Josef Dvořák

THE PERIPHERAL BLOOD LEUKOCYTE PHENOTYPE IN PATIENTS WITH BREAST CANCER: EFFECT OF DOXORUBICIN/PACLITAXEL COMBINATION CHEMOTHERAPY

Presence of functional immune system is critical for any attempt aimed at improving survival of breast cancer patients by strategies based on immune system manipulation. We evaluated by flow cytometry the phenotype of peripheral blood leukocyte of 43 breast cancer patients. In 11 patients, the phenotype was evaluated before and during the chemotherapy by combination of doxorubicin and paclitaxel (AT). Compared with controls breast cancer patients had significantly higher relative and absolute numbers of CD3−HLADR+, CD3−CD69+ and CD14+CD16−, and significantly lower percentages of CD3− and CD8−CD28+ cells. After one cycle of AT, the absolute numbers of CD3+, CD3−CD4−, CD3+CD8+ and CD8−CD28+ cells increased significantly. Present data show a presence of T-cell activation in breast cancer patients. Administration of AT may lead to an increase in functional T-cells in peripheral blood, indicating a potential for combining chemotherapy with immunotherapy in the treatment of breast cancer patients.

Intestinal permeability and vitamin A absorption in patients with chemotherapy-induced diarrhea.

Objective:Gastrointestinal toxicity is one of the most common side effects of anticancer therapy. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal toxicity. The aim of the present study was to investigate intestinal permeability and vitamin A absorption in patients with chemotherapy-induced diarrhea (CID). Methods:We have assessed intestinal permeability, by measuring absorption of lactulose, mannitol, xylose, and vitamin A absorption, in 11 patients with CID, 10 healthy controls, and 24 untreated patients with gastrointestinal tumors. Urinary lactulose, mannitol and xylose were measured by capillary gas chromatography and serum retinol and retinyl esters were determined by high performance liquid chromatography. The results obtained in patients and controls were compared by Mann-Whitney U test. Results:Lactulose/mannitol and lactulose/xylose ratios were increased and retinol esters (retinyl palmitate and retinyl stearate) were decreased significantly in patients with CID. Conclusions:Measurements of intestinal permeability and vitamin A absorption may represent sensitive tools in the assessment of CID.

Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum

BackgroundCombination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum.MethodsIntestinal permeability was assessed in 36 breast and ovarian cancer patients treated with paclitaxel/platinum combination by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose and mannitol after oral challenge. The significance of differences during the therapy compared to pre-treatment values was studied by Wilcoxon paired test. The differences between groups of patient were studied by Mann-Whitney U test. Fisher exact test was used to compare the frequency in different subgroups.ResultsAfter administration of the first dose, a significant (p < 0.05) decrease in xylose absorption and increased lactulose/mannitol, sucrose/mannitol, lactulose/xylose and sucrose/xylose ratios were observed, but these parameters returned subsequently to pre-treatment levels. Patients who experienced serious (grade 3 or 4) toxicity had at baseline significantly lower percentages of xylose, mannitol and sucrose, and higher lactulose/mannitol ratio. Nine of 13 (69%) patients with baseline lactulose/mannitol ratio 0.070 or above experienced serious toxicity compared to 4 out of 23 patients (17%) with the ratio below 0.070 (p = 0.002). Post-treatment lactulose, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were significantly increased in patients with serious toxicity.ConclusionA transient significant increase in lactulose/monosaccharide and sucrose/monosaccharide ratios was observed in ovarian and breast cancer patients treated with paclitaxel and platinum. Increased lactulose absorption, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were evident in patients with grade 3 or 4 toxicity, and increased baseline lactulose/mannitol ratio predicted serious toxicity.

Pegylated Liposomal Doxorubicin in Combination with Hyperthermia for Treatment of Skin Metastases of Breast Carcinoma: A Case Report

Background: Incorporation of doxorubicin hydrochloride into pegylated liposomes (PLD) may decrease chemotherapy side effects and increase the activity. Hyperthermia could further potentiate its effectiveness. Case Report: A patient with skin metastases of breast carcinoma was treated with intravenous infusion of PLD (Caelyx®) in combination with ultrasound hyperthermia. Each cycle consisted of infusion of 40 mg PLD absolute dose, followed by 2 fractions of hyperthermia 41–43 °C for 45 min 1 and 48 h after infusion. A complete remission was observed after the combination treatment with no significant toxicity. Conclusion: Present observations suggest that the combination of PLD with hyperthermia of skin metastases of breast carcinoma may be an active and well tolerated treatment.

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.

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.

IMRT using simultaneous integrated boost (66 Gy in 6 weeks) with and without concurrent chemotherapy in head and neck cancer – toxicity evaluation

