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Although the Sokal and Hasford scoring systems are well-known prognostic models specific to chronic myeloid leukemia (CML), whether they can effectively predict outcomes in elderly CML patients with comorbidities has not been fully elucidated. We evaluated the association between comorbidity at diagnosis with treatment outcome and survival in chronic phase CML patients. A questionnaire was administered to patients diagnosed with CML between 2001 and 2012 and treated with tyrosine kinase inhibitors (TKIs). The Charlson comorbidity index (CCI) was used to determine concomitant diseases. In total, 79 patients (33 females; median age, 57 years) were enrolled. CCI scores at diagnosis were between 2 and 11. At the last follow-up, 46 patients showed a major molecular response. Complete cytogenetic response was achieved in 73.4 % of the cases 12 months after TKI administration. We observed only five deaths during the 55.5-month median follow-up period. The risk categories (low/intermediate/high) associated with Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The 27 cases with a CCI score >3 had significantly poorer survival after diagnosis (52 cases had a CCI score <2). CCI scores were inversely associated to overall survival. Concomitant comorbidity at diagnosis is associated with poor outcome in CML patients treated with TKIs.

Fulminant hepatic failure (FHF) is a critical illness that can be comorbid to primary liver damage. FHF shows a high mortality rate, and patients with FHF require intensive therapy, including plasma apheresis. However, intensive care at the present is not enough to restore the severe liver damage or promote hepatocellular reproduction, and a standard therapy for the treatment of FHF has not been established. An 86-year-old female with FHF was admitted to our hospital. Her manifestation demonstrated a clinical situation of systemic inflammatory response syndrome (SIRS) and disseminated intravascular coagulation. A diagnosis of fulminant hepatitis was made according to the definition given in the position paper of the American Association for the Study of Liver Diseases. Her serum hepatocyte growth factor (HGF) level had increased to 11.84 ng/mL. The HGF level indicated massive liver damage as seen in FHF. Recombinant thrombomodulin (rTM) was administered daily from the admission day for 1 wk at 380 U/kg. The patient's white blood cells and C-reactive protein responded to the rTM treatment within a few days. The HGF level and PT recovered to the normal range. The levels of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) were suppressed by the administration of rTM. The patient's hepatic function (e.g., PT and albumin) completely recovered without plasma exchange. rTM may modulate the over-response of SIRS with the improvement of proinflammatory cytokines. The underlying mechanism is thought to be the inhibitory effect of rTM on high-mobility group box 1 (HMBG1). The pathogenesis of HMBG1 protein in fulminant hepatic failure has been already known. A novel favorable effect of rTM for SIRS would be promising for FHF, and the wide application of rTM for SIRS should be considered.

Background: Quality of life (QOL) measurement is a powerful instrument for assessing medical morbidity from the patient's perspective. We measured the QOL of patients undergoing autologous and allogeneic stem cell transplantation (SCT) in Japan to validate the FACT-BMT scale in comparison to SF-36., Methods: We performed a cross-sectional survey for transplant recipients receiving treatment at our outpatient clinic. Recipients undergoing autologous and allogeneic SCT between October 2002 and March 2006 were eligible. Participants completed both the Medical Outcomes Study 36-Item Short Form (SF-36) and a Functional Assessment of Cancer Therapy survey specific to bone marrow transplantation (FACT-BMT)., Results: Thirty-six patients were enlisted, including 24 post-autologous SCT patients and 12 post-allogeneic SCT patients. The median time required to answer all questions was 9 and 11 minutes for SF-36 and FACT-BMT surveys, respectively. Cronbach's a was over 0. 7 for all domains in both SF-36 and FACT-BMT. Inter-scale correlations between all domains except for BP in SF-36 and BMT in FACT-BMT had correlation coefficients greater than 0. 4. The internal consistencies of both surveys were confirmed in Japanese patients., Conclusions: Our study indicated the feasibility and partial validity of FACT-BMT in a one-time follow-up of QOL for Japanese patients after SCT.

