Contrast-enhanced CT rim sign may predict vestibular schwannoma adhesion and postoperative complications.

AIM: To investigate the clinical and radiological features to predict adhesion between vestibular schwannoma (VS) and brain tissue which is a critical risk factor for postoperative infarction and residual tumour. MATERIAL AND METHODS: One hundred and seven consecutive VS surgeries were analysed. After excluding cases without contrast-enhanced (CE) computed tomography (CT), Koos grades 1 and 2, and cases with incomplete clinical data, 44 patients were finally included in the study. Enhancement of the tumour capsule on the brainstem side on CE-CT was defined as the CE-CT rim sign, which was analysed along with clinical characteristics, including tumour adhesion and postoperative complications. RESULTS: Eight patients exhibited CE-CT rim signs; 17 had tumour adhesions. Four patients had postoperative infarction at the ipsilateral middle cerebellar peduncle; 18 exhibited postoperative infarction and/or residual tumour at the middle cerebellar peduncle. The CE-CT rim sign significantly correlated with tumour adhesion, postoperative infarction, and postoperative infarction and/or residual tumour in the cerebellar peduncle. Univariate regression analysis revealed that the CE-CT rim sign significantly correlated with tumour adhesion (odds ratio [OR] 6.81, 95% confidence interval [CI] 1.18-39.25, p=0.032) and postoperative infarction and/or residual tumour at the cerebellar peduncle (OR 6.00, 95% CI 1.04-34.31, p=0.044). CONCLUSION: The CE-CT rim sign was identified in 18.2% of patients with VS and significantly correlated with tumour adhesion and postoperative complications, such as postoperative infarction and residual tumour. This study highlights the importance of the preoperative CE-CT rim sign in VS, which is predictive of tumour adhesion and postoperative complications.

Lipoteichoic acids are embedded in cell walls during logarithmic phase, but exposed on membrane vesicles in Lactobacillus gasseri JCM 1131T.

Lipoteichoic acid (LTA) is a cell surface molecule specific to Gram-positive bacteria. How LTA localises on the cell surface is a fundamental issue in view of recognition and immunomodulation in hosts. In the present study, we examined LTA localisation using strain JCM 1131T of Lactobacillus gasseri, which is a human intestinal lactic acid bacterium, during various growth phases by immunoelectron microscopy. We first evaluated the specificity of anti-LTA monoclonal antibody clone 55 used as a probe. The glycerophosphate backbone comprising almost intact size (20 to 30 repeating units) of LTA was required for binding. The antibody did not bind to other cellular components, including wall-teichoic acid. Immunoelectron microscopy indicated that LTA was embedded in the cell wall during the logarithmic phase, and was therefore not exposed on the cell surface. Similar results were observed for Lactobacillus fermentum ATCC 9338 and Lactobacillus rhamnosus ATCC 7469T. By contrast, membrane vesicles were observed in the logarithmic phase of L. gasseri with LTA exposed on their surface. In the stationary and death phases, LTA was exposed on cell wall-free cell membrane generated by autolysis. The dramatic alternation of localisation in different growth phases and exposure on the surface of membrane vesicles should relate with complicated interaction between bacteria and host.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.

Constitutively active ABL family kinases, TEL/ABL and TEL/ARG, harbor distinct leukemogenic activities in vivo.

ABL (ABL1) and ARG (ABL2) are highly homologous to each other in overall domain structure and amino-acid sequence, with the exception of their C termini. As with ABL, translocations that fuse ARG to ETV6/TEL have been identified in patients with leukemia. To assess the in vivo leukemogenic activity of constitutively active ABL and ARG, we generated a bone marrow (BM) transplantation model using the chimeric forms TEL/ABL and TEL/ARG, which have comparable kinase activities. TEL/ABL rapidly induced fatal myeloid leukemia in recipient mice, whereas recipients of TEL/ARG-transduced cells did not develop myeloid leukemia, instead, they succumbed to a long-latency infiltrative mastocytosis that could be adoptively transferred to secondary recipients. Swapping of the C termini of ABL and ARG altered disease latency and phenotypes. In a detailed in vitro study, TEL/ARG strongly promoted mast cell differentiation in response to stem cell factor or interleukin-3, whereas TEL/ABL preferentially induced myeloid differentiation of hematopoietic stem/progenitor cells. These results indicate that ABL and ARG kinase activate distinct differentiation pathways to induce specific diseases in vivo, that is, myeloid leukemia and mastocytosis, respectively. Further elucidation of the differences in their properties should provide important insight into the pathogenic mechanisms of oncogenes of the ABL kinase family.

A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation.

