Recent and projected incidence trends and risk of anal cancer among people with HIV in North america.

BACKGROUND: Anal cancer risk is elevated among people with HIV (PWH). Recent anal cancer incidence patterns among PWH in the United States (US) and Canada remain unclear. It is unknown how the incidence patterns may evolve in future years. METHODS: Using data from the North American AIDS Cohort Collaboration on Research and Design, we investigated absolute anal cancer incidence and incidence trends in the US, Canada, and different US regions. We further estimated relative risk compared with persons without HIV, relative risk among various subgroups, and projected future anal cancer burden among US PWH. RESULTS: During 2001-2016, in the US, age-standardized anal cancer incidence declined 2.2%/year (95%CI=-4.4% to -0.1%), particularly in the Western region (-3.8%/year [95%CI=-6.5% to -0.9%]. In Canada, incidence remained stable. Considerable geographic variation in risk was observed by US regions (eg, over four-fold risk in the Midwest and Southeast compared to the Northeast among men who have sex with men [MSM] with HIV). Anal cancer risk increased with a decrease in nadir CD4 count and was elevated among those with opportunistic illnesses. Anal cancer burden among US PWH is expected to decrease in future years (through 2035), but >70% of cases will continue to occur in MSM with HIV and people with AIDS. CONCLUSION: Geographic variation in anal cancer risk and trends may reflect underlying differences in screening practices and HIV epidemic. MSM with HIV and PWH with AIDS will continue to bear most anal cancer burden, highlighting the importance of precision prevention.

Host Nuclear Genome Copy Number Variations Identify High-Risk Anal Precancers in People Living with HIV.

BACKGROUND: People living with HIV (PLWH) have substantially increased incidence of anal precancer and cancer. There are very little data regarding genomic disturbances in anal precancers among PLWH. Here, we identified specific chromosomal variants in anal squamous intraepithelial lesions. METHODS: We collected 63 anal biopsy specimens (27 low-grade intraepithelial lesions [LSIL] and 36 high-grade intraepithelial lesions [HSIL]) from PLWH obtained as part of anal cancer screening in our NYC-based health system. Data on patient demographics, anal cytological and high-risk human papillomavirus (HR-HPV) diagnoses were collected. Specimens were tested for a panel of chromosomal alterations associated with HPV-induced oncogenesis using Fluorescence In-Situ Hybridization (FISH) and analyses compared the associations of these alterations with clinical characteristics. RESULTS: Gains of 3q26, 5p15, 20q13 and cen7 were detected in 42%, 31%, 31%, and 19% of HSIL compared to 7%, 0%, 4%, and 0% of LSIL, respectively. Where at least one abnormality was seen, 89% had a 3q26 gain. In lesions with 5p15 gains, 20q13 gains co-occurred in 91% of cases, while cen7 gain only co-occurred with the other three alterations. Sensitivity and specificity of any alteration to predict HSIL was 47% (95% CI: 30-65%) and 93% (95% CI: 76%-99%) respectively. CONCLUSIONS: Genomic alterations seen in HPV-associated cancers may help distinguish anal LSIL from HSIL. 3q26 amplification may be an early component of anal carcinogenesis, preceding 5p16, 20q13 and/or chr7. IMPACT: We share insights on potential genomic biomarkers for discriminating high-risk anal precancers.

Discordance Between Insurance Coverage of Antiviral Medications and Nicotine Replacement Therapy Among Individuals With Human Immunodeficiency Virus Who Smoke.