It is important to diagnose infectious events in cancer patients during chemotherapy. Since many of them have complications of febrile neutropenia (FN), determining its cause is critical for their treatment course. We analyzed all febrile events (>38.0 degrees C, single axillary temperature) in hospitalized cancer patients treated at Shizuoka Cancer Center over a period of 8 months. Based on the clinical presentation at the onset, we estimated the cause of fever and classified it as infection, tumor fever, immunologic reaction or unknown. Clinical presentations found at the onset of FN were categorized into 4 groups: (1) oral mucositis, and (2) respiratory, (3) gastrointestinal and (4) cutaneous findings. We detected 85 febrile episodes (median age 58, range 26 approximately 86; 37 males and 48 females). Neutropenia was observed (500/mL) in 52. 9% (45/85) of the patients and clinical symptoms were detected in 74.1% (63/85). In eleven of 18 infection-proven cases, we successfully predicted the infection focus at the onset of fever. Multivariate analysis revealed that initial high fever, antimicrobial prophylaxis, cutaneous findings and severe neutropenia were important influencing factors in predicting infectious disease during FN. Physical examination can support the diagnosis of the cause of fever in FN patients.

It is important to correctly diagnose fungal bloodstream infection in cancer patients. Antifungal susceptibility testing (AST)supplies useful information for the management of invasive fungal infection. We analyzed fungi isolated from blood samples in Shizuoka Cancer Center over a period of 6 years, and detected 59 strains including yeast(57 isolates) and mold(Aspergillus fumigatus, Scedosporium sp). The clinical background was reviewed using the medical record. The major fungi isolated from blood were Candida albicans(39.0%), followed by C. glabrata(22.0%), C. parapsilosis (20.3%), and C. tropicalis(13.6%). AST was carried out for 32 strains out of 59, according to the National Committee of Clinical Laboratory Standards (NCCLS)M-27-A-2 method. Among 32 strains, 7 isolates were resistant to fluconazole and 8 to itraconazole. Through the research period, the distribution of MIC values for azole agents did not change widely; however, the values for micafungin increased between the former and latter periods. In order to estimate the efficacy of antifungal agents, it is thought that continuous monitoring and the establishment of a standard method to evaluate the sensitivity of antifungal drugs are necessary.

The adequate dose of imatinib has not been defined for the Japanese population. Indeed, about half of patients experience mild to moderate adverse events due to this drug, some of which result in intolerance. We reviewed a patients' cohort treated with imatinib in our hospital in 2007 for chronic myelogeneous leukemia (CML). The cohort included 14 patients (5 men and 9 women) whose median age was 53 (range 16-81). The disease status at onset was chronic phase in 13 patients and accelerated phase in 1. During the 2-year observation period, 2 patients (14%) failed to respond and 6 (42%) became intolerant to imatinib. After the appearance of the intolerance, 5 of the 6 patients were treated with a reduced dose of imatinib (300 mg/day in 4, 200 mg/day in 1). In 4 of these 6 intolerant cases, CR was maintained 2 years after the start of imatinib therapy. Nevertheless, 42% of patients were intolerant to imatinib therapy through 2 years, and progression-free survival was 86%. In conclusion, an adjusted dose exerting minimal toxicity and showing a favorable outcome should be researched in Japanese patients including the elderly.

We present a 22-year-old male diagnosed with pro T-acute lymphoblastic leukemia (ALL). His laboratory test showed 181,900/microL of WBC complicated with lymphoadenopathy, pleural effusion, pericardial effusion and hepatosplenomegaly at the onset. Flow cytometry analysis of the leukemic cells showed cCD3+, CD7+, CD2+, CD1a-, CD3-, CD5-, CD4-, CD8-, CD34+, and HLA-DR+ as a pro T-cell phenotype. The patient was treated with induction therapy followed by 3 courses of consolidation therapy and achieved his first complete remission. He underwent up-front stem cell transplantation (SCT) from an HLA-full matched sibling, with early relapse just before transplantation. The conditioning regimen consisted of fludarabine (100 mg/m2) and melphalan (180 mg/m2). He relapsed with an extramedullary mass (gingival, testis, and femoral muscles) 1 year after transplantation. Since bone marrow involvement was not apparent, he received involved field radiation therapy (25.2 Gy/14 frequencies) in each mass. Six months after extramedullary relapse, bone marrow relapse occurred, and the patient died of sepsis due to Pseudomonas aeruginosa during re-induction therapies. Based on the immature T cell phenotype frequently with myeloid markers, a graft-versus- leukemic effect might be expected after allogeneic SCT for Pro T-ALL and a positive indication of SCT for this disease should be considered.

