Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study.

The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42-75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1-6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1-98.3%), with a CR rate of 86.5% (95% CI 71.2-95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3-83.3%) and 88.9% (95% CI 73.1-95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.

Serum ferritin level is a prognostic marker in patients with peripheral T-cell lymphoma.

INTRODUCTION: The prognostic value of serum ferritin level in patients with peripheral T-cell lymphoma (PTCL) remains unknown. METHODS: We retrospectively analyzed clinical data from 78 consecutive patients with newly diagnosed PTCL that were treated with anthracycline-containing regimens between 1998 and 2011. RESULTS: The patients consisted of 50 males and 28 females with a median age of 64 years (range, 16-83 years). The subtypes of PTCL were 39 PTCL, not otherwise specified and 39 angioimmunoblastic T-cell lymphoma (AITL). The median observation period for the surviving patients was 50 months. The overall survival (OS) was poorer in patients with serum ferritin level above the upper normal limit (n = 28), compared with patients with serum ferritin level within normal range (n = 50; 4-year OS: 23% vs. 72%; P < 0.001). In the multivariate analysis, poor performance status (P = 0.006) and elevated serum ferritin level (P = 0.018) were independent risk factors for poor OS. CONCLUSION: Serum ferritin level is a useful prognostic marker for PTCL.

Fasciitis and myositis: an analysis of muscle-related complications caused by chronic GVHD after allo-SCT.

The muscle-related complications of fasciitis and myositis, caused by chronic GVHD after Allo-SCT are relatively rare, but at times will severely impair a patient's quality of life (QOL). We performed a retrospective analysis in Japanese Allo-SCT recipients to identify the incidence, risk factors and clinical features of fasciitis and myositis. In 1967 patients who underwent Allo-SCT between January 1994 and March 2005 and survived beyond 90 days post transplantation, eight patients developed fasciitis and nine patients developed myositis, with a 5-year cumulative incidence of 0.55% and 0.54%, respectively. The median time from SCT to the development of fasciitis and myositis was 991 and 660 days, respectively. PBSCT was a risk factor for developing fasciitis, but no risk factors were found for myositis. The response to immunosuppressive treatment was better in patients with myositis than fasciitis, and the overall survival after developing these symptoms was better in patients with myositis than those with fasciitis. An early diagnosis by a biopsy, which includes fascia and muscle or magnetic resonance imaging (MRI) and prompt treatment may be important to prevent an impairment of the patient's QOL with persistent disability.

Cytoplasmic and mitochondrial Ca levels in brown adipocytes.

AIM: We elucidated the mitochondrial functions of brown adipocytes in intracellular signalling, paying attention to mitochondrial activity and noradrenaline- and forskolin-induced Ca(2+) mobilizations in cold-acclimated rats. METHODS: A confocal laser-scanning microscope of brown adipocytes from warm- or cold-acclimated rats was employed using probes rhodamine 123 which is a mitochondria-specific cationic dye, and the cytoplasmic and mitochondrial Ca(2+) probes fluo-3 and rhod-2. X-ray microanalysis was also studied. RESULTS: The signal of rhodamine 123 in the cells was decreased by antimycin A which effect was less in cold-acclimated cells than warm-acclimated cells. Cytoplasmic and mitochondrial Ca(2+) in cold-acclimated brown adipocytes double-loaded with fluo-3 and rhod-2 were measured. Noradrenaline induced the rise in cytoplasmic Ca(2+) ([Ca(2+)](cyto)) followed by mitochondrial Ca(2+) ([Ca(2+)](mito)), the effect being transformed into an increase in [Ca(2+)](cyto) whereas a decrease in [Ca(2+)](mito) by antimycin A or carbonyl cyanide m-chlorophenylhydrazone (CCCP). Antimycin A induced small Ca(2+) release from mitochondria. CCCP induced Ca(2+) release from mitochondria only after the cells were stimulated with noradrenaline. Further, forskolin also elicited an elevation in [Ca(2+)](cyto) followed by [Ca(2+)](mito) in the cells. The Ca measured by X-ray microanalysis was higher both in the cytoplasm and mitochondria whereas K was higher in the mitochondria of cold-acclimated cells in comparison to warm-acclimated cells. CONCLUSIONS: These results suggest that noradrenaline and forskolin evoked an elevation in [Ca(2+)](cyto) followed by [Ca(2+)](mito), in which H(+) gradient across the inner membrane is responsible for the accumulation of calcium on mitochondria. Moreover, cAMP also plays a role in intracellular and mitochondrial Ca(2+) signalling in cold-acclimated brown adipocytes.