INTRODUCTION: Tobacco contributes to the leading causes of morbidity and mortality among persons with human immunodeficiency virus (PWHs). Nonetheless, medications for tobacco use disorder are widely underused, particularly among PWHs. We sought to characterize the extent to which insurance barriers impacted access to medications for tobacco use disorder and, in comparison, to access to antiretroviral therapy (ART). METHODS: This is a secondary analysis of data on individuals enrolled in a randomized clinical trial to address tobacco use involving nicotine replacement therapy and, for some, additionally, varenicline or bupropion. Medication prescriptions are transmitted electronically from the clinic to neighborhood pharmacies. Data sources included participant assessments and intervention visit tracking forms. RESULTS: Of 93 participants enrolled from September 2020 to July 2021, 20 (22%) were unable to fill or had difficulty filling their nicotine replacement therapy (NRT) prescriptions because of insurance barriers. These fell into 2 broad categories: enrollment in a publicly insured managed care plan in which the pharmacy benefit manager excluded nonprescription NRT and lack of understanding by the pharmacy of the scope of coverage. Of these 20 participants, 5 (25%) were unable to obtain medications at all, and 3 of these participants dropped out of the study. One additional participant paid out-of-pocket to obtain NRT. No participant was denied coverage of ART, bupropion, or varenicline. CONCLUSIONS: Gaps in insurance coverage may result in PWHs receiving ART without simultaneous medical management of their tobacco use. This may undermine the efficacy of antivirals. Mandated insurance coverage of nonprescription NRT may improve the health of PWHs who smoke.

The Benefits and Harms of Lung Cancer Screening in Individuals With Comorbidities.

Introduction: Individuals with a history of smoking and a high risk of lung cancer often have a high prevalence of smoking-related comorbidities. The presence of these comorbidities might alter the benefit-to-harm ratio of lung cancer screening by influencing the risk of complications, quality of life, and competing risks of death. Nevertheless, individuals with chronic diseases are underrepresented in screening clinical trials. In this study, we use microsimulation modeling to determine the impact of chronic diseases on lung cancer benefits and harms. Methods: We extended a validated lung cancer screening microsimulation model that comprehensively recapitulates an individual's lung cancer development, progression, detection, follow-up, treatment, and survival. We parameterized the model to reflect the impact of chronic diseases on complications from invasive testing, quality of life, and mortality in individuals in five-year age categories between the ages of 50 and 80 years. Outcomes included life-years (LY) gained per 100,000 in patients with chronic obstructive pulmonary disease, diabetes mellitus, heart disease, and history of stroke compared with screening-eligible individuals without comorbidities. Results: Among individuals between the ages of 50 and 54 years, we found that the presence of a comorbidity altered the LY gained from screening per 100,000 individuals depending on the comorbidity: 4296 LY with no comorbidities; 3462 LY, 3260 LY, 3031 LY, and 3257 LY with chronic obstructive pulmonary disease, heart disease, diabetes mellitus, and stroke, respectively. We observed greater reductions in LY gained in individuals with two comorbidities; we observed similar patterns for individuals between the ages of 55 and 59 years, 60 and 64 years, 65 and 69 years, 70 and 74 years, and 75 and 80 years. Conclusions: Comorbidities reduce LY gained from screening per 100,000 compared with no comorbidities, and our results can be used by clinicians when discussing the benefits and harms of screening in their patients with comorbidities.

State of the science and future directions for research on HIV and cancer: Summary of a joint workshop sponsored by IARC and NCI.

An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented.

Anal cancer screening results from 18-to-34-year-old men who have sex with men living with HIV.

Men who have sex with men living with HIV (MSM LWH) are at highest risk for human papillomavirus (HPV)-associated anal cancer. There is no consensus on the optimal screening initiation age. This study aimed to assess the prevalence and severity of anal HPV disease among MSM LWH under the age of 35, which is a currently proposed screening age threshold. Between 2014 and 2020, 1255 18-to-34-year-old MSM LWH underwent anal cytology screening. 916 were co-tested for high-risk HPV (HR-HPV). 467 underwent high-resolution anoscopy (HRA) and biopsy. Cancer registry data were queried. Predictors of abnormal cytology (ie, ≥ASCUS) and histological high-grade squamous intraepithelial lesions (HSIL) were evaluated using unadjusted logistic regression models. Median age was 28 years (range, 18-34). 19% received at least one dose of HPV vaccine. Abnormal cytology rate was 65%. HR-HPV and HPV16 prevalence were 87% and 30%. Biopsy results were benign (10%), LSIL (43%) and HSIL (47%). No cases of prevalent or incident anal cancers were detected. Findings were similar between age subgroups (18-24, 25-29 and 30-34) except for a higher prevalence of AIN 3 in the 30-34 group (19%). Abnormal cytology was significantly associated with HR-HPV infection. Histological HSIL was associated with HR-HPV infection and cytological LSIL or worse. The absence of anal cancer in a large cohort of MSM LWH under the age of 35, despite high prevalence of anal HR-HPV infection and precancer, supports an age-based anal cancer screening strategy for MSM LWH.

