Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study.

PURPOSE: To investigate the antitumor activity and toxicity of topotecan, used alone and in combination with conventional therapy, in patients with metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Forty-eight patients younger than 21 years of age with newly diagnosed metastatic RMS received 2.0 to 2.4 mg/m(2) of topotecan intravenously daily for 5 days every 21 days before standard therapy. Two courses were given in the absence of progressive disease or excessive toxicity and response was assessed. Patients with at least a partial response (PR) to topotecan proceeded to therapy with alternating courses of vincristine 1.5 mg/m(2), dactinomycin 1.5 mg/m(2), and cyclophosphamide 2.2 g/m(2) (VAC) and vincristine 1.5 mg/m(2), topotecan 0.75 mg/m(2) daily x 5, and cyclophosphamide 250 mg/m(2) daily x 5. Patients who did not respond to topotecan received continuation therapy with VAC alone. RESULTS: The overall response rate to topotecan was 46% (complete response, 4%; partial response 42%). Unexpectedly, patients with alveolar RMS had a higher rate of response (65%) than those with embryonal RMS (28%; P: = .08). The most common grade 3 or 4 toxicities were neutropenia (67%), anemia (33%), thrombocytopenia (25%), and infection (21%). Two-year failure-free survival and survival estimates were 24% and 46%, respectively. Response to window therapy did not correlate with survival. CONCLUSION: The high response rate and acceptable toxicity profile of topotecan in children with advanced RMS support further evaluation of this agent in phase III trials. The superior responses in alveolar RMS are of interest.

Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents.

PURPOSE: To determine the treatment outcome and clinical factors that are of prognostic significance for children and adolescents with relapsed or refractory Hodgkin's disease (HD) who received treatment with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS: Fifty-three consecutive children and adolescents 21 years of age or younger with relapsed or refractory HD underwent HSCT. RESULTS: At day 100 after transplantation, 29 patients (55%) were in a complete remission or maintained a continuous complete response, six (11%) had a partial response, and 11 (21%) failed to respond or had progressive disease. The failure-free survival (FFS) at 5 years was 31%, and overall survival was 43%. Twenty-one patients died of progressive HD, and nine died secondary to transplantation-related complications, including two secondary leukemias. Prognostic factors important for FFS were normal pretransplantation lactate dehydrogenase levels (5-year FFS = 42%), compared with patients with elevated LDH levels (5-year FFS = 0%) (P < .001), and disease sensitivity at the time of HSCT with FFS in untreated relapse, sensitive disease, and resistant disease 44%, 35%, and 9%, respectively (P = .06). There was no statistically significant difference in FFS or overall survival between age subgroups that were analyzed (< 13, 13 to 18, 19 to 21) or in comparison with an adult cohort. CONCLUSION: HSCT is an effective treatment modality that can result in long-term cures and should be considered for children and adolescents with relapsed HD.

Mortality while awaiting liver retransplantation: predictability of MELD scores.

INTRODUCTION: Model for End-stage Liver Disease (MELD) scores at the time of listing on the transplant waiting list have been shown to accurately predict 3-month mortality in adults. There is no data assessing the accuracy of the MELD scores in predicting mortality of patients awaiting liver retransplantation. We sought to determine the outcome of patients listed for retransplantation at a single center and the accuracy of MELD scores in predicting mortality on the transplant waiting list. METHODS: A retrospective review of adult patients at a single center listed for a second liver transplantation during the years 1993 to 2000. MELD scores and a concordance statistic were calculated at the time of initial listing and initial transplant as well as the time of relisting for a second transplant and at 2, 4, 6, 8, 12, and 24 weeks after relisting. RESULTS: Of the 63 patients in the study, 43 (68%) received a second transplant, and 20 (32%) died while awaiting retransplantation. Of the patients receiving a second transplant, 13 (30%) died within 1 year of receiving the transplant. The most common cause of death on the waiting list was sepsis (50%), hepatorenal syndrome (20%), and multiorgan failure (10%), whereas the majority of deaths posttransplantation were sepsis-related (69%). At the time of relisting the c-statistic for MELD scores predicting death after 1 week on the waiting list was 0.78 (P = .007). After 3 months on the waiting list, the c-stat was largely unchanged (0.76, P = .04). CONCLUSIONS: We have shown that MELD scores may predict mortality on the transplant waiting list for patients listed for a second transplant.

