Tudásmenedzsment és a felsőoktatási intézmény, mint vállalat = Knowledge Management and the University as a Company

Purpose: ALK rearrangement detection using FISH is the standard test to identify patients with non–small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH. Experimental Design: Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH–positive advanced NSCLC from four other hospitals were used for validation. Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC–positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH–positive but ALK-IHC–negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, P ¼ 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, P ¼ 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, P ¼ 0.01, respectively]. Conclusions: Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer

Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0–3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2–16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2–18.8) for CPE and 10.3 months (95% CI 7.1–15.5; hazard ratio (HR) 0.62, 95% CI 0.25–1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07–0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8–61.9 months) for CPE compared to 17.2 months (95% CI 11.5–45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22–1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19):an investigator-initiated, randomised, open-label, phase 2 trial

Background Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. Methods We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m(2) on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. Findings Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36.5 months (95% CI 34.2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6.2 months [95% CI 4.6-8.7]) than in the supportive care group (3.2 months [2.8-4.1]; hazard ratio [HR] 0.48 [95% CI 0.33-0.71]; p=0.0002). The benefit was confirmed by masked independent central review (HR 0.49 [0.33-0.72]; p=0.0002). Grade 3-4 adverse events occurred in 33 ( 52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. Interpretation Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma

The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer

The relationship between the magnitude of systemic inflammatory response and the nutritional/functional parameters in patients with inoperable non-small cell lung cancer were studied. The extent of weight loss, albumin, C-reactive protein, performance status and quality of life was measured in 106 patients with inoperable non-small cell lung cancer (stages III and IV). Survival analysis was performed using the Cox proportional hazard model. The majority of patients were male and almost 80% had elevated circulating C-reactive protein concentrations (>10 mg l−1). On multivariate analysis, age (P=0.012), tumour type (0.002), weight loss (P=0.056), C-reactive protein (P=0.047), Karnofsky performance status (P=0.002) and fatigue (P=0.046) were independent predictors of survival. The patients were grouped according to the magnitude of the C-reactive protein concentrations (⩽10, 11–100 and >100 mg l−1). An increase in the magnitude of the systemic inflammatory response was associated with increased weight loss (P=0.004), reduced albumin concentrations (P=0.001), reduced performance status (P=0.060), increased fatigue (P=0.011) and reduced survival (HR 1.936 95%CI 1.414–2.650, P<0.001). These results indicate that the majority of patients with inoperable non-small cell lung cancer have evidence of a systemic inflammatory response. Furthermore, an increase in the magnitude of the systemic inflammatory response resulted in greater weight loss, poorer performance status, more fatigue and poorer survival

Energy balance in nonsmall cell lung carcinoma patients before and after surgical resection of their tumors.

BACKGROUND: The purpose of this study was to investigate whether surgical removal of a tumor influences energy balance, body weight, and body composition in lung carcinoma patients. METHODS: In 53 nonsmall cell lung carcinoma (NSCLC) patients, resting energy expenditure (REE, measured by ventilated hood), energy intake (EI, determined by diet history), body weight, and body composition (fat free mass [FFM], measured by bioelectrical impedance analysis) were all determined before tumor resection. In 39 of 53 patients, REE, EI, body weight, and body composition were also measured 3, 6, and 12 months after tumor resection. RESULTS: Thirty-six of 53 patients (68%) were found to be hypermetabolic. Fourteen patients were excluded from the repeated measurements. Patients with curative tumor resection (n = 30) showed an increase in body weight over a 1-year period, in contrast to patients with tumor recurrence (n = 9), who lost weight (+3.5 vs. -3.6 kg, P < 0.005). The weight gain was caused predominantly by an increase in fat mass (FM), while the weight loss was caused for more than half by a decrease in FFM. Body weight was increased in hypermetabolic patients (n = 20) as well as patients with normal metabolism (n = 10) 1 year after successful removal of their tumors. However, although EI/REE was significantly increased in hypermetabolic patients (from 106% to 140%, P < 0.05), it was not changed in patients with normal metabolism. CONCLUSIONS: Hypermetabolic NSCLC patients undergoing curative resection show an improvement in energy balance caused by both a decrease in REE and an increase in EI. This positive energy balance results in weight gain, which is caused predominantly by an increase in FM

Expression of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in non-small-cell lung carcinoma.

Vascular cell adhesion molecules (VCAM) play an important part in the regulation of inflammation and are considered to be important in the process of malignant tumour growth. The present study describes the immunohistochemical staining patterns of E-selectin, intercellular adhesion molecule (ICAM)-1 and VCAM-1 on endothelial cells of the vessels in tumour stroma and other cell types in non-small-cell lung carcinoma (NSCLC; n = 43) in association with inflammatory cells. Expression of E-selectin was dominant on endothelial cells in the stromal areas of the tumour, especially at the borders, and was confined to endothelial cells. Moderate to strong staining for ICAM-1 was demonstrated on endothelial cell irrespective of size or localization of the vessels. Compared with ICAM-1, fewer vessels were positive for VCAM-1, and stained with lesser intensity. ICAM-1 expression was demonstrated on NSCLC cells, the basal cells of bronchial epithelium, type II pneumocytes, lymphocytes and fibroblasts. VCAM-1 was clearly expressed on NSCLC cells in 4 of the 43 cases and on lymphocytes and fibroblasts. The staining patterns observed on endothelial cells support the idea of an active status of NSCLC vessels. This phenotypic pattern looks similar to the vascular component of inflammation. The presence of ICAM-1 and VCAM-1 on NSCLC cells suggests a functional role in the process of chemotaxis for tumour cells