Concurrent POLE hotspot mutations and mismatch repair deficiency/microsatellite instability in endometrial cancer: A challenge in molecular classification.

OBJECTIVE: Endometrial carcinoma (EC) has different molecular subtypes associated with varied prognosis. We sought to characterize the molecular features of ECs with POLE hotspot mutations and concurrent mismatch repair (MMR) deficiency/high microsatellite instability (MSI). METHODS: We identified POLE-mutated (POLEmut), MMR-deficient (MMRd)/MSI-high (MSI-H), or combined POLEmut/MMRd ECs subjected to clinical tumor-normal panel sequencing between 2014 and 2023. Clonality of somatic mutations, MSI scoring, tumor mutational burden (TMB), proportion of somatic insertions and deletions (indels), and single base substitution (SBS) mutational signatures were extracted. RESULTS: We identified 41 ECs harboring POLE exonuclease domain hotspot mutations, 138 MMRd and/or MSI-H ECs, and 14 POLEmut/MMRd ECs. Among the 14 POLEmut/MMRd ECs, 11 (79 %) exhibited clonal POLE hotspot mutations; 4 (29 %) had a dominant POLE-related mutational signature, 4 (29 %) displayed dominant MMRd-related signatures, and 6 (43 %) had mixtures of POLE, aging/clock, MMRd, and POLEmut/MMRd-related SBS mutational signatures. The number of single nucleotide variants was higher in POLEmut/MMR-proficient (MMRp) and in POLEmut/MMRd ECs compared to POLE wild-type (wt)/MMRd EC (both p < 0.001). Small indels were enriched in POLEwt/MMRd ECs (p < 0.001). TMB was highest in POLEmut/MMRd EC compared to POLEmut/MMRp and POLEwt/MMRd ECs (both p < 0.001). Of 14 patients with POLEmut/MMRd EC, 21 % had a recurrence, versus 10 % of those with POLEmut/MMRp EC. Similar findings were noted in 3 POLEmut ECs in patients with Lynch syndrome; akin to somatic POLEmut ECs, these tumors had high TMB. CONCLUSION: POLEmut/MMRd ECs may be genetically distinct. Further studies are needed to assess the impact on outcomes and treatment response within this population.

ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability-high (MSI-H) molecular subtype.

Anti-HER2 therapy is indicated for erb-b2 receptor tyrosine kinase 2 (ERBB2)-amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2-mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2-mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor-normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2-amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2-mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2-amplified. Compared to ERBB2-wildtype ECs (with or without ERBB2 amplification), ERBB2-mutated/non-amplified ECs were enriched for the microsatellite instability-high (MSI-H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2-mutated/non-amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2-wildtype and ERBB2-amplified ECs.

Use of romiplostim for antineoplastic therapy-induced thrombocytopenia in gynecologic and breast cancers.

Objective: Romiplostim is used to treat chemotherapy-induced thrombocytopenia in a variety of tumor types; however, few studies have examined its use in breast and gynecologic cancers. We evaluated platelet response and durability of response to romiplostim in patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia. Methods: We retrospectively identified 33 patients with gynecologic or breast cancer who received romiplostim between 07/1/2021-07/31/2022 at an academic cancer center. Results: Thirty-three patients met inclusion criteria; 26 (79 %) had breast cancer, 4 (12 %) had ovarian cancer, and 3 (9 %) had endometrial cancer. Twenty patients (61 %) experienced treatment delays and 12 (36 %) required dose reductions prior to starting romiplostim for chemotherapy-induced thrombocytopenia, with some patients experiencing both. Eleven patients (33 %) did not undergo a dose reduction or delay prior to initiation of romiplostim. Median platelet count prior to romiplostim therapy was 53 k/mcL (range, 40.5-78.8). Median platelet count within 3 weeks following initiation of romiplostim was 147 k/mcL (range, 31-562). Twenty-one patients (64 %) achieved platelet correction within 3 weeks, of whom 10 (48 %) resumed anticancer therapy and maintained platelet levels above 100 k/mcL at 8 weeks. Twelve patients did not achieve platelet correction within 3 weeks of romiplostim initiation; 4 (33 %) required a treatment change secondary to persistent thrombocytopenia, 3 (25 %) required a treatment dose reduction, 3 (25 %) were deemed too ill to continue therapy, and 2 (17 %) required a treatment delay. Conclusions: Romiplostim facilitated the resumption of anticancer therapy in 64 % of patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia.

