Severe ventilator-associated pneumonia caused by methicillin-resistant Staphylococcus aureus and other pathogens: report of a case successfully managed by serial surveillance cultures of endotracheal aspirates.

Severe ventilator-associated pneumonia (VAP) caused by methicillin-resistant Staphylococcus aureus (MRSA) developed in a patient with acute respiratory distress syndrome. After tracheostomy, the patient was treated with antibiotic therapy guided by serial surveillance cultures of endotracheal aspirates. According to the result of the culture, the suitable antibiotic targeting the pathogen (e.g., MRSA, Pseudomonas aeruginosa, Klebsiella oxytoca) that had grown most predominantly in the culture was used until clinical resolution of VAP, leading to avoidance of overusing broad-spectrum antibiotics and ultimately a favorable outcome. During vancomycin (VCM) therapy for MRSA VAP, MRSA bacteremia occurred even though the trough value of VCM was sufficiently high. After the change from VCM to linezolid (LZD), the VAP improved promptly, indicating that LZD is superior to VCM in the treatment of MRSA pneumonia.

Blast phase of chronic myeloid leukemia presenting lymphoid phenotype with a chronic phase of extremely short duration.

Chronic myeloid leukemia (CML) is generally diagnosed in the chronic phase. We have recently encountered two CML-blastic phase (BP) cases, a 71-year-old woman and a 74-year-old man, who resembled de novo acute leukemia. The complete blood count was normal at least 11 and 13 months before the presentation, respectively. The leukemic cells showed predominant lymphoid phenotype. The blasts and granulocytes were positive for BCR-ABL, indicative of CML-BP. Both patients were successfully treated with prednisone and vincristine, followed by Imatinib. Our cases indicate rare presentations of CML-BP with an extremely short chronic phase. Ph-positive de novo acute leukemia should be carefully distinguished from CML-BP.

Therapy-related leukemia following chemoradiotherapy for esophageal cancer.

Chemoradiotherapy has improved the outcome of patients with esophageal cancer. Although a sufficiently long-time survival has resulted in the increase of several treatment-related late toxicities, little is still known about the incidence of secondary malignancies. In our hospital, 348 patients with esophageal cancer received chemotherapy consisting of nedaplatin and 5-fluorouracil and concurrent irradiation. Median and average follow-up durations were 8 and 21 months (1-92), respectively. Four patients developed leukemia after 19-48 months of follow-up. Two patients were diagnosed with overt leukemia from myelodysplastic syndrome presenting a complex karyotype, including the deletion of chromosome 5 or 7. Notably, one patient showed an additional chromosomal abnormality with t(9;22)(q34;q11). Other patients developed acute myeloid leukemia with t(9;22)(q34;q11) and Burkitt leukemia with t(8;14)(q24;q32). All patients eventually succumbed to leukemia. Platinum and fluorouracil have shown relatively lower risks for secondary malignancies in comparison with alkylating agents and topoisomerase II inhibitors. Especially, nedaplatin has never been described to introduce secondary neoplasms. Our report supports the idea that the concurrent administration of radiotherapy with these agents affects the risk of leukemia. Interestingly, rare balanced chromosomal abnormalities were observed in the present cases, thus providing new insights into the leukemogenesis of therapy-related leukemia.

[T-cell granular lymphocyte-proliferative disorder without severe infection for 13 years despite severe neutropenia].

A 68-year-old woman was referred to Oami Hospital for severe leukocytopenia. Laboratory data revealed severe leukocytopenia (0.8x10(9)/l), severe neutropenia (0.22x10(9)/l) and IgM-kappa monoclonal gammopathy. Granular lymphocytes accounted for more than 90% of leukocytes. Surface marker analysis revealed that these lymphocytes were CD3+, CD4-, CD8+ and CD16+, and monoclonal rearrangement of T-cell receptor genes was seen on Southern blot hybridization analysis. She was diagnosed with T-cell lineage granular lymphocyte proliferative disorder (T-GLPD). During 13-year follow-up without granulocyte-colony stimulating factor (G-CSF) administration, except for one hospitalization because of bacterial pneumonia, she has not experienced severe infection, despite severe neutropenia. T-GLPD should be kept in mind as a cause of leukocytopenia with or without monoclonal gammopathy, and surface marker or Southern blot hybridization analysis should be considered for determining the diagnosis. There are many reports about Caucasian patients with T-GLPD suffering from recurrent infections and dying of severe infection, but in Japanese T-GLPD patients, severe infection is very rare, as shown in the present case report.

