Nausea and emesis are significant side effects in patients undergoing stereotactic radiosurgery f... more Nausea and emesis are significant side effects in patients undergoing stereotactic radiosurgery for brain lesions in the region of the chemoreceptor trigger zone (area postrema of the brain). Even with the current antiemetic treatment (prochlorperazine +/- corticosteroids), those side effects remain significant. The purpose of this study is twofold: [1] to evaluate the efficacy of ondansetron in inhibiting nausea and emesis in stereotactic radiosurgery patients and [2] to demonstrate that ondansetron's locus of action is the central nervous system (CNS) chemoreceptor trigger zone in the area postrema. In a pilot study, 10 patients receiving > or = 350 cGy in a single fraction of radiosurgery to the region of the area postrema received 32 mg ondansetron iv 1 hour prior to treatment +/- corticosteroids. In a retrospective analysis these results were compared to those of patients with similar features (and matched for radiation dose to the area postrema and the dose of corticosteroids) who received prochlorperazine +/- corticosteroids. Nine of 10 patients in the ondansetron group had no nausea or emesis within 48 hours after treatment; one patient experienced one episode of emesis. In the prochloreperazine group, eight patients had symptoms, three patients needed hospitalization or a physician's care for emesis within 24 hours, and five had nausea with no specific treatment. These preliminary results suggest that ondansetron is a safe and efficient drug to prevent nausea and emesis in this patient group. The precise mechanism of action of ondansetron in these patients is unknown, but is likely due to the drug's serotonin-blocking effect within the CNS. A randomized, prospective study has been started at our institution to confirm these preliminary results.
Biochemical and Biophysical Research Communications, 1993
We report the presence of nitric oxide (NO) as measured through its product NO2 in human saliva. ... more We report the presence of nitric oxide (NO) as measured through its product NO2 in human saliva. The presence of NO is not due to oral bacterial activity but is due to a genuine release of NO from the salivary glands and can be detected in freshly secreted saliva collected from a mouth freshly rinsed with an antiseptic preparation to reduce the bacterial content significantly. In order to study the regulation of salivary NO we used lemon juice to increase salivary flow and detected an immediate transient reduction of salivary NO2 which rose to levels equal to and sometimes higher than basal levels in five minutes in most donors indicating salivary NO production might be under neural control. Salivary NO production may play a physiological role in both the natural antibacterial properties of salivary secretion and possibly in detoxification of oral carcinogens.
Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tis... more Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment deliv...
In order to investigate the biology of tumor cells which express MDR1 gene and to test the activi... more In order to investigate the biology of tumor cells which express MDR1 gene and to test the activity of different P-glycoprotein blocking agents in vivo, we established a nude mice model. Five Non Hodgkin's Lymphoma (NHL) tumor specimens were xenografted to nude mice. One of them, obtained from a chemotherapy-refractory patient gave rise to a mice transplantable model. This tumor xenograft model, IGR-NHL-90, showed overexpression of the human MDR1 gene. In this tumor model, histology, mitotic index, phenotypic and karyotypic traits remained stable at subsequent passages. The in vitro resistance of vincristine was reversed by verapamil for these NHL tumor cells, suggesting that the MDR1 resistance is a relevant mechanism in this model. In the absence of chemotherapy a higher biological aggressivity of the heterotransplanted NHL was noted in subsequent nude mice passages. This was associated with decreased passage time and higher MDR1 m-RNA transcript levels. Thus IGR-NHL-90 may re...
Activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt survival pathway protects against... more Activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt survival pathway protects against apoptotic stress stimuli. Therefore, compounds that down-regulate this pathway are of clinical interest for single and combined anticancer treatment modalities. Here we demonstrate that the cytotoxic effect of the protein kinase C (PKC)-inhibitor N-benzoylated staurosporine (PKC412) is mediated via the PI3K/Akt pathway. Dose-dependent down-regulation of the proliferative activity, activation of the apoptotic machinery, and cell killing by PKC412 (0-1 microM) in Rat1a-fibroblasts and H-ras-oncogene-transformed fibroblasts correlated with a decrease of Akt phosphorylation and a reduced phosphorylation of the endogenous Akt-substrate GSK3-alpha. Expression of the dominant-active myristoylated form of Akt abrogated this cytotoxic effect of PKC412. Experiments with Apaf-1-deficient cells revealed that PKC412-induced cytotoxicity depends on an intact apoptosome but that the decrease of Akt ph...
