A case of granulocyte-colony stimulating factor-producing hepatocellular carcinoma confirmed by immunohistochemistry.

Granulocyte-colony stimulating factor (G-CSF) is a naturally occurring glycoprotein that stimulates the proliferation and maturation of precursor cells in the bone marrow into fully differentiated neutrophils. Several reports of G-CSF-producing malignant tumors have been published, but scarcely any in the hepatobiliary system, such as in hepatocellular carcinoma (HCC). Here, we encountered a 69-yr-old man with a hepatic tumor who had received right hepatic resection. He showed leukocytosis of 25,450/microL along with elevated serum G-CSF. Histological examination of surgical samples demonstrated immunohistochemical staining for G-CSF, but not for G-CSF receptor. The patient survived without recurrence for four years, but ultimately passed away with multiple bone metastases. In light of the above, clinicians may consider G-CSF-producing HCC when encountering patients with leukocytosis and a hepatic tumor. More cases are needed to clarify the clinical picture of G-CSF-producing HCC.

Promising approach for aggressive NK cell leukaemia with allogeneic haematopoietic cell transplantation.

OBJECTIVES: Aggressive natural killer cell leukaemia (ANKL) is a malignant disorder of mature NK cells with a poor prognosis, for which no effective therapeutic approach has been established. We investigated the role of allogeneic haematopoietic cell transplantion (allo-HCT) in ANKL. PATIENTS AND METHODS: Three patients with ANKL received allo-HCT and seven did not. Epstein-Barr virus (EBV) viral load (VL) of the whole blood was measured with real-time quantitative polymerase chain reaction. RESULTS: We transplanted three patients using a myeloablative conditioning regimen with human leucocyte antigen (HLA) two-loci mismatched cord blood (n = 2), or HLA-matched sibling bone marrow (n = 1). In one patient, a second transplantation from the haploidentical mother was also performed at relapse. No patients were in complete remission (CR) at the time of conditioning. After allo-HCT, all three achieved and maintained CR. One died from sepsis and the other relapsed, received the second transplantation and achieved a second CR. EBV VL was quite high in all three at presentation and its significant reduction was observed after allo-HCT. Although their backgrounds were not different from those without allo-HCT, patients with allo-HCT had a better outcome. CONCLUSION: Allo-HCT might be a promising therapy for ANKL with curative potential.

Successful Empiric Therapy for Postsplenectomy Sepsis with Campylobacter fetus in an Abattoir Worker with Follicular Lymphoma.

Asplenia may yield an increased risk of fulminant sepsis with various pathogens. Human infection with Campylobacter fetus is rare, but it often presents with non-gastrointestinal tract infection among immunocompromised individuals. A 55-year-old abattoir worker presented with a fever. He had had splenectomy for follicular lymphoma and rituximab maintenance therapy by four months before the presentation. Blood cultures yielded C. fetus, and the administration of meropenem dissolved the bacteremia. Further maintenance therapy was withheld, and no recurrence of infection has been observed for seven years. Asplenia, occupational exposure, and/or rituximab maintenance therapy might have been precipitating factors of this rare infection.

Bortezomib maintenance therapy in transplant-ineligible myeloma patients who plateaued after bortezomib-based induction therapy: a multicenter phase II clinical trial.

In the era of novel therapeutic agents for multiple myeloma (MM), both the significance of achieving the plateau phase and the efficacy of subsequent maintenance therapy remain unclear. In the present study, we evaluated the efficacy and safety of bortezomib maintenance therapy (biweekly for 1 year) in transplant-ineligible MM patients who plateaued after bortezomib-based induction therapy. Of 36 evaluable patients, the overall response rate during induction therapy was 61%, with a stringent complete response in 6%, a complete response in 6%, a very good partial response in 17%, and a partial response in 33%. Twenty patients achieved the plateau phase and subsequently received bortezomib maintenance therapy. Median progression-free survival from the induction and maintenance therapies was 13.8 months (95% confidence interval, 11.4-23.7 months) and 10.7 months (95% confidence interval, 3.7-10.7 months), respectively. During maintenance therapy, there were no cases with grade ≥ 2 peripheral neuropathy, nor was there any improvement in the quality of the response. In conclusion, although maintenance therapy with biweekly bortezomib for up to 1 year was feasible, plateau-oriented bortezomib induction therapy followed by bortezomib maintenance therapy was not adequate in newly diagnosed transplant-ineligible MM patients.

