Epstein-Barr virus-associated enteropathy as a complication of infectious mononucleosis mimicking peripheral T-cell lymphoma.

A 32-year-old man presented with a fever. A laboratory examination detected atypical lymphocytes and liver enzyme elevation. The serological tests for Epstein-Barr virus (EBV) were consistent with an acute infection pattern. Computed tomograpy showed bowel wall thickening, and colonoscopy revealed numerous ulcerations. The histological findings from the biopsy specimens from the colon were consistent with peripheral T-cell lymphoma (PTCL), and in situ hybridization detected EBER-1 in the atypical lymphocytes. Because his clinical and endoscopic abnormalities improved without medication, we diagnosed the patient with EBV-associated enteropathy. We herein report a rare case of EBV-associated enteropathy that required careful differentiation from PTCL.

Phase I study of ofatumumab, a human anti-CD20 antibody, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.

OBJECTIVES: Ofatumumab is a human IgG1κ monoclonal antibody that targets a membrane proximal epitope encompassing the small and large loops of CD20. This Phase I study evaluated the safety, tolerability, efficacy and pharmacokinetics of ofatumumab monotherapy in Japanese patients with relapsed/refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma. METHODS: Ofatumumab was administered intravenously weekly for a total of eight doses (dose escalation: 500 and 1000 mg). Six patients (two chronic lymphocytic leukemia and four small lymphocytic lymphoma) were enrolled into two dose cohorts (500 mg, three patients; 1000 mg, three patients). All six patients received 300 mg ofatumumab at the first infusion and either 500 or 1000 mg at seven subsequent weekly infusions. RESULTS: No dose-limiting toxicities or serious adverse events were observed. Grade 3-4 adverse events observed were grade 3 lymphocytopenia (n = 1) and neutropenia (n = 1). Grade 1-2 infusion-related adverse events leading to temporary interruption of ofatumumab infusion were observed in all six patients on the first infusion day, and all patients completed the planned eight infusions. The overall response rate was 50% (3/6). CONCLUSIONS: Ofatumumab was well tolerated at doses up to 1000 mg and showed preliminary evidence of activity in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, warranting further investigations.

Diagnosis and evaluation of intestinal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation following reduced-intensity and myeloablative conditioning regimens.

Colonoscopic evaluation of mucosal tissues after allogeneic hematopoietic stem cell transplantation (HSCT) is very useful in evaluating pathogenesis and diagnosis of intestinal graft-versus-host disease (GVHD). However, information on the timing and sites of biopsies and the immunohistological evaluation of mucosal tissues for diagnosing intestinal GVHD, especially following reduced-intensity (RIC) regimens, remains very limited. A total of 33 patients with histologically proven GVHD after allogeneic HSCT with RIC (n = 23) and myeloablative conditioning (MAC, n = 10) regimens were enrolled in the present study. Colonoscopy was performed due to gastrointestinal symptoms, especially diarrhea and anorexia. Sites of biopsies with the worst histopathological grading were the terminal ileum in 67 % of patients. In the RIC group, the onset of diarrhea prior to colonoscopy examination was later (median: RIC, 57 vs. MAC, 27 days) and the number of patients who developed abdominal pain tended to be higher (RIC, 70 % vs. MAC, 30 %). A lower number of CD4+ cells and a higher ratio of Foxp3+ cells to CD4+ cells were detected in the involved lesions of intestinal GVHD following RIC. These differences in the RIC and MAC groups suggest that regimen-specific therapeutic strategies are required for diagnosing intestinal GVHD.

Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

As CD20 has become an established target for treating B-cell malignancies, there is interest in developing anti-CD20 antibodies with different functional activity from rituximab that might translate into improved efficacy. Obinutuzumab (GA101) is a glycoengineered, humanized type II anti-CD20 monoclonal antibody that has demonstrated superior activity to type I antibodies in preclinical studies and is currently being investigated in phase III trials. In this phase I dose-escalating study in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the primary endpoint was to characterize the safety of GA101; secondary endpoints were efficacy, pharmacokinetics and pharmacodynamics. Patients received up to nine doses of GA101 with up to 52 weeks' follow up. Most adverse events were grade 1 or 2 infusion-related reactions, and 10 grade 3/4 adverse events occurred. No dose-limiting toxicities were observed and the maximum tolerated dose was not identified. Out of 12 patients, 7 responded (end-of-treatment response rate 58%), with 2 complete responses and 5 partial responses. Responses were observed from low to high doses, and no dose-efficacy relationship was observed. B-cell depletion occurred in all patients after the first infusion and was maintained for the duration of treatment. Serum levels of GA101 increased in a dose-dependent fashion, although there was inter-patient variability. This phase I study demonstrated that GA101 has an acceptable safety profile and offers encouraging activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Bulky disease has an impact on outcomes in primary diffuse large B-cell lymphoma of the breast: a retrospective analysis at a single institution.

