Search

Gastrointestinal cancers (GICs) and neuroendocrine tumors (NETs) are often refractory to therapy after metastasis. Adoptive cell therapy using chimeric antigen receptor (CAR) T cells, though remarkably efficacious for treating leukemia, is yet to be developed for solid tumors such as GICs and NETs. Here we isolated a llama-derived nanobody, VHH1, and found that it bound cell surface adhesion protein CDH17 upregulated in GICs and NETs. VHH1-CAR T cells (CDH17CARTs) killed both human and mouse tumor cells in a CDH17-dependent manner. CDH17CARTs eradicated CDH17-expressing NETs and gastric, pancreatic and colorectal cancers in either tumor xenograft or autochthonous mouse models. Notably, CDH17CARTs do not attack normal intestinal epithelial cells, which also express CDH17, to cause toxicity, likely because CDH17 is localized only at the tight junction between normal intestinal epithelial cells. Thus, CDH17 represents a class of previously unappreciated tumor-associated antigens that is 'masked' in healthy tissues from attack by CAR T cells for developing safer cancer immunotherapy.

Type I gastric neuroendocrine tumors (GNETs) are typically managed either expectantly or endoscopically. In contrast, locoregional surgery has been recommended for patients with type III GNETs because of the risk of metastasis. This study aimed to identify predictors of outcome independent of type in a contemporary cohort of GNET patients. A single-institution retrospective cohort study of 121 patients with a pathologic diagnosis of primary GNET between January 2009 and June 2019 was performed. GNETs were designated as type 1 (n = 74) if atrophic gastritis was present, or as type III (n = 47) in the absence of atrophic gastritis. Demographic, clinical, and histopathologic factors were examined using Kaplan–Meier and multivariable Cox regression to assess the impact of various factors on recurrence and overall survival. Median follow-up for the entire cohort was 62.7 months. While there was no difference in OS in patients with different GNET types (p = 0.10), higher tumor grade (p = 0.02) and presence of nodal or distant metastases (p = 0.02) predicted worse survival on multivariable analysis. Among type III GNET patients, those with small (< 0.5 cm), grade 1 lesions (“low-risk”) were less likely to develop metastases (0% versus 33%, p < 0.01) and more likely to survive (100% versus 67%, p < 0.01) at 5 years. Size and tumor grade predict recurrence and survival in patients with GNETs irrespective of type. Small, low-grade type III GNETs are associated with minimal risk of progression and may be managed accordingly.

The purpose of the study was to evaluate prognostic factors for survival outcomes following embolotherapy for neuroendocrine tumor (NET) liver metastases.This was a multicenter retrospective study of 155 patients (60 years mean age, 57 % male) with NET liver metastases from pancreas (n = 71), gut (n = 68), lung (n = 8), or other/unknown (n = 8) primary sites treated with conventional transarterial chemoembolization (TACE, n = 50), transarterial radioembolization (TARE, n = 64), or transarterial embolization (TAE, n = 41) between 2004 and 2015. Patient-, tumor-, and treatment-related factors were evaluated for prognostic effect on hepatic progression-free survival (HPFS) and overall survival (OS) using unadjusted and propensity score-weighted univariate and multivariate Cox proportional hazards models.Median HPFS and OS were 18.5 and 125.1 months for G1 (n = 75), 12.2 and 33.9 months for G2 (n = 60), and 4.9 and 9.3 months for G3 tumors (n = 20), respectively (p 0.05). Tumor burden 50 % hepatic volume demonstrated 5.5- and 26.8-month shorter median HPFS and OS, respectively, versus burden ≤50 % (p 0.05). There were no significant differences in HPFS or OS between gut or pancreas primaries. In multivariate HPFS analysis, there were no significant differences among embolotherapy modalities. In multivariate OS analysis, TARE had a higher hazard ratio than TACE (unadjusted Cox model: HR 2.1, p = 0.02; propensity score adjusted model: HR 1.8, p = 0.11), while TAE did not differ significantly from TACE.Higher tumor grade and tumor burden prognosticated shorter HPFS and OS. TARE had a higher hazard ratio for OS than TACE. There were no significant differences in HPFS among embolotherapy modalities.

