ABSTRACT
BACKGROUND: The role of pembrolizumab in the treatment of poor performance status (PS) patients remains unclear. PATIENTS AND METHODS: We conducted a phase II trial to investigate the efficacy and safety of pembrolizumab as first-line therapy for non-small-cell lung cancer (NSCLC) patients with PSs of 2-3 and programmed cell death ligand 1 (PD-L1) expression ≥ 50%. The primary endpoint of this study was the objective response rate (ORR). RESULTS: Fourteen patients treated at eight institutions were enrolled. Most patients had PS 2 (12/14; 86%) and others had PS 3 (2/14; 14%). The ORR was 57.1% (95% confidence interval 28.9-82.3%), which met the primary endpoint. The median progression-free survival (PFS) and 1-year PFS rates were 5.8 months and 20.0%, respectively. At the time of data cut-off, one patient had received treatment for more than 1 year; another patient had received treatment for more than 2 years. Nine patients had improved PS with treatment (Wilcoxon signed-rank test, p = 0.003). Two patients had immune-related adverse events ≥ grade 3: grades 5 and 3 elevation in alanine and aspartate aminotransferases. Two PS 3-stage patients were diagnosed with clinically progressive disease prior to initial computed tomography; both died within 2 months. CONCLUSION: Pembrolizumab was effective for the treatment of NSCLC patients with a poor PS and PD-L1 level ≥ 50%. However, given the poor outcomes of the PS 3 patients, the drug is not indicated for such patients. Adverse events, including liver dysfunction, should be carefully monitored. REGISTRATION ID: UMIN000030955.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antibodies, Monoclonal, Humanized/adverse effects , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathologyABSTRACT
BACKGROUND: The aim of this multicenter, randomized phase II study was to analyze the feasibility and safety of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological stage I (tumor diameter > 2 cm) non-small cell lung cancer (NSCLC). METHODS: Patients were randomly assigned to receive adjuvant chemotherapy for 1 year comprising either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Group A) or a 2-week oral administration of S-1 (80 mg/m2/day) followed by 1 week of rest (Group B). The primary endpoint was feasibility, which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: Ninety-three patients were enrolled of whom 90 patients received S-1 treatment. Median follow-up was 66.9 months. The treatment completion rate based on an RDI of 70% or more for 6 months was 84.4% (95%CI; 70.5-93.5%) in group A and 64.4% (95%CI; 48.8-78.1%) in group B. There were no grade 4 adverse events in either group. Moderate or severe adverse events (grade 2 or grade 3) were significantly more frequent in group B (67%) compared with group A (29%, P = 0.001). The 5-year relapse-free survival rate was 87.0 and 80.9% for group A and B, respectively (P = 0.451). The 5-year overall survival rate for all patients (n = 93) was 100 and 89.4% for group A and B, respectively (P = 0.136). CONCLUSION: Alternate-day oral administration of S-1 for 1 year as adjuvant chemotherapy was demonstrated to be feasible with low toxicity in completely resected stage I (tumor diameter > 2 cm) NSCLC. TRIAL REGISTRATION: Trial registration number: UMIN000011994 . Date of registration: 10/8/2013.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Oxonic Acid/administration & dosage , Tegafur/administration & dosage , Adult , Aged , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Chemotherapy, Adjuvant , Drug Administration Schedule , Drug Combinations , Female , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Oxonic Acid/adverse effects , Tegafur/adverse effectsABSTRACT
BACKGROUND: Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. METHODS: An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. RESULTS: Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. CONCLUSION: Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. TRIAL REGISTRY: http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.
