Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts.

BACKGROUND: The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies. METHODS: We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR. RESULTS: Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity. CONCLUSIONS: The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.

Overcoming PARPi resistance: Preclinical and clinical evidence in ovarian cancer.

Ovarian cancer is the fifth cause of cancer-related deaths in women with high grade serous carcinoma (HGSOC) representing the most common histological subtype. Approximately 50 % of HGSOC are characterized by deficiency in homologous recombination (HR), one of the main cellular pathways to repair DNA double strand breaks and one of the well-described mechanisms is the loss of function of the BRCA1 or BRCA2 genes. Inhibition of the poly-ADP-ribose polymerase (PARP) is synthetic lethal with HR deficiency and the use of PARP inhibitors (PARPi) has significantly improved the outcome of patients with HGSOC with a greater benefit in patients with BRCA1/2 deficient tumors. However, intrinsic or acquired resistance to PARPi inevitably occurs in most HGSOC patients. Distinct heterogeneous mechanisms underlying the resistance to PARPi have been described, including a decrease in intracellular drug levels due to upregulation of multidrug efflux pumps, loss of expression/inactivating mutations in the PARP1 protein, restoration of HR and the protection of the replicative fork. Deciphering the molecular mechanisms of resistance to PARPi is of paramount importance towards the development of new treatment strategies and/or novel pharmacological agents to overcome this chemoresistance and optimize the treatment regimen for individual HGSOC patients. The current review summarizes the mechanisms underlying the resistance to PARPi, the available preclinical and clinical data on new combination treatment strategies (with chemotherapy, anti-angiogenic agents and immune checkpoint inhibitors) as well as agents under investigation which target the DNA damage response.

[Neonatal choledocholithiasis: a case report]. / Coledocolitiasi neonatale: descrizione di un caso.

Cholelithiasis as cause of jaundice in newborn is rare. Usually is associated with known predisposing factors as hemolysis, congenital anomalies of biliary tree, total parenteral nutrition, prolonged fasting. However there are recent signals in literature about idiopathic neonatal cholelithiasis, that seems to be more common than previously suspected. We describe a case of idiopathic neonatal choledochal lithiasis with spontaneous resolution in few days from jaundice beginning. The importance of ultrasonographic investigation for diagnosis and follow-up is confirmed. However, because it is often a self limiting phenomenon, an aggressive approach is not warranted in the asymptomatic infant.

[Sample studies of contraceptive behavior in a suburban area of Milan]. / Indagine campione sul comportamento contraccettivo in una zona periferica milanese

PIP: 430 women were interviewed about contraception and fertility in a new outpatient clinic in the suburbs of Milan. Age varied between 16-50, but 21% of patients were between 26-30. 90% of them were married, and 42.3% were housewives. About 50% had only elementary school education; 9 were unable to read or write. It is important to note that 38.9% of patients were immigrants from the south, where socioeconomic and educational conditions are at a much lower level. Poor information and sensitivity about any reliable contraceptive method was noted. 128 women, or 11%, stated they were not interested in the problem; 160 were afraid something could happen to their health because of oral contraceptive; 53 feared sterility as a consequence, and 48 had a partner against it. 25.8% of patients had never used any contraceptive method, 49.5% had used 1, and 24.7% several. 134 patients or 62.9% relied on coitus interruptus as the only contraceptive measure; 13.1% used the condom, and only 14% used an oral contraceptive. Given the situation, it is suprising to find that unwanted pregnancies accounted for only 23.3% of pregnancies. 51.2% of these unwanted pregnancies ended in induced abortion, 21.6% in spontaneous abortion. The article compares the Italian situation with the situation in other countries where the social and cultural level of patients is similar. A survey of physicians done in 1976 revealed that about 53% of general practitioners and 34% of obstetricians will give advice about contraception only if requested to. The proposed new family advisory bureaus, which will include family planning programs, will have to take into consideration the patients' psychological as well as medical problems.^ieng