Josef Dvorak

Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents.

The diagnosis and assessment of the severity of intestinal mucosal damage in cancer patients treated with cytotoxic drugs still rely on anamnestic data. There is cumulative evidence that measurement of intestinal permeability may represent a sensitive indicator of intestinal damage by cytotoxic agents. The intestinal permeability testing is based on differential permeability of tight junctions along the crypt-villus axis to nonmetabolized sugars. Cytotoxic drugs induce flattening of villi, leading to increased exposure of luminal contents to crypts and increased disaccharide absorption. An increased disaccharide/monosaccharide ratio and decreased xylose absorption have been described in patients treated with different cytotoxic drugs across a spectrum of malignant tumors that correlated with clinical manifestations, and were used to monitor the effect of therapeutic interventions.

Liposomal doxorubicin combined with regional hyperthermia: Reducing systemic toxicity and improving locoregional efficacy in the treatment of solid tumors

Summary Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes increases the therapeutic index, prolongs circulation time and enhances tumor localization. Pegylated liposomal doxorubicin (PLD) is an established therapeutic agent in epithelial ovarian carcinoma (EOC), breast carcinoma or Kaposi’s sarcoma, and PLD administration results in reduction of toxicity. Addition of regional hyperthermia increases liposome extravasation, induces the doxorubicin release from the liposomes, and the combination of hyperthermia and doxorubicin itself may be supra-additive, resulting in enhanced antitumor efficacy in the heated region. Encouraging results have been reported for the combination of PLD and hyperthermia in EOC, breast carcinoma and hepatocellular carcinoma.

Weekly Paclitaxel Combined with Local Hyperthermia in the Therapy of Breast Cancer Locally Recurrent after Mastectomy – a Pilot Experience

Background: The combination of chemotherapy and hyperthermia (HT) is a promising approach in the treatment of malignant tumors. In the present report we evaluate the efficacy and toxicity of a combination of weekly paclitaxel combined with local hyperthermia in breast cancer. Patients and Methods: 7 patients were treated for inoperable local recurrence of breast cancer after mastectomy, irradiation, and chemotherapy or hormonal therapy. They weekly received paclitaxel (60–80 mg/m²) in 3-h infusions followed by local HT 41–44 °C for 45 min for 6–18 cycles. Results: Objective local response was observed in all treated patients (complete response in 4 patients and partial response in 3 patients). There were no grade 3 or 4 toxicities, neurologic toxicity or hypersensitivity reactions. Local tolerance to this regimen was also good, with only 4 patients developing mild transient erythema. Conclusion: Our experience indicates that the combination of weekly paclitaxel and HT may be effective in the treatment of locally recurrent breast cancer after mastectomy.

Epidermal Growth Factor Receptor as a Predictor of Tumor Response to Preoperative Chemoradiation in Locally Advanced Gastric Carcinoma

