pp32 (ANP32A) Expression Inhibits Pancreatic Cancer Cell Growth and Induces Gemcitabine Resistance by Disrupting HuR Binding to mRNAs

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy

Regression of Barrett\u27s esophagus after magnetic sphincter augmentation: intermediate-term results.

BACKGROUND: Untreated gastroesophageal reflux disease (GERD) can lead to Barrett\u27s esophagus and an increased risk for esophageal adenocarcinoma. Magnetic sphincter augmentation (MSA) is a safe and effective modality for the treatment of GERD. Preliminary research on short-term outcomes after MSA demonstrated significant regression of Barrett\u27s. Further investigation is required to evaluate the long-term effect of this treatment. METHODS: A retrospective review of patients was conducted with biopsy-proven Barrett\u27s esophagus who underwent MSA between 2007 and 2019. As a part of their preoperative evaluation, patients underwent esophagogastroduodenoscopy (EGD) with biopsies of the distal esophagus and gastroesophageal junction including any abnormal-appearing segments, pH testing, and a videoesophagram. Patients were categorized according to the length of Barrett\u27s identified (ultrashort \u3c 1 cm, short 1-3 cm, long \u3e 3 cm). Improvement was defined as a decrease in length (e.g. long to short). RESULTS: There were 87 patients identified for study inclusion. 55 patients were male. The median body mass index was 26.95. The median age was 61.81 (49.79-68.29). Mean follow-up time was 2.35 ± (1.57) years. 7 (8.0%) of these patients began with long segment Barrett\u27s, 58 (66.7%) began with short segment disease, and 22 (25.3%) began with an ultrashort segment. Within this cohort, 74 (85.06%) had undergone postoperative biopsy. 7 out of 74 patients (9.46%) showed improvement in their intestinal metaplasia and 45/74 (60.81%) showed complete regression. Fisher\u27s exact test showed a significant decrease in Barrett\u27s length following MSA (p = 0.002). No patients progressed to dysplasia or neoplasia. There was a statistically significant decrease in the median Demeester score from 34.00 to 13.70 after surgery (p \u3c .001). CONCLUSION: MSA reduces esophageal acid exposure and can lead to reduction or resolution of Barrett\u27s esophagus. MSA is also effective at preventing progression of metaplasia to dysplasia or neoplasia. This effect remains consistent even after 2 years of follow-up

Less is more: cruroplasty alone is sufficient for revisional hiatal hernia surgery.

BACKGROUND: Recurrence of hiatal hernia after anti-reflux surgery is common, with past studies reporting recurrence rates of 10-15%. Most patients experience relief from GERD symptoms following initial repair; however, those suffering from recurrence can have symptoms severe enough to warrant another operation. Although the standard of care is to revise the fundoplication or convert to magnetic sphincter augmentation (MSA) in addition to redo cruroplasty, it stands to reason that with an intact fundoplication, a repeat cruroplasty is all that is necessary to alleviate the patients\u27 symptoms. In other words, only fix that which is broken. METHODS: A retrospective review of patients with symptomatic hiatal hernia recurrence who underwent reoperation between January 2011 and September 2018 was conducted. Patients who received revisional cruroplasty alone were compared with cruroplasty plus some other revision (fundoplication revision, or takedown and MSA placement). Demographics, operative details, and postoperative outcomes were collected. RESULTS: There were 73 patients identified. Median time to recurrence after the first procedure was 3.7 (1.9-8.2) years. Thirty-two percent of the patients had GERD symptoms for more than 10 years. Twenty-six patients underwent cruroplasty only. Forty-seven patients underwent cruroplasty plus fundoplication revision. There were no significant differences in operative times (2.4 h cruroplasty alone, 2.8 h full revision, p = 0.75) or postoperative complications between the two groups. Patients had a mean follow-up time of 1.64 years. Of the 73 patients, 8 had subsequent hiatal hernia recurrence. The recurrence rate for patients with cruroplasty alone was 11%, and the recurrence rate for the full revision group was 12% (p = 1.00). CONCLUSION: Leaving an intact fundoplication alone at the time of revisional surgery did not adversely affect surgical outcomes. This data suggests a role for hernia-only repair for recurrent hiatal hernias

Magnetic sphincter augmentation with hiatal hernia repair: long term outcomes.