The relationship between salivary secretion rate and masticatory efficiency.

In order to elucidate the relationship between the salivary secretion rate and masticatory efficiency, experimental hypo- and hyper-salivation were produced by the administration of atropine sulphate presenting an anticholinergic effect and pilocarpine hydrochloride having a muscarine effect orally in 10 healthy fully dentates. To confirm the pharmaceutical effect of these drugs, the unstimulated whole salivary secretion rate during 10 min, and masticatory efficiency using the sieve method were measured before and after medication. The unstimulated whole salivary secretion rate during 10 min decreased significantly by the administration of atropine sulphate (P < 0.05), and increased significantly by pilocarpine hydrochloride (P < 0.01). The masticatory efficiency after atropine sulphate medication was significantly lower than that before (P < 0.01). The increase in salivary secretion by pilocarpine hydrochloride did not lead to a higher masticatory efficiency. The evidence supports the understanding that saliva plays an important role in masticatory function.

CSF hypocretin measures in patients with obstructive sleep apnea.

The majority of patients with narcolepsy-cataplexy were reported to have very low cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels. The hypocretin-1 levels of secondary excessive daytime sleepiness (EDS) disorders are not known. In this study, we found that CSF hypocretin levels in the patients with obstructive sleep apnea syndrome were within the control range. The low hypocretin levels seem to reflect only the presence of cataplexy and DR2 positive in narcoleptics but not EDS itself.

Are high barometric pressure, low humidity and diurnal change of temperature related to the onset of asthmatic symptoms?

BACKGROUND: Meteorologic factors play a role in the expression of asthmatic symptoms; however, there are controversies about the causal relationship between meteorologic factors and asthma. The relationship between meteorologic parameters and emergency admissions for asthmatic symptoms in this hospital were analyzed. METHODS: A total of 205 patients (130 boys and 75 girls, 0.1-16.6 years of age) who were admitted to Hakodate Chuo General Hospital for asthmatic symptoms between 1 January and 31 December 1997 were submitted to our study. We divided a total of 365 days into two groups of days with and without any admissions. Meteorologic factors for the days with admissions and 1-3 days before hospitalization were compared with those of the days of no admissions. Statistical analysis was done with the Mann-Whitney U-test. RESULTS: On the days with admissions and 1 day before hospitalizations, barometric pressure was higher and relative humidity lower than on days with no admissions. The diurnal difference between maximum and minimum temperature for days 1 day before days with admissions was larger than that for 1 day before days with no admissions. CONCLUSIONS: It is thought that change in barometric pressure, relative humidity and temperature had some influence on the worsening of asthmatic symptoms.

Recognition of target DNA and transcription activation by the CO-sensing transcriptional activator CooA.

CooA from Rhodospirillum rubrum is a heme-based CO-sensing transcriptional activator, in which CO acts as a physiological effector. In this study, we examined the mechanism of site-specific recognition and transcriptional activation by CooA by elucidating the transcriptional activator activity of the mutant CooA proteins and the chimeric proteins derived from CRP and CooA and the promoter activity of the mutant promoters. Site-directed mutagenesis has revealed that Arg(177), Gln(178), and Ser(181) on the recognition helix of the helix-turn-helix motif in CooA are responsible for the site-specific recognition. The side chains of these amino acid residues at positions 177, 178, and 181 are believed to be hydrogen bonding to the G:A, T:A, and C:G pairs at positions 2/15, 3/14, and 4/13 in the CooA-dependent promoters to recognize the DNA site for CooA. The properties of the CRP/CooA chimeric proteins constructed in this work suggest that CooA activates transcription by a similar mechanism to that of CRP at Class II CRP-dependent promoters.

