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“Refractory GERD” is one the most common misnomers in the area of gastroesophageal reflux disease. The term implies reflux as the underlying etiology despite unresponsiveness to aggressive, often twice-daily proton pump inhibitor therapy. The term should be replaced with “refractory symptoms.” We must acknowledge that in many patients, symptoms of reflux often overlap with non-GERD causes such as gastroparesis, dyspepsia, hypersensitive esophagus, and functional disorders. Lack of response to aggressive acid suppressive therapy often leads to esophagogastroduodenoscopy followed by pH or impedance monitoring. In the majority of patients these tests are normal. The role of non-acid reflux measured by impedance pH testing in this group is uncertain at best and the results from this test alone should not be used to refer patients to surgical fundoplication. In patients unresponsive to acid suppressive therapy, reflux is most commonly not causal and a search for non-GERD causes must ensue.

Extraintestinal manifestations (EIM) of inflammatory bowel disease (IBD) occur rather frequently and may be found in up to 30% of patients. However, surprisingly few randomized, controlled studies have been conducted that were specifically aimed at the treatment of EIM of IBD patients. Therefore, most therapies of EIM are empiric or deduced from studies in populations with other type of patients. EIM may be associated with active IBD. Treatment of active IBD is, therefore, the mainstay of treatment of EIM. Lifestyle modification as a means of therapy is a recent subject of study in chronic conditions, such as IBD. Based on epidemiologic and experimental findings, EIM of various tracts can be modified by optimizing alimentary intake, refraining from sedentary lifestyle, and adapting smoking habits. Not many new drugs for treatment of EIM have been developed during the past few years; the role of infliximab has been extended in particular in Crohn’s disease-related EIM. Careful consideration of prescribed drugs remains necessary due to potential interaction with the course of IBD.

Gastrointestinal stromal tumors (GISTs) are rare tumors of the wall of the stomach and small bowel, and also occasionally arise in the mesentery, omentum, or retroperitoneum. The incidence of GIST in the United States is approximately 500 to 750 patients per 100,000 people. GISTs often present late in their clinical course unless they are the cause of gastrointestinal bleeding or perforation. Surgical resection is the standard of care for primary GIST. However, there is a high risk of recurrence in the peritoneum and liver. For metastatic GIST, imatinib mesylate is the standard of care. Two phase III studies presented in 2003 in abstract form show slightly different results. In the US study, 400 mg/d was found to be equivalent to 800 mg/d with respect to response, progression-free survival, and overall survival at 12 months. In the European/Australasian study, the response rate was the same with either dosage, but progression-free survival was better with 800 mg/d compared with 400 mg/d. Overall survival data for the latter study were too immature for analysis as of May 2003. Adjuvant or neoadjuvant therapy with imatinib is the topic of at least three studies through the American College of Surgeons Oncology Group and Radiation Therapy Oncology Group and the American College of Radiology Imaging Network. Every effort to enroll eligible patients on these studies should be made. New treatments for metastatic disease under investigation include a tyrosine kinase inhibitor with an expanded panel of targets compared with imatinib (SU011248), and the addition of a mammalian target of rapamycin (mTOR) inhibitor and the rapamycin derivative RAD001 to imatinib. Given the finding of a specific molecular defect to exploit, GISTs have gone from an orphan disease to a proving ground for tyrosine kinase-targeted therapy.

Chronic pancreatitis is the result of irreversible damage to pancreatic acinar cells, and can result in debilitating chronic pain for patients. Treatment centers on pain relief, often with chronic narcotic use. Surgical therapy consists of both resection procedures to remove affected pancreatic parenchyma and drainage procedures to facilitate drainage of the main pancreatic duct. Total pancreatectomy historically was utilized in extreme cases due to the brittle glucose control that followed from the total loss of islet cells. Total pancreatectomy with islet cell auto-transplantation (TP-AIT) is gaining in popularity due to the maintenance of beta cell mass and the ability of patients to potentially be insulin independent post-operatively. TP-AIT is very helpful in the treatment of pain for patients with chronic pancreatitis. The overall majority of patients have an improvement in pain and quality-of-life scores. AIT also allows the majority of patients to have minimal insulin requirements post-operatively. With proper patient selection, these outcomes can be achieved.

