[Show abstract][Hide abstract]ABSTRACT: This study was conducted to investigate the toxicity and efficacy of modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer with particular regard to oxaliplatin-induced neuropathy. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 3.0). The evaluation was especially focused on grade 2 oxaliplatin-induced neuropathy. The estimated median treatment time to occurrence of grade 2 sensory neuropathy was 7.3 months. The estimated median cumulative dose to occurrence of grade 2 sensory neuropathy was 931 mg/m(2). This study clarified the treatment time from first dose as well as the cumulative dose of oxaliplatin leading to grade 2 neuropathy. It may be important to institute some clinical countermeasures when grade 2 neuropathy occurs so as to reduce the chance of progression to irreversible grade 3 neuropathy.
[Show abstract][Hide abstract]ABSTRACT: A 75-year-old man presented to our hospital with multifocal thickening of the left pleura and left pleural effusion. Histology of the pleura showed uniform and bipolar spindle cells with moderate mitosis in a collagenised stroma. It further showed abundant blood vessels in a haemangiopericytoma-like pattern. These findings were strongly suggestive of malignant solitary fibrous tumour (SFT). The tumour showed negative staining for CD34. The loss of CD34 expression could imply histologically high-grade tumour, as reported previously. Imatinib, a multityrosine kinase inhibitor with targets, including platelet-derived growth factor receptor (PDGFR)-α and PDGFR-β, has antitumour activity in some patients with SFT. Unfortunately, imatinib treatment failed to control disease progression in the present case that expressed PDGFR-β, but not PDGFR-α. This report described a case of CD34-negative SFT resistant to imatinib.
[Show abstract][Hide abstract]ABSTRACT: Objective:
Erlotinib has been reported to be useful for treatment of non-small-cell lung cancer harboring mutation of the epidermal growth factor receptor gene EGFR-mt. However, no prospective trial has yet assessed the utility of erlotinib in Japanese patients.
Patients with EGFR-mt (exon 19/21) non-small-cell lung cancer who had previously received one to two chemotherapy regimens were enrolled in this trial. Erlotinib was initially administered at a dose of 150 mg/day orally until disease progression or unacceptable toxicities occurred. The primary endpoint was the objective response rate.
Twenty-six patients were enrolled between February 2009 and January 2011. Objective response was observed in 14 patients (53.8%, 95% confidence interval: 33.4-73.4%), and the disease control rate reached 80.8% (95% confidence interval: 60.7-93.5%). After a median follow-up time of 17.3 months (range: 5.8-29.5 months), the median progression-free survival was 9.3 months (95% confidence interval: 7.6-11.6 months). The median survival time is yet to be determined. Major toxicities were skin disorder and liver dysfunction; most episodes were grade 2 or less, and all were tolerable. Only one patient with grade 3 skin rash discontinued the study. No patients developed interstitial lung disease, and there were no treatment-related deaths.
This prospective study is the first to have investigated the usefulness of erlotinib in Japanese patients with previously treated EGFR-mt non-small-cell lung cancer. Although this trial could not meet the primary endpoint, erlotinib was well tolerated and showed clinical benefit such as promising disease control rate or progression-free survival in this population, similar to gefitinib.
Preview · Article · Apr 2013 · Japanese Journal of Clinical Oncology
[Show abstract][Hide abstract]ABSTRACT: Background
A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy.
Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m2 on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol.
Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1–16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred.
This study demonstrated that biweekly administration of 150 mg/m2 irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes.
[Show abstract][Hide abstract]ABSTRACT: The oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.
We describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient.
This is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.
