Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents.

PURPOSE: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent-related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent-related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center. PATIENTS AND METHODS: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent-related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period. RESULTS: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. CONCLUSION: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent-related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.

Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer.

The aim of this study was to test the efficacy of a chemotherapy combination of cisplatin, IFN alpha-2b, doxorubicin, Adriamycin, and 5-fluorouracil (PIAF) as treatment for radiologically measurable cancer of the biliary tree. Forty-one patients (19 gallbladder carcinoma and 22 cholangiocarcinoma) with unresectable, histologically confirmed adenocarcinoma were registered. Starting chemotherapy doses were as follows: cisplatin, 80 mg/m(2) i.v. over 2 h; doxorubicin, 40 mg/m(2) i.v. over 2 h; and 5-fluorouracil, 500 mg/m(2) by continuous infusion daily for 3 days. IFN alpha-2b (5 x 10(6) units/m(2)) was administered s.c. before the cisplatin and daily thereafter for a total of four doses. The overall response rate was 21.1% [95% confidence interval (CI), 10-37]. For cholangiocarcinoma and gallbladder carcinoma patients, the response rates were 9.5% (95% CI, 1-32%) and 35.3% (95% CI, 14-62%), respectively. Overall median survival time was 14 months (95% CI, 9.5-18.5), 18.1 months (95% CI, 12.1-24.1) for the cholangiocarcinoma patients, and 11.5 months (95% CI, 5.9-17.1) for the gallbladder carcinoma patients. This difference was not statistically significant. The most common grade III and IV toxicities were neutropenia (41%), thrombocytopenia (20%), nausea and vomiting (34%), and fatigue (20%). In conclusion, the PIAF combination seemed more active against gallbladder carcinoma than against cholangiocarcinoma but was associated with significant toxicity. Therefore, this regimen cannot be recommended for cholangiocarcinoma, but it may have a role in the treatment of gallbladder carcinoma, particularly among patients who were refractory to higher priority investigational agents.

Formulation Design and Optimization of Orodispersible Tablets of Quetiapine Fumarate by Sublimation Method.

The objective of present study was to formulate directly compressible orodispersible tablets of quetiapine fumarate by sublimation method with a view to enhance patient compliance. A full 3(2) factorial design was used to investigate the effect of two variables viz., concentration of Indion 414 and camphor. Indion 414 (3-5 % w/w) was used as superdisintegrant and camphor (5-15 % w/w) as subliming agent. The tablets were evaluated for thickness, weight variation, hardness, friability, content uniformity, wetting time, porosity, in vitro disintegration time and in vitro drug release. The formulation containing 5% w/w of Indion 414 and 5% w/w camphor was emerged as promising based on evaluation parameters. The disintegration time for optimized formulation was 18.66 s. The tablet surface was evaluated for presence of pores by scanning electron microscopy before and after sublimation. Differential scanning colorimetric study did not indicate any drug excipient incompatibility, either during mixing or after compression. The effect of independent variables on disintegration time, % drug release and friability is presented graphically by surface response plots. Short-term stability studies on the optimized formulation indicated no significant changes in drug content and in vitro disintegration time. The directly compressible orodispersible tablets of quetiapine fumarate with lower friability, greater drug release and shorter disintegration times were obtained using Indion 414 and camphor at optimum concentrations.

Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index.

We compared and evaluated available laboratory and clinical data on the use of concurrent gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and radiation in pancreatic cancer to provide guidance for subsequent prospective research initiatives. Preclinical data suggest that the timing of administration of gemcitabine with respect to radiotherapy is important, but this issue has not yet been confirmed by clinical data. Phase I clinical data indicate that the amount of acute toxicity from the combination of gemcitabine and radiotherapy is strongly related to the dose and schedule of administration of gemcitabine, as well as to the radiation field size. There also appears to be an inverse linear relationship between the maximum tolerated gemcitabine dose and radiation dose. Also important, but less clear, is the infusion rate of gemcitabine as it relates to the systemic efficacy of the drug. The combination of additional agents with gemcitabine and radiation appears to be feasible. Finally, the addition of radioprotectors may enable chemotherapy dose escalation, but safe escalation of the radiotherapy dose with newer techniques has not been established. Semin Oncol 28 (suppl 10):25-33.

Comparison of the urine-based ligase chain reaction test to culture for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in pediatric sexual abuse victims.

