Trustworthiness of Pretrained Transformers for Lung Cancer Segmentation (preprint)

We assessed the trustworthiness of two self-supervision pretrained transformer models, Swin UNETR and SMIT, for fine-tuned lung (LC) tumor segmentation using 670 CT and MRI scans. We measured segmentation accuracy on two public 3D-CT datasets, robustness on CT scans of patients with COVID-19, CT scans of patients with ovarian cancer and T2-weighted MRI of men with prostate cancer, and zero-shot generalization of LC for T2-weighted MRIs. Both models demonstrated high accuracy on in-distribution data (Dice 0.80 for SMIT and 0.78 for Swin UNETR). SMIT showed similar near-out-of-distribution performance on CT scans (AUROC 89.85% vs. 89.19%) but significantly better far-out-of-distribution accuracy on CT (AUROC 97.2% vs. 87.1%) and MRI (92.15% vs. 73.8%). SMIT outperformed Swin UNETR in zero-shot segmentation on MRI (Dice 0.78 vs. 0.69). We expect these findings to guide the safe development and deployment of current and future pretrained models in routine clinical use.

Unleashing the Power of Artificial Intelligence: Unraveling the Intricate Dynamics between Viral and Bacterial Infections, Immune Factors, COVID-19, and Cancer in Women's Health (preprint)

The intricate interplay between viral and bacterial infections, immune factors, COVID-19, and cancer in women's health has garnered significant attention in recent research. This comprehensive study aimed to unravel the complex dynamics between these factors and provide valuable insights into their implications for women's health. Through meticulous analysis of available data, this study elucidated the prevalence of viral and bacterial infections in women, encompassing influential pathogens such as influenza, human papillomavirus, Staphylococcus aureus, Escherichia coli, and Streptococcus pneumoniae. Additionally, it explored the relationship between specific cytokine types, including Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), Interferon-gamma (IFN-γ), and Interleukin-10 (IL-10), and viral infections. The prevalence of various cancer types, such as breast cancer, lung cancer, colorectal cancer, ovarian cancer, and cervical cancer, was also assessed. Furthermore, this study examined the correlations between immune factors and viral infections, uncovering significant associations that shed light on the intricate interplay between immune responses and viral infections. Immune markers such as IL-6, TNF-α, IFN-γ, Interleukin-1beta (IL-1β), and Interleukin-12 (IL-12) exhibited diverse levels of correlation with specific viral infections. These findings hold promise for disease prognosis and treatment optimization. Additionally, the association between bacterial infections and women's health conditions was explored, revealing the impact of pathogens like Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis on gynecological infections, reproductive disorders, and other relevant conditions. This highlights the need for effective strategies to prevent and manage bacterial infections, aiming to mitigate their adverse effects on women's health. In the context of COVID-19, this study investigated immune factors as predictors of disease outcomes in women. Various cytokines, including IL-6, TNF-α, IL-1β, IFN-γ, IL-10, IL-8, IL-4, IL-2, IL-12, and IL-17, demonstrated associations with disease severity, offering potential prognostic markers for identifying individuals at higher risk of severe illness. Furthermore, the relationship between viral and bacterial infections and cancer incidence in women was explored. Viral infections, such as human papillomavirus and influenza, showed associations with specific cancer types, including breast cancer, cervical cancer, lung cancer, skin cancer, and stomach cancer. Bacterial infections, such as Staphylococcus aureus and Escherichia coli, were linked to ovarian cancer, colorectal cancer, pancreatic cancer, bladder cancer, kidney cancer, and esophageal cancer. These findings provide valuable insights into the potential role of infectious etiologies in cancer development among women. In conclusion, this comprehensive study unveils the intricate dynamics between viral and bacterial infections, immune factors, COVID-19, and cancer in women's health. The findings emphasize the importance of considering the interconnectedness of these factors to enhance disease prevention, diagnosis, and treatment strategies in women. Further research is warranted to unravel the underlying mechanisms and translate these findings into clinical applications.

Ovarian Cancer Biomarkers in the COVID-19 Era.

