Endoscopic Submucosal Dissection for Large Colorectal Tumor in a Japanese General Hospital

Background and Aims. Endoscopic submucosal dissection (ESD) is not widely used in large colorectal lesions because of technical difficulty and possible complications. We aimed to examine the efficacy and safety of ESD for large colorectal neoplasms. Patients and Methods. During the past 5 years, 608 cases of colorectal neoplasm (≧20 mm) were treated by ESD. They were divided into Group A (20–49 mm, 511 cases) and Group B (≧50 mm, 97 cases). Results. The average age, lesion size, and procedure time were 67.4 years, 30.0 mm, and 60.0 min in Group A, and they were 67.1 years, 64.2 mm, and 119.6 min in Group B. En bloc resection rates were 99.2% and 99.0% (), and complication rates were 4.1% and 9.9% (). Complications in Group A consisted of perforation (2.7%), bleeding (1.2%), and ischemic colitis (0.2%). Those in Group B were perforation (8.2%) and bleeding (1.0%). Two cases in Group A and none in Group B required emergency surgery for perforation. Conclusions. There was no difference in efficacy between Groups A and B. Complications were more frequent in Group B, but all perforations in Group B were successfully managed conservatively. ESD can be effective and safe for large colorectal tumors

Feasibility of Endoscopy-Assisted Laparoscopic Full-Thickness Resection for Superficial Duodenal Neoplasms

Background. Superficial duodenal neoplasms (SDNs) are a challenging target in the digestive tract. Surgical resection is invasive, and it is difficult to determine the site and extent of the lesion from outside the intestine and resect it locally. Endoscopic submucosal dissection (ESD) has scarcely been utilized in the treatment of duodenal tumors because of technical difficulties and possible delayed perforation due to the action of digestive juices. Thus, no standard treatments for SDNs have been established. To challenge this issue, we elaborated endoscopy-assisted laparoscopic full-thickness resection (EALFTR) and analyzed its feasibility and safety. Methods. Twenty-four SDNs in 22 consecutive patients treated by EALFTR between January 2011 and July 2012 were analyzed retrospectively. Results. All lesions were removed en bloc. The lateral and vertical margins of the specimens were negative for tumor cells in all cases. The mean sizes of the resected specimens and lesions were 28.9 mm (SD ± 10.5) and 13.3 mm (SD ± 11.6), respectively. The mean operation time and intraoperative estimated blood loss were 133 min (SD ± 45.2) and 16 ml (SD ± 21.1), respectively. Anastomotic leakage occurred in three patients (13.6%) postoperatively, but all were minor leakage and recovered conservatively. Anastomotic stenosis or bleeding did not occur. Conclusions. EALFTR can be a safe and minimally invasive treatment option for SDNs. However, the number of cases in this study was small, and further accumulations of cases and investigation are necessary

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81–127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81–127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81–127–based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis

Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis

Urinary Transthyretin as a Biomarker in ATTRv Val50Met Amyloidosis

Transthyretin (TTR), the precursor protein for amyloidogenic TTR (ATTR) amyloidosis, forms tetramers and escapes glomerular filtration by binding with thyroxine and retinol-binding protein. However, variant TTRs are unstable as tetramers, so monomeric TTR has become the precursor protein of amyloid deposits, via protein misfolding. The aim of the study was to evaluate the utility of urinary TTR in the diagnosis of ATTRv amyloidosis. Urinary samples from healthy volunteers, ATTRv V50M amyloidosis patients, and asymptomatic carriers of the ATTRv V50M gene were analysed using ELISA. To analyse the different forms of TTR secreted to the urine, we performed Western blotting and mass spectrometry. Urinary TTR concentrations were significantly higher in the ATTRv V50M amyloidosis patients than they were in the healthy volunteers and asymptomatic carriers of the gene. Although the TTR concentrations were negligible in the healthy volunteers, they were correlated with disease progression and urinary albumin concentrations in the ATTRv V50M amyloidosis patients. The Western blotting and mass spectrometry revealed the presence of monomeric wild-type and variant TTRs in the urine. Urinary TTR concentrations may become a more sensitive biomarker of ATTRv progression than albumin