Subject(s)
Febuxostat/therapeutic use , Gout Suppressants/therapeutic use , Tumor Lysis Syndrome/prevention & control , Adult , Aged , Aged, 80 and over , Allopurinol/therapeutic use , Febuxostat/adverse effects , Female , Gout , Gout Suppressants/adverse effects , Humans , Hyperuricemia/prevention & control , Male , Middle Aged , Neoplasms/drug therapy , Thiazoles/therapeutic use , Tumor Lysis Syndrome/blood , Uric Acid/blood , Xanthine Oxidase , Young AdultABSTRACT
BACKGROUND: There are few reports concerning treatment strategies and their contributions to survival of patients with malignant mesothelioma (MM) in Japan. MATERIAL AND METHODS: We extracted all death cases due to MM between 2003 and 2008. The diagnosis of MM was confirmed in 929 cases. Histological subtypes was determined in 709 cases, including 396 (55.9%) epithelioid, 154 (21.7%) sarcomatoid, 126 (17.8%) biphasic, and 33 (4.7%) other types. RESULTS AND CONCLUSION: Median overall survival (OS) of all MM cases was 7.7 months (95% confidence interval, 7.1-8.3). Median OS of patients with epithelioid MM was significantly longer than that of patients with biphasic (p = 0.030) or sarcomatoid (p < 0.001) MM. Surgical resection was performed in 172 patients (18.5%) and 449 (48.3%) received systemic chemotherapy. Survival of patients treated with both surgery and systemic chemotherapy was favorable. Median OS of patients in the late phase of the study period (2006-2008) was significantly longer than that in the early phase (2003-2005) (8.1 vs. 7.5 months, p = 0.008). Independent favorable prognostic factors included age younger than 70 years, female gender, epithelioid subtype, and clinical stage I-III. Multivariate analysis demonstrated that patients who had radical surgery and systemic chemotherapy showed a longer survival, though this could be due to selection bias of patients.
Subject(s)
Lung Neoplasms/mortality , Lung Neoplasms/therapy , Mesothelioma/mortality , Mesothelioma/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Combined Modality Therapy , Female , Humans , Japan/epidemiology , Lung Neoplasms/diagnosis , Lung Neoplasms/epidemiology , Male , Mesothelioma/diagnosis , Mesothelioma/epidemiology , Mesothelioma, Malignant , Middle Aged , Prognosis , Retrospective Studies , Survival AnalysisABSTRACT
BACKGROUND: It is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC. METHODS: Elderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: We enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11). CONCLUSION: Although several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC. TRIAL REGISTRATION: Unique ID issued by UMIN: UMIN000007819 (Date of registration: Apr 25, 2012) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009128. Trial ID issued by jRCT: jRCTs061180089 (Date of registration: Mar 22, 2019, for a shift toward a "specified clinical trial" based on Clinical Trials Act in Japan) https://jrct.niph.go.jp/en-latest-detail/jRCTs061180089.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Aged , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/surgery , Lung Neoplasms/drug therapy , Lung Neoplasms/surgery , Tegafur/adverse effects , Neoplasm Staging , Chemotherapy, Adjuvant , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
In the present study, malignant mesothelioma (MM) cases in Japan were investigated retrospectively. We extracted records for 6030 cases of death due to MM between 2003 and 2008 to clarify the clinical features of MM, including its association with asbestos exposure (AE). Of all these cases, a clinical diagnosis of MM was confirmed for 929. The origin of MM included the pleura in 794 cases (85.5%), the peritoneum in 123 cases (13.2%), the pericardium in seven cases (0.8%), and the testicular tunica vaginalis in five cases (0.5%). The histological subtypes of MM included 396 epithelioid (55.9%), 154 sarcomatoid (21.7%), 126 biphasic (17.8%), and 33 cases (4.7%) classified as "other types". Of all the MM cases, AE was indicated in 76.8% and pleural plaques were detected in 34.2%. The number of asbestos particles was determined in 103 cases of MM. More than 1000 asbestos particles per gram dried lung tissue were detected in 74.8% of cases and more than 5000 particles were detected in 43.7% of cases. We compared patient characteristics and the diagnostic procedures for MM before and after the "Kubota shock". Compared with the early phase of this study (2003-2005), the median age at diagnosis of MM was higher, the number of cases without definite diagnosis of MM was lower, the proportion of cases diagnosed by thoracoscopy was higher, and the percentage of cases in which the occupational history was described in the medical records was significantly higher in the later phase (2006-2008). Our study confirmed that more than 70% of MM cases in Japan are associated with AE. The "Kubota shock" may affect some features pertaining to MM.