OBJECTIVES: Primary breast lymphoma (PBL) is rare, and its clinical behavior and standard initial treatment are not yet established. METHODS: We retrospectively analyzed the clinicopathological features and treatment outcomes of 14 patients with primary breast diffuse large B-cell lymphoma. RESULTS: There were nine patients with stage IE and five with stage IIE disease. The median largest tumor diameter was 4.5 cm, and five patients had bulky disease >5 cm. The complete response rate was 94%. However, the 5-year progression-free survival rate was 52% with a median follow-up of 5.2 years. Patients with bulky disease had an unfavorable prognosis. All five patients with bulky disease progressed or relapsed. Of the four patients that recurred in the central nervous system (CNS), three had bulky disease although some received rituximab. There were no CNS recurrences in the three patients who received CNS prophylaxis. All eight patients who responded to radiotherapy (RT) did not have recurrences in the ipsilateral breast, although one patient with bulky disease relapsed in the adjacent regional lymph nodes within the RT field despite immunochemotherapy. CONCLUSIONS: Patients with bulky disease had a poorer prognosis and recurred frequently in the CNS. CNS prophylaxis might yield better outcomes, but a larger, prospective trial is needed to elucidate the optimal initial treatment of PBL in the rituximab era.

Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma.

Patients with follicular lymphoma (FL), where position 158 of FcγR-IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F-carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F-carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody-dependent cell-mediated cytotoxicity. This dose-escalation, phase I study was conducted to assess the safety, pharmacokinetics and preliminary efficacy of LY2469298 in Japanese patients with previously treated, CD20-positive FL who had not relapsed or progressed within 120 days of prior rituximab. LY2469298 was administered by intravenous infusion at 100 or 375 mg/m(2) weekly for 4 weeks. Ten patients were enrolled (median age, 60 years); all had previously been treated with rituximab. Nine patients were F-carriers while one was homozygous for valine at position 158 of FcγRIIIa. No patients developed dose-limiting toxicities, and the most frequent adverse events were lymphopenia, pyrexia, leukopenia, chills and neutropenia. Five (50%) of the ten patients responded to LY2469298 treatment (three complete responses, one unconfirmed complete response and one partial response). Serum LY2469298 was eliminated in a biphasic manner and the pharmacokinetic profiles were not different from those in a preceding study in the United States. In conclusion, LY2469298 was well tolerated and clinical activity was observed in FL patients pretreated with rituximab, mostly consisting of F-carriers. Further investigation of FL is warranted.

Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL.

The feasibility and efficacy of cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL (intermediate DLBCL/BL) have never been reported. The effects of adding rituximab to CODOX-M/IVAC have not been published either. Fifteen consecutive patients with a median age of 39 years were treated with modified CODOX-M/IVAC regimen (particularly, reducing the dose of methotrexate to 3 g/m(2)) with or without rituximab at our institution. Although all patients developed grade 4 neutropenia and grade 3/4 thrombocytopenia/anemia, 93% had febrile neutropenia, 60% showed transaminase elevation, and 40% had mucositis/stomatitis (all grade 3), there were no treatment-related deaths. Two of nine patients treated with rituximab developed biphasic late-onset neutropenia. Thirteen patients (87%) showed complete responses. The remaining two patients had refractory disease; one had presented with peritoneal dissemination and complex chromosomal abnormalities, while the other had double IGH-MYC and IGH-BCL2 translocations. The estimated 5-year overall and progression-free survival were 87% each, with a median follow-up of 74 months. In conclusion, our modified CODOX-M/IVAC regimen is well tolerated and highly effective in Japanese adult patients with BL and intermediate DLBCL/BL, warranting a larger study for confirmation.

Pneumocystis jiroveci pneumonia in relation to CD4+ lymphocyte count in patients with B-cell non-Hodgkin lymphoma treated with chemotherapy.

