Suguru Yamamoto

Clinical Experience with Autofluorescence Imaging System in Patients with Lung Cancers and Precancerous Lesions

Background: It is important to detect preinvasive bronchial lesions before they become invasive cancer, because detection of early cancer is expected to lead to a cure. Autofluorescence bronchoscopy is a useful device in the detection of preinvasive and cancerous lesions. Recently, a new autofluorescence bronchoscopic system, autofluorescence imaging (AFI) system, has been developed. Objectives: We evaluated the efficacy of AFI in the diagnosis of precancerous and cancerous lesions. Methods: A total of 31 patients underwent both conventional white-light bronchoscopy (WLB) and AFI from January 2002 to September 2004. We evaluated autofluorescence findings using a four-point scale: AFI-I, II, III, and B. The findings in WLB were evaluated on a three-point scale: WLB-I, II, and III. Abnormal areas by WLB and AFI were biopsied for histopathological examinations. Results: A total of 64 lesions were evaluated. When the AFI-III finding was regarded as positive in AFI and WLB-III as positive in WLB, sensitivity for severe dysplasia or worse was 94.7% with AFI and 73.7% with WLB, respectively. Conclusions: AFI is an effective system for the detection of precancerous and cancerous lesions.

A retrospective analysis of 335 Japanese lung cancer patients who responded to initial gefitinib treatment.

BACKGROUND Gefitinib treatment results in considerably better progression-free survival compared with that of platinum doublets in the first line treatment of nonsmall-cell lung cancer (NSCLC) carrying an activating epidermal growth factor receptor (EGFR) mutation. Some patients who respond to gefitinib have an overall survival (OS) of more than 5 years, whereas other initial responders do less well. Although there has been considerable effort made to elucidate the mechanisms of acquired resistance, there have only been a few studies that addressed the effect of clinical backgrounds and treatment histories on the survival of the patients who had responded to an EGFR-tyrosine kinase inhibitor (TKI). In this study, we especially focused on the clinical benefit of EGFR-TKI administration after progression. PATIENTS AND METHODS We retrospectively analyzed consecutive patients with advanced NSCLC who were diagnosed before October 2010, treated with gefitinib after July 2002, and responded to it. The primary objective of this study was to evaluate how clinical backgrounds and treatment histories influence survival of the patients who respond to gefitinib. The secondary objectives were to evaluate the safety of long-term gefitinib use and to establish the optimal treatment sequence using a dynamic treatment regimen analysis (DTRA). RESULTS A total of 335 patients were recruited. Twenty-eight (8.4%) patients survived more than 5 years. Sixty-five and 93 patients received gefitinib as rechallenge and beyond progressive disease (BPD), respectively. A statistically significant difference in OS was observed between the patients who underwent gefitinib rechallenge and those who did not rechallenge (median: 1272 days vs. 774 days; p < 0.001), a result supported by a DTRA. Patients treated with gefitinib BPD also showed a tendency of longer survival. CONCLUSIONS Gefitinib rechallenge and BPD played a central role in long term survival of the patients who initially responded to gefitinib.

Phase II study of pemetrexed plus intermittent erlotinib combination therapy for pretreated advanced non-squamous non-small cell lung cancer with documentation of epidermal growth factor receptor mutation status

INTRODUCTION Erlotinib and pemetrexed have been approved for the second-line and maintenance treatment of non-small cell lung cancer (NSCLC). With the recommended doses determined by our previous phase I study, we conducted a phase II study to evaluate the efficacy and safety of combination of the two agents in pretreated non-squamous NSCLC patients. METHODS This study was performed in patients with stage IIIB/IV or post-surgically recurrent non-squamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m(2) of intravenous pemetrexed every 21 days and 150 mg of oral erlotinib on days 2-16 until disease progression, unacceptable toxicity, or withdrawal of consent. The expected response rate and threshold were defined as 33.5% and 10%, respectively. Assuming a one-sided alpha of 5%, a power of 80%, the possible deviation from assessment, 26 patients were necessary. RESULTS A total of 27 patients, 16 males and 11 females were recruited. Patients had the median age of 70 years (range, 48-80 years) and included 21 stage IV diseases, 22 adenocarcinomas. Epidermal growth factor receptor (EGFR) mutations were examined in all patients. One patient had positive EGFR mutation, but the other 26 patients had wild-type EGFR. The median number of treatment courses was 3 (range, 1 to over 19). The best overall response rate and disease control rate were 11.1% and 63.0%, respectively. The median progression-free survival and overall survival were 2.8 months (95% confidence interval (CI); 1.9-7.5 months) and 15.8 months (95% CI; 9.3 months to not available), respectively. Dermal, hepatic, gastrointestinal and hematological disorders were the frequently observed adverse events. One patient experienced grade 3 drug-induced interstitial lung disease. CONCLUSIONS We could not demonstrate the add-on effect of intermittent erlotinib on pemetrexed in a second-line setting for patients with non-squamous NSCLC without EGFR mutations.

