Prolonged Inflation Technique Using a Scoring Balloon for Severe Calcified Lesion.

Percutaneous coronary intervention for the treatment of a severe calcified lesion is still one of the most technically challenging areas of interventional cardiology. Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of in-stent restenosis and thrombosis, even when drug-eluting stents are used. In this report, we describe the usefulness of prolonged inflations using a scoring balloon catheter (Scoreflex) for severe calcified lesions. Prolonged inflation using a scoring balloon enables an adequate dilation for treatment of a severe calcified plaque that was unresponsive to conventional technique with or without rotational atherectomy.

Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study.

BACKGROUND: Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. METHODS: We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on day 1) plus AHTRT (1.5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095. FINDINGS: 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3.2 years (95% CI 2.4-4.1). In the irinotecan and cisplatin group, median overall survival was 2.8 years (95% CI 2.4-3.6); overall survival did not differ between the two groups (hazard ratio 1.09 [95% CI 0.80-1.46], one-sided stratified log-rank p=0.70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). INTERPRETATION: Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC. FUNDING: National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.

Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301).

BACKGROUND: It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC. METHODS: This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m(2) per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), stage (IIIA vs IIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a result of the second planned interim analysis. This study is registered with UMIN Clinical Trials Registry, number C000000060, and ClinicalTrials.gov, number NCT00132665. FINDINGS: 200 patients were enrolled from Sept 1, 2003 to May 27, 2010: 100 in the chemoradiotherapy group and 100 in the radiotherapy group. The second planned interim analysis was done 10 months after completion of patient accrual. At this time, median follow-up for censored cases was 19·4 months (IQR 10·3-33·5). In accordance with the prespecified stopping rule, the JCOG data and safety monitoring committee recommended early publication of this trial because the difference in overall survival favoured the chemoradiotherapy group. Median overall survival for the chemoradiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5-33·6) and 16·9 months (13·4-20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47-0·98, stratified log-rank test one-sided p value=0·0179). More patients had grade 3-4 haematological toxic effects in the chemoradiotherapy group than in the radiotherapy alone group, including leucopenia (61 [63·5%] vs none), neutropenia (55 [57·3%] vs none), and thrombocytopenia (28 [29·2%] vs two [2·0%]). Grade 3 infection was more common with chemoradiotherapy (12 patients [12·5%]) than with radiotherapy (four patients [4·1%]). Incidences of grade 3-4 pneumonitis and late lung toxicity were similar between groups. There were seven treatment-related deaths: three of 100 patients (3·0%) in the chemoradiotherapy group and four of 100 (4·0%) in the radiotherapy group. INTERPRETATION: For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population. FUNDING: Ministry of Health, Labour, and Welfare of Japan.

A randomized phase III study of docetaxel alone versus docetaxel plus S-1 in patients with previously treated non-small cell lung cancer: JMTO LC09-01.

BACKGROUND: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. METHODS: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). RESULTS: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. CONCLUSIONS: The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.

Standard versus low-dose nab-paclitaxel in previously treated patients with advanced non-small cell lung cancer: A randomized phase II trial (JMTO LC14-01).

BACKGROUND: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. CONCLUSION: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option.

A weekly combination of carboplatin and irinotecan for previously untreated extensive disease small-cell lung cancer, results of a minimum follow-up of 3 years: a multi-center Phase II trial JMTO LC02-02.

OBJECTIVE: We conducted a Phase II study to evaluate the efficacy and safety of a weekly combination of carboplatin and irinotecan regimen for patients with extensive disease small-cell lung cancer. METHODS: Patients with previously untreated extensive disease small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0, 1 or 2, were enrolled in this trial. Carboplatin area under the curve of two and irinotecan (50 mg/m(2)) were administered on days 1 and 8 every 3 weeks. Treatment was continued up to a maximum of six cycles. The expected response rate was 85%, and this regimen was considered sufficiently positive if >45 responses were observed in the 55 patients. RESULTS: Between December 2003 and September 2006, 56 patients were enrolled and 55 patients were eligible. Of 55 patients, 6 complete remissions and 37 partial remissions were achieved, and the response rate was 78.2% (95% confidence interval: 64.6-87.9). Major Grade 3 or more toxicities were leukocytopenia 3, neutropenia 15, anemia 7, infection 5, diarrhea 3, anorexia 7, nausea 6 and pneumothorax 1. The median survival was 13.9 months (95% confidence interval: 11.8-18.5) and the median progression-free survival was 5.7 months (95% confidence interval: 4.9-7.4). CONCLUSIONS: This Phase II trial of a weekly combination of carboplatin and irinotecan for extensive disease small-cell lung cancer was not positive for a response rate that is considered to be worthy of further Phase III trial.

