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Abstract Women with a history of vulvar cancer face a high risk of anal cancer; however, incidence according to histology, age-at, and time since vulvar cancer diagnosis remains unexplored. Using data from SEER-8 and SEER-17 registries, we identified 21,230 women with vulvar cancer, with 154,825 person-years follow-up from 1975 to 2021. We observed 95 anal cancer cases, resulting in an incidence of 61.4 per 100,000 person-years (95% CI, 49.6-75.0). Incidence was higher among women with vulvar squamous cell carcinoma (SCC) (78.7; 95% CI, 62.9-97.1) than vulvar non-SCC (19.8; 95% CI, 9.0-37.6). The highest incidence (>100 per 100,000) was observed in women <45 years old with vulvar SCC and those >10 years post-diagnosis. These findings could inform anal cancer screening guidelines, as women with vulvar cancer, particularly those diagnosed with SCC, may substantially benefit from heightened surveillance or targeted screening.

Importance The prognosis for patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is dismal, due in part to chemoresistance. Bacteria-mediated mechanisms of chemoresistance suggest a potential role for antibiotics in modulating response to chemotherapy. Objective To evaluate whether use of peritreatment antibiotics is associated with survival among patients with metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy. Design, Setting, and Participants Using the population-based Surveillance, Epidemiology, and End Results–Medicare linked database, this retrospective cohort study analyzed data for patients diagnosed with PDAC between January 1, 2007, and December 31, 2017. Data analysis was conducted between September 1, 2021, and January 15, 2023. The population-based sample included 3850 patients with primary metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy. Patients who received antibiotics were matched based on propensity scores to patients who did not receive antibiotics. Exposures Receipt of 5 or more days of oral antibiotics or 1 injectable antibiotic in the month before or after beginning first-line chemotherapy. Main Outcomes and Measures Overall survival and cancer-specific survival. The end of follow-up was December 31, 2019, for overall survival and December 31, 2018, for cancer-specific survival. Results Of the 3850 patients treated with first-line gemcitabine (3150 [81.8%]) or fluorouracil (700 [18.2%]), 2178 (56.6%) received antibiotics. The mean (SD) age at diagnosis was 74.2 (5.8) years and patients were predominantly women (2102 [54.6%]), White (3396 [88.2%]), and from metropolitan areas (3393 [88.1%]) in the northeastern or western US (2952 [76.7%]). In total, 1672 propensity-matched pairs were analyzed. Antibiotic receipt was associated with an 11% improvement in overall survival (hazard ratio [HR], 0.89; 95% CI, 0.83-0.96;P = .003) and a 16% improvement in cancer-specific survival (HR, 0.84; 95% CI, 0.77-0.92;P < .001) among patients treated with gemcitabine. In contrast, there was no association between antibiotic receipt and overall survival (HR, 1.08; 95% CI, 0.90-1.29;P = .41) or cancer-specific survival (HR, 1.12; 95% CI, 0.90-1.36;P = .29) among patients treated with fluorouracil. In a subgroup of gemcitabine-treated patients who received antibiotics, nonpenicillin β-lactams were associated with an 11% survival benefit (HR, 0.89; 95% CI, 0.81-0.97;P = .01). Conclusions and Relevance In this cohort study, receipt of perichemotherapy antibiotics was associated with improved survival among patients treated with gemcitabine, but not fluorouracil, suggesting that antibiotics may modulate bacteria-mediated gemcitabine resistance and have the potential to improve PDAC outcomes.

Abstract Background Pancreatic ductal adenocarcinoma is a clinically challenging malignancy largely because of its chemoresistance. Bacteria within the pancreatic ductal adenocarcinoma microbiome may mediate chemoresistance, suggesting that alteration of the microbiome with antibiotics could improve chemotherapy response. Methods We utilized the Surveillance, Epidemiology, and End Results Program–Medicare database to select patients with resected, early-stage pancreatic ductal adenocarcinoma diagnosed between 2007 and 2017. The primary outcome of this study was overall survival. Receipt of antibiotic treatment within 1 month after adjuvant chemotherapy initiation was determined from Medicare claims data. Propensity scores were used to match patients who received antibiotics with patients who did not receive antibiotics. The Kaplan-Meier method was used to calculate 5-year overall survival rates, and Cox regression analysis was used to assess the association between receiving antibiotics and overall survival. All hypotheses were 2 sided. Results Of the 712 patients with resected, early-stage pancreatic ductal adenocarcinoma, 629 (88.3%) were treated with adjuvant gemcitabine and 177 (24.9%) received antibiotics in the 1 month following chemotherapy initiation. The mean (SD) age at diagnosis was 73.7 (5.1) years, and patients were mostly women, White, and from metropolitan areas in the northeastern or western United States. A total of 143 propensity score–matched pairs were evaluated. Among patients treated with gemcitabine, antibiotic treatment was associated with a 37% improvement in overall survival and a 30% improvement in cancer-specific survival. Conclusions Antibiotic treatment in the 1 month following adjuvant gemcitabine initiation was associated with improved survival. These findings provide additional support for the hypothesis that antibiotic treatment may alter the pancreatic microbiome in a manner that reduces chemoresistance, potentially improving pancreatic ductal adenocarcinoma outcomes.