Previous studies have suggested that tacrolimus (TAC) is more potent than cyclosporine (CSA) for prophylaxis against acute GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). However, the target blood concentrations of these drugs in these studies were not consistent with the current recommendations. Therefore, we performed a randomized controlled trial to compare CSA and TAC with target blood concentrations of 500 and 15 ng/ml, respectively, to prevent acute GVHD after unrelated HSCT. A total of 107 patients were randomized into a CSA group (n=53) or a TAC group (n=54). During the first 4 weeks after HSCT, more than 90% of the patients achieved a mean blood concentration of between 80 and 120% of the target concentration. The incidences of grade II-IV and grade III-IV acute GVHD were 39.6 and 7.5% for the CSA group and 33.3 and 9.4% for the TAC group, respectively (P=0.41 and P=0.76). Other clinical outcomes, including overall survival, disease-free survival and the incidences of relapse, non-relapse mortality, and organ toxicities, were also equivalent. We concluded that the combinations of CSA and TAC with strict dose adjustment showed similar efficacies and toxicities as prophylaxis against acute GVHD after unrelated HSCT.

Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes.

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, -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<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.

Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR-ABL-positive ALL.

We investigated prognostic factors for the clinical outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. Among 100 adult patients who were prospectively enrolled in the JALSG Ph+ALL202 study, 97 patients obtained complete remission (CR) by imatinib-combined chemotherapy, among whom 60 underwent allo-HSCT in their first CR. The probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years after HSCT were 64% (95% CI, 49-76) and 58% (95% CI, 43-70), respectively. Prognostic factor analysis revealed that the major BCR-ABL transcript was the only unfavorable predictor for OS and DFS after HSCT by both univariate (HR, 3.67 (95% CI 1.49-9.08); P=0.005 and HR, 6.25 (95% CI, 1.88-20.8); P=0.003, respectively) and multivariate analyses (HR, 3.20 (95% CI, 1.21-8.50); P=0.019 and HR, 6.92 (95% CI, 2.09-22.9); P=0.002, respectively). Minimal residual disease status at the time of HSCT had a significant influence on relapse rate (P=0.015). Further study of the BCR-ABL subtype for the clinical impact on outcome of allo-HSCT in Ph+ALL is warranted.

[Cardiovascular surgery with multiple myeloma].

There are few case reports of cardiovascular surgery with multiple myeloma. We report 3 cases of cardiovascular surgery with multiple myeloma. CASE 1: A 73-year-old male hemodialytic patient with multiple myeloma was performed off-pump coronary artery bypass grafting (OPCAB) for angina. He was dead on the 72th postoperative day because of sepsis. CASE 2: A 68-year-old female patient with multiple myeloma was performed mitral valve replacement for mitral regurgitation. The postoperative course was uneventful. CASE 3: A 78-year-old male patient, the aorta was replaced with a artificial graft for impending rupture of thoracoabdominal aortic aneurysm. He was diagnosed with multiple myeloma after surgery. He was dead on the 99th postoperative day because of sepsis. One of the affecting prognosis factors is infection and it is intractable.

Secondary solid tumors after allogeneic hematopoietic SCT in Japan.

To evaluate the incidence and risk factors for secondary solid tumors in Japan after allogeneic hematopoietic SCT (allo-HSCT), 2062 patients who had received allo-HSCT between 1984 and 2005 were retrospectively analyzed. Twenty-eight patients who developed 30 solid tumors were identified a median of 5.6 years after transplantation. The risk for developing tumors was 2.16-fold higher than that of the age- and sex-adjusted general population. The cumulative incidence of solid tumors at 10 years after allo-HSCT was 2.4%. The risk was significantly higher for tumors of the skin, oral cavity and esophagus (standard incidental ratio 40.23, 35.25 and 10.73, respectively). No increase in gastric, colon or lung cancer, despite being the most prevalent neoplasm in the Japanese, was observed. In multivariate analysis, occurrence of chronic GVHD and malignant lymphoma as a primary disease was associated with a higher risk for developing solid tumors. Eighteen patients are still alive, and their 5-year probability of survival since diagnosis of solid tumors is 59.7%. Our data suggest that the incidence and risk factors of secondary solid tumors in Japanese allo-HSCT recipients are comparable to those reported in Western countries and emphasize that the early detection of solid tumors has a crucial role in improving OS.

AV-65, a novel Wnt/ß-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model.

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that ß-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/ß-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished ß-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment.

Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl(+) leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl(+) stem cells is needed to cure leukemias caused by Bcr-Abl(+) cells. Human Bcr-Abl(+) cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl(+) sublines by selection in long-term hypoxic cultures (1.0% O(2)). Interestingly, HA-Bcr-Abl(+) cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher beta-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl(+) cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl(+) cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl(+) leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl(+) leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment.

[Cardiac surgery in an octogenarian with idiopathic thrombocytopenic purpura: report of a case].

