Off label pharmacological therapy in patients with short bowel syndrome.

BACKGROUND: Short bowel syndrome is a disabling disease requiring long-term nutritional support and ancillary drugs. Aiming to analyze the most commonly prescribed drugs, a retrospective analysis was conducted is an outpatient cohort. PATIENTS AND METHODS: Stable patients (N= 37, 59.5% males, age 51.1 ± 20.1 years, body mass index 20.1 ± 7.9 kg/m2) with three or more appointments in the Outpatient Service during the last 18 months were retrospectively analyzed. regarding oral pharmacologic prescriptions. Medications were classified as on label or off label. RESULTS: A total of 257 oral prescriptions were retrieved from computer files, encompassing 17 different preparations. The majority was employed on label however 28.8% (74/257) were classified as off label and scrutinized with regard to indications. The main categories were pharmacologic modulators of gastrointestinal secretions and motility, along with antibiotics. Virtually all patients required one or more of such drugs, without differences regarding demographic or clinical variables. Adverse effects or premature drug discontinuation were not observed. CONCLUSIONS: This is the first study to our knowledge highlighting the importance of adjuvant drugs, particularly with unconventional indications, in the management of short bowel syndrome. Antidiarrheic agents, pancrelipase micropellets, antacids and antibiotics represented the most relevant off label prescriptions for this population.

Euglycemia and normolipidemia after anti-obesity gastric bypass.

UNLABELLED: Weight loss and resolution of comorbidities is well established after modern bariatric procedures, however chronology of glyco-lipidic biochemical response is still debated. OBJECTIVE: Aiming to analyze this variable as well as its correlation with food amount and composition, a prospective study was designed. METHODOLOGY: Eighty consecutive patients undergoing Roux-en-Y gastric bypass were investigated every three months until one year after surgery. Females only were accepted and variables included general and nutritional course as well as glucose and lipid measurements. Energy intake was documented including percentage of macronutrients in the diet. RESULTS: Surgery was successful with about 71% excess body weight loss at the end of the first year. Mean energy intake on the 4 postoperative quarters was respectively 519.6 +/- 306.6, 836.0 +/- 407.9, 702.1 +/- 313.1 and 868.8 +/- 342.8 kcal/day (mean +/- SD). Fat intake was initially low but reached 34.1 +/- 7.9% of total calories at final measurement. Blood glucose and lipid fractions tended to be borderline or abnormal preoperatively, and favorably changed by 12 months. Consumption of glucose-and lipid-lowering medication significantly diminished, but each of these was still necessary in 6.3% of the group. Correlation between body mass index and also calorie intake versus glucose and lipid measurements was highly significant (P = 0.000). CONCLUSIONS: 1) Energy intake after operation was very low; 2) Weight loss proceeded rapidly and correlated with meal pattern; 3) Improvement of glucose and lipid tests was adequate but took several quarters to normalize; 4) Decreased requirements for glucose- and lipid-lowering medication was significant but not absolute; 4) Fat percentage of total calories exceeded 30% at the end of the observation period, despite recommendations to the contrary.

Phase I trial of recombinant human gamma-interferon and recombinant human tumor necrosis factor in patients with advanced gastrointestinal cancer.

Recombinant human gamma-interferon and recombinant human tumor necrosis factor are two representatives of a new class of antineoplastic agents. In vitro studies have suggested synergistic cytotoxic activities when the agents are combined. We report a phase I study of these two agents when administered daily for 5 consecutive days every 2 weeks in patients with advanced gastrointestinal cancers. Toxicity resulting from these agents was significant with hyperbilirubinemia representing the dose-limiting toxicity. Significant, although transient, myelosuppression was also observed. The maximal tolerated doses were 150 micrograms/m2/day for 5 days for each agent. Suggestive antineoplastic activity in biliary and pancreatic cancer was observed. Phase II trials of this combination are currently in progress.

Therapy for metastatic colorectal cancer with hepatic artery infusion chemotherapy using a subcutaneous implanted pump.

