Phase II Study on Biweekly Combination Therapy of Gemcitabine plus Carboplatin for the Treatment of Elderly Patients with Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: The biweekly GEM plus CBDCA dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC. The biweekly GEM plus CBDCA regimen could be considered an alternative to the 3-week regimen in NSCLC. BACKGROUND: The gemcitabine (GEM)-carboplatin (CBDCA) combination is widely used for non-small cell lung cancer (NSCLC) and has some efficacy in elderly patients; however, a high incidence of thrombocytopenia is observed, and the optimal dosage and administration schedules are unknown. This multicenter phase II trial evaluated the efficacy and tolerability of GEM-CBDCA for elderly patients with chemotherapy-naive NSCLC. METHODS: Patients with chemotherapy-naive performance status 0-1 and with stage IIIB/IV NSCLC were administered chemotherapy biweekly (GEM 1,000 mg/m2 with CBDCA area under the blood concentration-time curve (AUC) 3 on days 1 and 15 every 4 weeks). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-eight patients were enrolled. Median age was 76 years (range, 70-83); 35 patients were men (73%), and 27 patients had adenocarcinoma (56%). The ORR was 29.2% (95% confidence interval [CI], 17.0-44.1). The median PFS, median OS, and 1-year survival was 5.9 months (95% CI, 4.1-6.6), 13.3 months (95% CI, 8.3-23.5), and 58%, respectively. Grade ≥3 hematological toxicities included neutropenia (29.2%), thrombocytopenia (4.2%), and anemia (20.8%). The incidence of grade ≥3 nonhematological toxicities was <5%. CONCLUSION: This GEM-CBDCA combination administered biweekly showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.

Randomized Phase II Study of First-Line Biweekly Gemcitabine and Carboplatin Versus Biweekly Gemcitabine and Carboplatin plus Maintenance Gemcitabine in Elderly Patients with Untreated Non-Small Cell Lung Cancer: LOGIK0801.

LESSONS LEARNED: The usefulness of maintenance gemcitabine (GEM) after biweekly carboplatin + GEM in elderly patients with non-small cell lung cancer could not be proved. Superior overall survival was obtained in the group that did not receive maintenance therapy. BACKGROUND: The primary objective of this randomized phase II study was to assess progression-free survival (PFS) in elderly patients with advanced non-small cell lung cancer (NSCLC) treated with gemcitabine (GEM) maintenance therapy versus best supportive care following first-line GEM plus carboplatin (CBDCA). METHODS: Elderly chemotherapy-naive patients with stage IIIB or IV NSCLC were randomly assigned 1:1 to the control arm or the study arm. All patients received biweekly combination therapy with GEM and CBDCA (1,000 mg/m2 GEM and CBDCA at an area under the curve [AUC] of 3 on days 1 and 15, every 4 weeks). In the study arm, patients with objective response or stable disease following three or four cycles of initial chemotherapy received maintenance GEM. RESULTS: Eighty-four patients were enrolled. The objective response rates (ORRs) were 17.5% in the control arm and 14.0% in the study arm. The most common toxicity was neutropenia (control arm: 47.5% and study arm: 69.8%). The median progression-free survivals were 4.99 months (control arm) and 4.44 months (study arm), and the median overall survivals (OSs) were 21.7 months (control arm) and 8.2 months (study arm). CONCLUSION: Our data do not support maintenance GEM after biweekly CBDCA+GEM in elderly patients with NSCLC.

KEYNOTE-025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1-positive advanced non-small-cell lung cancer.

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been shown to improve overall survival (OS) in patients with previously treated advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE-025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD-L1 TPS ≥1% and had received ≥1 platinum-doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD-L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD-L1 TPS ≥50%. Thirty-eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41-78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3-5 treatment-related adverse events (AE); 9 patients (24%) experienced immune-mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD-L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6-61). Among evaluable patients with PD-L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10-38). Median (95% CI) progression-free survival and OS were 3.9 (2.0-6.2) months and 19.2 (8.0-26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD-L1-expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE-010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.).

