Background: In the present study, we aimed to investigate whether early cardiac biomarker alterations and echocardiographic parameters, including left atrial (LA) strain, can predict ...anthracycline-induced cardiotoxicity (AIC) and thus develop a predictive risk score.Methods and Results: The AIC registry is a prospective, observational cohort study designed to gather serial echocardiographic and biomarker data before and after anthracycline chemotherapy. Cardiotoxicity was defined as a reduction in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and <55%. In total, 383 patients (93% women; median age, 57 46–66 years) completed the 2-year follow-up; 42 (11.0%) patients developed cardiotoxicity (median time to onset, 292 175–440 days). Increases in cardiac troponin T (TnT) and B-type natriuretic peptide (BNP) and relative reductions in the left ventricular global longitudinal strain (LV GLS) and LA reservoir strain LASr at 3 months after anthracycline administration were independently associated with subsequent cardiotoxicity. A risk score containing 2 clinical variables (smoking and prior cardiovascular disease), 2 cardiac biomarkers at 3 months (TnT ≥0.019 ng/mL and BNP ≥31.1 pg/mL), 2 echocardiographic variables at 3 months (relative declines in LV GLS ≥6.5%, and LASr ≥7.5%) was generated.Conclusions: Early decline in LASr was independently associated with subsequent cardiotoxicity. The AIC risk score may provide useful prognostication in patients receiving anthracyclines.
We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United ...States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.
A subset (1% to 5%) of non-small-cell lung carcinomas harbors the EML4-ALK fusion gene. Data from previous studies on the histomorphology of ALK-rearranged lung cancer are inconsistent, and the ...specific histologic parameters that characterize this subset and how accurately such parameters predict underlying ALK abnormality remain uncertain. To answer these questions, we performed a comprehensive histologic analysis of 54 surgically resected, extensively sampled ALK-rearranged lung carcinomas and compared them with 100 consecutive resections of ALK-wild-type lung cancers. All 54 cases showed at least a focal adenocarcinoma component, and 3 and 2 cases had additional squamous and sarcomatoid differentiation, respectively. Solid or acinar growth pattern, cribriform structure, presence of mucous cells (signet-ring cells or goblet cells), abundant extracellular mucus, lack of lepidic growth, and lack of significant nuclear pleomorphism were more common in ALK-positive cancers. Two recognizable constellations of findings, a solid signet-ring cell pattern and a mucinous cribriform pattern, were present at least focally in the majority (78%) of ALK-positive tumors, but were rare (1%) in ALK-negative tumors. Multivariate analysis showed that a combination of these 2 patterns was the most powerful histologic indicator of ALK rearrangement. Characteristic histologies were present both in primary sites and in metastases. Thus, histologic findings may help to identify cases for ALK testing. However, none of the histologic parameters were completely sensitive or specific to ALK rearrangement, and histomorphology should not replace confirmatory molecular or immunohistochemical studies. ALK-positive cancers commonly showed coexpression of thyroid transcription factor-1 and p63, and its significance is currently unclear.
Summary Background Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT3 )-receptor antagonist that has shown better efficacy than ondansetron and dolasetron in preventing ...chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy, and similar efficacy to ondansetron in preventing CINV in patients receiving highly emetogenic chemotherapy. In this phase III, multicentre, randomised, double-blind, double-dummy, stratified, parallel-group, active-comparator trial, we assessed the efficacy and safety of palonosetron versus granisetron for chemotherapy-induced nausea and vomiting, both of which were administered with dexamethasone in patients receiving highly emetogenic chemotherapy. Methods Between July 5, 2006, and May 31, 2007, 1143 patients with cancer who were receiving highly emetogenic chemotherapy (ie, cisplatin, or an anthracycline and cyclophosphamide combination AC/EC) were recruited from 75 institutions in Japan, and randomly assigned to either single-dose palonosetron (0·75 mg), or granisetron (40 μg/kg) 30 min before chemotherapy on day 1, both with dexamethasone (16 mg intravenously) on day 1 followed by additional doses (8 mg intravenously for patients receiving cisplatin or 4 mg orally for patients receiving AC/EC) on days 2 and 3. A non-deterministic minimisation method with a stochastic-biased coin was applied to the randomisation of patients. Covariates known to effect emetic risk, such as sex, age, and type of highly emetogenic chemotherapy, were used as stratification factors of minimisation to ensure balance between the treatment groups. Primary endpoints were the proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) during the acute phase (0–24 h postchemotherapy; non-inferiority comparison with granisetron) and the proportion of patients with a complete response during the delayed phase (24–120 h postchemotherapy; superiority comparison with granisetron). The non-inferiority margin was predefined in the study protocol as a 10% difference between groups in the proportion of patients with complete response. The palonosetron dose of 0·75 mg was chosen on the basis of two dose-determining trials in Japanese patients. All patients who received study treatment and highly emetogenic chemotherapy were included in the efficacy analyses (modified intention to treat). This trial is registered with ClinicalTrials.gov , number NCT00359567. Findings 1114 patients were included in the efficacy analyses: 555 patients in the palonosetron group and 559 patients in the granisetron group. 418 of 555 patients (75·3%) in the palonosetron group had complete response during the acute phase compared with 410 of 559 patients (73·3%) in the granisetron group (mean difference 2·9% 95% CI −2·70 to 7·27). During the delayed phase, 315 of 555 patients (56·8%) had complete response in the palonosetron group compared with 249 of 559 patients (44·5%) in the granisetron group (p<0·0001). The main treatment-related adverse events were constipation (97 of 557 patients 17·4% in the palonosetron group vs 88 of 562 15·7% in the granisetron group) and raised concentrations of serum aminotransferases (aspartate aminotransferase: 24 of 557 4·3% vs 34 of 562 6·0%; alanine aminotransferase: 16 of 557 2·9% vs 33 of 562 5·9%); no grade 4 main treatment-related adverse events were reported. Interpretation When administered with dexamethasone before highly emetogenic chemotherapy, palonosetron exerts efficacy against chemotherapy-induced nausea and vomiting which is non-inferior to that of granisetron in the acute phase and better than that of granisetron in the delayed phase, with a comparable safety profile for the two treatments. Funding Taiho Pharmaceutical (Tokyo, Japan).
