Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae ST258 isolated from a Japanese patient without a history of foreign travel - a new public health concern in Japan: a case report.

BACKGROUND: Thus far, studies on Klebsiella pneumoniae carbapenemase (KPC)-producing organisms have only been reported in those with a history of foreign travel, and a specific Japanese KPC-producing isolate has not yet been reported. CASE PRESENTATION: We describe a Japanese patient, with no history of travel to foreign countries, admitted due to aspiration pneumonia, and a KPC-producing isolate detected in his sputum. Fortunately, his pneumonia resolved. His close contacts did not have a history of foreign travel, and the isolate was not detected in other patients. CONCLUSIONS: The potential for KPC-producing organisms to become endemic in Japan is currently of great concern.

Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer.

OBJECTIVES: Gefitinib is a potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is a key drug for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). The pharmacokinetics of orally administered gefitinib varies greatly among patients. We prospectively evaluated the association of pharmacokinetics and pharmacogenomics with the safety and efficacy of gefitinib in patients with EGFR mutation-positive advanced NSCLC. PATIENTS AND METHODS: Pharmacokinetics was evaluated with samples of peripheral blood obtained on day 1 before treatment and 1, 3, 5, 8, and 24h after gefitinib (250 mg per day) was administered and on days 8 and 15 as the trough values. The plasma concentration of gefitinib was analyzed with high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, CYP3A4, CYP3A5, and CYP2D6 genes were analyzed with direct sequencing. RESULTS: The subjects were 35 patients (21 women; median age, 72 years; range, 53 to 90 years) with stage IV adenocarcinoma harboring EGFR mutations. The median peak plasma concentration (Cmax) was 377 (range, 168-781)ng/mL. The median area under the curve (AUC) of the plasma concentration of gefitinib from 0 to 24h was 4893 (range, 698-13991) ng/mL h. The common adverse events were skin toxicity (68% of patients), diarrhea (46%), and liver injury (63%). One patient died of drug-induced interstitial lung disease (ILD). The overall response rate was 82.9% (95% confidence interval, 66.4%-93.4%). The median progression-free survival time was 10 months, and the median survival time was 25 months. The pharmacokinetics and pharmacogenomics were not associated with significantly different toxicities, response rates, or survival times with gefitinib. However, the AUC and Cmax were highest and the trough value on day 8 was the second highest in one patient who died of drug-induced ILD. CONCLUSION: Elevated gefitinib exposure might be associated with drug-induced ILD.

QRS-based assessment of myocardial damage and adverse events associated with cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis (CS) generates myocardial scar and arrhythmogenic substrate. CS diagnosis according to the Japanese Ministry of Health and Welfare guidelines relies, among others, on cardiac magnetic resonance imaging with late gadolinium enhancement (CMR-LGE). However, access to CMR-LGE is limited. The electrocardiography-based Selvester QRS score has been validated for identifying myocardial scar in ischemic/nonischemic cardiomyopathy, but its efficacy has not been tested to evaluate CS. OBJECTIVE: The purpose of this study was to examine whether the QRS score can be applied to CS. METHODS: CS-associated myocardial scar was assessed by both CMR-LGE and QRS scoring in patients with extra-CS (n = 59). RESULTS: Of 59 patients, 35 (59%) were diagnosed with CS according to the Japanese Ministry of Health and Welfare guidelines. QRS-estimated scar mass positively correlated with that quantified by CMR-LGE (signal intensity ≥2SD above the reference; r = 0.68; P < .001). Receiver operating characteristic curves demonstrated optimal cutoffs of 9% CMR-LGE scar and 3-point QRS score to identify patients with CS. The areas under the curves of CMR-LGE and the QRS score were not significantly different (0.83 and 0.78, respectively; P = .27); both methods demonstrated similar diagnostic performance. A QRS score of ≥3 led to a higher incidence of CS-associated adverse events (death/fatal arrhythmia/heart failure hospitalization) than did a QRS score of <3 (35 ± 21 months of follow-up; P = .01). QRS score was an independent predictor of risk in multivariate analysis (P = .03). CONCLUSION: The Selvester QRS scoring estimates CS-associated myocardial damage and identifies patients with CS equally well as CMR-LGE. A higher QRS score is also associated with an increased risk of life-threatening events in CS, indicating its potential use as a risk predictor.

Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer.