p53 mutations are among the most common genetic alterations in human cancer and are frequently de... more p53 mutations are among the most common genetic alterations in human cancer and are frequently described in intrinsic or acquired radio- and chemotherapy resistance. Radiation-induced cell kill is not only mediated by DNA damage but also by the activation of signal transduction cascades generated at the plasma membrane like the sphingomyelin pathway. We used genetically defined wild-type p53 or p53-deficient mouse fibrosarcoma cells to investigate the p53-dependence of tumour response upon activation of the sphingomyelin pathway. Treatment of the tumour cells with neutral sphingomyelinase drastically reduced the amount of wild-type p53 fibrosarcoma cell proliferation over 72 h in a clear dose-response (0.2-1.0 U ml(-1) nSMase). Sphingomyelinase had no effect on cell proliferation in tumour cells lacking p53. Similarly, cell proliferation was abolished by C2-ceramide (5-20 microM) only in wild-type p53 cells. FACS-analysis revealed that C2-ceramide induced massive p53-dependent apopt...
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1999
Negative regulation of E2F-1 DNA binding function by cyclin A kinase represents part of an S-phas... more Negative regulation of E2F-1 DNA binding function by cyclin A kinase represents part of an S-phase checkpoint control system that, when activated, leads to apoptosis. In this study, we examined the cellular sensitivity and resistance of isogenic mouse fibrosarcoma cell lines, differing primarily in their p53 status, to ectopic expression of wild-type (wt) E2F-1 and cyclin A kinase binding-defective mutants of it. We found that E2F-1 (wt) potently affected the survival of p53+/+ tumor cells but not that of p53-/- cells. In contrast, expression of cyclin A kinase binding-defective E2F-1 species interfered with cell survival of fibrosarcoma cells irrespective of their p53 status. Finally, expression of E2F-1 (wt) in p53-/- fibrosarcoma cells enhanced the cytotoxic effect of ionizing radiation in vitro and in vivo in a mouse tumor model. These results suggest that E2F-1-dependent activation of an S-phase checkpoint is p53 independent and that E2F-1 possesses radiosensitizing properties ...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1997
The patterns of presentation, histologic pattern (nodular or diffuse), treatment, and long-term o... more The patterns of presentation, histologic pattern (nodular or diffuse), treatment, and long-term outcome were studied in patients with lymphocyte-predominant (LP) Hodgkin's disease (HD) to determine whether these patients should be treated differently than patients with other subtypes of HD. Pathology was reviewed for 97 patients with an initial diagnosis of LPHD made between 1970 and 1993. Seventy-five patients had LPHD on review: 55 had nodular LPHD, 14 had diffuse LPHD, and six had LP histology without subclassification. There were 60 males (80%) and 15 females (20%). Sixty-six patients (88%), presented with clinical stage (CS) I or II disease. Seventy-one patients were treated at the Joint Center for Radiation Therapy (JCRT) and were considered for analysis of treatment outcome. Sixty-one of these 71 were treated with radiation (RT) alone; 17 received mantle RT alone, 27 mantle and paraaortic RT, and seven total-nodal irradiation (TNI). Ten patients with subdiaphragmatic HD r...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1993
The great majority of relapses after the treatment for early-stage Hodgkin's disease are obse... more The great majority of relapses after the treatment for early-stage Hodgkin's disease are observed within 4 to 5 years after treatment completion. This study describes the characteristics and outcome of patients who had late relapses, which was defined as relapses that occurred 5 or more years after initial treatment start. A total of 1,082 adult patients with early clinical stage Hodgkin's disease were enrolled on three consecutive European Organization for Research and Treatment of Cancer (EORTC) protocols (H1, H2, and H5 trials) from 1964 to 1981. Of these, 1,044 patients satisfied the eligibility criteria with a supradiaphragmatic localization, age greater than 15 years, and initial complete remission. Overall, 341 patients (32.6%) relapsed, 304 (29.1%) early and 37 (3.5%) late. For each of these 37 late relapsers, questionnaires were sent to the participating centers and detailed information for 34 relapses was obtained. Cumulative probabilities for developing a late rel...
To analyze the impact of weight loss before and during chemoradiation on survival outcomes in pat... more To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer. From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end. The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 - 15.4 years) weight loss before treatment was associated with decrease...