An 81-year-old woman was referred to our hospital for surgical treatment for mitral valve regurgitation, tricuspid valve regurgitation and atrial fibrillatory bradycardia. The platelet count on admission was 4.9 x 10(4)/microl. and the results of other studies were compatible with idiopathic thrombocytopenic purpura. Although we performed high-dose transvenous immunoglobulin infusion (400 mg/kg/day) for 5 consecutive days, the platelet count showed no remarkable change. Because of progression of heart failure, we underwent cardiac operation under thrombocytopenic condition. Intra and post-operative platelet transfusion might contribute to postoperative course uneventful without bleeding tendency. In this case, high-dose immunoglobulin therapy was not effective. However the operative course was satisfactory with adequate surgical hemostasis and platelet transfusion.

Chronic osmotic stimuli increase salusin-beta-like immunoreactivity in the rat hypothalamo-neurohypophyseal system: possible involvement of salusin-beta on [Ca2+]i increase and neurohypophyseal hormone release from the axon terminals.

Salusin-alpha and -beta were recently discovered as bioactive endogenous peptides. In the present study, we investigated the effects of chronic osmotic stimuli on salusin-beta-like immunoreactivity (LI) in the rat hypothalamo-neurohypophyseal system. We examined the effects of salusin-beta on synaptic inputs to the rat magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) and neurohypophyseal hormone release from both freshly dissociated SONs and neurohypophyses in rats. Immunohistochemical studies revealed that salusin-beta-LI neurones and fibres were markedly increased in the SON and the magnocellular division of the paraventricular nucleus after chronic osmotic stimuli resulting from salt loading for 5 days and dehydration for 3 days. Salusin-beta-LI fibres and varicosities in the internal zone of the median eminence and the neurohypophysis were also increased after osmotic stimuli. Whole-cell patch-clamp recordings from rat SON slice preparations showed that salusin-beta did not cause significant changes in the excitatory and inhibitory postsynaptic currents of the MNCs. In vitro hormone release studies showed that salusin-beta evoked both arginine vasopressin (AVP) and oxytocin release from the neurohypophysis, but not the SON. In our hands, in the neurohypophysis, a significant release of AVP and oxytocin was observed only at concentrations from 100 nm and above of salusin-beta. Low concentrations below 100 nm were ineffective both on AVP and oxytocin release. We also measured intracellular calcium ([Ca(2+)](i)) increase induced by salusin-beta on freshly-isolated single nerve terminals from the neurohypophysis devoid of pars intermedia. Furthermore, this salusin-beta-induced [Ca(2+)](i) increase was blocked in the presence of high voltage activated Ca(2+)channel blockers. Our results suggest that salusin-beta may be involved in the regulation of body fluid balance by stimulating neurohypophyseal hormone release from nerve endings by an autocrine/paracrine mechanism.

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia.

Bcr-Abl is the cause of Philadelphia-positive (Ph(+)) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph(+) leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X(L), greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph(+) leukemic cells.

A third-generation bisphosphonate, minodronic acid (YM529), successfully prevented the growth of bladder cancer in vitro and in vivo.

Minodronic acid (YM529) is a third-generation bisphosphonate (BP) that has been shown to directly and indirectly prevent proliferation, induce apoptosis, and inhibit metastasis of various types of cancer cells. In this study, we have investigated the therapeutic efficacy of YM529 against bladder cancer, both in vitro and in vivo. YM529 inhibited geranylgeranylation as well as farnesylation and reduced the growth of all seven bladder cancer cell lines in a dose- and time-dependent manner in vitro. YM529 demonstrated a good synergistic or additive antiproliferative effect when administered in combination with cisplatin or paclitaxel. Immunohistochemical study revealed YM529 inhibited the prenylation of Rap1A in vivo. YM529 administered systemically did not markedly inhibit the growth of visceral metastases but it showed a significant anticancer effect on bone metastases monitored by an in vivo imaging system. Moreover, intravesical YM529 demonstrated significant growth inhibition in a bladder cancer orthotopic model. No adverse effects were associated with the systemic as well as the intravesical treatment regimens. In conclusion, our study suggests that YM529 may be a potent anticancer agent for bladder cancer. The efficacy and safety of this BP as an agent for combination chemotherapies against bladder cancer should be verified by early-phase clinical trials.

An unusual case of split cord malformation.

We present a variant of a split cord malformation with coexisting segmental spinal dysgenesis. CT myelography showed the left hemicord with a small remnant of subarachnoid space running through an intravertebral cleft in a spine anomaly. The left hemicord had no apparent intradual connection to the upper cord on any radiologic examination, though functional electrical stimulation studies revealed an intact efferent pathway that connected the left hemicord to the main spinal cord.