Existing and Developing Preclinical Models for Neurofibromatosis Type 1-Related Cutaneous Neurofibromas.

Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.

Allogeneic, off-the-shelf, SARS-CoV-2-specific T cells (ALVR109) for the treatment of COVID-19 in high-risk patients.

Defects in T-cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T-cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells, which would be available as a partially HLA-matched, off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T-cell target antigens, and generated and characterized polyclonal virus-specific T-cell lines with activity against multiple clinically important SARS-CoV-2 variants (including 'delta' and 'omicron'). The feasibility of making and safely utilizing such virus-specific T cells clinically was assessed by administering partially HLA-matched, third-party, cryopreserved SARS-CoV-2-specific T cells (ALVR109) in combination with other antiviral agents to four individuals who were hospitalized with COVID-19. This study establishes the feasibility of preparing and delivering off-the-shelf, SARS-CoV-2-directed, virus-specific T cells to patients with COVID-19 and supports the clinical use of these products outside of the profoundly immune compromised setting (ClinicalTrials.gov number, NCT04401410).

Preventive drugs for Huntington's disease: A choice-based conjoint survey of patient preferences.

Introduction: This research examined the perspective of the Huntington's disease (HD) community regarding the use of predictive biomarkers as endpoints for regulatory approval of therapeutics to prevent or delay the onset of clinical HD in asymptomatic mutation carriers. Methods: An online, choice-based conjoint survey was shared with HD community members including untested at-risk individuals, presymptomatic mutation carriers, and symptomatic individuals. Across 15 scenarios, participants chose among two proposed therapies with differing degrees of biomarker improvement and side effects or a third option of no treatment. Results: Two hundred and thirty-eight responses were received. Attributes reflecting biomarker efficacy (e.g., prevention of brain atrophy on magnetic resonance imaging, reduced mutant huntingtin, or reduced inflammation biomarkers) had 3- to 7-fold greater importance than attributes representing side effects (e.g., increased risk of heart disease, cancer, and stroke over 20 years) and were more influential in directing choice of treatments. Reduction in mutant huntingtin protein was the most valued attribute overall. Multinomial logit model simulations based on survey responses demonstrated high interest among respondents (87-99% of the population) for drugs that might prevent or delay HD solely based upon biomarker evidence, even at the risk of serious side effects. Conclusion: These results indicate a strong desire among members of the HD community for preventive therapeutics and a willingness to accept significant side effects, even before the drug has been shown to definitively delay disease onset if the drug improves biomarker evidence of HD progression. Preferences of the HD community should inform regulatory policies for approving preventive therapies.

Treatment-refractory ulcerative colitis responsive to indigo naturalis.

BACKGROUND: Indigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model. METHODS: This open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500 mg/day or 1.5 g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression. RESULTS: Ten of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN. CONCLUSION: IN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation. TRIAL REGISTRATION NUMBER: NCT02442960.

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).

A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018.

PURPOSE: The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies. METHODS: Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies. FINDINGS: In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case. IMPLICATIONS: In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs.

Statement for gastroesophageal reflux disease after peroral endoscopic myotomy from an international multicenter experience.

It has been 10 years since peroral endoscopic myotomy (POEM) was reported for the first time, and POEM has currently become the standard treatment for achalasia and related disorders globally because it is less invasive and has a higher curative effect than conventional therapeutic methods. However, there are limited studies comparing the long-term outcomes of POEM with those of conventional therapeutic methods, particularly in the occurrence of gastroesophageal reflux disease (GERD) after therapy. With this background, we held a consensus meeting to discuss the pathophysiology and management of GERD after POEM based on published papers and experiences of each expert and to discuss the prevention of GERD and dealing with anti-acid drug refractory GERD. This meeting was held on April 27, 2018 in Tokyo to establish statements and finalize the recommendations using the modified Delphi method. This manuscript presents eight statements regarding GERD after POEM.

Gastric myotomy length affects severity but not rate of post-procedure reflux: 3-year follow-up of a prospective randomized controlled trial of double-scope per-oral endoscopic myotomy (POEM) for esophageal achalasia.