[Prevention of hepatitis B virus reactivation in B-cell lymphoma patients receiving chemotherapy with rituximab].

Reactivation of hepatitis B virus (HBV) has been recognized as one of the most serious complications in patients receiving chemotherapy with rituximab. From October 2007 to December 2008, rituximab was administered to 123 B-cell lymphoma patients in our institute. Four patients with positive hepatitis B surface antigen (HBsAg) received preemptive entecavir, and none of them developed HBV reactivation. For 26 patients whose hepatitis B surface antibody (HBsAb) and/or hepatitis B core antibody (HBcAb) were positive, HBV-DNA was monitored for one year after completion of chemotherapy. During this period, HBV reactivation was observed in two patients. Hepatitis was prevented in one patient by the administration of entecavir at the time HBV-DNA turns positive. Another developed de novo hepatitis B due to failure of monitoring. Preemptive entecavir for HBsAg positive patients and HBV-DNA monitoring for HBsAb and/or HBcAb positive patients seem to be effective.

[Adult T-cell leukemia/lymphoma in a patient on hemodialysis-resistance to CHOP, but unexpected effect and remission achieved by sobuzoxane alone].

A 66-year-old man, on thrice-weekly hemodialysis for 7 years, was referred to Chiba Cancer Center Hospital in August 2006 because of a left axillary tumor. Computed tomography revealed several enlarged lymph nodes assembling at the left axilla. The serum soluble IL-2 receptor was 47,500 U/mL, and HTLV-1 antibody was positive. His parents came from Kyushu. The pathological diagnosis was peripheral T-cell lymphoma, CD4(+). He was clinically diagnosed as having an adult T-cell leukemia/lymphoma, lymphoma type, and clinical stage II. Two courses of CHOP therapy were given to the patient, without any response. Because the patient had to undergo hemodialysis consistently, we preferred mild salvage therapy to more intensive treatment. Then, sobuzoxane (SBZ), 1,600 mg/day in two divided doses, was administered orally for 5 days. Soon thereafter, unexpectedly, the axillary tumor rapidly became small, resulting in disappearance four months later. SBZ therapy, 800 mg/day x 3 days, was continued at intervals of 7 to 8 weeks until October 2008. At the time of reporting, May 2009, the patient was well without recurrence of ATLL, and the remission has lasted 26 months or more. The reason why CHOP-resistant ATLL responded dramatically to SBZ alone is not clear, but the plasma concentration of the metabolite of SBZ was possibly very high because of renal failure. Another possibility is that hemodialysis removed the growth factor(s) or anti-apoptotic factor(s) derived from ATLL cells.

[Antibiotic-associated diarrhea due to Clostridium perfringens].

A 40-year-old man undergoing allo-hematopoietic stem cell transplantation for chronic myelogenous leukemia and developing diarrhea was administered prophylactic antibiotics including levofloxacin, fluconazole, cotrimoxazole, and vancomycin. Stool specimens were positive for toxin A in enzyme immunoassay but negative for toxin B in cell culture assay with a neutralization test, indicating that toxin A detection was false-positive. Stool culture yielded enterotoxin producing Clostridium perfringens, not Clostridium difficile. Polymerase chain reaction (PCR) detected the gene encoding C. perfringens enterotoxin in DNA extracted from stool specimens, but not the toxin B gene. Laboratory tests for enterotoxic C. perfingens may therefore be necessary for diagnosing antibiotic-associated diarrhea when culture for C. difficile is negative.

[Hepatic hilus extramedullary plasmacytoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy in a relapsed multiple myeloma].

We report a rare case of multiple myeloma that developed extramedullary plasmacytoma at the hilus of the liver causing obstructive jaundice. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy was quite useful in the diagnosis. A 71-year-old man was diagnosed with stage IIIA multiple myeloma in June 2007 based on osteolytic lesions, increased atypical plasma cells in the bone marrow, and monoclonal (M) protein of IgA-lambda, IgG-lambda, BJP-lambda type. M-protein was decreased by MP therapy following radiotherapy for the cervical lesion. However, in February 2008, M-protein started to increase again. The patient presented with obstructive jaundice in the middle of March. Abdominal ultrasound and MRI demonstrated a 12-mm mass at the hilus of the liver and the upper biliary tract dilatation, and a stent was placed across the bile duct stricture. EUS-FNA biopsy from the hepatic hilar mass showed multiple sheets of atypical plasma cells consistent with extramedullary plasmacytoma. The abdominal and intracranial mass did not respond to bortezomib therapy and gradually developed. Radiotherapy and high dose dexamethazone therapy were performed with little effect. The patient died in June 2008. To our knowledge, this is the first reported case of extramedullary plasmacytoma diagnosed by EUS-FNA.

