Genetic Variants as Predictive Markers for Ototoxicity and Nephrotoxicity in Patients with Locally Advanced Head and Neck Cancer Treated with Cisplatin-Containing Chemoradiotherapy (The PRONE Study)

Ototoxicity and nephrotoxicity are potentially irreversible side effects of chemoradiotherapy with cisplatin in locally advanced head and neck cancer (LAHNC) patients. Several predictive genetic variants have been described, but as yet none in LAHNC patients. The aim of this study is to investigate genetic variants as predictors for ototoxicity and nephrotoxicity in LAHNC patients treated with cisplatin-containing chemoradiotherapy. Our prospective cohort of 92 patients was genotyped for 10 genetic variants and evaluated for their association with cisplatin-induced ototoxicity (ACYP2, COMT, TPMT and WFS1) and nephrotoxicity (OCT2, MATE and XPD). Ototoxicity was determined by patient-reported complaints as well as tone audiometrical assessments. Nephrotoxicity was defined as a decrease of ≥25% in creatinine clearance during treatment compared to baseline. A significant association was observed between carriership of the A allele for rs1872328 in the ACYP2 gene and cisplatin-induced clinically determined ototoxicity (p = 0.019), and not for ototoxicity measured by tone audiometrical assessments (p = 0.449). Carriership of a T allele for rs316019 in the OCT2 gene was significantly associated with nephrotoxicity at any time during chemoradiotherapy (p = 0.022), but not with nephrotoxicity at the end of the chemoradiotherapy. In conclusion, we showed prospectively that in LAHNC patients genetic variants in ACYP2 are significantly associated with clinically determined ototoxicity. Validation studies are necessary to prove the added value for individualized treatments plans in these patients

ST-Segment Elevation and Fractionated Electrograms in Brugada Syndrome Patients Arise From the Same Structurally Abnormal Subepicardial RVOT Area but Have a Different Mechanism

Brugada syndrome (BrS) is characterized by a typical ECG pattern. We aimed to determine the pathophysiologic basis of the ST-segment in the BrS-ECG with data from various epicardial and endocardial right ventricular activation mapping procedures in 6 BrS patients and in 5 non-BrS controls. In 7 patients (2 BrS and 5 controls) with atrial fibrillation, an epicardial 8×6 electrode grid (interelectrode distance 1 mm) was placed epicardially on the right ventricular outflow tract (RVOT) before video-assisted thoracoscopic surgical pulmonary vein isolation. In 2 other BrS patients, endocardial, epicardial RV (CARTO), and body surface mapping was performed. In 2 additional BrS patients, we performed decremental preexcitation of the RVOT before endocardial RV mapping. During video-assisted thoracoscopic surgical pulmonary vein isolation and CARTO mapping, BrS patients (n=4) showed greater activation delay and more fractionated electrograms in the RVOT region than controls. Ajmaline administration increased the region with fractionated electrograms, as well as ST-segment elevation. Preexcitation of the RVOT (n=2) resulted in ECGs that supported the current-to-load mismatch hypothesis for ST-segment elevation. Body surface mapping showed that the area with ST-segment elevation anatomically correlated with the area of fractionated electrograms and activation delay at the RVOT epicardium. ST-segment elevation and epicardial fractionation/conduction delay in BrS patients are most likely related to the same structural subepicardial abnormalities, but the mechanism is different. ST-segment elevation may be caused by current-to-load mismatch, whereas fractionated electrograms and conduction delay are expected to be caused by discontinuous conduction in the same area with abnormal myocardiu

Genetic Variants as Predictive Markers for Ototoxicity and Nephrotoxicity in Patients with Locally Advanced Head and Neck Cancer Treated with Cisplatin-Containing Chemoradiotherapy (The PRONE Study)

Ototoxicity and nephrotoxicity are potentially irreversible side effects of chemoradiotherapy with cisplatin in locally advanced head and neck cancer (LAHNC) patients. Several predictive genetic variants have been described, but as yet none in LAHNC patients. The aim of this study is to investigate genetic variants as predictors for ototoxicity and nephrotoxicity in LAHNC patients treated with cisplatin-containing chemoradiotherapy. Our prospective cohort of 92 patients was genotyped for 10 genetic variants and evaluated for their association with cisplatin-induced ototoxicity (ACYP2, COMT, TPMT and WFS1) and nephrotoxicity (OCT2, MATE and XPD). Ototoxicity was determined by patient-reported complaints as well as tone audiometrical assessments. Nephrotoxicity was defined as a decrease of ≥25% in creatinine clearance during treatment compared to baseline. A significant association was observed between carriership of the A allele for rs1872328 in the ACYP2 gene and cisplatin-induced clinically determined ototoxicity (p = 0.019), and not for ototoxicity measured by tone audiometrical assessments (p = 0.449). Carriership of a T allele for rs316019 in the OCT2 gene was significantly associated with nephrotoxicity at any time during chemoradiotherapy (p = 0.022), but not with nephrotoxicity at the end of the chemoradiotherapy. In conclusion, we showed prospectively that in LAHNC patients genetic variants in ACYP2 are significantly associated with clinically determined ototoxicity. Validation studies are necessary to prove the added value for individualized treatments plans in these patients

Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury

Nephrotoxicity is a common and dose-limiting side effect of platinum compounds, which often manifests as acute kidney injury or hypomagnesemia. This study aimed to investigate the genetic risk loci for platinum-induced nephrotoxicity. Platinum-treated brain tumor and head–neck tumor patients were genotyped with genome-wide coverage. The data regarding the patient and treatment characteristics and the laboratory results reflecting the nephrotoxicity during and after the platinum treatment were collected from the medical records. Linear and logistic regression analyses were performed to investigate the associations between the genetic variants and the acute kidney injury and hypomagnesemia phenotypes. A cohort of 195 platinum-treated patients was included, and 9,799,032 DNA variants passed the quality control. An association was identified between RBMS3 rs10663797 and acute kidney injury (coefficient −0.10 (95% confidence interval −0.13–−0.06), p-value 2.72 × 10−8). The patients who carried an AC deletion at this locus had statistically significantly lower glomerular filtration rates after platinum treatment. Previously reported associations, such as BACH2 rs4388268, could not be replicated in this study’s cohort. No statistically significant associations were identified for platinum-induced hypomagnesemia. The genetic variant in RBMS3 was not previously linked to nephrotoxicity or related traits. The validation of this study’s results in independent cohorts is needed to confirm this novel association

Prophylactic antibiotics reduce hospitalisations and cost in locally advanced head and neck cancer patients treated with chemoradiotherapy: A randomised phase 2 study

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