Phase II study of hepatic intraarterial epirubicin and cisplatin, with systemic 5-fluorouracil in patients with unresectable biliary tract tumors

BACKGROUND: Patients with unresectable biliary tract carcinomas have a very poor prognosis. To improve the efficacy and tolerance of the ECF regimen (epirubicin at a dose of 50 mg/m2, cisplatin at a dose of 60 mg/m2, and 5-fluorouracil [5-FU] at a dose of 200 mg/m2 per day by continuous infusion), the authors designed a novel approach that combined locoregional and systemic chemotherapy with the same agents at the same dosages. METHODS: Thirty consecutive patients with advanced or metastatic biliary tumors were treated with epirubicin at a dose of 50 mg/m2 and cisplatin at a dose of 60 mg/m2 administered as a bolus in the hepatic artery on Day 1, combined with systemic continuous infusion of 5-FU at a dose of 200 mg/m2 per day, from Day 1 to Day 14, every 3 weeks. RESULTS: Tumor sites were the intrahepatic bile ducts in 25 patients and the gallbladder in 5 patients. The overall response rate was 40% (12 of 30 patients), including 1 complete response and 11 partial responses. Stable disease was observed in 12 of 30 patients (40%) and progressive disease in 6 of 30 patients (20%). The median progression-free and overall survival periods were 7.1 and 13.2 months, respectively, and the 1-year and 2-year survival rates were 54% and 20%, respectively. Performance status improved in 9 of 30 patients (30%) and a weight gain of > 7% was observed in 4 of 30 patients (13%). The treatment was well tolerated with minimal hematologic toxicity. The major clinical problem was the deep venous thrombosis related to the central venous catheter, which occurred in 5 patients (17%). CONCLUSIONS: This novel combined locoregional and systemic chemotherapeutic regimen was found to be active and safe for patients with advanced biliary tract carcinoma.     

The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with α-[C]methyl-l-tryptophan: An autoradiographic study

Many experimental conditions are stressful for animals. It is well known that stress induces tryptophan hydroxylase (TPH) activation, resulting in increased serotonin (5-HT) synthesis. In our experimental procedure to measure 5-HT synthesis using alpha-[(14)C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method, the hind limbs of animals are restrained using a loose-fitted plaster cast such that the forelimbs of the animal remain free. The objective of the present investigation was to evaluate the changes, if any, in 5-HT synthesis, after injecting these restrained rats with the TPH activation inhibitor AGN-2979. The effect on regional 5-HT synthesis was studied using the alpha-MTrp autoradiographic method. The hypothesis was that the TPH activation inhibitor would reduce 5-HT synthesis, if TPH activation was induced by this restraint. The rats received injection of AGN-2979 (10 mg/kg, i.p.) or distilled water vehicle (1 mL/kg, i.p.) 1 h prior to tracer administration. The free- and total tryptophan concentrations were not significantly different between the treatment and control groups. The results demonstrate that 5-HT synthesis in AGN-2979 treated rats is significantly decreased (-12 to -35%) in both the raphe nuclei and their terminal areas when compared to the control rats. These findings suggest that restrained conditions, such as those used in our experimental protocol, induce TPH activation resulting in an increased 5-HT synthesis throughout the brain. The reduction in 5-HT synthesis in the AGN-2979 group is not related to a change in the plasma tryptophan. Because there was no activation in the pineal body, the structure having a different isoform of TPH, we can propose that it is only the brain TPH that becomes activated with this specific restraint.     

Origin of nasal polyps: an endoscopic autopsy study

OBJECTIVES/HYPOTHESIS: To further elucidate the natural history, etiology, and pathogenesis of nasal polyps, the present study of their anatomical site of origin was undertaken. The possibility for preferred areas or certain patterns in the places of origin was also considered. STUDY DESIGN: Autopsies were examined consecutively. METHODS: Endoscopic examination of the nasal cavity and paranasal sinuses, including endoscopic sinus surgery, was performed in 69 autopsies. The place of origin and attachment of each polyp was meticulously described. Polyps were photographically documented in situ and removed, together with the corresponding mucosa, for later histological examination. The cause of death of the patients was either cardiopulmonary disease or malignant diseases. Median age was 73 years (age range, 47-94 y). RESULTS: Nasal polyps were found in 22 of the 69 autopsies, corresponding to a frequency of 32%. In all, 54 polyps were found. Thirty-nine polyps were small (length, 2-5 mm), 10 were medium-sized, and 5 were large. No complaints of symptoms from the nasal polyps were registered. Most of the polyps (40 of 54 [74%]) originated in relation to sinus outlets. Most of these (34 of 54 [63%]) were found in the middle or superior meatus (13 of 54 [24%]). CONCLUSION: The results seemed to indicate that the frequency of nasal polyps is high and that most of the polyps originate from the mucosa of the ostia, clefts, and recesses in the ostiomeatal complex where the initial stage of sinonasal polyposis seems to take place. Continuous postmortem studies in autopsy materials and systematic endoscopic examinations for "silent," asymptomatic nasal polyps in various groups of patients will lead to a better understanding of the natural history of nasal polyps.     