Lipids increase after solitary pancreas transplantation.

OBJECTIVE: The aims of this study were to determine 1) changes in lipids after solitary pancreas transplantation (SPTX) in patients with type 1 diabetes and 2) factors that influence those changes. RESEARCH DESIGN AND METHODS: Lipids were evaluated prospectively in 24 patients who underwent SPTX. Three were excluded because of early graft failure. The remaining patients (n = 21; 13 men, 8 women) were studied for changes in lipids over time (pre-SPTX, 0-2, 3-6, 7-12, and > 12 months). Glycohemoglobin, serum creatinine, BMI, and medications were also analyzed for their effects on lipid changes. RESULTS: Cholesterol, HDL, and LDL decreased in the immediate postoperative period (0-2 months), whereas triglycerides (TGs) increased (P < 0.05). At 3-6 months, cholesterol, HDL, and TG were higher than before the SPTX, whereas LDL returned to pre-SPTX levels. After 12 months, HDL and TG remained higher than their pre-SPTX levels (P < 0.05). During the study, systolic and diastolic blood pressure increased, renal function decreased, glyco-hemoglobin improved, and weight was unchanged. Changes in cholesterol/HDL ratio, HDL, and TG correlated with changes in prednisone dose (P < 0.05), and changes in TG correlated with changes in creatinine (P < 0.05). The same pattern of lipids occurred in patients prescribed or not prescribed hypolipidemic agents. CONCLUSIONS: Lipids do not improve within the 1st year after SPTX, despite improved glycemic control and blood pressure control, and renal function is worse. These results are in contrast to those reported for combined kidney-pancreas transplantation, where lipids, blood pressure, and renal function improved immediately after transplant. Further studies are needed to determine whether lipids continue to change with time after SPTX. The impact of these changes after SPTX on overall cardiovascular risk is unknown.

Reproductive hormones after pancreas transplantation.

BACKGROUND: Reproductive hormone function after pancreas transplantation (PTX) is unknown as it has not been studied. METHODS: We prospectively studied PTX recipients to determine changes in reproductive hormones after PTX. Testosterone or estradiol, leutinizing hormone, follicle stimulating hormone, and prolactin were determined before and 1 year after PTX in 23 patients (10 women, 13 men) followed for more than 1 year after PTX. Of these, 11 received simultaneous kidney-PTX; 8 PTX only; and 4, PTX after kidney. Average age was 38.4+/-1.6 years and average duration of diabetes was 24.5+/-1.3 years. Nine (four women, five men) patients had been on dialysis pre-PTX. Sixteen of 23 patients were treated with cyclosporine and seven with FK-506 along with prednisone and azathioprine post-PTX. RESULTS: Mean testosterone in men was normal pre- and post-PTX. Two men had secondary hypogonadism pre-PTX with resolution in one and persistence in the other post-PTX. Five of the ten women had evidence of hypogonadism pre-PTX: three had primary hypogonadism and two had secondary hypogonadism. Post-PTX, 7 of 10 women had abnormal reproductive hormones: 4 had primary hypogonadism, 2 had secondary hypogonadism, and 1 developed hyperestrogenemia with elevated estradiol (482 pg/ml) and leutinizing hormone (41 IU/liter). Mean prednisone dose and cyclosporine trough level were higher in the women than the men (P<0.05). No cases of secondary hypogonadism that developed or resolved post-PTX were related to changes in prolactin, renal function, or hyperglycemia. CONCLUSIONS: Women are more likely than men to have reproductive hormone abnormalities pre- and post-PTX and the causes may be multiple.

Lack of utility of intestinal fatty acid binding protein levels in predicting intestinal allograft rejection.