Single transduction in the transcriptional activator CooA containing a heme-based CO sensor: isolation of a dominant positive mutant which is active as the transcriptional activator even in the absence of CO.

We constructed an in vivo reporter system to measure the activity of CooA as the transcriptional activator and showed that the recombinant CooA was active as the transcriptional activator in the presence of CO even in E. coli cells. A dominant positive mutant of CooA, in which Met131 was replaced by Leu, was isolated by a random mutagenesis with this reporter system. The electronic absorption spectra of M131L mutant were identical to those of wild type CooA in oxidized (Fe3+), reduced (Fe2+), and CO-bound (CO-Fe2+) state, indicating that the coordination structure and environment of the heme were not changed by this mutation. Methionine at position 131 was the carboxyl-terminal end of the heme-binding domain of CooA, which would be adjacent to the hinge region connecting the heme-binding domain and the DNA-binding domain.

[A case of pulmonary blastoma composed of histological features of both pulmonary blastoma and pulmonary endodermal tumor resembling fetal lung].

A case of pulmonary blastoma in a 71-year-old male was reported. Chest X-ray and CT scan showed a well demarcated mass lesion in the apical segment of the right lung. A polypoid tumor was detected in the apical branch of the right bronchus by bronchoscopy. The biopsy confirmed the diagnosis of pulmonary blastoma. The patient underwent a right upper lobectomy with lymph nodes dissection on Jan. 26, 1990. The resected tumor was really composed of two parts: a main tumor in the lung parenchyma and polypoid one protruding into the bronchus from the main tumor. The polypoid tumor exhibited typical features of pulmonary blastoma with both carcinomatous and sarcomatous components. The histology of the main tumor was identical to pulmonary endodermal tumor resembling fetal lung (PET). The metastases in the excised lymph nodes consisted entirely of carcinomatous elements. The patient died of brain stem metastasis a year after his operation. The present case, with typical pulmonary blastoma and PET present in the same tumor, supports the idea that pulmonary blastoma and PET belong to the same group neoplasma.

Biocompatibility of a heparin-bonded membrane oxygenator (Carmeda MAXIMA) during the first 90 minutes of cardiopulmonary bypass: clinical comparison with the conventional system.

We clinically compared a heparin-bonded Carmeda MAXIMA membrane oxygenator to a nonheparin-bonded MAXIMA in 20 patients undergoing coronary artery bypass grafting or valve replacement. Reductions of fibrinogen, factor XII, and high molecular weight kininogen were greater in the MAXIMA group. Serum C3a and free hemoglobin were lower in the Carmeda group. The level of C4a, though remarkably lower than that of C3a, was higher in the Carmeda group then in the MAXIMA group. Both oxygenators performed well in terms of blood gas exchange. We conclude that the heparin-bonded Carmeda oxygenator offers superior biocompatibility during cardiopulmonary bypass.

Polymannosylation to asparagine-19 in hen egg white lysozyme in yeast.

Complementary DNA encoding hen egg white lysozyme (HEWL) was subjected to site-directed mutagenesis to have the N-glycosylation signal sequence (Asn19-Tyr20-Thr21) by substituting Arg with Thr at position 21. The mutant lysozyme (R21T) was expressed in Saccharomyces cerevisiae carrying the yeast expression plasmid inserting the mutant HEWL cDNA. The mutant lysozyme was expressed in the glycosylated forms which are mainly a polymannosyl form with a small amount of oligomannosyl form. The polymannosyl lysozyme was susceptible to Endo H cleavage of the carbohydrate chain. The length of the polymannose chain was predicted to be approximately 340 residues/mol of lysozyme from carbohydrate analysis. According to the estimation with low-angle laser light scattering combined with HPLC, the average molecular weight of polymannosyl lysozyme was 75 kDa, which is consistent with the value obtained from the carbohydrate analysis. The size of polymannosyl lysozyme R21T is similar or somewhat larger than that of G49N reported previously. Thus, it was confirmed that the unusually large polymannose chain was attached to heterologous mutant lysozyme, regardless of the N-linked position, in yeast.