BACKGROUND: Since Inoue performed the first POEM in 2008, safety and efficacy have been well-established. Early studies focused on refining the technique and avoiding incomplete myotomy. Following the discovery that many patients with abnormal acid exposure are asymptomatic, the focus shifted to post-POEM reflux, but no studies have identified any associated procedural factors. In this study, we examined the intermediate-term results of our previous randomized controlled trial, with particular attention to post-POEM reflux. METHODS: Previously, 100 consecutive patients were randomized to either double- or single-scope POEM. Endoscopy was conducted 2 months post-POEM and annually thereafter. Patients were included in the present study if they completed endoscopy ≥ 6 months post-POEM, and the clinical results of both groups were analyzed with particular attention to clinical efficacy and post-POEM reflux. RESULTS: Median follow-up was 3 years, and most myotomies were performed in the posterior location. The final gastric myotomy length was longer in the double-scope group (3.3 vs. 2.6 cm). Clinical efficacy (≥ 80%) and rates of post-POEM reflux (~ 60%) were similar; however, there was a higher incidence of moderate esophagitis (Los Angeles Grade B) in the double-scope group (25% vs. 4%). There were no cases of severe esophagitis (Los Angeles Grade C/D). Among patients with normal endoscopy at 2 months, > 40% developed erosive esophagitis on intermediate-term follow-up. CONCLUSIONS: This is the first study to demonstrate a procedural factor that increases post-POEM esophagitis. Gastric myotomy > 2.5 cm results in increased rates of moderate esophagitis without improving clinical efficacy. Some patients developed esophagitis in a delayed fashion, emphasizing the importance of ongoing surveillance. We also believe that preserving the gastric sling fibers may help to reduce reflux rates. The double-scope method may help to control myotomy length (2.0-2.5 cm) and direction (lesser curve to avoid the gastric sling) to help maximize clinical efficacy while minimizing post-POEM reflux.

Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer.

In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11-78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT.

Peroral endoscopic myotomy (POEM) for complex achalasia and the POEM difficulty score.

BACKGROUND: Peroral endoscopic myotomy (POEM) for achalasia is technically challenging to carry out in patients with type III, multiple prior treatments, prior myotomy, and sigmoid type. Herein, we present a series of consecutive patients with complex achalasia and introduce the POEM difficulty score (PDS). AIM: To demonstrate the application and discuss the utility of PDS and present the feasibility, safety, and efficacy of POEM in complex achalasia patients. METHODS: Forty consecutive POEM were carried out with 28 meeting the criteria for complex achalasia. Primary outcome was clinical success (Eckardt score ≤3) at a minimum of 3 months follow-up. Secondary outcomes included adverse events, procedural velocity and PDS. RESULTS: Twenty-eight complex and 12 non-complex POEM procedures were carried out with 100% and 92% clinical success, respectively, without any major adverse events with a median follow up of 15 months (complex) and 8 months (non-complex). Mean velocities for non-complex, type III, prior myotomy, ≥4 procedures and sigmoid type were as follows: 4.4 ± 1.6, 4.8 ± 1.5, 5.9 ± 2.2, 6.9 ± 2.2 and 8.2 ± 3.2 min/cm, respectively. Median PDS for non-complex, type III, prior myotomy, ≥4 treatments and sigmoid type were 1 (0-3), 2 (0-4), 2.5 (1-6), 3 (2-6) and 3.5 (1-6), respectively. PDS was shown to correlate well with procedural velocity with a correlation coefficient of 0.772 (Spearman's P < 0.001). CONCLUSIONS: PDS identifies the factors that contribute to challenging POEM procedures and correlates well with procedural velocity. The order of increasing difficulty of POEM in complex achalasia appears to be type III, prior myotomy, ≥4 treatments and sigmoid type.

Cost variation and opportunities for cost reduction for laparoscopic cholecystectomy.

BACKGROUND: We performed 163 laparoscopic cholecystectomies at our institution during the third quarter of 2016. Direct supply cost per case varied from $524 to $1,022 among 14 surgeons. The purpose of this study was to determine the reasons for cost variation between high- and low-cost surgeons and identify opportunities for cost reduction. METHODS: Average cost of supplies per case was examined for laparoscopic cholecystectomy during a 6-month period. Two groups were created, with the 4 highest-cost surgeons comprising group A and the 2 lowest-cost surgeons comprising group B. The cost for each item was identified, and utilization was compared between groups. RESULTS: The average supply cost per case in group A was significantly greater than group B ($930 vs. $518). The difference persisted in subgroup analyses of both inpatients and patients with high American Society of Anesthesiologists scores. Compared with group A, surgeons in group B used reusable instruments more often and tended to choose lower-cost disposables. CONCLUSIONS: Significant variation in direct cost exists between surgeons performing laparoscopic cholecystectomy. Much of the cost difference can be accounted for by a relatively small number of high-cost instruments. We identified areas for cost savings by substituting lesser cost alternatives without compromising the quality of patient care.

