Effect of Dosing Interval Duration of Intermittent Ibandronate Treatment on the Healing Process of Femoral Osteotomy in a Rat Fracture Model

The effects of bisphosphonate treatment schedule on fracture healing have not previously been tested. We evaluated the effect of ibandronate dosing interval duration on healing following surgical “fracture” (osteotomy) using a rat femoral fracture model. Six-week-old rats (n = 160) underwent osteotomy and were then allocated into vehicle control (CNT) or an ibandronate treatment group: 5 μg/kg daily (DAY, 5 days/week), 75 μg/kg once every 3 weeks (I-3), 150 μg/kg once every 6 weeks (I-6), resulting in the same total ibandronate dose over the study. Rats were killed after 6 or 18 weeks. At 18 weeks, all fracture lines had disappeared in the CNT and I-6 groups; approximately 10% of fracture lines remained in the DAY and I-3 groups. Ibandronate-treated groups showed large callus areas around the fractures, which shrank between 6 and 18 weeks after surgery; the extent of shrinkage decreased with shorter dosing interval. In histomorphometry, callus remodeling was suppressed by ibandronate; this became more apparent at shorter dose intervals. The structural properties of osteotomized femora were increased in the DAY group compared with CNT, but intrinsic material properties reduced inversely and became closer to those of CNT in response to increased dosing interval. Ibandronate induced formation of large calluses around osteotomies but delayed woven bone remodeling into lamellar bone and reduced intrinsic material properties in a rat fracture model. Extending the dosing interval of intermittent ibandronate treatment appeared to reduce the suppression of callus remodeling caused by ibandronate, which would have delayed healing after osteotomy.     

Three-dimensional magnetic resonance imaging for stringent diagnosis of advanced fibrosis associated with nonalcoholic steatohepatitis

Background

The definitive diagnosis of nonalcoholic steatohepatitis (NASH) is currently based on histopathological assessment. This study aimed to elucidate the utility of a novel noninvasive method, three-dimensional magnetic resonance imaging (3D-MRI), for diagnosing advanced fibrosis in patients with NASH, using histopathological diagnosis as the reference standard.

Methods

This retrospective study included 30 consecutive patients who had been diagnosed with NASH by histopathology and had undergone 3D-MRI before biopsy. 3D-MRI provided a three-dimensional reconstruction of the liver from contrast-enhanced hepatobiliary phase MR images. In the present study, histopathological advanced fibrosis was defined as stage 3 and 4 NASH. Advanced fibrosis, diagnosed by 3D-MRI, was considered to be diffuse irregularity of the entire surface of the liver. The diagnostic features of 3D-MRI and the noninvasive evaluation systems (APRI, FIB-4 index, and BARD score) for identifying advanced and nonadvanced fibrosis of NASH were determined and compared.

Results

Nine (30 %) of the 30 study patients were diagnosed histopathologically with advanced fibrosis, and 11 (37 %) of 30 patients were diagnosed with advanced fibrosis using 3D-MRI. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 3D-MRI for diagnosing advanced fibrosis were 100, 90, 82, and 100 %, respectively. The sensitivities of APRI, the FIB-4 index, and BARD score ranged from 78 to 89 %, the specificities from 71 to 90 %, the PPVs from 54 to 78 %, and the NPVs from 88 to 94 %.

Conclusion

Compared with the common noninvasive methods for diagnosing advanced fibrosis associated with NASH, 3D-MRI was more accurate.     

Immune-related adverse events and prognosis in patients with upper gastrointestinal cancer treated with nivolumab

BackgroundImmune checkpoint inhibitors (ICIs) are increasingly being used for the treatment of upper gastrointestinal cancers [esophageal cancer and gastric cancer (GC)]. They cause imbalances in immunological tolerance, resulting in immune-related adverse events (irAEs). Although irAEs have been reported to be associated with the efficacy of ICIs in some cancers, the relationship between irAEs and prognosis of upper gastrointestinal cancers remains unknown. This study aimed to investigate the prognostic impact of irAEs in patients with advanced or recurrent upper gastrointestinal cancer treated with nivolumab.MethodsWe retrospectively divided the patients (n=96) who received nivolumab into two groups: the irAEs group (n=41) and non-irAEs group (n=55), according to the Common Terminology Criteria for Adverse Events ver. 5.0.ResultsirAEs were significantly associated with good performance status and high serum albumin levels (all P<0.05). The irAEs group had a significantly longer overall survival (OS) than the non-irAEs group [log-rank P=0.003; univariate hazard ratio (HR) =0.36, 95% confidence interval (CI) =0.21–0.65, P<0.01; multivariate HR =0.47, 95% CI =0.26–0.88, P=0.018]. Importantly, in both esophageal cancer and GC, the irAEs group experienced favorable clinical outcomes compared with the non-irAEs group. In the multivariate analysis, male sex (P<0.01), presence of irAEs (P=0.018), and good pretreatment performance status (P<0.01) were independent prognostic factors.ConclusionsAmong patients with upper gastrointestinal cancer treated with nivolumab, the prognosis of patients who developed irAEs was better than that of patients who did not develop irAEs. Long-term continuation of nivolumab by early detection of irAEs and an appropriate response to irAEs are important.     