Ovarian Cancer (OC) diagnosis is entrusted to CA125 and HE4. Since the latter has been found increased in COVID-19 patients, in this study, we aimed to evaluate the influence of SARS-CoV-2 infection on OC biomarkers. HE4 values above the cut-off were observed in 65% of OC patients and in 48% of SARS-CoV-2-positive patients (not oncologic patients), whereas CA125 values above the cut-off were observed in 71% of OC patients and in 11% of SARS-CoV-2 patients. Hence, by dividing the HE4 levels into quartiles, we can state that altered levels of HE4 in COVID-19 patients were mostly detectable in quartile I (151-300 pmol/L), while altered levels in OC patients were mostly clustered in quartile III (>600, pmol/L). In light of these observations, in order to better discriminate women with ovarian cancer versus those with COVID-19, we established a possible HE4 cut-off of 328 pmol/L by means of a ROC curve. These results demonstrate that the reliability of HE4 as a biomarker in ovarian cancer remains unchanged, despite COVID-19 interference; moreover, it is important for a proper diagnosis that whether the patient has a recent history of SARS-CoV-2 infection is determined.

Impact of COVID-19 on gamete quality and embryo development in patients with COVID-19 positive undergoing ART (preprint)

Backgroud:COVID-19 was recognized a public health issue and SARS-CoV-2 was assumed to infect human ovary and cross the blood–testis barrier. Method:To explore the infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients’ semen and follicular fluid and its potential clinical outcome. Ten female patients with an average age of 30.7±4.11years and eight male patients with an average age of 32.13±4.45 years diagnosed with COVID-19 and their spouses were negative to COVID-19 were included. Results: None of ten male and 8 female patients with COVID-19 affecting was absence of SARS-CoV-2 RNA in semen and follicular fluid. The sperm parameters, the rates of oocytes maturation, fertilization, cleavage and blastulation between the control and test group was not statistically significant (P>0.05),but the sperm quality, the oocyte maturation and fertilization, the blastulation showed a decline tendency in COVID-19 affected patients. Conclusion: COVID-19 affection may have an uncertian negative influence on the gamete quality and embryo development. Our new knowledge will help to evaluate the impact of COVID-19 on fertility in virus infected patients.

COVID-19 infection and women's health; which women are more vulnerable in terms of gynecological health? (preprint)

Background Given gender-specific differences and ACE2 commonly expressed in the ovaries and uterus, it may be important to know which women are at greater risk of COVID-19 infection. Therefore, this study sought to determine which women are more affected by COVID- 19 infection, especially in terms of gynecological pathologies.Methods This retrospective and descriptive study examined the effect and course of COVID-19 in terms of gynecological pathologies in a total of 380 women of reproductive age without systemic disease. General demographics, obstetric and gynecological conditions, and parameters related to COVID-19 were evaluated. All parameters were compared for three groups defined on the basis of COVID-19 severity (mild, moderate, and severe).Results A total of 380 women with a mean age of 35.39 ± 8.94 were included in the study. The mean body mass index (BMI) of the women was 24.35 ± 4.53. The proportion of women with at least one pregnancy history was 69.2%. The mean gravidity of the women was 1.47 ± 1.34 and the parity was 1.16 ± 1.02. Of the women, 112 (29.5%) mild, 207 (54.5%) moderate and 61 (16.0%) severe cases of COVID-19 were seen. The mean age and median BMI of the women were similar in all three groups (p = 0.163, p = 0.127, respectively). Severe disease rates (29.5%) were significantly higher in women with 2 or more cases of COVID-19 than mild disease (14%) (p = 0.018). Severe disease rates (57.4%) in women with at least one pregnancy history were statistically significantly lower than mild disease rates (78.6%) (p = 0.010). The median parity number was significantly higher in the mild disease group than in the moderate disease group (p = 0.021). The most common benign gynecological pathology in women was chronic urinary tract infection (13.2%). Other common pathologies were chronic vaginal infection (12.6%), and polycystic ovary syndrome (PCOS) (11.6%). A history of chronic urinary tract infection was statistically significantly higher in the severe disease group (24.6%), mild (8.9%, p = 0.015) and moderate (12.1%, p = 0.024) disease groups. PCOS, endometriosis (6.3%), abnormal uterine bleeding (AUB) (8.4%), and hormone therapy history (8.2%) were found to be higher in severe disease groups, although not statistically significant (p = 0.596, p = 0.074, p = 0.305, p = 0.059, respectively). The history of leiomyoma (7.1%) was higher in the mild and moderate disease groups than in the severe disease group, but it was not statistically significant (p = 0.794). Benign gynecological operation history (31.3%) was significantly higher in mild (36.6%, p = 0.007), and moderate (33.3%, p = 0.007) disease groups than in the severe group (9, 14.8%).Conclusion Certain obstetric and gynecological conditions are thought to affect COVID 19 susceptibility and severity in women without systemic disease.