INTRODUCTION: Magnetic sphincter augmentation (MSA) is a safe and effective treatment for patients with gastroesophageal reflux disease (GERD). MSA was initially indicated for patients with GERD and concomitant hiatal hernias \u3c 3 cm. However, excellent short- and intermediate-term outcomes following MSA and hiatal hernia repair in patients with hiatal hernias ≥ 3 cm have been reported. The purpose of this study is to assess long-term outcomes for this patient population. METHODS AND PROCEDURES: A retrospective review was performed of patients with GERD and hiatal hernias ≥ 3 cm who underwent MSA and hiatal hernia repair. Patients were treated at two tertiary medical centers between May 2009 and December 2016. Follow up included annual video esophagram, upper endoscopy, or both. Outcomes included pre- and post-operative GERD health-related quality of life (GERD-HRQL) scores, length and regression of Barrett\u27s esophagus, resolution of esophagitis, need for endoscopic dilations or implant removal, and clinically significant hiatal hernia recurrence (\u3e 2 cm) on videoesophagram or endoscopy. RESULTS: Seventy-nine patients (53% female) with a median age of 65.56 (58.42-69.80) years were included. Median follow up was 2.98 (interquartile range 1.90-3.32) years. Median DeMeester scores decreased from 42.45 (29.12-60.73) to 9.10 (3.05-24.30) (p \u3c 0.001). Severity of esophagitis (e.g. LA class C to class B) significantly improved (p \u3c 0.01). Forty percent of patients with Barrett\u27s esophagus experienced regression (p \u3c 0.01). Median GERD-HRQL scores improved from 21 to 2. Five (6.3%) hiatal hernia recurrences occurred, and 1 required re-operation. Age, body mass index, size of the initial hiatal hernia, and sex had no significant effect on whether a patient developed a recurrence. CONCLUSIONS: Magnetic sphincter augmentation in conjunction with large hiatal hernia repairs for patients with GERD achieves excellent long-term radiographic and clinical results, and a low overall need for reoperation, without the need for mesh

Hiatal hernia recurrence following magnetic sphincter augmentation and posterior cruroplasty: intermediate-term outcomes.

BACKGROUND: We have previously reported short-term outcomes after hiatal hernia repair (HHR) at the time of magnetic sphincter augmentation (MSA) for gastroesophageal reflux disease (GERD). Here we report intermediate-term outcomes and hernia recurrence rate after concomitant MSA and HHR. METHODS: This is a retrospective cohort study of patients who underwent repair of a hiatal hernia 3 cm or larger at the time of MSA implantation between May 2009 and December 2015. The primary endpoint was hiatal hernia recurrence identified by routine postoperative videoesophagography or endoscopy. Recurrence was defined by a 2 cm or greater upward displacement of the stomach through the diaphragmatic esophageal hiatus. Secondary endpoints included cessation of proton-pump inhibitor (PPI), persistent dysphagia requiring intervention, and GERD health-related quality-of-life (HRQL) scores 1 year from surgery. RESULTS: During the study period, 47 of 53 (89%) patients underwent concomitant MSA with HHR and complied with surveillance. Hiatal hernias ranged from 3 to 7 cm (mean 4 ± 1). Mean clinical follow-up time was 19 months (range 1-39). GERD-HRQL score decreased from 20.3 to 3.1 (p \u3c .001), 89% of patients remained off PPIs, and 97% of patients reported improvement or resolution of symptoms. Two recurrent hiatal hernias were identified on surveillance imaging for a recurrence rate of 4.3% at a mean 18 (± 10) months after initial operation. Persistent dysphagia occurred in 13% (6/47) over the first year, which resolved after a single balloon dilation in 67% (4/6). Two patients elected for device removal due to dilation-refractory dysphagia and persistent reflux symptoms. CONCLUSION: Concomitant magnetic sphincter augmentation and hiatal hernia repair in patients with gastroesophageal reflux disease and a moderate-sized hiatal hernia demonstrates durable subjective reflux control and an acceptable hiatal hernia recurrence rate at 1- to 2-year follow-up

Safety and efficacy of magnetic sphincter augmentation dilation.

BACKGROUND: The magnetic sphincter augmentation device (MSA) provides effective relief of gastroesophageal reflux symptoms. Dysphagia after MSA implantation sometimes prompts endoscopic dilation. The manufacturer\u27s instructions are that it be performed 6 or more weeks after implantation under fluoroscopic guidance to not more than 15 mm keeping 3 or more beads closed. The purpose of this study was to assess adherence to these recommendations and explore the techniques used and outcomes after MSA dilation. METHODS AND PROCEDURES: We conducted a multicenter retrospective review of patients undergoing dilation for dysphagia after MSA placement from 2012 to 2018. RESULTS: A total of 144 patients underwent 245 dilations. The median size of MSA placed was 14 beads (range 12-17) and the median time to dilation was 175 days. A second dilation was performed in 67 patients, 22 patients had a third dilation and 7 patients underwent 4 or more dilations. In total, 17 devices (11.8%) were eventually explanted. The majority of dilations were performed with a balloon dilator (81%). The median dilator size was 18 mm and 73.4% were done with a dilator larger than 15 mm. There was no association between dilator size and need for subsequent dilation. Fluoroscopy was used in 28% of cases. There were no perforations or device erosions related to dilation. DISCUSSION: There is no clinical credence to the manufacturer\u27s recommendation for the use of fluoroscopy and limitation to 15 mm when dilating a patient for dysphagia after MSA implantation. Use of a larger size dilator was not associated with perforation or device erosion, but also did not reduce the need for repeat dilation. Given this, we would recommend that the initial dilation for any size MSA device be done using a 15 mm through-the-scope balloon dilator. Dysphagia prompting dilation after MSA implantation is associated with nearly a 12% risk of device explantation