A prospective, randomized trial was performed to evaluate the long-term outcome and patient satisfaction of laparoscopic complete 360 degrees fundoplication compared with partial posterior 270 degrees fundoplication. Partial fundoplication is purported to have fewer side effects with a higher failure rate in controlling gastroesophageal reflux disease (GERD), while complete fundoplication is thought to result in more dysphagia and gas-related symptoms.Patients were randomized to either laparoscopic Nissen (LN) or laparoscopic Toupet (LT) fundoplication. Esophageal manometry, 24-h pH studies, a detailed questionnaire, and a visual analog symptom (VAS) score were completed before and after surgery. A final global outcome questionnaire was performed. Failure was defined as recurrent GERD requiring revision surgery, maintenance proton pump inhibitor (PPI) therapy, or surgery for postoperative dysphagia.One hundred patients were randomized to LN (50) or LT (50). There were no differences between LN and LT with respect to postoperative symptoms and physiological variables except a higher wrap pressure in the LN group (15.2 vs. 12.0 mmHg). Dysmotility improved in 8/14 (57%) and 6/11 (54%) patients in the LN group and the LT group, respectively, after surgery. There was no correlation between dysmotility and dysphagia both pre- and post surgery in the two groups. Recurrent symptoms of GERD occurred in 8/47 (17.0%) and 8/48 (16.6%) in the LN group and the LT group, respectively. Outcome of patients with dysmotility was similar to those with normal motility in both groups. At final follow-up (59.76 + or - 24.23 months), in the LN group, 33/37 (89.1%) would recommend surgery to others, 32/37 (86.4%) would have repeat surgery, and 34/37 (91.8%) felt they were better off than before surgery. The corresponding numbers for the LT group (follow-up = 55.18 + or - 25.97 months) were 35/36 (97.2%), 30/36 (83.3%), and 33/36 (91.6%).LN and LT are equally effective in restoring the lower esophageal sphincter function and provide similar long-term control of GERD with no difference in dysphagia. Esophageal dysmotility had no influence on the outcome of either operation.

We sought to evaluate safety and efficacy of IV pantoprazole when used as initial therapy in patients with gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) in a double-blind, placebo-controlled, randomized, parallel-group study. Patients were randomized to 7 days of once-daily IV or oral pantoprazole (40 mg) or placebo. Efficacy variables included maximal acid output, basal acid output, and changes from baseline in frequency/severity of GERD symptoms, and frequency of antacid usage. Seventy-eight patients were randomized (n=26/27/25 [IV/oral/placebo]). Mean maximal acid output was 8.4, 6.3, and 20.9 mEq/h for IV or oral pantoprazole, and placebo, respectively. For pantoprazole versus placebo, maximal and basal acid output were significantly lower (P

Accurate and cost-effective diagnosis ofHelicobacter pylori gastritis has taken on majorimportance. Several serologic tests for the diagnosis ofH. pylori infection are commercially available. Wecompared the performance of the FlexSure HP rapid IgGantibody test with the conventional HM-CAP ELISA toevaluate whether qualitative office-based serology isreliable enough to replace formal laboratory-based testing. We assessed H. pylori status byconcordance in 100 consecutive patients with antralbiopsy, rapid urease, and 1 μCi[14C]ureabreath tests. Both antibody tests had good sensitivityand specificity (>86%). Concordance between the two antibodytests occurred in 87/93 patients (94%). Based on ourdata, the office-based FlexSure HP performed equallywell as the laboratory-based formal ELISA and may be a better choice for initial serologicdiagnosis in untreated patients.

Giant gastric ulcers are defined as ulcers witha diameter greater than 3 cm. Previously they have notbeen described in lung transplant recipients. We reporta high incidence of symptomatic giant gastric ulcers and identify the risk factors for ulcerdevelopment in these patients. We examined the recordsof all 95 patients who had undergone lungtransplantation at our institution from November 1991 toJuly 1995. Fourteen of the patients who underwentlung transplantation developed symptoms that requiredesophagogastroduodenoscopy. Three of these patients(21%) were found to have giant gastric ulcers. The relative risk of giant gastric ulcer insymptomatic patients undergoing endoscopy after lungtransplantation is over 40 times that of populationcontrols. The patients who developed giant gastriculcers, despite H2 antagonist use, had allreceived bilateral lung transplantation and had receivednonsteroidal antiinflammatory drugs, cyclosporine, andhigh-dose intravenous corticosteroids. The risk ofdeveloping giant gastric ulcers is significantly increasedin patients who have undergone bilateral orthotopic lungtransplantation. Clinicians should be made aware of thiscomplication in order to avoid use of ulcerogenic medications in this population. Avoidance ofthese medications could potentially minimize the risk ofthis complication.