Troubleshooting common endoscopic malfunctions: a study integrating a preoperative checklist and troubleshooting guide into surgical resident training.

INTRODUCTION: This study assessed the utility of a checklist in troubleshooting endoscopic equipment. Prior studies have demonstrated that performance in simulated tasks translates into completion of similar tasks in the operating room. Checklists have been shown to decrease error and improve patient safety. There is currently limited experience with the use of simulation and checklists to improve troubleshooting of endoscopic equipment. We propose the use of a checklist during a simulated colonoscopy to improve performance during endoscopic troubleshooting. METHODS: This study randomized 20 surgical residents (PGY1-3) who were blinded to the purpose of the simulation. Participants were asked to complete two consecutive colonoscopies in a mock endoscopy suite. Prior to each trial, a standard set of equipment malfunctions were created; the equipment was returned to working order if the subjects were unable to successfully troubleshoot the equipment within the first 3 min of the simulation. Between trials, the intervention group was provided a troubleshooting checklist, which they were permitted to utilize during the second trial. The control group had no intervention. Scores were calculated for each task by subtracting time to completion from total time allowed (180 s), with 0 indicating the task was not completed. Groups were compared utilizing unpaired Student's t-test with p < 0.05 threshold for significance. RESULTS: Average scores were compared for 5 tasks in the first trial and 6 tasks in the second trial. During the first trial, there were no significant differences. However, during the second trial, there was a significant improvement with the checklist for 5/6 tasks. CONCLUSION: Use of a checklist, with no further intervention, significantly improves the ability of novice endoscopists to identify and remedy common equipment malfunctions. Introduction of a troubleshooting checklist may represent a simple and low-cost way to improve both efficiency and safety in the endoscopy suite.

Efficacy of a new hemostatic forceps during gastric endoscopic submucosal dissection: A prospective randomized controlled trial.

BACKGROUND AND AIM: Currently, endoscopic submucosal dissection (ESD) is a widely accepted standard treatment for early gastric cancer, but one challenging aspect of ESD is hemostasis. We developed a new hemostatic forceps (FD-Y0007) with the aim of achieving more effective hemostasis and investigated the hemostatic ability of the FD-Y0007 during gastric ESD in humans. METHODS: This study was a prospective randomized controlled trial, which was conducted at a cancer referral center. Sixty-six patients who were scheduled to undergo ESD were enrolled and randomly assigned to either the Coagrasper or the FD-Y0007, which was used for hemostasis throughout the case. The primary end point was the time required to obtain hemostasis, which was measured for the first episode of bleeding during each case. RESULTS: Hemostasis time for the first bleeding episode during ESD was 73.0 s for the Coagrasper and 21.5 s for the FD-Y0007 (P < 0.001). When all episodes of bleeding were included, hemostasis time was 56.8 s in the Coagrasper group and 25.5 s in FD-Y0007group (P < 0.0001). The frequency of adverse events (perforation: 3.4% vs 7.1%; delayed bleeding: 0% vs 0%) was not significantly different between the two groups. CONCLUSIONS: Compared with the Coagrasper, the FD-Y0007 efficiently reduces the hemostatic time during gastric ESD with no increase in adverse events.

Per Oral Endoscopic Myotomy for Achalasia: A Detailed Description of the Technique and Review of the Literature.

Historically, the most robust outcomes in treatment of achalasia were seen with surgical myotomy. Per oral endoscopic myotomy (POEM) introduced an endoscopic method for creating a surgical myotomy. Thousands of cases of POEM have been performed; however, there is no standard technique, and the rates of clinical success and adverse events vary widely among centers. This article presents a detailed description of the POEM technique, including the rationale and potential pitfalls of the main variations, in the context of the international literature.

Double-scope per oral endoscopic myotomy (POEM): a prospective randomized controlled trial.