Subject(s)
Asbestos/adverse effects , Mesothelioma/chemically induced , Mesothelioma/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Japan/epidemiology , Male , Mesothelioma/pathology , Middle Aged , Young AdultABSTRACT
Malignant pleural mesothelioma (MPM) usually develops pleural fluid. We investigated the value of DNA methylation in the pleural fluid for differentiating MPM from lung cancer (LC). Pleural fluid was collected from 39 patients with MPM, 46 with LC, 25 with benign asbestos pleurisy (BAP) and 30 with other causes. The methylation of O(6)-methylguanine-DNA methyltransferase (MGMT), p16(INK4a) , ras association domain family 1A (RASSF1A), death-associated protein kinase (DAPK), and retinoic acid receptor ß (RARß) was examined using quantitative real-time PCR. DNA methylation of RASSF1A, p16(INK4a), RARß, MGMT and DAPK was detected in 12 (30.8%), 3 (7.7%), 11 (28.2%), 0 (0.0%) and five patients (12.8%) with MPM, and in 22 (47.8%), 14 (30.4%), 24 (52.2%), 1 (2.2%) and six patients (13.0%) with LC, respectively. The mean methylation ratios of RASSF1A, p16(INK4a) and RARß were 0.37 (range 0.0-2.84), 0.11 (0.0-2.67) and 0.44 (0.0-3.32) in MPM, and 0.87 (0.0-3.14), 1.16 (0.0-5.35) and 1.69 (0.0-6.49) in LC, respectively. The methylation ratios for the three genes were significantly higher in LC than in MPM (RASSF1A, P = 0.039; p16(INK4a), P = 0.005; and RARß, P = 0.002). Patients with methylation in at least one gene were 3.51 (95% confidence interval, 1.09-11.34) times more likely to have LC. Hypermethylation seemed no greater with MPM than with BAP. Extended exposure to asbestos (â§30 years) was correlated with an increased methylation frequency (P = 0.020). Hypermethylation of tumor suppressor genes in pleural fluid DNA has the potential to be a valuable marker for differentiating MPM from LC.
Subject(s)
DNA Methylation/genetics , DNA, Neoplasm , Lung Neoplasms/diagnosis , Mesothelioma/diagnosis , Pleural Neoplasms/diagnosis , Aged , Aged, 80 and over , Asbestos/adverse effects , Body Fluids , DNA, Neoplasm/genetics , Diagnosis, Differential , Female , Gene Expression Profiling , Humans , Lung Neoplasms/genetics , Male , Mesothelioma/chemically induced , Mesothelioma/genetics , Middle Aged , Pleural Neoplasms/chemically induced , Pleural Neoplasms/genetics , Promoter Regions, Genetic/genetics , Real-Time Polymerase Chain ReactionABSTRACT
OBJECTIVE: The objective in our study was to examine baseline and other characteristics associated with survival in patients with malignant pleural mesothelioma in Japan. METHODS: Three hundred and fourteen patients with an adjudicated diagnosis of mesothelioma were examined. Survival was evaluated by the Kaplan-Meier method with the log-rank test. The Cox model was used to estimate the hazard ratio for the possible prognostic factors. RESULTS: Of 314 patients, 223 (71%) died and only 40 (13%) were still alive at the end of the observation period starting from the day of diagnosis, while 51 (16%) were transferred to other hospitals or had the last health service contact before the end of the study period yielding the median survival of 308 days. In the multivariate analysis, age older than 70 years (hazard ratio = 2.17; 95% confidence interval, 1.36-3.46), non-epithelioid type (hazard ratio = 1.58; 95% confidence interval, 1.15-2.18), poor performance status (hazard ratio = 3.22; 95% confidence interval, 1.19-8.74), high white blood cell count (hazard ratio = 1.49; 95% confidence interval, 0.99-2.26) and high C-reactive protein level (hazard ratio = 1.80; 95% confidence interval, 1.06-3.06) were negatively associated with survival, after adjustment for other factors. CONCLUSIONS: Some baseline conditions including old age, poor performance status, non-epithelioid type, high white blood cell count and high C-reactive protein level were determinants of poor survival of patients with malignant mesothelioma.