BACKGROUND: The urine-based ligase chain reaction (LCR) assay for Chlamydia trachomatis and Neisseria gonorrhoeae is an attractive alternative to culture because of the relative ease with which specimens may be collected, transported and processed. In addition LCR offers superior sensitivity while maintaining high specificity when compared with culture in various studies of adolescents and adults. A study comparing LCR to culture has not been published concerning children. METHODS: We conducted a prospective, comparison trial of the urine-based LCR test for Chlamydia trachomatis and Neisseria gonorrhoeae as compared with culture among children at a specialized referral center for evaluation for alleged sexual assault. Of the 1,010 children presenting to the center during the study period, 164 met the study requirements for risk of a sexually transmissible disease and collection of both culture and urine LCR specimens. RESULTS: Eight specimens tested positive by both methods for C. trachomatis. Another 10 specimens tested positive for C. trachomatis by LCR but were negative by culture. No patient with a negative LCR for C. trachomatis had a positive culture. For N. gonorrhoeae 2 specimens tested positive by both methods, and 3 specimens tested positive by LCR but negative by culture. No patient with a negative LCR for N. gonorrhoeae had a positive culture. CONCLUSIONS: The low prevalence of disease in the study population precluded statistical analysis. LCR may prove to be as specific and more sensitive than culture for the detection of C. trachomatis and N. gonorrhoeae in children. Further studies are needed.

Cytologic features of lymphoepithelial cyst of the pancreas: two preoperatively diagnosed cases based on fine-needle aspiration.

We describe the cytologic features seen in fine-needle aspiration (FNA) specimens from two cases of preoperatively diagnosed lymphoepithelial cyst (LEC) of the pancreas. Pancreatic LEC is a rare, true cyst of uncertain histogenesis that may clinically and radiologically mimic a pseudocyst or cystic neoplasm. Both our patients were middle-aged men who presented with vague abdominal pain. Computed tomography (CT) of the abdomen revealed a mass in or around the pancreas, and CT-guided percutaneous FNA (patient 1) and endoscopic ultrasound-guided FNA (patient 2) yielded paste-like yellow-gray material. Cytologic smears showed numerous anucleated squamous cells in a background of keratinous and amorphous debris. A few benign nucleated squamous cells and plate-like cholesterol crystals were also seen. Unlike LEC of the head and neck region, only rare lymphocytes and histiocytes were present. Pancreatic LEC was diagnosed based on these cytologic findings and was histologically confirmed following cyst enucleation (patient 1) and partial pancreatectomy (patient 2). We conclude that preoperative FNA and recognition of the characteristic cytologic pattern will enable conservative surgical management of pancreatic LEC. Diagn. Cytopathol. 1999;21:346-350.

Evaluation of sexual abuse in the pediatric patient.

Evaluating a patient for suspected child sexual abuse can be daunting for many pediatric primary care practitioners. The consequences of misdiagnosis can be devastating. Knowledge of common clinical presentations, both physical signs and symptoms and behavioral changes, is paramount. Sexual abuse allegations must be reported and investigated by child protection agencies or law enforcement. Practitioners must be aware of when and how to report suspected child sexual abuse, in addition to having a basic understanding of the medical examination and findings. With a caring, knowledgeable, and sensitive approach to allegations of sexual abuse, the practitioner can assist the child and his or her family through this very difficult process.

Adenovirus in cancer therapy: a gastrointestinal case study.

Approved clinical trials involving gene therapy have been taking place for less than 10 years. As more knowledge is gained about genetics and disease, nurses must have a fundamental understanding of what genes do, how gene therapy is administered, and the risks and potential benefits of treatment. New methods for the administration of adenoviral vectors for cancer treatment in the endoscopy lab are currently being developed. By staying abreast of new treatment methods using gene or viral therapy, the gastrointestinal nurse can actively participate in clinical trials. A basic background of genetics and gene therapy in cancer is discussed. Safety issues and nursing implications regarding the administration and recovery of patients following gene therapy in the GI endoscopy lab are also addressed. An actual case study of a patient who participated in a study utilizing an attenuated adenovirus as investigational therapy for pancreatic adenocarcinoma is presented.

The small bowel as a source of gastrointestinal blood loss.

The small bowel is a rare but important source of blood loss from the gastrointestinal (GI) tract. In approximately 5% of all patients with GI bleeding, no cause for the bleeding is evident even after an extensive workup. This bleeding is often termed "gastrointestinal bleeding of obscure origin" or "obscure gastrointestinal bleed" (OGIB). Recent advancements in enteroscopy have contributed to a better understanding of the small bowel as a source of bleeding. On average, 27% of patients with OGIB have been shown to have lesions in the small bowel, with common findings including arteriovenous malformations (AVMs) and small bowel tumors. The trend in primary diagnostic workup for obscure GI bleeding or suspected small bowel lesions is shifting toward enteroscopic examination. Availability of an accessory channel now offers the clinician management options such as endoscopic injection therapy, electrocautery, and polypectomy. The "gold standard" for examination of the entire small bowel is intraoperative enteroscopy. A newer technique involving laparascopic assistance may lower the morbidity associated with this examination. Combined hormonal therapy may be an alternative treatment for patients with AVMs or an unknown cause of bleeding after enteroscopic examination.