Purpose:The purpose of our study was a retrospective evaluation whether the intensity of epidermal growth factor receptor (EGFR) expression predicts tumor response to preoperative chemoradiotherapy in patients with locally advanced gastric carcinoma.Patients and Methods:Thirty-six patients with gastric adenocarcinoma (cT2–4 or N+) were studied. Preoperative treatment consisted of 30–45 Gy of gastric irradiation with continuous 5-fluorouracil and weekly cisplatin. Surgical resection was performed 4–6 weeks later. EGFR expression in pretreatment tumor biopsies was assessed by immunohistochemistry. Level of EGFR expression was determined from the intensity and extent of staining. Tumor response was defined as a reduction of at least one T-stage level and/or finding of intense tumor regression in histopathologic examination.Results:Seventeen patients responded to preoperative chemoradiation – 8 patients (22%) had pathologic complete response, 9 patients (25%) were downstaged. Positive EGFR expression was found in 8 tumors (22%), and represented a significant predictive marker of poor tumor response in multivariate logistic regression analysis (p = 0.015). Response to chemoradiotherapy was found in 60% (16/28) of EGFR negative patients and in 13% (1/8) of EGFR positive patients (p = 0.044). None of the eight EGFR positive patients achieved pathologic complete response in comparison with 8/28 (29%) of patients with EGFR negative staining (p = 0.16).Conclusion:EGFR may represent a molecular marker predictive for poor response to preoperative chemoradiotherapy in locally advanced gastric carcinoma.Ziel:Ziel dieser Studie war eine retrospektive Evaluierung, ob die Expressionsintensität des epidermalen Wachstumsfaktor-Rezeptors (EGFR) die Tumorantwort auf präoperative Chemoradiotherapie vorhersagt bei Patienten mit lokal fortgeschrittenem Magenkrebs.Patienten und Methodik:36 Patienten mit Adenokarzinom des Magens (cT2–4 oder N+) wurden untersucht. Die präoperative Behandlung bestand aus einer Bestrahlung des Magens mit 30–45 Gy mit fortlaufendem 5-Fluorouracil und wöchentlichem Cisplatin. Die operative Resektion wurde 4–6 Wochen später durchgeführt. Die Expression des EGFR in den vorbehandelten Biopsiepräparaten des Tumors wurde mittels Immunhistochemie gemessen. Die Höhe der EGFR-Expression wurde festgelegt nach der Intensität und dem Ausmaß der Färbung. Das Downstaging wurde definiert als eine Reduktion von mindestens einem T-Stadium und/oder einem Befund von Tumorregression in der histopathologischen Untersuchung.Ergebnisse:17 Patienten haben auf die präoperative Chemoradiotherapie angesprochen – 8 Patienten (22%) hatten eine pathologisch komplette Reaktion, 9 Patienten (25%) wurden „downgestaged“. Eine positive EGFR-Expression wurde in 8 Tumoren gefunden (22%), und stellte einen signifikanten Vorhersagefaktor dar für eine geringe Tumorantwort in multivariater logistischer Regressionsanalyse (p = 0,015). Eine Reaktion auf die Chemoradiotherapie wurde bei 60% (16/28) der EGFR-negativen Patienten festgestellt und bei 13% (1/8) der EGFR-positiven Patienten (p = 0,044). Keiner der 8 EGFR-positiven Patienten erreichte eine pathologisch komplette Reaktion im Vergleich zu 8/28 (29%) der Patienten mit EGFR-negativer Färbung (p = 0,16).Schlussfolgerung:Der EGFR stellt einen Vorhersagefaktor für eine geringe Reaktion auf die präoperative Chemoradiotherapie beim lokal fortgeschrittenen Magenkarzinom dar.

Breast cancer and cancer stem cells: a mini-review.

Breast cancer is the most common type of malignant disease in women worldwide. In developing countries the past few years have sustained an increasing incidence of this type of cancer. Currently, breast cancer is the second leading cause of death due to cancer in women. In 2008 alone it was diagnosed in more than 1 million patients and each year the number of breast cancer-related deaths is estimated to be ~450,000. The mortality rate in breast cancer patients has been decreasing over the years thanks to the development of early diagnostic methods and more effective treatments. But despite the new advances in cancer diagnosis and treatment, the risk of recurrence and metastasis is ever present. It has been theorized that cancer stem cells are involved in the process of tumor growth and metastases. Due to their self-renewing and differentiation capabilities, they are now considered the underlying factor in tumor recurrence and the main reason for therapy resistance. Therefore, the characterization of cancer stem cells may contribute to the development of more effective treatment strategies that should make it possible to eliminate cancer stem cells in order to prevent tumor relapse and metastasis in diagnosed patients.

Complete Response of Multiple Melanoma Brain Metastases after Treatment with Temozolomide

Background: Inoperable melanoma brain metastases are usually uniformly fatal, and complete response after cytotoxic therapy is rare. Case report: A patient with multiple inoperable melanoma brain metastases was treated with 6 cycles of oral temozolomide (300 mg once daily over 5 days every 28 days). A complete response was documented by magnetic resonance. Conclusions: The present observation suggests that temozolomide may be an active and well tolerated treatment for malignant melanoma brain metastases.

Pegylated liposomal doxorubicin in combination with hyperthermia in the treatment of a case of advanced hepatocellular carcinoma.

Background Currently, there is no standard treatment of inoperable advanced hepatocellular carcinoma. Study A patient with advanced hepatocellular carcinoma was treated with intravenous infusion of pegylated liposomal doxorubicin (PLD, Caelyx) in combination with ultrasound hyperthermia of the liver. Each cycle consisted of infusion of 60 mg of PLD followed by two fractions of hyperthermia 41°C to 43°C for 45 minutes 1 and 48 hours after infusion, respectively. Results A substantial regression of the tumor was observed on computed tomography scans. No toxicity of combined treatment was noted. Conclusions This may be the first report of the combination of PLD and hyperthermia in the treatment of advanced hepatocellular carcinoma. Our observation suggests that the combination of PLD with hyperthermia is technically feasible, well tolerated, and could have synergistic potential.

