Gynecologic cancer care in the first year of the COVID-19 pandemic.

OBJECTIVE: To analyze the impact of the early COVID-19 pandemic on the diagnosis and initiation of treatment for patients with gynecologic cancer. METHODS: Patients diagnosed with gynecologic cancer in the National Cancer Database during 2017-2020 were included. For the first aim, incidence rate ratios were calculated to compare gynecologic cancer diagnosis in the first year of the COVID-19 pandemic to the three years prior, and factors associated with a reduction in diagnosis were identified. For the second aim, patients who experienced an 8-week delay in cancer treatment were compared to those who did not. Multivariate logistic regression was used to identify factors associated with treatment delay. Propensity score analysis was utilized to compare the rate of cancer treatment delay in patients who were diagnosed with COVID-19 to those who were not. RESULTS: The incidence rate ratio of being diagnosed with gynecologic cancer in 2020 versus 2017-2019 was 0.90 (95%CI 0.90-0.91). Factors associated with increased risk of missed or delayed diagnosis in 2020 included cervical cancer, earlier cancer stage, younger age, lower levels of medical comorbidity, and lack of health insurance. In 2020, factors associated with treatment delay included COVID-19 diagnosis (aOR 1.50, 95%CI 1.35-1.67), in addition to race and ethnicity, insurance type, comorbidity, cancer stage, and primary site. The risk of treatment delay remained significantly elevated in patients diagnosed with COVID-19 after propensity-score matching. CONCLUSIONS: Gynecologic cancer diagnosis and timely provision of care were negatively impacted during the first year of the COVID-19 pandemic, with certain subgroups at elevated risk.

Small-Molecule-Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death.

High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061-induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.

Enhanced gastric decompression for palliation of malignant bowel obstruction.

BACKGROUND: Malignant bowel obstruction (MBO) is a sequela of advanced intraabdominal cancer and has a profound impact on quality of life. Common therapy is endoscopic decompressive gastrostomy tube placement. Standard gastrostomy tubes are poorly designed to completely evacuate the dependent portions of the stomach due to their location on the anterior gastric wall. In our institution we have begun placing the ASPIRE Assist gastrostomy tube (ASPIRE Bariatrics, Exton, PA) which includes a 15 cm long, 30Fr fenestrated gastric tube extension for enhanced gastric decompression. This tube is FDA indicated for gastric decompression and marketed for endoscopic weight loss. The purpose of this study is to review our experience managing MBO utilizing the ASPIRE Assist tube. METHODS: This is a retrospective analysis of outcomes at a single institution. All decompressive endoscopic gastrostomy tubes placed by two surgeons between November 2019 and July 2021 were reviewed. Endoscopic placement was performed utilizing standard safe tract and Ponsky pull techniques. RESULTS: Fourteen patients were identified (10F:4 M), mean age 70 (range 35-89). Primary cancer diagnoses included gynecologic (8), colorectal (3), bladder (1), small bowel (1), peritoneal serous (1). During the 12 months before decompressive gastrostomy tube placement, mean number of hospital admissions for MBO was 1.6 (range 1-3). Following tube placement, twelve patients had no further hospital admissions for MBO over their lifespan of mean 270 days (range 8-679 days). One patient had 1 admission for MBO in the 12 months before tube placement and 3 admissions in the 4 months after placement. A second patient had 2 admissions in the 12 months before tube placement and 1 admission in their 54-day lifespan after placement. There were no major complications. CONCLUSIONS: Endoscopic placement of the ASPIRE Assist gastrostomy tube is safe for palliation of MBO and may improve gastric decompression compared with standard endoscopic gastrostomy tubes. Enhanced gastric decompression can better manage symptoms, reduce hospital encounters, and improve quality of life. Further study is needed, however, our initial data appears promising.

Assessing the fear of COVID-19 scale among health care workers in Israel: a psychometric validation study.

We explored the psychometric properties of the Hebrew version of the Fear of COVID-19 (FCV-19S) scale among health care workers in a large medical center in Israel. Participants (N = 705) completed the FCV-19S scale, as well as resilience, subjective well-being, and meaning in life using validated scales. Results showed a two-factor structural model accounting for 79.33% of the total variance. Both factors were negatively associated with resilience and satisfaction with life. Results suggest the FCV-19S has good psychometric properties among health care workers and may be used to assess the effects of the pandemic in this population.

Current Life Experiences in Veterans with Limb Loss: A Description of Survey Methods and Summary Results.

PURPOSE: To present the methods and summary findings of a nationwide survey on the current life experiences of Operation Iraqi Freedom/Operation Enduring Freedom (OEF/OIF) Veterans with limb loss. METHODS: A questionnaire was sent to Veterans with items covering sample demographics, summaries of health status, prosthesis usage and fit, employment experience, and use and satisfactions with support services and providers. RESULTS: 158 Veterans completed the survey. Approximately 40% perceived their overall status, function and problems related to the prosthesis as "Average". 58% wore a prosthesis over 10 hours per day and 74% did not use additional walking aids. Approximately 75% had at least "Moderate" pain and residual limb health problems. 37% were employed though conditions often changed. Over 80% used healthcare, mental health counseling and education services. The Departments of Defense and VA were primary service providers. CONCLUSIONS: Respondents generally exhibited satisfactory life experiences. Results suggest a positive current status despite challenges that could impair health, functioning and quality of life. Support services were available as needed. Satisfaction with services and providers varied.

A changing world, again. How Appreciative Inquiry can guide our growth.