Social Drivers of COVID-19 Disease Severity in Pregnant Patients.

OBJECTIVE: While coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had global impact in all populations, certain groups of patients have experienced disproportionate rates of morbidity and mortality. The purpose of this study was to assess the relationship between COVID-19 disease severity, demographic variables, race and ethnicity, and social determinants of health among pregnant patients in a diverse urban population. STUDY DESIGN: A retrospective analysis was performed of all pregnant patients diagnosed with COVID-19 at two urban tertiary care centers in Houston, TX between March and August 2020. Maternal demographic, COVID-19 illness criteria, and delivery characteristics were collected. The Centers for Disease Control and Prevention Social Vulnerability Index (SVI) and COVID-19 Community Vulnerability Index (CCVI) were obtained based on a patients' census tract of residence. Analyses compared persons with asymptomatic, mild, or severe-critical disease at diagnosis. RESULTS: A total of 317 persons tested positive for COVID-19 during this time period. Asymptomatic persons were more likely to be diagnosed at later gestational ages, but there were no other differences in baseline maternal characteristics. Persons with more severe disease had greater social vulnerability specifically for housing and transportation than those with mild disease (mean SVI [standard error]: 0.72 [0.06] vs. 0.58 [0.2], p = 0.03). Total SVI, total CCVI, and other themed SVI and CCVI indices were not significantly different between groups. CONCLUSION: In this cohort of pregnant persons infected with SARS-CoV-2, an association was shown between disease severity and increased vulnerability in living conditions and transportation. Drivers of the pandemic and COVID-19 outcomes are complex and multifactorial, and likely change over time. However, continued efforts to accurately identify and measure social determinants of health in medicine will likely help identify geographic areas and patient populations that are at risk of higher disease burden. This could facilitate preventative and mitigation measures in these areas in future disaster or pandemic situations. KEY POINTS: · SVI and CCVI estimate social determinants of health.. · COVID-19 is associated with housing and transportation vulnerability.. · Social determinants contribute to disease burden in pregnancy..

Assessing the need for venous thromboembolism prophylaxis at the time of neoadjuvant chemotherapy for ovarian cancer: A literature review.

OBJECTIVE: Gynecologic cancers, especially ovarian cancer, are associated with a high incidence of venous thromboembolism (VTE). Recent data have shown the risk of VTE development is not only limited to the postoperative period; there also appears to be an increased risk during neoadjuvant chemotherapy (NACT) administration, prompting the need for better risk stratification in this setting. We sought to assess the risk of VTE development in patients with ovarian cancer undergoing NACT. METHODS: We performed a PubMed literature review using the following medical terms: advanced ovarian cancer, advanced peritoneal cancer, advanced fallopian tube cancer, thrombosis, thromboembolic events, and neoadjuvant chemotherapy. Eligible studies included patients with advanced ovarian, fallopian tube, or peritoneal cancer who underwent NACT and had VTE. VTE was defined as either a deep venous thrombosis or a pulmonary embolism. RESULTS: Seven relevant studies were identified; all 7 were published between 2017 and 2021. Across these studies, we identified 1427 patients who underwent NACT and either had VTE at presentation or developed VTE during their treatment course. Of these patients, 1171 underwent NACT and were at risk for VTE development and were included in our pooled analysis. Of these patients, 144 (12.3%) developed VTE. CONCLUSIONS: VTE prophylaxis may be considered in patients with ovarian cancer undergoing NACT.