COVID-19 mRNA Vaccine-Associated Uveitis Leading to Diagnosis of Sarcoidosis: Case Report and Review of Literature.

A 34-year-old Japanese person with male gender identity who had been taking intramuscular injection of methyltestosterone depot for 11 years after bilateral mastectomy noticed blurred vision 5 days after the second vaccination for COVID-19 (Tozinameran; Pfizer-BioNTech) in the interval of 3 weeks following the first vaccination. The patient was diagnosed as granulomatous iritis with mutton-fat keratic precipitates and small iris nodules at the pupillary margin in the right eye and began to have 0.1% betamethasone eye drops with good response. The patient, however, continued to have fever and malaise and showed a high level of serum soluble interleukin-2 receptor (sIL-2R) even 4 weeks after the second vaccination. Computed tomographic scan disclosed mediastinal and bilateral hilar small lymphadenopathy together with limited granular lesion in the right lung. Gallium-67 scintigraphy demonstrated high uptake not only in mediastinal and hilar lymph nodes but also in bilateral parotid glands. Right parotid gland biopsy revealed noncaseating granulomas and proved pathological diagnosis of sarcoidosis. The systemic symptoms were relieved by oral prednisolone 20 mg daily. Even though the causal relationship remains undetermined, this case is unique at the point that vaccine-associated uveitis led to the detection of pulmonary lesions and lymphadenopathy, resulting in clinical and pathological diagnosis of sarcoidosis. In literature review, 3 patients showed sarcoidosis-like diseases after COVID-19 vaccination: 2 patients were diagnosed clinically as Lofgren syndrome with acute onset of erythema nodosum and ankle swelling, with or without mediastinal and hilar lymphadenopathy, whereas 1 patient with mediastinal lymphadenopathy but no uveitis was diagnosed pathologically by biopsy as sarcoidosis.

A randomized phase II study of docetaxel or pemetrexed with or without the continuation of gefitinib after disease progression in elderly patients with non-small cell lung cancer harboring EGFR mutations (JMTO LC12-01).

BACKGROUND: Gefitinib (G) is a recommended molecular-targeted agent for elderly patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR-mutant NSCLC. METHODS: Elderly patients with EGFR-mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity. RESULTS: This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression-free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16-0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032). CONCLUSIONS: Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single-agent chemotherapy; however, it was associated with increased toxicity.

Evaluating the Safety of Simultaneous Intracranial Electroencephalography and Functional Magnetic Resonance Imaging Acquisition Using a 3 Tesla Magnetic Resonance Imaging Scanner.