INTRODUCTION: The enterocyte-specific protein, intestinal fatty acid binding protein (I-FABP), is detectable in serum only after intestinal injury. Previous studies in animals suggest that I-FABP might be a useful marker of intestinal allograft rejection. MATERIALS AND METHODS: I-FABP was repetitively measured in nine intestinal transplant recipients and correlated with findings of surveillance endoscopy. RESULTS: Average interval between I-FABP determination and biopsy was 3.4 days (SD=4.2 days). Average number of rejection episodes per patient totalled 1.6+/-1.2. General linear modeling demonstrated no tendency for increases in serum FABP to precede histologic graft rejection (P=0.263). Restriction of the analysis to I-FABP determinations 1 day before or on the day of biopsy failed to affect these results. Minor increases in I-FABP were often associated with histologically normal grafts, whereas rejection often occurred when I-FABP was not detectable. DISCUSSION: Serum I-FABP levels do not predict clinical intestinal allograft rejection.

Disaccharidase activities and fat assimilation in pediatric patients after intestinal transplantation.

BACKGROUND: Intestinal transplantation has become an accepted therapy for short bowel syndrome and other types of intestinal failure. In order to assess digestive capabilities and feeding practices in a group of 22 pediatric patients after intestinal transplantation, we assessed mucosal disaccharidase activities and assimilation of total dietary lipid and vitamin E. Twelve of the patients had undergone contemporaneous liver transplantation. METHODS: Mucosal biopsies were assayed for disaccharidase activities between 15 and 412 days after transplantation in 7 of the 22 when all were receiving some enteral nutrition and were free of rejection. Coefficients of lipid absorption were determined in those patients receiving total enteral feeding (two-thirds polymeric/one-third elemental) between 43 and 1032 days after transplantation; oral vitamin E tolerance tests were done at about the same time. RESULTS: Activities of lactase, sucrase, maltase, and palatinase consistently exceeded reference ranges (P<0.05). Mean coefficient of lipid absorption equaled 86+/-12% and was not influenced by duration of time after transplantation. No patient required dietary lipid restriction. No significant absorption of vitamin E was demonstrated until 160 days after transplantation. Vitamin E absorption did correlate with length of time elapsed after surgery (r=0.64, P<0.0011). CONCLUSIONS: The results of this investigation show that, in the absence of histologic or clinical indications of allograft rejection, pediatric intestinal transplant recipients do not have primary disaccharidase deficiencies. Similarly, absorption of usual dietary lipid content is adequate once weaning from parenteral nutrition is complete. In contrast, early assimilation of vitamin E is poor. Vitamin E absorption subsequently improves, but the mechanism is obscure.

Central nervous system dysfunction as the first manifestation of multiple organ dysfunction syndrome in stem cell transplant patients.

Development of CNS dysfunction in the setting of hematopoietic stem cell transplant (HSCT) has been previously shown to predict for subsequent second organ dysfunction and death. In this paper, we describe the characteristics of this isolated CNS dysfunction, and its relationship to multiple organ dysfunction syndrome (MODS) after HSCT. Twenty-one of 186 patients undergoing HSCT developed CNS dysfunction as their first organ dysfunction a mean of 22.8 +/- 0.9 days after the start of the preparative regimen. Compared with 137 patients who developed no organ dysfunction, patients presenting with CNS dysfunction were more likely to have undergone allogeneic HSCT (P = 0.001) and to have received a total body irradiation-based regimen (P = 0.001), and were less likely to have been transplanted for lymphoma (P = 0.008). Patients who developed CNS dysfunction were more likely to die than those with no organ dysfunction (P < 0. 001). Of the 21 patients who developed CNS dysfunction, 48% resolved their dysfunction by a mean of 4.6 days later without progression to second organ dysfunction, and 90% of these patients survived to day 100. Fifty-two percent of patients with CNS dysfunction progressed to second organ dysfunction (pulmonary or hepatic) a mean of 5.5 days later, and only 36% survived to day 100 (P = 0.02). The patients who progressed to second organ dysfunction and those who did not were not different in terms of type of HSCT (allogeneic vs autologous), stem cell source (blood vs bone marrow), age, diagnosis or preparative regimen. Development of CNS dysfunction in the setting of HSCT, as with other organ dysfunctions (such as hepatic veno-occlusive disease), probably represents an early manifestation of a systemic disorder predisposing for MODS, increasing the risk of transplant-related mortality. Early systemic therapies directed at modulating this systemic disorder are probably indicated. Bone Marrow Transplantation (2000) 25, 79-83.