Deployment and assessment of a deep learning model for real-time detection of anal precancer with high frame rate high-resolution microendoscopy.

Anal cancer incidence is significantly higher in people living with HIV as HIV increases the oncogenic potential of human papillomavirus. The incidence of anal cancer in the United States has recently increased, with diagnosis and treatment hampered by high loss-to-follow-up rates. Novel methods for the automated, real-time diagnosis of AIN 2+ could enable "see and treat" strategies, reducing loss-to-follow-up rates. A previous retrospective study demonstrated that the accuracy of a high-resolution microendoscope (HRME) coupled with a deep learning model was comparable to expert clinical impression for diagnosis of AIN 2+ (sensitivity 0.92 [P = 0.68] and specificity 0.60 [P = 0.48]). However, motion artifacts and noise led to many images failing quality control (17%). Here, we present a high frame rate HRME (HF-HRME) with improved image quality, deployed in the clinic alongside a deep learning model and evaluated prospectively for detection of AIN 2+ in real-time. The HF-HRME reduced the fraction of images failing quality control to 4.6% by employing a high frame rate camera that enhances contrast and limits motion artifacts. The HF-HRME outperformed the previous HRME (P < 0.001) and clinical impression (P < 0.0001) in the detection of histopathologically confirmed AIN 2+ with a sensitivity of 0.91 and specificity of 0.87.

Clinical Characteristics and Outcomes of Patients With Mpox Who Received Tecovirimat in a New York City Health System.

Background: The 2022 global mpox outbreak was notable for transmission between persons outside of travel and zoonotic exposures and primarily through intimate contact. An understanding of the presentation of mpox in people with human immunodeficiency virus (HIV) and other immunocompromising conditions and knowledge of the efficacy of tecovirimat continue to evolve. Methods: This retrospective study describes clinical features and outcomes of persons with mpox who received tecovirimat. Data were obtained via medical record review of patients prescribed tecovirimat in a health system in New York City during the height of the outbreak in 2022. Results: One hundred thirty people received tecovirimat between 1 July and 1 October 2022. People with HIV (n = 80) experienced similar rates of recovery, bacterial superinfections, and hospitalization compared to patients without immunocompromising conditions. Individuals determined to be severely immunocompromised (n = 14) had a higher risk of hospitalization than those without severe immunocompromise (cohort inclusive of those with well-controlled HIV, excluding those without virologic suppression, n = 101): 50% versus 9% (P < .001). Hospitalized patients (n = 18 [13% of total]) were primarily admitted for bacterial superinfections (44.4%), with a median hospital stay of 4 days. Of those who completed follow-up (n = 85 [66%]), 97% had recovery of lesions at time of posttreatment assessment. Tecovirimat was well tolerated; there were no reported severe adverse events attributed to therapy. Conclusions: There were no significant differences in outcomes between people with HIV when evaluated as a whole and patients without immunocompromising conditions. However, mpox infection was associated with higher rates of hospitalization in those with severe immunocompromise, including patients with HIV/AIDS. Treatment with tecovirimat was well tolerated.Key Points: In our mpox cohort, people with HIV had similar rates of recovery and complications as those without HIV or other immunocompromising conditions. Severe immunocompromise was associated with a higher hospitalization rate. Tecovirimat was well tolerated, with minimal side effects.