Novel Therapeutics in Ovarian Cancer: Expanding the Toolbox.

Despite high response rates to initial therapy, most patients with ovarian cancer will ultimately recur and go on to develop resistance to standard treatments. Novel therapies have been developed to overcome drug resistance and alter the tumor immune microenvironment by targeting oncogenic pathways, activating the innate immune response, and enhancing drug delivery. In this review, we discuss the current and future roles of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, and mirvetuximab in the treatment of ovarian cancer. We explore the emerging role of therapeutic targets, including DNA repair pathway inhibitors and novel antibody-drug conjugates. Furthermore, we delve into the role of immunotherapeutic agents such as interleukins as well as immune-promoting agents such as oncolytic viruses and cancer vaccines. Innovative combination therapies using these agents have led to a rapidly evolving treatment landscape and promising results for patients with recurrent ovarian cancer.

Infectious morbidity of speculum versus digital examinations in preterm prelabor rupture of membranes: a systematic review and meta-analysis.

OBJECTIVE: To estimate the effect of speculum examination only versus digital cervical examination on maternal infectious morbidity in women with preterm prelabor rupture of membranes by performing a systematic review and meta-analysis. MATERIALS AND METHODS: We explored MEDLINE, Scopus, Embase, CINAHL, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials for studies comparing the rate of a composite maternal infectious morbidity (either chorioamnionitis, endometritis or both) in women with preterm prelabor rupture of membranes that underwent a speculum only versus digital cervical examination at the time of diagnosis. Two reviewers separately ascertained studies, obtained data, and gauged study quality. The rate of a composite maternal infectious morbidity (either chorioamnionitis, endometritis or both) were compared and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: Four cohort studies, reporting on 1213 women were identified. The median point prevalence of the composite maternal infectious morbidity was 26% (interquartile range 15-35%) in women who had a speculum examination only compared to 33% (interquartile range 22-42%) in women who underwent a digital examination. The overall maternal composite infectious morbidity rate in women that had a speculum examination only was less compared to women that had undergone a digital examination (pooled OR 0.75, 95% CI 0.58-0.98, I2 17%). The weighted mean length of latency in women with preterm prelabor rupture of membranes was longer in individuals evaluated by speculum only versus digital examination, 6.6 d versus 2.9 d (mean difference 4.5 d, 95% CI 1.4 to 7.8, I2 99%). CONCLUSION: Speculum examination only in women with preterm prelabor rupture of membranes is associated with less maternal infectious morbidity and longer latency periods.

Case report: Sentinel lymph node mapping of endometrial carcinoma occurring in uterine didelphys.

•In a bleeding postmenopausal woman with didelphys uterus, endometrial biopsy should be taken from both uterine cavities.•Sentinel lymph node mapping has not been previously described in the setting of endometrial cancer and uterine didelphys.•Routine sentinel lymph node mapping was successfully performed in a patient with endometrial cancer and uterine didelphys.

Successful Pregnancy after Intervention for Spindle-Cell Embryonal Rhabdomyosarcoma: A Case Report.

BACKGROUND: Embryonal rhabdomyosarcoma, the most common soft tissue malignancy in childhood, is treated with surgery and chemotherapy. Because of the young age at the time of presentation, a discussion of future reproduction is appropriate and conservative management should be considered. We present a case of embryonal rhabdomyosarcoma that was successfully and conservatively managed with chemotherapy, allowing for future pregnancies. CASE: A 17-year-old nulliparous woman with embryonal rhabdomyosarcoma underwent 6 cycles of chemotherapy with adriamycin, dacarbazine, cyclophosphamide, and vincristine, resulting in radiographic resolution of the disease. She was able to conceive without medical intervention and to have successful vaginal deliveries. SUMMARY AND CONCLUSION: The standard of care for embryonal rhabdomyosarcoma is surgery and chemotherapy; however, conservative management should be considered when preservation of fertility is a goal.

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.

Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53-/- ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment.

Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy.

Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches.

