Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Large-scale clinico-genomic profile of non-small cell lung cancer with KRAS G12C: Results from LC-SCRUM-Asia study.

INTRODUCTION: KRAS G12C is an oncogenic driver mutation, accounting for approximately 14% of Caucasian patients with non-small cell lung cancer (NSCLC). Recently, several KRAS G12C-targeted drugs have been developed; however, the clinico-genomic characteristics of NSCLC patients with KRAS G12C remain unclear. MATERIALS AND METHODS: Based on the large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia) database, the clinico-genomic characteristics and therapeutic outcomes of NSCLC patients with KRAS G12C were evaluated. RESULTS: From March 2015 to March 2021, 10,023 NSCLC patients were enrolled in LC-SCRUM-Asia. KRAS mutations were detected in 1258 patients (14 %), including G12C in 376 (4.0 %), G12D in 289 (3.1 %) and G12V in 251 (2.7 %). The proportions of males and smokers were higher in patients with KRAS G12C than in those with KRAS non-G12C mutations (males: 73 % vs 63 %, p < 0.001; smokers: 89 % vs 76 %, p < 0.001). KRAS G12C-positive tumors showed a higher tumor mutation burden (TMB) (mean, 8.1 mut/Mb, p < 0.001) and a higher percentage of tumors with programmed cell death ligand-1 (PD-L1) expression ≥50 % (52 %, p = 0.08). The overall survival in patients with KRAS G12C (median, 24.6 months) was not different between patients with other mutation subtypes (G12V: 18.2 months, p = 0.23; G12D: 20.6 months, p = 0.65; other KRAS mutations: 18.3 months, p = 0.20). Among KRAS-mutated patients who received immune checkpoint inhibitors (ICIs), the progression-free survival in G12C-positive patients (median, 3.4 months) was similar to that in G12V-positive patients (4.2 months, p = 0.90), but significantly longer than that in G12D- (2.0 months, p = 0.02) and other KRAS mutation-positive patients (2.5 months, p = 0.02). CONCLUSIONS: The frequencies of KRAS G12C were lower in Asian than in Caucasian NSCLC patients. Among the KRAS-mutated NSCLC patients, G12C-positive tumors showed increased immunogenicity, such as high TMB and high PD-L1 expression, and potential sensitivity to ICIs.

The impact of tertiary lymphoid structures on clinicopathological, genetic and gene expression characteristics in lung adenocarcinoma.

INTRODUCTION: Tertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS. METHODS: A total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed. RESULTS: Among the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS-) (hazard ratio [HR], 0.47; 95 % confidence interval [CI]: 0.23-0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18-0.72, p < 0.01). PD-L1 expression was not significantly different between TLS+ and TLS- patients (p = 0.54). TMB in TLS+ was similar to that in TLS- patients (p = 0.39); however, it tended to be lower than that in TLS- especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+. CONCLUSIONS: TLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses.

Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer.

Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a BRAF V600E mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with BRAF V600E mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression.

Comparison of the efficiency of endobronchial ultrasound-guided transbronchial needle aspiration using a 22G needle versus 25G needle for the diagnosis of lymph node metastasis in patients with lung cancer: a prospective randomized, crossover study.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is generally performed for the diagnosis of hilar/mediastinal lymph node metastasis in patients with lung cancer. Recently, a 25-gauge (G) needle became available, but robust evidence of its usefulness in routine clinical practice is still lacking. METHODS: A prospective randomized crossover trial was performed, in which patients with suspected hilar/mediastinal lymph node metastasis of lung cancer underwent EBUS-TBNA. The primary endpoint was the rate of yield histology specimens containing malignant cells. RESULTS: From December 2018 to February 2020, 102 patients were randomly assigned to EBUS-TBNA using a 22G needle first, followed by a 25G needle (n=50) or EBUS-TBNA using a 25G needle first, followed by a 22G needle (n=52). There was no difference in the diagnostic yield of malignancy between the histology specimens obtained by using the 22G and 25G needles (75% vs. 75%, respectively, P=0.37). The sizes of the tissue samples (16.4 vs. 4.9 mm2, respectively) and number of malignant cells in the tissue samples (626 vs. 400, respectively) were both significantly higher when using the 22G needle than when using the 25G needle. CONCLUSIONS: No significant difference in the diagnostic yield between the 22G and 25G needles was observed for the diagnosis of lymph node metastasis of lung cancer, suggesting that needles of either gauge could be used for the biopsy. However, we would recommend use of the 22G needle, because it provided larger specimens and specimens containing larger numbers of malignant cells. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000036680).

