A review on mechanisms of resistance to PARP inhibitors

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP?ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA?associated cancers, especially high?grade OC and breast cancers. They lead to synthetic lethality in BRCA?mutated cells by stalling the replication forks in homologous recombination?deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA?associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance

A rare case of blood stream infection due to Candida ciferii in an immuno-compromised patient

Invasive infections related to yeast are increasingly observed in immune-compromised patients in hospitals.Fungal infections have increased morbidity and mortality and prolonged hospital stay which can lead to rise in medical care costs. Non-albicans Candida species have been increasingly found as causative agents in human infections with important therapeutic implications. We present a case of a 37-year-old, female patient, known case of B cell Acute Lymphoblastic Leukaemia admitted in a tertiary care hospital in central India for supportive care and chemotherapy. Patient was responding well to chemotherapy. On post induction day 20, she complained of high-grade fever with abdominal pain.Two sets of blood culture were sent to Microbiology Diagnostic Laboratory for diagnosis. She was started on Injection Magnex Forte (Cefoperazone-Sulbactum) empirically.The Gram stain of positive blood culture showed Gram positive budding yeast like cells in all four bottles.The organism was identified as C. ciferrii on Vitek 2 with 95% identification.Antibiotic susceptibility testing showed sensitive to Amphotericin B MIC ?0.25 and voriconazole MIC ?0.12. It was resistant to fluconazole MIC ?64 ?g/ml.