Effects of nandrolone propionate on experimental tumor growth and cancer cachexia.

We studied the tumor host response to excessive doses of an anabolic steroid (nandrolone propionate, 2.5 mg 20 g intraperitoneally every second day for 11 days) with respect to body composition and tumor cell kinetics in MCG 101 sarcoma-bearing mice (C57BL/6J) with progressive cachexia. Although survival and food intake were not affected, a significant weight gain was observed that was essentially attributed to water retention. Net protein content was increased only to a minor extent (15%), of which only the liver accounted for a significant part of the body compartments. Hepatic protein accumulation was obviously caused by decreased protein degradation, since hepatic RNA content was unchanged. After anabolic steroid administration, reduced histochemical staining of succinate dehydrogenase was observed in skeletal muscles rich in oxidative type 1 fibers, but it was not different from that of tumor-bearing control animals, which was also confirmed by measurements of citrate synthase and cytochrome c oxidase activities in skeletal muscle and liver tissue. The anabolic steroid had no significant effect on tumor growth in terms of weight progression, energy state, polyamine synthesis rate, cell division rate, and cell cycle cytocompartments. We conclude that anabolic steroid supplementation is not therapeutically beneficial in counteracting progressive weight loss in experimental cancer.

Nitrate and nitrite concentrations in human saliva for men and women at different ages and times of the day and their consistency over time.

Salivary nitrite arises from nitrate and is the main source of gastric nitrite, a precursor of carcinogenic N-nitroso compounds. We examined nitrate and nitrite levels in unstimulated saliva from subjects consuming low-nitrate low-vitamin C diets. When saliva was collected from six men at nine times of the day (Experiment 1), night time nitrite levels were significantly higher than day time values and nitrite varied more than nitrate. When saliva was collected from 29 subjects aged 19-37 or 60-84 years at four times of the day during 1991-1993 (Experiment 2), all older subjects and older men had significantly higher nitrite levels than the corresponding younger subjects, night time nitrite levels in men were significantly raised, and nitrate and nitrite levels in the same samples were closely correlated. Saliva was collected at 6.00 a.m. on two successive days in 1997 from 16 subjects who had collected saliva in 1991-1993 (Experiment 3). Nitrate and nitrite levels on day 1 of experiment 3 were closely correlated with those on day 2. Nitrate and nitrite levels on days 1 and 2 of Experiment 3 were correlated with the corresponding parameters in Experiment 2 with P = 0.04 and 0.08 for day 1, and 0.10 and 0.28 for day 2, respectively. Hence, saliva nitrite levels rose at night and were higher in older people, especially older men, and saliva nitrate and nitrite levels varied little from day to day, but varied more after 4-6 years.

Proliferative pattern of head and neck cancer.

Tumor growth is primarily dependent on the fraction size of growing cells, their growth and proliferative rate, and the fractional cell death. In the present study, we focused specifically on the proliferative characteristics of squamous cell carcinomas of the head and neck region by using monoclonal antibodies and immunohistochemical methods. We studied two normally occurring antigens representative of cell proliferation: (1) ribonucleotide reductase, which is an independent cytoplasmatic enzyme and is intimately integrated in DNA synthesis, and (2) Ki-67, which is a nuclear antigen being expressed only in replicative cells. We also used intravenously injected bromodeoxyuridine (BRDU) for specific detection of tumor cells in the S phase of the cell cycle. In addition, in vivo injections of BRDU were also given to tumor-bearing mice to illustrate tumor cell kinetics by means of flow cytometry. The main observation was morphologic heterogeneity, with a high frequency of proliferative cell clusters in the cancer specimens interspersed among quiescent cells, which was demonstrated by the three monoclonal antibodies independent of each other. The experimental studies clearly visualized the transfer of BRDU throughout the tumor cell cycle. We conclude that immunohistochemical analysis provides valuable qualitative information on the proliferative pattern of tumor growth and, together with dynamic flow cytometry, may improve the clinical basis for individualized management of the cancer patient.