Abstract Tobacco use disorder (TUD) is a major threat to health among people with HIV (PWH), but it is often untreated. Among HIV clinicians and staff, we sought to characterize practices, attitudes, and confidence addressing TUD among PWH to identify potential opportunities to enhance provision of care. Cross-sectional deidentified, web-based surveys were administered from November 4, 2020 through December 15, 2020 in HIV clinics in three health systems in the United States Northeast. Surveys assessed provider characteristics and experience, reported practices addressing tobacco use, and knowledge and attitudes regarding medications for TUD. Chi-square tests or Fisher’s exact tests were used to examine differences in responses between clinicians and staff who were prescribers versus nonprescribers and to examine factors associated with frequency of prescribing TUD medications. Among 118 survey respondents (56% prescribers), only 50% reported receiving prior training on brief smoking cessation interventions. Examining reported practices identified gaps in the delivery of TUD care, including counseling patients on the impact of smoking on HIV, knowledge of clinical practice guidelines, and implementation of assessment and brief interventions for smoking. Among prescribers, first-line medications for TUD were infrequently prescribed and concerns about medication side effects and interaction with antiretroviral treatments were associated with low frequency of prescribing. HIV clinicians and staff reported addressable gaps in their knowledge, understanding, and practices related to tobacco treatment. Additional work is needed to identify ways to ensure adequate training for providers to enhance the delivery of TUD treatment in HIV clinic settings. Clinicians and staff who work with patients living with HIV reported addressable gaps in knowledge, understanding, and practices related to treating tobacco use disorder.

Abstract Background We ascertained incidence of opportunistic infections (OIs) in people with human immunodeficiency virus (PWH) with cancer undergoing chemotherapy with non-human immunodeficiency virus (HIV) comparators. Methods We identified 2106 PWH and 2981 uninfected Veterans with cancer who received at least 1 dose of chemotherapy between 1996 and 2017 from the Veterans Aging Cohort Study. We ascertained incident OIs within 6 months of chemotherapy amongst zoster, cytomegalovirus, tuberculosis, Candida esophagitis, Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, Cryptococcosis, atypical Mycobacterium infection, Salmonella bacteremia, histoplasmosis, coccidioidomycosis, or progressive multifocal leukoencephalopathy. We used Poisson methods to calculate OI incidence rates by HIV status, stratifying for hematological and nonhematological tumors. We compared OI rates by HIV status, using inverse probability weights of HIV status, further adjusting for PCP prophylaxis. Results We confirmed 106 OIs in 101 persons. Adjusted OI incidence rate ratios (IRRs) indicated higher risk in PWH for all cancers (IRR, 4.8; 95% confidence interval [CI], 2.8–8.2), hematological cancers (IRR, 8.2; 95% CI, 2.4–27.3), and nonhematological cancers (IRR, 3.9; 95% CI, 2.1–7.2). Incidence rate ratios were not significantly higher in those with CD4 >200 cells/mm3 and viral load <500 copies/mL (IRR, 1.8; 95% CI, 0.9–3.2). All PCP cases (n = 11) occurred in PWH, with 2 microbiologically unconfirmed cases among 1467 PWH with nonhematological cancers, no PCP prophylaxis, and CD4 counts >200/mm3. Conclusions Veterans with HIV undergoing chemotherapy had higher rates of OIs than uninfected Veterans, particularly those with hematological cancers, but not in PWH with HIV controlled disease. Our study does not support systematic PCP prophylaxis in solid tumors in PWH with HIV controlled disease.

Non-AIDS-defining cancers are a growing source of morbidity for people with HIV globally. Although people living with HIV have a disproportionately increased risk of developing virally mediated cancers, cancer burden for common non-AIDS-defining cancers that are not virally associated and are linked to ageing, such as prostate cancer, is becoming higher than for virally mediated cancers. Ageing, behavioural, and HIV-specific factors drive the incidence and affect the outcomes of non-AIDS-defining cancers, presenting different challenges for addressing global morbidity and mortality from non-AIDS-defining cancer. Although large population-based studies have shown that people living with HIV with non-AIDS-defining cancers have poorer cancer outcomes than do people without HIV, current guidelines emphasise that people living with HIV with non-AIDS-defining cancers should receive standard, guideline-based treatment, and infectious disease and oncology providers should work closely to address potential drug interactions between antiretroviral therapy and antineoplastic treatment. Most trials target preventive measures focusing on non-AIDS-defining cancers. However, treatment trials for the optimal management of people living with HIV and non-AIDS-defining cancer, including interventions such as immunotherapies, are needed to improve non-AIDS-defining cancer outcomes.