Subject(s)
Biomarkers, Tumor/blood , Mesothelioma/mortality , Pleural Neoplasms/mortality , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , Female , Humans , Japan/epidemiology , Kaplan-Meier Estimate , Leukocyte Count , Male , Mesothelioma/blood , Mesothelioma/pathology , Middle Aged , Multivariate Analysis , Odds Ratio , Pleural Neoplasms/blood , Pleural Neoplasms/pathology , Prognosis , Proportional Hazards Models , Retrospective Studies , Risk FactorsABSTRACT
PURPOSE: In order to evaluate the incidence of an adverse event encountered when using a new therapeutic intervention, it is essential to know the background rate of this adverse event in the same patient population. Interstitial lung disease (ILD) often develops in Japanese patients receiving treatment with anti-neoplastic agents or other drugs. In our study, we estimated the background rate of ILD in patients with malignant mesothelioma (MM). METHODS: We conducted a retrospective cohort study of 328 Japanese patients diagnosed with MM during the period between 1996 and 2006. RESULTS: After the diagnosis of MM had been made, 21 (15 new and 6 exacerbation) of the 328 patients developed ILD. The crude baseline rate of ILD was estimated to be 0.023 (95%CI, 0.009-0.054) per patient-year, and the baseline rate using the Poisson regression model was estimated to be 0.032 (95%CI, 0.017-0.059) per patient-year where major therapeutic interventions were incorporated in the model. The risk of ILD was increased by surgical excision (rate ratio, 8.87; 95%CI, 2.39-33.0), pleurodesis with picibanil (rate ratio, 5.14; 95%CI, 1.63-16.3), and systemic chemotherapy using vinorelbine (rate ratio, 5.95; 95%CI, 1.22-29.0). CONCLUSIONS: Our results have implications for evaluating the safety outcomes of future studies in patients receiving treatment for MM. The development of ILD in such studies at an incidence rate higher than 0.02-0.03 per patient-year might indicate an excess occurrence as a result of a therapeutic intervention.
Subject(s)
Lung Diseases, Interstitial/epidemiology , Mesothelioma/epidemiology , Pleurodesis/adverse effects , Vinblastine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Cohort Studies , Female , Humans , Incidence , Japan/epidemiology , Lung Diseases, Interstitial/etiology , Male , Mesothelioma/therapy , Middle Aged , Picibanil/administration & dosage , Pleurodesis/methods , Poisson Distribution , Regression Analysis , Retrospective Studies , Risk Factors , Vinblastine/adverse effects , Vinblastine/therapeutic use , VinorelbineABSTRACT
A 62-year-old man with left chest pain had left pleural effusion pointed out on a chest radiograph. Chest CT scans showed multiple nodules on the left parietal pleura and pleural effusion. He was referred to our hospital and we performed thoracoscopic examination. Malignant pleural mesothelioma (biphasic type) was diagnosed, based on the pathological findings of a parietal nodular mass, including immunohistological analysis. Chemotherapy using carboplatin and pemetrexed reduced the size of tumor and left pleural effusion. This is a rare case with atypical CT findings of malignant pleural mesothelioma.
Subject(s)
Mesothelioma/diagnostic imaging , Pleural Neoplasms/diagnostic imaging , Humans , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
INTRODUCTION: Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice. METHODS: We constructed an umbrella-type lung cancer patient registry (CS-Lung-003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS-Lung-003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017. DISCUSSION: We successfully launched the umbrella-type CS-Lung-003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment. KEY POINTS: CS-Lung-003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.
Subject(s)
Lung Neoplasms/epidemiology , Female , Humans , Lung Neoplasms/pathology , Male , Prospective Studies , RegistriesABSTRACT
BACKGROUND: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study. METHODS: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m2, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate. DISCUSSION: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.