Bortezomib, a proteasome inhibitor, has been used for patients with refractory multiple myeloma. We present a 58-year old man who had IgG-gamma-type multiple myeloma, refractory for MP (melphalan-predonisolone) and VAD (vincrisitine-doxorubicin-dexamethasone) therapy. He was complicated with reactivation of varicella-zoster virus (VZV) 4 weeks before bortezomib administration. Two weeks of consolidation treatment with standard dose valaciclovir caused VZV infection to settle down and, after a further 2 weeks, VZV remission was confirmed. Bortezomib was started at a dose of 1.3 mg/m2 with prophylactic use of valaciclovir for VZV reactivation, post-herpetic neuralgia exacerbated the following day and grade 3 neuralgia developed the following week without recurrence of skin eruption. Neuralgia improved after the cessation of bortezomib with various supportive treatments and interventions. Although the reactivation of VZV was suspicious, no apparent skin lesions were observed. Although the mechanisms of post-herpetic neuralgia and chemotherapy-induced neuropathy are different, bortezomib might enhance post-herpetic neuralgia independent of the manner of viral reactivation.

The standard treatment for refractory oral chronic graft versus host disease (GVHD) has not been established. We present a case of AML accompanied by oral chronic GVHD in a 55-year-old man after allogeneic stem cell transplantation. The stomatitis of the patient was prolonged for a year and resistant to standard immunosuppressant therapy, including systemic administration of prednisolone and tacrolimus; however, local injection of 0.2% dexamethasone (0.5 mg per cm2) into the ulcerative area was drastically effective in improving refractory mucositis and mitigated a vicious cycle of mucosal damage and poor oral hygiene.

Standard salvage chemotherapy for refractory or relapsed malignant lymphoma has not been defined. The efficacy and feasibility of the ACES regimen, consisting of carboplatin at 100 mg/m(2) on day 1 to 4, etoposide at 80 mg/m(2) on day 1 to 4, high-dose Ara-C at 2 g/m(2) on day 5 and methylprednisolone at 500 mg/day for 5 days, for refractory or relapsed lymphoma were retrospectively reviewed in comparison with the ESHAP regimen. The subjects were 29 patients, including 7 aggressive follicular lymphomas, 16 large B cell lymphomas and 6 Hodgkin lymphomas. Characteristics of patients with ESHAP (19 cases) and the ACES (10 cases) group were as follows: male/female ratio, 10/9 and 3/7; median age, 49 (range, 31-72) and 54 (22-65); and initial clinical stage (I and II / III / IV), 5/8/6 and 1/1/8, respectively. Among the 29 patients, complete response was achieved in 68% (13/19) in ESHAP and 40% (4/10) in ACES.Progression-free survival and overall survival were 31.3% and 34.3%, respectively. Hematological toxicity was not significantly different between the two groups, and renal toxicity was significantly higher in ESHAP (52%) than ACES (0%). We concluded that the ACES regimen had a possibility of effective consolidation therapy for the elderly aiming to undergo autologous stem cell transplantation.

Chemotherapy-susceptive multiple myeloma (MM) has an indication for high-dose melphalan (HDM) followed by autologous stem cell transplantation (auto-SCT). HDM was a most simple and convenient regimen among various preparatory regimens, because of rapid infusion divided over 2 days. In order to assess the potential of auto-SCT by HDM in a outpatient setting, we evaluated the toxicities of HDM compared with the ICE regimen generally applied to patients with refractory or relapsed lymphoma. We reviewed 27 cases of auto-SCT from April 2003 to December 2004. The preparatory regimen was HDM (melphalan 200 mg/m(2)) for 18 cases of multiple myeloma and ICE therapy (ifosfamide 12 g/m (2), carboplatin 1,200 mg/m(2), etoposide 800 mg/m2) for 9 malignant lymphomas. Gastrointestinal (GI) adverse events for a patient per hospital day were 0.93 for myeloma and 0.95 for lymphoma (no significant differences), with GI toxicity of more than grade 3, 0.08 and 0.12, respectively (p=0.07). Hematological toxicity was not significantly different between the 2 therapies. The clinical toxicity of HDM was milder compared to ICE, especially regarding the speculated GI-associated nutritional disorders. We thus concluded that outpatient auto-SCT could be validated first in myeloma patients treated by HDM with careful supportive treatments, thereby avoiding regimen-related severe adverse events.