Tobacco use disorder (TUD) is a major threat to health among people with HIV (PWH), but it is often untreated. Among HIV clinicians and staff, we sought to characterize practices, attitudes, and confidence addressing TUD among PWH to identify potential opportunities to enhance provision of care. Cross-sectional deidentified, web-based surveys were administered from November 4, 2020 through December 15, 2020 in HIV clinics in three health systems in the United States Northeast. Surveys assessed provider characteristics and experience, reported practices addressing tobacco use, and knowledge and attitudes regarding medications for TUD. Chi-square tests or Fisher's exact tests were used to examine differences in responses between clinicians and staff who were prescribers versus nonprescribers and to examine factors associated with frequency of prescribing TUD medications. Among 118 survey respondents (56% prescribers), only 50% reported receiving prior training on brief smoking cessation interventions. Examining reported practices identified gaps in the delivery of TUD care, including counseling patients on the impact of smoking on HIV, knowledge of clinical practice guidelines, and implementation of assessment and brief interventions for smoking. Among prescribers, first-line medications forTUD were infrequently prescribed and concerns about medication side effects and interaction with antiretroviral treatments were associated with low frequency of prescribing. HIV clinicians and staff reported addressable gaps in their knowledge, understanding, and practices related to tobacco treatment. Additional work is needed to identify ways to ensure adequate training for providers to enhance the delivery ofTUD treatment in HIV clinic settings. Keywords: HIV, Tobacco, Smoking, Varenicline, Nicotine replacementtherapy, Implementation science

Single-molecule FRET (smFRET) is a versatile technique to study the dynamics and function of biomolecules since it makes nanoscale movements detectable as fluorescence signals. The powerful ability to infer quantitative kinetic information from smFRET data is, however, complicated by experimental limitations. Diverse analysis tools have been developed to overcome these hurdles but a systematic comparison is lacking. Here, we report the results of a blind benchmark study assessing eleven analysis tools used to infer kinetic rate constants from smFRET trajectories. We test them against simulated and experimental data containing the most prominent difficulties encountered in analyzing smFRET experiments: different noise levels, varied model complexity, non-equilibrium dynamics, and kinetic heterogeneity. Our results highlight the current strengths and limitations in inferring kinetic information from smFRET trajectories. In addition, we formulate concrete recommendations and identify key targets for future developments, aimed to advance our understanding of biomolecular dynamics through quantitative experiment-derived models. The ability to infer quantitative kinetic information from single-molecule FRET (smFRET) data can be challenging. Here the authors perform a blind benchmark study assessing different analysis tools used to infer kinetic rate constants from smFRET trajectories, testing on simulated and experimental data.

While previous cost-effectiveness studies on pembrolizumab in stage IV non-small cell lung cancer (NSCLC) have found these regimens to be cost-effective, their reliance on randomized controlled trial (RCT) data with strict inclusion criteria limits generalizability to patients with comorbidities. We estimated the cost-effectiveness of first-line pembrolizumab for patients with various comorbidities. In our base case analysis, we studied pembrolizumab plus chemotherapy (pembrolizumab combination therapy) versus chemotherapy alone. In a secondary analysis, we considered only patients with PD-L1 expression of at least 50% (PD-L1-high) and evaluated pembrolizumab monotherapy, pembrolizumab combination therapy, and chemotherapy alone. Microsimulation models were developed for the base case and the PD-L1-high analyses. To estimate outcomes of patients with differing comorbidities, we combined survival data from patients with few or no comorbidities from the RCTs with estimates from the general population obtained from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Comorbidity burden level was divided into three groups based on the Charlson score (equal to 0, 1, or 2+); patients with various other specific comorbidities were also analyzed. Incremental cost-effectiveness ratios (ICER) were compared to a willingness-to-pay (WTP) threshold of $100,000/quality-adjusted life-year (QALY). In the Charlson 0, Charlson 1, and Charlson 2+ patient populations, estimated ICERs for pembrolizumab combination therapy in the base case model were $173,919/QALY, $175,165/QALY, and $181,777/QALY, respectively, compared to chemotherapy. In the PD-L1-high model, the Charlson 0, Charlson 1, and Charlson 2+ patients had ICERs of $147,406/QALY, $149,026/QALY, and $154,521/QALY with pembrolizumab combination therapy versus chemotherapy. Pembrolizumab monotherapy was weakly dominated for each comorbidity group in the PD-L1-high model. For patients with stage IV NSCLC and varying comorbidity burden, first-line treatment with pembrolizumab does not represent a cost-effective strategy compared to chemotherapy. Resources should be focused on collecting immunotherapy survival data for more representative NSCLC patient populations.