An increasing incidence of Pneumocystis jiroveci pneumonia (PCP) in patients with B-cell non-Hodgkin lymphoma (B-NHL) receiving rituximab treatment has been reported. We reviewed patients with B-NHL who underwent chemotherapy from 2004 to 2008 at our institution to identify risk factors for PCP development during and after chemotherapy. Among 297 patients with B-NHL, six developed PCP. Of 121 patients (41%) who received PCP prophylaxis with sulfamethoxazole­trimethoprim during chemotherapy, none developed PCP (0%), while among 176 patients (59%) who had no prophylaxis, six (3.4%) developed PCP at a median of 2 months (range: 1­3 months) after starting chemotherapy. Patients with CD4+ lymphocyte counts ≤200/mm3 before chemotherapy had a higher risk of developing PCP (p=0.045), while a history of rituximab treatment was not related to PCP. CD4+ lymphocyte counts ≤200/mm3 during and after chemotherapy were observed in 18.9% of patients.

Phase I study of inotuzumab ozogamicin (CMC-544) in Japanese patients with follicular lymphoma pretreated with rituximab-based therapy.

Inotuzumab ozogamicin (CMC-544), an antibody-targeted chemotherapeutic agent composed of an anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic antibiotic, specifically targets the CD22 antigen present in >90% of B-lymphoid malignancies, rendering it useful for treating patients with B-cell non-Hodgkin lymphoma (B-NHL). This phase I study evaluated the safety, tolerability, efficacy, and pharmacokinetics of inotuzumab ozogamicin in Japanese patients. Eligible patients had relapsed or refractory CD22-positive B-NHL without major organ dysfunction. Inotuzumab ozogamicin was administered intravenously once every 28 days (dose escalation: 1.3 and 1.8 mg/m(2)). All 13 patients had follicular lymphoma, were previously treated with > or =1 rituximab-alone or rituximab-containing chemotherapy, and were enrolled into two dose cohorts (1.3 mg/m(2), three patients; 1.8 mg/m(2), 10 patients). No patient had dose-limiting toxicities, and the maximum tolerated dose, previously determined in non-Japanese patients (1.8 mg/m(2)), was confirmed. Drug-related adverse events (AEs) included thrombocytopenia (100%), leukopenia (92%), lymphopenia (85%), neutropenia (85%), elevated AST (85%), anorexia (85%), and nausea (77%). Grade 3/4 drug-related AEs in > or =15% patients were thrombocytopenia (54%), lymphopenia (31%), neutropenia (31%), and leukopenia (15%). The AUC and C(max) of inotuzumab ozogamicin increased dose-dependently with pharmacokinetic profiles similar to non-Japanese. Seven patients had complete response (CR, 54%) including unconfirmed CR, four patients had partial response (31%), and two patients had stable disease (15%). The overall response rate was 85% (11/13). Inotuzumab ozogamicin was well tolerated at doses up to 1.8 mg/m(2) and showed preliminary evidence of activity in relapsed or refractory follicular lymphoma pretreated with rituximab-containing therapy, warranting further investigations. This trial was registered in ClinicalTrials.gov (NCT00717925).

[A case of portal-systemic shunt-through inferior mesenteric vein and right internal iliac vein-encephalopathy cured by balloon-occluded retrograde transvenous obliteration].

We encountered a case of portal-systemic shunt encephalopathy cured by balloon-occluded retrograde transvenous obliteration (B-RTO). A 73-year-old man had been observed for membranous nephropathy at our hospital since 1987. There was no past history of liver dysfunction. He was admitted with encephalopathy. Abdominal enhanced computed tomography showed a portosystemic shunt through the inferior mesenteric vein and right internal iliac vein. We diagnosed hepatic encephalopathy due to this porto-systemic shunt, and B-RTO was performed. After B-RTO, he has not had repeated encephalopathy. B-RTO can be effective for portosystemic encephalopathy. Inferior mesenteric-right internal iliac shunt encephalopathy is rare and our patient is the first case of B-RTO performed in cases with this shunt.

[Assessment of anesthesiologist's stress of working overnight using profile of mood states].

