58.4 months. The histologic scores in the endoscopically involved mucosa of the index biopsies were not associated with subsequent extension of disease, overall. However, among extender cohort, the index histology scores correlated with biopsy scores at extension (r = 0.455, P = 0.044) and index severity was associated with a shorter time to extension (r =  - 0.611, P = 0.003). Furthermore, female patients had a shorter time to extension (P = 0.013)., Conclusions: Histological severity of limited UC is not an independent predictor of extension in UC. However, among patients who subsequently extend, severe inflammation at baseline correlates with shorter progression time and severe inflammation when extension occurs. Patients with limited UC but severe histologic inflammation may warrant more frequent endoscopic surveillance., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Prior studies have demonstrated a relationship between underlying tumor genetics and lymphocyte infiltration in meningiomas. In this study, the authors aimed to further characterize the relationship between meningioma genomics, CD4+ and CD8+ T-cell infiltration, and oncological outcomes of meningiomas. Understanding specific characteristics of the inflammatory infiltration could have implications for treatment and prognostication., Methods: Immunohistochemically stained meningioma slides were reviewed to assess the CD4+ and CD8+ cell infiltration burden. The relationship between immune cell infiltration and tumor genomics was then assessed using an adjusted ANOVA model. For a specific gene identified by the ANOVA, the relationship between that mutation and tumor recurrence was assessed using Cox regression., Results: In immunohistochemically stained samples from a subcohort of 25 patients, the mean number of CD4+ cells was 42.2/400× field and the mean number of CD8+ cells was 69.8/400× field. Elevated CD8+ cell infiltration was found to be associated with the presence of a mutation in the gene encoding for DNA polymerase epsilon, POLE (51.6 cells/hpf in wild-type tumors vs 95.9 cells/hpf in mutant tumors; p = 0.0199). In a retrospective cohort of 173 patients, the presence of any mutation in POLE was found to be associated with a 46% reduction in hazard of progression (HR 0.54, 95% CI 0.311-0.952; p = 0.033). The most frequent mutation was a near-C-terminal nonsense mutation., Conclusions: A potential association was found between mutant POLE and both an increase in CD8+ cell infiltration and progression-free survival. The predominant mutation was found outside of the known exonuclease hot spot; however, it was still associated with a slight increase in mutational burden, CD8+ cell infiltration, and progression-free survival. Alterations in gene expression, resulting from alterations in POLE, may yield an increased presentation of neoantigens, and, thus, greater CD8+ cell-mediated apoptosis of neoplastic cells. These findings have suggested the utility of checkpoint inhibitors in the treatment of POLE-mutant meningiomas.

Background: Pandemics are unpredictable and can rapidly spread. Proper planning and preparation for managing the impact of outbreaks is only achievable through continuous and systematic collection and analysis of health-related data. We describe our experience on how to comply with required reporting and develop a robust platform for surveillance data during an outbreak., Materials and Methods: At Mount Sinai Health System, New York City, we applied Visiun, a laboratory analytics dashboard, to support main response activities. Epic System Inc.'s SlicerDicer application was used to develop clinical and research reports. We followed World Health Organization (WHO); federal and state guidelines; departmental policies; and expert consultation to create the framework., Results: The developed dashboard integrated data from scattered sources are used to seamlessly distribute reports to key stakeholders. The main report categories included federal, state, laboratory, clinical, and research. The first two groups were created to meet government and state reporting requirements. The laboratory group was the most comprehensive category and included operational reports such as performance metrics, technician performance assessment, and analyzer metrics. The close monitoring of testing volumes and lab operational efficiency was essential to manage increasing demands and provide timely and accurate results. The clinical data reports were valuable for proper managing of medical surge requirements, such as healthcare workforce and medical supplies. The reports included in the research category were highly variable and depended on healthcare setting, research priorities, and available funding. We share a few examples of queries that were included in the designed framework for research projects., Conclusion: We reviewed here the key components of a conceptual surveillance framework required for a robust response to COVID-19 pandemics. We demonstrated leveraging a lab analytics dashboard, Visiun, combined with Epic reporting tools to function as a surveillance system. The framework could be used as a generic template for possible future outbreak events., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Pathology Informatics.)

Purpose: While SWI/SNF chromatin remodeling complex alterations occur in approximately 20% of cancer, the frequency and potential impact on clinical outcomes in meningiomas remains to be comprehensively elucidated., Methods: A large series of 255 meningiomas from a single institution that was enriched for high grade and recurrent lesions was identified. We performed next-generation targeted sequencing of known meningioma driver genes, including NF2, AKT1, PIK3CA, PIK3R1, and SMO and SWI/SNF chromatin remodeling complex genes, including ARID1A, SMARCA4, and SMARCB1 in all samples. Clinical correlates focused on clinical presentation and patient outcomes are presented., Results: The series included 63 grade I meningiomas and 192 high-grade meningiomas, including 173 WHO grade II and 19 WHO grade III. Samples from recurrent surgeries comprised 37.3% of the series. A total of 41.6% meningiomas were from the skull base. NF2, AKT1, PIK3CA, PIK3R1, and SMO were mutated in 40.8, 7.1, 3.5, 3.9, and 2.4% of samples, respectively. ARID1A, SMARCA4, and SMARCB1 mutations were observed in 17.3, 3.5, and 5.1% of samples, respectively. A total of 68.2% of ARID1A-mutant meningiomas harbored a p.Gln1327del in-frame deletion. ARID1A mutations were seen in 19.1% of Grade I, 16.8% of Grade II, and 15.8% of Grade III meningiomas (P = 0.9, Fisher's exact). Median overall survival was 16.3 years (95% CI 10.9, 16.8). With multivariable analysis, the presence of an ARID1A mutation was significantly associated with a 7.421-fold increased hazard of death (P = 0.04)., Conclusion: ARID1A mutations occur with similar frequency between low and high-grade meningiomas, but ARID1A mutations are independently prognostic of worse prognosis beyond clinical and histopathologic features., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Meningiomas are the most common primary central nervous system tumor. Emerging data supports that higher mutational burden portends worse clinical outcomes in meningiomas. However, there is a lack of imaging biomarkers that are associated with tumor genomics in meningiomas., Methods: We performed next-generation targeted sequencing in a cohort of 75 primary meningiomas and assessed preoperative imaging for tumor volume and peritumoral brain edema (PTBE). An Edema Index was calculated., Results: Meningiomas that were high grade (WHO grade II or grade III) had significantly larger tumor volume and were more likely to present with PTBE. Moreover, PTBE was associated with brain invasion on histopathology and reduced overall survival. There was a direct association between Edema Index and mutational burden. For every one increase in Edema Index, the number of single nucleotide variants increased by 1.09-fold (95% CI: 1.02, 1.2) (P = 0.01)., Conclusion: These data support that Edema Index may serve as a novel imaging biomarker that can inform underlying mutational burden in patients with meningiomas.