Randomized Phase II Study of Weekly Paclitaxel plus Carboplatin Versus Biweekly Paclitaxel plus Carboplatin for Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: This clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3-weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non-small cell lung cancer (NSCLC).The weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3-weekly regimen in Japanese patients with NSCLC. BACKGROUND: Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non-small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients. METHODS: Chemonaive patients with IIIB/IV NSCLC and a performance status of 0-1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks). RESULTS: A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression-free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W). CONCLUSION: The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3-weekly regimen in NSCLC treatment.

Risk Factors Associated with Cisplatin-Induced Nephrotoxicity in Patients with Advanced Lung Cancer.

Cisplatin (CDDP) combination chemotherapy is widely administered to patients with advanced lung cancer. The dose depends on multiple factors, including whether the tumor is non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC). Although efficacy is limited by cisplatin-induced nephrotoxicity (CIN), little is known about the risk factors for this complication. The aim of this study was to identify the risk factors for CIN in patients with advanced lung cancer, both NSCLC and SCLC. We retrospectively reviewed clinical data for 148 patients who underwent initial chemotherapy including CDDP ≥50 mg/m2 per patient per day for the first course at Kyushu Medical Center between October 2010 and September 2013. All data were collected from the electronic medical record system. Nephrotoxicity was defined as an increase in serum creatinine concentration of at least grade 2 during the first course of CDDP chemotherapy, as described by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. CIN was observed in nine patients. Univariate analysis revealed that cardiac disease and lower baseline serum albumin (Alb) values conferred a higher risk of nephrotoxicity (p<0.05). The cut-off value of Alb was 3.8 g/dL, calculated by receiver operating characteristics (ROC) curves. Multivariable logistic regression analysis revealed that cardiac disease (odds ratio=11.7; p=0.002) and hypoalbuminemia (odds ratio=6.99 p=0.025 significantly correlated with nephrotoxicity. In conclusion, cardiac disease and low baseline Alb values are possible risk factors for CIN.

[A case of pulmonary Langerhans cell histiocytosis with panhypopituitarism].

A 34-year-old woman developed polydipsia, polyuria, amenorrhea and loss of pubic hair in 2001, but did not seek medical advice. On September 7th, 2009, she was admitted to our hospital complaining of acute exacerbation of dyspnea on exertion. Chest computed tomography (CT) showed multiple cystic lesions, predominantly in bilateral lower lung fields. Non-segmental, diffuse ground-glass attenuated areas and thickened bronchovascular bundles were also seen in bilateral lung fields. Pathological findings of lung specimens from a surgical lung biopsy (right S6 and S8) 14 years previously showed infiltration of S100 protein-positive histiocytoid cells in the bronchiolar wall. As a result, pulmonary Langerhans cell histiocytosis (PLCH) was diagnosed. Moreover, panhypopituitarism due to LCH was identified on endocrine testing. Dyspnea on exertion, reduction of carbon-monoxide diffusing capacity (D(LCO)) and ground-glass attenuation areas on CT were improved by smoking cessation alone, and she was discharged. However, similar acute deterioration of PLCH recurred 4 months after first admission. Her dyspnea on exertion, reduction of D(LCO) and ground-glass attenuation areas on CT were improved again by 500 mg/day methylprednisolone pulse therapy for 3 days. This case was a unique combination of panhypopituitarism and the appearance and disappearance of ground-glass attenuation areas on CT, paralleling PLCH disease activity.

[A case of small cell lung cancer (extensive disease) with liver metastasis acquiring stable disease by hepatic arterial infusion chemotherapy].