Chemokine system and tissue infiltration in aggressive NK-cell leukemia.

NK cell-type lymphoproliferative disease of granular lymphocytes can be subdivided into aggressive NK-cell leukemia (ANKL) and chronic NK-cell lymphocytosis (CNKL). Hepatosplenomegaly is observed in ANKL patients, and hepatic failure is a common cause of death. Significant numbers of ANKL cells were pathologically observed in sinusoidal and interlobular regions of the liver, and in the splenic red pulp. In our previous study, ANKL cells were simultaneously positive for CXCR1 and CCR5. So, in order to elucidate the mechanism in the systemic migration of ANKL cells, we investigated the expression of the corresponding chemokines in ANKL compared with CNKL. The serum level of IL-8, MIP-1alpha and MIP-1beta was significantly elevated in ANKL patients, and ANKL cells were highly positive for IL-8, RANTES, MIP-1alpha and MIP-1beta according to intracellular staining and RT-PCR. These chemokines were also positively stained in hepatocytes. The interaction between Fas and Fas ligand (FasL) is supposed to be one of the mechanisms for liver dysfunction in ANKL. The serum concentration of soluble FasL was significantly high in ANKL patients, and ANKL cells expressed FasL protein in the cytoplasm. These results suggest that the chemokine system plays an important role in the transmigration of FasL-expressing ANKL cells.

Phase II study of intensified rituximab induction and maintenance for low grade B cell lymphoma.

Rituximab has markedly improved the outcomes of B cell lymphoma, and its maintenance has been shown to be beneficial in low grade B cell lymphoma (LGBCL). We conducted a multicenter, phase II trial of intensive rituximab induction and maintenance therapy for LGBCL to optimize the rituximab monotherapy. Patients with newly diagnosed or rituximab naïve relapsed LGBCL received 8 weekly rituximab as induction, then continued maintenance therapy with rituximab for 4 weeks at 6-month intervals. The primary endpoint was the overall response rate (ORR). Forty-five patients were enrolled from 2005 to 2009 and 36 were eligible. The ORR was 83.3% (30/36) with a complete response rate of 72.2% (26/36). The 3-year progression-free survival (PFS) was 76.7% with a median follow-up of 43.0 months. Five grade three toxicities were observed (no grade 4). Our findings suggest that this regimen demonstrates high activity with durable PFS and minimal toxicity in LGBCL patients.

Thrombotic thrombocytopenic purpura associated with pegylated-interferon alpha-2a by an ADAMTS13 inhibitor in a patient with chronic hepatitis C.

A deficiency of ADAMTS13 leads to platelet clumping and/or thrombi formation, finally resulting in thrombotic thrombocytopenic purpura (TTP). In this study, a 62-year-old male with chronic hepatitis C developed TTP a month after long-term pegylated-interferon (PEG-IFN) treatment. The observed low level of activity of plasma ADAMTS13 following PEG-IFN treatment was shown to gradually increase with the improvement of TTP, while the titer of an inhibitory anti- ADAMTS13 IgG antibody decreased concomitant with the increase in ADAMTS13 activity. Serial determination of ADAMTS13 activity and its inhibitor may provide useful information for the diagnosis and treatment of IFN-associated TTP, as well as its pathogenesis.

Fatal Encephalopathy Associated with Influenza in a Health Care Professional.

A 41-year-old nurse was referred to our hospital with a fever and disturbed consciousness. She tested positive for influenza antigen. CT and MRI findings revealed low density and intensity areas in the right occipital and lateral lobes with remarkable brain edema, which led to a diagnosis of influenza encephalopathy. Influenza A antibodies in the serum were below the detection limit despite the patient receiving previous vaccination three months earlier. A PCR analysis revealed that the influenza HA gene was classified into clade 3C.2a, subclass AH3N2. The present case indicates the potential development of encephalopathy in adults under certain conditions.

Persistent Infection of Drug-resistant Influenza A Virus during Chemotherapy for Malignant Lymphoma.