The aim of this study was to investigate the relationship of the number of circulating tumor cells (CTCs) with the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We prospectively evaluated CTCs in the peripheral blood of patients with previously untreated metastatic NSCLC. From May 2008 through August 2010, 33 patients (23 men and 10 women; median age, 64 years; range, 46-74 years) were enrolled. All patients received combination chemotherapy with gemcitabine and carboplatin. The CTCs were captured from samples of peripheral blood with a semiautomated system using an antibody against epithelial cell adhesion molecule. Blood samples with one or more CTC per 7.5 ml were defined as positive. Of total 33 patients, 12 (36.4%) had positive CTCs and 5 (15.2%) had five or more CTCs before chemotherapy. There were no differences in response rates to cytotoxic chemotherapy between CTC-positive patients and CTC-negative patients. On the other hand, the rate of progressive disease in cytotoxic chemotherapy was significantly higher in CTC-positive patients (66.7%) than in CTC-negative patients (23.8%, p = 0.02). In conclusion, the number of CTCs could be a useful predictive factor for the effectiveness of cytotoxic chemotherapy in patients with metastatic NSCLC.

Evaluation of the safety and efficacy of combination chemotherapy with vinorelbine and platinum agents for patients with non-small cell lung cancer with interstitial lung disease.

BACKGROUND: Acute chemotherapy-associated exacerbation of interstitial lung disease (ILD) can occur in patients with non-small cell lung cancer (NSCLC). The safety and efficacy of cytotoxic chemotherapy has not yet been established for NSCLC with ILD. Thus, patients with advanced NSCLC with ILD usually receive only best supportive care. The aim of this study was to assess the safety and efficacy profiles of the combination chemotherapy of vinorelbine and a platinum agent in patients with advanced NSCLC with ILD. PATIENTS AND METHODS: Nineteen patients with advanced NSCLC with ILD treated with vinorelbine and a platinum agent, either cisplatin or carboplatin, were retrospectively reviewed to examine acute exacerbation of ILD, toxicity, response rate, and survival time. Additionally, possible predictive factors for acute chemotherapy-associated exacerbation of ILD were analyzed. RESULTS: The response rate was 42.1%, the progression-free survival time was 4.4 months, the median survival time was 7.4 months, and the one-year survival rate was 36.8%. Neutropenia was the most frequent grade 3 to 4 toxicity and it occurred in 63.2% of patients. Acute chemotherapy-associated exacerbation of ILD occurred in three patients (15.8%) and caused the death of one of these patients (5.3%). No variables were identified as being predictive factors for acute chemotherapy-associated exacerbation of ILD. CONCLUSION: The combination chemotherapy with vinorelbine and a platinum agent can be considered as a treatment option for patients with advanced NSCLC with ILD, with careful management after sufficient evaluation of the risks and the benefits.

Ultrasound visibility of regional anesthesia catheters: an in vitro study.

BACKGROUND: Ultrasound subjective visibility of in-plane needles is correlated with the intensity difference between the needle surface and the background. Regional anesthesia catheters are difficult to visualize by an ultrasound. In the present study, we investigated the ultrasound visibility of the catheters. METHODS: Six catheters were placed at 0° and 30° relative to and at a depth of 1 cm below the pork phantom surface. Ultrasound images of in-plane catheters were evaluated, subjectively and objectively. Outer and inner objective visibilities were defined as the difference in the mean pixel intensity between the catheter surface and adjacent background, and between the surface and the center of the catheter, respectively. Evaluations were made based on the portion of the catheters. A P value < 0.05 was considered significant. RESULTS: Subjective visibility was more strongly correlated with the inner objective visibility than with the outer objective visibility at both angles. Metallic 19-gauge catheters were more subjectively visible than the non-metallic 20-gauge catheters at 30° degrees (P < 0.01). Subjective, and outer and inner objective visibility were significantly lower at 30° than at 0° (P < 0.01, P < 0.01, P = 0.02). Perifix ONE at 0° and Perifix FX at 30° were the most visible catheters (P < 0.01 for both). CONCLUSIONS: Subjective visibility of catheters can not be evaluated in the same manner as that of the needles. For the best possible visualization, we recommend selecting a catheter with a structure that enhances the dark at the center of catheter, rather than basing the catheter selection on the bore size.

New anthranilic acid derivative, EAntS-GS, attenuates Freund's complete adjuvant-induced acute pain in rats.

