Christian Lersch

The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons.

The chemotherapeutic oxaliplatin causes a sensory-motor neuropathy with predominantly hyperpathic symptoms. The mechanism underlying this hyperexcitability was investigated using rat sensory nerve preparations, dorsal root ganglia and hippocampal neurons. Oxaliplatin resulted in an increase of the amplitude and duration of compound action potentials. It lengthened the refractory period of peripheral nerves suggesting an interaction with voltage-gated Na(+) channels. Application of oxaliplatin to dorsal root ganglion neurons resulted in an increase of the Na(+) current, a block of the maximal amplitude and a shift of the voltage-response relationship towards more negative membrane potentials. The effect was detectable on 13 of 18 tested cells. This observation, together with the absence of any effect on Na(+) currents of hippocampal neurons, suggests that the interaction of oxaliplatin is restricted to one or more channel subtypes. The effect of oxaliplatin could be antagonised by the Na(+) channel blocker carbamazepine which could be used to reduce side effects of oxaliplatin therapy in patients.

High Incidence of Angina pectoris in Patients Treated with 5-Fluorouracil A Planned Surveillance Study with 102 Patients

Objective: Angina pectoris, arrhythmic sudden death and myocardial infarction, all these cardiac events have occasionally been reported during 5-fluorouracil (5-FU) chemotherapy. Underlying mechanisms leading to these events are unknown; damage to the myocytes or vasospasms have been discussed. Methods: 102 consecutive and unselected patients were monitored with 12-lead ECG, echocardiography and radionuclide ventriculography prior to the first cycle of 5-FU chemotherapy and 3 months from baseline. Results: 19% of the patients developed reversible symptoms of angina pectoris during treatment which lasted up to 12 h after cessation of the infusion. Most of the 19 patients showed corresponding ECG changes. 6 out of the 19 patients with severe angina pectoris had subsequent coronary angiography. In none of these patients the coronary angiography showed coronary artery disease, but it showed low ventricular function (ejection fraction <50%) in 2 patients. The ejection fraction did not increase over time. Arrhythmias were screened for with Holter monitoring during 5-FU chemotherapy. The frequency of bradycardia and ventricular extrasystoles increased significantly (p < 0.05) during treatment compared to arrhythmias in Holter monitoring 3 months later. Furthermore the Qtc time in the ECG 3 months later was significantly prolonged (p < 0.05) compared to baseline values. Conclusions: The incidence of angina pectoris in patients during 5-FU treatment seems higher than previously suspected. As myocardial ischemia can be fatal, attentiveness to these symptoms and immediate treatment are crucial.

Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma

BackgroundPatients with advanced gallbladder and biliary tract carcinoma face a dismal prognosis, as no effective palliative chemotherapy exists. The antitumor effect of gemcitabine is schedule-dependent rather than dose-dependent. We evaluated the activity of a prolonged infusion of gemcitabine in advanced gallbladder and biliary tract carcinomas.MethodsNineteen consecutive eligible patients were enrolled. All patients were required to have histologically confirmed diagnosis and measurable disease. Gemcitabine was infused over 24 hours at a dose of 100 mg/m2 on days 1, 8, and 15. Treatment was repeated every 28 days until progression of disease or limiting toxicity. Tumor response was evaluated every second course by computed tomography (CT) scans.ResultsEighteen patients were evaluable for response. A total of 89 cycles of therapy were administered. One partial response was observed (6%; 95% confidence interval (CI): 0–27%) and ten additional patients had stable disease for at least two months (disease control rate 61%; 95% CI: 36–83%). The therapy was well tolerated, with moderate myelosuppression as the main toxicity. The median time to tumor progression and median overall survival was 3.6 months (95% CI 2.6–4.6 months) and 7.5 months (95% CI 6.5–8.5 months), respectively.ConclusionWeekly 24-hour gemcitabine at a dose of 100 mg/m2 is well tolerated. There was a relatively high rate of disease control for a median duration of 5.3 months (range 2.8–18.8 months). However, the objective response rate of this regimen in gallbladder and biliary tract carcinomas was limited.