We herein report the case of an 80-year-old man with malignant lymphoma who became persistently infected with influenza A virus. Although he was repeatedly treated with NA inhibitors, such as oseltamivir or peramivir, nasal cavity swab tests for influenza A antigen continued to be positive for more than 2 months. Virological analyses revealed that he was infected with the NA inhibitor-resistant A (H3N2) virus possessing an R292K substitution in the NA protein. These findings suggest that a drug-resistant influenza virus strain might selectively survive antiviral therapy in elderly patients with refractory malignant lymphoma undergoing multiple chemotherapies.

Phase II clinical study of cladribine in the treatment of hairy cell leukemia.

We conducted a phase II clinical study to evaluate the therapeutic efficacy of cladribine (2-chlorodeoxyadenosine [2-CdA]) in the treatment of Japanese patients with hairy cell leukemia (HCL). Seven patients with classic HCL and 3 with a prolymphocytic HCL variant were administered 2-CdA (0.09 mg/kg per day) by continuous intravenous infusion for 7 days. Seven patients responded to this therapy, with 5 patients achieving a complete response (CR). After a median follow-up of 792 days (range, 599-1253 days), there were no cases of clinical relapse, and the median duration of the response in the responders was 670+ days (range, 470+ to 1121+ days). The median duration of the CR in the CR patients was 953+ days (range, 480+ to 1121+ days). At treatment initiation, most patients had hematologic impairment as a manifestation of HCL. During the early stage after administration, further hematologic impairment occurred, but subsequent peripheral blood counts gradually recovered as 2-CdA treatment showed antitumor activity. Infections occurred at a high incidence at this time, but all cases could be controlled with appropriate treatment. 2-CdA was surmised to represent a useful therapeutic approach for Japanese patients with HCL.

Two Cases of Thymic Carcinoma Initially Presenting as Bone Metastasis: A Clinical Report and the Usefulness of CD5 Immunohistochemistry for Assessing Bone Lesions.

Thymic carcinoma frequently spreads to the pleural space, regional lymph nodes, liver and lungs. However, an initial clinical presentation involving spinal or multiple bone metastases in patients with thymic carcinoma is extremely rare. We experienced two cases of thymic carcinoma that initially presented with spinal compression and severe pain due to multiple bone metastases, respectively. Both patients were histologically diagnosed with metastatic thymic squamous cell carcinoma based on the findings of specimens resected from the metastatic bone lesions. We herein describe the clinical courses of these cases and review the characteristics of bone metastasis of thymic carcinoma.

t(8;21;14)(q22;q22;q24) is a novel variant of t(8;21) with chimeric transcripts of AML1-ETO in acute myelogenous leukemia.

We report a male patient with acute myelogenous leukemia (AML; French-American-British M2) associated with AML1-ETO. Cytogenetic studies showed a complex karyotype including a novel translocation (8;21;14)(q22;q22;q24) in all analyzed cells. This three-way translocation was confirmed with spectral karyotyping. Reverse transcription-polymerase chain reaction analysis for AML1-ETO chimeric transcripts showed the presence of the fusion product with the expected size. Translocation (8;21;14)(q22;q22;q24) is a novel variant of t(8;21)(q22;q22), possibly having a common molecular pathogenetic mechanism.

Idiopathic myelofibrosis with refractory massive ascites.

A 55-year-old woman presented with massive refractory ascites in the course of idiopathic myelofibrosis. The ascites was exudative, and a cytological examination revealed granulocytes of varying maturity, erythroblasts, and megakaryocytes with trisomy 8. The ascites was assumed to have developed from peritoneal extramedullary hematopoiesis. An abnormal karyotype in the cells in the ascitic fluid, which was the same abnormality as in peripheral blood, helped to prove extramedulary hematopoiesis in this case, which can be an aid in making a differential diagnosis in cases of ascites associated with myelofibrosis.

Tumor lysis syndrome in a chronic lymphocytic leukemia patient with pleural effusion after oral fludarabine and cyclophosphamide therapy.

Tumor lysis syndrome (TLS) is a rare complication of the treatment for chronic lymphocytic leukemia (CLL). Since the advent of new therapeutic agents with higher response rates, however, TLS has been observed with increasing frequency. An 84-year-old woman with a nine-year history of untreated CLL presented with exacerbating dyspnea due to pleural effusion. CLL cells without Richter transformation were observed in the pleural effusion at a high concentration, as well as in lymph nodes and bone marrow. After 5 days of oral fludarabine and cyclophosphamide (FC) therapy, the patient developed TLS, which necessitated rescue with hemodialysis. Although transient exacerbation of pleurisy occurred, the effusion cytology ameliorated, and she eventually achieved complete remission after additional two courses of FC and rituximab. Sequestration of fludarabine in the pleural effusion may be attributable to the development of TLS.