Sixty-two patients with metastatic colorectal carcinoma involving the liver were treated by hepatic intra-arterial chemotherapy using an implantable infusion pump. The 53 patients with metastases confined to the liver had a median survival (MS) of 17 months and an objective response rate of 32%. Four patients (8%) demonstrated a complete response (CR), with normal abdominal computed tomography (CT) scan results and plasma carcinoembryonic antigen (CEA) levels, and 13 patients (25%) demonstrated a partial response (PR), with at least a 50% decrease in the liver lesions by CT scan and at least a 50% decrease in CEA levels. Thirty patients (57%) had stable disease (S), and six patients (11%) had no response (NR). Nine patients with extrahepatic tumor plus hepatic metastases had an MS of only 4.9 months. None of these patients had an objective response, and only four patients had S. Quality of response was clearly associated with longevity. Forty patients treated with floxuridine (FUDR) and mitomycin (M) (F + M) showed a 20% objective response rate, while the 13 patients treated with FUDR and dichloromethotrexate (DCMTX) (F + D) attained a 69% objective response rate. Although F + D treatment appears to be superior, there may have been selection biases that make such an observation only preliminary. Twenty-six (49%) of the 53 patients developed hepatitis during infusion chemotherapy, which resolved after temporary cessation of the chemotherapy. Of the 17 patients with CR or PR, 12 patients (71%) had hepatitis, whereas only 14 (39%) of the 36 patients with S or NR had hepatitis. Eleven patients had evidence of peptic ulceration by endoscopic examination during the infusion chemotherapy. All the ulcers healed after chemotherapy was discontinued.

Ifosfamide and mesna: marginally active in patients with advanced carcinoma of the pancreas.

Ifosfamide, an analogue of cyclophosphamide, has therapeutic activity against a wide variety of human malignancies. In a phase II trial in carcinoma of the pancreas, we treated 31 patients who had not received prior chemotherapy with a median ifosfamide dose of 2 g/m2/d (range, 1.5 to 2 g/m2/d) administered intravenously (IV) over one hour for five consecutive days every 3 weeks. 2-mercaptoethane sulphonate (mesna), an acrolein antagonist with known uroendothelial protective properties, was administered IV at a dose of 400 mg/m2 over 15 minutes before the daily dose of ifosfamide and repeated every four hours for two additional doses. Among 30 evaluable patients, one patient achieved a complete remission (26+ months) and another patient had a partial remission (4 months). The median duration of survival of all patients from the start of ifosfamide therapy was only 3 months (range, 1 to 26+ months). Treatments were generally well tolerated. The most common toxic effects included granulocytopenia, nausea and vomiting, malaise, anorexia, and mild hematuria. Mesna offers an adequate protection against uroendothelial injury caused by ifosfamide. Despite the previously reported response rate of greater than 20% at the same or lower doses of ifosfamide in other studies, our data suggest that ifosfamide is only marginally active against cancer of the pancreas and appears to be of minimal value in the treatment of patients with this tumor.

Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma.

We conducted a phase II clinical trial of fluorouracil (5FU) and recombinant interferon alfa-2a (rIFN alpha-2a) in 52 previously untreated patients with bidimensionally measurable metastatic colorectal cancer. During week 1, 5FU was administered as a continuous intravenous infusion, 750 mg/m2/d for 5 consecutive days. Intravenous bolus administration of 5FU 750 mg/m2 was given weekly for 7 weeks starting on day 12. rIFN alpha-2a (Roferon; Hoffman-LaRoche, Nutley, NJ), 9 x 10(6) U, was administered subcutaneously three times weekly during weeks 1 to 8. Patients were evaluated for response on week 9. Of 52 patients enrolled in the study, 51 were assessable for toxicity, and 45 were assessable for response. Fifteen patients experienced partial response, and one patient achieved a clinical complete response for an overall response rate of 35% (95% confidence interval [CI], 22%, 50%). Median duration of response is 7.5 months (range, 4 to 11 months). Seventy percent of patients entered on the study are alive with a median follow-up duration of 7 months. Twenty-five percent of patients developed grade 4 toxicity, and 82% developed grade 3 toxicity. One drug-related death in the presence of sepsis was reported, and two treatment-related seizures occurred. Our experience with this schedule produced a lower response rate with greater toxicity than previously reported. Current randomized trials comparing this schedule of 5FU with rIFN alpha-2a to 5FU plus folinic acid (leucovorin) or single-agent 5FU may determine its role in the treatment of advanced colorectal carcinomas.