Outcomes of liver transplantation for hepatitis B: a single-center study of 35 patients.

BACKGROUND: Results of liver transplantation (LT) for hepatitis B (HBV) have improved in the past decade but recently drug resistance has been described, the clinical significance of which is unclear. The aims of this study were to evaluate outcomes of LT for HBV and describe the prevalence of drug resistance. METHODS: A retrospective chart analysis and review of the organ transplant database was performed to identify all patients transplanted for HBV between December 1982 and April 2004 who survived more than 3 months. RESULTS: Thirty-five patients were transplanted for HBV during this period: 27 men and 8 women. Median age at LT was 48.8 years (range 18.9 to 74.3). Four patients were transplanted for fulminant liver failure and 31 for decompensated cirrhosis. Intramuscular HBIG was administered to 8 patients and intravenous HBIG to 32 patients, data were unavailable for three patients. Lamivudine was prescribed for 18 patients (58%) pre-OLT and for 31 patients (88.6%) post-LT. Drug-resistant HBV developed in two patients (5.71%) receiving lamivudine and HBIG. Adefovir substitution resulted in improvement in liver function tests, in HBV DNA and in histology in both patients. Twenty-five patients are currently alive with and 1-year survival of 95% and a 5-year survival of 75%. Causes of death were respiratory failure (n = 3), metastatic cancer of unknown primary (n = 2), renal failure (n = 2), sepsis (n = 1), cerebrovascular accident (n = 1), and cerebral edema (n = 1). CONCLUSIONS: LT for HBV shows survival rates comparable to other liver transplant recipients. Lamivudine resistance was rare in this series but responded to adefovir substitution.

Outcomes of liver transplantation for cryptogenic cirrhosis: a single-center study of 71 patients.

UNLABELLED: Cryptogenic cirrhosis (CC) is emerging as an important indication for orthotoptic liver transplantation (OLT) in the United States. Our aim was to identify risk factors associated with nonalcoholic steatohepatitis (NASH) in patients with CC and to evaluate outcomes following OLT. PATIENTS AND METHODS: A chart review was performed on patients transplanted for CC at the University of Nebraska Medical Center between October 1993 and May 2003. RESULTS: Seventy-one patients were identified (37 were men and 34 women). Average age was 53.5 years. Mean cholesterol and triglyceride levels increased from 174.8 to 222.3 mg/dL (P <.05) and from 162.60 to 279.66 mg/dL (P <.05), respectively. The prevalence of diabetes mellitus also increased from 37.14% to 54.93% (P <.05). Incidental hepatocellular carcinoma was present in six patients and high-grade dysplasia in one patient. Steatohepatitis developed in eight patients and recurrent cryptogenic disease in four, of whom one required retransplantation for decompensated liver disease. Rejection occurred in 24 patients. Cumulative incidence of graft failure at 1 year was 4% (95% CI 0% to 10%) and at 5 years was 7% (95% CI 0% to 18%). Survival at 1 year was 85% (95% CI 77% to 94%) and at 5 years was 73% (95% CI between 61% to 86%). CONCLUSIONS: Cryptogenic liver disease is an important cause of decompensated cirrhosis; NASH appears to be an intermediate stage in the development of this disease in a subset of patients. Short-term and 5-year survival rates in this series appear comparable to other liver transplant recipients, supporting liver transplantation as an acceptable treatment for CC.

Cell proliferative modulation of MCG 101 sarcoma from mice exposed to hyperbaric oxygenation.