The association between Selenium and Epithelial Ovarian Cancer (EOC) among women; A protocol of a systematic review and meta-analysis (preprint)

Introduction: Selenium (Se) may have a protective effect against some selected cancers. Ovarian cancer is ranked as one of the major killers of all gynecological malignancies worldwide. The objective of this study is to find the relationship between selenium intake and Epithelial Ovarian Cancer risk in women who have not had an oophorectomy. Methods: A comprehensive electronic search was carried out according to the prepared strategy from the starting date of the PubMed/Medline, EMBASE, Scopus, Proquest, and Web of Science databases up to 30th of September 2022 without limitations related to language and publication status. Studies were screened by COVIDENCE. Cohort studies, case-control studies, cross-sectional analytical studies, ecological studies, and randomized control studies were included, and descriptive studies were excluded from the systematic review. The exposure of interest is high selenium intake from either food sources or supplements and also high measures of selenium in blood, toenails, or other biological samples, and high measures of serum selenoproteins. Data extraction will be done. New Castle Ottawa Scale will be used to assess the bias of observational studies. The findings will be synthesized first via a narrative description. If data permits results will be displayed via forest plots. All analyses will be conducted using STATA-17. Discussion: Ovarian cancer is the most fatal gynecological malignancy among women. Due to the lack of recommended screening tools, the identification of modifiable effective risk factors and preventive tools are essential to reduce ovarian cancer burden. Selenium is a powerful antioxidant, therefore it prevents cell damage. It was proven in some studies that selenium protects against the development of some selected cancers. Therefore it is envisaged to find whether there is an inverse relationship between selenium and ovarian cancer for future preventive strategies. Systematic review registration: Registered in the International Prospective Register of Systematic Reviews (PROSPERO)- CRD42022356472

Why Did Downstaging in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) Not Result in a Mortality Benefit: Exploratory Analysis of a Randomised Controlled Trial (preprint)

