Introduction
BCOR‐CCNB3 sarcoma (BCS) is one of the histological types classified as an undifferentiated small round cell sarcoma of bone and soft tissue. This sarcoma frequently develops in males ...under 20 years of age. Histologically, a delicate capillary network has been reported as a conspicuous finding. In this study, the cytological findings of BCS were observed in two cases of primary lesions and one case of a lung metastatic lesion. The cytological findings of BCS were compared with its histological mimics, and the characteristic findings of BCS were examined.
Methods
Three cases of BCS were studied, and a cytological comparison was performed with 8 cases of Ewing sarcoma (ES) and 10 cases of synovial sarcoma (SS; monophasic type: 7 cases, biphasic type: 2 cases, poorly differentiated: 1 case).
Results
In all BCS cases, small clusters with thin and delicate vascular cores and tiny vascular fragments were conspicuous. In ES and SS cases, although small clusters with vascular cores were observed, the vascular cores were thicker than in BCS, and no tiny vascular fragments appeared in most cases. Cytomorphological differences of tumour cells were also observed among BCS, ES, and SS. Predominantly rounded nuclei with fine chromatin and inconspicuous nucleoli can be cytological clues for BCS.
Conclusions
BCS shows characteristic cytological findings that make the diagnosis of BCS more likely than that of ES and SS. Cytological evaluation is a useful tool for appropriate differential diagnosis that leads to a more accurate final diagnosis and rapid treatment.
BCS sarcoma shows characteristic cytological findings compared to its histological mimics, ES and SS. Cytological evaluation is a useful tool for appropriate differential diagnosis that leads to a more accurate final diagnosis and rapid treatment.
Polypharmacy, common in patients with diabetes, may cause adverse drug reactions. The number of antidiabetic and non-antidiabetic drugs prescribed to patients in different age groups remains unclear. ...The aim of this study was to examine the number and class of antidiabetics and non-antidiabetics prescribed to Japanese patients with diabetes, stratified by age for reducing polypharmacy. This cross-sectional study examined all prescriptions of patients prescribed antidiabetics at 257 pharmacies of Matsumotokiyoshi Holdings in Japan from May 2018 to March 2019. Total prescription numbers including antidiabetic drugs were 263,915 in this study. Mean numbers of antidiabetic drugs per prescription were 1.71, 2.17, and 1.52 in the patient age groups of 10–19, 50–59, and 90–99 years, respectively. Count of antidiabetics was not related to age. However, the mean total number of drugs prescribed increased with age, which was 2.22 and 7.99 in the age groups of 10–19 and 90–99 years, respectively. The linear regression coefficient (b) according to age was 0.07 (p < 0.001) for 10–99 years. The mean non-antidiabetic number of agents prescribed increased with age among 10–99 years (b = 0.07, p < 0.001). Among outpatients treated for diabetes, dipeptidyl peptidase-4 inhibitors (29%) and antihypertensive, β-blocking and renin-angiotensin system blocking drugs (32%) were the most prescribed antidiabetics and non-antidiabetics in all ages, respectively. The number of prescribed antidiabetic agents did not increase with age, whereas the total and non-antidiabetic numbers of medications prescribed increased linearly. For reduction of polypharmacy in older people with diabetes, we need to focus on non-antidiabetics.
X-linked nephrogenic diabetes insipidus (NDI) is caused by variations in arginine vasopressin receptor 2 (AVPR2). Some patients show partial resistance to arginine vasopressin (AVP). A 19-month-old ...Japanese boy presented with polydipsia since infancy. His mother had a history of polydipsia during pregnancy, and his maternal granduncle also had polydipsia. Intermediate urine osmolality and markedly high plasma AVP levels were observed in the water deprivation test. Subsequent pitressin administration caused no further elevation in urine osmolality. We diagnosed the patient with partial NDI, initiated therapy with hydrochlorothiazide, and placed him on a low-sodium diet. Although his urine volume decreased by 20–30% after the initiation of therapy, progressive hydronephrosis and growth retardation developed 2 years later. We investigated his genetic background by multiplex targeted sequencing of genes associated with inherited renal diseases, including AVPR2 and aquaporin-2 (AQP2). We identified a hemizygous missense variant in AVPR2 NM_000054:c.371A>G,p.(Tyr124Cys) in the boy and a heterozygous variant in the mother at the same locus. Distinguishing partial NDI from primary polydipsia is difficult because of its mild symptoms. Markedly elevated plasma AVP levels with intermediate urine osmolality may suggest partial NDI, and genetic analysis can be useful for such patients.