Nausea and emesis are significant side effects in patients undergoing stereotactic radiosurgery f... more Nausea and emesis are significant side effects in patients undergoing stereotactic radiosurgery for brain lesions in the region of the chemoreceptor trigger zone (area postrema of the brain). Even with the current antiemetic treatment (prochlorperazine +/- corticosteroids), those side effects remain significant. The purpose of this study is twofold: [1] to evaluate the efficacy of ondansetron in inhibiting nausea and emesis in stereotactic radiosurgery patients and [2] to demonstrate that ondansetron's locus of action is the central nervous system (CNS) chemoreceptor trigger zone in the area postrema. In a pilot study, 10 patients receiving > or = 350 cGy in a single fraction of radiosurgery to the region of the area postrema received 32 mg ondansetron iv 1 hour prior to treatment +/- corticosteroids. In a retrospective analysis these results were compared to those of patients with similar features (and matched for radiation dose to the area postrema and the dose of corticosteroids) who received prochlorperazine +/- corticosteroids. Nine of 10 patients in the ondansetron group had no nausea or emesis within 48 hours after treatment; one patient experienced one episode of emesis. In the prochloreperazine group, eight patients had symptoms, three patients needed hospitalization or a physician's care for emesis within 24 hours, and five had nausea with no specific treatment. These preliminary results suggest that ondansetron is a safe and efficient drug to prevent nausea and emesis in this patient group. The precise mechanism of action of ondansetron in these patients is unknown, but is likely due to the drug's serotonin-blocking effect within the CNS. A randomized, prospective study has been started at our institution to confirm these preliminary results.
Biochemical and Biophysical Research Communications, 1993
We report the presence of nitric oxide (NO) as measured through its product NO2 in human saliva. ... more We report the presence of nitric oxide (NO) as measured through its product NO2 in human saliva. The presence of NO is not due to oral bacterial activity but is due to a genuine release of NO from the salivary glands and can be detected in freshly secreted saliva collected from a mouth freshly rinsed with an antiseptic preparation to reduce the bacterial content significantly. In order to study the regulation of salivary NO we used lemon juice to increase salivary flow and detected an immediate transient reduction of salivary NO2 which rose to levels equal to and sometimes higher than basal levels in five minutes in most donors indicating salivary NO production might be under neural control. Salivary NO production may play a physiological role in both the natural antibacterial properties of salivary secretion and possibly in detoxification of oral carcinogens.
Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tis... more Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment deliv...
In order to investigate the biology of tumor cells which express MDR1 gene and to test the activi... more In order to investigate the biology of tumor cells which express MDR1 gene and to test the activity of different P-glycoprotein blocking agents in vivo, we established a nude mice model. Five Non Hodgkin's Lymphoma (NHL) tumor specimens were xenografted to nude mice. One of them, obtained from a chemotherapy-refractory patient gave rise to a mice transplantable model. This tumor xenograft model, IGR-NHL-90, showed overexpression of the human MDR1 gene. In this tumor model, histology, mitotic index, phenotypic and karyotypic traits remained stable at subsequent passages. The in vitro resistance of vincristine was reversed by verapamil for these NHL tumor cells, suggesting that the MDR1 resistance is a relevant mechanism in this model. In the absence of chemotherapy a higher biological aggressivity of the heterotransplanted NHL was noted in subsequent nude mice passages. This was associated with decreased passage time and higher MDR1 m-RNA transcript levels. Thus IGR-NHL-90 may re...
Activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt survival pathway protects against... more Activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt survival pathway protects against apoptotic stress stimuli. Therefore, compounds that down-regulate this pathway are of clinical interest for single and combined anticancer treatment modalities. Here we demonstrate that the cytotoxic effect of the protein kinase C (PKC)-inhibitor N-benzoylated staurosporine (PKC412) is mediated via the PI3K/Akt pathway. Dose-dependent down-regulation of the proliferative activity, activation of the apoptotic machinery, and cell killing by PKC412 (0-1 microM) in Rat1a-fibroblasts and H-ras-oncogene-transformed fibroblasts correlated with a decrease of Akt phosphorylation and a reduced phosphorylation of the endogenous Akt-substrate GSK3-alpha. Expression of the dominant-active myristoylated form of Akt abrogated this cytotoxic effect of PKC412. Experiments with Apaf-1-deficient cells revealed that PKC412-induced cytotoxicity depends on an intact apoptosome but that the decrease of Akt ph...