Suprahepatic gallbladder with hypoplasia of the right lobe of the liver.

One of the rarest congenital anomalies of the gallbladder is the suprahepatic variant of this organ. Three cases of this ectopia were seen in a ten-year period, all of which associated with hypoplasia of the right lobe of the liver and upward displacement of the hepatic flexure of the colon, which overlapped the liver border. All patients complained of recurrent pain in the right upper quadrant of the abdomen, suggestive of biliary disease, but only one case had calculi in the gallbladder that was acute cholecystitis. Two patients underwent cholecystectomy, and operative findings confirmed the preoperative diagnosis. It is speculated that the primary defect in this modality of suprahepatic gallbladder might be hypoplasia or atrophy of the right lobe of the liver of a congenital nature, with subsequent vicious orientation of the gallbladder and upward displacement of the colon.

Phase II study of adriamycin with sequential methotrexate and 5-fluorouracil (AMF) in gastric carcinoma.

The purpose of this study was to evaluate the response rate, methotrexate plasma levels, and toxicity of a three-drug regimen in patients with gastric carcinoma. A total of 37 patients with advanced measurable adenocarcinoma of the stomach were treated with Adriamycin, methotrexate, and 5-fluorouracil (AMF). Adriamycin and methotrexate were given as i.v. infusions on day 1; 24 h following methotrexate administration, patients received an i.v. infusion of 5-fluorouracil concomitantly with oral leukovorin factor (given over 48 h). Methotrexate levels were monitored regularly in all patients, and courses were repeated every 3 weeks. The median dose levels per course were 50 mg/m2 (range, 40-60 mg/m2) for Adriamycin, 1,000 mg/m2 (range, 650-1,250 mg/m2) for 5-fluorouracil, and 500 mg/m2 (range, 160-625 mg/m2) for methotrexate. Of 36 evaluable patients, 8 (22%) achieved an objective response, including 1 complete remission. Stable disease was noted in 11 patients and a minor tumor regression occurred in 1. The median survival duration of all patients was 6 months (range, 2-31+ months). AMF was well tolerated; toxicities were mild to moderate, most frequently involving nausea and vomiting, mucositis, and neutropenia with or without fever. There was no death directly attributable to chemotherapy. Although the AMF regimen used a well-documented preclinical concept of synergism between methotrexate and 5-fluorouracil, response and survival results suggest a modest activity of this combination in patients with gastric cancer. Better preclinical models are necessary for the development of effective combination chemotherapy.

Evaluation of continuous-infusion alpha-difluoromethylornithine therapy for colorectal carcinoma.

A total of 32 evaluable patients with measurable advanced colorectal carcinoma were treated with continuous-infusion alpha-difluoromethylornithine (DFMO) at a median daily dose of 8 g/m2 (range, 6-14 g/m2). DFMO was infused over 24 h daily for 28 days, followed by a rest period of 7 days. Of the 32 patients, 14 had received no prior chemotherapy. A total of 65 courses was given, with the median being 2 (range, 1-9 courses). None of the patients achieved a partial or complete response; however, 3 patients achieved a minor response and 14 had stable disease. The frequent toxic effects of DFMO included thrombocytopenia (which was dose-limiting), malaise, nausea, vomiting, reversible hearing loss, and diarrhea. Our data suggest that continuous-infusion DFMO therapy is feasible and results in only mild gastrointestinal toxicity. Although DFMO proved to be ineffective as a single agent in this trial, it could probably best be used in combination with cytotoxic agents known to enhance its antitumor activity in a preclinical setting.

Endoscopic laser therapy in colorectal carcinoma.

