Treatment of chronic lymphocytic leukemia with bendamustine in an HIV-infected patient on antiretroviral therapy: a case report and review of the literature.

Few reports have described the coincidence of chronic lymphocytic leukemia (CLL) and HIV. We administered bendamustine to an HIV-positive refractory CLL patient and obtained a significant objective response. Our results indicate that bendamustine can be used in HIV-infected CLL patients. We also reviewed 12 cases of CLL with HIV infection.

The role of Cas-L/NEDD9 as a regulator of collagen-induced arthritis in a murine model.

Cas-L/NEDD9 is a cytoplasmic docking protein downstream of ß1 integrin-mediated signaling pathway and is essential for cellular migration and ß1 integrin-mediated costimulation of T cells. We previously found that increased number of Cas-L positive leukocytes migrated into the inflamed joints of HTLV-I tax transgenic mice which spontaneously develop polyarthritis, suggesting a role of Cas-L in rheumatoid arthritis (RA) pathophysiology. Our current study expanded these findings on the role of Cas-L/NEDD9 in the development of RA by analyzing the pathophysiological changes in a Nedd9(-/-) mouse collagen-induced arthritis (CIA) model. Nedd9(-/-) mice exhibited a decrease in arthritis severity as compared to Nedd9(+/+) mice. In addition, as being conducted bone marrow transplantation experiments with a CIA model, Nedd9(-/-)→Nedd9(+/+) transplant showed a decrease in the incidence and severity score of arthritis, compared to those of Nedd9(+/+)→Nedd9(-/-) transplant. For analysis of serum levels of various cytokines, IL-1ß, IL-6, IL-17, TNF-α, IFN-γ and anti-collagen antibody were decreased, while IL-4 and IL-10 levels were increased, in Nedd9(-/-) mice as compared to those in Nedd9(+/+) mice. Furthermore, collagen-mediated cellular responses of lymphocytes isolated from spleen or affected lymph nodes of Nedd9(-/-) mice were reduced. Our results strongly suggest that Cas-L/NEDD9 plays a pivotal role in the pathophysiology of CIA, and that Cas-L/NEDD9 may be a potential molecular target for the treatment of RA.

The prevalence of opportunistic infections and malignancies in autopsied patients with human immunodeficiency virus infection in Japan.

BACKGROUND: Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. METHODS: A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985-2012 were retrospectively reviewed. Clinical data were collected from patient medical records. RESULTS: Mean CD4 counts of patients were 77.0 cells/µL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/µL in naïve patients (ART (-) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (-) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (-) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (-) patients (1.5%; P = 0.026). CONCLUSIONS: The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (-) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (-) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART.

CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia/lymphoma.

PURPOSE: Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia-lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development. EXPERIMENTAL DESIGN: We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis. RESULTS: HTLV-I-infected cells were efficiently enriched in CADM1(+) subpopulations (D, CADM1(pos)CD7(dim) and N, CADM1(pos)CD7(neg)). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts. CONCLUSION: The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1(+) cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs.

Classification of AIDS-related lymphoma cases between 1987 and 2012 in Japan based on the WHO classification of lymphomas, fourth edition.

The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus-1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS-related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS-related lymphoma according to the revised classification. In this retrospective study, 207 AIDS-related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B-cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non-GC type. Non-GC-type cases showed a significantly lower 1-year survival rate (43%) than the GC-type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B-cell lymphoma arising in Kaposi sarcoma-associated herpesvirus-associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART-naïve patients (1.4%). Statistical analyses identified CD10 negativity, BCL-6 negativity, Epstein-Barr virus positivity, and Kaposi sarcoma-associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.

The CD3 versus CD7 plot in multicolor flow cytometry reflects progression of disease stage in patients infected with HTLV-I.

PURPOSE: In a recent study to purify adult T-cell leukemia-lymphoma (ATL) cells from acute-type patients by flow cytometry, three subpopulations were observed in a CD3 versus CD7 plot (H: CD3(high)CD7(high); D: CD3(dim)CD7(dim); L: CD3(dim)CD7(low)). The majority of leukemia cells were enriched in the L subpopulation and the same clone was included in the D and L subpopulations, suggesting clonal evolution. In this study, we analyzed patients with indolent-type ATL and human T-cell leukemia virus type I (HTLV-I) asymptomatic carriers (ACs) to see whether the CD3 versus CD7 profile reflected progression in the properties of HTLV-I-infected cells. EXPERIMENTAL DESIGN: Using peripheral blood mononuclear cells from patient samples, we performed multi-color flow cytometry. Cells that underwent fluorescence-activated cell sorting were subjected to molecular analyses, including inverse long PCR. RESULTS: In the D(%) versus L(%) plot, patient data could largely be categorized into three groups (Group 1: AC; Group 2: smoldering- and chronic-type ATL; and Group 3: acute-type ATL). Some exceptions, however, were noted (e.g., ACs in Group 2). In the follow-up of some patients, clinical disease progression correlated well with the CD3 versus CD7 profile. In clonality analysis, we clearly detected a major clone in the D and L subpopulations in ATL cases and, intriguingly, in some ACs in Group 2. CONCLUSION: We propose that the CD3 versus CD7 plot reflects progression of disease stage in patients infected with HTLV-I. The CD3 versus CD7 profile will be a new indicator, along with high proviral load, for HTLV-I ACs in forecasting disease progression.