BACKGROUND: In recent years, workload for a doctor has been increasing, because hospital managers are trying to improve the efficiency of management. As a result, many doctors are expected to work harder. We studied how anesthesiologists are stressed by their work, especially on working overnight, using the Profile of Mood States(POMS). METHODS: Thirty six anesthesiologists working in our hospital are studied. We asked them to answer POMS questionnaires three times at 8:00 before overnight work, 8:00 and 17:00 the following day. RESULTS: Mean working time for overnight job is 32 +/- 4.3 hours and mean sleeping time is 3.0 +/- 1.3 hours (mean +/- SD). The Profile of Mood States has six subscores (depression, fatigue, vigor, confusion, tension/anxiety, and anger). After working overnight, fatigue and confusion scores were significantly increased and vigor scores were significantly decreased, compared with the sores at 8.00 before overnight work. CONCLUSIONS: We studied anesthesiologist's stress of working overnight, using the Profile of Mood States. As a result, after overnight work, fatigue, confusion and vigor scores were significantly exacerbated. We speculate that the anesthesiologists are building up so much stress when they work overnight as on call.

[Airway access using an endotracheal tube changer for safe extubation in an infant with a difficult airway].

We present a case where airway access was maintained using an endotracheal tube changer (ETC) after extubation in an infant with a difficult airway. A 4-month-old male infant with bilateral cleft lip and palate, micrognathia, schizencephaly, undescended testis, and abnormality of chromosomes 10 was scheduled for bilateral cleft lip repair. After anesthesia induction with thiamylal and vecuronium, we found that laryngoscopy was difficult (Cormack and Lehane grade III) despite external laryngeal compression. Since there was no fiberoptic bronchoscopy for an infant in our department, and the fact that epiglottis could be visualized with external laryngeal compression, three anesthesiologists attempted tracheal intubation in turn and intubation was successful at last. The surgery was concluded uneventfully; but since endotracheal intubation had been difficult, special care was taken for extubation. We used an ETC for tracheal tube passing into the endotracheal tube at the time of extubation. Although using the ETC in infant with difficult airway for extubation remains controversial, we believe that for a difficult airway, even in an infant, a flexible ETC is a useful device for temporal airway access after extubation.

Olprinone decreases elevated concentrations of cytokine-induced neutrophil chemoattractant-1 in septic rats.

PURPOSE: The diaphragm is one of the organs directly affected by abdominal sepsis. Evidence suggests that sepsis induces diaphragmatic fatigability and that activated neutrophils play a crucial role in the development of diaphragmatic fatigability. In the present study, we investigated whether olprinone, a phosphodiesterase inhibitor, influenced the kinetics of cytokine-induced neutrophil chemoattractant-1 (CINC-1) in the diaphragm under abdominal septic conditions. METHODS: Male Wistar rats were randomly assigned to a sham group, a cecal ligation and perforation group, and a phosphodiesterase inhibitor-pretreated group. To measure serial changes in CINC-1 concentrations, the right hemidiaphragm was removed at 4, 8, and 16 h after the surgical procedure in each group. RESULT: In the cecal ligation and perforation group, CINC-1 concentrations in the diaphragm were significantly elevated compared with those in the sham group at both 4 and 8 h after the cecal ligation and perforation procedure. In the phosphodiesterase inhibitor-pretreated group, olprinone significantly attenuated the elevated CINC-1 concentrations at both 4 and 8 h after the surgical procedure. However, we observed no statistically significant differences in CINC-1 concentrations between the cecal ligation and perforation group and the phosphodiesterase inhibitor-pretreated groups at 16 h after the surgical procedure. CONCLUSION: Olprinone decreases elevated CINC-1 concentration in the diaphragm under septic conditions. This suggests that olprinone may inhibit neutrophil recruitment to the diaphragm.

[Issues on package inserts of percutaneous tracheostomy kits].

BACKGROUND: Percutaneous tracheostomy using a dedicated kit, which has been a common surgical procedure in intensive care settings, must be carefully performed with sufficient knowledge regarding both the technique and the kit. The aim of this study was to investigate the accuracy and adequacy of information contained in package inserts of kits, as the primary official documents for providing information on safe and sure performance of the procedure. METHODS: We investigated the contents of package inserts for three percutaneous tracheostomy kits available in Japan, and ascertained whether the distributors of the kits showed the contents on the Internet. RESULTS: Package inserts did not necessarily provide accurate and sufficient information in terms of generic names, warnings, contraindications, indication for use, instructions for use and/or handling, cautions or clinical records. Not all distributors followed the ordinance from the Pharmaceuticals and Medical Devices Agency to show this information to the public. CONCLUSIONS: The importance of package inserts in safety measures related to medical devices has been growing since the enforcement of the revised Pharmaceutical Affairs Law in 2005. The significance of package inserts must be emphasized, and distributors of kits need to be encouraged to improve inserts.