New approaches to managing congenital diaphragmatic hernia

A number of new techniques have been studied for managing newborns with congenital diaphragmatic hernia and respiratory insufficiency. Among these have been the techniques of delayed approach to the repair of the diaphragmatic hernia; permissive hypercapnia; nitric oxide and surfactant administration; intratracheal pulmonary ventilation; liquid ventilation; perfluorocarbon-induced lung growth; and lung transplantation. These interventions are at various stages of development and evaluation of effectiveness. All, however, are being explored in the hopes of improving outcome in patients with congenital diaphragmatic hernia who continue to have significant morbidity and mortality in the newborn period.     

Extracorporeal life support for severe acute respiratory distress syndrome in adults

OBJECTIVE: Severe acute respiratory distress syndrome (ARDS) is associated with a high level of mortality. Extracorporeal life support (ECLS) during severe ARDS maintains oxygen and carbon dioxide gas exchange while providing an optimal environment for recovery of pulmonary function. Since 1989, we have used a protocol-driven algorithm for treatment of severe ARDS, which includes the use of ECLS when standard therapy fails. The objective of this study was to evaluate our experience with ECLS in adult patients with severe ARDS with respect to mortality and morbidity. METHODS: We reviewed our complete experience with ELCS in adults from January 1, 1989, through December 31, 2003. Severe ARDS was defined as acute onset pulmonary failure, with bilateral infiltrates on chest x-ray, and PaO2/fraction of inspired oxygen (FiO2) ratio < or =100 or A-aDO2 >600 mm Hg despite maximal ventilator settings. The indication for ECLS was acute severe ARDS unresponsive to optimal conventional treatment. The technique of ECLS included veno-venous or veno-arterial vascular access, lung "rest" at low FiO2 and inspiratory pressure, minimal anticoagulation, and optimization of systemic oxygen delivery. RESULTS: During the study period, ECLS was used for 405 adult patients age 17 or older. Of these 405 patients, 255 were placed on ECLS for severe ARDS refractory to all other treatment. Sixty-seven percent were weaned off ECLS, and 52% survived to hospital discharge. Multivariate logistic regression analysis identified the following pre-ELCS variables as significant independent predictors of survival: (1) age (P = 0.01); (2) gender (P = 0.048); (3) pH < or =7.10 (P = 0.01); (4) PaO2/FiO2 ratio (P = 0.03); and (5) days of mechanical ventilation (P < 0.001). None of the patients who survived required permanent mechanical ventilation or supplemental oxygen therapy. CONCLUSION: Extracorporeal life support for severe ARDS in adults is a successful therapeutic option in those patients who do not respond to conventional mechanical ventilator strategies.     

Role of Computer Analysis in Gastric Cancer Surgery: Evaluation of the WinEstimate v. 2.5 Computer Program

To identify the group of patients with gastric cancer who can benefit from extensive lymphadenectomy and to offer a rational approach to lymph node dissection, it is important to know the incidence of metastases at each lymph node station. A computer program was developed for assessment of lymph node involvement and survival time in each individual case according to preoperative variables. In patients who have undergone R0 resection with D2 lymphadenectomy, differences between the individual results generated by the computer and the actual data were compared. A cutoff point of 10% in the prediction of metastases was used as a positive result. The computer program made false predictions in 9% of patients for the pN status (3% lower and 6% higher than the actual status). Computerized prediction of 5-year survival was close to the rate calculated by the Kaplan-Meier method (55.5% vs 56.1%). Preoperative computer analysis of patient data and tumor characteristics offers a rational approach to individualizing tumor therapy] where the extent of lymph node dissection is tailored to the type, site, and stage of the tumor, thereby minimizing the disadvantages (morbidity, mortality) associated with the extensive operative procedure.     

Delayed versus immediate surgery in acute appendicitis: do we need to operate during the night?

Background/purpose

Over the last 4 years, the authors changed their management of acute nonperforated appendicitis from emergent surgery within the first 2 to 6 hours of admission to initiation of antibiotic therapy with operation within 24 hours of admission in those seen in the late evening or early morning. They examined, therefore, whether a delay in operation for acute appendicitis would affect outcome measures of patient morbidity and resource use.

Methods

The medical records of 126 patients with acute appendicitis occurring between 1998 and 2001 were retrospectively reviewed. Incidence of perforation at surgery, length of stay (LOS), hospital charges, operating time, and complications as a function of duration between emergency room (ER) triage and operation (ER-OR) or admission and operation (Admit-OR) were analyzed by Student’s t test, and regression analysis with P less than .05 considered significant.

Results

Thirty-eight children (26%) were operated on within 6 hours of ER triage, whereas the remaining 88 children (74%) were operated on between 6 and 24 hours from ER triage. No significant difference was noted in perforation rate, LOS, costs, or operative time, nor were substantial changes in complications noted between those with an ER-OR ≤6 hours and greater than 6 hours. Likewise, no significant differences in these outcome measures were noted for Admit-OR greater than 6 when compared with ≤6 hours. Only costs with ER-OR greater than 12 hours and LOS with Admit-OR greater than 6 hours were significantly (without Bonferroni correction) different than ≤ 6 hours. Multivariable linear regression analysis identified only LOS as a significant predictor of time to OR.

Conclusions

In children with acute appendicitis, delaying surgery until the daytime hours did not significantly affect operating time, perforation rate, or complications. Delayed management allows greater efficiency and effective use of physician and hospital resources, including decreased resident involvement in operations during the night.