Nephronectin is upregulated in acute and chronic hepatitis and aggravates liver injury by recruiting CD4 positive cells.

Nephronectin (Npnt) is an extracellular matrix protein known to play a critical role in kidney development; however, its physiological role in the liver remains elusive. Here we show that Npnt expression is upregulated in mouse models of both acute and chronic hepatitis induced by Concanavalin A (Con A) and 3,5-diethocarbonyl-1,4-dihydrocollidine (DDC), respectively. In both models, Npnt was localized in inflammatory foci and was mainly secreted from mesenchymal cells and in part by cholangiocytes. Interestingly, ectopic expression of Npnt in hepatocytes induced the development of granuloma-like cell clusters mainly composed of CD4(+) T cells or NKT cells but did not induce apparent hepatitis. Furthermore, we found that Npnt exacerbated the Con A-induced acute hepatitis. These results indicate that Npnt plays an important role in the initiation of hepatitis by recruiting CD4(+) T cells or NKT cells into the foci of inflammation. In addition, we reveal that Npnt expression is also upregulated in human hepatitis. Therefore, Npnt may be a potential therapeutic target for acute and chronic hepatitis.

Imatinib mesylate directly impairs class switch recombination through down-regulation of AID: its potential efficacy as an AID suppressor.

Activation-induced cytidine deaminase (AID) is essential for class switch recombination and somatic hypermutation. Its deregulated expression acts as a genomic mutator that can contribute to the development of various malignancies. During treatment with imatinib mesylate (IM), patients with chronic myeloid leukemia often develop hypogammaglobulinemia, the mechanism of which has not yet been clarified. Here, we provide evidence that class switch recombination on B-cell activation is apparently inhibited by IM through down-regulation of AID. Furthermore, expression of E2A, a key transcription factor for AID induction, was markedly suppressed by IM. These results elucidate not only the underlying mechanism of IM-induced hypogammaglobulinemia but also its potential efficacy as an AID suppressor.

Case of secondary syphilis presenting with unusual complications: syphilitic proctitis, gastritis, and hepatitis.

We report the first known case of syphilis with simultaneous manifestations of proctitis, gastritis, and hepatitis. The diagnosis of syphilitic proctitis and gastritis was established by the demonstration of spirochetes with anti-Treponema pallidum antibody staining in biopsy specimens. Unusual manifestations of secondary syphilis completely resolved after 4 weeks of antibiotic therapy.

Neurocysticercosis case with tuberculoma-like epithelioid granuloma strongly suspected by serology and confirmed by mitochondrial DNA.

An Indian woman with multiple and nodular cerebral lesions presenting epithelioid granulomas was diagnosed as suspected malignant tumours and the biopsy was carried at local hospital in Japan. The specimen was pathologically diagnosed as tuberculoma. However, due to her nationality, the authors suspected it to be neurocysticercosis (NCC) and carried out serology and applied mitochondrial DNA analysis of Taenia solium. These diagnostic tools revealed it as NCC radiologically and pathologically mimicking central nervous tuberculomas. Molecular confirmation of NCC cases is strongly recommended when we can get the biopsy specimens.

Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402.

BACKGROUND: The tumor associated antigen (TAA) gp100 was one of the first identified and has been used in clinical trials to treat melanoma patients. However, the gp100 epitope peptide restricted to HLA-A*2402 has not been extensively examined clinically due to the ethnic variations. Since it is the most common HLA Class I allele in the Japanese population, we performed a phase I clinical trial of cancer vaccination using the HLA-A*2402 gp100 peptide to treat patients with metastatic melanoma. METHODS: The phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80°C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-γ- ELISPOT and MHC-Dextramer assays. RESULTS: No related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8+ gp100-in4+ CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4. CONCLUSION: Our results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications.

Fluorescence lymph node mapping in living mice using quantum dots and a compression technique.

