Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer.

Ovarian cancer is one of the most common gynecologic cancers and has the highest mortality rate of any other cancer of the female reproductive system. Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery accompanied by pre- or postoperative platinum-based chemotherapy. Nevertheless, up to 80% of the patients relapse within the following 12-18 months from the completion of the treatment and then receive first-line chemotherapy depending on platinum sensitivity. Mutations in BRCA1/2 genes are the most significant molecular aberrations in EOC and serve as prognostic and predictive biomarkers. Poly ADP-ribose polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality. They have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. Olaparib, rucaparib, and niraparib have all obtained Food and Drug Administration (FDA) and/or the European Medicine Agency (EMA) approval for the treatment of EOC in different settings. Immune checkpoint inhibitors (ICI) have improved the survival of several cancers and are under evaluation in EOC. However, despite the success of immunotherapy in other malignancies, the use of antibodies inhibiting the immune checkpoint programmed cell death (PD-1) or its ligand (PD-L1) obtained modest results in EOC so far, with median response rates of up to 10%. As such, ICI have not yet been approved for the treatment of EOC. We herein provided a comprehensive insight into the most recent progress in synthetic lethality PARP inhibitors, along with the mechanisms of resistance. We also summarised data regarding the role of immune checkpoint inhibitors, the use of vaccination therapy, and adoptive immunotherapy in treating epithelial ovarian cancer.

Case of cerebral venous thrombosis on a patient with background of nephrotic syndrome.

Hypercoagulability is a well-described feature of nephrotic syndrome. The risk of developing a venous thrombus is higher at the time of diagnosis or shortly after. The resulting deep vein thrombosis involves the pulmonary, the deep veins of the lower limbs and renal veins, as described in the literature. We present a case of a man in his 20s with background of nephrotic syndrome, diagnosed at an age of 3 years old, with multiple relapses and on maintenance immunosuppression which is unusual, in two respects: First, the site of thrombosis was in the cerebral venous sinus and second, the onset of the thrombotic episode was years after the initial diagnosis. This case report also focuses on the perspective of the patient, who experienced a rare complication after more than two decades of living with the condition. In a literature search with the search words of 'nephrotic syndrome' AND 'cerebral venous thrombosis in adults', written in English and published from 1970 to 2/2021, we could only find a review article including 5 cases and 10 individual case reports, of which there were only 16 number of cerebral sinus venous thrombosis reported.

BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations.

Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.

The Experience of a Single NHS England Trust on the Impact of the COVID-19 Pandemic on Junior and Middle-Grade Doctors: What Is Next?

The COVID-19 pandemic has undoubtedly affected all national healthcare systems at different levels. In countries heavily hit by the pandemic, it was reported that healthcare workers were asked to work long hours, had increased workload, were faced with difficult decisions, and that the resources were stretched. As such, the COVID-19 pandemic would create the perfect storm for burnout in healthcare workers. Within this context, we conducted a survey in a district general hospital in Southeast England. We focused on doctors in training, in different specialties. This survey included parts of the Maslach Burnout Inventory for healthcare professionals, along with other relevant questions, such as the financial impact and seeking of psychological support. The results showed moderate levels of emotional exhaustion, but high levels of personal satisfaction, a positive impact on doctors finances and very low levels of seeking support.

Unraveling the Wide Spectrum of Melanoma Biomarkers.

The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow's original report on "melanoma and prognostic values of thickness", providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.

Cancer-Associated Thrombosis: A New Light on an Old Story.

Cancer-associated thrombosis (CAT) is a rising and significant phenomenon, becoming the second leading cause of death in cancer patients. Pathophysiology of CAT differs from thrombosis in the non-cancer population. There are additional risk factors for thrombosis specific to cancer including cancer type, histology, and treatment, such as chemotherapy. Recently developed scoring systems use these risk factors to stratify the degree of risk and encourage thromboprophylaxis in intermediate- to high-risk patients. Anticoagulation is safely used for prophylaxis and treatment of CAT. Both of these have largely been with low-molecular-weight heparin (LMWH), rather than the vitamin K antagonist (VKA); however, there has been increasing evidence for direct oral anticoagulant (DOAC) use. Consequently, international guidelines have also adapted to recommend the role of DOACs in CAT. Using DOACs is a turning point for CAT, but further research is warranted for their long-term risk profile. This review will discuss mechanisms, risk factors, prophylaxis and management of CAT, including both LMWH and DOACs. There will also be a comparison of current international guidelines and how they reflect the growing evidence base.