[Complete response achieved after rituximab plus CHOP therapy in a patient with rapidly progressing Waldenstrom's macroglobulinemia].

A 62-year-old man presented with lymphocytosis, anemia, thrombocytopenia, abdominal lymphadenopathies, and gross splenomegaly. He had a high serum immunoglobulin M (IgM) of 1,150 mg/dl and IgM-kappa type monoclonal protein was detected. Bone marrow examination demonstrated massive infiltration of CD19+CD20+CD5-CD10-CD23-lymphoplasmacytic cells, and the diagnosis of Waldenstrom's macroglobulinemia (WM) was made. The serum levels of soluble interleukin-2 receptor and beta2-microglobulin were also elevated to 14,300 U/ml and 6.2 mg/l, respectively. The high tumor burden and aggressive clinical features prompted the initiation of CHOP therapy. After three courses of CHOP, the patient recovered from anemia and the serum IgM level decreased to 615 mg/dl. Then we administered rituximab in combination with CHOP (R-CHOP therapy). After an additional five courses of R-CHOP, bone marrow tumor cells, splenomegaly and lymphadenopathies entirely disappeared and IgM-type monoclonal protein also became negative on immunofixation studies. Thus, a complete response (CR) was achieved and the patient has remained in CR for 12 months. Although new therapeutic options for WM including combination chemotherapy have recently been explored, complete response rates defined by immunofixation remain low. Our case indicates that R-CHOP therapy is fully effective and tolerable for aggressive type WM.

[Hepatitis B virus reactivation after cessation of prophylactic lamivudine therapy in B-cell lymphoma patients treated with rituximab combined CHOP therapy].

Here we report three cases of hepatitis B virus (HBV) reactivation after cessation of preemptive lamivudine therapy in B-cell lymphoma patients treated with rituximab plus CHOP (R-CHOP). Two patients received eight cycles of R-CHOP, and one received two cycles of R-CHOP followed by two courses of rituximab. As all the patients were HBV surface antigen (HBsAg) positive, lamivudine was administered simultaneously with R-CHOP to prevent virus reactivation. All the patients developed hepatitis due to HBV reactivation 6, 8 and 13 months after completion of chemotherapy, and 4, 2 and 2 months after cessation of lamivudine, respectively. They were treated with either lamivudine or entecavir and all achieved full recovery. When HBV carriers undergo immunosuppressive anticancer treatment, prophylactic antiviral therapy is well recognized as effective. However, the optimal method of prophylaxis has not yet been established. Since the introduction of rituximab, new problems such as delayed HBV reactivation from HBsAg positive patients and de novo hepatitis B from HBsAg negative patients have emerged. Guidelines for prophylactic antiviral therapy in the era of rituximab need to be established.

Autologous hematopoietic stem cell transplantation in extranodal natural killer/T cell lymphoma: a multinational, multicenter, matched controlled study.

Extranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity and the most common type of non-B cell extranodal lymphoma in Asia. This retrospective analysis studied the potential survival benefits of hematopoeitic stem cell transplantation (HSCT) compared with a historical control group. A total of 47 patients from 3 previously published series of HSCT were matched according to NK/T cell lymphoma International Prognostic Index (NKIPI) risk groups and disease status at transplantation with 107 patients from a historical control group for analysis. After a median follow-up of 116.5 months, the median survival time was not determined for the HSCT group, but it was 43.5 months for the control group (95% confidence interval [CI] = 6.7 to 80.3 months; P = .127, log-rank test). In patients who were in complete remission (CR) at the time of HSCT or at surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027). In contrast, in subgroup analysis on non-CR patients at the time of HSCT or non-HSCT treatment, disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% for HSCT vs 28.6% for non-HSCT; P = .141). The impact of HSCT on the survival of all patients was significantly retained at the multivariate level with a 2.1-fold (95% CI =1.2- to 3.7-fold) reduced risk of death (P = .006). HSCT seems to confer a survival benefit in patients who attained CR on postremission consolidation therapy. These findings suggest that, in particular, patients in CR with high NKIPI risk scores at diagnosis should receive full consideration for HSCT.