► We established an integrated analysis system of amplicons. ► Applying this system to 17q12–21 amplicon, we identified GRB7 as an ERBB2-dependent oncogene. ► GRB7 modulates the ERBB2 signaling ...pathway through enhanced phosphorylation of ERBB2 and Akt. ► BPS domain of GRB7 suppresses, while, the other domains are required for GRB7-mediated transforming activity.
Gene amplification is a major genetic alteration in human cancers. Amplicons, amplified genomic regions, are believed to contain “driver” genes responsible for tumorigenesis. However, the significance of co-amplified genes has not been extensively studied. We have established an integrated analysis system of amplicons using retrovirus-mediated gene transfer coupled with a human full-length cDNA set. Applying this system to 17q12–21 amplicon observed in breast cancer, we identified GRB7 as a context-dependent oncogene, which modulates the ERBB2 signaling pathway through enhanced phosphorylation of ERBB2 and Akt. Our work provides an insight into the biological significance of gene amplification in human cancers.
Wisteria floribunda
agglutinin-positive human Mac-2-binding protein (WFA
+
-M2BP) was developed recently as a predictive marker of progression to liver fibrosis and hepatocellular carcinoma (HCC) in ...patients seropositive for hepatitis C virus (HCV). We retrospectively analyzed 16 HCV-seropositive patients who received systemic chemotherapy for hematologic malignancies to evaluate the usefulness of WFA
+
-M2BP for predicting HCV-related complications. These were defined as the onset of significant liver damage (LD) with increased HCV RNA levels, leading to interrupted or discontinued chemotherapy or the occurrence of HCC after chemotherapy. Baseline WFA
+
-M2BP levels were determined using preserved serum samples. The median level of WFA
+
-M2BP was 1.59 cutoff index (C.O.I.) value range 0.38–6.66. With a median follow-up of 623 days (range 120–2404), LD and HCC were observed in three and two patients, respectively. Detectable HCV RNA and WFA
+
-M2BP ≥2.0 C.O.I. at baseline were identified as risk factors for these HCV-related complications (
P
= 0.034 and
P
= 0.005, respectively). The sensitivity, specificity, and positive and negative predictive values of the WFA
+
-M2BP level (cutoff point: 2.0 C.O.I.) for the occurrence of HCV-related complications were 100.0, 81.8, 71.4, and 100.0 %, respectively. WFA
+
-M2BP may be a useful marker for the prediction of HCV-related complications in HCV-seropositive patients following systemic chemotherapy.
Background: Bortezomib (BTZ), a proteasome inhibitor (PI), mainly targets the beta 5 subunit of the 20S proteasome, and is widely used in the treatment of multiple myeloma (MM). However, inhibitory ...effects on other subunits of the proteasome are not well understood. Therefore, we examined the anti-MM activity of novel syringolin analogs that inhibit the activity of both beta 5 and 2 subunits. After examination, we investigated the activity of compound 19a, developed as a syrbactin-class PI to improve cytotoxic activity and membrane permeability (Chiba T et al. Angew Chem Int Ed. 2014).
Materials and method: First, the cytotoxic and inhibitory effects of compound 19a on 20S proteasomes of MM cells, including BTZ-resistant MM cells and primary samples derived from MM patients, were examined. The primary MM specimens were collected after obtaining written informed consent at Nagoya City University Hospital, and the mechanism of antitumor activity of compound 19a on MM cells was evaluated by focusing on the unfolded protein response and endoplasmic reticulum (ER) stress. Finally, to evaluate the toxicity of compound 19a, BALB/c mice were intraperitoneally injected with either 19a or BTZ and body weight change was analyzed. These in vivo experiments were performed in accordance with the United Kingdom Coordinating Committee on Cancer Research Guidelines for the Welfare of Animals in Experimental Neoplasia, Second Edition, and were approved by the Ethics Committee of the Center for Experimental Animal Science, Nagoya City University Graduate School of Medical Sciences.