The patient was a 58-year-old male with small cell lung cancer [T2N1M1 (HEP) ED case] who was treated systemic chemotherapy with 2 courses of CDDP+CPT-11 and 3 courses of CBDCA+PTX. After 5 courses of chemotherapy, the total response was stable disease (SD). Because the primary lesion had achieved a minor response, however, liver metastasis evidenced no change. Because of his good performance status, he was immediately treated by hepatic arterial infusion chemotherapy ( HAI) using CPT-11 to control the liver metastasis. After the HAI of weekly CPT-11 during eleven months until progression of primary lung lesion, no change in size of the liver metastasis was recognized with decreasing ProGRP (18,400 -->5,800). HAI is considered very useful for disease control without progression and for good quality of life.

Pretreatment prognostic nutritional index as a novel biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have been established as a novel strategy for non-small cell lung cancer (NSCLC) therapy. However, a definitive biomarker that can predict response to ICI therapy remains unestablished. The prognostic nutritional index (PNI) is used to assess immune-nutritional conditions and is a prognostic factor in patients with various malignancies; however, its usefulness as a biomarker of response to ICI therapy and survival outcomes in NSCLC patients is unknown. Thus, we retrospectively analyzed the clinicopathological features of advanced-stage or recurrent NSCLC patients treated with ICI therapy to identify predictors of response to ICI therapy and investigate the effects of pretreatment PNI levels on survival after ICI therapy. MATERIALS AND METHODS: We selected 102 consecutive NSCLC patients who were treated with ICI therapy from November 2015 to February 2019. We measured their pretreatment PNI levels and performed univariate and multivariate Cox regression analyses of progression-free survival (PFS) or overall survival (OS) after ICI therapy. RESULTS: Pretreatment PNI levels were significantly associated with response to ICI therapy (objective response rate:P = 0.0131; disease control rate: P = 0.0002), PFS (P = 0.0013), and OS (P = 0.0053). In univariate and multivariate analyses of the associations between PNI, C-reactive protein (CRP) or neutrophil-lymphocyte ratio (NLR) and PFS or OS, NLR and PNI, but not CRP, are independent prognostic factors for PFS (NLR: relative risk [RR]=1.655, 95% confidence interval [CI]: 1.012-2.743, P = 0.0449, PNI: RR=1.704, 95% CI: 1.039-2.828, P = 0.0346). Only PNI showed a trend towards being an independent prognostic factor for OS (RR=1.606, 95% CI: 0.952-2.745, P = 0.0761). CONCLUSION: The pretreatment PNI has the potential to be a simple and novel predictive biomarker of ICI response in NSCLC patients and might help to identify patients who will obtain a survival benefit from ICI therapy.

Gefitinib Plus Bevacizumab vs. Gefitinib Alone for EGFR Mutant Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: A phase II trial was conducted to assess the efficacy and safety of gefitinib plus bevacizumab for EGFR mutation-positive non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to receive either gefitinib at 250 mg/day alone or with bevacizumab at 15 mg/kg every 3 weeks. RESULTS: Ten patients were allocated to the gefitinib group (group A) and 6 to the gefitinib plus bevacizumab group (group B). Median survival time (80%CI) for progression-free survival (PFS) was 15.1 months for group A, and 5.4 months for group B. Overall survival probability at 1 year (95%CI) was 0.750 for group A, and 0.667 for group B. The response rate was 44 % for group A and 50 % for group B. Adverse events occurred at a similar frequency in both groups. CONCLUSION: PFS was shorter in group B than group A, and therefore there was no basis to proceed to a phase III trial.

Elevation of pulmonary CD163+ and CD204+ macrophages is associated with the clinical course of idiopathic pulmonary fibrosis patients.