Combination chemotherapy with intermittent erlotinib and pemetrexed for pretreated patients with advanced non-small cell lung cancer: a phase I dose-finding study

BackgroundErlotinib and pemetrexed have been approved for the second-line treatment of non-small cell lung cancer (NSCLC). These two agents have different mechanisms of action. Combined treatment with erlotinib and pemetrexed could potentially augment the antitumor activity of either agent alone. In the present study, we investigated the safety profile of combined administration of the two agents in pretreated NSCLC patients.MethodsA phase I dose-finding study (Trial registration: UMIN000002900) was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m2 of pemetrexed intravenously every 21 days and erlotinib (100 mg at Level 1 and 150 mg at Level 2) orally on days 2–16.ResultsTwelve patients, nine males and three females, were recruited. Patient characteristics included a median age of 66 years (range, 48–78 years), stage IV disease (nine cases), adenocarcinoma (seven cases) and activating mutation-positives in the epidermal growth factor receptor gene (two cases). Treatment was well-tolerated, and the recommended dose of erlotinib was fixed at 150 mg. Dose-limiting toxicities were experienced in three patients and included: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required reduction of the second dose of pemetrexed and grade 3 diarrhea. No patient experienced drug-induced interstitial lung disease. Three patients achieved a partial response and stable disease was maintained in five patients.ConclusionsCombination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated, with promising efficacy against pretreated advanced nonsquamous NSCLC.

Crazy-paving sign in high-resolution computed tomography in parainfluenza virus pneumonia

Abstract The crazy-paving sign is the appearance of a smooth linear pattern superimposed on an area of ground-glass opacity on thin-section computed tomography (CT). A 69-year-old woman was admitted to our hospital for treatment of pneumonia. Thoracic CT showed a crazy-paving sign in the right lung field on admission. She received ceftriaxone and clarithromycin, and the symptoms and infiltration shadow promptly disappeared. Serologic testing revealed a greater than 4-fold increase in the IgG titer for parainfluenza virus I. To our knowledge, there is no previous report of the crazy-paving sign in associated with viral pneumonia in a non-immunocompromised host or with parainfluenza pneumonia.

Pretreatment Glasgow prognostic score and prognostic nutritional index predict overall survival of patients with advanced small cell lung cancer

Background Various biomarkers have been shown to predict prognosis in various types of cancers. However, these biomarkers have not been studied in advanced small cell lung cancer (SCLC). The modified Glasgow prognostic score (mGPS) is based on serum albumin level and C-reactive protein (CRP). The prognostic nutritional index (PNI) is a combination of serum albumin level and absolute lymphocyte count. This study aimed to evaluate the prognostic value of mGPS and PNI in SCLC. Methods We retrospectively reviewed and calculated mGPS and PNI for patients with stage IIIB or IV SCLC who initiated platinum-based combination chemotherapy between November 2007 and June 2016. We compared overall survival (OS) and progression-free survival (PFS) between high and low groups of these two biomarkers. Univariate and multivariate Cox hazard analyses assessed the prognostic value of these biomarkers. Results We reviewed 97 SCLC patients. The OS of patients with mGPS 0–1 and higher PNI was significantly longer than that of those with mGPS 2 and lower PNI. The PFS of mGPS 0–1 was significantly longer than that of mGPS 2, while there was no significant difference in PFS according to PNI. Multivariate analyses found mGPS 0–1 (hazard ratio [HR] 2.34, 95% confidence interval [CI] 1.27–4.31, P<0.01) and higher PNI (HR 0.50, 95% CI 0.31–0.78, P<0.01) as prognostic factors for longer OS. However, neither biomarker was predictive of PFS. Conclusion Our study was a small retrospective study; however, the data demonstrate that pretreatment mGPS and PNI are independent predictors of OS in patients with advanced SCLC. The pretreatment assessment of mGPS and PNI may be useful for identification of patients with poor prognosis. We recommend pretreatment measurement of serum albumin, C-reactive protein, and absolute lymphocyte count.