We developed a nutritional pathway for autologous stem cell transplantation (SCT) to be applied in our transplantation unit. We performed autologous SCT for 37 patients with malignant lymphoma and multiple myeloma during from April 2003 to July 2005. For 10 of them who underwent SCT since 2005,we intervened with nutritional support using our original nutritional pathway,to monitor the clinical course of SCT from the aspect of dietetics with a dietician making assessments of the individual nutrition status. From comparing the 2 groups with (n=27) or without (n=10) the nutritional pathway, oral intake at day 14 was significantly increased from 1,038 kcal to 1,440 kcal,and at discharge developed from 1,167 kcal to 1,446 kcal without statistical significance. Patients whose body weight decreased more than 5% were reduced from 52%(14/27) to 10%(1/10),and 3 days reduction of the CVC insertion period was observed after the intervention. Although the long-term clinical outcome was not fully evaluated, the efficacy of nutritional pathway for autologous SCT was suggested.

Pseudomonas aeruginosa (P. aeruginosa) is a common nosocomial pathogen that often causes pneumonia, especially in immunocompromised patients including cancer bearing-hosts. In cancer patients who have great risk of gram-negative bacteria leading to fatal infection, P. aeruginosa bacteremia easily results in septicemia with shock and life-threatening complications such as vital organ failure. Among those complications, necrotizing pneumonia is an infectious disease of lung caused by P. aeruginosa characterized by rapid cavitation and progressive clinical course, which is fatal not only in cancer patients but also in healthy hosts. P.aeruginosa is one of the pathogens targeted for empirical therapy neutropenic patients. Three case series of necrotizing pneumonia were reviewed in this report. All three had hematological malignancies and were immunocompromised. One of the three cases,a 30-year-old man with malignant lymphoma, recovered from pneumothorax and pyothorax complicated with lung cavitation. The other two patients died with a short course; a 55-year-old man with chronic myelogeneous leukemia within 7 hours, and a 54-year-old man with malignant lymphoma within 2 days after the onset of pneumonia, respectively. In these 3 cases, there were no obvious associations between prognosis and neutrophil counts, duration of neutropenia and steroid administration.

Lesions of the central nervous system (CNS) in acute myeloid leukemia (AML) have a wide range of causes. Apart from infection, virus, fungus and bacteria have to be excluded. Other causes including involvement of leukemia, toxic encephalopathies induced by chemotherapy and radiation therapy, and vascular lesions must be diagnosed differentially for advanced treatment or follow-up. While ultimate diagnosis rests on the collection of cerebrospinal fluid, it is not enough for essential diagnosis. Imaging techniques such as head MRI are powerful tools for diagnosis of intracranial organic lesions, especially in this setting involving leukemia, progressive multifocal leukoencephalopathy (PML) by JC virus infection and treatment-related disseminated necrotizing leukoencephalopathy. A 50-year-old man with AML, who relapsed three times,progressed to an acute consciousness disturbance and was complicated with multiple CNS lesions. He presented with a vesicle formation on his skin, which was pathologically diagnosed as virus infection 1 week after CNS lesions appeared. He was considered to have systemic herpes infection. In this case, considered judgment with multiple approaches would be needed for diagnosis in some cases of AML with the CNS infiltration shadow.