BACKGROUND: M2-like/repair macrophages are thought to contribute to fibrotic process of idiopathic pulmonary fibrosis (IPF). We analyzed the association between pulmonary accumulation of M2-like macrophages and survival in IPF patients. METHODS: Lung tissues were obtained by surgical lung biopsy from patients with IPF (n=16), nonspecific interstitial pneumonia (NSIP, n=8) and control subjects (n=14). Samples were also obtained at autopsy from 9 patients who died of acute exacerbation (AE) of IPF. Lung specimens and/or human peripheral blood mononuclear cells-derived macrophages were evaluated by immunohistochemistry for expression of CD68 (pan-macrophage marker), CD163, and CD204 (M2-like macrophage markers), and by in situ mRNA hybridization and ELISA for production of transforming growth factor-ß1 (TGF-ß1). RESULTS: CD68+, CD163+, and CD204+ cell counts and CD163+/CD68+ and CD204+/CD68+ cell ratios were comparable in IPF and NSIP lung tissues and significantly higher than in control tissues. IPF-AE lung samples contained significantly elevated CD68+ and CD163+ cell counts and CD163+/CD68+ cell ratio compared with IPF samples, whereas CD204+ cell counts and CD204+/CD68+ cells ratio did not differ. High CD163+/CD68+ and CD204+/CD68+ cell ratios were significantly associated with shorter overall survival and time-to-AE in IPF patients. In vitro-differentiated human CD163+ and CD204+ macrophages both secreted TGF-ß1; however, the novel IPF drug pentraxin 2/serum amyloid protein could suppress secretion only by CD204+ macrophages. CONCLUSIONS: Pulmonary accumulation of CD163+ and CD204+ macrophages is associated with worse clinical course in IPF patients. Suppression of macrophage activation and TGF-ß1 secretion may be a potential therapeutic target for IPF.

Randomized phase II study of pemetrexed or pemetrexed plus bevacizumab for elderly patients with previously untreated non-squamous non-small cell lung cancer: Results of the Lung Oncology Group in Kyushu (LOGIK1201).

OBJECTIVES: To evaluate the efficacy and safety, we conducted a randomized phase II study of pemetrexed (Pem) versus Pem + bevacizumab (Bev) for elderly patients with non-squamous non-small cell lung cancer (NSqNSCLC). PATIENTS AND METHODS: The eligibility criteria were as follows: NSqNSCLC, no prior therapy, stage IIIB/IV disease or postoperative recurrence, age: ≥75 years, performance status (PS): 0-1, and adequate bone marrow function. The patients were randomly assigned (1:1 ratio) to receive Pem or Pem + Bev. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the response rate, OS, toxicities, and cost-effectiveness. RESULTS: Forty-one patients were enrolled and 40 (20 from each group) were assessable. Their characteristics were as follows: male/female = 23/17; median age (range) = 78 (75-83); stage IIIB/IV/postoperative recurrence = 1/30/9; PS 0/1 = 11/29. All cases involved adenocarcinoma. There was no significant intergroup difference in PFS and the median PFS (95% confidence interval) values of the Pem and Pem + Bev groups were 5.4 (3.0-7.4) and 5.5 (3.6-9.9) months, respectively (p = 0.66). The response rate was significantly higher in the Pem + Bev group (15% vs. 55%, p = 0.0146), and there was no significant difference in OS (median: 16.0 vs. 16.4 months, p = 0.58). Grade 3 and 4 leukopenia, neutropenia, and thrombocytopenia were seen in 10 and 30, 20 and 55, and 5 and 5 cases, respectively. Drug costs were higher in the Pem + Bev group (median: 1,522,008 vs. 3,368,428 JPY, p = 0.01). No treatment-related deaths occurred. CONCLUSIONS: Adding Bev to Pem did not result in improved survival in the elderly NSqNSCLC patients. Compared with Pem + Bev, Pem monotherapy had similar effects on survival, a more favorable toxicity profile, and was more cost-effective in elderly NSqNSCLC patients. Pem monotherapy might be one of the optional regimen for NSqNSCLC patients aged ≥75 years.

Well-differentiated fetal adenocarcinoma of the lung: early-phase sequential high-resolution computed tomographic findings.

Well-differentiated fetal adenocarcinoma is a rare primary adenocarcinoma originating in the lung. We present an early phase case that was followed up for 2 years with chest roentgens and high-resolution computed tomography. Multicentric origin was suspected in the sequential high-resolution computed tomography study findings.