Background: The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown., Methods: Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1-25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study., Results: One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1-25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1-25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1-25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3, P = 0.03. NF2 mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes. NF2 mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1-25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes, P = 0.046., Conclusions: Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden. NF2 mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10 -8 , tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.

Background: Emerging evidence suggests that STK11 mutations may influence clinical outcome and response to immunotherapy in cancer., Materials and Methods: Next-generation targeted sequencing of STK11 mutation status in a large cohort of 188 meningiomas., Results: STK11 loss-of-function mutations were identified in 3.7% of meningiomas. STK11 mutations were found in both low- and high-grade lesions and samples from primary and recurrent disease. There was a 2.8-fold increased risk of death for patients whose meningioma harbored an STK11 mutation, after controlling for lesion grade and occurrence status. The median overall survival for patients with STK11-mutated meningiomas was 4.4 years compared with 16.8 years., Conclusion: These data identify recurrent STK11 mutations in a subset of meningiomas. Genotyping of STK11 is encouraged for meningioma patients undergoing immunotherapy-based therapy.

Background: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood., Methods: We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis., Results: Alcohol use was positively associated with PD ( P trend = 0.01), unassociated with DA ( P trend = 0.23), and inversely associated with NDA ( P trend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD ( P trend = 0.0008), unassociated with DA ( P trend = 0.93), and positively associated with NDA ( P trend <0.0001). These trends were stronger in normal and overweight women than in obese women., Conclusions: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA., Impact: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health., (©2020 American Association for Cancer Research.)

Importance: Mammography screening currently relies on subjective human interpretation. Artificial intelligence (AI) advances could be used to increase mammography screening accuracy by reducing missed cancers and false positives., Objective: To evaluate whether AI can overcome human mammography interpretation limitations with a rigorous, unbiased evaluation of machine learning algorithms., Design, Setting, and Participants: In this diagnostic accuracy study conducted between September 2016 and November 2017, an international, crowdsourced challenge was hosted to foster AI algorithm development focused on interpreting screening mammography. More than 1100 participants comprising 126 teams from 44 countries participated. Analysis began November 18, 2016., Main Outcomes and Measurements: Algorithms used images alone (challenge 1) or combined images, previous examinations (if available), and clinical and demographic risk factor data (challenge 2) and output a score that translated to cancer yes/no within 12 months. Algorithm accuracy for breast cancer detection was evaluated using area under the curve and algorithm specificity compared with radiologists' specificity with radiologists' sensitivity set at 85.9% (United States) and 83.9% (Sweden). An ensemble method aggregating top-performing AI algorithms and radiologists' recall assessment was developed and evaluated., Results: Overall, 144 231 screening mammograms from 85 580 US women (952 cancer positive ≤12 months from screening) were used for algorithm training and validation. A second independent validation cohort included 166 578 examinations from 68 008 Swedish women (780 cancer positive). The top-performing algorithm achieved an area under the curve of 0.858 (United States) and 0.903 (Sweden) and 66.2% (United States) and 81.2% (Sweden) specificity at the radiologists' sensitivity, lower than community-practice radiologists' specificity of 90.5% (United States) and 98.5% (Sweden). Combining top-performing algorithms and US radiologist assessments resulted in a higher area under the curve of 0.942 and achieved a significantly improved specificity (92.0%) at the same sensitivity., Conclusions and Relevance: While no single AI algorithm outperformed radiologists, an ensemble of AI algorithms combined with radiologist assessment in a single-reader screening environment improved overall accuracy. This study underscores the potential of using machine learning methods for enhancing mammography screening interpretation.

Background: Pancreatic cystic lesions are often challenging entities for diagnosis and management. EUS-FNA diagnostic accuracy is limited by paucicellularity of cytology specimens and sampling errors. Needle-based confocal laser endomicroscopy (nCLE) provides real-time imaging of the microscopic structure of the cystic lesion and could result in a more accurate diagnosis., Aims and Objectives: To determine the diagnostic utility of in vivo nCLE and EUS-FNA in the diagnosis and histologic characterization of pancreatic cystic lesions (PCL)., Materials and Methods: All patients diagnosed with PCL who had undergone nCLE and FNA over a 10-year period within a major urban teaching hospital were included in this study. All gastroenterology reports of the nCLE images and corresponding pathologist findings from the EUS-FNA were collected and compared with, a final diagnosis prospectively collected from clinicopathological and imaging data., Results: A total of n =32 patients were included in this study, which consisted of n =13 serous cystadenoma (SCA), n =7 intraductal papillary mucinous neoplasms (IPMN), n =2 mucinous cystic neoplasms (MCN), n =3 well-differentiated neuroendocrine tumors, n =2 cysts, n =2 benign pancreatic lesions, n =1 adenocarcinoma, n =1 gastrointestinal stromal tumor (GIST) and n =1 lymphangioma. The overall diagnostic rate was higher in nCLE (87.5%) vs. EUS-FNA (71.9%) While the diagnostic accuracy of nCLE and EUS-FNA were comparable in characterization of benign vs. malignant lesions, the nCLE diagnosis demonstrated higher accuracy rate in identifying mucinous cystic neoplasms compared to EUS-FNA., Conclusion: nCLE is a useful companion diagnostic tool for pancreatic cystic lesions and could assist the cytopathologist to better triage the sample for required ancillary testing and treatment planning. The combination of nCLE and EUS-FNA may be especially helpful in reducing the proportion of cases categorized as non-diagnostic., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Journal of Pathology Informatics.)