Results: The cytotoxic activity of compound 19a, observed in various MM cell lines at nanomolar concentrations, was found to be similar to the activity observed when BTZ-resistant MM and T-cell lymphoma cell lines were tested. More precisely, the two BTZ-resistant cell lines KMS-11/BTZ and OPM-2/BTZ showed 44.4-fold and 52.1-fold higher resistance, respectively, to BTZ than that shown by their parental cell lines KMS-11 and OPM-2. However, the two BTZ-resistant cells showed only 3.2-fold (IC50: 18.0 nM) and 4.3-fold (IC50: 5.1 nM) higher resistance to compound 19a than that shown by their parental cell lines KMS-11 (IC50: 5.7 nM) and OPM-2 (IC50: 1.2 nM), suggesting that compound 19a exhibits less cross-resistance to BTZ. Evaluation of 20S proteasome activity showed time-dependent inhibition of both beta 5 and 2 subunits in MM cells on treatment with compound 19a. Treatment with 10 nM 19a induced remarkable apoptosis of the MM cells, accompanied by elevated CHOP and NOXA expression, indicating excessive ER stress. A similar activity was also observed in primary MM samples derived from the patients. Furthermore, to clarify the effect of beta 2 inhibition on anti-MM activity, two MM cell lines, U266 and AMO1, and one T-cell lymphoma cell line, Hut78, were transfected with either siRNA-targeting PSMB7 encoding beta 2 subunit or control siRNA and were subjected to the analysis of cell growth and viability. Specific knocking down of PSMB7 was observed, which resulted in the progression of apoptosis of the two MM cell lines and Hut78 when compared with the control. In addition, knocking down of both PSMB7 and PSMB5 encoding beta 5 subunits triggered more potent apoptosis of U266 and Hut78 cells when compared with the knocking down of either PSMB7 or PSMB5 alone. This result suggests that dual-inhibitory activities of beta 5 and 2 subunits have an additive or a synergistic effect on cytotoxicity when compared with single inhibitory activity. Finally, to examine the toxicity of compound 19a, BALB/c mice were administrated with it in a dose-escalation manner and subjected to the analysis of alteration of body weight. No significant difference in loss of body weight was observed between 19a-treated and BTZ-treated mice when administered with the same dose. Study of in vivo cytotoxic activity of 19a on xenografted MM cells is currently underway.
Conclusion: We demonstrated the cytotoxic activity of a syringolin analog on various MM cells at nanomolar levels, which was attributed to the dual inhibition of beta 5 and 2 subunits of the 20S proteasome. Compound 19a, as a dual inhibitor of beta 2 and 5, was observed to be a more potent PI than BTZ, and could overcome the acquired BTZ resistance. The findings provide new insight into the treatment of relapse and/or refractory MM.
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Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Iida:Janssen Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.
Background: Several studies have demonstrated that aberrant expression of microRNAs in multiple myeloma (MM) cells is associated with the pathogenesis and development of MM. Recently, circulating ...serum microRNAs have been recognized as novel biomarkers in tumor biology and have predictive value in determining the efficacy of various drugs. However, little is known regarding the role of circulating serum microRNAs in patients with MM in terms of MM biology and the clinical efficacy of anti-MM drugs. In this study, we evaluated the expression levels of serum microRNAs in patients with MM, including newly diagnosed (ND) and relapsed and/or refractory (RR) cases. We also evaluated the correlation of the expression levels of serum microRNAs with the clinical efficacy of bortezomib (BTZ)-containing treatment.
Materials & Methods: Fifteen serum samples from healthy donors and 62 from 10 patients with NDMM and 52 patients with RRMM were collected and subjected to comprehensive microRNA analysis using next-generation sequencing (NGS). First, we compared the microRNA expression levels between healthy donors and patients with MM. Next, using 52 serum samples collected from patients with NDMM and RRMM who received BTZ plus low-dose dexamethasone (Bd) therapy, the correlation between the response to Bd therapy and specific serum microRNA expression profiles was determined.
Results: Approximately 150-250 microRNAs were detected by small RNA analysis of serum samples using NGS. The expression levels of 32 serum microRNAs were higher in MM than in healthy donors (Mann-Whitney U test, P < 0.05). Among them, 5 microRNAs (mir-10a, 10b, 92a, 378a, and 378d) had higher expression in RRMM than in NDMM. These microRNAs are involved in the biology and oncogenesis of several solid tumors, including MM. The mir-92a expression level has been associated with the response to chemotherapy and disease progression in MM.
Regarding the correlation between microRNA expression levels and the clinical efficacy of Bd therapy, expression levels of 14 microRNAs were associated with progression-free survival (PFS) in Bd therapy (Spearmanfs rho < -0.2, P < 0.05). Among them, 5 microRNAs (mir-22, 146a, 193b, 584, and 1307) showed high correlation with PFS (Spearmanfs rho < -0.4, P < 0.002). These microRNAs are involved in angiogenesis, proliferation, and apoptosis in several solid tumors and MM. Next, we divided the 52 samples into two groups according to PFS: short (<6 months; n = 27) or long (≥6 months; n = 25). The short-PFS group showed lower expression of 5 microRNAs (mir-22, 146a, 193b, 320b, and 320c) than the long-PFS group did (Mann-Whitney U test, P < 0.01).