The spectrum of imaging appearances of müllerian duct anomalies: focus on MR imaging

Müllerian duct anomalies (MDAs) are the result of incomplete development, vertical or lateral fusion, or absorption of the müllerian ducts. The range of anomalies includes uterovaginal agenesis or hypoplasia, unicornuate uterus, uterus didelphys, bicornuate uterus, septate uterus, and arcuate uterus. Correct diagnosis and classification of these anomalies are essential because pregnancy outcomes and treatment options vary between the types of anomaly. Furthermore, early identification of MDAs helps to avoid prolonged symptomatic periods and the complications that may subsequently arise, such as infertility, endometriosis, and neoplasm. Although many of these abnormalities are initially diagnosed by ultrasound or hysterosalpingography, MR imaging is the most accurate noninvasive modality available for classification of the various anomalies because of its better anatomic assessment compared with other diagnostic modalities. Familiarity with the wide variety of MDA presentations can help in the planning of appropriate treatment.     

Advantages of using the midline incision right retroperitoneal approach for abdominal aortic aneurysm repair

This study was conducted to compare the midline incision right retroperitoneal approach for repairing abdominal aortic aneurysms (AAA) with the transperitoneal approach. The intra- and postoperative course of 15 patients who underwent AAA repair using the transperitoneal approach between 1987 and 1991 and another 15 patients who underwent AAA repair using the retroperitoneal approach between 1991 and 1994 were evaluated. The incidence of postoperative wound complications was also assessed. There was no operative or hospital death in either group. Although a significantly longer interval was required from the incision to the aortic clamp using the extraperitoneal method, there were no statistical differences in the aortic clamping time, total operation time, or blood loss between the two groups. On the other hand, there was a statistically significant improvement in bowel function and a significant reduction in the length of postoperative hospitalization following the extraperitoneal procedure. Furthermore, no wound complications such as those associated with the left flank incision developed after the extraperitoneal procedure. Thus, we recommend the midline incision right retroperitoneal approach for AAA as it does not involve muscle division and is associated with fewer complications.     

Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB)

PURPOSE: Severe myoclonic epilepsy in infancy (SMEI) is a distinct epilepsy syndrome. Patients with borderline SMEI (SMEB) are a subgroup with clinical features similar to those of core SMEI but are not necessarily consistent with the accepted diagnostic criteria for core SMEI. The aim of this study was to delineate the genetic correlation between core SMEI and SMEB and to estimate the frequency of mutations in both phenotypes. METHODS: We examined 96 healthy volunteers and 58 unrelated individuals whose clinical features were consistent with either core SMEI (n = 31) or SMEB (n = 27). We screened for genetic abnormalities within exons and their flanking introns of the genes encoding major subunits of the Na+ channels (SCN1A, SCN2A, SCN1B, and SCN2B) by using a direct sequencing method. RESULTS: In both core SMEI and SMEB, various mutations of SCN1A including nonsense and missense mutations were identified, whereas no mutations of SCN2A, SCN1B, and SCN2B were found within the regions examined. All mutations were heterozygous and not found in 192 control chromosomes. Mutations were identified in 26 (44.8%) of the 58 individuals and were more frequent (p < 0.05) in core SMEI (19 of 31) than in SMEB (seven of 27), as assessed by the continuity-adjusted chi2 test. Mutations resulting in a molecular truncation were found only in core SMEI. Among the mutations, two missense mutations were found in both core SMEI and SMEB. CONCLUSIONS: Our findings confirm that SMEB is part of the SMEI spectrum and may expand the recognition of SMEI and suggest other responsible or modifying genes.     

Antigen receptor-mediated B cell death is blacked by signaling via CD72 or treatment with dextran sukfate and is defective in autoimmunity-prone mice

Mature B cells undergo programmed cell death when surface(s)IGis extensively multimerized. A signal that blocks death of Bcells is thus required for activation of B cells in responseto antigen stimulation.Here we show that only a few diversetransmembranesignals capable of Inducing activation and proliferation ofB cell blocked sig-mediated death of normal mature B cells,fromdeath.The results suggest that a specific signal is requiredfor abrogating B cell death induced by sigcross-linking.Signalingvia IL-4 receptor and CD40, both of which are derived from activatedT cells, blocked sig-mediated death,as decribed previously.Signalingthrough a B cell antigen CD72,a counter-receptor of the pan-Tantigen CD4,also blocked death of anti-Ig-treated mouse spleenB cells.CD72 signalmay play a role in survival of B cells atthe initial step of T B interaction, where resting T cells recongnizeantigens such as llpopolyasccharide and dextran sulfate,andspleen B cells from New Zealand mice, which are prone to autoantibody-dependentautoimmune diseases,were resistant to required in antibody responseto freigin antigens regardless of T independence or T dependenceand in autoantibody production.     

Oligoclonal Immunoglobulin Gene Rearrangements in Philadelphia Chromosome-positive Common Acute Lymphoblastic Leukemia

The occurrence of more than two rearranged bands of immunoglobulin heavy chain (IgH) genes in B precursor acute lymphoblastic leukemia (ALL) has recently been documented. To elucidate the nature of such leukemias, we studied 30 patients with common ALL, including 6 patients with Philadelphia chromosome (Ph¹)-positive ALL, by immunophenotyping and genotyping. In 10 of the 30, Southern blotting showed oligoclonal patterns of IgH gene arrangements, which were frequently detected in Ph¹-positive ALL. In one patient of the 10, three rearranged bands of Ig k chain genes were detected. Ph¹ abnormality and co-expression of myeloid associated antigens were found in 5 and 5 of the 10, respectively. Detection of multiple fragments of IgH genes would be suggestive of multipotent progenitor origin of these ALL.