Background: Methicillin-resistant Staphylococcus aureus (MRSA) causes life-threatening infections in both community and hospital settings and is a leading cause of health care-associated infections (HAIs). We sought to describe the molecular epidemiological landscape of patients with MRSA bloodstream infections (BSIs) at an urban medical center by evaluating the clinical characteristics associated with the two dominant endemic clones., Methods: Comprehensive clinical data from the electronic health records of 227 hospitalized patients ≥18 years old with MRSA BSI over a 33-month period in New York City were collected. The descriptive epidemiology and mortality associated with the two dominant clones were compared using logistic regression., Results: Molecular analysis revealed that 91% of all single-patient MRSA BSIs were due to two equally represented genotypes, clonal complex (CC) 5 (n = 117) and CC8 (n = 110). MRSA BSIs were associated with a 90-day mortality rate of 27%. CC8 caused disease more frequently in younger age groups (56 ± 17 vs 67 ± 17 years old; P < .001) and in those of nonwhite race (odds ratio [OR], 3.45; 95% confidence interval [CI], 1.51-7.87; P = .003), with few other major distinguishing features. Morbidity and mortality also did not differ significantly between the two clones. CC8 caused BSIs more frequently in the setting of peripheral intravenous catheters (OR, 5.96; 95% CI, 1.51-23.50; P = .01)., Conclusions: The clinical features distinguishing dominant MRSA clones continue to converge. The association of CC8 with peripheral intravenous catheter infections underscores the importance of classical community clones causing hospital-onset infections. Ongoing monitoring and analysis of the dynamic epidemiology of this endemic pathogen are crucial to inform management and prevent disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Cadmium is a known carcinogen that has been implicated in prostate cancer, but how it affects prostate carcinogenesis in humans remains unclear. Evidence from basic science suggests that cadmium can bind to the androgen receptor causing endocrine disruption. The androgen receptor is required for normal prostate development and is the key driver of prostate cancer progression. In this study, we examined the association between cadmium content and androgen receptor protein expression in prostate cancer tissue of African American (N = 22) and European American (N = 30) men. Although neither overall tumor cadmium content (log transformed) nor androgen receptor protein expression level differed by race, we observed a race-cadmium interaction with regard to androgen receptor expression (P = 0.003) even after accounting for age at prostatectomy, smoking history, and Gleason score. African American men had a significant positive correlation between tumor tissue cadmium content and androgen receptor expression (Pearson correlation = 0.52, P = 0.013), while European Americans showed a non-significant negative correlation between the two (Pearson correlation = -0.19, P = 0.31). These results were unchanged after further accounting for tissue zinc content or dietary zinc or selenium intake. African American cases with high-cadmium content (>median) in tumor tissue had more than double the androgen receptor expression (0.021 vs. 0.008, P = 0.014) of African American men with low-cadmium level. No difference in androgen receptor expression was observed in European Americans by cadmium level (high 0.015 vs. low 0.011, P = 0.30). Larger studies are needed to confirm these results and if upheld, determine the biologic mechanism by which cadmium increases androgen receptor protein expression in a race-dependent manner. Our results suggest that cadmium may play a role in race disparities observed in prostate cancer., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Purpose: The potential effects of statins on clinical and histopathologic variables, prostate size, or PSA density (PSAD) and resulting influences on active surveillance eligibility have not been adequately explored. This study examines the effect of statins on prostate specimens following prostatectomy., Materials and Methods: Patients that received robotic-assisted laparoscopic prostatectomy (RALP) (n = 2,632) were dichotomized according to preoperative statin use. Logistic regression was used to evaluate associations between statin use and patient clinical and pathological characteristics., Results: Men using statins at the time of prostatectomy were older (61.6 &plusmn; 6.4 versus 58.8 &plusmn; 7.2 years, P &lt; .001), and had poorer health status (P &lt; .001). Biopsy Gleason grade, clinical stage and prostate size were similar among the two groups, although statin users had lower diagnostic PSA levels (5.5 &plusmn; 3.6 versus 6.3 &plusmn; 4.9 ng/mL, P &lt; .001) and PSAD (.12 versus .13, P = .001)., Conclusion: Men taking statins at the time of prostatectomy had similar histopathologic characteristics to non-users, despite having significantly lower serum PSA, being older and having similar sized prostates. This supports prior studies suggesting a PSA reduction effect of statins may warrant consideration of statin usage in decisionalgorithms for active surveillance.

Metastatic urachal carcinoma is a rare, understudied, and aggressive malignancy with limited treatment options. Histologically, urachal carcinomas resemble enteric adenocarcinomas and anecdotally respond to systemic therapies utilized in colorectal cancer. Targeted exome sequencing of archival primary tumor tissue from a patient with metastatic urachal cancer revealed EGFR amplification and wild-type KRAS. The patient was treated with cetuximab, a monoclonal antibody directed against EGFR, as a single agent, and achieved a response lasting more than 8 mo. Subsequent whole-exome sequencing revealed no additional alterations likely to be associated with cetuximab sensitivity. Formalin-fixed, paraffin-embedded tumor specimens from nine additional urachal cancers were subjected to targeted exome sequencing. Mitogen-activated protein kinase (MAPK) pathway mutations were found in four of the nine samples, but no EGFR amplification was detected. Importantly, APC mutations were detected in two of the nine patients. To our knowledge, this is the first report of a response to single-agent cetuximab in a patient with metastatic urachal cancer and of molecular analysis to probe the basis for sensitivity. On the basis of these findings and the histologic, and now genomic, similarities with colorectal cancer, monoclonal antibodies directed at EGFR could be used in the treatment of metastatic urachal cancer., Patient Summary: Urachal cancers are morphologically and genomically similar to colon adenocarcinomas and may respond to drugs targeting the epidermal growth factor receptor., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Patients with colitis have an increased risk of colorectal cancer, compared with persons without colitis. Many studies have shown chromoendoscopy (CE) to be superior to standard methods of detecting dysplasia in patients with colitis at index examination. We performed a prospective, longitudinal study to compare standard colonoscopy vs CE in detecting dysplasia in patients with inflammatory bowel diseases in a surveillance program., Methods: We analyzed data from 68 patients (44 men, 24 women) diagnosed with ulcerative colitis (n = 55) or Crohn's disease (n = 13) at Mount Sinai Medical Center from September 2005 through October 2011. The patients were followed from June 2006 through October 2011 (median, 27.8 months); each patient was analyzed by random biopsy, targeted white light examination (WLE), and CE. Specimens were reviewed by a single blinded pathologist. The 3 methods were compared by using the generalized estimating equations method, and the odds ratios (ORs) for detection of dysplasia were calculated (primary outcome). Time to colectomy was analyzed by using the Cox model., Results: In the 208 examinations conducted, 44 dysplastic lesions were identified in 24 patients; 6 were detected by random biopsy, 11 by WLE, and 27 by CE. Ten patients were referred for colectomy, and no carcinomas were found. At any time during the study period, CE (OR, 5.4; 95% confidence interval [CI], 2.9-9.9) and targeted WLE (OR, 2.3; 95% CI, 1.0-5.3) were more likely than random biopsy analysis to detect dysplasia. CE was superior to WLE (OR, 2.4; 95% CI, 1.4-4.0). Patients identified as positive for dysplasia were more likely to need colectomy (hazard ratio, 12.1; 95% CI, 3.2-46.2)., Conclusions: In a prospective study of 68 patients with inflammatory bowel diseases, CE was superior to random biopsy or WLE analyses in detecting dysplasia in patients with colitis during an almost 28-month period. A negative result from CE examination was the best indicator of a dysplasia-free outcome, whereas a positive result was associated with earlier referral for colectomy., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Given that randomized trials exploring adjuvant chemotherapy for bladder cancer have been underpowered and/or terminated prematurely, yielding inconsistent results and creating an evidence gap, we sought to compare the effectiveness of cystectomy versus cystectomy plus adjuvant chemotherapy in real-world patients., Patients and Methods: We conducted an observational study to compare the effectiveness of adjuvant chemotherapy versus observation postcystectomy in patients with pathologic T3-4 and/or pathologic node-positive bladder cancer using the National Cancer Data Base. We compared overall survival using propensity score (-adjusted, -stratified, -weighted, and -matched) analyses based on patient-, facility-, and tumor-level characteristics. A sensitivity analysis was performed to examine the impact of performance status., Results: A total of 5,653 patients met study inclusion criteria; 23% received adjuvant chemotherapy postcystectomy. Chemotherapy-treated patients were younger and more likely to have private insurance, live in areas with a higher median income and higher percentage of high school-educated residents, and have lymph node involvement and positive surgical margins (P < .05 for all comparisons). Stratified analyses adjusted for propensity score demonstrated an improvement in overall survival with adjuvant chemotherapy (hazard ratio, 0.70; 95% CI, 0.64 to 0.76), and similar results were achieved with propensity score matching and weighting. The association between adjuvant chemotherapy and improved survival was consistent in subset analyses and was robust to the effects of poor performance status., Conclusion: In this observational study, adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer. Although neoadjuvant chemotherapy remains the preferred approach based on level I evidence, these data lend further support for the use of adjuvant chemotherapy in patients with locally advanced bladder cancer postcystectomy who did not receive chemotherapy preoperatively., (© 2016 by American Society of Clinical Oncology.)

