Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers.

Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

The diagnostic yield of the routine EEG at a tertiary care center in Saudi Arabia: A retrospective study.

BACKGROUND: The Routine Electroencephalography (REEG) records cerebral electrical activity to aid in the diagnosis and classification of Epilepsy. Indiscriminate use of the REEG may lower its clinical yield. The pretest clinical variables contributing to the yield of the REEG outcome have not been well-established in the context of developing healthcare systems where REEG utilization may differ from well-established centers. The aim of this study is to determine the yield of the REEG and the pretest clinical variables predicting the yield of the REEG at a single center in the context of the developing healthcare system in Saudi Arabia. MATERIALS AND METHODS: We reviewed REEG reports at a single center in Jeddah, Saudi Arabia between 2015 and 2018. We collected demographic and clinical data from the patients' electronic files. Patients of age ≥18-year-old were included. We collected age, gender, nationality, the indication for the REEG, co-morbidities, antiseizure medicines (ASMs), and details related to the yield of the REEG (normal or abnormal, epileptiform or non-epileptiform, focality, and the presence of rhythmic or periodic patterns or seizures). RESULTS: We included 500 records. Fifty-nine percent were females. The mean age was 39 ±â€¯17 years. Of the recorded REEGs, 42.4% were abnormal, 14.6% of them showing definite epileptiform discharges and 85.4% showing only slowing. Half of the REEGs of individuals previously diagnosed with epilepsy revealed abnormal findings. ASM use was associated with slowing in the REEG (p < .05). Using logistic regression, history of a previous stroke and use of carbamazepine or lamotrigine were predictors of the presence of abnormalities in the REEG, while use of ≥2 ASMs predicted the presence of epileptiform discharges. Stroke also predicted abnormal slowing alongside increased age. CONCLUSION: The clinical yield of the REEG in this sample of patients from a single institution in the context of a developing healthcare system was relatively low. History of stroke and being on more than one ASM may predict that the REEG will show relevant abnormalities.

Similar overall survival with reduced vs. standard dose bevacizumab monotherapy in progressive glioblastoma.

INTRODUCTION: Bevacizumab has demonstrated activity in glioblastoma (GBM), but the true benefits and optimal dose-schedule are debated. A lower dose-schedule than standard-dose bevacizumab (10 mg/kg 2-weekly) might offer similar benefits with lower costs. At our Institution, patients are randomly assigned at time of primary diagnosis to Neuro-Oncologists, who have varying practices in terms of bevacizumab dose-schedule upon progression. METHODS: In a retrospective analysis we examined overall survival (OS), measured from first administered bevacizumab dose until death, according to dose-schedule. Patients with de novo WHO Grade IV GBM who received standard- or reduced-dose (5 mg/kg 2-weekly) bevacizumab were included. MGMT methylation status and time from diagnosis to bevacizumab start were examined as prognostic variables. Clinical benefit and a comparative cost analysis were assessed. RESULTS: In total, 1127 bevacizumab doses were administered to 118 patients [Median: 7, Range: 1-44]. Median OS (mOS) was 5.8 months. 69 (59%) patients received standard-dose bevacizumab (mOS: 5.97 months) and 49 patients received reduced-dose (mOS: 5.7 months). No statistically significant difference in OS between dosing schedule was seen (HR: 1.11, P-value: .584). Patients with MGMT methylated tumors (43%) had improved OS compared to those with unmethylated tumors; 7.03 vs 4.97 months (HR: 0.61, P-value: .027). If all patients were treated with reduced-dose bevacizumab, an estimated €2.4M cost reduction would be observed. CONCLUSIONS: In this retrospective study, reduced-dose bevacizumab schedule resulted in similar OS to standard-dose bevacizumab monotherapy with substantial cost savings. MGMT methylation appears to convey a survival benefit in the setting of bevacizumab treatment for progressive GBM.

Effect of Perioperative Nutritional Supplementation on Postoperative Complications-Systematic Review and Meta-Analysis.

BACKGROUND: Perioperative carbohydrate loading, increased protein intake, and immunonutrition may decrease postoperative complications. Studies on the topic have led to controversial results. METHODS: We searched Medline, EMBASE, and CENTRAL up to August 2018 for randomized trials comparing the effect of perioperative nutritional supplements (intervention) versus control on postoperative complications in patients undergoing gastrointestinal cancer surgery. Secondary outcomes included infectious complications and length of hospital stay (LOS). Random effects model was used to estimate the pooled risk ratio (RR) of treatment effects. Pooled mean difference (MD) was used to compare LOS. Heterogeneity was assessed using I2. Sources of heterogeneity were explored through subgroup analysis by nutritional supplementation protocol, type of surgery, and type of nutritional supplement. Risk of bias and quality of the evidence were assessed. RESULTS: Of 3951 articles, we identified 56 trials (n = 6370). Perioperative nutrition was associated with a lower risk of postoperative complications (RR 0.74, 95% confidence interval (CI) 0.69-0.80); postoperative infections (RR 0.71, 95% CI 0.64-0.79, n = 4582); and postoperative non-infectious complications (RR 0.79, 95% CI 0.71-0.87, n = 4883). There were no significant heterogeneity outcomes analyzed (I2 = 14%, 1%, and 7%, respectively). LOS was shorter for the intervention group, MD - 1.58 days; 95% CI - 1.83 to - 1.32; I2 = 89%). Subgroup analysis did not identify sources of heterogeneity. The quality of evidence for postoperative complications was high and for LOS was moderate. CONCLUSION: Perioperative nutritional optimization decreases the risk of postoperative infectious and non-infectious complications. It also decreases LOS in patients undergoing gastrointestinal cancer surgery, but these findings should be taken with caution given the high heterogeneity.