Preoperative neoadjuvant chemoradiation for locally advanced gastric adenocarcinoma

Abstract Aims and Background To evaluate toxicity and the radical resection rate in gastric adenocarcinoma treated with preoperative neoadjuvant chemoradiation. Materials & Methods 32 patients, 22 males and 10 females with gastric adenocarcinoma, were treated with chemoradiation and hyperthermia. Results The neoadjuvant regimen was completed as planned in 19/32 (59 %) patients; in the remaining patients the intensity of chemotherapy had to be reduced because of haematological and gastrointestinal toxicity. Surgical stage was as follows: 2 patients pathologically complete response, 3 patients AJCC stage I.A, 5 patients stage I.B, 7 patients stage II, 7 patients stage III.A, 1 patient stage III.B, 7 patients stage IV. R0 resection was achieved in 19/32 (59%) patients, R1 in 2/32 (6%) patients and R2 in 11 (34%) patients. Downstaging after neoadjuvant chemoradiotherapy was achieved in 17/32 (53%) patients. At the date of evaluation (31 March 2009), 4 patients were still alive 58, 81, 86 and 98 months from the date of diagnosis. Median survival was 18 months (95% confidence interval: 13–38 months). One-year survival was 69% (95% confidence interval: 53%–85%). Four-year survival was 19% (95% C.I.: 5%–34%). Conclusions Preoperative neoadjuvant chemoradiotherapy has acceptable toxicity, and can lead to a high rate of R0 resections.

Dissociated invasively growing cancer cells with NF-kappaB/p65 positivity after radiotherapy: a new marker for worse clinical outcome in rectal cancer? Preliminary data

Objectives Nuclear factor-kappaB (NF-κB), especially p65 subunit, seems to be associated with origin and progression of cancer. The aim of the study was to determine expression of NF-κB/p65 in rectal cancer patients before and after radiotherapy as well as to assess the relationship between NF-κB/p65 expression, other tumor characteristics, and disease progression. Further aim was to evaluate whether expression of NF-κB/p65 in tumor tissue may serve as a predictive marker of patient outcome. Patients and methods Twenty-five patients with rectal cancer undergoing pre-operative radiotherapy were included in the study. Unirradiated rectal cancer specimens were obtained from diagnostic colonoscopy. Irradiated rectal cancer specimens were obtained from surgically removed part of the rectum with the tumor. NF-κB/p65 expression was determined by immunohistochemistry. Results Cytoplasmic positivity in cancer cells and nuclear positivity in lymphocytes were detected. In post-radiotherapy specimens single tumor cells or small clones of them deeply infiltrating the wall of the rectum, that were characterized by high NF-κB/p65 expression, were found. Patients with presence of these cells in post-radiotherapy specimens have worse clinical outcome in terms of overall survival and disease-free interval. Conclusion While the NF-κB/p65 positive staining of the epithelial cells did not have any clinical implications in this study, it may be of clinical significance in the future. Residual invasively growing cancer cells with high NF-κB/p65 positivity found in specimens after radiotherapy and surgery may be used to find what patients have a worse outcome. Thus, patients being at risk of cancer progression and requiring more aggressive anti-cancer therapy may be identified.

Peri-ictal headache due to epileptiform activity in a disconnected hemisphere

A 4-year-old girl with intractable epilepsy due to left-side hemispheric cortical dysplasia underwent a hemispherotomy. She was seizure-free after the surgery. EEG showed persistent abundant epileptiform activity over the left (disconnected) hemisphere, including ictal patterns that neither generalised nor had clinical correlates. Antiepileptic medication was completely withdrawn four years following the surgery. One week after the withdrawal, she developed episodes of intense left-sided hemicranias (ipsilateral to the surgery) with vomiting and photophobia that did not resemble her habitual seizures and were unresponsive to non-steroidal anti-inflammatory drugs. Video-EEG showed association of the headache attacks with ictal patterns over the disconnected hemisphere. Brain MRI revealed increased signal changes in the left hemisphere. Attacks responded promptly to i.v. midazolam and carbamazepine at a low dose. Mechanisms underlying peri-ictal headache originating in the disconnected hemisphere are discussed. [Published with video sequences].