Background: To address the disparity in UKCTOCS between decrease in advanced stage disease and lack of mortality reduction in tubo-ovarian cancer (OC) in the multimodal screening (MMS) compared to no screening (C) group, we undertook exploratory analyses by histotype. Methods: In UKCTOCS, 202562(50625 MMS;50623 USS;101314C) eligible women were randomised (2001-5) and followed up till 30June2020. Screening group participants underwent annual screening till 31Dec2011. An outcomes committee adjudicated on OC diagnosis, histotype, stage and cause of death. Treatment details were extracted from hospital records. In women diagnosed with cancer (high-grade serous, HGSC; non-high-grade serous, non-HGSC) at censorship (31Dec2014), we compared descriptive statistics(p-values) and survival from randomisation (Versatile test) in MMS and USS group separately to the C group.Findings: In both the MMS(259/50625) and C(520/101314) groups, 0.51% developed HGSC. In HGSC, on an intention-to-screen analysis, there was a reduction in advanced(III/IV/unable to stage) stage disease(MMS75%195/259; C86%,446/520;p=0·0003), higher rates of primary surgery(MMS61%,158/259; C42%,219/520;p<0·0001), zero residual disease(MMS 46%,119/259; C30%,157/520;p<0·0001) and treatment including surgery and chemotherapy(MMS74%,192/259; C64%,331/520;p=0·003) in the MMS compared to C group. There was no difference in those receiving first line combination chemotherapy(MMS55%, 142/259; C56%, 293/520;p=0·687). There was evidence of improvement in survival from randomisation in HGSC in MMS(MMS21%,54/259; C14%,74/520;p=0·042) in the case only analysis. No differences were observed in the comparisons in USS or non-HGSC in the MMS versus C group.Interpretation: Our findings provide robust evidence for the first time that screening can detect HGSC earlier and result in improved treatment outcomes. The lack of overall mortality benefit is likely related to the magnitude of early detection and treatment improvement as well as tumour biology. The findings do not support use of surrogate end points in place of disease-specific mortality.Funding National Institute for Health Research, MRC, Cancer Research UK, The Eve Appeal.Trial Registration: This trial is registered with ISRCTN number 22488978; ClinicalTrials.gov number NCT00058032.Funding: The Long Term Follow Up (LFTU) UKCTOCS is supported by National Institute for Health Research (NIHR HTA grant 16/46/01), Cancer Research UK (CRUK) and The Eve Appeal. UKCTOCS was funded by Medical Research Council (G9901012 and G0801228), CRUK (C1479/A2884), and the Department of Health, with additional support from The Eve Appeal. Researchers at UCL are supported by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre and MRC CTU at UCL core funding (MR_UU_12023).Declaration of Interest: UM has stock ownership awarded by University College London (UCL) in Abcodia, which holds the licence for ROCA (between 1 April 2011 and 30 October 2021). She has received grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. She holds patent number EP10178345.4 for Breast Cancer Diagnostics. MP has received grants and AG-M, MB, and AR, have been funded by grants from MRC, CRUK, NIHR, and The Eve Appeal. UM, SA and AG-M received research funding from iLOF (intelligent Lab on Fiber), Micronoma, Imperial College London, QIMR Berghofer Medical Research Institute, Innovate UK, Mercy Bioanalytics, University of Innsbruck, NHMRC and MRC Proximity to Discovery Industrial Connectivity Award. UM has received an honorarium from NY Obstetrical Society and reimbursements for invited talks from NY Obstetrical Society (USA), National Cancer Policy Forum (USA), and Robinson College, Cambridge. She is a member of ACED (International Alliance for Cancer Early Detection) Gynaecological Cancers Working Group, and a member of Advisory Boards or Committees for Tina’s Wish, Mixed COVID Vaccines study, India, Yorkshire Cancer Research, GEM3, NOVEL, and PROTECTOR. UM and SA received research funding from RNA Guardian and Dana Faber. MP was a member of the EME funding committee while the project was active. MB reports funding from NIHR UCL Hospitals Biomedical Research Centre. SA received funding from Abcodia. AG-M is a member of ACED (International Alliance for Cancer Early Detection) Gynaecological Cancers Working Group, and Co-Director Research Domain Trials for ACED. RM has received grants from The Eve Appeal, Rosetrees Charity, and Barts Charity, Yorkshire Cancer Research, Ovacure, BGCS, GSK, personal fees from AstraZeneca and consulting fees from Everything Genetics Limited. AMcG was a member of NIHR HTA and EME Editorial Board from 1 April 2012 to 31 March 2022. LJF received a grant form MRC for the psycho-social arm of the UKCTOCS study 2001-2013. SJS holds the (expired) patent for ROCA, patented and owned by Massachusetts General Hospital and Queen Mary University of London, licenced to Abcodia. He reports personal fees from Abcodia, Guardant Health, and Freenome, outside the submitted work, funding from NIHR, NCI and Mercy Bioanalytics and consulting fees from Guardant Health. He participates on Board of SISCAPA Assay Technologies and has stock ownership for this. IJJ reports grants from Eve Appeal Charity, Medical Research Council, Cancer Research UK, and NIHR during the conduct of the study. He co-invented the ROCA in 1995, it was patented by Massachusetts General Hospital and Queen Mary University of London and is owned by these universities. Massachusetts General Hospital and Queen Mary University of London granted a licence to ROCA to Abcodia in 2014. IJJ is a board member, shareholder, and consultant to Abcodia and has rights to royalties from sales of the ROCA. He founded (1985), was a trustee of (2012–14), and is now an Emeritus trustee (2015–present) of The Eve Appeal, one of the funding agencies for UKCTOCS. NS received an honorarium from Astra-Zeneca-MSD and GlaxoSmithKline for participation in Advisory board. All other authors declare no competing interests.Ethical Approval: Approved by the UK North West MREC (00/8/34) on June 23, 2000.