BACKGROUND: Acute and chronic pain commonly accompany various clinical conditions such as contusion, fracture, osteoarthritis, peripheral neuropathy, and postherpetic neuralgia. Recent studies have found that antioxidative drugs can have analgesic effects. The present study tested the hypothesis that a new anthranilic acid derivative, EAntS-GS, exerts antinociceptive effects on inflammatory pain in a rat model. METHODS: We induced subacute pain with a plantar injection of Freund's complete adjuvant (FCA) in Sprague-Dawley rats. EAntS-GS (1 mg/kg subcutaneous injection or 1% application) was administered every 12 h beginning 24 h after FCA administration, and the plantar test was used to determine its effect on pain. Levels of myeloperoxidase, inducible nitric oxide synthase (iNOS), and protease activated receptor 2 (PAR2) were measured to elucidate the mechanism of action of EAntS-GS. RESULTS: EAntS-GS significantly reduced FCA-induced pain and myeloperoxidase, iNOS, and PAR2 levels. Our findings suggest that the new anthranilic acid derivative, EAntS-GS, exerts antinociceptive effects, and that the mechanism involves iNOS and PAR2. CONCLUSION: We conclude that EAntS-GS should be considered a new therapeutic tool to treat acute and chronic pain.

[Three cases of Mycobacterium kansasii pulmonary diseases in previously healthy young women].

Mycobacterium kansasii pulmonary diseases account for 20% of cases of non-tuberculous mycobacteria. Most patients are male. However, a recent study has found that radiological examinations in female patients often reveal nodular, bronchiectatic opacities. We describe 3 young women with cavitary opacities. Patient 1 was a 35-year-old woman in whom thin-walled cavitary opacities were detected in the upper lobe during a routine checkup. Sputum examination and fiberoptic bronchoscopy led to a diagnosis of M. kansasii pulmonary disease. Patient 2 was a 23-year-old woman who presented with hemoptysis. Thin-walled cavitary opacities were detected in the right upper lobe. Infection with M. kansasii was diagnosed after a sputum examination. Patient 3 was a 43-year-old woman in whom thin-walled cavitary opacities were detected in the left upper lobe during a routine checkup. Infection with M. kansasii was diagnosed after a fiberoptic bronchoscopic examination. Patient 1 was successfully treated with rifampicin, ethambutol, and levofloxacin, and patients 2 and 3 were successfully treated with isoniazid, rifampicin, and ethambutol. The possibility of M. kansasii pulmonary diseases should be considered in a previously healthy young woman with thin-walled cavitary opacities in the upper lobe.

[A case of pulmonary aspergilloma concomitant with allergic bronchopulmonary aspergillosis].

A 69-year-old man with pulmonary aspergilloma was admitted to the hospital because of persistent cough and slight fever. Antifungal agents were administered on a diagnosis of chronic necrotizing pulmonary aspergillosis or symptomatic aspergilloma. Despite the antifungal treatment, wheezing developed, suggesting a complication of allergic bronchopulmonary aspergillosis (ABPA). Finally, a definitive diagnosis of ABPA was made using the Rosenberg-Patterson criteria. Inhaled corticosteroid therapy reduced his wheezing. This case study indicates that there is a possibility that aspergilloma might coexist with ABPA. Therefore, we should pay attention to the possible complication of ABPA when treating pulmonary aspergilloma.

Phase II trial of the combination of carboplatin and irinotecan in elderly patients with small-cell lung cancer.

AIM: The aim of the present phase II study was to assess the antitumour activity and safety of the combination of irinotecan and carboplatin in elderly patients with small-cell lung cancer (SCLC). MATERIAL AND METHODS: Patients with previously untreated SCLC were eligible if they had a performance status of 0-2, were 70 years or older, and had adequate organ function. Patients were treated with carboplatin at an area under the plasma concentration versus time curve of 5 min/ml on day 1 and with irinotecan at 50mg/m(2) on days 1 and 8 every 3 weeks. RESULTS: Thirty patients (26 men and 4 women; median age, 76 years; age range, 70-86 years) were enrolled. Eight patients had limited disease (LD) and 22 patients had extensive disease (ED). The overall response rate was 83.3% (95% confidence interval: 65.3-94.4%). Response rates did not differ significantly between patients with LD (87.5%) and those with ED (81.8%; p=0.71). The median survival time was 14 months overall and was significantly longer in patients with LD (26 months) than in patients with ED (11 months; p=0.025). The median progression free survival time was 6 months overall and was significantly longer in patients with LD (12 months) than in patients with ED (6 months; p=0.016). Grade 3-4 toxicities included neutropenia in 83% of patients, thrombocytopenia in 47%, anaemia in 60%, infection in 23%, and diarrhoea in 20%. There were no treatment-related deaths. CONCLUSIONS: This chemotherapy is safe and effective for elderly patients with SCLC.

