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Biomedical subjects

H I Robins

Publications and source records attributed to H I Robins.

At least 37 records · Page 2Linked to original sources
PubMed1999

Whole body hyperthermia induction of soluble tumor necrosis factor receptors: implications for rheumatoid diseases.

OBJECTIVE: To test the hypothesis that 41.8 degrees C x 60 min whole body hyperthermia (WBH) induces increased serum levels of soluble necrosis factor receptors (sTNF-R). METHODS: We tested the serum of cancer patients for changes in sTNF-RI and RII levels, as a function of time, pre and post: (1) WBH alone, (2) WBH and chemotherapy, i.e., melphalan (L-PAM), and (3) L-PAM alone. RESULTS: For sTNF-RI there was a marked increase (over pre-treatment values, i.e., 86%) in serum levels after WBH alone (n = 3), which peaked 2.5 h post-WBH; L-PAM (iv) only resulted in a dip in sTNF-RI seen 40 min postadministration; the combination (WBH + L-PAM), resulted in both the dip at 40 min and the increase at 2.5 h post-treatment. For sTNF-RII both WBH alone (n = 3) and WBH + L-PAM (n = 2), there was an increase in receptor serum levels of 25% and 30%, respectively, which peaked 5.5 h post-treatment, and remained elevated at 24 h. L-PAM alone resulted in a dip in levels only at 40 min post-treatment. sTNF-RI and RII levels returned to baseline values within 7 days post-treatment. CONCLUSION: 41.8 degrees C WBH results in transient increases in TNF-RI and RII. These results may have therapeutic implications for the application of WBH to TNF mediated disease processes.

Adult↗
PubMed1998

Whole-body hyperthermia combined with ifosfamide and carboplatin causes hypotension and nephrotoxicity.

It was previously postulated on the basis of clinical data that the cardiovascular sequelae of extracorporeal whole-body hyperthermia (e-WBH), i.e., hypotension (which requires catecholamine support) results in unique nephrotoxicity in combination with select chemotherapeutic agents. In an attempt to explain this phenomenon, we mimicked e-WBH physiological conditions in a rat model. Animals were treated with and without ifosfamide (IFO) and/or carboplatin (CBDCA) at 37 degrees C or 41.5-41.8 degrees C, with blood pressure monitoring and catecholamine support comparable to the clinical setting. Ex vivo post-treatment data (24 h) from artificially perfused kidneys (i.e., histology, urine volume, perfusion rate, glomerular filtration rate, and the reabsorption of sodium, glucose, and water) demonstrated unique toxicity including proximal tubular necrosis for the combination of WBH and IFO, for WBH and CBDCA and for WBH and IFO plus CBDCA, but not for IFO and CBDCA without WBH. These data, considered together with results derived from a subsequent clinical trial and the laboratory work of others were consistent with the hypothesis.

Animals↗
PubMed1998

A therapeutic trial of radiation therapy with Vincristine, etoposide, and Procarbazine (VVP) in high grade intracranial gliomas--an Eastern Cooperative Oncology Group Study (E2392).

This study is a combined modality Phase II therapeutic trial to determine the efficacy of the novel combination of VP-16, Vincristine and Procarbazine in addition to postoperative radiation therapy in patients with high grade intracranial gliomas. Thirty three patients (median age 51 years) were entered (27 with glioblastoma multiforme, 6 with anaplastic astrocytoma). Toxicity was manageable with no lethal toxicities. Five of seven life threatening toxicities were hematologic. Median overall survival was 14.2 months. These data suggest this regimen is effective treatment for patients with high grade gliomas.

Administration, Oral↗
PubMed1998

Phase I study of paclitaxel in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report.