Hepatotoxicity of anticholesterol, cardiovascular, and endocrine drugs and hormonal agents.

Drugs in these categories may have effects on several organs in addition to the liver. For example, amiodarone may produce thyroid and corneal injury apart from or in addition to the phospholipidosis seen in the liver. Oral contraceptive steroids remain a rare but important concern for developing hepatic adenomas and possibly hepatocellular carcinoma, as well as a risk factor for developing Budd-Chiari syndrome in long-term users. Among the antihyperlipidemic agents, nicotinic acid, especially the sustained release formulations, may produce severe of even fatal hepatic injury. Increasing numbers of reports of hepatotoxicity from newer beta blockers and angiotensin-converting enzyme inhibitors require ongoing vigilance in patients receiving these medications.

Gastroesophageal junction adenocarcinoma.

The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing in association with the epidemiologic rise in distal esophageal adenocarcinoma and gastric cardial (AEG type III) tumors. The overall survival rate is poor in most patients with AEG because lymph node or visceral metastases are frequently present at the time patients become symptomatic. A few patients are identified early in the disease because of screening for gastroesophageal reflux and Barrett's esophagus. Early stage AEG (T1N0 or T2NO, carcinoma in situ, or severe dysplasia ) can in many instances be cured with surgery alone. Ablative treatments for early stage AEG, including endoscopic fulguration by cautery and laser or photodynamic therapy, are investigational at this time. Locoregionally advanced AEG (T3, T4, N1, or M1a ) without distant systemic metastases (M1b) has a poor overall survival rate with surgery alone or definitive chemotherapy and radiation therapy without surgery. Analysis of the use of multimodality treatment strategies for locoregionally advanced AEG types I and II have demonstrated improved survival rates in two small phase III trials with preoperative concurrent chemoradiotherapy followed by surgical resection. In contrast, three small phase III trials with preoperative concurrent or sequential chemoradiotherapy in patients with predominantly squamous cell carcinoma did not demonstrate any clear survival advantage. Additionally, a randomized phase III study evaluating preoperative chemotherapy without radiation therapy in esophageal cancer (predominantly adenocarcinoma) has demonstrated no survival benefit. In light of these results, additional large randomized phase III studies are needed to confirm the potential benefit of preoperative concurrent chemoradiotherapy. At the present time, preoperative chemoradiotherapy remains investigational. For locoregionally advanced gastric adenocarcinoma, including AEG type III, postoperative concurrent 5-fluorouracil (5-FU)-based chemoradiotherapy is associated with improved survival as demonstrated in a recently completed random assignment trial (INT 0116). As a result, surgery with postoperative chemoradiotherapy has recently become the standard of care for patients with AJCC stage II and III gastric adenocarcinoma (including patients with AEG type III). Metastatic AEG (M1b) should be treated with palliative chemotherapy (in good performance patients) or supportive care (poor performance) in asymptomatic patients. Radiation therapy and endoscopic stent placement (expandable wire mesh) can be used to palliate dysphagia in patients with M1b disease. The development of expandable stents and improved radiotherapy has obviated surgical bypass to palliate patients with symptomatic, metastatic AEG.

Obliteration of esophageal varices using EUS-guided sclerotherapy with color Doppler.

BACKGROUND: The current standard treatment of bleeding esophageal varices is band ligation. Although endoscopic sclerotherapy has largely been supplanted by band ligation, there are still clinical situations in which injection methods are useful. Endoscopic ultrasound (EUS) may allow for a more complete evaluation of esophageal varices and perforating veins and may allow for more effective delivery of sclerosant. Our aim was to evaluate the use of color Doppler EUS-guided sclerotherapy for the obliteration of esophageal varices. METHODS: Five patients with esophageal varices (Child's A = 1, B = 2, C = 2) underwent dynamic EUS-guided sclerotherapy with color flow Doppler. EUS sclerotherapy was performed using Varijet (2.5 mm catheter) injector needles and sodium morrhuate directed at the perforating vessels until flow was completely impeded (2 to 4 mL per injection site). Data collected included (1) sessions to obliteration, (2) episodes of recurrent bleeding, (3) complications, and (4) mortality. RESULTS: Patients undergoing EUS-sclerotherapy required 2.2 sessions to achieve obliteration of varices. No patient had a recurrence of bleeding and no deaths occurred. One patient developed an esophageal stricture that responded to balloon dilation. CONCLUSIONS: Dynamic EUS-guided sclerotherapy with color flow Doppler may be safely and effectively used for the treatment of esophageal varices. It allows for effective delivery of sclerosant with favorable outcomes. Prospective, multicenter, randomized trials are warranted.