The lymphatic system is essential in oncology and immunology, and in vivo fluorescence imaging plays a major role in assessing the lymphatic drainage. We investigated non-invasive fluorescence lymph node mapping in mice with special reference to the assessment of deep abdominal lymph nodes. Quantum dots were injected subcutaneously into the rear footpads of mice, and the time course of the fluorescent signal was assessed. Visualization of abdominal lymph nodes was compared with and without compression of the abdomen with transparent, colorless tape at injection doses of 1, 5, and 20 pmol. Popliteal, sacral, iliac, and renal lymph nodes were delineated by non-invasive imaging. Lymph node signals increased up to 3 h after injection. Compression of the abdomen markedly improved the visualization of the iliac nodes, which were invisible at 5 pmol without compression and visible at 1 pmol with compression. Fluorescence lymph node mapping using quantum dots allowed the visualization of deep abdominal lymph nodes in addition to superficial nodes in intact mice, with the aid of a simple compression technique.

Microscopic polyangiitis initiated with liver dysfunction, calf pain and fever of unknown origin.

We report herein a case of microscopic polyangiitis (MPA), presenting onset with a spiking fever, liver/biliary dysfunction without jaundice and calf pain without elevation of serum creatine phosphokinase. During 1 month of careful examinations for initial diagnosis, the patient developed renal dysfunction and pulmonary hemorrhage. Based on the results of positive MPO-ANCA, renal and pulmonary involvements, the patient was diagnosed with MPA and treated with high-dose prednisolone and oral cyclophosphamide. Soon after initiation of the treatment, symptoms such as fever, calf pain, liver/biliary dysfunction and renal dysfunction disappeared with decrease of MPO-ANCA titer to the normal level.

Gastrointestinal bleeding during anti-angiogenic peptide vaccination in combination with gemcitabine for advanced pancreatic cancer.

Most pancreatic cancer patients are diagnosed at the advanced stages, and no therapy is superior to gemcitabine alone. To confirm the feasibility and efficacy of a novel clinical intervention using tumor vessel-specific anti-angiogenic peptide vaccination, we conducted a clinical phase I/II trial using HLA-A*2402/A*0201-restricted vascular endothelial growth factor receptor type 1 (VEGFR1)-derived peptide vaccination in combination with gemcitabine for advanced pancreatic cancer (http://www.clinical-trials.gov; NCT00683358 and NCT00683085). Four of the enrolled patients (n = 2 for HLA-A*2402 and n = 2 for HLA-A*0201 protocol, respectively), defined as having progressive disease according to the Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v.1.0), failed to respond to the therapy. Another two patients enrolled in HLA-A*2402 protocol dropped out of the study due to rapid disease progression. Grade 2-3 hematologic toxicities were observed in all cases, but the treatment was well tolerated with minimal systemic adverse events. One case in HLA-A*2402 protocol and another case in HLA-A*0201 protocol suffered complicated gastrointestinal (GI) bleeding during vaccination. The causal relationship between GI bleeding and VEGFR1-peptide vaccination is unclear according to the pathologic examination. These studies terminated prematurely because of the advanced stage of the disease in the enrolled patients on entry to the study. Despite GI bleeding, peptide vaccination provides a feasible treatment option for many advanced pancreatic cancer patients.

An adult case of Henoch-Schönlein purpura complicating common peroneal nerve mononeuropathy.

We present an adult patient with Henoch-Schönlein Purpura who developed mononeuropathy in the common peroneal nerve. Upon admission, the patient had palpable purpura in the arms and legs, polyarthralgia, abdominal pain, and leukocytoclastic vasculitis in the skin biopsy. These symptoms disappeared with 30 mg daily of oral prednisolone. One month later, after induction therapy, fever, livedo reticularis and peripheral mononeuropathy developed with hypocomplementemia and the patient was treated successfully with glucocorticoid pulse therapy.

[Severe systemic edema correlated with serum VEGF titer in a patient with angioimmunoblastic T-cell lymphoma].

A 73-year-old woman was admitted with generalized lymphadenopathy, marked protrusion of the abdomen, severe systemic edema, oliguria, and dyspnea. Histological examination of a cervical lymph node specimen showed a typical structure of angioimmunoblastic T-cell lymphoma. CT scan revealed whole paraaortic lymphadenopathy, marked edematous lesions in the subcutaneous tissues and mesenterium, but small amounts of pleural effusion and ascites. This patient achieved complete remission after 5 courses of chemotherapy, a first course of CHOP followed by 4 courses of hyper CVAD plus high-dose MTX/AraC regimen alternatively. Her body weight was 58 kg on the day of admission and decreased to 41kg after 5 courses of chemotherapy, accompanied with symptomatic improvement. We checked the kinetics of serum Vascular endothelial growth factor (VEGF) concentrations during the 5 courses of chemotherapy. Pretreatment serum level of VEGF was high and declined gradually within the normal range. The serum VEGF value was positively correlated with body weight (r = 0.95). Immunohistochemical study of the biopsy specimen revealed that endothelia of the venules and some dendritic cells were positive for VEGF. We speculated that significant edematous changes in this patient were associated with VEGF, which is known as a vascular permeability factor based on its ability to induce vascular leakage.