ABSTRACT
A total of 152 patients with asbestos-related lung cancer recognized by the criteria of Japanese compensation law for asbestos-related diseases were examined and compared with 431 patients with non-asbestos-related lung cancer. Male comprised 96% of patients. Ages ranged from 50 to 91 years with a median of 72 years. Eighty-nine percent were smokers or ex-smokers. Almost all patients had occupational histories of asbestos exposure. The median duration of asbestos exposure was 31 years and the median latency period was 47 years. Thirty-four percent of patients exhibited asbestosis and 81% exhibited pleural plaques by radiography. Regarding asbestos particles in the lung for 73 operated or autopsied patients, 62% had more than 5,000 particles per gram. On the other hand, 100% of non-asbestos-related lung cancer patients had <5000 particles per gram with a median of 554 particles. The number of asbestos bodies in the lung, male gender, absence of symptoms, smoking index, and early stage of cancer were significantly much more than those of non-asbestos-related lung cancer. In this study, a diagnosis of asbestos-related lung cancer was made in 34% of patients by asbestosis, in 62% by presence of both pleural plaques and more than 10 years' occupational asbestos exposure, and in 4% by more than 5000 asbestos particles per gram of lung tissue. Occupational histories, duration of asbestos exposure, and pleural plaques are common categories for the recognition of asbestos-related lung cancer in Japan.
Subject(s)
Asbestos/toxicity , Lung Neoplasms/chemically induced , Occupational Exposure/adverse effects , Adult , Aged , Aged, 80 and over , Female , Humans , Japan , Lung Neoplasms/mortality , Male , Middle AgedABSTRACT
Defects in human leukocyte antigen (HLA) class I expression may allow tumor cells to escape immune recognition. T cell infiltration is associated with a good prognosis in many cancers. However, the role of HLA class I expression and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM) has not been fully analyzed. In the present study, we investigated the immune profiles and conducted outcome analyses of MPM patients. HLA class I expression and TILs (CD4(+), CD8(+), and NK cells) were detected by immunohistochemistry in a series of 44 MPM cases. To detect HLA class I expression, specimens were stained with the anti-pan HLA class I monoclonal antibody EMR8-5. The expression of HLA class I was positive in all patients. There was no case that showed negative HLA class I expression. The density of CD4(+) and CD8(+) TILs were strongly correlated (R = 0.76, p < 0.001). A high density of CD8(+) TILs was a significantly better prognostic factor for the survival of patients with extrapleural pneumonectomy (p < 0.05). Multivariate analysis revealed that a high density of CD8(+) TILs is an independent prognostic factor for patients who underwent extrapleural pneumonectomy. The presence of intratumoral CD8(+) T cells was correlated with an improved clinical outcome, raising the possibility that CD8(+) T cells might play a pivotal role in the antitumor immune response against MPMs. Thus, the stimulation of CD8(+) lymphocytes might be an efficacious immunotherapy for MPM patients.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Mesothelioma/immunology , Mesothelioma/physiopathology , Pleural Neoplasms/immunology , Pleural Neoplasms/physiopathology , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Staging , PrognosisABSTRACT
Tuberculosis is a leading cause of mortality due to an infectious agent worldwide. It often affects multiple organs by hematogenous spread of Mycobacterium tuberculosis, but knee-joint involvement is extremely rare, comprising approximately 0.1% of all forms of tuberculosis. We present a case of tuberculous pleuritis with knee-joint involvement. Cytological and biochemical analysis of the pleural fluid and a biopsy specimen of the cervical lymph node indicated tuberculosis, but a definitive diagnosis was not given. A confirmed diagnosis was finally obtained through PCR analysis of the synovial fluid. Tuberculosis should be included in the differential diagnosis in patients with persistent pain and swelling of the knee. PCR analysis of the synovial fluid is a quick and useful method for the diagnosis.