A prospective, double-blind trial of L-hyoscyamine versus glucagon for the inhibition of small intestinal motility during ERCP.

BACKGROUND: Glucagon is often used to inhibit duodenal motility and enhance cannulation during ERCP. Levsin is an antimuscarinic, anticholinergic agent that may be as effective as glucagon. METHODS: Three hundred eight patients requiring an antimotility agent during ERCP were randomized in a double-blind prospective study to intravenous Levsin or glucagon. Parameters recorded included difficulty of procedure, predrug and postdrug motility grade, effectiveness of medication, patients requiring "crossover" drug, side effects, and cost per case. RESULTS: One hundred fifty-three patients were randomized to glucagon and 155 to Levsin. The two groups were equally matched with regard to patient and procedure characteristics. Of statistical significance were the following: (1) 12 patients in the Levsin group required crossover compared to 1 patient in the glucagon group, (2) Levsin was slightly less effective in inhibiting motility, but this did not adversely influence procedure difficulty, (3) Levsin was associated with more minor side effects (nausea, vomiting, and pain) at 2 hours after the procedure (Levsin 36 of 143, glucagon 24 of 152, p = 0.045) but there was no difference in pancreatitis (glucagon 6, Levsin 8), (4) Levsin was associated with a significant cost advantage (Levsin $10.45/case, glucagon $29.51/case, p < 0.001). CONCLUSION: Levsin may provide a reasonable alternative antimotility agent during ERCP. Levsin does not appear to alter the rate of significant postprocedure complications. The cost benefit advantage appears to be substantial.

Dynamic imaging of the pancreas using real-time endoscopic ultrasonography with secretin stimulation.

BACKGROUND: Obstructive disorders of the pancreas, including strictures, stones, sphincter of Oddi dysfunction, and pancreas divisum, are diagnostic and therapeutic challenges. Conventional extracorporeal ultrasound with secretin stimulation has been used as a noninvasive study to detect obstruction and predict outcome of therapy. Inconsistent results have been obtained because of the inherent limitations of standard ultrasonography. The aim of this study was to evaluate the behavior of the main pancreatic duct by endoscopic ultrasonography during secretin stimulation and to diagnose obstructive disorders of the pancreas. METHODS: Secretin-stimulated endoscopic ultrasound (SSEUS, 1 IU/kg secretin) was performed in 20 control subjects (no pancreatic or biliary disease), 40 patients with symptomatic chronic pancreatitis, 40 patients with symptomatic pancreas divisum, 20 patients with suspected sphincter of Oddi dysfunction, and 20 patients with suspected occlusion of pancreatic duct stents. Ductal diameter was measured by endoscopic ultrasonography at baseline and at 1-minute intervals, after administration of secretin, for 15 minutes. A result was determined to be abnormal when a 1 mm or greater dilation of the pancreatic duct was observed from baseline after secretin administration. RESULTS: Of the 40 patients with symptomatic chronic pancreatitis, SSEUS correctly predicted obstructive pathology (stones, strictures) in 12 of 13 patients (92%). Of the 40 patients with symptomatic pancreas divisum, 22 underwent stent therapy (16 of 22 with resolution of symptoms). SSEUS accurately predicted response to stent therapy in 13 patients (81%). Seven of twenty patients with suspected sphincter of Oddi dysfunction had abnormal sphincter manometry. SSEUS accurately predicted sphincter dysfunction in only 4 of 7 patients (57%). Finally, 20 patients with suspected occlusion of pancreatic duct stents were studied. Of the 14 stent occlusions confirmed at ERCP, SSEUS correctly predicted premature occlusion in 12 patients (86%). CONCLUSIONS: SSEUS appears to be a useful diagnostic modality in the evaluation of patients with suspected obstructive disorders of the pancreas and it can predict which patients may respond to endoscopic therapy.

Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.