Development of primary central nervous system lymphoma associated with human immunodeficiency virus and JC virus infection.

We report here a case of a 37-year-old man with human immunodeficiency virus (HIV) infection followed by JC virus (JCV) infection and primary central nervous system lymphoma (PCNSL). The patient had been infected with HIV type 1 due to blood products for hemophilia A during infancy. He had progression of nervous symptoms and was diagnosed with progressive multifocal leukoencephalopathy (PML) clinically at the age of 36, when his CD4-positive lymphocyte counts ranged between 350 and 450/µl. Oral mefloquine, intravenous methylprednisolone pulse therapy, and intravenous immunoglobulin were not effective for the PML, and the patient entered a vegetative state. Brain biopsy revealed JCV infection without pathological findings of PML. Eight months after the clinical diagnosis of PML, he developed respiratory failure and brain magnetic resonance imaging revealed a mass lesion in the brain stem. The patient died 19 months after the diagnosis of PML. Autopsy findings were compatible with PCNSL. EBV-encoded small RNA-1-positive cells were not detected. We present a case of JCV-positive PCNSL with HIV infection complicated with clinical PML.

Prognosis of mature T cell lymphoma is poorer than that of diffuse large B cell lymphoma in IPI low-risk group, but not in intermediate- and high-risk groups.

Mature T cell lymphoma has been noted for poor prognosis when compared with B cell lymphoma, even in the pre-rituximab era. To confirm this difference, a retrospective cohort study was conducted. One hundred-and nineteen patients with mature T cell lymphoma and 568 patients with diffuse large B cell lymphoma (DLBCL) who did not receive rituximab as first induction were studied. Overall survival (OS) was worse for patients with international prognostic index (IPI) scores indicating low-risk mature T cell lymphoma than for those with DLBCL (3-year OS 87 % vs. 58 %, P = 0.001), but not in other risk groups. Prognosis of mature T cell lymphoma was significantly poorer in the IPI low-risk group, as compared with DLBCL.

Clinical characteristics of human immunodeficiency virus-associated Hodgkin lymphoma patients in Japan.

The incidence of Hodgkin lymphoma (HL) is paradoxically increasing in the combination anti-retroviral therapy (cART) era. However, there has been no nationwide survey of human immunodeficiency virus (HIV)-associated HL (HIV-HL) in Japan. We retrospectively examined the clinical characteristics and outcomes of 19 newly diagnosed HIV-HL patients at 11 HIV/AIDS and hematology regional hospitals in Japan between 1991 and 2010. At the time of HL diagnosis, 79 % of patients were receiving cART. All the patients, but one received HL diagnoses in the cART era. The median CD4+ cell count at HIV-HL diagnosis was 169/µl. Mixed-cellularity classical Hodgkin lymphoma was the most common subtype occurring in 68 % of the patients; 89 % of the patients were positive for Epstein-Barr virus. Of these 19 patients, 84 % were in advanced stages, with bone marrow involvement observed in 47 % of the patients; 58 % had extranodal sites. All the treated patients were given cART concurrent with HL therapy. The complete remission rate of the treated patients was 87 %. The median OS of the entire cohort was 17 months. These results suggest that the characteristics of HIV-HL in Japan are more aggressive than those of non-HIV-associated HL in Japan, but standard chemotherapy is effective and feasible.

Granulocyte-colony stimulating factor-producing pancreatic adenosquamous carcinoma showing aggressive clinical course.

Herein, we encountered an 89-year-old woman with pancreatic cancer who presented with fever without infective focus, leukocytosis of 45,860 /microL, and elevation of serum granulocyte-colony stimulating factor (G-CSF). The patient could not receive any curative therapy due to an extremely aggressive clinical course. Specimens taken at necropsy revealed an adenosquamous carcinoma positive for G-CSF by immunohistochemistry; it was only the second reported case to date. She was finally diagnosed with G-CSF-producing pancreatic cancer. In light of the above, clinicians should consider the presence of G-CSF-producing tumors, including pancreatic cancer, when presented with patients showing leukocytosis of unknown origin and fever without infective focus.