Real-World Experience of Nivolumab in Non-small Cell Lung Cancer in Korea.

PURPOSE: The introduction of immune checkpoint inhibitors represents a major advance in the treatment of lung cancer, allowing sustained recovery in a significant proportion of patients. Nivolumab is a monoclonal anti-programmed death cell protein 1 antibody licensed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. In this study, we describe the demographic and clinical outcomes of patients with advanced NSCLC treated with nivolumab in the Korean expanded access program. MATERIALS AND METHODS: Previously treated patients with advanced nonsquamous and squamous NSCLC patients received nivolumab at 3 mg/kg every 2 weeks up to 36 months. Efficacy data including investigator-assessed tumor response, progression data, survival, and safety data were collected. RESULTS: Two hundred ninety-nine patients were treated across 36 Korean centers. The objective response rate and disease control rate were 18% and 49%, respectively; the median progression-free survival was 2.1 months (95% confidence interval [CI], 1.87 to 3.45), and the overall survival (OS) was 13.2 months (95% CI, 10.6 to 18.9). Patients with smoking history and patients who experienced immune-related adverse events showed a prolonged OS. Cox regression analysis identified smoking history, presence of immune-related adverse events as positive factors associated with OS, while liver metastasis was a negative factor associated with OS. The safety profile was generally comparable to previously reported data. CONCLUSION: This real-world analysis supports the use of nivolumab for pretreated NSCLC patients, including those with an older age.

Association between thyroid cancer and epidermal growth factor receptor mutation in female with nonsmall cell lung cancer.

BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC). METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models. RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P < 0.001), EGFR mutations were positively associated with a personal history of thyroid cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023). CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.

Prognostic Value of SUVmax Measured by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography in Patients with Gallbladder Cancer.

OBJECTIVE: The aim of this study is to investigate the prognostic value of F-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET)/computed tomography (CT) in gallbladder cancer patients. METHODS: From June 2004 to June 2010, a total of 50 patients with gallbladder cancer who underwent diagnostic staging with F-18 FDG PET/CT following curative or palliative treatments were retrospectively evaluated. For the analysis, all patients were classified by age, sex, maximum standardized uptake value (SUVmax), lymph node (LN) or distant metastasis, serum level of CA19-9 and CEA, type of treatment and American Joint Committee on Cancer (AJCC) stage. RESULTS: The median survival for the 50 patients was 245 days and the median SUVmax in PET/CT was 8.3 (range, 0-19.7). Patients with SUVmax < 6 survived significantly longer than patients with SUVmax ≥ 6 (median 405 days vs 203 days, p = 0.0400). On Kaplan-Meier analysis, SUVmax (p = 0.0400), stage (p = 0.0001), CA19-9 (p = 0.013), CEA (p = 0.006), LN metastasis (p = 0.0001), distant metastasis (p = 0.0020), type of treatment (p = 0.0001) were significantly associated with overall survival. Multivariate analysis study revealed that the patients with lower SUVmax measured from initial staging PET/CT (p = 0.0380), no LN metastasis (p = 0.0260), a lower stage (p = 0.026) and curative treatment (p = 0.0005) had longer survivals. CONCLUSIONS: The present study shows that SUVmax on F-18 FDG PET/CT can provide prognostic information in patients with gallbladder cancer.

Differences in clinical presentation of non-small cell lung cancer in never-smokers versus smokers.

OBJECTIVES: This study was conducted to evaluate whether or not tumor spread and the diagnostic process in non-small cell lung cancer (NSCLC) is different based on smoking history. METHODS: Associations between smoking status and clinical presentation were evaluated controlling for the effect of histology. Lung cancer with delayed diagnosis (LCDD) and incidental detection (LCID) were determined based on medical records. RESULTS: Of 914 patients, frequency of distant metastases was more common in never-smokers than in smokers (59% and 36%, respectively; P<0.001). Although never-smokers were more likely to have LCDD than smokers (18% and 11%, respectively; P=0.038), LCDD were not significantly associated with frequency of distant metastases [49% (LCDD) vs. 42% (non-LCDD); P=0.189] as well as tumor [29% (T3-4) vs. 24% (T1-2); P=0.134] and node [43% (N2-3) vs. 44% (N0-1); P=0.838] stage. Interestingly, never-smokers are more likely to have LCID than smokers (31% and 19%, respectively; P=0.010). In survival analysis, LCID (P=0.001; HR, 0.63) remained a prognostic factor, while LCDD did not. CONCLUSIONS: This study suggests distinct metastatic pattern and diagnostic processes of never-smokers. The link between survival and incidental detection was also indicated.

Role of adjuvant chemotherapy in malignant mucosal melanoma of the head and neck.

The objective of this study was to analyze the role of adjuvant chemotherapy and prognostic factors in malignant mucosal melanoma of the head and neck (HNMM). Thirty-two patients with mucosal melanoma of the head and neck who received local treatment with or without adjuvant chemotherapy were reviewed. Clinicopathologic parameters including anatomic sites, gender, age (60 vs.>60years), stage, level of invasion, p53 and MDM2 [murine double minute 2] expressions, performance status, and adjuvant chemotherapy were evaluated. The patients' median age was 62years, and 16 (50%) received adjuvant chemotherapy. Expressions of p53 and MDM2 were demonstrated in six of 24 and three of 26 cases, respectively. Predictors of poor survival according to univariate analysis were level of invasion and anatomic location of the primary tumor. Patients who received adjuvant chemotherapy had prolonged survival (p=0.002), which was also shown in the multivariate Cox regression model (HR, 0.24; p=0.014). Our analysis suggests a significant role of adjuvant chemotherapy and different patterns of p53 and MDM2 expression in HNMM relative to cutaneous melanomas. However, since this study is retrospective and observational, with a small sample size, further studies are needed to confirm the definitive role of adjuvant chemotherapy in the treatment of malignant mucosal melanoma of the head and neck.

Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1alpha.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcriptional factor which is activated by hypoxia and associated with cell survival, proliferation and drug resistance. Recent studies have shown that the down-stream molecules of the epidermal growth factor receptor (EGFR) signal are involved in the hypoxia-dependent or -independent HIF-1alpha protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1alpha expression. In our data, treatment of gefitinib suppressed induced HIF-1alpha by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1alpha mRNA. The effect of gefitinib on down-regulation of HIF-1alpha was reversed by transfection of constitutively active form of Akt. The cellular response to gefitinib was similar in both normoxia and hypoxia condition. However, the response to conventional chemotherapeutic drugs decreased >50% under hypoxia condition and they did not change HIF-1alpha expression. In addition, the suppression of HIF-1alpha using siRNA overcame partially hypoxia-induced drug resistance. In conclusion, gefitinib was able to circumvent hypoxia-induced drug resistance suggesting that the effective suppression of HIF-1alpha by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.

Presence of malignant mesothelial cells in the sputum.

Malignant pleural mesothelioma and peripheral adenocarcinoma, of the lung, also known as pseudomesotheliomatous adenocarcinoma, have similar clinical and radiological characteristics and even similar microscopic findings, and this makes it difficult to differentiate them. Malignant pleural mesothelioma rarely invades the bronchial lamina or bronchioloalveolar spaces, and tumor cells are not usually found in the sputum. Therefore, the appearance of tumor cells in sputum more likely supports the diagnosis of peripheral lung cancer. We report a rare case in which malignant pleural mesothelioma cells were found in the sputum. For the differential diagnosis of a mass involving both the pleura and lung, physicians should consider that malignant mesothelial cells can be found in the sputum, although this is very rare.