Although a variety of surgical and nonsurgical techniques are available to palliate the symptoms of advanced colorectal carcinoma, the ideal approach remains undetermined. Such an approach must include efficacy, safety, convenience, and cost effectiveness. While much remains to be learned about the role of lasers in the management of colorectal carcinoma, endoscopic laser therapy fulfills many of the requirements of an ideal palliative therapy. Although differences in approaches and techniques exist, most investigators worldwide have achieved similar results with the Nd:YAG laser. International results and our own experience show that the laser is highly effective, with success rates approaching 90 per cent. The complications of laser therapy have included bleeding, perforation, abscess, and fistula formation as well as post-laser stricturing with an overall rate of 6 per cent. Since the procedure can be done as an outpatient and involves minimal preparation, endoscopic laser therapy certainly is a convenient form of palliative therapy. In times of increasing cost containment, analysis has been done to determine the cost effectiveness of laser therapy compared with abdominal perineal resection. Mellow and McCoy, using data from a private university affiliated hospital in the southwestern United States, have shown the cost of an abdominal perineal resection is nearly five times that of initial therapy with the Nd:YAG laser. Analysis of laser costs for both initial inpatient and outpatient therapy are presented in Table 6. Because follow-up laser treatments are required at 8- to 10-week intervals, an additional five to seven treatments can be anticipated in the following year. Presuming a median survival of 12 months, the total lifetime cost for outpatient laser therapy is less than half the overall cost of abdominal perineal resection. Endoscopic laser therapy has emerged as an excellent palliative therapy for advanced colorectal carcinoma. Unfortunately, we have reached a plateau in our clinical understanding and utilization of the Nd:YAG laser for vaporization and coagulation of tumors. The continued growth of laser applications will be dependent on better understanding of the fundamentals of the laser tissue interaction. By expanding knowledge of optical and thermal properties of tissue, we will be able to explore the utilization of new wavelengths and their application to ablation, coagulation, and excision. The use of dyes that would be taken up selectively by malignant tissue may help identify and allow more effective ablation of tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Energy replacement during parenteral nutrition in surgery, sepsis and cancer.

For many years, the increased nutritional requirements of surgical, septic and cancer patients were identified, but no effective therapy existed for averting their negative calorie and nitrogen balance. Parenteral nutrition offered an answer in many of these situations. However, abnormalities in liver function, ventilatory load, hyperglycemia and a disturbed metabolic homeostasis showed that in excessive amounts, glucose can behave as a relatively toxic substance. For cases with increased energy expenditure, new alternatives had to be devised in order to avoid excessive glucose intakes. One obvious possibility in these cases was to refrain from offering more than the basal caloric needs, until the patient had passed the period of acute injury, or other measures had effectively controlled the sepsis or cancer. Other options included the partial substitution of glucose by lipids or amino acids. Preliminary information suggests that this approach could lead to better nutritional outcome and survival rates, but additional studies are required.

The influence of nutritional status on skin anergy in experimental cancer.

Malignant tumours as well as severe malnutrition can interfere with carcass weight, serum albumin and delayed hypersensitivity tests. In order to identify the separate effects of these two phenomena, Wistar rats were submitted to various nutritional manipulations prior to Walker-256 carcinosarcoma inoculation (TU). Six groups of well-nourished rats with positive response to the Keyhole Limpet Haemocyanin (KLH) test were studied. Three TU-bearing groups were established, [1] protein-deprived before and after TU (group DDT), [2] protein deprived before TU and later brought back to normal chow (group DNT), and [3] those receiving a complete diet throughout the experiment (group NNT). Identical control groups without TU, sham-injected, were called DDC, DNC and NNC. Tumour size and body weight were measured daily. KLH tests were done sequentially and serum albumin was determined at sacrifice. Results indicated that cancer produced marked changes in immune response. Malnutrition was responsible for anergy and weight loss, and further aberrations tended to occur when both conditions were present. Feeding was able to restore body weight and KLH response in tumour-bearing as well as in control rats, but subsequent deterioration occurred in cancer bearing rats after the first week of tumour development. It is concluded that cancer potentiates the effects of malnutrition, on body weight and immune response, but temporary recovery could be demonstrated after adequate refeeding.

Better palliation of colorectal carcinoma with laser therapy.

For a number of years now, the Neodymium-YAG laser has been used to treat advanced obstructing or bleeding colorectal carcinomas. International results show significant improvement of symptoms in over 85% of patients treated and a complication rate of approximately 6%. Thirty patients with advanced colorectal carcinoma have been so treated at our institution. We achieved excellent control of symptoms, with no complications, and none of the patients required surgical intervention. We conclude that endoscopic laser therapy of colorectal carcinoma is a safe and effective modality for the palliation of symptoms of advanced disease.