A patient with advanced breast cancer and hyperthyroidism associated with struma ovarii.

Not required for Clical Vignettes.

In silico designed mRNA vaccines targeting CA-125 neoantigen in breast and ovarian cancer.

Somatic mutation-derived neoantigens are associated with patient survival in breast and ovarian cancer. These neoantigens are targets for cancer, as shown by the implementation of neoepitope peptides as cancer vaccines. The success of cost-effective multi-epitope mRNA vaccines against SARS-Cov-2 in the pandemic established a model for reverse vaccinology. In this study, we aimed to develop an in silico pipeline designing an mRNA vaccine of the CA-125 neoantigen against breast and ovarian cancer, respectively. Using immuno-bioinformatics tools, we predicted cytotoxic CD8+ T cell epitopes based on somatic mutation-driven neoantigens of CA-125 in breast or ovarian cancer, constructed a self-adjuvant mRNA vaccine with CD40L and MHC-I -targeting domain to enhance cross-presentation of neoepitopes by dendritic cells. With an in silico ImmSim algorithm, we estimated the immune responses post-immunization, showing IFN-γ and CD8+ T cell response. The strategy described in this study may be scaled up and implemented to design precision multi-epitope mRNA vaccines by targeting multiple neoantigens.

The impact of lag time to cancer diagnosis and treatment on clinical outcomes prior to the COVID-19 pandemic: A scoping review of systematic reviews and meta-analyses.

Background: The COVID-19 pandemic has disrupted cancer care, raising concerns regarding the impact of wait time, or 'lag time', on clinical outcomes. We aimed to contextualize pandemic-related lag times by mapping pre-pandemic evidence from systematic reviews and/or meta-analyses on the association between lag time to cancer diagnosis and treatment with mortality- and morbidity-related outcomes. Methods: We systematically searched MEDLINE, EMBASE, Web of Science, and Cochrane Library of Systematic Reviews for reviews published prior to the pandemic (1 January 2010-31 December 2019). We extracted data on methodological characteristics, lag time interval start and endpoints, qualitative findings from systematic reviews, and pooled risk estimates of mortality- (i.e., overall survival) and morbidity- (i.e., local regional control) related outcomes from meta-analyses. We categorized lag times according to milestones across the cancer care continuum and summarized outcomes by cancer site and lag time interval. Results: We identified 9032 records through database searches, of which 29 were eligible. We classified 33 unique types of lag time intervals across 10 cancer sites, of which breast, colorectal, head and neck, and ovarian cancers were investigated most. Two systematic reviews investigating lag time to diagnosis reported different findings regarding survival outcomes among paediatric patients with Ewing's sarcomas or central nervous system tumours. Comparable risk estimates of mortality were found for lag time intervals from surgery to adjuvant chemotherapy for breast, colorectal, and ovarian cancers. Risk estimates of pathologic complete response indicated an optimal time window of 7-8 weeks for neoadjuvant chemotherapy completion prior to surgery for rectal cancers. In comparing methods across meta-analyses on the same cancer sites, lag times, and outcomes, we identified critical variations in lag time research design. Conclusions: Our review highlighted measured associations between lag time and cancer-related outcomes and identified the need for a standardized methodological approach in areas such as lag time definitions and accounting for the waiting-time paradox. Prioritization of lag time research is integral for revised cancer care guidelines under pandemic contingency and assessing the pandemic's long-term effect on patients with cancer. Funding: The present work was supported by the Canadian Institutes of Health Research (CIHR-COVID-19 Rapid Research Funding opportunity, VR5-172666 grant to Eduardo L. Franco). Parker Tope, Eliya Farah, and Rami Ali each received an MSc. stipend from the Gerald Bronfman Department of Oncology, McGill University.

Application of machine learning techniques for predicting survival in ovarian cancer.