p53 mutations are among the most common genetic alterations in human cancer and are frequently de... more p53 mutations are among the most common genetic alterations in human cancer and are frequently described in intrinsic or acquired radio- and chemotherapy resistance. Radiation-induced cell kill is not only mediated by DNA damage but also by the activation of signal transduction cascades generated at the plasma membrane like the sphingomyelin pathway. We used genetically defined wild-type p53 or p53-deficient mouse fibrosarcoma cells to investigate the p53-dependence of tumour response upon activation of the sphingomyelin pathway. Treatment of the tumour cells with neutral sphingomyelinase drastically reduced the amount of wild-type p53 fibrosarcoma cell proliferation over 72 h in a clear dose-response (0.2-1.0 U ml(-1) nSMase). Sphingomyelinase had no effect on cell proliferation in tumour cells lacking p53. Similarly, cell proliferation was abolished by C2-ceramide (5-20 microM) only in wild-type p53 cells. FACS-analysis revealed that C2-ceramide induced massive p53-dependent apopt...
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1999
Negative regulation of E2F-1 DNA binding function by cyclin A kinase represents part of an S-phas... more Negative regulation of E2F-1 DNA binding function by cyclin A kinase represents part of an S-phase checkpoint control system that, when activated, leads to apoptosis. In this study, we examined the cellular sensitivity and resistance of isogenic mouse fibrosarcoma cell lines, differing primarily in their p53 status, to ectopic expression of wild-type (wt) E2F-1 and cyclin A kinase binding-defective mutants of it. We found that E2F-1 (wt) potently affected the survival of p53+/+ tumor cells but not that of p53-/- cells. In contrast, expression of cyclin A kinase binding-defective E2F-1 species interfered with cell survival of fibrosarcoma cells irrespective of their p53 status. Finally, expression of E2F-1 (wt) in p53-/- fibrosarcoma cells enhanced the cytotoxic effect of ionizing radiation in vitro and in vivo in a mouse tumor model. These results suggest that E2F-1-dependent activation of an S-phase checkpoint is p53 independent and that E2F-1 possesses radiosensitizing properties ...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1997
The patterns of presentation, histologic pattern (nodular or diffuse), treatment, and long-term o... more The patterns of presentation, histologic pattern (nodular or diffuse), treatment, and long-term outcome were studied in patients with lymphocyte-predominant (LP) Hodgkin's disease (HD) to determine whether these patients should be treated differently than patients with other subtypes of HD. Pathology was reviewed for 97 patients with an initial diagnosis of LPHD made between 1970 and 1993. Seventy-five patients had LPHD on review: 55 had nodular LPHD, 14 had diffuse LPHD, and six had LP histology without subclassification. There were 60 males (80%) and 15 females (20%). Sixty-six patients (88%), presented with clinical stage (CS) I or II disease. Seventy-one patients were treated at the Joint Center for Radiation Therapy (JCRT) and were considered for analysis of treatment outcome. Sixty-one of these 71 were treated with radiation (RT) alone; 17 received mantle RT alone, 27 mantle and paraaortic RT, and seven total-nodal irradiation (TNI). Ten patients with subdiaphragmatic HD r...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1993
The great majority of relapses after the treatment for early-stage Hodgkin's disease are obse... more The great majority of relapses after the treatment for early-stage Hodgkin's disease are observed within 4 to 5 years after treatment completion. This study describes the characteristics and outcome of patients who had late relapses, which was defined as relapses that occurred 5 or more years after initial treatment start. A total of 1,082 adult patients with early clinical stage Hodgkin's disease were enrolled on three consecutive European Organization for Research and Treatment of Cancer (EORTC) protocols (H1, H2, and H5 trials) from 1964 to 1981. Of these, 1,044 patients satisfied the eligibility criteria with a supradiaphragmatic localization, age greater than 15 years, and initial complete remission. Overall, 341 patients (32.6%) relapsed, 304 (29.1%) early and 37 (3.5%) late. For each of these 37 late relapsers, questionnaires were sent to the participating centers and detailed information for 34 relapses was obtained. Cumulative probabilities for developing a late rel...
To analyze the impact of weight loss before and during chemoradiation on survival outcomes in pat... more To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer. From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end. The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 - 15.4 years) weight loss before treatment was associated with decrease...
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Papers by S. Bodis