Differential sensitivity of inbred mouse strains to ovarian damage in response to low-dose total body irradiation†.

Radiation induces ovarian damage and accelerates reproductive aging. Inbred mouse strains exhibit differential sensitivity to lethality induced by total body irradiation (TBI), with the BALB/cAnNCrl (BALB/c) strain being more sensitive than the 129S2/SvPasCrl (129) strain. However, whether TBI-induced ovarian damage follows a similar pattern of strain sensitivity is unknown. To examine this possibility, female BALB/c and 129 mice were exposed to a single dose of 1 Gy (cesium-137 γ) TBI at 5 weeks of age, and ovarian tissue was harvested for histological and gene expression analyses 2 weeks post exposure. Sham-treated mice served as controls. 1 Gy radiation nearly eradicated the primordial follicles and dramatically decreased the primary follicles in both strains. In contrast, larger growing follicles were less affected in the 129 relative to BALB/c strain. Although this TBI paradigm did not induce detectable ovarian fibrosis in either of the strains, we did observe strain-dependent changes in osteopontin (Spp1) expression, a gene involved in wound healing, inflammation, and fibrosis. Ovaries from BALB/c mice exhibited higher baseline Spp1 expression that underwent a significant decrease in response to radiation relative to ovaries from the 129 strain. A correspondingly greater change in the ovarian matrix, as evidenced by reduced ovarian hyaluronan content, was also observed following TBI in BALB/c mice relative to 129 mice. These early changes in the ovary may predispose BALB/c mice to more pronounced late effects of TBI. Taken together, our results demonstrate that aspects of ovarian damage mirror other organ systems with respect to overall strain-dependent radiation sensitivity.

"Closing the Gap": Provider Recommendations for Implementing Birth Point of Care HIV Testing.

Delays in traditional HIV DNA PCR testing for early infant diagnosis (EID) at 6 weeks of age result in late antiretroviral treatment (ART). Birth point of care (POC) testing is an emerging strategy with the potential to streamline EID services. We elicited providers' recommendations for introducing birth POC testing to guide strategies in Kenya and similar settings. We conducted formative interviews with 26 EID providers from four Kenyan hospitals prior to POC implementation. Providers discussed the need for comprehensive training, covering both EID and POC-specific topics for all key personnel. Providers highlighted equipment considerations, such as protocols for maintenance and safe storage. Providers emphasized the need for maternal counseling to ensure patient acceptance and most agreed that specimen collection for birth POC testing should occur in the maternity department and supported a multidisciplinary approach. Though most providers supported ART initiation based on a positive birth POC result, a few expressed concerns with result validity. To maximize implementation success, provider training, equipment security, maternal counseling, and logistics of testing must be planned and communicated to providers.

Health Disparities in Presentation, Treatment, Genomic Testing, and Outcomes of Pancreatic Cancer in Hispanic and Non-Hispanic Patients.

BACKGROUND: There are few conflicting results regarding the treatment and outcomes of Hispanic patients with pancreatic cancer. This study comprehensively evaluated the differences in baseline characteristics, treatments, genomic testing, and outcomes among Hispanic (H) and Non-Hispanic (NH) patients with early-stage (ES) and late-stage (LS) pancreatic cancer (PC). METHODS: This is a retrospective analysis from 2013 to 2020 of 294 patients with pancreatic ductal adenocarcinoma; data collected included patient demographics, clinical characteristics, treatment regimens, response, germline and somatic genetic testing, and survival outcomes. Excluded those with insufficient data. Univariate comparisons used parametric and nonparametric tests as appropriate to evaluate for differences between H and NH groups. Fisher's exact tests were performed to evaluate the difference in frequency. Kaplan-Meier and Cox regression analysis assessed the survival. RESULTS: The analysis included 198 patients who had a late-stage disease and 96 patients with early-stage disease at the time of diagnosis. Among the early-stage patients, the median age at diagnosis was 60.7 years in the H versus 66.7 years in the NH (p = 0.03). No other differences were observed in baseline characteristics, treatments offered, and median overall survival (NH 25 vs. H 17.7 months, p = 0.28). Performance status, negative surgical margins, and adjuvant therapy were clinically significant and univariable with improved OS (p < 0.05), regardless of ethnicity. Hispanic patients with early pancreatic cancer were noted to be at a greater risk of death with a statistically significant hazard ratio of 3.1 (p = 0.005, 95% CI, 1.39-6.90). Among the late-stage patients, Hispanic patients with ≥ 3 predisposing risk factors for pancreatic cancer were 44% vs. 25% of NH (p = 0.006). No significant differences were noted in baseline characteristic treatments, progression-free, and median overall survivals (NH 10.0 vs. 9.2 months, p = 0.4577). In the late-stage genomic testing, germline testing performed in NH 69.4% vs. H 43.9% (p = 0.003) revealed no difference among groups. For the somatic testing, the pathogenic variants with actionable mutations were 2.5% of NH and 17.6% of H patients (p = 0.03). CONCLUSION: Hispanic patients with early-stage pancreatic adenocarcinoma present at a younger age and with more risk factors in the late stage. These patients have significantly lower overall survival compared to their non-Hispanic counterparts. Hispanic patients in our study were 2.9 less likely to receive germline screening and more like to have somatic genetic actionable pathogenic variants. Overall, only a minority of all patients were enrolled in a pancreatic cancer clinical trial or offered genomic testing, highlighting a critical need and missed opportunity in advancing progress and improving outcomes for this disease, mainly in the underrepresented Hispanic population.

Cholangiocarcinoma: a review of the literature and future directions in therapy.

Cholangiocarcinomas (CCA) are a group of rare cancers with an incidence of about 1.26 per 100,000 people. The disease reflects one of three different subtypes: intrahepatic, perihilar or hilar and distal cholangiocarcinoma. The preferred modality of definitive therapy is surgical resection with or without adjuvant therapy, however the majority of patients with this disease do not present at an early stage. Some efforts to improve survival rates have come in the form of offering neoadjuvant therapy prior to surgical resection or liver transplantation. Some new protocols are in the process of development for neoadjuvant therapy. Despite advancements in locally advanced or borderline resectable lesions, most patient present at an advanced stage. The mainstay of treatment for advanced stage disease is chemotherapy regardless of location. The mainstay of treatment in fit patients is the combination of gemcitabine and cisplatin. The addition of nab-paclitaxel to this backbone is currently being evaluated in phase III trial. In addition, the role of targeted therapy is currently being studied extensively through multiple different mutational pathways including isocitrate dehydrogenase-1 (IDH1), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and ERBB2 (HER2/neu). CCA remains a significant challenge in medicine, however recent studies have shown that there is significant interest in advancing therapy in the form of neoadjuvant, adjuvant and palliative intent treatment.