BACKGROUND: Chronic pancreatitis in its early stages may defy diagnosis despite existing diagnostic modalities. Endoscopic retrograde pancreatography (ERCP), secretin test, and conventional ultrasound are insensitive in detecting the early stages of chronic pancreatitis. The aim of this study was to determine whether endoscopic ultrasonography (EUS) high-resolution imaging allows for the detection of chronic pancreatitis as compared with clinical history, ERCP, and secretin test. METHODS: Eighty consecutive patients with recurrent pancreatitis underwent ERCP, EUS, and secretin test. EUS evaluated parenchymal changes: echogenic foci (calcification), prominent interlobular septae (fibrosis), small cystic cavities (edema), lobulated outer gland margin (fibrosis/atrophy), and heterogeneous parenchyma; and ductal changes: dilation, irregularity, echogenic wall (fibrosis), side-branch ectasia, and echogenic foci (stones). EUS criteria for chronic pancreatitis included mild (1 to 2 features), moderate (3 to 5 features), and severe (more than 5 features). RESULTS: Abnormal studies were EUS = 63, ERCP = 36, and secretin test = 25. Secretin test had 100% agreement with normal and severe chronic pancreatitis by EUS criteria, but agreement was poor for mild (13%) and moderate (50%) disease. Alternatively, the agreement between ERCP- and EUS-specific criteria was excellent for normal (100%), moderate (92%), and severe (100%) chronic pancreatitis and poor for mild (17%) disease. When the 2-test modality (ERCP and secretin test) was compared with EUS alone, no enhancement in agreement was seen. CONCLUSION: Using the above criteria EUS may assist in the diagnosis of chronic pancreatitis not established by ERCP or secretin test. Excellent agreement can be expected between EUS and ERCP in the diagnosis of chronic pancreatitis with the exception of mild changes noted on EUS (kappa statistics = 0.82: 95% CI [0.70, 0.95]). Long-term follow-up of the patients with mild EUS changes will determine the validity of EUS in diagnosing the early stages of chronic pancreatitis.

Endoscopic retrieval of proximally migrated biliary and pancreatic stents: experience of a large referral center.

BACKGROUND: Proximal migration of a biliary or pancreatic stent is an infrequent event but its management can be technically challenging. METHODS: Review of all cases of proximally migrated biliary and pancreatic stents over a 10-year period at a referral pancreatic-biliary center. Data abstracted from patient records included indication for stenting, method of presentation, success of attempt, and method used. Successful methods were determined by reviewing procedure reports. Follow-up was attempted in all patients in whom stent retrieval had failed. RESULTS: Thirty-three proximally migrated bile duct stents, and 26 proximally migrated pancreatic duct stents were identified. Most of the patients were without symptoms. Eighty-five percent of common bile duct stents and 80% of pancreatic duct stents were successfully extracted endoscopically. Seventy-one percent (34 of 48) were retrieved with a basket or balloon. Of the stents not retrieved, two patients did not return for repeat ERCP, three patients with malignant common bile duct strictures were managed with placement of a second stent, three patients with pancreatic duct stents have remained without symptoms with no further retrieval attempts, and three patients with proximally migrated pancreatic duct stents required surgery because of pain and failure of multiple endoscopic retrieval attempts. CONCLUSION: Over 80% of proximally migrated bile duct and pancreatic duct stents may be extracted endoscopically. Few patients will require surgery.

Evaluating the child for sexual abuse.

Child victims of sexual abuse may present with physical findings that can include anogenital problems, enuresis or encopresis. Behavioral changes may involve sexual acting out, aggression, depression, eating disturbances and regression. Because the examination findings of most child victims of sexual abuse are within normal limits or are nonspecific, the child's statements are extremely important. The child's history as obtained by the physician may be admitted as evidence in court trials; therefore, complete documentation of questions and answers is critical. A careful history should be obtained and a thorough physical examination should be performed with documentation of all findings. When examining the child's genitalia, it is important that the physician be familiar with normal variants, non-specific changes and diagnostic signs of sexual abuse. Judicious use of laboratory tests, along with appropriate therapy, should be individually tailored. Forensic evidence collection is indicated in certain cases. Referral for psychologic services is important because victims of abuse are more likely to have depression, anxiety disorders, behavioral problems and post-traumatic stress disorder.

Transforming growth factor beta1 is expressed in the jejunum after experimental Cryptosporidium parvum infection in humans.

Biopsies from volunteers challenged with Cryptosporidium parvum were examined for transforming growth factor beta1 (TGF-beta1). None of the prechallenge biopsies exhibited TGF-beta. Seven of 12 volunteers with oocyst shedding expressed TGF-beta versus 2 of 13 volunteers without detected oocysts. The association of TGF-beta expression with oocyst excretion and the timing of symptoms suggests that TGF-beta mediates intestinal healing.