Preoperative assessment in cases of adult megacolon suffering from moderate malnutrition.

Acquired megacolon is a chronic disease associated with constipation and malnutrition. Surgical treatment may be required for the alleviation of the intestinal symptoms, emphasizing the interest of nutritional assessment in this population. In a prospective study of 33 patients suffering from acquired megacolon and requiring either anterior resection or pull-through operation, standard anthropometric and biochemical measurements as well as the PNI of Buzby and Mullen were preoperatively assessed. Mean age of the population was 49 +/- 13 y, with 17 males and 16 females. The combined nutritional score indicated 63.6% of the population were malnourished (21/33) of the patients, whereas the Prognostic nutritional index (PNI) revealed 3 high-risk cases (9.1%), 9 with moderate risk (27.3%), and reduced risk for all others. Indeed, 39.4% (13/33) of the patients displayed surgical or septic problems. Chi-square analysis confirmed that both studied criteria were significantly associated with complications (p < 0.05), as morbidity was restricted predominantly to cases with unfavorable Prognostic nutritional index (PNI) results or clear signs of nutritional deficit. Both PNI and conventinoal nutritional assessment are valuable tools for the screening of these surgical candidates. Artificial alimentation was not used in this experience, but deserves consideration in selected patients. Nutritional status improved in the late postoperative period, with normalization of bowel function.

Refeeding procedures after 43 days of total fasting.

Refeeding syndrome encompasses fluid and electrolyte imbalances and metabolic, intestinal, and cardiorespiratory derangements associated with appreciable morbidity and mortality. Although refeeding syndrome has been well documented in concentration-camp subjects, and more recently during parenteral therapy of critically ill patients, little is known about the importance of refeeding syndrome during recovery from a hunger strike. Thus, we studied the response to a four-step dietary replenishment routine in eight hunger strikers who refused food for 43 d. In this retrospective, observational study, we assessed the safety and efficacy of the refeeding procedure and analyzed the clinical and nutritional course of the cohort during both starvation and refeeding, mainly on the basis of clinical as well as a few biochemical determinations. During starvation, average weight loss was about 18% and, with the exception of occasional oral vitamins and electrolytes, the subjects consumed only water. Available body-composition and biochemical profiles showed no clinically significant changes during starvation, but one-half of the group displayed spontaneous diarrhea at some time before refeeding. Stepwise nutritional replenishment lasted for 9 d, after which all patients tolerated a full, unrestricted diet. Only one episode of diarrhea occurred during this phase, and both clinical and biochemical indexes confirmed a favorable clinical course, without any manifestation of refeeding syndrome. In conclusion, we observed the following: 1) Hypophosphatemia and other micronutrient imbalances did not occur, nor was macronutrient intolerance detected. 2) Despite some episodes of diarrhea, nutritional replenishment was not associated with significant enteral dysfunction. 3) There was some fluid retention, but this was mild. 4) Acute-phase markers were abnormally elevated during the refeeding phase, without associated sepsis or inflammation.

Nutritional management of thoracic duct fistulas. A comparative study of parenteral versus enteral nutrition.

Thoracic duct fistulas represent one of the serious technical complications of head and neck surgery, and reoperation for control of the leakage involves considerable morbidity and mortality. In an attempt to define the possibilities of both enteral and parenteral nutrition in the treatment of this problem, two comparable groups of patients were given, respectively, one or the other of these modalities. Significant advantages for parenteral nutrition could be demonstrated regarding duration of therapy (p less than 0.05), closure rate (p less than 0.05), and nutritional response (p less than 0.05). These results strongly recommended the utilization of parenteral nutrition in the primary therapy of thoracic duct fistulas.

Anthropometric assessment of nutritional depletion after surgery injury.