Phase II Trial of Carboplatin and Pemetrexed Plus Bevacizumab with Maintenance Bevacizumab as a First-line Treatment for Advanced Non-squamous Non-small Cell Lung Cancer in Elderly Patients.

BACKGROUND/AIM: The combination of platinum-doublet chemotherapy with bevacizumab has been established as a first-line treatment option in non-elderly patients with non-squamous (non-sq) non-small cell lung cancer (NSCLC). However, the safety and efficacy of this regimen have not yet been fully established in elderly patients. PATIENTS AND METHODS: Chemo-naïve patients with non-sq NSCLC, aged ≥75 years, having a good performance status (Eastern Cooperative Oncology Group performance status 0-1) and adequate organ function were considered eligible. Patients received carboplatin (area under the curve=5 mg/ml/min), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) every 3 weeks for up to 4 cycles, followed by maintenance bevacizumab. The primary endpoint was the objective response rate (ORR; target=50%, threshold=30%; Simon's two-stage design), and the secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Twelve patients were enrolled from June 2013 to July 2017. The study was closed because of slow patient accrual. The median patient age was 80 years. Eleven patients (92%) completed 4 cycles of induction chemotherapy. Seven patients achieved a partial response (PR), yielding an ORR of 58%. The median PFS was 8.4 [95% confidence interval (CI)=4.4-10.5] months, and the median OS was 33.9 (95%CI=13.2-43.3) months. Toxicities were generally mild and consistent with previous reports. There were no treatment-related deaths. CONCLUSION: A regimen comprising carboplatin and pemetrexed plus bevacizumab followed by maintenance bevacizumab is feasible and potentially efficacious in elderly patients with non-sq NSCLC.

Preventive effect of kampo medicine (hangeshashin-to, TJ-14) plus minocycline against afatinib-induced diarrhea and skin rash in patients with non-small cell lung cancer.

PURPOSE: Diarrhea and oral mucositis induced by afatinib can cause devastating quality of life issues for patients undergoing afatinib treatment. Several studies have shown that hangeshashin-to (TJ-14) might be useful for chemotherapy-induced diarrhea and oral mucositis. In this study, we investigated the prophylactic effects of TJ-14 for afatinib-induced diarrhea and oral mucositis and minocycline for afatinib-induced skin rash. PATIENTS AND METHODS: First- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have become the standard first-line treatment in patients with EGFR-mutated non-small cell lung cancer. The incidence of diarrhea was higher with afatinib than with gefitinib, and we conducted a single-arm Phase II study with afatinib. Patients who had previously undergone treatment with afatinib were ineligible. Both TJ-14 (7.5 g/day) and minocycline (100 mg/day) were administered simultaneously from the start of afatinib administration. The primary end point was the incidence of ≥ grade 3 (G3) diarrhea (increase of ≥7 stools/day over baseline) during the first 4 weeks of treatment. The secondary end points were the incidence of ≥ G3 oral mucositis (severe pain interfering with oral intake) and $ G3 skin toxicity (severe or medically significant but not immediately life-threatening). RESULTS: A total of 29 patients (nine men and 20 women; median age, 66 years; performance status, 0/1/2: 18/10/1) were enrolled from four centers. Four patients had undergone prior treatment with chemotherapy, including gefitinib or erlotinib. In all, 20 (68.9%) patients and one (3.4%) patient had diarrhea of any grade and ≥ G3, respectively. One (3.4%) patient had ≥ G3 oral mucositis; no patients had ≥ G3 skin rash. A total of 18 (62%) of the 29 patients achieved a partial response. CONCLUSION: The present study indicated a trend in which TJ-14 reduced the risk of afatinib-induced diarrhea and minocycline reduced the risk of afatinib-induced skin rash.

The usefulness of monomeric periostin as a biomarker for idiopathic pulmonary fibrosis.