BACKGROUND: Ovarian cancer is the fifth leading cause of mortality among women in the United States. Ovarian cancer is also known as forgotten cancer or silent disease. The survival of ovarian cancer patients depends on several factors, including the treatment process and the prognosis. METHODS: The ovarian cancer patients' dataset is compiled from the Surveillance, Epidemiology, and End Results (SEER) database. With the help of a clinician, the dataset is curated, and the most relevant features are selected. Pearson's second coefficient of skewness test is used to evaluate the skewness of the dataset. Pearson correlation coefficient is also used to investigate the associations between features. Statistical test is utilized to evaluate the significance of the features. Six Machine Learning (ML) models, including K-Nearest Neighbors , Support Vector Machine (SVM), Decision Tree (DT), Random Forest (RF), Adaptive Boosting (AdaBoost), and Extreme Gradient Boosting (XGBoost), are implemented for survival prediction in both classification and regression approaches. An interpretable method, Shapley Additive Explanations (SHAP), is applied to clarify the decision-making process and determine the importance of each feature in prediction. Additionally, DTs of the RF model are displayed to show how the model predicts the survival intervals. RESULTS: Our results show that RF (Accuracy = 88.72%, AUC = 82.38%) and XGBoost (Root Mean Squad Error (RMSE)) = 20.61%, R2 = 0.4667) have the best performance for classification and regression approaches, respectively. Furthermore, using the SHAP method along with extracted DTs of the RF model, the most important features in the dataset are identified. Histologic type ICD-O-3, chemotherapy recode, year of diagnosis, age at diagnosis, tumor stage, and grade are the most important determinant factors in survival prediction. CONCLUSION: To the best of our knowledge, our study is the first study that develops various ML models to predict ovarian cancer patients' survival on the SEER database in both classification and regression approaches. These ML algorithms also achieve more accurate results and outperform statistical methods. Furthermore, our study is the first study to use the SHAP method to increase confidence and transparency of the proposed models' prediction for clinicians. Moreover, our developed models, as an automated auxiliary tool, can help clinicians to have a better understanding of the estimated survival as well as important features that affect survival.

Assessment of Hospital Volume in the Surgical Management of Endometrial and Ovarian Cancer: A Polish Population-Based Study.

BACKGROUND Surgery is a cornerstone in management of ovarian and endometrial cancer. The European Society of Gynecological Oncology introduced quality indicators to improve management of these cancers. The optimal annual number of surgeries per unit was established for high-quality surgical treatment. MATERIAL AND METHODS The database of the National Health Fund on surgical management of endometrial and ovarian cancer was analyzed. Patients treated between 2017 and 2020 were included. Departments where patients underwent surgery were divided according to number of surgeries performed per year in endometrial cancer: ≥80, 79-50, 49-20, 19-0; and ovarian cancer: ≥100, 99-50, 49-20, 19-0. Optimal number of surgeries per center was defined as at least 100 and 80 surgeries per year in ovarian and endometrial cancer, respectively. RESULTS Totally, there were 22 325 surgeries in 316 units and 10 381 surgeries in 251 units due to endometrial and ovarian cancer, respectively. Most surgeries in endometrial cancer (n=15 077; 67.5%) and ovarian cancer (n=9642; 92.88%) were performed in departments that did not meet optimal criteria in number of surgeries. Between 2017 and 2019, an increasing trend in number of surgeries per year in endometrial and ovarian cancer was found. In 2020, there was a decrease in the number of surgeries by 7.8% (n=453) and 8.6% (n=234) in endometrial and ovarian cancer, respectively. CONCLUSIONS In Poland, surgical treatment of ovarian and endometrial cancer is decentralized. Most cancer patients underwent surgery in low-volume general gynecologic departments. The COVID-19 pandemic impaired cancer management, leading to a decreased number of surgeries.