Potential Benefits of Bevacizumab Combined With Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Cancer Patients With EGFR Mutation.

BACKGROUND: Oncogenic EGFR signaling has been shown to upregulate vascular endothelial growth factor A (VEGFA) expression involved in tumor angiogenesis. However, the clinical benefits of bevacizumab plus cytotoxic chemotherapy for EGFR mutation-positive patients remain unclear. This study aimed to investigate VEGFA messenger RNA expression in patients with EGFR mutation, and to further compare the efficacy of bevacizumab combined with platinum-based chemotherapy between EGFR-mutant and wild-type patients. PATIENTS AND METHODS: Gene expression of various proangiogenic factors was analyzed in nonsquamous, non-small-cell lung cancer (NSCLC) patients using The Cancer Genome Atlas dataset. Additionally, clinical data of patients receiving carboplatin and pemetrexed (CPem; n = 104) or bevacizumab plus CPem (BevCPem; n = 55) at Nagoya University hospital were retrospectively assessed for progression-free survival and best overall response rate (ORR). RESULTS: Among various proangiogenic factors, only VEGFA expression was significantly higher in patients with advanced nonsquamous NSCLC with EGFR mutation compared to wild-type patients (P = .0476). Progression-free survival in the BevCPem group was significantly longer in patients with EGFR mutation than in wild-type patients (10.5 vs. 6.6 months; Wilcoxon P = .0278), while the difference in the CPem group was not significant (6.6 vs. 4.5 months; Wilcoxon P = .1822). The ORRs in the BevCPem group were 54.5% and 36.4% for EGFR-mutant and wild-type patients, respectively, and the ORRs in the CPem group were 35.5% and 28.8 % in EGFR-mutant and wild-type patients, respectively. CONCLUSION: VEGFA messenger RNA expression was significantly increased in advanced nonsquamous NSCLC harboring EGFR mutation, and BevCPem provided better clinical benefits to patients with EGFR mutation than wild-type carriers.

Mesothelial Cells Create a Novel Tissue Niche That Facilitates Gastric Cancer Invasion.

Peritoneal mesothelial cells (PMC) cover organ surfaces in the abdominal cavity. In this study, lineage tracing revealed that the PMCs guide cancer cell invasion in the gastric wall and in peritoneal metastatic lesions. Serosal PMCs covering the stomach surface entered the gastric wall to create a novel niche that favored gastric cancer cell invasion. PMC infiltration was induced by incorporation of cancer cell-derived, Wnt3a-containing extracellular vesicles. Infiltrated PMCs in turn promoted subserosal invasion of cancer cells. Mutual attraction between cancer cells and PMCs accelerated tumor invasion in the gastric wall, and PMC-led cancer cell invasion in disseminated tumors within the abdominal wall and diaphragm. Addition of the carboxyl terminus of Dickkopf-1 attenuated directional invasion of PMCs toward cancer cells both in vitro and in the gastric wall in vivo PMCs were sensitive to the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF), as ALDH activity is elevated in PMCs. Wnt3a upregulated ALDH, and addition of DSF inhibited the invasive properties of PMCs, whereas DSF pretreatment suppressed gastric infiltration of PMCs and subserosal invasion by cancer cells. Our results suggest that stabilization of PMCs may become an effective therapy for the prevention of local invasion and metastasis of gastric cancer. Cancer Res; 77(3); 684-95. ©2016 AACR.