Jameson Forster

Treatment of gastroparesis: a multidisciplinary clinical review

Abstract  This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Absence of the interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings

The interstitial cells of Cajal (ICCs) are fundamental in the generation of gastric slow waves. The role of these cells in gastroparesis has not been established. We studied 14 gastroparetic patients (9 diabetic, 4 idiopathic, and 1 postsurgical) for whom standard medical therapy had failed and who had been treated with a gastric electrical stimulator for at least 3 months. All patients had a full-thickness antral gastric wall biopsy at the time of surgery. The biopsy samples were stained with c -kit and scored for the presence of ICCs. Baseline electrogastrogram recordings were obtained for 30 minutes in the fasting state and for 2 hours after a test meal. The patients assessed their total symptom score at baseline and at 3 months. Five patients had almost no ICCs and were compared with nine patients with 20% to normal cell numbers. Both groups did respond symptomatically to gastric electrical stimulation. However, patients with depleted ICCs had significantly more tachygastria and had significantly greater total symptom scores at baseline and after 3 months of gastric electrical stimulation. ICCs are absent in some patients (up to a third) with diabetic or idiopathic gastroparesis, and the absence of these cells is associated with abnormalities of gastric slow waves, worse symptoms, and less improvement with gastric electrical stimulation.

Symptom responses, long-term outcomes and adverse events beyond 3 years of high-frequency gastric electrical stimulation for gastroparesis.

Abstract  The aims were to determine symptom responses and long‐term outcomes in gastroparetic patients receiving gastric electrical stimulation (GES) therapy beyond 3 years by presenting per protocol analysis and intention‐to‐treat (ITT) analysis. Data collected at baseline, 1 year and beyond 3 years in 55 patients included total symptom scores (TSS), nutritional status, weight, hospitalizations, the use of prokinetic and/or antiemetic medications, HbA1c in diabetics and adverse events. Of the 55 patients, 10 died of non‐pacemaker‐related complications, six had the devices removed and two could not be reached. The remaining 37 patients had the device activated for a mean of 45 months. Both per protocol and ITT analysis demonstrated that TSS, hospitalization days and the use of medications were all significantly reduced at 1 year and were sustained beyond 3 years. Average TSS decreased by 62.5% for the 37 patients completing 3 years of GES. At implantation, 15/37 patients required nutritional support and only five continued beyond 3 years. Mean HbA1c level in diabetics was significantly reduced from 9.5 to 7.9% at 3 years. We conclude that a significant improvement in symptoms and all measures of clinical outcome can be maintained for greater than 3 years with GES in patients with refractory gastroparesis.

Mechanisms of Acetaminophen-induced Cell Death in Primary Human Hepatocytes

UNLABELLED Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5mM, 10mM or 20mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24h and 48h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6h after APAP and a partial protection when given at 15 h. CONCLUSION These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic.

Chronic gastric electrical stimulation for gastroparesis reduces the use of prokinetic and/or antiemetic medications and the need for hospitalizations.

To investigate the effect of chronic gastric electrical stimulation (GES) on the daily use of prokinetics and antiemetics, hospitalizations, total symptom score (TSS), SF-36 status for health-related quality of life (HQOL), and gastric emptying of a solid meal, we evaluated 37 gastroparetic patients preoperatively and 1 year after undergoing GES implant. Prokinetic and antiemetic use was significantly reduced. Of 27 patients on at least one prokinetic at baseline, 8 were off at 1 year. Twenty-six patients requiring antiemetics before surgery decreased to 17. Mean TSS was significantly reduced and the reduction for patients off medications was significantly better than for patients still on medications. Overall SF-36 scores for HQOL were significantly improved, and patients off antiemetics had a significantly higher HQOL score than for patients on antiemetics at 1 year. Hospitalizations decreased from 50 ± 10 days for the year prior to GES therapy to 14± 3 days (P < 0.05). However, gastric emptying was not significantly improved. Conclusions are as follows. (1) Chronic GES significantly reduced the use of prokinetic/antiemetic medications and the need for hospitalization in gastropraretic patients, whose clinical and quality of life outcomes also significantly improved (2) These data provide evidence of the positive economic impact of this new therapy on long-term clinical outcomes in gastroparetic patients not responding to standard medical therapy.