Brief Report: The Virome of Bladder Tumors Arising in People Living With HIV.

BACKGROUND: People living with HIV (PLWH) have elevated risk for developing virus-related cancers. Bladder cancer risk is not increased in PLWH but is elevated among immunosuppressed solid organ transplant recipients (SOTRs). BK polyomavirus and, to a lesser extent, other viruses have been detected in bladder cancers from SOTRs. OBJECTIVE: To characterize the virome of bladder tumors in PLWH. DESIGN: Retrospective case series. METHODS: We sequenced DNA and RNA from archived formalin-fixed bladder tumors from PLWH. Nonhuman reads were assembled and matched to a database of known viruses. RESULTS: Fifteen bladder tumors from PLWH (13 carcinomas, 2 benign tumors) were evaluated. Fourteen tumors were in men, and the median age at diagnosis was 59 years (median CD4 count 460 cells/mm3). All but 1 tumor yielded both sufficient DNA and RNA. One bladder cancer, arising in a 52-year-old man with a CD4 count of 271 cells/mm3, manifested diverse Alphatorquevirus DNA and RNA sequences. A second cancer arising in a 58-year-old male former smoker (CD4 count of 227 cells/mm3) also showed Alphatorquevirus and Gammatorquevirus DNA sequences. Neither tumor exhibited viral integration. CONCLUSIONS: Alphatorqueviruses and Gammatorqueviruses are anelloviruses, which have also been detected in bladder cancers from SOTRs, but anelloviruses are common infections, and detection may simply reflect increased abundance in the setting of immunosuppression. The lack of detection of BK polyomavirus among bladder tumors from PLWH parallels the lower level of bladder cancer risk seen in PLWH compared with SOTRs, indirectly supporting a role for BK polyomavirus in causing the excess risk in SOTRs.

The World Health Organization classification of pancreaticobiliary cytopathology stratifies risk of malignancy and outcome for endoscopic ultrasound-guided fine-needle aspiration of the pancreas.

BACKGROUND: The World Health Organization (WHO) has recently published a classification for reporting pancreaticobiliary cytopathology with differences compared to the Papanicolaou Society of Cytopathology (PSC) classification. METHODS: Retrospective data were collected from pancreatic endoscopic ultrasound-guided fine-needle aspirations from 2014 to 2017 at a pancreatic cancer center. Absolute risk of malignancy (AROM), relative risk (to benign), performance characteristics, and overall survival were calculated for the entire cohort with comparison of cysts and solid lesions. RESULTS: In total, 2562 cases were included: 16% cyst (n = 411) and 84% solid (n = 2151). The histologic confirmation rate was 43% (n = 1101) and the median follow-up (for benign) was 56 months. For WHO I-VII, overall AROM (%) was 23, 22, 62, 13, 65, 97, and 100; cyst AROM was 7, 0, 19, 13, 38, 78, and 100; and solid AROM was 50, 29, 70, 15, 100, 99, and 100. For PSC I-VI, overall AROM (%) was 23, 29, 64, 0 (IVa), 60 (IVb), 97, and 100; cyst AROM was 7, 0, 19, 0, 21, 78, and 100; and solid AROM was 50, 35, 73, 0, 92, 99, and 100. The difference in relative risk for a cyst (vs. solid) overall was 0.38 for WHO and 0.26 for PSC. WHO and PSC categories showed stratification for the probability of overall survival. CONCLUSIONS: Cystic versus solid lesion type can dramatically affect AROM, particularly for nondiagnostic (I), benign (II), atypical (III), and WHO V categories. WHO IV conveys a similarly low AROM for cystic and solid types. Both classifications stratify the probability of overall survival, including the newly introduced categories WHO IV and WHO V.

