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Objective: To investigate the impact of chemotherapy on the uterus., Design: Cross-sectional pilot study., Setting: Single university fertility clinic., Patients: Twelve patients with a history of alkylating agent chemotherapy exposure after Hodgkin lymphoma (cancer) vs. 12 normally menstruating women (controls)., Interventions: The inclusion criteria were age of 18-45 years and consent for endometrial biopsy. The exclusion criteria were the absence of the uterus, completed pelvic radiation, uterine or cervical cancer, and metastatic cancer. Each participant underwent endometrial biopsy and pelvic ultrasound. All study visits were conducted in the late proliferative phase of the menstrual cycle., Main Outcome Measures: Uterine volume, blood flow, endometrial thickness, histology, deoxyribonucleic acid methylation pattern, and relative ribonucleic acid (RNA) expression level during the same phase of the menstrual cycle., Results: In the study group, visits were conducted at a median of 31.5 (13.5-42.5) months after chemotherapy. The median uterine volume among cancer survivors was 36 (11.3-67) cm 3 , and that of the general population controls was 39 (13-54) cm 3 . On histologic examination, there were no cytologic or architectural atypia. The RNA-sequencing analysis revealed poor clustering of both control and treatment samples. However, we identified 3 differentially expressed genes on RNA-sequencing, but there was no concordance found among the differentially expressed genes and deoxyribonucleic acid methylation changes suggesting most likely false-positive results., Conclusions: Approximately 2.5 years after chemotherapy, a time at which several survivors of Hodgkin lymphoma may resume family-building, endometrial thickness and endometrial histology were not significantly affected by a history of alkylating agent chemotherapy exposure., (© 2022 The Authors.)

A diagnosis of perineural invasion (PNI) is widely accepted as an unfavorable prognostic factor in various solid malignancies. Although PNI has been described as a high-risk parameter in oral squamous cell carcinoma (OSCC), its role in the current staging manuals of the American Joint Committee on Cancer (AJCC) is rather subordinate. We analysed the prognostic value of PNI on survival and recurrence in a large, multicenter OSCC cohort and a population-based approach. A total of 493 OSCC patients with primary tumor resection to negative margins and concomitant neck dissection between 2010 and 2017 were enrolled. PNI was evaluated in relation to overall survival (OAS) and recurrence-free survival (RFS) using uni- and multi-variable Cox regression. The median follow-up time was 5.0 years and PNI was diagnosed in 48 patients (9.7%). A pathohistological verification of PNI correlated significantly with a deteriorated OAS in uni- (HR 2.312; 95% CI 2.312-3.493, p = 0.001) and multivariable Cox regression (HR 1.820; 95% CI 1.164-2.847, p = 0.009). Additionally, a diagnosis of PNI correlated with increased cumulative, as well as distant, metastasis 5-year-recurrence rates ( p = 0.027 and p = 0.011, respectively). The application of adjuvant radiotherapy (RT) or radiochemotherapy (RCT) in patients with PNI did not alter OAS or RFS in survival analysis when compared to patients without PNI. The results underline the adverse impact of PNI on the survival and recurrence of surgically treated OSCC patients. Based on our findings, we highly recommend an emphasis on PNI in the TNM staging concept.

Microsatellite instability (MSI) is caused by defective mismatch repair in 15-20% of colorectal cancers (CRCs). Higher mutation loads in tumors with mismatch repair deficiency can predict response to pembrolizumab, an anti-programmed death 1 (PD-1) immune checkpoint inhibitor. We analyzed the mutations in 113 CRCs without MSI (MSS) and 29 CRCs with MSI-High (MSI-H) using the 50-gene AmpliSeq cancer panel. Overall, MSI-H CRCs showed significantly higher mutations than MSS CRCs, including insertion/deletion mutations at repeat regions. MSI-H CRCs showed higher incidences of mutations in the BRAF, PIK3CA, and PTEN genes as well as mutations in the receptor tyrosine kinase families. While the increased mutations in BRAF and PTEN in MSI-H CRCs are well accepted, we also support findings of mutations in the mTOR pathway and receptor tyrosine kinase family genes. MSS CRCs showed higher incidences of mutations in the APC, KRAS and TP53 genes, confirming previous findings. NGS assays may be designed to detect driver mutations for targeted therapeutics and to identify tumors with high mutation loads for potential treatment with immune checkpoint blockade therapies. Further studies may be warranted to elucidate potential targeted therapeutics against mutations in the mTOR pathway and the receptor tyrosine kinase family in MSI-H CRCs as well as the benefit of anti-PD-1 immunotherapy in hypermutated MSS CRCs or other cancers.

Single mouse cardiomyocytes were exposed to defined ischemia. We designed chambers on glass chips with a volume of 192 pL (picochambers). After a picochamber was loaded with a single cardiomyocyte, P(O2) in the picochamber was equilibrated with that in the headspace, where it was controlled in the critical range between <0.2 and 10 mm Hg. Because the extracellular fluid volume in a picochamber was restricted, these conditions are close to tissue ischemia. Responses of the sarcolemmal K(ATP)-channel current (I(KATP)), the production of reactive oxygen species (ROS), and the mitochondrial membrane potential (delta psi) of single cardiomyocytes to graded ischemia and, in particular, to rapid changes of the ischemic grade by defined oxygen steps were studied. The results show that I(KATP) is readily activated during ischemia and that the grade of ischemia tightly controls the amplitude of I(KATP). Furthermore, maximal ischemia-induced I(KATP) was similar when it followed either reoxygenation or reperfusion, suggesting that there is no major autocrine modulation of maximal I(KATP) during ischemia. A P(O2) staircase from <0.2 to 10 mm Hg increased the ROS signal, starting already at a P(O2) of approximately 0.3 mm Hg. With a similar P(O2) staircase, delta psi first hyperpolarized and then, above 1 mm Hg, depolarized. The depolarizing response of delta psi at a P(O2) of >1 mm Hg could be blocked by increasing the antioxidant defense with glutathione-monoethyl ester. It is concluded that in an ischemic cardiomyocyte I(KATP) is essentially controlled by Po(2) and that at low P(O2) delta psi is balanced by oxygen-induced hyperpolarization and ROS-induced depolarization.