Full-text · Article · Nov 2010 · BMC Gastroenterology
[Show abstract][Hide abstract]ABSTRACT: BIBF 1120 is an oral multitargeted tyrosine kinase inhibitor that blocks the activity of vascular endothelial growth factor (VEGF) and other growth factor receptors. We have done a phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamic biomarkers of BIBF 1120. Patients with advanced refractory solid tumors were treated with BIBF 1120 at oral doses of 150 to 250 mg twice daily. Drug safety and pharmacokinetics were evaluated, as were baseline and post-treatment levels of circulating CD117-positive bone marrow-derived progenitor cells and plasma soluble VEGF receptor 2 as potential biomarkers for BIBF 1120. Twenty-one patients were treated at BIBF 1120 doses of 150 (n = 3), 200 (n = 12), or 250 mg twice daily (n = 6). Dose-limiting toxicities of reversible grade 3 or 4 elevations of liver enzymes occurred in 3 of 12 patients at 200 mg twice daily and 3 of 6 patients at 250 mg twice daily. Stable disease was achieved in 16 (76.2%) patients, and median progression-free survival was 113 days (95% confidence interval, 77-119 d). Pharmacokinetic analysis indicated that the maximum plasma concentration and area under the curve for BIBF 1120 increased with the dose within the dose range tested. Levels of CD117-positive bone marrow-derived progenitors and soluble VEGF receptor 2 decreased significantly during treatment over all BIBF 1120 dose cohorts. In conclusion, the maximum tolerated dose of BIBF 1120 in the current study was determined to be 200 mg twice daily, and our biomarker analysis indicated that this angiokinase inhibitor is biologically active.
Full-text · Article · Oct 2010 · Molecular Cancer Therapeutics
[Show abstract][Hide abstract]ABSTRACT: Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC).
Eligible patients received paclitaxel (200 mg/m(2)) and carboplatin (area under the curve [AUC]of 6 mg min mL(-1)) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle.
Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics.
The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL(-1) and paclitaxel 200 mg/m(2) is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.
Full-text · Article · Sep 2009 · Investigational New Drugs
[Show abstract][Hide abstract]ABSTRACT: A 53-year-old man was admitted to our department because of interstitial pneumonia found on chest computed tomography when he was given a diagnosis of amyopathic dermatomyositis. Bronchoalveolar lavage (BAL) fluid showed an increased total cell count and lymphocytosis. An acute exacerbation of interstitial pneumonia occurred just after the BAL. Although the administration of corticosteroid and immunosuppressant for the progressive interstitial pneumonia produced temporary improvement, left hemothorax suddenly occurred soon after initiating treatment. The hemothorax was improved by thoracic drainage alone, but the patient died due to progressive worsening of interstitial pneumonia. In this case, we could not clarify the etiological mechanism of the hemothorax, however, there was a possible link with amyopathic dermatomyositis-associated interstitial pneumonia.
[Show abstract][Hide abstract]ABSTRACT: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC.
[Show abstract][Hide abstract]ABSTRACT: Multidrug-resistant Pseudomonas aeruginosa, especially metallo-beta-lactamase (MBL)-producing P. aeruginosa, is an important pathogen in nosocomial infection and emergence of this pathogen has revived interest in polymyxin B (PMB) and colistin (COL). In this study, we evaluated the efficacies of PMB, COL and other antipseudomonal agents against IMP-type MBL-producing P. aeruginosa both in vitro and in vivo. A total of 75 isolates of bla(IMP)-positive P. aeruginosa obtained from clinical specimens (94.6% of isolates demonstrated resistance to beta-lactam, fluoroquinolone and aminoglycoside agents) were evaluated in the in vitro study. More than 90% of the examined isolates were susceptible to PMB (minimum inhibitory concentration for 50/90% of the isolates (MIC(50)/MIC(90)) 4/4 mg/L), although COL was less potent (MIC(50)/MIC(90) 8/16 mg/L). Cyclophosphamide-treated mice were intraperitoneally inoculated with bla(IMP)-positive P. aeruginosa. Treatment with PMB, but not COL, imipenem/cilastatin or aztreonam, significantly improved the survival rate and decreased the number of bacteria in the blood in a dose-dependent manner. Our results indicate that, among the agents studied, PMB is the most effective agent against bla(IMP)-positive P. aeruginosa.