Comparison of Stage I Non-Small-Cell Lung Cancer Treatments for Patients Living With HIV: A Simulation Study.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is a leading cause of death for people living with HIV (PWH). Nevertheless, there are no clinical trial data regarding the management of early-stage lung cancer in PWH. Using data from large HIV and cancer cohorts we parameterized a simulation model to compare treatments for stage I NSCLC according to patient characteristics. MATERIALS AND METHODS: To parameterize the model we analyzed PWH and NSCLC patient outcomes and quality of life data from several large cohort studies. Comparative effectiveness of 4 stage I NSCLC treatments (lobectomy, segmentectomy, wedge resection, and stereotactic body radiotherapy) was estimated using evidence synthesis methods. We then simulated trials comparing treatments according to quality adjusted life year (QALY) gains by age, tumor size and histology, HIV disease characteristics and major comorbidities. RESULTS: Lobectomy and segmentectomy yielded the greatest QALY gains among all simulated age, tumor size and comorbidity groups. Optimal treatment strategies differed by patient sex, age, and HIV disease status; wedge resection was among the optimal strategies for women aged 80 to 84 years with tumors 0 to 2 cm in size. Stereotactic body radiotherapy was included in some optimal strategies for patients aged 80 to 84 years with multimorbidity and in sensitivity analyses was a non-inferior option for many older patients or those with poor HIV disease control. CONCLUSION: In simulated comparative trials of treatments for stage I NSCLC in PWH, extensive surgical resection was often associated with the greatest projected QALY gains although less aggressive strategies were predicted to be non-inferior in some older, comorbid patient groups.

Impact of diabetes on stage I lung cancer treatment patterns and prognosis in older adults: A population-based cohort study.

Background: Diabetes is a common comorbidity in patients with early-stage non-small cell lung cancer (NSCLC), a growing population due to increased LC screening. However, it is unknown if diabetes is associated with less aggressive NSCLC treatment and worse NSCLC outcomes. This study aimed to investigate treatment patterns and outcomes of older patients with Stage I NSCLC and diabetes. Methods: Using national cancer registry data linked to Medicare, we identified patients ≥65 years old with Stage I NSCLC. Patients were categorized as having no diabetes, diabetes without severe complications (DM-c), or diabetes with ≥1 severe complication (DM + c). We used multinomial logistic regression to assess the association of diabetes and NSCLC treatment. The association of diabetes category with NSCLC and non-NSCLC survival was analyzed with Fine-Grey competing-risks regression. Results: In 25,358 patients (75% no diabetes, 12% DM-c and 13% had DM + c), adjusted analyses showed that DM-c and DM + c were associated with increased odds of receiving limited resection rather than lobectomy (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.07-1.37 and OR 1.42, 95% CI 1.26-1.59, respectively). Competing risk regression showed diabetes was associated with increased risk of non-NSCLC death (DM-c hazard ratio [HR] 1.16, 95% CI: 1.08-1.25, DM + c HR 1.49, 95% CI: 1.40-1.59), but not NSCLC-specific death. Conclusion: This study uncovers critical information on how diabetes is associated with less aggressive early-stage NSCLC care in older patients. This study also confirms that diabetes increases death from non-lung cancer causes and managing comorbidities is crucial to improving outcomes in older early-stage NSCLC survivors.

Evaluation of 2-year outcomes in infants born to mothers with and without NAFLD in pregnancy.