Effect of low-molecular-weight heparin on survival in patients with advanced pancreatic adenocarcinoma.

This retrospective analysis aimed to identify whether low-molecular-weight heparins (LMWH) might improve survival in patients receiving chemotherapeutic treatment for advanced pancreatic adenocarcinoma. Two hundred forty-three patients who had received chemotherapy for advanced pancreatic adenocarcinoma were identified from a prospectively maintained database. Of these, 30 patients had to be excluded from analysis due to insufficient documentation. Of the remaining 213 patients 94 patients had been treated with LMWH, whereas 119 patients served as controls. Outcome was assessed in relation to overall survival, which was calculated from the date of initiation of chemotherapy to the date of death. There was no significant difference (hazard ratio, 0.8; 95% confidence interval (CI), 0.6 to 1.1; P = 0,2) between the two groups in terms of overall survival. The median survival was 7.1 months (95% CI, 5.8-8.4 months) in the LMWH group and 5.9 months (95% CI, 5.1-6.7 months) in the non-LMWH group. A positive effect of LMWH was seen in patients with metastatic disease (hazard ratio for LMWH vs. non-LMWH, 0,6; 95% CI, 0,4 to 0,8; P = 0,006) in contrast to those without metastatic disease (hazard ratio for LMWH vs. non-LMWH, 1; 95% CI, 0.6 to 1.7; P = 0,96). The median survival of patients with metastatic disease was 6,6 months (95% CI, 5-8, 2 months) and 3.8 months (95% CI, 2.5-5.1 months) for the LMWH group and the non-LMWH group, respectively. In conclusion, we found for metastatic pancreatic adenocarcinoma a survival advantage for patients receiving LMWH. Nevertheless, our observations need confirmation by prospective randomized studies.

Effect of substance P on immunoglobulin and interferon-gamma secretion by cultured human duodenal mucosa

Recently, we have demonstrated a substance P (SP)-dependent modulation of in vitro IgM and interferon-gamma (IFN-gamma) secretion by human peripheral blood mononuclear cells, as well as lymphokine activities in supernatants of cultured duodenal mucosa. Therefore we investigated other local immunoregulatory effects of SP. Duodenal biopsies of 7 healthy subjects were cultured with Pokeweed mitogen (PWM, 1 microgram/ml) for 4 days at 37 degrees C in 1 ml medium each. SP was added in concentrations ranging from 10(-12)M to 10(-6)M on day 1. Fresh media with fresh PWM were added every day. IgG, IgM, IgA (ELISA) and IFN-gamma (RIA) were determined in the culture supernatants. Values were referred to 5 mg biopsy weight and expressed as % change in basal PWM pulsed secretion, or as units/ml. 10(-6) M and 10(-12) M SP increased secretion of all immunoglobulin isotypes. Compared to controls, 10(-6) M and 10(-12) M SP led to an increase in IgM secretion of up to 73 +/- 23% and 41 +/- 32% and to an increase in IgA secretion up to 96 +/- 35% and 25 +/- 33%, respectively (alpha = 0.02 for both isotypes at 10(-6) M). 10(-12) M to 10(-6) M SP led to a significant dose-dependent increase in IFN-gamma secretion from 7.08 +/- 1.65 up to 21.8 +/- 12.6 units/ml/5 mg. The maximum effect could be seen on culture days 3 and 4. We were able to demonstrate for the first time that SP stimulates PWM pulsed immunoglobulin and IFN-gamma secretion by human duodenal immunocompetent cells. These results support the hypothesis of local neuropeptidergic-immune interactions.

Multimicrobial sepsis including Clostridium perfringens after chemoembolization of a single liver metastasis from common bile duct cancer.