Gait analysis following single-shot hyaluronic acid supplementation: a pilot randomized double-blinded controlled trial.

OBJECTIVES: Viscosupplementation with new-generation, polyol-containing, cross-linked hyaluronic acid (HA) gels reduces joint inflammation in patients with knee osteoarthritis. Gait analysis is a complementary outcome measure to standard patient-reported scores and physical measures for testing the effect of HA injection. This three-arm, prospective, randomized, controlled, double-blind, feasibility pilot study investigated which gait parameters are more sensitive following a single bolus injection of polyol-containing HA for knee osteoarthritis. METHODS: Twenty-two patients with Ahlbäck grade II-III knee osteoarthritis were randomly allocated into three groups: (1) HA + mannitol (n = 9), (2) HA + sorbitol (n = 5), and (3) saline placebo (n = 8). Patients were assessed by blinded observers prior to injection and at 4 weeks post-injection (4W). Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Society score (KSS), EuroQol in five-dimensions (EQ-5D), VAS pain, and VAS stiffness. Gait was assessed over 30 m using a portable inertial-based data logger (Physilog®). RESULTS: Differences between 4W and baseline were statistically significant for the mannitol-containing viscosupplement, with a median increase of 0.076 m/s on gait speed (p = 0.039), 0.055 m on stride length (p = 0.027), and 15 points on the KSS (p = 0.047). In contrast, the HA + sorbitol and saline groups demonstrated no significant changes from baseline to 4W in any gait parameters or self-reported outcome measures (all p > 0.3). The observed increase in gait speed is approximately 13% greater than the mean difference between healthy subjects and those with knee osteoarthritis, is clinically important, and thus is a sensitive gait parameter. CONCLUSIONS: This study demonstrated gait speed and stride length are the most relevant gait parameters to investigate when assessing the effect of polyol-containing HA viscosupplementation. This study supports the need for a larger, randomized, controlled, clinical trial to assess the effect of a single-bolus HA injection versus multiple injections in people with knee osteoarthritis using both gait performance and self-reported parameters of knee function. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov on August 20, 2018, and assigned #NCT03636971. LEVEL OF EVIDENCE: I.

Epigenetic therapy for ovarian cancer: promise and progress.

Ovarian cancer is the deadliest gynecologic malignancy, with a 5-year survival rate of approximately 47%, a number that has remained constant over the past two decades. Early diagnosis improves survival, but unfortunately only 15% of ovarian cancers are diagnosed at an early or localized stage. Most ovarian cancers are epithelial in origin and treatment prioritizes surgery and cytoreduction followed by cytotoxic platinum and taxane chemotherapy. While most tumors will initially respond to this treatment, recurrence is likely to occur within a median of 16 months for patients who present with advanced stage disease. New treatment options separate from traditional chemotherapy that take advantage of advances in understanding of the pathophysiology of ovarian cancer are needed to improve outcomes. Recent work has shown that mutations in genes encoding epigenetic regulators are mutated in ovarian cancer, driving tumorigenesis and resistance to treatment. Several of these epigenetic modifiers have emerged as promising drug targets for ovarian cancer therapy. In this article, we delineate epigenetic abnormalities in ovarian cancer, discuss key scientific advances using epigenetic therapies in preclinical ovarian cancer models, and review ongoing clinical trials utilizing epigenetic therapies in ovarian cancer.

Insurance coverage of pediatric burns: Switzerland versus USA.

Burn care and research have significantly improved over the past years. However, insurance coverage of such treatments does not reflect the improvements in this multi-disciplinary field. Government insurance policies in first world countries renown for burn care treatment, such as Switzerland and the United States, have not adapted to the complexity and longitudinal nature of burn care. Using case studies from both countries, we have analyzed both the institutional and policy approach to pediatric burn treatment coverage. Subsequently, by presenting the Shriners burn care model, we offer a policy recommendation to both the Swiss and the American governments to better their present legislation and infrastructure on pediatric burn coverage.