Assessment of the Epidemic Potential of the Marek’s Disease Virus in the Russian Federation (preprint)

Abstract. Marek's disease virus is an oncogenic avian herpesvirus and the problem of oncogenicity of this virus for humans remains unexplored. This pathology appeared in broiler chickens of 30 days and older, that is from now on the contact with poultry meat carries the risk of infecting people. This article analyzes the risks of the emergence of the epidemic potential of the Marek's disease virus in the Russian Federation taking into account the characteristics of modern pig and poultry farming. It was found that COVID 19 can serve as an additional factor in reducing the resistance of the population to herpesvirus infections. The COVID 19 epidemic is accompanied by folic acid deficiency which also increases the risk of contamination of diseases associated with DNA viruses, including an extended risk of animal viruse infection. Since, according to our estimates, Marek's disease occurred in at least 25% of broiler poultry farms in the Russian Federation, a possible expand in mortality from neoplasms of the reproductive system for the Russian Federation as a whole can contribute to the dynamics of oncological diseases of reproductive organs and breast cancer. Since 2011 a contagious form of intestinal pathology, vesicular enteritis, has widely spread at poultry farms in the Russian Federation. During periods of extending incidence of vesicular enteritis, we recorded cases of inflammation of the facial nerves and subfebrile temperature in contact persons, bursts of oncological diseases in veterinary personnel (ovarian cancer, breast cancer), abnormal and synchronous increases in the incidence of infectious larengotracheitis and Marek's disease in chickens under the age of 40 days which requires additional monitoring studies.

Impact of the COVID-19 Pandemic on Diagnosis and Management of Gynecological Cancer: A Single-Center Analysis.

Background and Objectives: The COVID-19 pandemic impacted health systems worldwide, particularly cancer care. Because the actual implications of these changes on gynecological oncology healthcare are still unclear, we aim to evaluate the impact of this pandemic on the diagnosis and management of gynecological cancer. Materials and Methods: This is a single-center retrospective observational study, including patients diagnosed with gynecological malignancies between January 2019 and December 2021. Patients were included into three groups based on the timing of cancer diagnosis: pre-pandemic (2019), pandemic with high restrictions (2020) and pandemic recovery (2021). Results: Overall, 234 patients were diagnosed with gynecological cancer during the period of study. A decrease in the number of newly diagnosed cervical cancers and other rare tumors (leiomyosarcoma, invasive hydatidiform mole) was apparent in 2020. Some aggressive histological types of endometrial and ovarian cancer were more commonly diagnosed in the pandemic recovery group (p < 0.05), although no differences were demonstrated concerning tumor staging in all gynecological cancers. The median time between the first multidisciplinary team meeting and the treatment initiation was higher after the COVID-19 pandemic in endometrial cancer (23.0 vs. 34.0 vs. 36.0 days, p < 0.05). Patients with ovarian cancer were more frequently proposed for neoadjuvant therapy in 2020 compared to the other periods (33.3% vs. 55.0% vs. 10.0% p < 0.05). A significant reduction in the laparoscopic approach was observed during 2020 in endometrial cancer (32.1% vs. 14.3% vs. 36.4%, p < 0.05). No significant differences were registered regarding median hospitalization days or intra- and post-operative complications between these periods. Conclusions: The COVID-19 pandemic had a significant impact on the diagnosis and management of most gynecological malignancies, namely, on time to first treatment, chosen oncological therapies and surgical approaches. These results suggest important clinical and healthcare implications that should be addressed in future prospective studies.

Transcriptional changes of tissue-specific genes in multiple endocrine organs: a study of lethal COVID-19 cases (preprint)

Altered blood hormone and metabolite levels during and post-COVID-19 have been extensively reported. Yet, studies of gene expression at the tissue level that can help identify the causes of endocrine dysfunctions are scarce. We analyzed transcript levels of endocrine-specific genes in five endocrine organs of lethal COVID-19 cases. Overall, 116 autoptic specimens from 77 individuals (50 COVID-19 and 27 uninfected controls) were included. All samples were tested for SARS-CoV-2 genome. Investigated organs included adrenals, pancreas, ovary, thyroid and white adipose tissue (WAT). Transcript levels of 42 endocrine-specific and 3 IFN-stimulated genes (ISGs) were measured and compared between COVID-19 cases (virus-positive and virus-negative in tissue) and uninfected controls. ISG transcript levels were enhanced in tissues positive for SARS-CoV-2. Endocrine-specific genes (e.g., HSD3B2, INS, IAPP, TSHR, FOXE1, LEP, CRYGD) were deregulated in COVID-19 cases in an organ-specific manner. Transcription of organ-specific genes was suppressed in virus-positive specimens of ovary, pancreas and thyroid but enhanced in adrenals. In WAT of COVID-19 cases transcription of ISGs and leptin was enhanced independently of the presence of virus. Our findings suggest that, in COVID-19, endocrine dysfunctions may arise especially when SARS-CoV-2 invades endocrine organs and that transcriptional alterations of endocrine-specific genes may contribute to endocrine manifestations.