Hepatocellular carcinoma is the fifth leading cause of cancer worldwide and its incidence is increasing. Surveillance programs allow doctors to identify patients at early stages of the disease, when the tumor may be curable by radical treatments such as resection, liver transplantation, or local ablation. In the West, these treatments can be applied to 30% to 40% of patients. Resection yields favorable results in patients with single tumors and a well-preserved liver function (5-year survival rate is 60%). Recurrence complicates two thirds of the cases, and there is no effective adjuvant treatment. Liver transplantation is the best treatment for patients with single tumors that are less than 5 cm in diameter and liver failure, or in those presenting with three nodules less than 3 cm, but organ shortage greatly limits its applicability. Long-term survival is expected to be around 50% to 70% at 5 years depending upon the drop-out rate of patients on the waiting list. Chemoembolization and local ablation are the neo-adjuvant treatments applied to patients on the waiting list to prevent tumor progression; no controlled study proving their efficacy has yet been published. In nonsurgical candidates, percutaneous treatments (ethanol injection or radiofrequency ablation) are the best therapeutic approach and improve survival in Child-Pugh A class patients with small tumors that achieve initial complete response (5-year survival rate is 40% to 50%). At more advanced stages, chemoembolization, a technique combining intra-arterial chemotherapy and selected ischemia, has shown to slightly improve survival in a meta-analysis of randomized trials. No survival advantages have been demonstrated with intra-arterial or systemic chemotherapy, hormonal compounds, or radiation. New agents, such as inhibitors of the tyrosine kinase receptors of growth factors and antiangiogenic agents, are currently being tested in phase II/III trials.

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) occurs at the late phase in hepatitis B virus (HBV) infection’s natural history. The disease is characterized by progressive liver damage due to variants with mutations in the precore/core promoter region that reduce or abolish HBeAg expression. Chronic HBeAg-negative disease’s prognosis is poor, with only rare incidences of spontaneous remission. Recent studies in Europe, Asia, and the United States all have reported an increased prevalence of HBeAg-negative and a decreased prevalence of HBeAg-positive chronic hepatitis; this may be related to increased awareness, decrease in new HBV infections, and aging of existing carriers. The end point of therapy for HBeAg-negative CHB patients is difficult to assess. In most studies, HBV DNA suppression and normalization of serum alanine aminotransaminase levels have been used to indicate therapeutic response. Six drugs currently are licensed for the treatment of CHB infection. These are the immunomodulatory agents (conventional interferon-α-2b and pegylated interferon-α-2a) and the nucleoside/nucleotide analogues (lamivudine, adefovir dipivoxil, entecavir, and telbivudine). Sustained treatment response rates generally are poor due to the high probability of relapse, particularly following nucleoside/nucleotide analogue therapy. As not all patients can tolerate or will respond to interferon-based therapy, maintenance therapy with nucleoside/nucleotide therapy is the alternative. However, this latter approach can lead to development of viral resistance and long-term safety concerns.

Conditions that necessitate surgery frequently arise in patients with chronic liver disease and cirrhosis. Because cirrhosis has the ability to cause physiologic derangements in every organ system in the body, clinicians face significant challenges in preoperative preparation of the patient with cirrhosis in order to decrease postoperative morbidity and mortality. Emergent operations add an extra dimension of complexity to the clinical picture, due to limited preoperative time to prepare the patient with cirrhosis for surgery. In cases of severely decompensated cirrhosis, clinicians should have in their armamentarium possible alternatives to surgery that can be used to temporize the emergent nature of the disease and improve patient outcomes. The classification of cirrhotic liver disease by Child and Turcotte was initially utilized to predict mortality in patients undergoing surgically placed shunts for portal hypertensive bleeding. Subsequent studies have pointed to the fact that other general and thoracic surgery procedures can be assigned predicted mortality rates according to a similar classification scheme, the modified Child-Pugh score. Patients with cirrhosis facing surgery should undergo a careful history and physical examination and should be accurately placed into a designated Child-Pugh category. Because the modified Child-Pugh class is the most reliable determinant of postoperative morbidity and mortality, every attempt should be made to upgrade a patient’s class in a favorable direction prior to surgery. Patients should be carefully evaluated for the presence of ascites and dietary alterations. In addition, medical management with diuretics should be employed to prevent postoperative ascites leak and possible infectious complications including bacterial peritonitis. Perhaps one of the most feared complications in the patient with cirrhosis facing surgery is hemorrhage. Because the liver is vital in maintenance of coagulation homeostasis, several pharmacologic adjuncts may be administered to correct any coagulopathy in the peri-operative period. Several diseases such as cholelithiasis and peptic ulcer disease are known to be more prevalent in the cirrhotic patient, and clinicians treating these diseases should have a thorough understanding of the pathophysiology of cirrhosis and portal hypertension. Patients with cirrhosis and portal hypertensive bleeding that are considered good surgical candidates (ie, Child-Pugh class A) may benefit from surgical portasystemic shunt in contrast to angiographically placed portacaval shunt (ie, transjugular intrahepatic portosystemic shunt [TIPS]) due to the lack of durable patency and cost effectiveness in the latter. In patients with cirrhosis awaiting orthotopic liver transplantation, TIPS may be a lifesaving temporizing technique that is utilized as a bridge to transplantation.