The natural course of idiopathic pulmonary fibrosis (IPF) is variable. Predicting disease progression and survival in IPF is important for treatment. We previously demonstrated that serum periostin has the potential to be a prognostic biomarker for IPF. Our aim was to use monomeric periostin in a multicenter study to evaluate its efficacy in diagnosing IPF and predicting its progression. To do so, we developed a new periostin kit to detect only monomeric periostin. The subjects consisted of 60 IPF patients in a multicenter cohort study. We applied monomeric periostin, total periostin detected by a conventional kit, and the conventional biomarkers-KL-6, SP-D, and LDH-to diagnose IPF and to predict its short-term progression as estimated by short-term changes of %VC and % DL, CO. Moreover, we compared the fraction ratios of monomeric periostin to total periostin in IPF with those in other periostin-high diseases: atopic dermatitis, systemic scleroderma, and asthma. Monomeric periostin showed the greatest ability to identify IPF comparable with KL-6 and SP-D. Both monomeric and total periostin were well correlated with the decline of %VC and % DL, CO. Clustering of IPF patients into high and low periostin groups proved useful for predicting the short-term progression of IPF. Moreover, the relative ratio of monomeric periostin was higher in IPF than in other periostin-high diseases. Measuring monomeric periostin is useful for diagnosing IPF and predicting its short-term progression. Moreover, the ratio of monomeric periostin to total periostin is elevated in IPF compared to other periostin-high diseases.

A multicenter phase II study of carboplatin and paclitaxel with a biweekly schedule in patients with advanced non-small-cell lung cancer: Kyushu thoracic oncology group trial.

PURPOSE: This multicenter phase II study was conducted to investigate the efficacy and safety of carboplatin in combination with paclitaxel administered according to a biweekly schedule as a first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligibility criteria included histologically or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, and measurable or evaluable disease. Paclitaxel (140 mg/m(2)) was administered intravenously on day 1, in combination with carboplatin at an area under the concentration time curve (AUC) of 3, every 2 weeks. RESULTS: Seventy-four patients (45 men) with a median age of 62 years (range 40-74) and a median ECOG performance status of 1 (range 0-2) were enrolled. The response rate was 35.1% [95% confidence interval (CI): 24.4-47.1%], with 26 partial responses. The median survival was 357 days, and the median time to progression was 218 days. Toxicity was generally mild; National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grades 3 and 4 neutropenia was observed in 50.0% of the patients, and grades 3 and 4 nausea/vomiting in 4.1%. CONCLUSIONS: Biweekly carboplatin combined with paclitaxel demonstrated anti-tumor activity in advanced NSCLC, with response and survival rates similar to those of carboplatin combined with paclitaxel administered every 3 weeks but with a more favorable toxicity profile, and the present data indicate that the regimen is suitable for use on an outpatient basis.

Pulmonary metastasis of endometrial stromal sarcoma.

Multiple round opacities suggestive of metastatic lung tumors were incidentally found on a chest x-ray film in a 43-year-old woman. The patient underwent hysterectomy for "myoma uteri" three years previously. Extensive examinations could not specify the primary neoplastic lesions. Morphological characteristics of the thracoscopically resected lung tumors suggested low-grade endometrial stromal sarcoma (ESS), and immunostaining revealed that the tumor cells were positive for progesterone and estrogen receptors, CD10 and vimentin, confirming a diagnosis of ESS. ESS is an uncommon uterine neoplasm, however, may be mistaken as benign tumors such as epithelioid leiomyoma, and occasionally metastasizes to remote organs such as lungs even after long disease-free period, posing diagnostic challenge.

[A case of carcinoma with sarcomatoid elements in the middle mediastinum].