BACKGROUND: Since its introduction in 2010, per oral endoscopic myotomy (POEM) has offered an alternative to laparoscopic Heller myotomy for the treatment of achalasia. A gastric myotomy length of 3 cm has been recommended; however, it can be difficult to ensure that adequate submucosal dissection has been performed during the procedure. Commonly accepted endoscopic markers of the gastric side can be inaccurate, particularly in patients with prior endoscopic treatments, such as balloon dilation or Botox injection of the lower esophageal sphincter. We hypothesized that the use of a second endoscope would result in a more complete gastric myotomy. METHODS: One hundred consecutive achalasia patients were randomized into single- and double-scope POEM groups. In the treatment group, a second endoscope was used to obtain a retroflexed view of the gastric cardia, while the dissecting scope transilluminated from the end of the submucosal tunnel. Prospectively collected data were analyzed, including myotomy lengths, procedure times, adverse events, and clinical outcomes. RESULTS: POEM was completed with high rates of technical (98-100%) and clinical success (93-97%) in both groups, with a low rate of serious adverse events (2%). The second endoscope resulted in a 17 min increase in procedure time (94 vs. 77 min), myotomy extension in 34% of cases, and an increase in the average gastric myotomy length from 2.6 to 3.2 cm (p = 0.01). CONCLUSION: A second endoscope is useful for ensuring a complete gastric myotomy during POEM. With minimal increase in procedure time and no increase in morbidity, it may be particularly useful in cases of sigmoid esophagus or otherwise altered anatomy that makes identification of the gastroesophageal junction difficult.

Single-incision cholecystectomy in a patient with situs inversus totalis presenting with cholelithiasis: A case report.

Laparoscopic cholecystectomy has become the gold standard for the treatment of cholelithiasis, and many reports of single-incision laparoscopic cholecystectomy have been published in the past few years. Situs inversus totalis is a very rare condition, but the variant anatomy should not preclude a minimally invasive approach to surgery. We report a case of successful single-port laparoscopic cholecystectomy in a patient with situs inversus totalis, describe the technical advantages, and review the literature.

Endoscopic features of early-stage signet-ring-cell carcinoma of the stomach.

AIM: To identify the features of early signet ring cell gastric carcinoma using magnification endoscopy with narrow band imaging (NBI). METHODS: A retrospective review was conducted of 12 cases of early signet ring cell gastric carcinoma who underwent treatment in a single institution between January 2009 and April 2013. All patients had magnification endoscopy with NBI and indigo carmine contrast to closely examine the mucosal architecture, including the microvasculature and arrangement of gastric pits. Histologic examination of the final endoscopic submucosal dissection or gastrectomy specimen was performed and compared with the endoscopic findings to identify patterns specific to signet ring cell carcinoma. RESULTS: Twelve patients with early signet ring cell gastric carcinoma were identified; 75% were male, and average age was 61 years. Most of the lesions were stage T1a (83%), while the remainder were T1b (17%). The mean lesion size was 1.4 cm(2). On standard endoscopy, all 12 patients had a pale, flat lesion without any evidence of mucosal abnormality such as ulceration, elevation, or depression. On magnification endoscopy with NBI, all of the patients had irregularities in the glands and microvasculature consistent with early gastric cancer. In addition, all 12 patients exhibited the "stretch sign", an elongation or expansion of the architectural structure. Histologic examination of the resected specimens demonstrated an expanded and edematous mucosal layer infiltrated with tumor cells. CONCLUSION: The "stretch sign" appears to be specific for signet ring cell carcinoma and may aid in the early diagnosis and treatment of this aggressive pathology.

Per-Oral Endoscopic Myotomy: A Series of 500 Patients.

BACKGROUND: After the first case of per-oral endoscopic myotomy (POEM) at our institution in 2008, the procedure was quickly accepted as an alternative to surgical myotomy and is now established as an excellent treatment option for achalasia. This study aimed to examine the safety and outcomes of POEM at our institution. STUDY DESIGN: Per-oral endoscopic myotomy was performed on 500 consecutive achalasia patients at our institution between September 2008 and November 2013. A review of prospectively collected data was conducted, including procedure time, myotomy location and length, adverse events, and patient data with short- (2 months) and long-term (1 and 3 years) follow-up. RESULTS: Per-oral endoscopic myotomy was successfully completed in all patients, with adverse events observed in 3.2%. Two months post-POEM, significant reductions in symptom scores (Eckardt score 6.0 ± 3.0 vs 1.0 ± 2.0, p < 0.0001) and lower esophageal sphincter (LES) pressures (25.4 ± 17.1 vs 13.4 ± 5.9 mmHg, p < 0.0001) were achieved, and this persisted at 3 years post-POEM. Gastroesophageal reflux was seen in 16.8% of patients at 2 months and 21.3% at 3-year follow-up. CONCLUSIONS: Per-oral endoscopic myotomy was successfully completed in all cases, even when extended indications (extremes of age, previous interventions, or sigmoid esophagus) were used. Adverse events were rare (3.2%), and there were no mortalities. Significant improvements in Eckardt scores and LES pressures were seen at 2 months, 1 year, and 3 years post-POEM. Based on our large series, POEM is a safe and effective treatment for achalasia; there are relatively few contraindications, and the procedure may be used as either first- or second-line therapy.