Trajectory of chemotherapy for patients with EGFR wild-type advanced pulmonary adenocarcinoma: a single-institution retrospective study

Background Pulmonary adenocarcinoma, recently benefited by new cytotoxic and molecularly targeted drugs, has been classified by driver mutations, such as EGFR mutations. The aim of this study was to research the proportions of patients treated with first- to third-line chemotherapy and to find influential factors for the introduction of chemotherapy and survival benefit from chemotherapy. Materials and methods Data were collected retrospectively on patients who met the following criteria: adenocarcinoma, diagnosed between June 2007 and March 2015 at our hospital, stage IIIB or IV, and EGFR wild type. A nonchemotherapy group of patients who did not receive chemotherapy was compared with a chemotherapy group of patients who received it. The patients who had received first- to third-line chemotherapy between June 2007 and November 2015 at our hospital were also analyzed. Results During the study period, 46 patients did not receive chemotherapy, while 148, 89, and 48 received first-, second- and third-line chemotherapy, respectively. As predictive factors for unlikely chemotherapy, multivariate logistic analysis detected Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, hemoglobin <13.2 g/dL, creatinine clearance (Ccr) <50.4 mL/min, and CRP ≥0.53 mg/dL. As factors predicting shorter survival after chemotherapy, multivariate Cox proportional-hazard analyses detected age ≥75 years, ECOG PS ≥2, lower lymphocyte counts, and higher CRP for the first line; female, higher neutrophil counts, lower lymphocyte counts, reduced Ccr, hyponatremia, and shorter interval between first- and second-line chemotherapy for the second line; and age ≥75 years, body mass index <18.5 kg/m2, higher neutrophil counts, lower lymphocyte counts, hyponatremia, higher lactate dehydrogenase, and higher CRP for the third line. Conclusion Approximately 76% of patients were treated with first-line chemotherapy. Of those patients, 61% and 34% proceeded to second- and third-line chemotherapy, respectively. For patients with poor PS, anemia, reduced Ccr, and higher CRP, it is difficult to introduce chemotherapy.

Retrospective analysis of outcomes and prognostic factors of chemotherapy for small-cell lung cancer

Background Small-cell lung cancer (SCLC) is responsive to initial chemotherapy but becomes resistant to cytotoxic drugs. The aim of this study was to evaluate what proportion of patients with SCLC had received the first- and further-line chemotherapy and which patients had benefited from chemotherapy. Methods We retrospectively reviewed medical records of patients with SCLC who had been treated with the best supportive care alone and the first-, second-, or third-line chemotherapy at the Osaka Police Hospital from June 2007 until March 2015. Results Among 145 patients diagnosed with SCLC and eligible for analysis, 118 patients received chemotherapy. We added five patients who initiated the second-line chemotherapy during the study period at our institution. Sixty-five and 31 patients received the second- and third-line chemotherapies, respectively. Multivariate logistic regression analysis detected age ≥75 years (odds ratio, 2.80; 95% confidence interval, 1.01–7.75; P=0.047) and European Clinical Oncology Group Performance Status (ECOG PS) 3–4 (14.3; 4.86–41.9; P<0.01) as factors disturbing the introduction of chemotherapy. Multivariate Cox hazard analyses also detected ECOG PS 2–4 (3.34; 2.00–5.58; P<0.01) as a factor decreasing overall survival after the first-line chemotherapy, and C-reactive protein level ≥1.0 mg/dL (2.67; 1.30–5.47; P<0.01) and progression-free survival after the first-line chemotherapy ≥6 months (2.85; 1.50–5.43; P<0.01) as factors influencing overall survival after the second-line chemotherapy. Conclusion Approximately two-thirds and one-third of the patients who receive chemotherapy proceed to the second- and third-line chemotherapies, respectively. Several factors, such as age, ECOG PS, C-reactive protein level, and progression-free survival after previous treatment may be useful when considering the introduction of further-line chemotherapy.