Phase II study of sodium valproate in combination with oral etoposide in platinum-resistant ovarian cancer.

Patients with platinum-resistant ovarian cancer (PROC) have limited therapeutic options and poor survival. There is a need for the development of newer therapies. Sodium valproic acid (VPA) is a short-chain fatty acid histone deacetylase (HDAC) inhibitor with antitumor activity in preclinical models of PROC. Synergism with conventional cytotoxic agents like etoposide has been demonstrated. In this prospective, single-arm, open-label, phase 2 study, we included patients ≥ 18 years with histologically or cytologically confirmed PROC and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-3. Patients received oral VPA 60 mg/kg/day in three divided doses for 3 days (D1-D3), followed by oral etoposide 50 mg once daily for two consecutive weeks (D4-D17). Serum samples were collected to assess peak VPA drug levels. The primary endpoint was the overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. We sought to show an improvement in response rate from 25% (historically with oral etoposide) to 40% with the addition of VPA. 27 patients were enrolled in the study, and 18 [median age: 52 (45-59) years; serous histology:17 (94%); ECOG-PS 2 or 3: 14 (78%)] were evaluable for the response after 4 months. Nine patients were lost from follow-up before achieving the primary endpoint (mainly due to Covid-related lockdown issues). The median number of prior lines of treatment was 2 (1-3). ORR was 0% according to GCIG criteria. The disease was stable in two patients [clinical benefit rate (CBR) of 11%]. The median OS and PFS were 7 months and 2 months, respectively. Grade ≥ 3 adverse events were reported in 6 (33%) patients. The addition of valproic acid to oral etoposide in patients with PROC and poor general condition was not helpful and failed to improve responses compared to those historically achieved with single-agent etoposide. However, further phase 2 randomized controlled trials with larger sample size can be done to confirm the findings.

Management of Gynecologic Cancer During COVID-19 Pandemic: South Asian Perspective.

Management of gynecological cancers has suffered during the pandemic, partly due to lockdown and partly due to directing resources to manage COVID-19 patients. Modification of gynecological cancer management during this pandemic is recommended. Cervical cancer patients who present with stage IA1 disease can have a delay of up to 8 weeks for surgical treatment, considering the slow tumor growth rate. Women with stages IA2, IB1, IB2, IIA1 must undergo radical hysterectomy and lymphadenectomy within 6 to 8 weeks. In areas where surgical treatment is not available, patients should be referred for radiation therapy/areas with adequate surgical expertise. The surgical option is attractive for early cancers during the COVID era, as it involves a single visit compared to the multiple visits required for chemoradiation. The value of lymph node staging needs to be reconsidered. Neoadjuvant chemotherapy should be given preference over primary cytoreductive surgery for advanced ovarian cancers. Surgeries, which demand extended surgical time such as Hyperthermic Intraperitoneal Chemotherapy and pelvic exenterations, should be avoided during this pandemic. For patients scheduled for interval surgery after two or three neoadjuvant cycles, six cycles of chemotherapy should be considered before surgery is performed. For early-stage, low-grade endometrial cancer, consideration should be given to medical management until surgery is possible. The above recommendations have been made keeping in mind the geography, patient load, and availability of resources available to health care providers from southeast Asia. They might not be applicable globally and every practitioner should take call regarding patient's management as per availability of resources and loco-regional circumstances. The implementation of recommended international guidelines for the management of gynecologic cancers should take precedence. Each modification to the standard approach should be approved by a multidisciplinary team depending on the condition of the patients and the locoregional circumstances.