The antinociceptive effects of estradiol on adjuvant-induced hyperalgesia in rats involve activation of adrenergic and serotonergic systems.

PURPOSE: Estradiol is a female hormone required for maintaining pregnancy and developing follicles in the ovary. Estradiol has been shown to perform a variety of physiological activities, including pain reduction. In this study, we tested the hypothesis that estradiol exerts antinociceptive effects in a rat model of inflammatory hyperalgesia. METHODS: We established a subacute hyperalgesia model using plantar injection of Freund's complete adjuvant (FCA) in Sprague-Dawley rats. We administered estradiol every 24 h, beginning 12 h after FCA administration, and used the plantar test to determine its effect on hyperalgesia. To determine the mechanism of action of estradiol, we evaluated the role of the opioid antinociceptive system using naloxone and the role of the descending pain inhibitory system using the α-2-receptor antagonist yohimbine and the serotonin receptor antagonist methysergide. RESULTS: Administration of FCA induced hyperalgesia, which was significantly reduced by estradiol treatment compared to controls. Moreover, this effect was not antagonized by naloxone, but was attenuated by α-2-receptor and serotonin-receptor antagonists. CONCLUSION: Estradiol is known to perform a variety of physiological functions. Our findings suggest that one such function is antinociception via an interaction with α-2 receptors and serotonin receptors.

Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer.

Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55-73 years). Patients received the combination of amrubicin (30 mg/m(2) on days 1-3) plus carboplatin (with a target area under the concentration-versus-time curve of 4 mg min/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0-57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7-84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9-15.4%; p=0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1-42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p=0.004). The median progression-free survival (PFS) time was 3 months (range: 1-14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p=0.01). The most frequent grade 3-4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3-4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC.

Are levels of pro-gastrin-releasing peptide or neuron-specific enolase at relapse prognostic factors after relapse in patients with small-cell lung cancer?

The purposes of this study were to assess the relationship of serum levels of pro-gastrin-releasing protein (ProGRP) and neuron-specific enolase (NSE) at relapse with survival after relapse and the response to salvage therapy and to assess whether serum levels of ProGRP and NSE at relapse are useful markers for detecting relapse earlier than are symptoms or radiographic findings in patients with small-cell lung cancer (SCLC). The subjects of this study were 103 patients with SCLC who had achieved a complete response (CR) or partial response (PR) to first-line chemotherapy. We retrospectively evaluated whether ProGRP or NSE increased earlier than symptoms or radiographic findings appeared, and the association between response to salvage therapy and levels of ProGRP or NSE at relapse. In addition, we evaluated the association between survival after relapse and clinical and demographic factors at relapse, including age, sex, response to first-line treatment, sensitivity to first-line treatment, stage, performance status (PS), and serum levels of ProGRP, NSE, and lactate dehydrogenase. At relapse, 69.3% of patients had elevated serum levels of ProGRP, 60.2% had elevated serum levels of NSE, and 81.3% had elevated serum levels of either ProGRP or NSE. However, almost all asymptomatic relapses were detected with radiographic studies. The rate of CR to salvage chemotherapy was significantly lower in patients with elevated levels of NSE (2.2%) than in patients without (26.7%; p=0.001). Univariate analysis showed that sensitivity to first-line treatment, serum levels of NSE, stage, and PS at relapse were prognostic factors for survival after relapse. Multivariate analysis showed that sensitivity to first-line treatment, serum levels of NSE, and PS at relapse were independent prognostic factors after relapse. In conclusion, serum levels of ProGRP and NSE at relapse are not useful markers for detecting relapse earlier than are symptoms or radiographic findings. On the other hand, the serum level of NSE at relapse is a useful predictive marker for CR to salvage chemotherapy and a useful prognostic factor after relapse in patients with SCLC who have achieved a CR or PR to first-line chemotherapy.

Phase II study of S-1, a novel oral fluoropyrimidine, and biweekly administration of docetaxel for previously treated advanced non-small-cell lung cancer.