Background: The unsurpassed sensitivity of intracranial electroencephalography (icEEG) and the growing interest in understanding human brain networks and ongoing activities in health and disease have make the simultaneous icEEG and functional magnetic resonance imaging acquisition (icEEG-fMRI) an attractive investigation tool. However, safety remains a crucial consideration, particularly due to the impact of the specific characteristics of icEEG and MRI technologies that were safe when used separately but may risk health when combined. Using a clinical 3-T scanner with body transmit and head-receive coils, we assessed the safety and feasibility of our icEEG-fMRI protocol. Methods: Using platinum and platinum-iridium grid and depth electrodes implanted in a custom-made acrylic-gel phantom, we assessed safety by focusing on three factors. First, we measured radio frequency (RF)-induced heating of the electrodes during fast spin echo (FSE, as a control) and the three sequences in our icEEG-fMRI protocol. Heating was evaluated with electrodes placed orthogonal or parallel to the static magnetic field. Using the configuration with the greatest heating observed, we then measured the total heating induced in our protocol, which is a continuous 70-min icEEG-fMRI session comprising localizer, echo-planar imaging (EPI), and magnetization-prepared rapid gradient-echo sequences. Second, we measured the gradient switching-induced voltage using configurations mimicking electrode implantation in the frontal and temporal lobes. Third, we assessed the gradient switching-induced electrode movement by direct visual detection and image analyses. Results: On average, RF-induced local heating on the icEEG electrode contacts tested were greater in the orthogonal than parallel configuration, with a maximum increase of 0.2°C during EPI and 1.9°C during FSE. The total local heating was below the 1°C safety limit across all contacts tested during the 70-min icEEG-fMRI session. The induced voltage was within the 100-mV safety limit regardless of the configuration. No gradient switching-induced electrode displacement was observed. Conclusion: We provide evidence that the additional health risks associated with heating, neuronal stimulation, or device movement are low when acquiring fMRI at 3 T in the presence of clinical icEEG electrodes under the conditions reported in this study. High specific absorption ratio sequences such as FSE should be avoided to prevent potential inadvertent tissue heating.

Quality-of-life evaluation for advanced non-small-cell lung cancer: a comparison between vinorelbine plus gemcitabine followed by docetaxel versus paclitaxel plus carboplatin regimens in a randomized trial: Japan Multinational Trial Organization LC00-03 (BRI LC03-01).

BACKGROUND: A randomized trial of vinorelbine plus gemcitabine followed by docetaxel (VGD) versus paclitaxel plus carboplatin (PC) in patients with advanced non-small-cell lung cancer showed no difference in overall survival (median survival time: 13.6 versus 14.1 months) between the two treatment groups. We report here the results of quality-of-life (QOL) study initiated in the mid-course of this randomized trial. METHODS: The patients themselves assessed the Functional Assessment of Cancer Therapy (FACT)-Lung (FACT-L), FACT-Taxane and the Functional Assessment of Chronic Illness Therapy - Spirituality (FACIT-Sp) QOL instruments at baseline and 6, 12 and 18 weeks after the treatment. The primary endpoint was a comparison of total QOL score for each assessment instrument between the two groups. RESULTS: Sixty-eight patients from the trial (VGD, 34; PC, 34) who submitted baseline questionnaires and at least one questionnaire over the course of treatment were eligible. Longitudinal analysis showed a significant difference in slope of the FACT-Taxane score (p = 0.004) between treatment regimens over time, but no difference was found in FACT-L score (p = 0.311) and FACIT-Sp score (p = 0.466) between the two groups. CONCLUSIONS: The significant difference in slope of FACT-Taxane score favored the VGD regimen. These data should be considered in treatment decision-making for patients with advanced non-small-cell lung cancer. TRIAL REGISTRATION: NCT00242983.

A phase II study of cisplatin and irinotecan as induction chemotherapy followed by concomitant thoracic radiotherapy with weekly low-dose irinotecan in unresectable, stage III, non-small cell lung cancer: JCOG 9706.