Subject(s)
Knee Joint/microbiology , Mycobacterium tuberculosis/isolation & purification , Polymerase Chain Reaction/methods , Synovial Fluid/microbiology , Tuberculosis, Osteoarticular/diagnosis , Tuberculosis, Pleural/diagnosis , Diagnosis, Differential , Humans , Knee Joint/pathology , Male , Mycobacterium tuberculosis/classification , Mycobacterium tuberculosis/genetics , Pleural Effusion/microbiology , Tuberculosis , Tuberculosis, Osteoarticular/microbiology , Tuberculosis, Osteoarticular/pathology , Tuberculosis, Pleural/microbiology , Tuberculosis, Pleural/pathology , Young AdultABSTRACT
BACKGROUND: In 2003, the number of deaths due to malignant mesothelioma in Japan was 878; however, only 85 cases of mesothelioma due to asbestos exposure were authorized for compensation. The reasons for this discrepancy require evaluation. METHOD: We examined medical records, X-rays, and pathology results to evaluate mesothelioma cases in Japan between 2003 and 2005; used a questionnaire to identify occupational and environmental histories, and determined the concentration of asbestos fibers in pathology specimens. RESULTS: We identified 442 definite cases of malignant mesothelioma with a median age of 68 years. There were 316 malignant mesothelioma cases with occupational asbestos exposure, 12 cases with neighborhood exposure and 5 cases with likely domestic exposure. Most (78%) of the 87 cases exceeded 1,000 asbestos particles per gram of dry lung tissue. CONCLUSION: We conclude that 79.2% of cases of mesothelioma in Japan in recent years were caused by asbestos exposure.
Subject(s)
Asbestos/toxicity , Mesothelioma/etiology , Neoplasms/etiology , Occupational Exposure/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Female , Humans , Japan/epidemiology , Kaplan-Meier Estimate , Male , Medical Records , Mesothelioma/classification , Mesothelioma/diagnosis , Mesothelioma/mortality , Middle Aged , Neoplasms/classification , Neoplasms/diagnosis , Neoplasms/mortality , Retrospective Studies , Surveys and Questionnaires , Workers' Compensation , Young AdultABSTRACT
BACKGROUND: Gefitinib is effective in patients with lung adenocarcinoma. Smoking status also affects the responsiveness to gefitinib, but it has not been fully evaluated whether a sex difference exists in the influence of smoking on the efficacy of gefitinib in patients with lung adenocarcinoma. METHODS: We reviewed the clinical records of 260 Japanese patients with lung adenocarcinoma who received gefitinib therapy (250 mg/day), and whose smoking status was known. Tumour response and survival were evaluated and stratified by smoking status and gender. RESULTS: Among the 260 patients, 157 were male (60%). Median pack-years was 40 (range 8-160) and 23 (range 1-74) in male and female smokers, respectively. Objective response was observed in 62 (23.8%) of the 260 patients, and 1-year overall survival and progression-free survival were 45.1 and 24.3%, respectively. Multivariate analysis revealed that smoking status (pack-years) was an independent predictive factor for response to gefitinib [odds ratio (OR) = 0.971, 95% confidence interval (CI) = 0.947-0.995; P = 0.0159] in male patients, but not in female patients (OR = 0.999, 95%CI = 0.957-1.042). Additionally, pack-years significantly influenced the overall survival in males (hazard ratio = 1.010; 95%CI = 1.002-1018, P = 0.0169), while differential survival of females was not significantly predicted by this factor (P = 0.7639). CONCLUSIONS: In male patients with lung adenocarcinoma, cumulative smoking significantly affected response and survival following gefitinib treatment, while in female patients, responsiveness to gefitinib was independent of smoking status. These results suggest that the influence of smoking habit on responsiveness to gefitinib is gender specific.
