IntroductionInterleukin-13 (IL-13) and IL-4 are related multifunctional cytokines with similar biological activities on human B cells and monocytes. [1][2][3][4][5][6][7] The cognate receptors for these cytokines are complex and have been shown to share 2 chains with each other. [8][9][10][11][12] The IL-4 receptor system is well characterized and has been shown to be composed of a primary IL-4 binding protein, IL-4R␣ (also known as IL-4R␤). 13 This chain forms a heterodimer with either the IL-2R␥ c chain (type I IL-4R) or IL-13R␣1 (also known as IL-13R␣Ј) (type II IL-4R) for signaling. 11,[14][15][16][17] In some situations, all 3 chains (IL-4R␣, IL-2R␥ c , and IL-13R␣1) may constitute the IL-4R complex; however, whether all 3 chains are simultaneously required for IL-4 function is not known.In contrast, the receptor for IL-13 is less well characterized. We have studied the structure of IL-13R in various cell types and reported that IL-13 binds to 2 isoforms of an approximate 65-kDa protein in human renal cell carcinoma cells. [8][9][10][11][12] One of these proteins also binds 14 On the basis of the binding characteristics, cross-linking, and displacement of radiolabeled IL-4 and IL-13 in various cell types, we hypothesized that, as is the case for the IL-4R system, IL-13R may also be composed of 3 different types. [9][10][11][12] More recently, 2 different chains of the IL-13R system have been cloned. The murine and human IL-13R␣1 chain was first cloned. 14,18 This chain can bind IL-13 with low affinity, but, when coupled with the IL-4R␣ chain, the heterodimer binds IL-13 with high affinity and mediates IL-13-induced signaling. 14,18 The second chain of the IL-13R, termed IL-13R␣2 (also known as IL-13R␣), has also been cloned from a human renal cell carcinoma cell line (Caki-1). This chain shares approximately 50% homology with the IL-5R at the DNA level. It contains a very short intracellular domain and binds IL-13 with high affinity. 19 On the basis of the above studies, we have proposed that the type I IL-13R complex is composed of both chains of IL-13R (IL-13R␣1 and IL-13R␣2) and IL-4R␣ chain. Although IL-13 binds to all 3 chains, only the IL-13R␣1 and IL-4R␣ chains form a productive complex. Because of this arrangement, IL-13 binds to these cells strongly. Only IL-13, not IL-4, is able to displace the binding of 125 I-IL-13. In the type II IL-13R system, IL-13R␣2 is not present, and the IL-13R␣1 chain forms a complex with the IL-4R␣ chain. In these cells both interleukins compete for the binding of their radiolabeled cognaters. 12 The structure of the type III IL-13R is similar to that of type II receptors except that these cells also express the IL-2R␥ c chain. Although it appears that the IL-2R␥ c chain does not bind IL-13, it does affect IL-13 binding and function in some cell types. 20,21 After binding to their receptors, both IL-4 and IL-13 signal through phosphorylation-dependent activation of Jak kinases and signal transduction and activator of transcription (STAT) protein. 11,17,22 In particular,...

Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkin's lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain.

We clinicopathologically studied 23 surgically resected cases of combined hepatocellular and cholangiocarcinoma (HCC-CC). The frequency of this cancer in our subjects, who had primary liver cancer and who underwent hepatectomy, was 6.3%. The mean age of patients was 64.0 years old and the male: female ratio was 1.9:1. Serum alpha-fetoprotein was positive in 70% of cases and its levels were relatively low (< or = 1000 ng/mL) in most cases. The positive rate of serum carcinoembryonic antigen was 18% and its levels were also low. In regard to hepatitis virus markers, 17% of the 20 combined HCC-CC cases were positive to HBs antigen and 70% were positive to the HCV antibody. Of the 23 combined HCC-CC cases, 9 cases (39%) were associated with liver cirrhosis. Tumours were classified macroscopically into a separated type (HCC and CC are clearly separated 17%), a HCC-predominant type (resembles HCC 49%), and a CC-predominant type (resembles CC 34%). The separated and HCC-predominant types were associated with liver cirrhosis in 50 and 55% of cases, respectively. These cases with liver cirrhosis presented the features of HCC more apparently, while those without liver cirrhosis presented the features of CC. Histologically, all cases were classified into either Type I (HCC and CC were clearly distinguished; 17%), Type II (HCC and CC were contiguous and shared transitional features; 66%), and Type III (cancer cells were able to be evaluated as either HCC or CC and were considered to be an intermediate type; 17%). Immunohistological stains for cytokeratin were useful to distinguish HCC and CC. Specifically, CC was positive to cytokeratin 7 and 19. The tumour, in which HCC and CC were almost indistinguishable, such as Type III), indicates the presence of intermediate tumour cells that can differentiate either to HCC or CC.

