Successful treatment with bortezomib for POEMS syndrome, overcoming complicated severe heart block.

Cardiac bradyarrhythmia and conduction disorder may be rare, but recurrent adverse events caused by bortezomib. Here we report a case with POEMS syndrome presenting severe heart block after bortezomib plus dexamethasone therapy. After permanent pacemaker implantation, bortezomib was restarted and maintained, resulting in sustained complete response for POEMS syndrome.

Improvement of immune thrombocytopenia with imatinib therapy following chronic myeloid leukemia.

Immune thrombocytopenia (ITP) and chronic myeloid leukemia (CML) are rarely observed concurrently. Here we report the case of a patient with ITP who developed CML that has been well controlled with tyrosine kinase inhibitor (TKI) therapy. A 55-year-old man was diagnosed with ITP. No cytogenetic abnormalities were found at the time of initial diagnosis. Four years later, he began corticosteroid therapy for progression of thrombocytopenia. At that time, the Philadelphia (Ph) chromosome was observed in 7 of 20 bone marrow (BM) cells, suggesting concurrent CML in the subclinical stage. Prednisolone resulted in a partial response. Seven months after starting prednisolone, he exhibited hematological features of CML with an increase in Ph-positive cells. TKI therapy with imatinib mesylate was started to treat CML and maintained at a daily dose of 400 mg. The patient achieved and sustained a major molecular response. His platelet count also increased, enabling discontinuation of corticosteroid therapy. TKIs have been reported to show various immunological off-target effects. In this case, off-target effects of TKI might have improved ITP by suppressing the autoimmune response. Alternatively, reconstitution of immune systems by Ph-negative cells or cancellation of immunoreaction against CML could have exerted favorable effects on ITP.

Biallelic BCL6 rearrangements by dual t(3;14)(q27;q32) and t(3;22)(q27;q11) translocations in diffuse large B-cell lymphoma.

3q27 chromosomal translocation involving the BCL6 gene is one of the most frequent forms of cytogenetic abnormality observed in B-cell lymphoma. We report a case with diffuse large B-cell lymphoma (DLBCL) presenting dual 3q27 translocations. The patient was a 71-year-old man who presented with swelling of multiple abdominal lymph nodes (LNs) and obstructive jaundice. LN biopsy exhibited dense proliferation of atypical large cells expressing CD20, MUM1/IRF4, BCL2, BCL6, and MYC, but not CD10. He was diagnosed with non-GCB/ABC type DLBCL and showed an initially good response to R-CHOP chemotherapy, but relapsed soon after the completion of therapy. Chromosomal analysis of the biopsied LN exhibited multiple abnormalities including t(3;14)(q27;q32) and t(3;22)(q27;q11). Fluorescence in situ hybridization (FISH) using BCL6 break-apart probes confirmed chromosomal breaks occurring on both BCL6 alleles. Molecular analysis revealed two independent rearrangements of BCL6, either with the IGH or the IGL gene. 3q27 breakpoints were located 1.2kb apart from each other within the first intron of BCL6, while the IGH and IGL breaks occurred at the 5' of IGHG2 and within IGLV3-1, respectively. The results suggest that biallelic BCL6 rearrangements might be a rare but recurrent genetic event in B-cell lymphoma.

Factors that cause endodontic failures in general practices in Japan.

BACKGROUND: Bacterial biofilms that develop on root surfaces outside apical foramens have been found to be associated with refractory periapical periodontitis. However, several other factors cause endodontic failures apart from extraradicular biofilms. The aim of this study was to identify the factors causing endodontic failures in general practices in Japan. METHODS: Patients diagnosed as having refractory periapical periodontitis by general practitioners and who requested endodontic treatment at Osaka University Dental Hospital were selected by checking medical records from April 2009 to March 2013. Factors causing endodontic failures were identified. RESULTS: A total of 103 teeth were selected, and 76 teeth completed root-canal treatment. Tooth extractions were required for 18 teeth after or without endodontic treatment. Six teeth required apicoectomy after endodontic treatment. One tooth needed hemisection. One tooth needed intentional replantation. One tooth needed adhesion and replantation. The main causes of treatment failure were open apices (24 teeth), perforation (18 teeth), and root fracture (13 teeth). In six teeth with open apices that required apicoectomy or extraction, extraradicular biofilms may have been related to endodontic failure. CONCLUSIONS: Most endodontic cases diagnosed with refractory periapical periodontitis by general practitioners were compromised by any other factors rather than extraradicular biofilms.