Triceps skinfold (TS), arm muscle circumference (AMC) and body weight (BW) were studied prospectively in 20 adults, admitted to elective operations on the digestive tract, in order to evaluate these anthropometric parameters in planned surgical procedures performed in non-critically ill, non-stressed patients. Mean duration of the preoperative period was 19.2 days (range 1--38), and of the postoperative period, 14.1 days (range 6--31). Mean changes for BW were, respectively, -0.2% and -2.5%, AMC decreased -0.5% before operation and -3.4% afterwards, and TS was reduced to -1.9% in the preoperative phase, and to -8.4% postoperatively. These results are consistent with minimal anthropometric changes during the presurgical stay, with more striking decreases after operative injury. Postoperative findings were further examined in relationship to degree of surgical trauma and length of postoperative hospitalization. After the arbitrary selection of a 10% reduction as the limit for significant decrease in any of the analysed parameters, the percentage of impaired measurements was determined in the sub-groups of medium and large operations, two consecutive procedures, as well as postoperative stay of 6 to 14 days, 15 to 21 days, and over 3 wks. Decreased parameters comprised 6.0% (2/33) of the observations after moderate surgical manipulation, 27.7% (5/18) after serious trauma, and 66.6% (6/9) after two operations. Simarilarly they represented 2.7% (1/36) of the findings in patients discharged within 2 weeks, 33.3% (4/12) in those staying between 2--3 weeks, and 66.6% (8/12) in the cases remaining for longer periods. Despite the limited sensitivity of anthropometric parameters in the detection of acute moderate changes in body constitution, they were useful in separating the patients undergoing medium surgical injury from those subjected to more severe metabolic stress, when only changes greater than 10% of initial value were considered.

Nutritional abnormalities in nonhospitalized patients with primitive cardiomyopathy.

The present investigation was aimed at studying the influence of primitive myocardial disease on the nutritional status of nonhospitalized patients. In a group of 93 consecutive cases, without additional organic disabilities of known nutritional deficits, a simplified protocol of anthropometric and biochemical measurements was applied, including weight/height, triceps skinfold, arm muscle circumference, albumin, cholesterol, hemoglobin, and creatinine excretion. All these findings were analyzed in the light of the left ventricular functional status, as assessed by phonomechanographic parameters. The conclusions were: (1) primitive cardiomyopathy with significant ventricular impairment is associated with some signs of malnutrition; (2) triceps skinfold is the most affected index in those cases.

A randomized study of two schedules of copovithane in patients with advanced colorectal carcinoma.

Copovithane (BAY i 7433), a copolymer of 1,3-bis(methylaminocarboxyl)-2-methylenepropanecarbamate and N-vinyl pyrrolidone, has antitumor activity in vitro and in vivo. The mechanism of this polymer is unknown. Thirty patients with advanced colorectal carcinoma with measurable tumors were treated in an open randomized study with two schedules of copovithane (schedule A: 6 g/m2 i.v. over 30 min daily for 5 consecutive days and repeated every 3 weeks; schedule B: 10 g/m2 i.v. over 30 min once a week until progression, unacceptable toxicity, or up to 18 months). Fifteen patients received copovithane on a weekly schedule, and 15 patients received it on an intermittent schedule. None of the patients on either schedule achieved a complete or partial remission. Copovithane was ineffective against colorectal carcinoma by both schedules selected in this study.

Hepatitis in patients receiving intraarterial chemotherapy for metastatic colorectal carcinoma.

Fifty-one patients with metastatic colorectal carcinoma confined to the liver received intraarterial chemotherapy through the hepatic artery via a subcutaneous pump. The chemotherapy consisted of sequential 14-day infusions of floxuridine (FUDR) and dichloromethotrexate (DCMTX) or a 14-day infusion of FUDR and bolus mitomycin (MMC). Twenty-four patients (47%) developed hepatitis with an elevation of hepatic serum transaminase (serum glutamic oxaloacetic transaminase, SGOT, or serum glutamic-pyruvic transaminase, SGPT). The median time to develop hepatitis was 11 weeks after initiation of chemotherapy. The morphologic effects of chemotherapy were evaluated in eight patients with hepatitis. All the patients with hepatitis had normalization of the serum transaminases after temporary cessation of chemotherapy. There was a trend toward a greater chance of remission in patients who developed hepatitis. Sixty-seven percent of the patients with a therapeutic response had hepatitis, whereas only 33% of the patients without a response had hepatitis. However, this difference was not statistically significant. The occurrence of hepatitis was not related to FUDR dose, drug program (FUDR-DCMTX vs. FUDR-MMC), pump flow rate, hepatic arterial anatomy, sex, or age of the patients.