Greater curvature myotomy is a safe and effective modified technique in per-oral endoscopic myotomy (with videos).

BACKGROUND: Per-oral endoscopic myotomy (POEM) for achalasia with esophagocardiomyotomy in the lesser curvature (LC myotomy) is now established and accepted widely. However, in some cases LC myotomy is precluded by previous procedures, such as Heller myotomy, or by other anatomic considerations that obscure the normal dissection planes. It may also be difficult to identify the esophagogastric junction (EGJ), which can result in an incomplete gastric myotomy and poor rates of symptom relief. On the other hand, the angle of His is always located in the greater curvature of the stomach and serves as a consistent, definite landmark of the gastric side. OBJECTIVE: To evaluate esophagocardiomyotomy in the greater curvature (GC myotomy) as an alternative POEM technique in cases where a prior LC myotomy or supervening anatomic constraints make identification of the EGJ technically challenging. DESIGN: Prospective. SETTING: Single-center study. PATIENTS: Twenty-one achalasia patients who received POEM with GC myotomy. INTERVENTIONS: POEM. MAIN OUTCOME MEASUREMENTS: Efficacy and safety of GC myotomy measured in terms of reduction in lower esophageal sphincter (LES) pressures, improvement in Eckardt scores, and development of intraoperative or postoperative adverse events. RESULTS: Identification of the EGJ was achieved in all cases, resulting in a mean gastric myotomy length of 2.6±1.1 cm. Mean LES pressure and Eckardt symptom scores decreased significantly (21.2±7.3 vs 10.5±2.7 mm Hg, 5 [2-8] vs 1 [0-5], respectively) (P<.01). Endoscopic evidence of gastroesophageal reflux was identified in 52% of patients (11/21) postmyotomy; however, only 9.5% (2/11) were symptomatic, and these patients were successfully controlled with proton pump inhibitors. No severe adverse events were encountered. LIMITATIONS: Single center. CONCLUSIONS: GC myotomy is a promising, safe modification of the POEM technique and may be especially useful in cases of redo POEM, POEM post-Heller myotomy, or when the EGJ is difficult to recognize because of supervening anatomic constraints.

Complications of laparoscopic transgastric ERCP in patients with Roux-en-Y gastric bypass.

BACKGROUND: The altered anatomy of Roux-en-Y gastric bypass presents a challenge when duodenal access is required for ERCP. One technique, laparoscopic transgastric ERCP, was first described in 2002. Since that time, a total of 77 laparoscopic or percutaneous transgastric ERCPs have been reported. The largest case series includes 26 ERCPs, and no reports specifically address complications. We reviewed our experience with 85 transgastric ERCPs and report the limitations and complications associated with access and ERCP. METHODS: Retrospective review was conducted of gastric bypass patients who underwent transgastric ERCP in our practice from 2004-2014. RESULTS: Forty-one patients underwent 85 transgastric ERCPs during the study period. Conversion from laparoscopic to open procedure occurred in 4.8%, and selective cannulation rate was 93%. Forty-seven percent of cases were repeat ERCPs performed through a gastrostomy tube tract. During 15-month median follow-up, the overall complication rate was 19%, with 88% of complications related to access rather than ERCP. Most complications were minor; there were no deaths or cases of severe pancreatitis. Additional intervention, including repair of a posterior stomach laceration or transfusion for bleeding, occurred in 4.7% of cases. Operative intervention occurred in two cases: repair of a duodenal perforation, and debridement of an abdominal wall abscess. Post-ERCP hyperamylasemia was common but did not result in increased length of stay or significant clinical pancreatitis. CONCLUSIONS: Roux-en-Y gastric bypass eliminates the normal approach to the duodenum for ERCP. Transgastric access has a high rate of successful cannulation but is associated with complications. Conversion to open procedure occurred in 4.8%, and 16% developed a complication related to the access site, though the rate of operative intervention was low (2.4%). Our study is limited by its retrospective design, which may underestimate the complication rate, and by our homogenous patient population (94% female, 68% sphincter of Oddi dysfunction).