Primordial oscillations in life: Direct observation of glycolytic oscillations in individual HeLa cervical cancer cells.

We report the first direct observation of glycolytic oscillations in HeLa cervical cancer cells, which we regard as primordial oscillations preserved in living cells. HeLa cells starved of glucose or both glucose and serum exhibited glycolytic oscillations in nicotinamide adenine dinucleotide (NADH), exhibiting asynchronous intercellular behaviors. Also found were spatially homogeneous and inhomogeneous intracellular NADH oscillations in the individual cells. Our results demonstrate that starved HeLa cells may be induced to exhibit glycolytic oscillations by either high-uptake of glucose or the enhancement of a glycolytic pathway (Crabtree effect or the Warburg effect), or both. Their asynchronous collective behaviors in the oscillations were probably due to a weak intercellular coupling. Elucidation of the relationship between the mechanism of glycolytic dynamics in cancer cells and their pathophysiological characteristics remains a challenge in future.

Fabrication of Biomimetic Bone Tissue Using Mesenchymal Stem Cell-Derived Three-Dimensional Constructs Incorporating Endothelial Cells.

The development of technologies to promote vascularization of engineered tissue would drive major developments in tissue engineering and regenerative medicine. Recently, we succeeded in fabricating three-dimensional (3D) cell constructs composed of mesenchymal stem cells (MSCs). However, the majority of cells within the constructs underwent necrosis due to a lack of nutrients and oxygen. We hypothesized that incorporation of vascular endothelial cells would improve the cell survival rate and aid in the fabrication of biomimetic bone tissues in vitro. The purpose of this study was to assess the impact of endothelial cells combined with the MSC constructs (MSC/HUVEC constructs) during short- and long-term culture. When human umbilical vein endothelial cells (HUVECs) were incorporated into the cell constructs, cell viability and growth factor production were increased after 7 days. Furthermore, HUVECs were observed to proliferate and self-organize into reticulate porous structures by interacting with the MSCs. After long-term culture, MSC/HUVEC constructs formed abundant mineralized matrices compared with those composed of MSCs alone. Transmission electron microscopy and qualitative analysis revealed that the mineralized matrices comprised porous cancellous bone-like tissues. These results demonstrate that highly biomimetic bone tissue can be fabricated in vitro by 3D MSC constructs incorporated with HUVECs.

Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs.

A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.

Improved reproducibility of simple quantitative indices from 99mTc-GSA liver functional imaging.

OBJECTIVE: We evaluated intra- and interoperator reproducibilities in calculating the conventional indices HH15 and LHL15 from (99m)Tc-diethylenetriamine pentaacetic acid galactosyl human serum albumin ((99m)Tc-GSA) scintigraphy, and proposed new, simple methods for the calculation of quantitative indices. METHODS: The results of (99m)Tc-GSA scintigraphy in 33 patients were retrospectively analyzed. Heart and liver ROIs were drawn manually to cover cardiac blood pool and entire liver, respectively, and HH15 and LHL15 were calculated. In addition, square regions of interest (ROIs) of fixed sizes were placed at the highest activity in blood pool and the liver. Using the square heart ROI, sHH15, an equivalent of HH15, was computed. Fractional liver uptake at 15 min (FLU15) was calculated using the square heart and liver ROIs. Intra- and interoperator reproducibilities, as well as correlation with Indocyanine green retention rate at 15 min (ICG R15), were assessed for these four indices by linear regression analysis. RESULTS: Substantial intra- and interoperator variabilities were found for HH15 and LHL15. The correlation coefficients for intra- and interoperator comparisons were 0.884 and 0.869 for HH15, respectively, and 0.919 and 0.917 for LHL15, respectively. The use of square ROIs instead of hand-drawn ROIs improved reproducibility. The correlation coefficients for intra- and interoperator comparisons were 0.988 and 0.973 for sHH15, respectively, and 0.989 and 0.975 for FLU15, respectively. Correlation with ICG R15 was better for sHH15 (r = 0.619) and FLU15 (r = -0.656) than for HH15 (r = 0.439) and LHL15 (r = -0.490). CONCLUSIONS: HH15 and LHL15 showed substantial intra- and interoperator variabilities, and the use of square ROIs are indicated to provide better reproducibility.