Nonalcoholic fatty liver disease (NAFLD) affects an estimated 17% of pregnant patients in the USA. However, there are limited data on the impact of maternal NAFLD on pediatric outcomes. We prospectively evaluated outcomes in infants born to mothers with and without NAFLD in pregnancy over their first 2 years of life. Maternal subjects were identified through an ongoing prospective study in which pregnant individuals were screened for NAFLD. Pediatric outcomes of infants born to these mothers-including adverse neonatal outcomes and weight and weight-for-length percentile at 6, 12, 18, and 24 months-were prospectively evaluated. Multivariate logistic regression was performed to evaluate the association of maternal NAFLD with pediatric outcomes, as well as to adjust for potentially confounding maternal characteristics. Six hundred thirty-eight infants were included in our cohort. The primary outcomes assessed were weight and growth throughout the first 2 years of life. Maternal NAFLD was also not associated with increased infant birth weight or weight-for-gestational-age percentile or weight or weight-for-length percentile over the first 2 years of life. Maternal NAFLD was significantly associated with very premature delivery before 32 weeks, even after adjustment for confounding maternal characteristics (aOR = 2.83, p = 0.05). Maternal NAFLD was also significantly associated with neonatal jaundice, including after adjusting for maternal race (aOR = 1.67, p = 0.03). However, maternal NAFLD was not significantly associated with any other adverse neonatal outcomes.    Conclusion: Maternal NAFLD may be independently associated with very premature birth and neonatal jaundice but was not associated with other adverse neonatal outcomes. Maternal NAFLD was also not associated with any differences in infant growth over the first 2 years of life. What is Known: • Maternal NAFLD in pregnancy may be associated with adverse pregnancy and neonatal outcomes, but the findings are inconsistent across the literature. What is New: • Maternal NAFLD is not associated with any differences in weight at birth or growth over the first 2 years of life. • Maternal NAFLD is associated with very premature delivery and neonatal jaundice, but is not associated with other adverse neonatal outcomes.

Neutrophil-to-lymphocyte ratio as a predictor of surgical outcomes in head and neck cancer.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is a biomarker of systemic inflammation that is associated with adverse oncologic and surgical outcomes. We investigated the use of NLR as a prognostic indicator of complications of head and neck cancer (HNC) surgeries. METHODS: We conducted a retrospective study of 11 187 Veterans who underwent HNC surgery between 2000 and 2020. We calculated preoperative NLR values and fit logistic regression models adjusting for potential confounding factors, comparing high-NLR patients to low-NLR patients. RESULTS: The cohort had a median age of 63 and was 98% men. High-NLR patients had increased odds of 30-day mortality (p < 0.001), having 1+ perioperative complications (p < 0.001), sepsis (p = 0.03), failure to wean from mechanical ventilation (p = 0.04), pneumonia (p < 0.001), and pulmonary embolism (p = 0.02) compared with low-NLR patients. CONCLUSION: NLR was a robust, independent predictor of 30-day mortality, having 1+ surgical complications, sepsis, failure to wean from mechanical ventilation, pneumonia, and pulmonary embolism.

Timely adherence to follow-up after high-risk lung cancer screenings.

OBJECTIVE: To achieve the lung cancer screening (LCS) mortality benefit in clinical trials, timely, real-world follow-up of abnormal test results is necessary. Presently, annual LCS rates are lower than in trials, and adherence to follow-up after suspicious findings has not been well studied. This study examined timely adherence to follow-up recommendations after positive low-dose computed tomography (LDCT) screenings. METHODS: This retrospective study included individuals from two academic primary care practices in New York City who met United States Preventative Services Task Force LCS eligibility and had a positive LDCT scan between 2013 and 2020. They were recommended for shorter interval follow-up repeat computed tomography (CT), CT biopsy, or positron emission tomography/CT. Adherence was completion of the prescribed imaging by 15 days after the recommended 7-, 30-, and 90-day follow-up and by 30 days after the 180-day recommended follow-up. RESULTS: Among 106 individuals with a positive LDCT scan, 64 (60%) were adherent to follow-up recommendations. Adherence was 72%, 63%, and 42% for recommended follow-ups of 30, 90, and 180 days, respectively. Being male was a predictor of a lower adherence rate. Among 23 individuals newly diagnosed with lung cancer after a positive LDCT scan, 83% were adherent to follow-up testing and 82% of cancers were Stage 1A or limited stage. CONCLUSIONS: There was variable adherence to the LCS follow-up recommendations despite positive screening CT, suggesting that even in a well-established screening program there may not be an efficient, systematic approach for follow-up. The delays in repeat testing potentially undermine the benefits of early detection.

Association of Antibiotic Receipt With Survival Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Receiving Chemotherapy.