OBJECTIVE: It is important to identify optimal regimens of cisplatin-based, third-generation chemotherapy and thoracic radiotherapy for patients with unresectable, Stage III, non-small cell lung cancer. METHODS: Patients with unresectable, Stage III non-small cell lung cancer were treated with the following regimen: cisplatin 80 mg/m(2) on days 1 and 29, with irinotecan 60 mg/m(2) on days 1, 8, 15, 29, 36, and 43 and 30 mg/m(2) on days 57, 64, 71, 78, 85 and 92. Thoracic radiotherapy was started on day 57 at 2 Gy/day (total 60 Gy). RESULTS: From February 1998 to January 1999, 68 patients were enrolled. Grade 3/4 toxicities during induction chemotherapy primarily included neutropenia (73.5%) and diarrhea (20.6%), while Grade 3/4 toxicities during concomitant thoracic radiotherapy with irinotecan consisted of neutropenia (18.4%), esophagitis (4.1%) and hypoxia (6.5%). There was one treatment-related death due to radiation pneumonitis. The response rate was 64.7% (95% confidence interval, 52.2-75.9%). The median survival time was 16.5 (95% confidence interval, 12.6-19.8) months. The 1- and 2 year survival rates were 65.8% (95% confidence interval, 54.4-77.1%) and 32.9% (95% confidence interval, 21.6-44.1%), respectively. Overall, only 36 (56%) completed both the scheduled chemotherapy and thoracic radiotherapy. CONCLUSIONS: Induction chemotherapy with cisplatin plus irinotecan followed by low-dose irinotecan and concomitant thoracic radiotherapy was feasible according to the prespecified decision criteria in this study for patients with unresectable Stage III non-small cell lung cancer. We did not decide to select this regimen for further investigations because approximately half of the patients completed the scheduled treatment.

Clinical implication of the antidiuretic hormone (ADH) receptor antagonist mozavaptan hydrochloride in patients with ectopic ADH syndrome.

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life.

Multicenter, phase II, placebo-controlled, double-blind, randomized study of aprepitant in Japanese patients receiving high-dose cisplatin.

Aprepitant is a new neurokinin-1 (NK(1) ) receptor antagonist developed as a treatment for chemotherapy-induced nausea and vomiting (CINV). To evaluate the efficacy and safety of aprepitant used in combination with standard therapy (granisetron and dexamethasone), we conducted a multicenter, phase II, placebo-controlled, double-blind, randomized study in Japanese cancer patients who received cancer chemotherapy including cisplatin (≥70mg/m(2) ). Aprepitant was administered for 5days. A total of 453 patients were enrolled. In the three study groups, (i) standard therapy, (ii) aprepitant 40/25mg (40mg on day 1 and 25mg on days 2-5) and (iii) aprepitant 125/80mg (125mg on day 1 and 80mg on days 2-5), the percentage of patients with complete response (no emesis and no rescue therapy) was 50.3% (75/149 subjects), 66.4% (95/143 subjects) and 70.5% (103/146 subjects), respectively. This shows that efficacy was significantly higher in the aprepitant 40/25mg and 125/80mg groups than in the standard therapy group (χ(2) test [closed testing procedure]: P=0.0053 and P=0.0004, respectively) and highest in the aprepitant 125/80mg group. The delayed phase efficacy (days 2-5) was similar to the overall phase efficacy (days 1-5), indicating that aprepitant is effective in the delayed phase when standard therapy is not very effective. In terms of safety, aprepitant was generally well tolerated in Japanese cancer patients. (ClinicalTrials.gov number, NCT00212602.)

MRI of the neck at 3 Tesla using the periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) (BLADE) sequence compared with T2-weighted fast spin-echo sequence.

PURPOSE: To evaluate motion artifacts, tissue contrasts, and lesion detectability in the neck with the periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) (BLADE) technique. MATERIALS AND METHODS: A total of 46 patients referred for MRI of the neck were included in a comparison of T2-weighted BLADE (T2W-BLADE) sequence and T2W fast spin-echo (T2W-FSE) sequence. All examinations were performed at 3T using the same parameters. Two observers evaluated unlabelled images for motion artifacts, the preferred image quality, and lesion detectability. Region of interest (ROI)-based quantitative measurements were performed to assess tissue contrasts. The frequency of occurrence of the different assessed artifacts and the lesion detectability was tested using McNemar's test. Tissue contrasts were compared using the Wilcoxon paired test. Reader agreement was assessed using kappa test. RESULTS: T2W-BLADE showed less ghosting and pulsation artifacts than T2W-FSE (P < 0.01). T2W-BLADE images were rated as better than or equal to T2W-FSE images in majority cases (93.5%; kappa = 0.64). There was not significant difference in tissue contrasts between T2W-BLADE and T2W-FSE. A total of 32 lesions were present in 32 patients and equally well seen on T2W-BLADE and T2W-FSE. CONCLUSION: T2W-BLADE can reduce motion artifacts and provide tissue contrasts and lesion detectability equivalent to T2W-FSE.

Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, given weekly to advanced solid tumor patients for 3 weeks.

TZT-1027 is a novel synthetic dolastatin 10 derivative that inhibits tubulin polymerization. A phase I study was conducted to determine the maximum tolerated dose (MTD) of TZT-1027, and to assess its pharmacokinetic profile in Japanese patients with advanced solid tumors following administration of the drug weekly for 3 weeks. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and met the following criteria: performance status ≤2 and acceptable organ function. The MTD was defined as the highest dose at which more than two-thirds of the patients experienced grade 4 hematological toxicity or grade 3/4 non-hematological toxicity during weekly TZT-1027 administration for 3 weeks. Forty patients were enrolled in the present study. Twelve doses between 0.3 and 2.1 mg/m2 were evaluated. Grade 4 neutropenia was the principal dose-limiting toxicity (DLT). At a dose of 2.1 mg/m2, two patients developed DLT: one patient developed grade 4 neutropenia, grade 3 myalgia, and grade 4 constipation, and the other one developed grade 4 neutropenia and grade 3 constipation. At a dose level of 1.8 mg/m2, toxicity was acceptable and no DLT was observed. The area under the curve and maximum concentration of TZT-1027 tended to increase linearly with the dose. The DLT observed were neutropenia, myalgia, and constipation, and the MTD was 2.1 mg/m2. The recommended dose for a phase II study was determined to be 1.8 mg/m2 for the drug administered weekly for 3 weeks.

Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study.

BACKGROUND: Platinum-containing two-drug combinations improve survival and cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). However, survival benefit is modest and platinum-containing regimens cause substantial toxic effects. We did a prospective randomised open-label phase III study to compare an experimental platinum-free, triplet, sequential regimen of vinorelbine plus gemcitabine followed by docetaxel with the standard platinum-containing, doublet regimen paclitaxel plus carboplatin in patients with advanced NSCLC. METHODS: Between March, 2001, and April, 2005, patients with stage IIIB (positive pleural effusion) or IV NSCLC, performance status 0 to 1, and adequate organ function, were randomly assigned to experimental treatment or to standard treatment. Randomisation was done centrally by use of a dynamic balancing algorithm. Patients were stratified by weight loss, lactate dehydrogenase concentration, and disease stage. Patients in the experimental group were scheduled to receive intravenous vinorelbine (25 mg/m(2)) plus gemcitabine (1000 mg/m(2)) on days 1 and 8 every 21 days for three cycles, followed by intravenous docetaxel (60 mg/m(2)) on day 1 every 21 days for three cycles. Patients in the standard group were scheduled to receive intravenous paclitaxel (225 mg/m(2)) plus carboplatin (area under the curve=6) for 3 h on day 1, every 21 days for six cycles. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, response, and toxic effects. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00079287. FINDINGS: Of the 401 patients enrolled and randomised in the trial, five patients in the experimental group and three in the standard group were ineligible for analysis; thus 196 patients in the experimental group and 197 in the standard group were included in analyses. Patient characteristics were well-balanced between the two groups with regard to major prognostic factors. Median overall survival was 13.6 months (range 12.0-16.4) in the experimental group versus 14.1 months (11.9-17.5) in the standard group (p=0.97). 49 of 196 patients (25%) in the experimental group had a partial response compared with 73 of 197 patients (37%) in the standard group (p=0.012). There were no complete responses. Median progression-free survival was 5.5 months (95% CI 4.9-6.3) in the experimental group compared with 5.8 months (5.3-6.1) in the standard group (p=0.74). The incidence of grade 3 and 4 neutropenia, neuropathy, arthralgia, and myalgia was lower in the experimental group than in the standard group, although the incidence of pulmonary toxic effects was higher. INTERPRETATION: Although platinum-containing regimens remain the standard treatment for advanced NSCLC, non-platinum regimens could provide equivalent efficacy with a different toxicity profile.