Summary Aim To evaluate the toxicity of intensity-modulated radiotherapy with simultaneous integrated boost (SIB-IMRT) in head and neck cancer patients treated using a protocol comprising 66 Gy to the PTV1 (planning target volume; region of macroscopic tumour) and 60 Gy and 54 Gy to the regions with high risk (PTV2) and low risk (PTV3) of subclinical disease in 30 fractions in six weeks. Material and Methods Between December 2003 and February 2006, 48 patients (median age 55; range 25–83, performance status 0–1) with evaluable non-metastatic head and neck cancer of various localizations and stages (stages: I–1; II–8; III–12; IV–27 patients, resp.) were irradiated according to the protocol and followed (median follow-up 20 months; range 4–42). Ten patients underwent concurrent chemotherapy (CT) and in 15 patients the regimen was indicated postoperatively because of close or positive margins. In all cases the regimen was used as an alternative to conventional radiotherapy (70 Gy in 7 weeks). The acute and late toxicities were evaluated according to RTOG and RTOG/EORTC toxicity scales, respectively. Results All patients finished the treatment without the need for interruption due to acute toxicity. No patient experienced grade 4 toxicity. More severe acute toxicity was observed in patients with CT, but the most severe toxicity was grade 3. Grade 3 toxicity was observed in the skin, mucous membrane, salivary glands, pharynx/oesophagus and larynx in 8.4%, 35.4%, 39.6% and 2.1%, in the CT subgroup in 10%, 100%, 90%, 10%, respectively. The trend of impairment of acute toxicity by concurrent chemotherapy was statistically confirmed by Fishers exact test (for mucous membranes p=0.000002 and pharyngeal/oesophageal toxicity p=0.0004). The most severe late toxicity was grade 2 subcutaneous tissue (34.2%), mucous membrane (36.8%) and larynx (11.1%), grade 3 in salivary gland (2.6%) and grade 1 in skin (84.2%) and spinal cord (5.4%). The late toxicity was not increased by chemotherapy. Conclusion In light of the toxicity profile we consider the presented regimen to be an alternative to conventional radiotherapy 70 Gy in 7 weeks. The addition of CT requires more intensive supportive care.

Endovascular brachytherapy of transjugular intrahepatic portosystemic shunt

Purpose: To evaluate the technical feasibility and efficacy of endovascular brachytherapy with Iridium-192 in the prevention of restenosis caused by neointimal hyperplasia of transjugular intrahepatic portosystemic shunt (TIPS).Materials and Methods: The endovascular brachytherapy with high dose rate automatic afterloading system was performed in six patients with recurrent of stenosis of TIPS. We used a single dose fraction of 12 Gy delivered at 3 millimeter (mm) from the source axis to the stenotic vessel segment in five patients with spiral Z-stent, and 15 Gy at 5 mm in one patient with Wallstent.Results: Follow-up time ranged from 148 to 639 days. In one patient, restenosis occurred in the treated vessel segment, diagnosed 71 days after endovascular brachytherapy by doppler ultrasound. All other patients were, during the follow-up time, without restenosis in the irradiated vessel segment. Radiation-associated side effects were not observed.Conclusions: Endovascular brachytherapy of TIPS is technically feasible and may be done as a part of the percutaneous revision of the shunt. This pilot study may be the largest experience of treating TIPS restenosis in humans to date. For definitive conclusions, a lot of studies are needed.

Intestinal permeability, vitamin A absorption and serum alpha-tocopherol during therapy with gefitinib.

Abstract Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal toxicity of anticancer therapy. We have assessed intestinal permeability (by measuring absorption of lactulose, mannitol, and xylose), vitamin A absorption and serum alpha-tocopherol in patients with non-small cell lung carcinoma or head and neck carcinomas treated with gefitinib. Lactulose, mannitol and xylose were determined by capillary gas chromatography, and retinol, alpha-tocopherol, retinyl stearate and retinyl palmitate were determined by high-performance liquid chromatography. Compared to healthy controls, patients had significantly increased lactulose/mannitol ratio and lower postprandial retinyl palmitate and retinyl stearate concentrations. Compared with pre-treatment values, xylose absorption was decreased and lactulose/mannitol and lactulose/xylose ratios were increased during the therapy. A significant decrease of serum alpha-tocopherol was evident throughout the course of therapy. In contrast, only minor alterations of vitamin A absorption were observed. In conclusion, an alteration in intestinal permeability reflected in increased lactulose/mannitol and lactulose/xylose ratios was observed during gefitinib therapy. Potential association between decreased serum alpha-tocopherol concentrations and the toxicity of gefitinib therapy should be further investigated.

Treatment of Metastatic Renal Cell Carcinoma

INTRODUCTION Renal cell cancer accounts for approximately 2-3% of all cases of malignancy. The incidence of kidney cancer in the Czech Republic is the highest in the world. Approximately 70% of renal cell carcinomas are clear-cell renal cancer. Various treatment options for metastatic renal cell cancer (mRCC) have been developed. Treatment regimens comprise antiangiogenic drugs in combination with vascular endothelial growth factor receptor inhibitors, mTOR inhibitors, and immunotherapy. AIM This review provides an overview of the current treatment options for mRCC. Patients with a good performance status and a low systemic disease burden are candidates for cytoreductive nephrectomy. Ablative methods, such as stereotactic radiotherapy, can be used in patients with oligometastatic disease. Sunitinib and pazopanib are preferred first-line treatments for mRCC and provide similar outcomes. Second-line and higher line treatments markedly changed with the development of new drugs, such as cabozantinib and the immunotherapy nivolumab. The optimal treatment sequence for mRCC is discussed. Ongoing studies are evaluating combined treatments and searching for potential biomarkers. However, the tumor heterogeneity of renal cell cancer complicates the use of biomarkers. CONCLUSION The results of clinical trials have markedly changed the treatment guidelines for mRCC. New strategies include combinatorial approaches, which mainly incorporate immunotherapy.Key words: renal cancer - targeted therapy - immunotherapy - metastases - biomarkers The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 19. 12. 2017Accepted: 7. 1. 2018.