Clinical response to gastric electrical stimulation in patients with postsurgical gastroparesis

BACKGROUND & AIMS The aim of this study was to report the long-term clinical response to high-frequency gastric electrical stimulation (GES) in 16 patients with postsurgical gastroparesis who failed standard medical therapy. METHODS Clinical data collected at baseline and after 6 and 12 months of GES included (1) severity and frequency of 6 upper gastrointestinal (GI) symptoms by using a 5-point symptom interview questionnaire and total symptom score, (2) health-related quality of life including physical composite score and mental composite score, (3) 4-hour standardized gastric emptying of a solid meal by scintigraphy, and (4) nutritional status. RESULTS The severity and frequency of all 6 upper GI symptoms, total symptom score, physical composite score, and mental composite score were significantly improved after 6 months and sustained at 12 months ( P < .05). All patients had delayed gastric emptying at baseline. Gastric emptying was not significantly faster at 12 months, although 3 normalized. At implantation, 7 of 16 patients required nutritional support with a feeding jejunostomy tube; after GES, 4 were able to discontinue jejunal feeding. The mean number of hospitalization days was significantly reduced by a mean 25 days compared with the prior year. One patient had the device removed after 12 months because of infection around the pulse generator. CONCLUSIONS Long-term GES significantly improved upper GI symptoms, quality of life, the nutritional status, and hospitalization requirements of patients with postsurgical gastroparesis. Although vagal nerve damage or disruption was part of the underlying pathophysiology, GES therapy was still effective and is a potential treatment option for the long-term management of postsurgical gastroparesis. A controlled clinical trial of GES for PSG patients (who are refractory to medical therapy) is indicated given these encouraging results.

Significance of lymph node metastases in patients with pancreatic cancer undergoing curative resection

BACKGROUND Recent reports suggest an improved survival following resection for patients with pancreatic carcinoma. However, the prognosis for patients with lymph nodes metastases remains uncertain. The purpose of this study was to determine if the presence of lymph node metastases significantly alters survival in patients with otherwise potentially curable pancreatic carcinoma. PATIENTS AND METHODS Between 1970 and 1995, 401 patients with pancreatic adenocarcinoma, including 327 patients with pancreatic head tumors, were evaluated and treated. RESULTS One hundred (31%) patients underwent pancreatoduodenectomy. Operative mortality was 3% and morbidity was 22%. Median survival for 97 patients discharged from the hospital following resection was 14 months (range 2 to 293). The estimated 1-, 2-, and 5-year survivals were 61%, 43%, and 20%, respectively. Median survival was 11.5 months (range 2 to 87) for patients with positive lymph nodes (n = 56) and 24 (range 0 to 293) months for patients with negative lymph nodes (n = 41; P = 0.0003). Ten patients (10%) survived longer than 5 years, and 9 (90%) of them had negative lymph nodes. Elderly patients (> or = 70 years) had a median survival twice as long as younger patients (24 versus 12 months, P = 0.03). CONCLUSIONS Lymph node metastases are found in 56% of patients undergoing resection. Pancreatoduodenectomy can be performed with low operative mortality in patients of all ages. It offers good palliation for patients with lymph nodes metastases and encouraging long-term survival rates as well as a chance for cure in patients with negative lymph nodes.