Epidermal growth factor receptor gene amplification and gefitinib sensitivity in patients with recurrent lung cancer.

To evaluate the epidermal growth factor receptor (EGFR) protein expression, gene mutations and amplification as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib, we have performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We investigated the EGFR amplification and EGFR protein expression statuses in 27 surgically treated non-small-cell lung cancer (NSCLC) cases. These patients experienced relapse after surgery and received gefitinib 250 mg/day. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis and sequences, and already reported. EGFR mutations were found from 15/27 lung cancer patients. EGFR mutation status was significantly correlated with better prognosis (log-rank test P=0.0023). Smoking status (never smoker vs. smoker, P=0.0032), and pathological subtypes (adenocarcinoma vs. non-adenocarcinoma, P=0.0011), but not EGFR amplification (P=0.1278), were correlated with survival of lung cancers. EGFR IHC results were correlated with FISH results (P=0.0125), but not correlated with prognosis (P=0.7921). Thus, the EGFR gene amplification or protein expression is not a predictor of gefitinib efficacy in Japanese patients with NSCLC. We have also evaluated the EGFR mutation status and clinico-pathological features for 27 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. The EGFR mutation status, especially exon19 mutation was correlated with good response to gefitinib than exon 21 point mutation.

EGFR polymorphism of the kinase domain in Japanese lung cancer.

BACKGROUND: Mutations of the epidermal growth factor receptor (EGFR) gene at kinase domain have been reported in non-small-cell lung cancer (NSCLC), and some common somatic mutations in EGFR have been examined for their ability to predict sensitivity to gefitinib or erlotinib. However, EGFR mutations at exon 20 have been reported to predict resistance to gefitinib therapy. MATERIALS AND METHODS: We investigated the EGFR mutations and/or polymorphism statuses at kinase domain in 303 surgically treated non-small cell lung cancer (NSCLC) cases. One hundred ninety-four adenocarcinoma cases were included. The presence or absence of EGFR polymorphism of kinase domains was analyzed by direct sequences. We have also investigated EGFR polymorphism status at exon 20 for 23 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. RESULTS: EGFR mutations at kinase domain were found in 75 of 303 lung cancer patients. During sequencing of EGFR tyrosine kinase domain in tumors, 86 EGFR polymorphism (G2607A) cases were identified at exon 20. G2067A polymorphism was significantly higher in nonadenocarcinomas (37.4%) than in adenocarcinoma (25.3%, P = 0.0415). The polymorphism status did not correlate with gender, smoking (never smoker versus smoker), and EGFR mutations. In 46 total gefitinib treated NSCLC patients, there was a tendency toward better prognosis in EGFR wild type (GG) patients than AG + AA patients. EGFR polymorphism in Japanese lung cancers seemed to be less frequent than Caucasian lung cancers. CONCLUSIONS: EGFR-tyrosine kinase polymorphism might be associated with clinicopathological background of lung cancers.

Lung cancer in patients with chronic pyothorax.

BACKGROUND AND OBJECTIVE: The aim of this study was to describe the features of lung cancers associated with chronic tuberculous pyothorax. METHODS: Clinicopathological data from patients with coexisting lung cancer and chronic latent pyothorax caused by tuberculosis (TB) were analysed, and cancer tissue samples were investigated for the presence of Epstein-Barr virus. RESULTS: Twelve patients were identified, and all had a history of tuberculous pleuritis or surgical intervention for TB. The interval between the onset of TB and lung cancer was more than 30 years in nine patients and the most frequent symptom was chest pain (six patients). All cancers were in the ipsilateral lung to the pyothorax, and in nine of the 12 patients the cancers were located adjacent to the pyothorax. In situ hybridization analysis for Epstein-Barr virus-encoded small RNA failed to show positive signals in any of the six cancer tissues examined. CONCLUSIONS: Lung cancer associated with chronic pyothorax always developed in the ipsilateral lung to the pyothorax, and there was no evidence for the presence of Epstein-Barr virus in the cancer tissues examined.