Outcomes and prognostic factors of chemotherapy for patients with locally advanced or metastatic pulmonary squamous cell carcinoma

Background Pulmonary squamous cell carcinoma has not benefited from improvements in chemotherapy over the past decade, compared with non-squamous non-small-cell lung cancer. Nowadays, treatment strategies differ between squamous and non-squamous non-small-cell lung cancers. This study aimed to investigate the percentage of patients treated with first-, second-, or third-line chemotherapy and the characteristics of patients for whom chemotherapy has been beneficial. Method Data on patients with stage IIIB or IV squamous cell carcinoma diagnosed between June 2007 and March 2015, and on patients who had received first-, second-, or third-line chemotherapy between June 2007 and November 2015 at our hospital, were retrospectively extracted from our institutional medical charts. We also compared patients who were treated with chemotherapy (chemotherapy group) and patients who were not (non-chemotherapy group) using multivariate logistic regression and multivariate Cox hazard analyses, respectively. Results During the study period, 103, 63, and 32 patients received first-, second-, and third-line chemotherapy, respectively. Fifty-one patients did not receive chemotherapy. Factors predicting unlikely chemotherapy included age ≥75 years, Eastern Cooperative Oncology Group (ECOG)-performance status (PS) ≥2, Charlson comorbidity index ≥2, hemoglobin <12.2 g/dL, red cell distribution width ≥13.9%, and serum sodium <140 mEq/L. Factors predicting survival for each line of chemotherapy included the following: ECOG-PS ≥2 for first-line; ECOG-PS ≥2 and lymphocyte count for second-line; and ECOG-PS ≥2, body mass index <18.5 kg/m2, and hemoglobin and lactate dehydrogenase levels for third-line. Conclusion Approximately 66% of patients received first-line chemotherapy. Of those, 66% and 33% received second- and third-line chemotherapy, respectively. ECOG-PS was always an essential prognostic factor when considering introducing chemotherapy and proceeding with additional chemotherapy. Other markers, such as lymphocyte count, body mass index, anemia, and lactate dehydrogenase level, may be useful depending on the patient and line of chemotherapy.

Combination chemotherapy of gemcitabine and vinorelbine for pretreated non-small- cell lung cancer: a retrospective study

Background Advanced non-small-cell lung cancer (NSCLC) eventually progresses after first-line chemotherapy, and usually requires salvage treatment. Although neither gemcitabine nor vinorelbine is approved as a candidate drug in the second- or further-line for NSCLC, they can be alternative drugs in terms of anti-tumor effects and toxicities. Actually, in our institution, we often use a combination of these two anti-tumor drugs in our daily practice. Methods We retrospectively reviewed 85 patients with advanced NSCLC who had received combination chemotherapy of gemcitabine and vinorelbine after a platinum-based regimen from June 2007 to June 2014 in Osaka Police Hospital, and performed Cox proportional hazard analyses in order to detect predictive factors for progression-free survival (PFS). Results Patient characteristics included a mean age of 65.5 years, 56 males, 54 adenocarcinoma, 53 European Clinical Oncology Group performance status 0–1. Thirteen and 35 patients received the study treatment as the second- and third-line treatment, respectively. The overall response rate, disease control rate, PFS, and overall survival were 4.7% (95% confidence interval 1.3%–11.6%), 30.6% (21.0%–41.5%), 2.1 months (1.7–2.8 months), and 6.9 months (5.0–11.0 months). Twenty-one and six patients experienced grade 4 neutropenia and febrile neutropenia, respectively. European Clinical Oncology Group performance status 0–1 was detected as a factor predicting longer PFS by univariate (hazard ratio, 1.63; 95% confidence interval, 1.28–2.08; P<0.001) and multivariate (1.65, 1.27–2.14, P<0.001) analyses. Conclusion This combination was ineffective and harmful to pretreated patients with NSCLC. We do not recommend this regimen as a later-line treatment option.