Tumor cell kinetics were studied in C57 Bl/J mice with a transplantable sarcoma, MCG 101, exposed to hyperbaric oxygen (HBO2), 2.8 atm abs, 2 hours daily for 9 days or until spontaneous death. The isoenzymatic pattern of lactate dehydrogenase (LDH) confirmed that there was a significant shift toward aerobic metabolism in tumor tissue as well as in the liver and skeletal muscle. Recruitment of cells from the G0G1 state into DNA synthesis was associated with an increased mobilization of substrates for polyamine synthesis in terms of an elevated ornithine decarboxylase (ODC) activity. However, cell cycle turnover in terms of bivariate flow cytometric analysis after bromodeoxyuridine (BrdUrd) injection, final tumor weight, and survival time were not changed compared with the controls. Tumor cell metabolism demonstrated evidence of an unchanged net energy utilization, in that activities (V(max) of phosphofructokinase (PFK) and LDH were not significantly changed. When the tumor-bearing animals were exposed to advanced HBO2 pressure (3.7 atm abs) for 3 h as a single dose, the DNA distribution and growth rate were not changed immediately. However, 3.5 h later we observed a DNA pattern similar to that after repeated HBO2 treatments, 2.8 atm abs, concomitant with a preponderance of cells in the late S-phase, which is consistent with a block at the entry of G2M. We conclude that MCG 101 sarcoma recovers from HBO2 exposure by an accumulation of cells in the S-phase without significant changes of net tumor growth. This may have relevance to clinical radiocurability.

The time and financial impact of training fellows in endoscopy. CORI Research Project. Clinical Outcomes Research Initiative.

OBJECTIVE: To use a national endoscopy database (Clinical Outcomes Research Initiative, CORI) to determine 1) if fellow involvement increases procedure time; and 2) the financial impact of fellow participation for academic centers compared to private practice. METHODS: CORI database from 4/1/97 to 4/1/99 was used to compare endoscopists from private practices, academic medical centers, and Veterans Administration hospitals, with or without fellows-in-training. Data were captured in a computer-generated endoscopy report and transmitted to a central database for analysis. Duration of procedure (minutes) was recorded for diagnostic esophagogastroduodenoscopy (EGD), EGD with biopsy, diagnostic colonoscopy, and colonoscopy with biopsy, in ASA 1 patients. Financial outcomes used 1999 Medicare reimbursement rates for respective procedures and were calculated as procedures per hour on a theoretical practice of 4000 procedures. RESULTS: Teaching fellows endoscopy added 2-5 min for EGD, with or without biopsy, and 3-16 min for colonoscopy, with or without biopsy. Calculating the number of procedures/h of endoscopy, the reimbursement loss resulting from using fellows-in-training in a university setting would be half a procedure/h. In Veterans Administration hospitals, training of fellows would lose a full procedure/h. In a model of 1000 procedures each of EGD, EGD with biopsy, colonoscopy, and colonoscopy with biopsy, the reimbursement difference between private practice physicians or academic attending physicians and procedures involving fellows-in-training would be $500,000 to $1,000,000/yr. CONCLUSIONS: Fellow involvement prolonged procedure time by 10-37%. Thus, per-hour reimbursement is reduced at teaching institutions, causing financial strain related to these time commitments.

Ketamine inhibits the proinflammatory cytokine-induced reduction of cardiac intracellular cAMP accumulation.