Fatal fulminant Clostridium difficile colitis during CHOP therapy for lymphoma: an autopsy case.

Although Clostridium difficile colitis is a common problem during chemotherapy, fulminant expression is rarely observed. Here, we describe a 68-year-old woman who developed fatal colitis due to Clostridium difficile infection. The patient was treated with CHOP therapy for relapsed lymphoma. In the nadir phase, she developed severe bloody diarrhea with a high fever and died within 12 hours after the beginning of symptoms. Clostridium difficile was identified in her stool and an autopsy showed hemorrhagic necrosis on the whole colon and rectum. This case demonstrates the substantial incidence of an unexpected feature with Clostridium difficile infection even with popular chemotherapy.

Expression of the fetal-oncogenic fibroblast growth factor-8/17/18 subfamily in human hematopoietic tumors.

The fibroblast growth factors (FGFs) are involved in hematopoiesis and tumorigenesis. However, little is known about the contribution of the FGFs identified within the past 10 years to leukemogenesis. To elucidate whether these FGFs (FGF-8, -9, -10, -11, -12, -13, -14, -16, -17, -18, -19, -20, and -21) are expressed in leukemic cells, we performed RT-PCR analyses using 28 cell lines. The members of a fetal-oncogenic subfamily, FGF-8/-17/-18, were often expressed (53.5%, 25.0%, and 32.1%) with the co-expression of their receptors. Realtime quantitative-PCR analysis showed that FGF-8/-17 were aberrantly expressed in patients with acute leukemia. Moreover, cell proliferation assays revealed the proliferation activity of FGF-17 on leukemic cells expressing its receptors. These results demonstrated that certain recently identified FGFs play an important role in the growth of leukemic cells, possibly with an autocrine mode of action, and that these FGFs will become novel biomarkers for hematopoietic tumors.

Therapy-related myelodysplastic syndrome with trisomy 1q due to der(1;7) and megakaryoblastic proliferation developing during complete remission of therapy-related acute myeloid leukemia with t(8;21).

Therapy-related acute myeloid leukemia (t-AML) with t(8;21) and therapy-related myelodysplastic syndrome (t-MDS) with trisomy 1q due to der(1;7) developed in the same patient with T-cell lymphoma at intervals of six years. After the development of t-MDS with trisomy 1q, during complete remission of t-AML, the number of megakaryoblasts increased to maximally 74% of leukocytes in the blood. This is a very rare case of two separate therapy-related myeloid malignancies (early t-AML and late t-MDS) and is also a notable case of t-MDS with trisomy 1q due to der(1;7) accompanied by megakaryoblastic proliferation.

[A nosocomial outbreak of diarrhea caused by toxin A-negative, toxin B-positive Clostridium difficile in a cancer center hospital].

Between February and July 2001, 15 patients were diagnosed as Clostridium difficile-associated diarrhea in a ward of hematological neoplasm and lung cancer in a cancer center hospital. Of these 15 patients, 10 had malignant lymphoma, and 12 and 11 had exposure to antimicrobial agents and cancer chemotherapy, respectively, before the onset of diarrhea. Toxin A-positive, toxin B-positive (A+ B+) C. difficile was recovered from five patients and the remaining 10 patients suffered from diarrhea caused by toxin A-negative, toxin B-positive (A- B+) strains. All of the 10A- B+ isolates represented an identical banding pattern by PCR ribotyping and classified into one type (two subtypes) by pulsed field gel electrophoresis typing, indicating that a nosocomial outbreak of diarrhea caused by A- B+ C. difficile occurred among the patients hospitalized on this ward. Detection of toxin A in stool specimens by a toxin A detection kit was performed on 14 patients. Although two patients who carried A+ B+ strains were positive for toxin A assay, toxin A detection test was negative in 12 patients including 10 patients with A- B+ C. difficile infection. Diagnosis of C. difficile-associated diarrhea by combination of toxin A assay in feces and culture of C. difficile could successfully lead to recognition of an outbreak caused by A- B+ C. difficile in a cancer center hospital.