Acquisition protocols and correction methods for estimation of the heart-to-mediastinum ratio in 123I-metaiodobenzylguanidine cardiac sympathetic imaging.

UNLABELLED: Septal penetration of high-energy photons affects quantitative results in imaging of (123)I-labeled tracers. We investigated acquisition protocols (collimator choice and energy window setting) and correction methods for estimating the heart-to-mediastinum (H/M) ratio in cardiac (123)I-metaiodobenzylguanidine (MIBG) imaging. METHODS: Four hours after (123)I-MIBG injection, 40 patients successively underwent planar anterior chest imaging with the medium-energy (ME) (ME method) and low-energy high-resolution (LEHR) (LEHR method) collimators. A 20% energy window was used for both collimators. Another 40 patients were imaged successively with the ME collimator and a 20% window (ME method), the low-medium-energy (LME) collimator and a 20% window (LME20 method), and the LME collimator and a 15% window (LME15 method). The H/M ratios obtained by the LEHR, LME20, and LME15 methods were corrected using their correlations with the H/M ratio obtained by the ME method (empiric correction). The (123)I-dual-window (IDW) correction was also applied to remove the influence of high-energy photons. RESULTS: Without correction, severe underestimation of the H/M ratio was shown for the LEHR method using the ME method as a standard, and this underestimation increased with increasing H/M ratios. Underestimation substantially decreased using the LME20 method and further using the LME15 method. Empiric correction reduced the error in the H/M ratio by the LEHR method, but the error was still evident. After empiric correction, the H/M ratios with the LME collimator were comparable to those with the ME collimator. The IDW correction only partially reduced underestimation by the LEHR method and caused a small overestimation for the LME15 method. CONCLUSION: The use of an LME collimator appears to be acceptable for cardiac (123)I-MIBG imaging as an alternative to an ME collimator, and the application of a 15% energy window is recommended when an LME collimator is used. Empiric correction is also expected to improve exchangeability between H/M ratios calculated with ME and LME collimators. Neither the use of an LEHR collimator nor the use of IDW correction is recommended.

Development of a phantom to evaluate the positioning accuracy of patient immobilization systems using thermoplastic mask and polyurethane cradle.

PURPOSE: The purpose of this study was to develop a new phantom to evaluate the positioning accuracy of patient immobilization systems. METHODS: The phantom was made of papers formed into a human shape, paper clay, and filling rigid polyester. Acrylonitrile butadiene styrene (ABS) pipes were inserted at anterior-posterior (A-P) and right-left (R-L) directions in the phantom to give static load by pulling ropes through the pipes. First, the positioning precision of the phantom utilizing a target locating system (TLS) was evaluated by moving the phantom on a couch along inferior-superior (I-S), A-P, and R-L directions in a range from -5 mm to +5 mm. The phantom's positions detected with the TLS were compared with values measured by a vernier caliper. Second, the phantom movements in a tensile test were chosen from patient movements determined from 15 patients treated for intracranial lesions and immobilized with a thermoplastic mask and polyurethane cradle. The phantom movement was given by minimum or maximum values of patient movements in each direction. Finally, the relationship between phantom movements and the static load in the tensile test was characterized from measurements using the new phantom and the TLS. RESULTS: The differences in all positions between the vernier caliper measurement and the TLS detected values were within 0.2 mm with frequencies of 100%, 95%, and 90% in I-S, A-P, and R-L directions, respectively. The phantom movements according to patient movements in clinical application in I-S, A-P, and R-L directions were within 0.58 mm, 0.94 mm, and 0.93 mm from the mean value plus standard deviation, respectively. The regression lines between the phantom movements and static load were given by y = 0.359x, y = 0.241x, and y = 0.451x in I-S, A-P, and R-L directions, respectively, where x is the phantom movement (mm) and y is the static load (kgf). The relationship between the phantom movements and static load may represent the performance of inhibiting patient movements, so the accuracy of the immobilization system in the intracranial lesion will be estimated in advance by basic tensile test on the new phantom. CONCLUSIONS: The newly developed phantom was useful to evaluate the accuracy of immobilization systems for a Cyberknife system for intracranial lesions.