Paraneoplastic pemphigus (PNP) is a rare autoimmune bullous disease associated with neoplasm, which is clinically characterized by mucocutaneous lesions resembling pemphigus vulgaris or erythema multiforme. A case presented with PNP refractory to chemotherapy including rituximab, predonisolone and cyclophosphamide (RCHOP regimen). A 36-year-old man, who had been diagnosed as extended follicular lymphoma, presented with a polymorphous skin eruption of the trunk, sclera conjunctivitis, and severe mucosal erosions of the lips and oral cavity. He was diagnosed as pemphigus pathologically by a biopsy of the oral mucosa. However, 3 courses of rituximab and CHOP therapy, which exert a partial response with lymphoma lesions, did not prove effective for oral stomatitis due to pemphigus. He received corticosteroid therapy (prednisolone 40 mg/day) and went into a state of temporally remission regarding pemphigus. However, the mucosal lesions were again exacerbated despite control of the lymphoma status after chemotherapy. Oral stomatitis extended to the upper respiratory system through the larynx and resulted in bronchiolitis obliterance clinically presented likely as severe chronic obstructive pulmonary disease (COPD). Because it is known that PNP refractory to long-term steroid and cytoreductive therapy has a progressive character and poor prognosis, supportive care would be warranted for these patients.

Background: Patients who exhibit gastrointestinal (GI) involvement due to graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) are often recommended to withhold oral intake (NPO) to avoid further damage to the GI mucosa. However, it is possible that continuing oral intake could be beneficial in many patients compared to total parenteral nutrition (TPN)., Objective: The primary objective of this prospective study was to evaluate whether programmed step-ladder oral dieting (enteral nutrition; EN) is feasible and beneficial for these patients., Methods: A total of 18 patients who exhibited GI-acute GVHD (stage I to III gut GVHD) after SCT received an EN dieting program, and changes in clinical and laboratory parameters were compared to those in a control cohort of 17 patients who were placed on NPO with TPN. Patients with GVHD were included prospectively and those with intestinal bleeding/obstruction, severe pancreatitis, and cytomegalovirus enterocolitis were excluded., Results: None of the patients in the EN group experienced significant adverse events, including exacerbation of GI symptoms. Although there was no statistically significant difference in the volume or frequency of diarrhea or the time to complete dietary recovery, parameters including body weight and serum levels of total protein and albumin tended to improve faster in the EN group., Conclusion: The EN diet is safely applicable to patients suffering from GI involvement by GVHD.

Cancer patients receive intensive chemotherapy by central venous catheter (CVC). Generally, there is a major risk of CVC-related thrombosis and infection due to their hematological and immunological status, respectively. Recently, catheter-induced thrombosis caused by CVC-related bloodstream infection (BSI) has drawn attention in cancer patients. We observed a cohort of patients who received central venous catheterization for one year and described 2 cases of severe thrombosis associated with catheterization and its related infection. In both cases, neutropenic fever was followed by extended subcutaneous swelling with tenderness around the CVC-inserted site after intensive chemotherapy for malignant lymphoma. Chest CT revealed more severe thrombosis around the subclavian and cervical veins, but no mural thrombus on the contralateral site, in both cases. The thrombus included the air cavity, and was thought to be a sign of septic thrombi. Although the issue of the mechanism of infectious thrombosis associated with CVC insertion was not fully addressed, this rare but severe complication of CVC insertion should be studied descriptively and prevented by identification of risks and clinical signs.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common nosocomial pathogens among hospital-acquired infections, and immunocompromised patients are highly susceptive to infection. The molecular typing of isolated strains is a common method for tracing an outbreak of MRSA, but experience with this approach is still limited in the hematopoietic stem cell transplantation (HSCT) ward., Methods: We experienced 6 cases of MRSA infection/colonization in our 26-bed HSCT ward during a 4-week period. This unusual outbreak strongly suggested that the same MRSA strain was involved despite strict isolation and aseptic patient care. Clarification of the transmission pattern was critical, and we applied pulsed-field gel electrophoresis (PFGE) and amplified fragment length polymorphism (AFLP) assays for evaluation., Results and Conclusion: In four of the six cases, the pattern of bands examined by PFGE and AFLP analyses supported the idea that direct person-to-person transmission was very unlikely and the outbreak was coincidental. This experience highlights the clinical value of molecular typing methods for the clinical epidemiological assessment of MRSA outbreak., ((c) 2006 Wiley-Liss, Inc.)