The hepatocyte growth factor/MET pathway has been shown to cause tumor progression in several types of carcinomas. The aim of this study was to examine the correlations between c-MET/phospho-MET ...expression as well as MET gene copy number alterations and overall survival (OS) in non-small cell lung carcinomas (NSCLCs).
We analyzed 906 NSCLCs including 704 adenocarcinomas (ADCs), 150 squamous cell carcinomas (SCCs), 43 sarcomatoid carcinomas, and 9 large cell carcinomas. The mutational status of epidermal growth factor receptor and K-ras and anaplastic lymphoma kinase rearrangements were retrospectively examined. We performed immunohistochemistry to detect c-MET/phospho-MET expression and MET gene copy number using bright-field in situ hybridization (BISH).
c-MET/phospho-MET expression and MET BISH positivity were observed in 22.2%, 5.6%, and 10.9% of NSCLCs, respectively; they were more prevalent in ADCs (27.3%, 6.9%, and 11.5%, respectively) and sarcomatoid carcinomas (20.9%, 9.3%, and 36.6%, respectively) than in SCCs and large cell carcinomas. Among ADCs, poorly differentiated cases exhibited c-MET expression and MET BISH positivity more commonly than well-differentiated ones. An analysis of all patients revealed that c-MET/phospho-MET expression and MET BISH positivity were not correlated with OS. However, when SCC cases were excluded, both univariate (p=0.019) and multivariate (p=0.020) analyses revealed a significant correlation between MET BISH positivity and OS.
c-MET/phospho-MET expression and MET BISH positivity differed according to histological type. Among ADCs, c-MET expression and MET BISH positivity were more common in poorly differentiated cases. MET BISH positivity was an independent prognostic factor in nonsquamous NSCLCs.
This study provides the benchmark statistics on medically treated patients with non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in Japan. Demographic background, treatment, and ...prognosis were obtained from patients with lung cancer pathologically diagnosed in 2012, who received nonsurgical treatment. Descriptive statistics and their associations with survival were analyzed. In total, 12 320 patients were registered from 314 institutions in Japan. The median age was 70 years, and 73% of the patients were male. The number (%) of stages I, II, III, and IV diseases were 468 (3.8%), 421 (3.4%), 3260 (26.5%), and 8171 (66.3%), respectively. NSCLC and SCLC accounted for 9872 (80.1%) and 2353 (19.1%) patients, respectively. Thoracic radiotherapy‐based therapy, chemotherapy, and palliative care alone were administered to 2572 (20.9%), 7790 (63.2%), and 1952 (15.8%) patients, respectively. Clinical TNM stage was one of the strongest prognostic factors with the 3‐year survival rates of 62.9%, 47.3%, 40.0%, 27.8%, 37.5%, 26.5%, and 18.2% for stages IA, IB, IIA, IIB, IIIA, IIIB, and IV, respectively. Among 6158 patients with NSCLC treated with chemotherapy, the 3‐year survival rate was 33.4% in patients receiving epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) at some point in their clinical course, whereas it was 17.4% in patients who did not. The 3‐year survival rate of SCLC was only 15.9%. In conclusion, approximately two‐thirds of the patients were diagnosed as stage IV at the initial diagnosis. Use of EGFR‐TKIs significantly improved the survival of patients with NSCLC.
This study provides the benchmark statistics on medically treated patients with lung cancer in Japan. Here, 3‐year survival rates of patients treated with concurrent chemoradiotherapy (n = 1689), sequential chemoradiotherapy (n = 221), thoracic radiotherapy alone (n = 662), chemotherapy alone (n = 7790) and palliative care alone (n = 1952) were 43.6%, 29.1%, 40.0%, 19.9%, and 0.3.4%, respectively.
After 4 weeks of the last dose of nivolumab, a 59-year-old man with stage IV melanoma was subject to treatment with ipilimumab. After 5 weeks, the patient developed severe hepatitis, showing markedly ...elevated levels of both aspartate aminotransferase and alanine aminotransferase (>2000 U/l). Using pulse steroid therapy with 1000 mg/d of methylprednisolone, liver function initially improved, but then deteriorated upon dosage reduction. Subsequently, mycophenolate mofetil (MMF) was administered at a dose of 2 g/d in addition to the corticosteroid, which resulted in aspartate aminotransferase and alanine aminotransferase levels gradually improving to grade 1, and the corticosteroid dose was successfully reduced to 0.5 mg/kg/d of oral prednisolone. Liver function then remained stable when MMF was tapered. In conclusion, the use of MMF improved liver function in this patient with steroid-refractory hepatitis induced by immune checkpoint inhibitor administration.
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