A 65-year-old woman underwent resection of a distal common bile duct carcinoma (Whipple’s procedure). Twelve months later a single hepatic metastasis was detected and a chemoembolization was performed. Immediately after chemoembolization the patient developed a multimicrobial sepsis including Clostridium perfringens. CT scans depicted pathognomonic signs of gas-containing abscess in the necrotic liver metastasis. She was subsequently treated with broad-spectrum antibiotics, abscess drainage and hyperbaric oxygen therapy. We conclude that antibiotic prophylaxis is recommendable for chemoembolization of liver metastasis in patients with risk factors like intestinal biliary reflux (bilioenteric anastomosis or papillotomy and biliary stenting) and bile duct cancer, otherwise severe sepsis including clostridium bacteremia may occur.

Advanced Hemodynamic Monitoring before and after Transjugular Intrahepatic Portosystemic Shunt: Implications for Selection of Patients—A Prospective Study

PURPOSE To investigate immediate and short-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on cardiocirculatory, hepatic, and renal function and characterize predictors for TIPS outcome in terms of organ function after TIPS. MATERIALS AND METHODS This prospective study was approved by the ethics committee at a university hospital and was conducted in a medical intensive care unit. Informed consent was obtained. Twenty patients with indication for TIPS were enrolled. Monitoring of hemodynamic and hepatic function (transpulmonary thermodilution, indocyanine green plasma disappearance rate [ICG-PDR]) was performed. Biochemical markers of organ function were obtained. Statistical analysis (Wilcoxon test, Spearman correlation, multivariate linear regression analysis, receiver operating characteristic [ROC] analysis) was performed. RESULTS After TIPS, central venous pressure (median, 11 vs 15 cm H(2)O; P < .001), cardiac index (3.4 vs 3.8 L/min/m(2); P = .001), and global end-diastolic volume index (GEDVI) (726 vs 775 mL/m(2); P = .003) increased significantly. Portosystemic pressure gradient (28 vs 11 cm H(2)O; P < .001) and systemic vascular resistance index (1610 vs 1384 dyn · sec · cm(-5) · m(2); P = .015) decreased significantly. Creatinine (1.1 vs 1.1 mg/dL; P = .008) and blood urea nitrogen (BUN) (27 vs 21 mg/dL; P = .006) decreased significantly. Bilirubin (1.8 vs 2.2 mg/dL; P = .032) and international normalized ratio (1.4 vs 1.5; P = .022) increased significantly. ICG-PDR significantly deteriorated after TIPS (P = .006). Higher baseline creatinine was independently associated with a decrease in creatinine after TIPS (R = 0.816, P < .001). ROC analysis identified baseline BUN (P = .026, area under ROC curve [AUC] = 0.818), cystatin C (P = .033, AUC = 0.805), and creatinine (P = .052, AUC = 0.779) as predictors of a decrease in creatinine of 0.5 mg/dL or greater and/or 25% or greater. An increase in bilirubin of 1 mg/dL or greater 1 week after TIPS was significantly associated with high baseline BUN (P = .007, AUC = 0.893) and high central venous pressure (P = .040, AUC = 0.800). Lower baseline alanine aminotransferase (P = .002, AUC = 1.000) and cardiac power index · GEDVI (P = .005, AUC = 0.960) predicted favorable TIPS outcome (creatinine decrease of ≥ 0.2 mg/dL without model for end-stage liver disease score increase of more than one point). CONCLUSION Patients with renal insufficiency, compensated hepatocellular function, decreased cardiac preload, and decreased cardiac performance benefit most from TIPS.

