Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).

Upregulation of trefoil factor 3 (TFF3) after rectal cancer chemoradiotherapy is an adverse prognostic factor and a potential therapeutic target.

PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.

Strategies for maintenance therapy in advanced non-small cell lung cancer: current status, unanswered questions and future directions.

Systemic chemotherapy (CT) with platinum-based doublets result in modest improvements in both overall survival (OS) and quality of life in good performance status patients with advanced non-small cell lung cancer (NSCLC). However, although substantial progress has been made in the therapeutic options currently available for these patients, the overall outcome remains poor. Maintenance therapy for patients who achieved at least stable disease after first-line treatment has been an area of intense investigation in recent years as a way of improving outcomes in metastatic NSCLC. Several alternative strategies for prolongation of initial treatment have been evaluated. These include the prolongation of the initial combination CT regimen until disease progression, unacceptable toxicity or a predefined greater number of cycles, continuation with a lower intensity version of the first-line CT regimen or administration of a new active agent immediately after completion of the first-line therapy (switch-maintenance or early second-line therapy). Treatments that have been studied in randomized trials to date include CT, molecularly targeted agents, and immunotherapy approaches. Phase III trials have not revealed a survival benefit for extended first-line CT with combination regimens for more than 4-6 cycles. Nevertheless, early second-line therapy with pemetrexed in nonsquamous tumours and erlotinib have demonstrated to improve OS results, especially in select patient groups characterized by histology and/or molecular profile. This article reviews recent data with maintenance therapy in advanced NSCLC and discusses the implications for routine patient care and future drug development.

Early and prolonged intake of partially hydrogenated fat alters the expression of genes in rat adipose tissue.

OBJECTIVE: Our previous study indicated that partially hydrogenated fat (PHF) diets, rich in trans-isomers, alter plasma lipids and increase the lipogenesis rate on adipose tissue in rats at a young age. In the present study we investigated the effects of dietary PHF on the expression of genes associated with glucose and lipid metabolism in rat adipose tissue. METHODS: Female Wistar rats were fed normolipidic diets containing PHF (rich in trans-fatty acids and poor in polyunsaturated fatty acids [PUFAs]), soy oil (rich in omega-6 PUFAs), and fish oil (rich in omega-3 PUFAs) during gestation and lactation; young male pups were fed the same diets from weaning until 120 d of life. The mRNA expression of peroxisome proliferator-activated receptor-gamma, tumor necrosis factor-alpha, resistin, adiponectin, and leptin were analyzed in retroperitoneal adipose tissue (RET) using real time polymerase chain reaction. RESULTS: The PHF group showed the highest triacylglycerol, glucose, and insulin levels and the lowest plasma adiponectin level. The RET of PHF incorporated trans-fatty acids, whereas fish oil and soy oil groups had increased omega-3 and omega-6 PUFAs, respectively. In the RET the PHF group had the highest resistin and tumor necrosis factor-alpha levels and the lowest adiponectin and peroxisome proliferator-activated receptor-gamma gene expressions, whereas the fish oil group had the highest peroxisome proliferator-activated receptor-gamma and the lowest leptin gene expression. CONCLUSION: Prolonged intake of PHF has a negative effect on the expression of genes in RET when compared with diets with omega-6 and omega-3 PUFAs. These changes may be an effect of the smaller proportions of PUFAs in this fat, instead of being only caused by trans-fatty acids.

Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study.

BACKGROUND: Adequate prognostic markers to predict outcome of patients with lung cancer are still needed. The aim of this study was to assess whether choline kinase alpha (ChoKalpha) gene expression could identify patients with different prognoses. ChoKalpha is an enzyme involved in cell metabolism and proliferation and has a role in oncogene-mediated transformation in several human tumours, including lung cancer. METHODS: 60 patients with non-small-cell lung cancer (NSCLC) who had undergone surgical resection in a single centre were enrolled into the study as the training group. We used real-time reverse-transcriptase PCR (RT-PCR) to measure ChoKalpha gene expression and analyse the association between ChoKalpha expression and survival in evaluable patients. Additionally, a second group of 120 patients with NSCLC from a different hospital were enrolled into the study as the validation group. We did an overall analysis of all 167 patients who had available tissue to confirm the cut-off point for future studies. The primary endpoints were lung-cancer-specific survival and relapse-free survival. FINDINGS: Seven of the 60 patients in the training group were not evaluable due to insufficient tissue. In the 53 evaluable patients, the cut-off for those with ChoKalpha overexpression was defined by receiver operator under the curve (ROC) methodology. 4-year lung-cancer-specific survival was 54.43% (95% CI 28.24-80.61) for 25 patients with ChoKalpha expression above the ROC-defined cut-off compared with 88.27% (75.79-100) for 28 patients with concentrations of the enzyme below this cut-off (hazard ratio [HR] 3.14 [0.83-11.88], p=0.07). In the validation group, six of the 120 enrolled patients were not evaluable due to insufficient tissue. For the other 114 patients, 4-year lung-cancer-specific survival was 46.66% (32.67-59.65) for those with ChoKalpha expression above the ROC-defined cut-off compared with 67.01% (50.92-81.11) for patients with concentrations of ChoKalpha below the cut-off (HR 1.87 [1.01-3.46], p=0.04). A global analysis of all 167 patients further confirmed the association between ChoKalpha overexpression and worse clinical outcome of patients with NSCLC: 4-year lung-cancer-specific survival for ChoKalpha expression above the ROC-defined cut-off was 49.00% (36.61-60.38) compared with 70.52% (59.80-76.75) for those with concentrations of ChoKalpha below the cut-off (HR 1.98 [1.14-3.45], p=0.01). The overall analysis confirmed the cut-off for ChoKalpha expression should be 1.91-times higher than concentrations noted in healthy tissues when ChoKalpha is used as an independent predictive factor of relapse-free and lung-cancer-specific survival in patients with early-stage NSCLC. INTERPRETATION: ChoKalpha expression is a new prognostic factor that could be used to help identify patients with early-stage NSCLC who might be at high risk of recurrence, and to identify patients with favourable prognosis who could receive less aggressive treatment options or avoid adjuvant systemic treatment. New treatments that inhibit ChoKalpha expression or activity in patients with lung cancer should be studied further.