Photodegradative surfactants: photolyses of p-alkylbenzyltrimethylammonium and alkylbenzyldimethylammonium halides in aqueous solution.

A series of benzyl-containing ammonium salts, p-alkylbenzyltrimethylammonium halides (C(n)BA: 1a-c) and alkylbenzyldimethylammonium halides (C(n)AB: 2a-d), have been prepared and their photodegradabilities in aqueous solutions have been compared. The photolytic decomposition proceeded by heterolytic and homolytic cleavages of the benzyl-nitrogen bond. The conversion yields were almost the same for all surfactants, whereas the product yields were slightly dependent on the alkyl-chain length. After irradiation, C(8)BA (1b) and C(12)BA (1c) were converted to non-surfactants, whereas C(12)AB (2c) and C(16)AB (2d) still remained surface-active. Their solution properties were concomitantly changed.

[Systemic capillary leak syndrome presenting remarkable erythrocytosis].

Systemic capillary leak syndrome (SCLS) is a disorder characterized by hypotension, edema, and an increased hematocrit (Ht) due to sudden leakage of plasma into the extravascular space through some unknown mechanism, in which monoclonal gammopathy is observed. A 30-year-old man visited our emergency department because of abdominal pain, and was admitted to our hematology department because of a markedly increased hemoglobin concentration reaching 26.2 g/dl. The polycythemia was thought to be pseudo-polycythemia due to hemoconcentration, and we diagnosed the patient as having SCLS based on the triad of increased hematocrit, whole-body edema which was especially marked in the lower extremities, and monoclonal gammopathy. The patient recovered after administration of extracellular fluids and albumin, but the attacks recurred. Prophylaxis with terbutaline sulfate, theophylline and corticosteroid reduced the frequency of severe attacks. Because there is possibility that patients with SCLS may be admitted to hematology departments due to severe erythrocytosis, we report this case to increase the awareness of hematologists that SCLS is one of the important differential diagnoses of erythrocytosis.

Efficacy of carboplatin with an MEP (mitoxantrone, etoposide and prednisone) regimen for relapsed and CHOP-resistant diffuse large B-cell lymphomas.

Mitoxantrone, etoposide and prednisone (MEP)-based regimens using granulocyte colony-stimulating factor (G-CSF) were designed for relapsed and CHOP-resistant diffuse large B-cell lymphomas in a single institution, and the therapeutic effects and adverse reactions were studied. In a total of 49 patients, the MEP regimen had a 41% (9/22) overall response rate compared with 48% (13/27) for the MEP plus carboplatin (C-MEP) regimen (Chi-squared test, P=0.602). Among 38 CHOP-resistant patients, however, the overall response rate to C-MEP [42% (10/24)] was significantly superior compared with MEP [7% (1/14)] (P=0.023), and the overall survival to C-MEP was superior compared with MEP (P=0.088). Taken together, our results, although non-randomized, suggest that a combination of MEP with carboplatin is better than MEP alone in CHOP-resistant diffuse large B-cell lymphomas.