Effect of thyrotropin-releasing hormone on immune functions of peripheral blood mononuclear cells

The tripeptide thyrotropin-releasing hormone (TRH) works as a hypothalamic hormone, but is found also outside the brain in intrinsic nerve fibers of the gastrointestinal tract. There is evidence that TRH modulates the activity of immunocompetent cells, although there are only very few data on TRH-mediated immune effector functions. Since we could recently show that TRH inhibits monocyte activities we were also interested in other possible TRH modulated immune functions. Peripheral blood mononuclear cells (PBMC) from ten healthy subjects were cultured for 7 days and pulsed with 0.125 and 0.250 microgram/ml Pokeweed mitogen (PWM). 10(-12) to 10(-6) M TRH was added simultaneously with PWM. Lymphocyte proliferation [(3H]thymidine incorporation), interferon-gamma (IFN-gamma) activity (RIA) and immunoglobulin activities (IgG, IgM, IgA; ELISA) were determined in the supernatants. We could demonstrate a TRH-dependent decrease in PWM-pulsed IgG activity with significant (alpha = 0.05) values at 10(-8) and 10(-10) M (-29 +/- 6%/-16 +/- 3% for PWM 0.125 microgram/ml and -17 +/- 9%/-11 +/- 9% for PWM 0.250 microgram/ml). This inhibitory effect could be abolished by an anti-TRH antiserum. There was no TRH effect on IgM and IgA activities, IFN-gamma activity and lymphocyte proliferation compared with the PWM stimulated values alone. The described TRH effect on the polyclonal IgG response by PBMC gives further evidence for a functional link between the immune system and the endocrine system, although its underlying mechanism is not yet clear.

Soluble interleukin-2 receptor and soluble CD8 in liver cirrhosis and obstructive jaundice.

Activated lymphocytes secrete soluble interleukin‐2 receptor (sIL‐2R); CD8‐positive lymphocytes secrete soluble CD8 (sCD8). Liver dysfunction in cirrhosis and obstructive jaundice is known to result in depressed cellular immunity. To evaluate whether this is due to real inactivation of the immune system, we measured sIL‐2R and sCD8 in the serum of 46 patients with liver cirrhosis, 25 patients with obstructive jaundice, 32 patients with alcoholic liver disease without evidence of cirrhosis, 23 healthy persons and 43 patients with unrelated disease. sIL‐2R in patients with cirrhosis (mean ± s.e.m. 1499.140 U/ml) and obstructive jaundice (1517 ± 204) was significantly increased compared with healthy subjects (363 ± 29) and patients with unrelated diseases (685 ± 92); sCD8 was significantly increased in patients with cirrhosis (737 ± 63) but not in patients with obstructive jaundice (419 ± 32) compared with healthy subjects (322 ± 23) and patients with unrelated diseases (375 ± 22). No difference was found between patients with cirrhosis due to alcohol abuse (n= 15) and chronic hepatitis B (n = 6). The Child‐Pugh score had no significant influence on the sIL‐2R or sCD8 value. In obstructive jaundice, sIL‐2R correlated with alkaline phosphatase as marker of cholestasis (r= 0.43). These data show that in spite of the apparent depressed cellular immune defense both in liver cirrhosis and obstructive jaundice there is a general activation of the immune system but the CD8+ cell compartment is only activated in liver cirrhosis. The great changes of sIL‐2R and sCD8 in liver dysfunction are important for the interpretation of studies using these serum proteins as markers for immune activation.

Toxicity of a 24-hour infusion of gemcitabine in biliary tract and pancreatic cancer: A pilot study

The antitumor activity of gemcitabine is not dose-response related but schedule-dependent. Based on the results of a published phase I study in patients with non-small-cell lung cancer we started a pilot study of a 24-hr infusion of gemcitabine in patients with adenocarcinoma of the pancreas and biliary tract cancer. Twenty-five patients were enrolled and received a 24-hr infusion of gemcitabine once weekly on three consecutive out of 4 weeks. Dose levels of gemcitabine ranged from 100 to 150 mg/m2. One of 13 chemotherapy-naive patients had a partial response. Dose-limiting toxicity (DLT) was thrombocytopenia in pretreated patients and neutropenia in chemotherapy-naive patients. Other toxicities were oral mucositis, fever, flu-like symptoms, and asthenia. Maximum tolerated dose (MTD), especially in pretreated patients, was 100 mg/m2.