COVID-19 is an interconnecting, cascading tsunami of up-rootedness and change on many levels. The global challenge we face is twofold: 1) how do we sustain our psychological, physical, social and economic capital and wellbeing in a time of great uncertainty; and 2) how do we adapt and create a new existence in an altered reality? Appreciative Inquiry (AI) is a well-documented approach to helping individuals and systems move from a deficit-based paradigm to a strengths-based perspective. AI holds myriad potential benefits for individuals, communities, and macro systems to build resilience and promote growth during and after COVID-19. This article will provide an overview of AI and its relevance to the current situation, as well as provide specific strategies for how people and systems can use AI as they transition through the pandemic and afterward.

The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis.

Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma-specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations. SIGNIFICANCE: This study characterizes a highly recurrent, disease-specific PP2A PPP2R1A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development.See related commentary by Haines and Huang, p. 4009.

Factors Influencing Functional Outcomes and Return-to-Work After Amputation: A Review of the Literature.

Purpose Amputation is a life changing event that can significantly impact an individual's physical and mental well-being. Our objective was to review literature exploring the impact of amputation upon a person's functioning and inclusion in the workplace. Methods Medline, CINAHL, and PsycINFO were searched using keywords related to amputation, employment and community reintegration. Eligible studies were published since 2000 and one of the following study designs: randomized controlled trial, non-randomized controlled trial, retrospective study, prospective study, concurrent cohort study, or cross sectional study. Studies for civilians with amputation as well as service members and Veterans with amputation were considered for inclusion. Results The search identified 995 articles, 25 of which met inclusion/exclusion criteria and were included in the review. While strong evidence for correlations and predictors of outcomes after amputation were limited, multiple factors were identified as contributing to physical functioning and employment after amputation. Conclusions Outcomes after amputation can vary widely with many potentially inter-related factors contributing. The factors identified may also serve to inform the development of interventions aiming to improve functional performance and reintegration after amputation. Furthermore, the review highlights the need for more high quality prospective studies.

Standardization of Laparoscopic Operative Reporting: Improving Gynaecological Surgeon Communication.

OBJECTIVE: No standardization of quality of operative reporting currently exists, and this represents a missed opportunity for communication among health care providers. This study proposed a method to improve operative notes by structuring the findings by six anatomical zones of the pelvis. Objective I was to validate the method of documenting six zones of the pelvis by using intraoperative photography. Objective II was to compare this method with dictations from operative reports created before introducing this method. METHODS: This retrospective cohort study evaluated pre- and post-intervention results of using six zones to guide operative reporting. Reports were collected from participating surgeons and were scored using a validated scoring tool. Each participant was taught to photograph six zones and use the zones in the operative report. Pre- and post-intervention cases were compared using generalized linear mixed models. RESULTS: Scores of study participants using the zones were significantly higher than those without (P <0.0001). Surgeons showed an ability to improve their reporting. The detail illustrated in the cases was qualitatively richer, and the anatomy within the six zones was referenced more frequently. CONCLUSION: Compared with reports without the technique, incorporating the six zones greatly enhances operative reporting and likely would improve communication among care providers. More reliable communication of intraoperative findings has the potential to enhance the value of laparoscopy greatly as a diagnostic tool across gynaecological subspecialties.

Operation Enduring Freedom and Operation Iraqi Freedom Veterans with amputation: An exploration of resilience, employment and individual characteristics.

BACKGROUND: Since 2002 approximately 1,700 US military service members have experienced trauma related amputations from injuries incurred in Afhanistan and Iraq (Fisher, 2015). OBJECTIVE: This study explores the variables of resilience, individual characteristics, and employment status of a sample of these Veterans who served in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) and sustained an amputation. METHODS: Veterans identified through the VA Corporate Data Warehouse (N = 165) completed a survey on their experiences following amputation. RESULTS: Results indicate that several variables were significantly related to resilience, to include employment status, pain status, and prosthetic use. CONCLUSION: Recommendations for future research and practice are provided.

Diagnosis and management of endometrial hyperplasia.

Endometrial hyperplasia (EH), with or without atypia, is a common gynecologic diagnosis and a known precursor of endometrial carcinoma, the most common gynecologic malignancy. During the reproductive years, the risk of EH is increased by conditions associated with intermittent or absent ovulation, in particular, polycystic ovary syndrome. After menopause when ovulation has ceased, EH is more common in women with conditions that increase levels of circulating estrogen such as obesity or estrogen replacement therapy. Women with EH are at increased risk for both concurrent and subsequent endometrial cancer. The risk of coexisting cancer in women with a diagnosis of EH at endometrial sampling is due to limitations in both endometrial sampling and the diagnostic reproducibility among pathologists. These diagnostic uncertainties add to the complexity of managing EH. This review offers a rational approach to prevention, diagnosis, and treatment of EH, including hormone therapy and conservative surgical methods.

Workplace discrimination and cumulative trauma disorders: the national EEOC ADA research project.

Employment discrimination of persons with cumulative trauma disorders (CTDs) was explored using the Integrated Mission System dataset of the US Equal Employment Opportunity Commission. Demographic characteristics and merit resolutions of the Charging Parties (persons with CTD) were compared to individuals experiencing other physical, sensory and neurological impairments. Factors compared also included industry designation, geographic region, and size of Respondents against which allegations were filed. Persons with CTD had proportionately greater allegations among large Respondents (greater than 500 workers) engaged in manufacturing, utilities, transportation, finance insurance and real estate. The types of discrimination Issues that were proportionately greater in the CTD group included layoff, failure to reinstate, and failure to provide reasonable accommodation. The CTD group was significantly less likely than the comparison group to be involved in discrimination Issues such as assignment to less desirable duty, shift or work location; demotion; termination, or failure to hire or provide training. Persons with CTD had higher proportions of merit Resolutions where allegations were voluntarily withdrawn by the Charging Party with benefits.