Background & Aims: Epidemiology studies have consistently found an increased risk of oral malignancies in organ transplant recipients, patients with graft-versus-host disease, and people with human immunodeficiency virus infection. We assessed the risk of oral cancer in patients with inflammatory bowel diseases (IBD)., Methods: We collected data on 7294 patients with IBD (3785 women) seen at Mount Sinai Medical Center, New York, from 2000 through 2011. The expected incidence of oral cancer was calculated for each sex-specific and 5-year age-specific stratum by specific incidence rates using the Surveillance, Epidemiology and End Results 18 registry data (2000-2011), adjusted for age to the 2000 United States population (census P25-1130)., Results: Eleven patients (7 men) were found to have biopsy-proven oral cancer. Six patients had cancer of the tongue; 2 patients had cancer of the hard palate; and the remaining 3 had tonsillar, buccal, or mandibular sarcoma. Before the cancer diagnosis, IBD had been treated in 4 patients with azathioprine or mercaptopurine, in 1 patient with infliximab, and 3 in patients with combination of biologic agents and azathioprine; 4 of the patients had not been treated for IBD. The age- and sex-adjusted standardized incidence ratio (SIR) for oral cancer in patients with IBD was 9.77 (95% confidence interval [CI], 5.14-16.98). In women, the SIR was 12.07 (95% CI, 3.84-29.11), and in men the SIR was 8.49 (95% CI, 3.71-16.78). The age-adjusted SIR for tongue cancer was 18.91 (95% CI, 7.66-39.33): 17.06 for men (95% CI, 5.42-41.15) and 22.10 for women (95% CI, 3.70-73.01)., Conclusions: We found patients with IBD to be at increased risk for oral cancers, especially tongue cancer. Women are at higher risk than men., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Theory: Although medical students begin medical school with better mental health than their peers, during medical school students have a higher prevalence of psychological distress. Medical students often do not seek help for mental health concerns. The use of approach coping strategies and social support has been shown in other populations to be related to mental health resiliency., Hypotheses: The rates of depression and burnout in this medical student population are expected to be high, with the majority not seeking help for their psychological distress in accordance with studies of medical students across the nation. Perceptions of stigma are hypothesized to be a potential source of this lack of care-seeking behavior. Approach coping strategies and social support are speculated to have an inverse relationship with the prevalence of depression and burnout in the medical student population., Method: Validated measures of depression and burnout along with items pertaining to diagnosis and treatment of mental health issues, specific coping strategies used during stressful times, and perceptions of social support were used in a cross-sectional study of students at the University of North Dakota School of Medicine and Health Sciences (UND SMHS)., Results: The overall survey response rate was 64%. Seventeen percent had moderate to severe depression, and 49% had burnout. Of depressed respondents, 81% were undiagnosed. When asked why depression develops, 23% responded that it was due to an inability to cope. A significantly greater risk of depression was associated with inadequate support from family and friends (p = .002), fellow medical students (p = .01), and the UND SMHS (p = .003). Greater use of approach-oriented coping strategies than avoidant-oriented strategies was associated with significantly decreased risk of burnout (p = .02) and was inversely correlated with depression (rs = -0.27, n = 153, p = .001)., Conclusions: This study outlines associations among approach-oriented coping strategies, social support, and resiliency to mental health issues among medical students. This study also supports the existing literature that stigma regarding mental health issues is present in the medical community. Further multi-institutional, longitudinal research to delineate whether interventions that promote approach coping style and utilization of social support lead to decreased rates of mental health issues is necessary. The development of these interventions will need to be a multifaceted approach that includes promotion of care-taking behaviors but also focuses on institutional cultural change in order to empower students to participate in these resiliency strategies.