Key Points• Auto-HSCT in CR1 provides long-term remission in BPDCN patients.• RIC allo-HSCT and MAC allo-HSCT results are comparable.We sought to clarify the role of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN). We retrospectively identified 25 BPDCN patients (allo-HSCT, n 5 14; auto-HSCT, n 5 11) from registry data of the Japan Society for Hematopoietic Cell Transplantation and analyzed clinicopathologic data and clinical outcomes after transplantation. The median age at HSCT was 58 years (range, 17-67 years). All 11 patients who underwent auto-HSCT were in the first complete remission (CR1). With a median follow-up of 53.5 months, the overall survival rates at 4 years for patients who underwent auto-HSCT and allo-HSCT were 82% and 53% (P 5 .11), respectively, and progression-free survival rates were 73% and 48% (P 5 .14), respectively. Auto-HSCT for BPDCN in CR1 appears to provide promising results and deserves further evaluation in the setting of prospective trials. (Blood. 2015;125(23):3559-3562)

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Summary:A limited number of patients with adult T cell leukemia/lymphoma (ATL) who received autologous stem cell transplantation (ASCT) have been reported. We report here a case of fatal systemic Candida krusei infection in a female patient with ATL undergoing ASCT. All of the eight patients (including seven patients in the literature) with ATL who received ASCT developed relapse of ATL or death due to ASCT complication, irrespective of subtype or remission state of ATL, source or selection of SCT or conditioning regimen. At present, ASCT appears to provide little benefit for ATL in contrast to that for other types of aggressive non-Hodgkin's lymphoma. Keywords: ATL; HTLV-1; auto-BMT; auto-PBSCT Adult T cell leukemia/lymphoma (ATL) is a distinct clinicopathological entity, ie peripheral T lymphocytic malignancy caused by human T lymphotropic virus type 1 (HTLV-1). 1,2 Despite recent progress in combination chemotherapy for non-Hodgkin's lymphoma (NHL), acute and lymphoma types of ATL generally have a very poor prognosis with less than 1 year median survival because of infectious complications due to T cell immunodeficiency, multidrug resistance of ATL cells, large tumor burden with multi-organ failure and/or hypercalcemia. [3][4][5] At present, there is no standard therapy for ATL in contrast to CHOP therapy for aggressive NHL. 3,6 High-dose ablative therapy and autologous stem cell transplantation (ASCT) have been shown to be superior to non-ablative therapy in aggressive NHL as initial and salvage treatment. 7,8 High-dose therapy and ASCT has been reported in a limited number of patients with ATL, but most of those were in the form of an abstract. [9][10][11][12][13][14] We report here a case of fatal systemic Candida krusei (C. krusei) infection in a female patient with ATL undergoing ASCT, and review the reported ATL cases that received this therapy.

This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, À 2-30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P o 0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival.

Key Points• ATL patients who relapsed after allogeneic HSCT have a very high mortality rate and present a serious therapeutic challenge.• No large study exists that assesses the role of salvage therapies for relapsed ATL after HSCT; this is the first report summarizing the outcome.Adult T-cell leukemia/lymphoma (ATL) relapse is a serious therapeutic challenge after allogeneic hematopoietic stem cell transplantation (allo-SCT). In the present study, we retrospectively analyzed 35 patients who experienced progression of or relapsed persistent ATL after a first allo-SCT at 3 institutions in Nagasaki prefecture (Japan) between 1997 and 2010. Twenty-nine patients were treated by the withdrawal of immune suppressants as the initial intervention, which resulted in complete remission (CR) in 2 patients. As the second intervention, 9 patients went on to receive a combination of donor lymphocyte infusion and cytoreductive therapy and CR was achieved in 4 patients. Of 6 patients who had already had their immune suppressants discontinued before the relapse, 3 patients with local recurrence received local cytoreductive therapy as the initial treatment, which resulted in CR for more than 19 months. Donor lymphocyte infusion-induced remissions of ATL were durable, with 3 cases of long-term remission of more than 3 years and, interestingly, the emergence or progression of chronic GVHD was observed in all of these cases. For all 35 patients, overall survival after relapse was 19.3% at 3 years. The results of the present study suggest that induction of a graft-versus-ATL effect may be crucial to obtaining durable remission for ATL patients with relapse or progression after allo-SCT. (Blood. 2013;121(1):219-225)