Subject(s)
Adenocarcinoma/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Smoking/epidemiology , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/secondary , ErbB Receptors/antagonists & inhibitors , Female , Gefitinib , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Sex Factors , Survival Rate , Treatment OutcomeABSTRACT
An 87-year-old woman was admitted because of high fever, progressive dyspnea and abnormal shadows on chest roentgenogram. Laboratory investigation on admission demonstrated a normal white cell count with neutrophilia (4000/microl, 90.5% neutrophils), an erythrocyte sedimentation rate of 10 mm/h and C-reactive protein value of 9.0mg/dl. Roentgenogram and computed tomographic scan of the chest shows bilateral infiltration and diffuse ground glass opacity, indicating acute respiratory distress syndrome (ARDS), but disseminated nodules, indicating miliary tuberculosis, were not found. Blood gas analysis demonstrated severe hypoxemia (PaO2 43.2Torr with 6L/ min oxygen). Based on the diagnosis of acute pneumonia and ARDS, intravenous administration of sivelestat sodium hydrate (100 mg/day), and continuous infusion of hydrocortisone (200 mg/day) were started. PaO2/FiO2 ratio improved but X-ray findings showed no improvement and a blood test revealed pancytopenia. Bone marrow biopsy revealed necrotizing epithelioid granuloma and acid-fast bacilli. A polymerase chain reaction (PCR) test detected Mycobacterium tuberculosis. Mycobacterium tuberculosis was also detected in sputum and urine. Therefore, we diagnosed miliary tuberculosis and transferred the patient to an infectious disease hospital. Miliary tuberculosis complicated with ARDS is relatively rare and the prognosis is extremely poor. Miliary tuberculosis should be kept in mind as a cause of ARDS.
Subject(s)
Respiratory Distress Syndrome/diagnosis , Tuberculosis, Miliary/diagnosis , Aged, 80 and over , Diagnosis, Differential , Female , HumansABSTRACT
It is well established that patients with silicosis are at high risk for lung cancer; however, it is difficult to detect lung cancer by chest radiography during follow-up treatment of patients with silicosis because of preexisting diffuse pulmonary shadows. The purpose of this study is to evaluate the usefulness of detection of serum DNA methylation for early detection of lung cancer in silicosis. Serum samples from healthy controls (n = 20) and silicosis patients with (n = 11) and without (n = 67) lung cancer were tested for aberrant hypermethylation at the promoters of the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), p16(INK4a), ras association domain family 1A (RASSF1A), the apoptosis-related gene death-associated protein kinase (DAPK) and retinoic acid receptor beta (RARbeta) by methylation-specific polymerase chain reaction. Aberrant promoter methylation in at least one of five tumor suppressor genes was detected more frequently in the serum DNA of silicosis patients with lung cancer than in that of patients without it (P = 0.006). Furthermore, the odds ratio of having lung cancer was 9.77 (P = 0.009) for those silicosis patients with methylation of at least one gene. Extended exposure to silica (>30 years) was correlated with an increased methylation frequency (P = 0.017); however, methylation status did not correlate with age, smoking history or radiographic findings of silicosis. These results suggest that testing for aberrant promoter methylation of tumor suppressor genes using serum DNA may facilitate early detection of lung cancer in patients with silicosis.
Subject(s)
DNA Methylation , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Lung Neoplasms/diagnosis , Promoter Regions, Genetic/genetics , Silicosis/genetics , Tumor Suppressor Proteins/genetics , Adenocarcinoma/diagnosis , Adenocarcinoma/etiology , Aged , Aged, 80 and over , Apoptosis Regulatory Proteins/genetics , Calcium-Calmodulin-Dependent Protein Kinases/genetics , Carcinoma, Small Cell/diagnosis , Carcinoma, Small Cell/etiology , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/etiology , Case-Control Studies , Cyclin-Dependent Kinase Inhibitor p16/genetics , Death-Associated Protein Kinases , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/etiology , Male , Middle Aged , O(6)-Methylguanine-DNA Methyltransferase/genetics , Polymerase Chain Reaction , Receptors, Retinoic Acid/genetics , Silicosis/blood , Silicosis/complicationsABSTRACT
BACKGROUND: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. METHODS: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0-1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) (Level 1), were studied in the dose-escalation Phase I (Step 1). The RD determined in Step 1 was carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18-38. RESULTS: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level -1 (pemetrexed 500 mg/m(2), cisplatin 60 mg/m(2)). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3-61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. CONCLUSION: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.