Serrated colorectal polyps, which, besides hyperplastic polyps, comprise sessile serrated adenomas/polyps and traditional serrated adenomas, are presumptive precursors of at least 20% of sporadic colorectal carcinomas; however, their significance in patients with inflammatory bowel disease is unclear. We retrospectively evaluated 78 serrated polyps, removed over a 14-year period from 6602 inflammatory bowel disease patients undergoing endoscopic surveillance, with respect to morphologic, clinicopathologic, and molecular features, and compared rates of advanced neoplasia (high-grade dysplasia and carcinoma) development following the index serrated polyp diagnosis to reference inflammatory bowel disease cohorts without serrated polyps. Serrated polyps negative for dysplasia, which morphologically resembled sporadic sessile serrated adenoma/polyps, occurred mainly in females, in the proximal colon, and contained BRAF mutations. Serrated polyps with low-grade dysplasia resembled sporadic traditional serrated adenomas and occurred mainly in males, in the distal colon, and contained KRAS mutations. Serrated polyps indefinite for dysplasia were morphologically heterogeneous, but similar to serrated polyps positive for low-grade dysplasia with respect to male predominance, left-sided location, and KRAS mutation rates. Rates of prevalent neoplasia associated with serrated polyps positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 76, 39, and 11%, respectively (P<0.001). Actuarial 10-year rates of incident advanced neoplasia after an initial diagnosis of serrated polyp positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 17, 8, and 0%, respectively, the first and last being significantly different (P=0.02) and comparable to those of corresponding reference populations of inflammatory bowel disease patients with and without low-grade dysplasia at baseline, respectively. We conclude that in serrated polyps from inflammatory bowel disease patients, dysplasia grade correlates with morphology, sex, anatomic location, BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.

The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II-III adult cancer clinical trials initiated between 2005-2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Longitudinal studies report racial disparities in prostate cancer (PCa) including greater incidence, more aggressive tumor biology, and increased cancer-specific mortality in African American (AA) men. Regret concerning primary treatment selection is underevaluated in patients with PCa. We investigated the relationships between clinicopathologic variables across racial and socioeconomic lines following robotic-assisted laparoscopic prostatectomy., Materials and Methods: We assessed treatment decisional regret using a validated questionnaire in a total of 484 white and 72 AA patients with PCa who were followed up for a median of 16.6 months post-robotic-assisted laparoscopic prostatectomy. Socioeconomic status (SES) information was aggregated from 2010 US census zip code data. Perioperative clinicopathologic characteristics and functional outcomes were compared between groups. Univariate and multivariate regression analyses were used to evaluate the influence of race, aggregate SES, and other clinical and demographic characteristics on decisional regret., Results: The majority (87.7%) of the population was not regretful of their decision to undergo treatment. However, a greater proportion of AA vs. white patients were regretful (20.6% vs. 11.2%, respectively; P = 0.03). AA and white men were similar on all functional, clinical, and pathologic features with the exception of younger age among AA men (56 vs. 60 y, respectively; P<0.001). Although there were significant differences in SES by race (P<0.001), regret did not differ by SES (β =-1.53; P = 0.15). Race, postoperative sexual dysfunction, pad usage, and length of hospital stay, however, were significantly associated with decisional regret., Conclusions: AA men were more regretful than white men, after adjusting for clinicopathologic characteristics and postoperative functional outcomes., (© 2013 Published by Elsevier Inc.)

Purpose: Reporting adverse events is a critical element of a clinical trial publication. In 2003, the Consolidated Standards of Reporting Trials (CONSORT) group generated recommendations regarding the appropriate reporting of adverse events. The degree to which these recommendations are followed in oncology publications has not been comprehensively evaluated., Methods: A review of citations from PubMed, Medline, and Embase published between Jan 1, 2009 and December 31, 2011, identified eligible randomized, controlled phase III trials in metastatic solid malignancies. Publications were assessed for 14 adverse event-reporting elements derived from the CONSORT harms extension statement; a completeness score (range, 0 to 14) was calculated by adding the number of elements reported. Linear regression analysis identified which publication characteristics associated with reporting completeness., Results: A total of 175 publications, with data for 96,125 patients, were included in the analysis. The median completeness score was eight (range, three to 12). Most publications (96%) reported only adverse events occurring above a threshold rate or severity, 37% did not specify the criteria used to select which adverse events were reported, and 88% grouped together adverse events of varying severity. Regression analysis revealed that trials without a stated funding source and with an earlier year of publication had significantly lower completeness scores., Conclusion: Reporting of adverse events in oncology publications of randomized trials is suboptimal and characterized by substantial selectivity and heterogeneity. The development of oncology-specific standards for adverse event reporting should be established to ensure consistency and provide critical information required for medical decision-making.

Objectives: Metabolic syndrome (MetS), the constellation of obesity and related risk factors for cardiovascular disease, is an expanding epidemiologic concern in the United States and the developed world. However, the relationship between MetS and prostate cancer remains to be definitively assessed. We evaluated the association between obesity and MetS with prostate cancer pathology and surgical and functional outcomes., Materials and Methods: A total of 2,639 patients underwent robotic-assisted laparoscopic prostatectomy (RALP) for localized prostate cancer between March 2003 and July 2012. Of them, 186 patients met the criteria for MetS as defined by the presence of obesity (body mass index [BMI] ≥ 30 kg/m(2)) in conjunction with 2 or more of the following: hypertension (HTN), dyslipidemia (D), and diabetes (DM). Additionally, reference cohorts of (1) 663 nonobese men without HTN, D, or DM; (2) 184 obese patients without HTN, D, or DM; and (3) 211 obese men with solitary risk factors were identified for comparison. Demographic, histopathologic, and perioperative clinical parameters were compared., Results: In comparison with patients without MetS, patients with MetS had larger prostates (Odds Ratio (OR) = 1.609, 95% Confidence Interval (CI) = 1.04-2.49, P = 0.03), increased blood loss (OR = 1.592, 95% CI = 1.15-2.21, P = 0.01), and surgical complexity (OR = 4.940, 95% CI = 2.29-10.69, P<0.001). There was no statistical difference observed between these groups in regard to complication rates, pathologic grade, stage, and postoperative continence or erectile function. With the exception of larger prostates found among men with MetS, men with obesity alone and obesity with 1 additional risk factor appeared similar to those with MetS., Conclusions: Patients with MetS had similar perioperative, histopathologic, and functional outcomes compared with reference cohorts undergoing RALP. RALP is safe, feasible, and efficacious in men with MetS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Context: Corpora amylacea (CA) are inclusions with starch-like composition that occur in various conditions. We have observed CA in gastrointestinal leiomyomas (GILM) and hypothesised that they differ from intracytoplasmic hyaline globules (HG) of GILM. We aimed to investigate the anatomical distribution, prevalence, staining characteristics and ultrastructural features of CA and compare them with HG of GILM., Design: Slides from a consecutive series of resected GILM and bland spindle cell tumours were examined for CA and HG. Special stains, electron microscopy and elemental analysis were performed on select leiomyomas., Results: CA occurred in 13/35 GILM (37%) from the following sites: oesophagus (4/8), stomach (5/7) including one frozen section, small intestine (1/2) and large intestine (3/18), but were not identified in 19 gastrointestinal stromal tumours (12 gastric, 7 small intestinal; p=0.0019), five schwannomas (three gastric, two small intestinal; p=0.154) and 35 non-GILM (p=0.0001). The densities of CA ranged from one per 4-200 mm(2). CA stained intensely with periodic acid Schiff after diastase predigestion (PASD), Alcian blue and ubiquitin, and faintly in peripheral zones for desmin and smooth muscle actin. Ultrastructurally, CA consisted of an electron-dense outer layer and a fibrillar core with scattered particle matter. HG were present in all leiomyomas, but showed variable staining for PASD, negative staining for Alcian blue and ubiquitin, and positive staining for smooth muscle markers., Conclusions: CA are a distinctive histological feature of approximately one third of GILM with different composition to HG. These differences may represent divergent degenerative processes or different stages of a single degenerative process over time.

