Background: Chemotherapy‐induced toxicities frequently occur in non‐small cell lung cancer (NSCLC) patients treated with platinum‐based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy‐induced toxicity in a large cohort of NSCLC patients.Methods: A multicentre prospective follow‐up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II–IV) treated with first‐line platinum‐based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m²) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy‐induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non‐haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose‐limiting toxicity (DLT) (treatment switch, delay, de‐escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI).Results: In total, 297 patients (male n = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% (n = 108) of the patients, 24.6% (n = 73) experienced any non‐haematological toxicity grade ≥2, and 55.6% (n = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31–4.45, P = 0.005) and age at diagnosis >65 years (ORadj 1.76, 95% CI 1.07–2.90, P = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non‐haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23–4.04, P = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23–0.74, P = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT.Conclusions: Non‐small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy.

Background: In addition to radiological evaluation, biomarkers may be useful in providing early information on the response to treatment, and supporting clinical decision‐making. The objective of this study was to investigate carcinoembryonic antigen (CEA) and lactate dehydrogenase (LDH) as biomarkers for early assessment of response in patients with advanced non‐small cell lung cancer (NSCLC) treated with platinum‐based chemotherapy.Methods: A retrospective follow‐up study was conducted from 2012 to 2017 among 593 consecutive patients with advanced NSCLC treated with first‐line platinum‐based chemotherapy in a large teaching hospital in the Netherlands. Pretreatment biomarker levels and changes from pretreatment levels were studied for association with radiologic response (partial response [PR] or complete response [CR], according to RECIST 1.1) using multivariate logistic regression, and with overall survival using COX proportional hazard modeling. Patient and disease characteristics such as age and disease stage were taken into account as potential confounding factors.Results: Decreases in CEA and LDH (≥ 20%), particularly early in treatment, were significantly associated with better radiological response. Increases in these biomarkers (≥ 20%) and high pretreatment LDH levels (≥ 247 U/L) were significantly associated with lower overall survival.Conclusions: Our results support determination of CEA and LDH levels for earlier assessment of response to platinum‐based chemotherapy in patients with advanced NSCLC. Hence, routine determination and evaluation of CEA and LDH levels, prior to each cycle of platinum‐based chemotherapy in advanced NSCLC, should be considered as part of daily clinical practice.Key points: Significant findings of the study: Serum biomarkers in monitoring of treatment in advanced NSCLC would be useful. CEA and LDH decrease (≥ 20%) is favorable for achieving radiological response. High LDH levels and CEA/LDH increase (≥ 20%) is associated with reduced survival. What this study adds: Monitoring of CEA seems to be particularly relevant in early stage of treatment. CEA and LDH determination should be considered as part of daily clinical practice.

Summary: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFR<60 ml/min/1.73 m2). Furthermore, the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and stroke at one-year was evaluated. Patients with CKD (n=180) had significantly higher platelet reactivity, regardless of the platelet function test used. Patients with CKD more frequently had high on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) regardless of the platelet function test used. After adjustment for potential confounders, this was no longer significant. The event-rate was the highest in patients with both high on-treatment platelet reactivity (HPR) and CKD compared to those with neither high on-treatment platelet reactivity nor CKD. In conclusion, the magnitude of platelet reactivity as well as the incidence of HPR was higher in patients with CKD. However, since the incidence of HPR was similar after adjustment, a higher rate of co-morbidities in patients with CKD might be the major cause for this observation rather than CKD itself. CKD-patients with HCPR were at the highest risk of long-term cardiovascular events.Clinical Trial Registration: www.clinicaltrials.gov: NCT00352014.

Introduction: The introduction of immune checkpoint inhibitors heralded a new era in the treatment of non-small cell lung cancer. However, nivolumab, an anti-PD-1 antibody, can cause serious adverse events that are mostly autoimmune related. Case Presentation: A 58-year-old woman was treated with nivolumab as second-line therapy for stage IV adenocarcinoma. The patient developed a nivolumab-induced recurrent pneumonitis preceding durable clinical remission after seven cycles of nivolumab. Although high-dose glucocorticosteroids were tapered to conform to contemporary guidelines, recurring episodes of pneumonitis occurred without nivolumab rechallenge. In addition, carcinoembryonic antigen (CEA) serum levels were associated with treatment response, since CEA decline correlated with a near complete radiological response and, conversely, elevated CEA serum levels were associated with progressive disease. Conclusions: In this case, we described recurrence of nivolumab-induced pneumonitis as a serious adverse event in immune checkpoint inhibitors. Our case illustrates that immune-related adverse events may correlate with antitumour activity, even after treatment discontinuation. In addition, this case suggests the possible clinical utility of CEA serum levels for the assessment of (durable) effects of immunotherapy.

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10⁻⁸) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10⁻⁷) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1–12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8–12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5–21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice.