Jaroslav Cerman

Successful management of infusion reaction accompanying the start of cetuximab therapy

IntroductionCetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma after failure of standard chemotherapy. Rare infusion reactions that resulted in the cessation of therapy have been described after cetuximab administration.Case descriptionWe have observed severe infusion reactions accompanied by a loss of consciousness in two patients. The patients were transferred to intensive care unit, and the treatment was continued after administration of corticosteroids under careful monitoring of vital signs without any further serious reactions. In both cases, benefit of therapy with cetuximab could be demonstrated.ConclusionThis experience indicates that cetuximab can be continued in patients who experience infusion reactions. Surveillance in the intensive care unit is mandatory during readministration of the drug.

Small bowel permeability in patients with cytostatic therapy

The purpose of this study was to examine the influence of cytostatic therapy on the barrier function of the small bowel. In 16 patients with tumors in the gastrointestinal tract with metastatic involvement of the liver, small bowel permeability was measured using the lactulose/mannitol test. The patients were treated for 5 d with fluorouracil (750-1000 mg/d) and leucovorin (25-50 mg/d). The examination was performed on the first day, at the beginning of the cytostatic therapy, and also 5, 12, and 28 d after the therapy had begun. In comparing the start and the end of this therapy, the index of permeability was significantly increased (as measured 7 d after the end of therapy). These results show the damage of small bowel barrier after cytostatic therapy.

Urinary Neopterin and Microalbuminuria in Patients Treated by Low-density Lipoprotein Apheresis

Abstract Low-density lipoprotein (LDL)-apheresis is a method of extracorporeal elimination of LDL-cholesterol in patients with severe primary lipoprotein disorders. LDL-cholesterol activates macrophages, which play an important role in atheromatous plaque formation. In the present study, we have investigated urinary neopterin, a specific marker of macrophage activation and microalbuminuria, an indicator of generalized vascular dysfunction, after a single LDL-apheresis procedure in 10 patients with severe primary lipoprotein disorder. The urinary neopterin/creatinine ratio was increased in patients compared to controls. No significant changes of the neopterin/creatinine and albumin/creatinine ratios were observed after LDL-apheresis, except a significant (p < 0.006) decrease of urinary neopterin/creatinine ratio in the evening after the apheresis. This decrease showed significant negative correlation with the pre-apheretic levels of atherogenic cholesterol fractions (p < 0.05) and with cholesterol decrease during the apheresis (p < 0.05). Urinary albumin/creatinine ratio correlated positively with total and LDL-cholesterol levels before the apheresis and with the evening urinary neopterin/creatinine ratio after the apheresis, but did not correlate with glycemia and triacylglycerides. Elevated urinary neopterin in the patients with severe primary lipoprotein disorders reflects the presence of atherosclerosis. A single LDL-apheresis procedure did not significantly affect microalbuminuria. The decrease of urinary neopterin in the evening after the apheresis corresponds with the diurnal rhythm of neopterin excretion and was less pronounced in patients with more severe hypercholesterolemia. The correlations between microalbuminuria, neopterin and pre-apheretic cholesterol concentrations indicate a possible connection between microvascular dysfunction, macrophage activity and severity of hyperlipidemia, but these results should be interpreted with caution because of small number of subjects evaluated.

Hepatic arterial administration of activated leukocytes in patients with liver metastases.

BACKGROUND Liver is the most common site of metastatic disease. Hepatic arterial infusion (HAI) of cytotoxic drugs may achieve high objective response rate. METHODS Peripheral blood mononuclear cells were obtained by leukapheresis after stimulation with subcutaneous GM-CSF in six patients and with subcutaneous interleukin-2 (IL-2) in four patients, all with nonresectable hepatic metastases not responsive to conventional regimens. After the cytokine stimulation, the cells were administered by HAI either alone, or after HAI of melphalan (50 mg). RESULTS Mean number of 23.1 +/- 4.6 x 10(9) and 19.0 +/- 9.7 x 10(9) mononuclear cells were obtained through leukapheresis after GM-CSF and IL-2 priming, respectively. Significant cytotoxic activity was observed only after short IL-2 stimulation. A marked decrease in tumor markers was observed in two patients treated by combination of melphalan and activated leukocytes. CONCLUSIONS HAI is a technically feasible way of regional delivery of a high number of activated leukocytes obtained after short ex vivo activation.

Hypomagnesaemia in patients with metastatic colorectal carcinoma treated with cetuximab.

BACKGROUND/AIMS Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma. Among the side-effects of cetuximab hypomagnesaemia has been described, but the information is still limited. METHODOLOGY We have evaluated retrospectively serum magnesium, potassium, calcium, creatinine and albumin in 51 consecutive patients with metastatic colorectal carcinoma treated with cetuximab, mostly combined with irinotecan-based combination chemotherapy. RESULTS A significant decrease of serum magnesium, potassium, calcium and corrected serum calcium, creatinine and albumin concentrations was already evident one week after the start of treatment. Hypomagnesaemia of any grade was detected in 56% of evaluable patients, but grade 3 or grade 4 hypomagnesaemia was observed in 6% and 4% of patients, respectively. Grade 1 hypokalemia was detected in 47%, grade 3 in 17% and grade 4 hypokalemia was detected in 6% of the patients. Among evaluable patients grade 1 hypocalcaemia was detected in (36%), grade 2 hypocalcaemia in 42%, grade 3 in 4% and grade 4 in 13% of patients. Baseline hypocalcaemia of grade 1 or higher was associated with significantly inferior survival. CONCLUSIONS Asymptomatic hypomagnesaemia, hypokalemia and hypocalcaemia are common in metastatic colorectal carcinoma patients treated with cetuximab. Hypocalcaemia is a predictor of poor prognosis.

Gamma irradiation of human leukaemic cells HL-60 and MOLT-4 induces decrease in Mcl-1 and Bid, release of cytochrome c, and activation of caspase-8 and caspase-9

Purpose: Apoptosis is significantly controlled by proteins of Bcl-2 (B-cell lymphoma 2) family promoting cell death or maintaining cell survival. We selected two representatives of Bcl-2 family (anti-apoptotic Mcl-1 – myeloid cell line-1 and pro-apoptotic Bid – Bcl-2 homology domain 3 interacting death agonist), cytochrome c (cyt-c), and two initial caspases (-8 and -9) to evaluate their function in ionizing radiation (IR)-induced apoptosis in human leukaemic cell lines diverging in p53 (TP53 tumor suppressor gene) status. Materials and methods: A total of 30 μg of proteins of whole-cell lysates or 10 μg of mitochondrial protein fractions were electrophoretically separated and analyzed by Western-blotting. Results: Here we show that in both HL-60 (p53 null) and MOLT-4 (p53 wild type) leukaemic cells the amount of Mcl-1 initially increased after irradiation by sublethal but not by lethal dose and later (when apoptosis occurred) it decreased in a dose-dependent manner. Caspase-8 was cleaved and afterwards the amount of Bid decreased as it was truncated. We also found cyt-c release from the inner mitochondrial membrane space into cytoplasm to be dose-dependent and it was followed by induction of apoptosis. In the p53-null cells caspase-8 was activated prior caspase-9, whereas the cells harboring p53 exhibited a simultaneous activation of both initial caspases. Conclusion: IR induced a decrease in Mcl-1, activation of Bid, caspase-8, and -9, and release of cyt-c. Presented data indicate that both extrinsic and intrinsic apoptosis signalling pathways were activated in HL-60 and MOLT-4 cells upon exposure to IR regardless to the p53 status.

Intestinal permeability in patients with metastatic colon cancer treated with patupilone.

Abstract Background: Only a limited number of cytotoxic drugs have shown activity in metastatic colorectal carcinoma. Patupilone is a novel agent with promising activity in this common cancer. Diarrhea represents the dose-limiting toxicity of patupilone. Measurement of intestinal permeability is one of the potential methods of non-invasive laboratory assessment of gastrointestinal toxicity. Methods: We have assessed intestinal permeability by measuring absorption of lactulose, mannitol and xylose in 27 previously treated patients with metastatic colorectal cancer enrolled in a phase I trial of patupilone. Results: Lactulose/mannitol and lactulose/xylose ratios increased after the treatment. Significantly higher lactulose/mannitol ratio was observed in patients who had severe diarrhea. Moreover, patients who subsequently had an adverse event of grade 3 or higher had significantly higher baseline lactulose/mannitol or lactulose/xylose ratios. Conclusions: Measurement of intestinal permeability using the lactulose/mannitol test may represent a biomarker for the monitoring, or even prediction of toxicity of cytotoxic drugs, including patupilone.

HEPATIC ARTERIAL INFUSION CHEMOTHERAPY IN GASTRIC CANCER: A REPORT OF FOUR CASES AND ANALYSIS OF THE LITERATURE

Aims and background Gastric cancer is associated with high mortality. Although the liver is a common site of metastases in this tumor, the experience with liver-directed therapies is limited. Methods We report a single-center experience involving four patients with liver metastases from gastric cancer treated by hepatic arterial infusion (HAI). In addition, we performed a search for reports on HAI in gastric cancer metastatic to the liver and used the studies with data on survival of individual patients for a pooled analysis. Results Among three valuable patients, one had a complete response, one had stable disease and one had progressive disease. The patient with complete response is still alive 41 months after the diagnosis of liver metastases, while the other patients died 6, 22 and 31 months after the diagnosis. Objective responses were observed in 48% of the 25 patients in the pooled analysis. Objective response and limited hepatic involvement were independent predictors of survival in these patients. Conclusions Although isolated liver involvement in metastatic gastric cancer is rare, HAI seems to be similarly effective in these patients as in patients with liver metastases from colorectal cancer. The prognosis is significantly better in gastric cancer patients who have limited hepatic involvement and attain an objective response after HAI.

The role of apoptosis in pituitary adenomas in the field of conventionally used therapeutic approaches.

Abstract: The aim of the study was to investigate the mechanism of action of somatostatin analogues (SSA), ionizing radiation, and their combination on pituitary adenoma cells with special emphasis on proliferative and apoptotic activity. In the 14 GH‐secreting adenomas pretreated with SSA before surgery, more prominent regressive changes were found accompanied by compensatory increase in perivascular fibrosis than in the reference group of 17 unpretreated adenomas. The proliferative Ki‐67 labeling index was significantly lower in the treated group (median 1.6 per 1000) than in the untreated patients (median 5.0 per 1000). Apoptosis was detected in only 2 of the 14 pretreated adenomas, and it was more frequent (9/17) and more prominent in the untreated group. In cell lines, the SSA had minimal antiproliferative effect, and they were unable to induce apoptosis. Ionizing radiation at doses of 5–20 Gy induced apoptosis in the corticotroph cell line AtT20 with no cell‐cycle block. In the somatotroph GH3 cell line, the early (premitotic) apoptosis was detectable using only a high dose of 200 Gy; after irradiation with doses of 20–50 Gy, apoptosis appeared with the latency of 48–72 hours, and was preceded by cell‐cycle arrest in the G2/M phase. The treatment with somatostatin‐14 during irradiation increased the percentage of apoptotic cells in culture 10 days after irradiation (11% versus 3% using 20 Gy).

Pneumocystis pneumonia during medicamentous treatment of Cushing's syndrome--a description of two cases.

Only a few cases of pneumocystis pneumonia (PCP) in Cushings syndrome have been published in the literature so far. In the majority of these patients, the pneumonia occurred after reduction of the hypercortisolism with medicamentous treatment. We report two cases of PCP during conservative treatment of hypercortisolism. We describe clinical, imaging and laboratory findings in two patients and review published cases of pneumocystits pneumonia in Cushings syndrome. A 60-year-old woman and 20-year-old man with Cushings syndrome due to ectopic ACTH syndrome were treated at our department. Both developed pneumocystis pneumonia early after treatment with ketoconazole and ethomidate bromide had been introduced and the levels of cortisol rapidly decreased. PCP prophylaxis in patients with high cortisolemia should be started before treatment of hypercortisolism in current practice. Gradual lowering of plasma cortisol should also reduce the risk of infection by Pneumocystis jiroveci.