Purpose: National guidelines recommend adjuvant intravesical Bacillus Calmette-Guérin (BCG) therapy for higher-risk non-muscle-invasive bladder cancer (NMIBC). Although a survival benefit has not been demonstrated, randomized trials have shown reduced recurrence and delayed progression after its use. We investigated predictors of BCG receipt and its association with survival for older patients with NMIBC., Patients and Methods: We identified individuals with NMIBC registered in the Surveillance, Epidemiology, and End Results-Medicare database from 1991 to 2003. We used logistic regression to compare those treated with BCG within 6 months of initial diagnosis with those not treated, adjusting for demographic and clinical factors. Cox proportional hazards modeling was used to analyze the association between BCG and overall survival (OS) and bladder cancer-specific survival (BCSS) for the entire cohort and within tumor grades., Results: Of 23,932 patients with NMIBC identified, 22% received adjuvant intravesical BCG. Predictors of receipt were stages Tis and T1, higher grade, and urban residence. Age > 80 years, fewer than two comorbidities, and not being married were associated with decreased use. In the survival analysis, BCG use was associated with better OS (hazard ratio [HR], 0.87; 95% CI, 0.83 to 0.92) in the entire cohort and BCSS among higher-grade cancers (poorly differentiated: HR, 0.78; 95% CI, 0.72 to 0.85; undifferentiated: HR, 0.66; 95% CI, 0.56 to 0.77)., Conclusion: Despite guidelines recommending its use, BCG is administered to less than one quarter of eligible patients. This large population-based study found improved OS and BCSS were associated with use of adjuvant intravesical BCG among older patients with NMIBC. Better-designed clinical trials focusing on higher-grade cancers are needed to confirm these findings.

Background: Several environmental risk factors are known to predispose individuals to pancreatic cancer, and up to 15% of pancreatic cancers have an inherited component. Understanding metachronous cancer associations can modify pancreas cancer risk. The objective of this study was to investigate the association of nonpancreatic cancers with subsequent pancreatic adenocarcinoma., Methods: The authors used data from the US Surveillance, Epidemiology, and End Results (SEER) registries to identify 1,618,834 individuals who had a primary malignancy and subsequent pancreatic adenocarcinoma (n = 4013). Standardized incidence ratios were calculated as an approximation of relative risk (RR) for the occurrence of pancreatic adenocarcinoma after another primary malignancy., Results: Among patients who were diagnosed with a first primary malignancy at ages 20 to 49 years, the risk of subsequent pancreatic adenocarcinoma was increased among patients who had cancers of the ascending colon (relative risk [RR], 4.62; 95% confidence interval [CI], 1.86-9.52), hepatic flexure (RR, 5.42; 95% CI, 1.12-15.84), biliary system (RR, 13.14; 95% CI, 4.27-30.66), breast (RR, 1.32; 95% CI, 1.09-1.59), uterine cervix (RR, 1.61; 95% CI, 1.02-2.41), testes (RR, 2.78; 95% CI, 1.83-4.05), and hematopoietic system (RR, 1.83; 95% CI, 1.28-2.53). Among patients who had a first malignancy at ages 50 to 64 years, the risk was increased after cancers of the stomach (RR, 1.88; 95% CI, 1.13-2.93), hepatic flexure (RR, 2.25; 95% CI, 1.08-4.13), lung and bronchus (RR, 1.46; 95% CI, 1.16-1.82), pharynx (RR, 2.26; 95% CI, 1.13-4.04), and bladder (RR, 1.24; 95% CI, 1.03-1.48). Among patients who had a primary cancer after age 65 years, the risk was increased after cancers of the stomach (RR, 1.79; 95% CI, 1.23-2.53), hepatic flexure (RR, 1.76; 95% CI, 1.06-2.75), biliary system (RR, 2.35; 95% CI, 1.17-4.20), and uterus (RR, 1.23; 95% CI, 1.03-1.47)., Conclusions: The results from the current population-based data set suggested that pancreatic adenocarcinoma is associated with certain primary cancers. Genetic predisposition and common environmental and behavioral risk factors all may contribute to this observation. Specific tumor associations will guide future risk-stratification efforts., (Copyright © 2011 American Cancer Society.)

Background: The pathologic identification of 12 or more lymph nodes (LN) after colectomy for colon cancer became a quality indicator for surgery in 2001. We investigated whether this new standard of care was differentially adopted across racial and socioeconomic lines., Methods: We identified 111,339 stage I to III colon cancer patients identified as black or white in the Surveillance, Epidemiology, and End Results database from 1988 to 2004 who underwent colectomy. We did multivariable logistic regression to investigate the influence of race, area socioeconomic status (SES), and other clinical and demographic characteristics on the number of LNs examined., Results: Between 1988 and 2004, white patients were more likely than black patients to have > or =12 LNs identified (odds ratio, 1.06; 95% confidence interval, 1.02-1.10) after adjustment for age, year of diagnosis, sex, marital status, tumor grade, stage, and subsite within the colon. After adjustment for SES, race was no longer significant (adjusted odds ratio, 1.00; 95% confidence interval, 0.96-1.04). There was, however, a significant positive trend between a patient's SES and having > or =12 LNs examined (P(trend) < 0.0001), with a 30% increased odds comparing the highest to the lowest quintiles of SES. We found that the association between SES and the dissection of > or =12 LNs was only present in individuals diagnosed after 1999., Conclusions: The association between high SES and the examination of > or =12 LNs was only apparent from 2000 onward, and coincides with its dissemination and acceptance as a new standard of care. This suggests that the emergence of LN dissection as a quality indicator may have been more rapidly disseminated into higher SES groups.