PURPOSE: We examined the safety and efficacy of the combination of S-1 and biweekly docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with previously treated advanced NSCLC were eligible if they had a performance status of 2 or less, were 80 years or younger, and had adequate organ function. Forty-nine patients (38 men and 11 women; median age, 66 years; range 43-79 years) were enrolled. Patients were treated with the combination of 80 mg/m(2) per day of S-1 for 14 consecutive days and 35 mg/m(2) of docetaxel on days 1 and 15 every 4 weeks. RESULTS: The overall response rate was 16.3% (95% confidence interval, 7.6-30.5%). The disease-control rate was 49.0% (95% confidence interval, 34.4-63.7%). The median survival time after this treatment was 9 months (range 1-22 months). The median progression-free survival time was 3 months (range 1-11 months). Response rates and survival times did not differ significantly according to the histological type. Grade 3-5 toxicities included neutropenia in 51.0% of patients, thrombocytopenia in 2.0%, anemia in 20.4%, infection in 24.5%, anorexia in 12.2%, diarrhea in 14.3%, nausea in 6.1%, and dehydration in 4.2%. There was 1 treatment-related death due to severe anorexia, stomatitis, diarrhea, and, as consequence, dehydration. CONCLUSIONS: The combination of S-1 and biweekly docetaxel is an acceptable therapeutic option in patients with previously treated advanced NSCLC regardless of the histological type.

Myelosuppression induced by concurrent chemoradiotherapy as a prognostic factor for patients with locally advanced non-small cell lung cancer.

The aim of the present study was to assess whether myelosuppression during concurrent chemoradiotherapy is a prognostic factor for patients with locally advanced non­small cell lung cancer (NSCLC). We retrospectively analyzed 86 patients with NSCLC who received concurrent platinum-based chemoradiotherapy. Patients were classified into two groups (grades 0-2 and 3-4) according to the most severe neutropenia, anemia or thrombocytopenia observed during concurrent chemoradiotherapy, and survival time and progression-free survival (PFS) time were analyzed. Univariate analysis revealed that overall survival time was significantly longer in patients with grade 0-2 anemia than in those with grade 3-4 anemia (p=0.02). Survival time did not differ significantly on the basis of the severity of neutropenia or thrombocytopenia. Although pre-treatment white blood cell count was a further prognostic factor in univariate analysis, multivariate analysis revealed that the only independent prognostic factor for overall survival time was anemia. Disease stage was an independent prognostic factor for PFS (p=0.04), whereas neutropenia, anemia and thrombocytopenia were not. In conclusion, the severity of anemia during concurrent chemoradiotherapy may be a useful prognostic factor in patients with locally advanced NSCLC.

Trial spinal cord stimulator reimplantation following lead breakage after third birth.

BACKGROUND: Many studies have reported lead migration and breakage as complications of epidural spinal cord stimulation. In cases where rapid changes in physique such as those caused by pregnancy are expected, it is unclear whether extra consideration regarding possible adjustments and care to avoid complications such as lead breakage are required. OBJECTIVE: This article presents a case in which spinal cord stimulation was used to manage these complications in a woman during the perinatal period. DESIGN: Case report. SETTING: Pain management clinic. METHODS: The patient was a 36-year-old female, approximate weight of 100 pounds, and 5-foot 1 inch in height, whose chief complaint was lower back and bilateral leg pain. The pain could not be alleviated by conservative therapies such as nerve blockade, oral medications with non-steroidal anti-inflammatory drugs, antidepressants, anticonvulsants or physical therapy. A spinal cord stimulator was implanted at another facility, which relieved the pain. The patient subsequently had 2 vaginal births without any problems relating to the stimulation sites, and both infants were healthy. She experienced lead breakage after the third vaginal birth that led to the subsequent reimplantation procedure. RESULTS: The patient had 2 subsequent vaginal births following the initial implantation with no problems related to the stimulation sites, and both infants were healthy. At age 34, following her third vaginal birth, the stimulator became ineffective and was removed. The withdrawn lead wire was found to be broken in 2 places. LIMITATIONS: A case report. CONCLUSION: Pregnancy following implantation of a spinal cord stimulator might result in lead breakage as abdominal girth increases. The present case exemplifies how pregnancy following implantation of a spinal cord stimulator might cause lead breakage as abdominal girth increases. Extra care is required to prevent lead breakage when anchors are fixed.