Gastric Electrical Stimulation Improves Outcomes of Patients With Gastroparesis for up to 10 Years

BACKGROUND & AIMS We assessed the long-term clinical outcomes of gastric electrical stimulation (GES) therapy with Enterra (Enterra Therapy System; Medtronic, Minneapolis, MN) in a large cohort of patients with severe gastroparesis. METHODS Gastroparesis patients (n=221; 142 diabetic, 48 idiopathic, and 31 postsurgical) treated with Enterra (Medtronic) for 1-11 years were retrospectively assessed; 188 had follow-up visits and data were collected for at least 1 year (mean 56 months, range 12-131 months). Total symptom scores (TSSs), gastric emptying, nutritional status, weight, hospitalizations, use of prokinetic and/or antiemetic medications, levels of HbA1c levels (in diabetic patients), and adverse events were evaluated at the beginning of the study (baseline) and during the follow-up period. RESULTS TSS, hospitalization days, and use of medications were significantly reduced among all patients (P<.05). More patients with diabetic (58%) and postsurgical gastroparesis (53%) had a greater than 50% reduction in TSS than those with idiopathic disease (48%; P=.32). Weight significantly increased among all groups, and 89% of J-tubes could be removed. At end of the follow-up period, all etiological groups had similar, abnormal delays in mean gastric retention. Thirteen patients (7%) had their devices removed because of infection at the pulse generator site. CONCLUSIONS GES therapy significantly improved subjective and objective parameters in patients with severe gastroparesis; efficacy was sustained for up to 10 years and was accompanied by good safety and tolerance profiles. Patients with diabetic or postsurgical gastroparesis benefited more than those with idiopathic disease.

Effect of high‐frequency gastric electrical stimulation on gastric myoelectric activity in gastroparetic patients

Abstract  The aim of this study was to investigate the effect of gastric electrical stimulation (GES) on gastric myoelectric activity (GMA) and to identify possible mechanisms that could help explain how high‐frequency GES is effective in treating nausea and vomiting associated with gastroparesis. Fifteen gastroparetic patients who received high‐frequency GES were enrolled. Two pairs of temporary pacing wires were implanted on the serosa of the stomach along the greater curvature during surgery for placement of the permanent stimulation device. Two‐channel serosal recordings of GMA before and during GES were measured. A gastric emptying test and severity of nausea and vomiting were assessed at baseline and at 3 months of GES. Power spectral and cross correlation analyses revealed that impaired propagation of slow waves (50%), tachygastria (30%) and abnormal myoelectric responses to a meal (50%) were the main abnormalities observed at baseline. GES with a high frequency significantly enhanced the slow wave amplitude and propagation velocity, and resulted in a significant improvement in nausea and vomiting but did not entrain the gastric slow wave or improve gastric emptying after 3 months of GES.

The role of pancreatojejunostomy in patients without dilated pancreatic ducts

OBJECTIVE To determine the safety and efficacy of longitudinal pancreatojejunostomy in patients with chronic pancreatitis and intractable pain who do not have a markedly dilated pancreatic duct. BACKGROUND Ductal decompression by side-to-side, longitudinal pancreatojejunostomy has become the operation of choice for patients with chronic pancreatitis and intractable pain when the pancreatic duct is markedly dilated. However, markedly dilated pancreatic ducts are found in less than 40% of patients with disabling pain. PATIENTS AND METHODS Twenty-eight consecutive patients with intractable pain from chronic pancreatitis, most of whom had minimal or no dilation of the pancreatic duct, were treated with side-to-side, longitudinal pancreatojejunostomy between 1970 and 1993. RESULTS There were 18 (64%) males and 10 (36%) females. The mean age was 41 years (range 11 to 72). The etiologies for chronic pancreatitis were alcohol (82%), gallstones (7%), trauma (7%), and familial trait (4%). Intractable pain was present for a mean of 4 years (range 0.5 to 12). Thirteen patients (46%) were dependent on narcotics prior to surgery. Twenty-five patients (89%) had minimal (< 8 mm) or no dilation of the pancreatic duct and 3 (11%) had markedly dilated pancreatic ducts (> 10 mm). All experienced complete pain relief in the immediate postoperative period. Twenty-four patients (86%) have remained free of pain after a mean follow-up of 3.5 years (range 1 to 8). CONCLUSIONS In patients with chronic pancreatitis and intractable pain, small pancreatic duct size should not be considered a contraindication to side-to-side, longitudinal pancreatojejunostomy.