Background: : Esophagectomy has been the traditional treatment of choice for early stage esophageal cancer. However, esophagectomy is associated with high mortality and morbidity in the elderly, and these patients often receive chemoradiation instead. The authors of this report compared outcomes of esophagectomy versus chemoradiation in a population-based sample of elderly patients with early stage esophageal cancer., Methods: : The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients aged > or =65 years who were diagnosed with stage I or II esophageal cancer from 1991 to 2002. The associations of treatment with esophagectomy or chemoradiation were assessed along with demographic and clinical variables. A survival analyses was performed to compare outcomes with treatment modality and was adjusted for potential confounders., Results: : Seven hundred thirty patients with stage I or II esophageal cancer were identified who underwent esophagectomy (n = 341; 46.7%) or chemoradiation (n = 389; 53.3%). Older age, squamous cell histology, and lower socioeconomic status were associated with increased odds of receiving chemoradiation. In multivariate analyses, chemoradiation was associated with worse disease-specific survival (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.64-2.64) and overall survival (HR, 1.92; 95%CI, 1.58-2.34). The receipt of chemoradiation was associated with worse survival for patients with adenocarcinoma (HR, 3.01; 95%CI, 2.24-4.04), but there was no significant difference for patients with squamous cell carcinoma (HR, 1.33; 95%CI, 0.98-1.80)., Conclusions: : Compared with chemoradiation, esophagectomy may be associated with improved survival for early stage esophageal cancer in the elderly. The current results suggest that there also may be a subset of patients with squamous cell carcinoma for whom chemoradiation is adequate therapy. A randomized trial would be useful to determine the optimal treatment for elderly patients with early stage esophageal cancer. Cancer 2009. (c) 2009 American Cancer Society.

Background: Although >70% of younger women with nonmetastatic breast cancer (BC) received adjuvant chemotherapy, only approximately 15% to 20% of elderly women with BC received chemotherapy. The decision to treat may be associated with nonmedical factors, such as patient, physician, or practice characteristics. In the current study, the association between oncologist characteristics and the receipt of chemotherapy in elderly women with BC was evaluated., Methods: Women aged >65 years who were diagnosed with American Joint Committee on Cancer stages I to III BC between 1991 and 2002 were identified in the Surveillance, Epidemiology, and End Results-Medicare database. The Physician Unique Identification Number was linked to the American Medical Association Masterfile to obtain information on oncologists. Investigated was the association between demographic, tumor, and oncologist-related factors and the receipt of chemotherapy, using Generalized Estimating Equations to control for clustering. Patients were defined as low risk (estrogen/progesterone receptor positive, stage I/II disease) and high risk (estrogen/progesterone receptor-negative, stage II/III disease)., Results: Of 42,544 women identified, 8714 (20%) were treated with adjuvant chemotherapy. In a hierarchical analysis, women who underwent chemotherapy were more likely be treated by oncologists primarily employed in a private practice (odds ratio [OR], 1.40; 95% confidence interval [95% CI], 1.23-1.59) and who graduated after 1975 (OR, 1.12; 95% CI, 1.01-1.26) and were less likely to have an oncologist trained in the United States (OR, 0.83; 95% CI, 0.74-0.93). The association between a private practice setting and the receipt of chemotherapy was found to be similar for patients at high risk (OR, 1.55) and low risk (OR, 1.35) for cancer recurrence., Conclusions: Elderly women with BC treated by oncologists who were employed in a private practice were more likely to receive chemotherapy. Efforts to determine whether these associations reflected experience, practice setting, insurance type, or other economic incentives are warranted.

Background: Most women with localized breast cancer have a choice between mastectomy and breast conserving surgery (BCS). Aside from clinical factors, this decision may be associated with surgeon and patient characteristics. We investigated the effect of surgeon characteristics on the BCS rate., Methods: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify women >65 years, diagnosed with stages I-II BC, between 1991 and 2002, and used the Physician Unique Identification Number linked to the American Medical Association Masterfile to obtain information on surgeons. We investigated the association of patient demographic, tumor, and surgeon-related factors with receipt of BCS, using Generalized Estimating Equations to control for clustering., Results: Of 56,768 women with breast cancer, 30,006 (53%) underwent BCS, whereas 26,762 (47%) underwent mastectomy. Between 1991 and 2002, the proportion of patients undergoing BCS increased from 35% to 60%. In a multivariate analysis, patients who received BCS were younger, of higher SES, and had more favorable tumor characteristics. They were also more likely to be black and live in metropolitan areas. Women who underwent BCS were more likely to have surgeons who were female (OR = 1.40; 95% CI: 1.25-1.55), US-trained (OR = 1.12; 95% CI: 1.02-1.22), with a larger patient panel (OR = 1.29; 95% CI: 1.21-1.39), and completed training after 1975 (OR = 1.16; 95% CI: 1.08-1.25), than surgeons of patients who underwent mastectomy., Conclusions: Surgeon characteristics, such as gender, training, year of graduation, and volume, are small but significant independent predictor of BCS. Efforts to differentiate whether these associations reflect patients' preferences, quality of physician training, surgeon attitudes, physician-patient communication, or other effects on decision-making are warranted.