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 ß-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.

Automated In Vivo High-Resolution Imaging to Detect Human Papillomavirus-Associated Anal Precancer in Persons Living With HIV.

INTRODUCTION: In the United States, the effectiveness of anal cancer screening programs has been limited by a lack of trained professionals proficient in high-resolution anoscopy (HRA) and a high patient lost-to-follow-up rate between diagnosis and treatment. Simplifying anal intraepithelial neoplasia grade 2 or more severe (AIN 2+) detection could radically improve the access and efficiency of anal cancer prevention. Novel optical imaging providing point-of-care diagnoses could substantially improve existing HRA and histology-based diagnosis. This work aims to demonstrate the potential of high-resolution microendoscopy (HRME) coupled with a novel machine learning algorithm for the automated, in vivo diagnosis of anal precancer. METHODS: The HRME, a fiber-optic fluorescence microscope, was used to capture real-time images of anal squamous epithelial nuclei. Nuclear staining is achieved using 0.01% wt/vol proflavine, a topical contrast agent. HRME images were analyzed by a multitask deep learning network (MTN) that computed the probability of AIN 2+ for each HRME image. RESULTS: The study accrued data from 77 people living with HIV. The MTN achieved an area under the receiver operating curve of 0.84 for detection of AIN 2+. At the AIN 2+ probability cutoff of 0.212, the MTN achieved comparable performance to expert HRA impression with a sensitivity of 0.92 ( P = 0.68) and specificity of 0.60 ( P = 0.48) when using histopathology as the gold standard. DISCUSSION: When used in combination with HRA, this system could facilitate more selective biopsies and promote same-day AIN2+ treatment options by enabling real-time diagnosis.

Diagnostic features of low- and high-grade mucinous neoplasms in pancreatic cyst FNA cytology.

BACKGROUND: Pancreatic cyst cytology evaluates for neoplastic mucin and epithelial grade. This study describes cytological features of low- and high-grade mucinous neoplasms (MNs) using gastrointestinal contaminants for comparison. METHODS: Histologically confirmed pancreatic cystic neoplasms were reviewed by a panel of cytopathologists to identify which, among 26 selected cytologic features, correlate significantly with low- and high-grade MN. A test for greater than or equal to four of eight high-grade features (three-dimensional architecture, high nuclear:cytoplasmic ratio, moderate nuclear membrane abnormalities, loss of nuclear polarity, hyperchromasia, >4:1 nuclear size variation in one cluster, karyorrhexis, and necrosis) was assessed for identifying a high-grade neoplasms. Additional characteristics of the cohort such as cyst fluid carcinoembryonic antigen results, molecular testing, Papanicolaou Society of Cytopathology classification, and select high-risk clinical features are described. RESULTS: Endoscopic ultrasound fine-needle aspirations from 134 MN and 17 serous cystadenomas containing gastrointestinal contaminants were included. The MN consisted of 112 (84%) intraductal papillary MNs (low-grade = 69, 62%; high-grade = 24, 21%; and invasive = 19, 17%) and mucinous cystic neoplasms (low-grade = 20, 90%; high-grade = 2, 10%). Half had greater than five clusters of epithelium for analysis. Compared with gastrointestinal contaminants, mucin from MN was thick and colloid-like (40% vs. 6%, p < .01), covered >20% of the smear area (32% vs. none, p < .01), and contained histiocytes (46% vs. 18%, p = .04). Greater than or equal to four of eight select high-grade features was present in 36% of high-grade MN with sensitivity 37% and 98% specificity. CONCLUSION: Colloid-like features, >20% of smear, and histiocytes correlated with MN. Testing for greater than or equal to four high-grade features had low sensitivity and high specificity for high-grade MN.

Tumor Growth Rate Informs Treatment Efficacy in Metastatic Pancreatic Adenocarcinoma: Application of a Growth and Regression Model to Pivotal Trial and Real-World Data.

BACKGROUND: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.