UNLABELLED: The proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), are increased in heart failure and sepsis, clinical conditions for which the IV anesthetic ketamine is useful. The proinflammatory cytokines cause beta-adrenergic receptor (betaAR) hypofunction secondary to reduced function of the enzyme adenylylcyclase (AC). In this study, we evaluated the effect of ketamine alone, TNF-alpha and IFN-gamma, and ketamine plus TNF-alpha and IFN-gamma, on isoproterenol (ISO, a betaAR agonist) and forskolin (FSK, an activator of AC)-induced intracellular accumulation of cAMP. An in vitro culture of a rat heart cell line (H9c2) was labeled with [3H]adenine to produce [3H]ATP, and we measured the intracellular accumulation of [3H]cAMP after stimulation with ISO or FSK to convert the [3H]ATP to [3H]cAMP. Pretreatment with either cytokine alone did not significantly affect ISO or FSK-induced intracellular cAMP accumulation, whereas the combination of TNF-alpha and IFN-gamma caused a significant (P < 0.05 compared with untreated cells) reduction. Pretreatment with ketamine caused a significant (P < 0.05 compared with untreated cells) increase in ISO or FSK-induced cAMP accumulation. Pretreatment of the H9c2 cells with ketamine, plus the combination of TNF-alpha and IFN-gamma, inhibited the reduction of ISO or FSK-induced intracellular cAMP accumulation caused by the proinflammatory cytokines alone. These results demonstrate that the combination of the proinflammatory cytokines TNF-alpha and IFN-gamma reduce poststimulation (ISO or FSK) intracellular cAMP accumulation. This action of the proinflammatory cytokines is consistent with the observation of betaAR hyporesponsiveness to betaAR agonist therapy in sepsis and heart failure. Ketamine augments the poststimulation cAMP accumulation in H9c2 cells while inhibiting the cytokine-induced reduction of cAMP accumulation. This may partly explain the improvement in cardiac function after ketamine use in clinical conditions known to have increased systemic levels of proinflammatory cytokines, such as sepsis and heart failure. IMPLICATIONS: Tumor necrosis factor-alpha and interferon-gamma reduced poststimulation intracellular cAMP levels, whereas ketamine inhibits this action of the proinflammatory cytokines. Because cAMP is the second messenger for the beta-adrenergic receptor, this may be a mechanism for improved blood pressure and cardiac output in sepsis and heart failure after ketamine use.

Gender differences in colorectal polyps and tumors.

OBJECTIVES: To use a national endoscopy database (CORI) to determine 1) whether gender differences are noted in the prevalence and location of polyps and tumors; 2) whether women have a higher rate of right-sided polyps or tumors; and 3) whether age influences these results. METHODS: CORI database from April 1, 1997 to February 19, 1999, captured in a computer-generated report, was analyzed. Polyps for this study were defined as sessile or pedunculated and as >9 mm. Tumors were defined as lesions characteristic of adenocarcinoma (mass, apple-core). Pure right-sided colon (PRS) was defined as cecum, ascending, hepatic flexure; right-sided as PRS plus the transverse colon; and left-sided as the splenic flexure, descending, sigmoid and rectum. RESULTS: Men have a greater risk of polyps [odds ratio (OR), 1.5] and tumors (OR, 1.4) than women. The risk of finding polyps and tumors at colonoscopy increases with age, with the highest risk noted in those >69 yr of age relative to patients <50 yr of age (polyps, OR = 2.7; tumors, OR = 4.0). Right-side polyps and pure right-sided polyps as defined by the study design were noted to be more frequent than left-sided polyps in patients >60 yr of age. Women have a greater risk of developing pure right-sided polyps (OR, 1.2), tumors (OR, 1.6) and right-sided tumors (OR, 1.5) than men. CONCLUSIONS: Men have a higher prevalence of colon polyps and tumors than women. A progressive risk of polyp or tumor formation is noted with aging. Women had a greater number of pure right-sided polyps and tumor development. Colonoscopy is needed to correctly diagnose an increasing prevalence of right-sided pathology in the elderly.

Effects of low doses of erythromycin on the 13C Spirulina platensis gastric emptying breath test and electrogastrogram: a controlled study in healthy volunteers.