Helicobacter pylori is a common cause of gastritis. No single test is 100% accurate for H. pylori diagnosis. In order to determine whether the presence of typical histological features of H. pylori gastritis may yield diagnostic information, we compared antral histology by HE stain to the presence of organisms as detected on Thiazine stain of antral specimens, CLOtest, urea breath test and anti-H. pylori serology in 50 consecutive patients. Patients were diagnosed as having active H. pylori infection if at least two of these tests were positive. Patients with only one test positive (N = 5) were considered indeterminate for H. pylori and were excluded, resulting in 19 patients (42%) being classified as H. pylori positive. All slides were reviewed by a single blinded expert gastrointestinal pathologist and graded 0 (none) to 3 (severe) for the presence of acute (polymorphonuclear cells) or chronic (lymphocytes, monocytes, plasma cells) inflammation, lymphoid aggregates, and intestinal metaplasia. Active infection was associated with the presence of both acute and chronic inflammation (P0.0001) but not lymphoid aggregates (P = 0.09) or intestinal metaplasia (P = 0.10). The best positive predictors of infection were the presence of any acute inflammation (PPV = 86%) and the combination of any acute and chronic inflammation (PPV = 92%). The best negative predictor was absence of chronic inflammation (NPV = 100%). The presence of moderate to severe (grade 2 or 3) acute or chronic inflammation were each 100% predictive of infection. Moderate to severe chronic inflammation had both 100% sensitivity and specificity for active H. pylori infection, while moderate to severe acute inflammation was only 26% sensitive but 100% specific. The presence of any acute, or the combination of acute and chronic gastritis, is predictive of active H. pylori infection. Moreover, the predictive value correlates closely with the severity of the inflammation. The absence of chronic inflammatory cells rules out active H. pylori infection. These findings support the use of HE histology-determined features in conjunction with other tests to diagnose H. pylori infection.

We reviewed the discharge records of all diabetic ketoacidosis hospitalizations over 30 months for the presence of clinically significant upper gastrointestinal hemorrhage. Of 284 hospitalizations in 193 patients, hemorrhage occurred in 26 hospitalizations (9%) in 25 patients (13%). None required invasive therapy to achieve hemostasis, and there were no bleeding recurrences and no deaths due to bleeding. Endoscopy in eight revealed esophagitis in all (five had erosions or ulcerations), one Mallory-Weiss tear, five with gastritis (mild in four), four with duodenitis (one erosive), one duodenal ulcer, and no gastric ulcers. Hemorrhage patients had a longer diabetes duration (14.85 vs 9.16 years, P < 0.02), and more nephropathy (40% vs 11%, P < 0.001), retinopathy (28% vs 12%, P < 0.03) and gastroparesis (36% vs 10%, P < 0.002) than those without hemorrhage. Ulcer medication (42% vs 23%, P < 0.03) or anticoagulant (12% vs 1%, P < 0.005) but not nonsteroidal antiinflammatory drug usage (12% vs 12%) was higher in the hemorrhage group. Admission glucose (P < 0.02), BUN (P < 0.04), and creatinine (P < 0.02) levels were higher in hemorrhage patients, but arterial pH, serum ketones, hemoglobin, platelet count, and coagulation values were not. Hemorrhage patients required more blood transfusions (27% vs 10%, P < 0.003) and intensive care unit admissions (69% vs 43%, P < 0.009). Total (15% vs 3%, P < 0.003) and intensive care unit mortality (22% vs 6%, P < 0.026) were higher in the hemorrhage group. We conclude that upper gastrointestinal hemorrhage complicates 9% of diabetic ketoacidosis hospitalizations. Blood transfusion may be required, but the bleeding is self-limited and not severe. The most common lesion is erosive esophagitis. Hemorrhage correlates with glucose level, admission to the intensive care unit, duration of diabetes, the presence of diabetic complications, and portends a high non-bleeding-related mortality.

An antibiotic combination that includes a proton pump inhibitor such as omeprazole and an antibiotic such as clarithromycin is likely to become the new standard regimen for treatment of Helicobacter pylori gastritis because this combination is extremely effective and very well tolerated. The current report highlights a potentially significant pharmakokinetic drug interaction between clarithromycin and carbamazepine in two patients with long-standing epilepsy who were given such therapy for Helicobacter pylori gastritis. In both cases, clarithromycin therapy was temporally related to an increase in serum carbamazepine levels, which returned to the therapeutic range following cessation of clarithromycin therapy. The potential implications of this newly recognized drug interaction are discussed.