Nasal NK/T-cell lymphoma is EB virus-associated aggressive lymphoma, which is more prevalent in Asia. Previously, this lymphoma which was recognized as lethal midline granuloma, commonly presents with midline facial destructive lesions. In early stage I/II disease, radiation therapy exerts a powerful treatment outcome, however, toxic adverse events are indispensable and the tolerability of radiation therapy with chemotherapy has not been fully studied. It is imperative to offer an appropriate treatment for cure of this disease. We report consecutive 4 cases of nasal NK/T-cell lymphoma, which was treated with 56 Gy intensified local radiation therapy followed by systemic chemotherapy. Two cases complicated with grade 3 stomatitis during the treatment course and 3 cases were hospitalized due to the decrease of oral intake. The scheduled radiation chemotherapy was completed and resulted in complete response of disease in all cases. High intensified radiation therapy followed by chemotherapy may be effective for localized nasal NK/T-cell lymphoma.

Valpha24+ NKT is an innate lymphocyte with potential antitumor activity. Clinical applications of Valpha24+ natural killer (NK) T cells, which are innate lymphocytes with potential antitumor activity, require their in vitro expansion. To avoid the potential dangers posed to patients by fetal bovine serum (FBS), the authors evaluated non-FBS culture conditions for the selective and efficient expansion of human Valpha24+ NKT cells. Mononuclear cells (MNCs) and plasma from the peripheral blood of normal healthy donors were used before and after G-CSF mobilization. MNCs and plasma separated from apheresis products were also used. MNCs were cultured for 12 days in AIM-V medium containing alpha-galactosylceramide (alpha-GalCer) (100 ng/mL) and IL-2 (100 U/mL) supplemented with FBS, autologous plasma, or autologous serum. The cultured cells were collected and their surface markers, intracellular cytokines, and cytotoxicity were evaluated. The highest expansion ratio for Valpha24+ NKT cells was obtained from G-CSF-mobilized MNCs cultured in medium containing 5% autologous plasma. Cultures containing MNCs and autologous plasma obtained before and after G-CSF mobilization had approximately 350-fold and 2,000-fold expansion ratios, respectively. These results suggest that G-CSF mobilization conferred a proliferative advantage to Valpha24+ NKT cells by modifying the biology of cells and plasma factors. Expanded Valpha24+ NKT cells retained their surface antigen expression and production of IFN-gamma and exhibited CD1d-independent cytotoxicity against tumor cells. Valpha24+ NKT cells can be efficiently expanded from G-CSF-mobilized peripheral blood MNCs in non-FBS culture conditions with alpha-GalCer and IL-2.

Patients who require management in the intensive care unit (ICU) for complications after allogeneic hematopoietic stem-cell transplantation (HSCT) generally have a poor outcome. We retrospectively studied whether the risk-prediction stratification systems commonly used for patients admitted to the ICU, that is, the Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III systems, could be useful for identifying patients who should receive intensive care earlier. We reviewed the medical records of 210 patients who underwent allogeneic HSCT and found that 18 (8.6%) had been admitted to the ICU for acute respiratory failure (n=9), acute renal failure (n=7), and septic shock (n=2). The median APACHE II and III scores were, respectively, 16 (10-27) and 55 (22-87) at the onset of complications and 26 (15-43) and 101 (65-157) upon admission to the ICU. Thus, both the APACHE II and APACHE III scores at ICU admission were higher than those at the onset of complications (P <0.0001). Seventeen patients (94%) subsequently died, with a median ICU stay of 7.5 days (1-51 days), as a result of multiorgan failure (n=14), respiratory failure (n=2), and septic shock (n=1). The APACHE II and III scores of the sole surviving patient were, respectively, 21 and 71 at the onset and 24 and 86 upon transfer to the ICU. Thus, the APACHE scores in this study were lower than those reported for other surgical or medical patients treated in the ICU, despite their uniform poor prognosis. Although nine patients had developed grade III to IV acute graft-versus-host disease, which is the most common cause of morbidity and mortality after allogeneic HSCT, this was not fully evaluated in the current scoring systems. Application of these systems to HSCT will require adequate modification, with particular attention to organ dysfunction secondary to graft-versus-host disease.