Measurements of binary diffusion coefficients, retention factors and partial molar volumes for myristoleic acid and its methyl ester in supercritical carbon dioxide.

The binary diffusion coefficients, D(12), and retention factors for myristoleic acid and its methyl ester at infinite dilution were measured by the chromatographic impulse response technique in supercritical carbon dioxide at temperatures of 313.2, 333.2 and 343.2 K and pressures from 9.2 to 30 MPa for the acid, and from 8.0 to 14 MPa for the ester. Although the D(12) values were represented by the two correlations, the D(12)/T vs. CO(2) viscosity and the Schmidt-number correlations, which are valid for more than 40 compounds that we have measured so far, significant temperature dependences were observed for the ester. Moreover, the D(12) values for the ester at 313.2 K downward deviated from the background values around 400 kg m(-3), where the partial molar volumes, obtained from the correlation between the retention factors measured and CO(2) densities, showed large negative values.

[Cricoarytenoid arthritis diagnosed after tracheostomy in a rheumatoid arthritis patient].

A 65-year-old woman was scheduled for total knee replacement. She had been suffering from rheumatoid arthritis for 22 years. She also had a history of occasional acute dyspnea, which had been diagnosed as asthmatic bronchitis. Preoperative examinations of the airway revealed limited neck flexion, a small jaw, and normal mouth opening. After epidural catheterization, anesthesia was induced with propofol, and a #3 laryngeal mask airway (LMA) was inserted. However, her lungs could not be ventilated through the LMA. Despite repeated attempts, proper placement of the LMA could not be achieved. Hence, a 7.0 mm ID armored endotracheal tube was inserted through an intubating LMA. Anesthesia was maintained with nitrous oxide and sevoflurane in oxygen. The surgery proceeded uneventfully. Five minutes after extubation, inspiratory dyspnea occurred. The patient's trachea was re-intubated nasally with a bronchofiberscope. Since the bronchofiberscopy revealed remarkable laryngeal edema, percutaneous tracheostomy was performed. On the 3 rd postoperative day, cricoarytenoid arthritis that had caused occasional airway obstruction was diagnosed, although her laryngeal edema disappeared. She went home with a permanent tracheostomy. Although cricoarytenoid arthritis is a common occurrence in patients with rheumatoid arthritis, the diagnosis can be difficult. A scrupulous preoperative evaluation and awareness of cricoarytenoid arthritis are necessary for optimal anesthetic management.

Effect of Ulinastatin, a human urinary trypsin inhibitor, on the oleic acid-induced acute lung injury in rats via the inhibition of activated leukocytes.

BACKGROUND: The acute respiratory distress syndrome (ARDS) is often caused by fat tissue embolism. One of the most common animal models of ARDS is produced by direct administration of oleic acid (OA). Activated leukocytes are critically involved in the pathological mechanism in this model. Human urinary trypsin inhibitor (UTI) is known to inhibit production of tumor necrosis factor (TNF)-alpha, which potently stimulates leukocyte activation. The purpose of this study was to clarify whether UTI improves OA-induced lung injury in rats by inhibiting activated leukocytes via TNF-alpha production. MATERIALS AND METHODS: Rats were subjected to a single intravenous administration of OA into the pedicle vein. Acute lung injury was evaluated by arterial blood gases and histological changes in lungs. Pulmonary vascular permeability, accumulation of neutrophils, and the levels of TNF-alpha in lung tissues were also examined. Rats were divided into four experimental groups: a sham operated, OA, OA + UTI, and OA + nitrogen mustard (NM)-induced leukocytopenia group. UTI was intravenously administered 30 min before OA administration. Leukocytopenia was induced by the administration of NM. RESULTS: UTI significantly improved the OA-induced histological changes for 4 h after OA administration. The OA-induced reduction of PaO2, the increase of pulmonary vascular permeability, and the levels of MPO activity and TNF-alpha in lung tissues were significantly improved in rats administrated UTI. The effects in the leukocytopenia group were similar to those in the UTI-administered group. CONCLUSION: Leukocytes play a critical role in the development of OA-induced lung injury. It was suggested that UTI contributed to the reduction in the OA-induced lung injury by inhibiting TNF-alpha and thereby suppressing leukocyte.