BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

There are currently no universally accepted indications and criteria for additional surgical resection of the colorectum after endoscopic resection of the submucosal invasive cancer. The purpose of the present study is to establish accurate indications and criteria for additional surgical resection of the colorectum, based on the prediction of lymph node metastasis, after endoscopic resection of the submucosal invasive cancer. We investigated 140 submucosal invasive colorectal cancers and analyzed the pathologic factors of lymph node metastasis. The tumors were evaluated for pathologic factors in the invasive area of the submucosal carcinoma and were compared between the cases with lymph node metastasis and those without lymph node metastasis. Lymph node metastasis was observed in 13 cases (9%). Univariate logistic regression analysis showed that the depth of invasion, cribriform-type structural atypia, absence of lymphoid infiltration, lymphatic permeation, and venous permeation were statistically significant as risk factors for lymph node metastasis. Multivariate logistic regression analysis showed that the important risk factors included, in decreasing order, lymphatic permeation, absence of lymphoid infiltration, cribriform-type structural atypia, venous permeation, and depth of invasion. Submucosal invasion of 2 mm or more, and/or, depth of lymphatic permeation of 2 mm or more are risk factors for lymph node metastasis. The pathologic criteria based on our results for additional colectomy enables greater accuracy selection of patients who will undergo further surgical treatment after endoscopic resection. Keywords: colorectal cancer; submucosal invasive cancer; criteria for additional colectomy; risk factor of lymph node metastasis Endoscopic resection has become the established standard treatment for mucosal carcinoma and adenoma of the colon. Submucosal invasive cancer may not be diagnosed, in some cases, until after endoscopic resection. Thus, pathologists are increasingly encountering submucosal invasive colorectal carcinomas, which are endoscopically resected. Since 10% or less of cases of submucosal invasive cancer had metastasized to the lymph nodes according to previous reports, 1-7 additional surgical resection of the colorectum after endoscopic resection of submucosal invasive cancer is needed for curative treatment. However, there are currently no universally accepted indications and criteria for additional surgical resection of the colorectum after endoscopic resection of submucosal invasive cancer. As a result, many cases (the remainder, except cases with lymph node metastasis, ie, about 90% of the total cases) involving additional surgical resection of the colorectum constitute overtreatment. Establishment of accurate criteria for additional surgical resection of the colorectum, based on the prediction of lymph node metastasis, after endoscopic resection of submucosal invasive cancer is more than necessary. Thus, toward this goal, we investigated and analyzed the pathologic factors of lymph no...

BackgroundHepatectomy is recommended as the most effective therapy for liver metastasis from colorectal cancer (CRCLM). It is crucial to elucidate the prognostic clinicopathological factors.MethodsEighty-three patients undergoing initial hepatectomy for CRCLM were retrospectively analyzed with respect to characteristics of primary colorectal and metastatic hepatic tumors, operation details and prognosis.ResultsThe overall 5-year survival rate after initial hepatectomy for CRCLM was 57.5%, and the median survival time was 25 months. Univariate analysis clarified that the significant prognostic factors for poor survival were depth of primary colorectal cancer (≥ serosal invasion), hepatic resection margin (< 5 mm), presence of portal vein invasion of CRCLM, and the presence of intra- and extrahepatic recurrence. Multivariate analysis indicated the presence of intra- and extrahepatic recurrence as independent predictive factors for poor prognosis. Risk factors for intrahepatic recurrence were resection margin (< 5 mm) of CRCLM, while no risk factors for extrahepatic recurrence were noted. In the subgroup with synchronous CRCLM, the combination of surgery and adjuvant chemotherapy controlled intrahepatic recurrence and improved the prognosis significantly.ConclusionsOptimal surgical strategies in conjunction with effective chemotherapeutic regimens need to be established in patients with risk factors for recurrence and poor outcomes as listed above.

These results suggest that chymase-dependent angiotensin II formation may play an important role in hepatic fibrosis of patients with cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) can develop into end-stage disease that includes cryptogenic cirrhosis and hepatocellular carcinoma. Bacterial endotoxin, for example lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. The aim of this study was to assess the role of LPS in the development of NAFLD. Twenty-one male Zucker (fa/fa) rats were divided into three groups: rats fed for twelve weeks on a diet rich in disaccharide (D12 group), rats similarly managed but treated with LPS (LPS group), and those on the same diet for 24 weeks (D24 group). Histological examination demonstrated that this protocol induced hepatic steatosis in the LPS and D24 groups. Significant, marked accumulation of lipid droplets was observed in the LPS group, compared with the D24 group. Rats from the LPS group showed a decrease in plasma adiponectin levels, an increase in plasma leptin levels, and greater expression of FAS and SREBP-1c mRNA in the liver, compared with rats from the D24 group. These finding coincided with histological findings. We therefore suggest that LPS may accelerate the progression of hepatic steatosis.