Among them, mir-146a can regulate TRAF6, NF-kB, and TNF-axis, and is regulated by the c-Myc at the transcriptional level. c-Myc-mediated mir-146a overexpression can reduce CXCR4 expression. Several studies suggest that CXCR4 expression is an important factor for MM cells to migrate and interact with stromal cells; lower expression is recognized as a poor prognostic factor in the survival of patients with MM. Therefore, we hypothesized that BTZ-insensitive clone has high mir-146a expression along with low CXCR4 expression, suggesting that low dependence on stromal cells may contribute to the resistance to BTZ activity.
Conclusion: We have demonstrated that the expression levels of several serum microRNAs are associated with the progression of MM and may serve as predictive markers in BTZ-containing therapies in MM. Further validation studies in a larger number of patients is needed and the origin of these serum microRNAs, together with the functional consequences of aberrant expression, must be pursued. Our findings can contribute in developing circulating microRNA analysis as a potential strategy in determining useful biomarkers for diagnosis and therapeutic outcomes in MM.
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Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.
Proteasome inhibitors (PIs) in combination with immunomodulatory drugs (IMiDs) have been shown to be effective against relapsed/refractory multiple myeloma (RRMM). To determine the optimal dosing ...schedule of once weekly bortezomib (BTZ) combined with lenalidomide (LEN) and dexamethasone (DEX), especially in the outpatient setting, we conducted a phase I dose escalation study. A 21-day cycle of BTZ 1.3 mg/m
2
on days 1 and 8, LEN 10 mg/day (cohort 1) or 15 mg/day (cohort 2) on days 1–14, and DEX 20 mg/day on days 1, 2, 8, and 9 was administered. Three patients were enrolled in each cohort. No dose-limiting toxicity was observed in either cohort. Although hematological toxicities estimated as >grade 3 were common, non-hematological toxicities of grade 3 or higher were rare. Two cases of newly diagnosed peripheral neuropathy (PN) were observed, while no grade 3/4 PN was observed. Two patients achieved partial response and two achieved stable disease. The recommended doses of BTZ and LEN were determined to be 1.3 mg/m
2
and 15 mg, respectively. Combination therapy of once weekly BTZ with LEN and DEX was well tolerated and shows promise as a regimen for patients with RRMM previously treated with both PIs and IMiDs.
Afuresertib (AFU), a novel inhibitor of the serine/threonine kinase AKT, has clinical efficacy as a monotherapy against hematological malignancies and is expected to be used in combination with ...standard therapies for multiple myeloma (MM). To develop a more effective and less toxic combination of immunomodulatory drugs (IMiDs) for therapy, the antitumor effect of sub-optimal doses of AFU, pomalidomide plus dexamethasone (PD), and the AFU-PD combination on MM cells were examined in the present study. Two MM cell lines, XG-7 and U266, with low sensitivity to both PD and AFU monotherapies, were subjected to these combinations and analyzed. Although the cell lines showed a slight reduction in viability with the sub-optimal doses of each monotherapy, the combination of the treatments resulted in a reduction in cell viability and the progression of apoptosis. Co-treatment with sub-optimal doses of PD and AFU enhanced caspase activation and highly suppressed the expression of IKZF1 and IKZF3. In addition, this combination promoted the dephosphorylation and stabilization of 4EBP1, an inhibitor of eIF4E activation, which led to the impairment of eIF4E-mediated translational activity. Furthermore, AFU showed a sufficient inhibitory effect on the phosphorylation of FOXO1, a tumor suppressor, in monotherapy or in combination with PD, which may be attributable to the activation of FOXO1, the subsequent inhibition of tumor growth, and the induction of cell death. In conclusion, the combination therapy with sub-optimal doses of PD and AFU exhibited potent antitumor activity in MM cells and may provide a novel strategy for the treatment of patients who experienced intolerable toxicity or insufficient response during IMiD therapy.
To investigate the efficacy of intracerebral (IC) immunization in preventing viral spread in the brain, we immunized mice with inactivated rabies virus via the subcutaneous (SC) or IC route, followed ...by administration of a lethal dose of rabies virus (challenge virus standard strain), directly into the brains of immunized mice. Progressive paralytic neurological signs were observed in control and 75% of SC immunized mice, whereas only 20% of IC immunized mice exhibited symptoms. Neutralizing antibody titers in blood plasma were significantly elevated in SC and IC immunized mice, with the highest levels seen in IC immunized mice. Analysis of whole brain lysates revealed a strong induction of immunoglobulin in the brains of IC immunized mice that had virus neutralizing activity. Histopathological examination of brain tissue revealed mild encephalitis and disseminated viral antigen in control and SC immunized mice, but rare in IC immunized mice. These results suggest that IC immunization induces a preventive humoral immune response against intracerebrally inoculated rabies virus. Induction of neutralizing antibody in cerebrospinal fluid represents a putative therapeutic measure for the treatment of rabid animals and humans.
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