No preview · Article · Sep 2008 · International Journal of Antimicrobial Agents
[Show abstract][Hide abstract]ABSTRACT: A 72-year-old man, a Shiitake mushroom grower over fifty years, was admitted to our hospital because of bilateral chest interstitial shadow with chronic cough and breathlessness. Chest computed tomography showed traction bronchiectasis, subpleural micro-cystic changes and partial ground-glass opacities in both lungs, and mild mediastinal lymphadenopathy. A diagnosis of chronic hypersensitivity pneumonitis induced by Shiitake mushrooms was comprehensively confirmed by occupational history, radiological findings, and positive findings of an incidental environmental provocation test and lymphocyte stimulation test for Shiitake mushroom extracts. We reviewed the clinical features in five patients with chronic hypersensitivity pneumonitis induced by Shiitake mushrooms reported in Japan. There was a tendency toward increasing lymphocytes and high CD4/CD8 ratio in bronchoalveolar lavage fluids. Treatment with steroids seems to have a limited effect, while avoidance of the antigen is important.
[Show abstract][Hide abstract]ABSTRACT: A 30-year-old man, who had kept a dog for nine years and often ate raw beef liver, visited a hospital because of a chest nodular shadow in the left lung field found on a checkup examination. Chest computed tomography obtained 8 days after the checkup showed no abnormal shadow in the left lung but two nodular shadows with halos in the right upper and lower lobes. Peripheral blood eosinophil counts and serum IgE values were elevated. Immunological examination including microplate ELISA showed a high titer of specific antibody against Toxocara canis in the serum. He was successfully treated with albentazole. Parasitic disease, especially toxocariasis, is an important consideration in the differential diagnosis of migratory nodular shadow with a halo on chest computed tomography, and serology is useful in diagnosis screening.
[Show abstract][Hide abstract]ABSTRACT: A 63-year-old man had undergone excision of a growing mass with a wide margin in the left supraclavicular fossa. A diagnosis of fibrosarcomatous variant of dermatofibrosarcoma protuberans (DFSP-FS) was made. Three years later, an abnormal chest shadow was detected on a medical checkup. Chest computed tomography showed a heterogeneously-enhanced 2-cm coin lesion with a distinct border in the right lower lobe and a 3-mm nodule in the left lower lobe. Transbronchial lung biopsy specimens from the right lung revealed a DFSP pattern. We then performed right basal segmentectomy and partial resection of the left lower lobe. DFSP is a relatively rare skin tumor that is considered to be intermediate malignancy. It frequently recurs locally but rarely has systemic metastasis. However, DFSP-FS, a subtype of DFSP, has an increased likelihood of systemic metastasis. The lung is the most common site of metastasis of DFSP-FS. DFSP-FS sometimes recurs even a long time after excision. Therefore, long-term follow-up, including chest X-ray and CT are important in DFSP-FS patients.
[Show abstract][Hide abstract]ABSTRACT: We report a case of small cell lung cancer (SCLC) developing after prolonged treatment (more than 2 years) for primary adenocarcinoma of the lung, and we show that both the SCLC and non-small cell lung cancer (NSCLC) tissues obtained from the same site share the same deletion in exon 19 of EGFR. This case suggests that the activating EGFR mutations may confer the pathogenesis of a subset of SCLC.
[Show abstract][Hide abstract]ABSTRACT: A 61-year-old woman who had been followed up after resection of lung cancer (adenosquamous cell carcinoma), was admitted to our hospital because of recurrence. She received systemic anticancer chemotherapy and the chief adverse event was leukopenia (Grade 3). Nineteen days after initiating chemotherapy, she suffered painful vesicular eruption on the right upper limb and the right upper hemithorax which was diagnosed as herpes zoster. After treatment with anti-viral drugs the vesicular eruption disappeared, but chest X-ray film revealed a right diaphragmatic relaxation. Although herpes zoster virus usually affects sensory nerves and causes painful vesicular eruption, it can also damage motor nerves. Herpes zoster virus almost affects cranial nerves, but it should be considered as the cause of diaphragmatic paralysis in this case.