OBJECTIVE: Electrogastrography and stable isotope gastric emptying breath tests (GEBTs) are relatively simple, noninvasive tests of gastric motor function that may be useful in monitoring the effects of therapeutic interventions. It was our primary objective to examine the effects of low dose i.v. erythromycin on the results of the 13C Spirulina platensis GEBT and electrogastrography. We were also interested in evaluating the reproducibility of these tests. METHODS: In 10 healthy subjects (five female, ages 23-37 yr), we simultaneously performed the GEBT, using a prepackaged meal (340 kcal), and electrogastrography on each of four different occasions separated by at least 1 wk. After performance of baseline studies, they were repeated in random order after the infusion of 50 mg of erythromycin (Er50), 100 mg erythromycin (Er100), and a placebo (saline). Breath samples were obtained at baseline and at 75, 90, and 180 min after the meal and T1/2 and Tlag calculated. Electrogastrography recordings began 30 min before the test meal and continued for 2 h after the meal. RESULTS: Baseline and placebo T1/2 and Tlag were similar. Er50 resulted in a modest acceleration of gastric emptying (T1/2 Er50 vs baseline vs placebo = 104.0 vs 132.7 vs 125.5 min) and reduction in lag time (Tlag Er50 vs baseline vs placebo = 47.2 vs 61.5 vs 56.2 min). A similar decrease was seen in response to Er100. The baseline and placebo fasting and fed electrogastrography parameters were similar. After infusion of Er100, the percentage of normal slow waves in the first postprandial hour decreased relative to baseline and placebo (percent normogastria Er100 vs baseline vs placebo = 64.1+/-7.5 vs 82.4+/-6.4 vs 79.7+/-5.5). This corresponded with an increase in percent tachygastria during the same period and an overall decrease in the mean dominant frequency. Similar but less striking changes were seen after administration of Er50. Replicate GEBTs showed a high degree of reproducibility both within and between individuals for T1/2 and Tlag. In contrast, replicate electrogastrograms revealed moderate to high variability for all parameters except the dominant frequency. CONCLUSION: The stable isotope GEBT utilizing 13C S. platensis demonstrates responsiveness to the prokinetic effects of low dose i.v. erythromycin and good reproducibility.

Gastric myoelectrical activity and its relationship to the development of nausea and vomiting after intensive chemotherapy and autologous stem cell transplantation.

OBJECTIVES: Gastric motor dysfunction may be responsible, in some patients, for the nausea and emesis that occur after high-dose chemotherapy (HDT) and autologous stem cell transplantation (SCT). Because gastric myoelectrical abnormalities may result in nausea and vomiting in other contexts, we sought to define the prevalence of these abnormalities and their relationship to the development of nausea and vomiting in patients undergoing autologous HDT and SCT, and to determine whether electrogastrography (EGG) could serve to detect gastric motor dysfunction in this population. METHODS: We prospectively studied patients with a variety of malignancies who received standard transplantation doses of chemotherapeutic agents and antiemetics. Gastric emptying scintigraphy was performed before HDT. Gastric myoelectrical activity was assessed before HDT and on days 0, 7, 14, 21, and 28 from SCT using cutaneous EGG electrodes and a portable EGG recorder, and was analyzed by means of a dedicated software program after removal of motion artifact. Symptom assessment was obtained daily from initiation of HDT to 28 days after SCT. RESULTS: A total of 25 patients were studied: 13 women and 12 men, with a median age of 50 yr (range = 32-65 yr). Before HDT, gastric emptying scintigraphy was normal in all patients (median T(1/2) of 50 min [range = 22-75 min]) and only one patient had mild nausea and anorexia. Nausea, emesis, and anorexia occurred in all patients, peaked in severity at day +7 from SCT and, with the exception of anorexia, had returned toward baseline levels by day +28. Fasting dysrhythmias were present in 63% of the studies at baseline. Serial EGG recordings revealed significant slowing of the dominant frequency with a consequent decrease in tachygastria and increase in normogastria and bradygastria as the symptoms peaked in severity with a subsequent return to baseline values at the study's end. The only clinical variable that was predictive of symptom severity was gender. Women had a higher risk of developing anorexia (score > or = 2) at day +14 compared to men (odds ratio = 11.2; 95% CI = 1.7-76.9; p = 0.01). CONCLUSIONS: Baseline abnormalities in gastric myoelectrical activity occur frequently in patients who undergo HDT and autologous SCT despite normal gastric emptying scintigraphy and an absence of symptoms. Although slowing of the dominant frequency was seen as symptoms worsened, we failed to identify any EGG parameter at baseline that could predict the severity of nausea, vomiting or anorexia after transplantation.