Background: Adjuvant radiotherapy following breast conservation surgery (BCS) is considered to be an indicator of quality of care for the majority of women with breast cancer, but many women do not receive adjuvant radiotherapy. We investigated the association of surgeon-related factors with receipt of adjuvant radiotherapy after BCS., Methods: We used the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database to identify women aged 65 years or older with stage I/II breast cancer who were diagnosed between 1991 and 2002 and underwent BCS. We collected demographic and clinical data from SEER and treatment information from Medicare claims data. The American Medical Association Masterfile was used to obtain information on surgeons' characteristics, including sex, medical school location (United States or elsewhere), and type of degree (MD or Doctorate in Osteopathic Medicine [DO]). The associations of patient (age, race, rural vs urban residence, comorbidities, marital status), tumor (hormone receptor status, grade, stage), and surgeon-related factors with receipt of adjuvant radiotherapy were analyzed using Generalized Estimating Equations to control for clustering. All statistical tests were two-sided., Results: Of 29,760 women in our sample, 22,207 (75%) received radiotherapy. Patients who received adjuvant radiotherapy were younger, had fewer comorbidities, and were more likely to be white, married, from an urban area, and diagnosed in a later year compared with those who did not. They were also more likely to have a surgeon who was female (79% vs 73%), had an MD degree (75% vs 68%), or was US trained (75% vs 70%). The multivariable analysis confirmed the association of radiotherapy with having a surgeon who was female (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.06 to 1.27), had an MD degree (OR = 1.55; 95% CI = 1.24 to 1.91), was US trained (OR = 1.12; 95% CI = 1.01 to 1.25), or had more than 15 patients (OR = 1.18; 95% CI = 1.10 to 1.28)., Conclusions: Surgeon characteristics were associated with patients' receipt of adjuvant radiotherapy after BCS after controlling for patient and tumor characteristics, although the individual effect sizes were small for surgeon sex, location of training, and type of medical degree. More research is warranted to confirm the associations to determine whether they reflect surgeon behavior, patient response, or physician-patient interactions.

Background and Aims: The extent of use of liver transplantation on a population scale to treat hepatocellular carcinoma (HCC) in the United States is unknown. We assessed recent predictors of use of liver transplantation and its effect on survival for those with nonmetastatic HCC., Methods: The Surveillance, Epidemiology, and End Results (SEER) program is a collection of population-based cancer registries. We identified adults registered in SEER with HCC between 1998 and 2002. We examined determinants for receipt of a liver transplant in univariate and multivariable analyses. Kaplan-Meier survival curves were constructed for those who received and did not receive a transplant for HCC., Results: We identified 1,156 adults with small (5 cm or less) nonmetastatic HCC. Approximately 45% were white, 29% Asian, 17% Hispanic, and 9% African American. Only 21% received a transplant. More recent year of diagnosis, younger age, being married, white race, and smaller tumor size each predicted receipt of transplant. African Americans and Asians were about half as likely to receive a transplant as compared with white patients (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.21-0.90 for African Americans, and 0.57, 95% CI 0.36-0.89 for Asians). Hispanics trended in the same direction, but this was not statistically significant (OR 0.66, 95% CI 0.39-1.12). Those who underwent liver transplantation for localized HCC had 3- and 5-yr survivals of 81% and 75%, respectively., Conclusions: Only one-fifth of those with small, nonmetastatic HCC received liver transplantation. Transplanted patients have long-term survival similar to that of the best single-institution studies. However, marked racial variations were seen, with African Americans and Asians significantly less likely to receive a transplant after controlling for other variables.

The authors reframe a curriculum change from a traditional lecture-based to an integrated patient-centered approach as an intervention for changing the culture and hidden curriculum of an institution in ways that promote professionalism. Within this context, the authors articulate some of the inherent process and relational factors brought about by these curricular changes that are essential elements of this intervention process. In 1998 the University of North Dakota School of Medicine and Health Sciences (UNDSMHS) introduced a new preclinical patient-centered learning (PCL) curriculum for first- and second-year medical students. Case-based, small-group learning forms the critical foundation of the PCL process, and an integrated basic and clinical science didactic component supports this process. At the student level, the case-based PCL process generates innovative opportunities for professionalism education from the explicitly articulated formal content that arises naturally from the cases, but more importantly from the implicit values inherent to the PCL small-group process itself--humanism, accountability, pursuit of excellence, and altruism. Further, the organizational changes necessary for the transformation to the PCL curriculum required process changes at student, faculty, and administrative levels that have resulted in a cultural shift toward relationship centeredness within the institution. The authors describe the evolution and structure of the PCL curriculum at UNDSMHS and how this curricular transformation has served as an intervention that promotes professionalism and institutional culture change through (1) processes at the student level that present new opportunities for professionalism education, and (2) processes at student, faculty, administrative, and institutional levels that have created an institutional culture that supports, models, and promotes relationship-centered professional values.

Objectives: Prostate-specific antigen (PSA) based end points are commonly used to report outcomes after treatment for prostate cancer. This study examines the influence of follow-up length on biochemical control (bNED) rates., Methods: We reviewed 437 patients with clinically localized prostate cancer treated with conformal radiotherapy without neoadjuvant androgen deprivation. Biochemical failure was defined as three consecutive PSA increases or an increase large enough to prompt androgen deprivation therapy. The failure date was projected back to the midpoint between the PSA nadir and the first PSA increase (or between the nadir and the initiation of androgen deprivation therapy). The analysis was performed by censoring patients with longer follow-up in a stepwise fashion, thus creating smaller subgroups with shorter follow-up intervals. Subgroup 1 (n = 191) and subgroup 2 (n = 273) were defined to include those patients monitored for up to 2 years and up to 3 years, respectively., Results: The median follow-up intervals for subgroup 1, subgroup 2, and the original study population were 1.1, 1.5, and 2.5 years. No significant differences were seen in pretreatment prognostic factors among the three groups. The 2-year bNED of subgroup 1, subgroup 2, and the original population was 86%, 77%, and 73%, respectively. Although subgroup 1 had a superior bNED compared with the original population (P = 0.04), no differences in clinical recurrence rates were seen among any of the three groups., Conclusions: Because of projecting the biochemical failure dates back according to commonly used bNED definitions, control rates are highly dependent on the length of follow-up.

Melanin-concentrating hormone (MCH) is a hepadecapeptide hormone that is synthesized in the CNS and is responsible for melanosome aggregation in the teleost fish. Recent evidence suggests that this peptide hormone has a unique distribution in the mammalian brain, which leads to the speculation that it may serve as a neuromodulator. The present study was undertaken to explore the comparative effects of MCH to those of alpha-melanocyte-stimulating Hormone (MSH) (a neuropeptide that is known to influence learning) on the rate of extinction of a passive avoidance response in rats. Both MCH and MSH were administered SC at 10 micrograms per animal. Treatment with MCH appeared to hasten, whereas treatment with MSH appeared to delay, extinction of the passive avoidance response.

This article criticizes the predominant analysis of heroin use as a social aberration and argues instead that the normal structure and functioning of U.S. capitalism generate both the market for the drug and the industry which supplies it. The structure of the distribution industry is much like those for comparable legal goods, but with distinctive features which provide reduced risk for dealers and long-term stability for the industry as a whole. The expansionary dynamic of the industry and the key role of syndicates in it are analyzed. The heroin industry is deeply integrated into the economy, and far-reaching social and economic change will be necessary if heroin use is to be significantly reduced.