We describe a 63-year-old man who, while under treatment as an outpatient for adult onset Still's disease (AOSD), developed edema of the extremities and mediastinal tumor was observed on a chest X-ray film and a chest CT scan. He was not pathologically diagnosed at first and received radiation therapy with a total dose of 30 Gy. Transbronchial biopsy was carried out because the tumor enlarged, and the tumor invasion was observed in the left lumen of the main bronchus. Histological findings suggested a diagnosis of carcinoma with sarcomatoid elements (CSE). Further radiation therapy with a dose of 20 Gy was unsuccessful; his condition gradually worsened and the patient died. The autopsy findings demonstrated that CSE developed in the middle mediastinum, and the other organs were not involved. From an embryologic standpoint, there seemed to be some possible differential diagnoses, such as a pleomorphic carcinoma as a subtype of lung cancer, and CEA as a metastatic mediastinal lymph node cancer of unknown origin or a primary mediastinal lymph node cancer. Like the present case, tumors developed in the middle mediastinum with rapid progression are rare. We report a case, that was difficult to diagnose and treat.

A multicenter phase II trial of S-1 combined with bevacizumab after platinum-based chemotherapy in patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: This phase II trial investigated the efficacy and safety of S-1 plus bevacizumab (SB) after failure of platinum-based chemotherapy in patients with non-squamous non-small cell lung cancer (non-sq NSCLC). METHODS: Patients with non-sq NSCLC who had undergone prior platinum-based chemotherapy, regardless of the use of bevacizumab, were eligible. S-1 (80 mg/m(2)) was administered orally twice daily for 14 days, and bevacizumab (15 mg/kg) on day 1 every 3 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty-eight patients (14 males and 14 females; median age 62 years; performance status 0/1/2: 21/7/0) were accrued from 4 centers. Almost half (n = 15, 53.6 %) of these had received prior bevacizumab therapy. The median PFS and overall survival were 3.2 months [95 % confidence interval (CI) 2.2-4.0 months] and 11.4 months (95 % CI 8.9-13.9 months), respectively. Prior exposure to bevacizumab did not affect the PFS. An objective response was observed in 4 patients, the response rate and disease control rate being 14.3 and 85.7 %, respectively. The treatment was well tolerated, the most common treatment-related side effects being anorexia (75 %) and fatigue (68 %). CONCLUSION: Although SB was well tolerated, this combination did not provide any additional benefit in terms of PFS for patients with non-sq NSCLC after failure of platinum-based chemotherapy. It will be important to clarify the most suitable agent for use with bevacizumab, and the optimal timing of bevacizumab therapy for lung cancer.

A retrospective cohort study of outcome in systemic sclerosis-associated interstitial lung disease.

BACKGROUND: The relationship between the histological pattern and survival in systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unclear. In patients with SSc-ILD, we investigated whether the clinical data obtained by non-invasive examinations could be used for prognostic evaluation, and attempted to clarify whether complicating acute exacerbation (AE) and the selection of pharmacological therapy were associated with survival. METHODS: Thirty-five patients with SSc-ILD, who had not been diagnosed by surgical lung biopsy were analyzed, retrospectively. The HRCT findings were evaluated by 2 radiologists and classified into "CT-UIP" or "CT-inconsistent with UIP" patterns based on whole lung interpretations. HRCT scores were calculated based on the extent of abnormality evidenced by HRCT. The log-rank test was used to determine variables, including clinical parameters and histories. RESULTS: Twelve (34%) of the 35 patients died during a median follow-up period of approximately 7.9 years. The log-rank test showed that a higher mortality was associated with higher age, a CT-UIP pattern, a higher score for ground-glass attenuation with traction bronchiectasis on HRCT, and complicating AE, whereas a lower mortality was significantly associated with the use of immunosuppressants. A CT-UIP pattern was significantly associated with a higher incidence of later AE. CONCLUSION: Treatment with immunosuppressants was associated with a longer survival, and complicating AE is a predictor of shortened survival in SSc-ILD patients. Among the clinical parameters determined by non-invasive examinations, a CT-UIP pattern and the extent of fibrotic lesions on HRCT, but not a histological pattern of UIP, may be predictors of shortened survival.