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel administered as a 3-hour infusion in patients with recurrent malignant glioma. PATIENTS AND METHODS: Patients were stratified by starting dose of paclitaxel and concurrent anticonvulsant (AC) use and were treated in cohorts of three patients. The starting dose was 240 mg/m2 administered intravenously with escalations of 30 mg/m2 until the MTD was established. Pharmacokinetic data were obtained for each patient for the first infusion. Tumor response was assessed at 6-week intervals and treatment was continued until documented tumor progression, unacceptable toxicity, or a total of 12 paclitaxel infusions. RESULTS: From April 1995 to December 1996, 34 patients were treated; 27 patients in the AC group and seven patients in the non-AC group. The MTD for patients who received ACs was established at 360 mg/m2 and the dose-limiting toxicity (DLT) was central neurotoxicity, characterized as transient encephalopathy and seizures. In contrast, the MTD for patients who did not receive ACs was 240 mg/m2, and myelosuppression, gastrointestinal toxicity, and fatigue were the DLTs. Pharmacokinetic data confirmed that the plasma drug levels and clearance rates were similar for patients in both groups at the respective dose levels that produced DLTs. CONCLUSION: The pharmacokinetics of paclitaxel are altered by ACs, and significantly larger doses of the drug can be administered to patients with brain tumors on AC therapy. The toxicity profile is different for patients on AC therapy treated at these higher doses. A phase II study has been initiated that uses a dose of 330 mg/m2 for patients on AC therapy and 210 mg/m2 for patients not on AC therapy.

Adult↗
PubMed1997

Optimization of chemotherapy administration for clinical 41.8 degrees C whole body hyperthermia.

Preclinical data is consistent with the concept that the timing of chemotherapy during radiant heat-whole body hyperthermia (WBH) should affect therapeutic index. In order to test this hypothesis, a controlled clinical investigation was initiated. Patients received carboplatin (CBDCA) on an early or late schedule with respect to achieving target temperature (i.e. 41.8 degrees C) in alternating treatment cycles. The first cycle was randomized between patients regarding the early or late schedule for two planned sets per patient (i.e. four cycles). Ifosfamide, etoposide and granulocyte colony stimulating factor were delivered during all cycles with a standardized schedule. A total of 53 cycles involving 17 patients were analyzed. Detailed toxicity evaluation (i.e. delay in therapy secondary to thrombocytopenia, need for platelet transfusions, and days of hospitalization) taken collectively demonstrated a statistically and clinically significant advantage to delivering CBDCA 10 min after target temperature, during the plateau phase of WBH.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

In vitro studies of the hyperthermic enhancement of activated ifosfamide (4-hydroperoxy-ifosfamide) and glucose isophosphoramide mustard.

PURPOSE: To study the effect of hyperthermia on the cytotoxicity of glucose isophosphoramide mustard (D-19575), a derivative of ifosfamide, which does not require activation and preclinically demonstrates less nephrotoxicity and myelosuppression than ifosfamide. METHODS: In vitro studies (using a crystal violet cell survival assay) of the interaction of hyperthermia with D-19575, as well as the activated form of ifosfamide (4-hydroperoxy-ifosfamide, D-18851), were performed using L929 and OVCAR-3 cell lines held at various temperatures (i.e. 37 degrees C (control), 40.5 degrees C, 41.8 degrees C, 42.5 degrees C, and 43 degrees C) for 65 min. RESULTS: The following thermal enhancement ratios (TER) were demonstrated: D-19575 in L929 1.2, 2.0 and 2.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in L929 1.7 at 41.8 degrees C; for D-19575 in OVCAR-3 2.1, 3.2 and 3.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in OVCAR-3 4.6 at 41.8 degrees C. CONCLUSION: The significant observed increase in cytotoxicity of D-19575 caused by hyperthermia taken together with its known preclinical toxicity profile, encourage its further preclinical and ultimately clinical testing, including its use with whole body and regional hyperthermia.

Antineoplastic Agents↗
PubMed1997

Phase I clinical trial of melphalan and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes. PATIENTS AND METHODS: Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1) thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n = 6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY). RESULTS: Comparisons of mean WBC count and platelet nadirs for L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no instances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail. CONCLUSION: We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.

Adult↗
PubMed1996

Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8 degrees C whole body hyperthermia in patients with refractory sarcoma.

Two earlier studies resulted in the design of a phase II trial of 41.8 degrees C (x 60 min) extracorporeal whole body hyperthermia (WBH) with ICE, i.e. ifosfamide (5 g/m2), carboplatin (300 mg/m2), and etoposide given with WBH, as well as, day 2 and 3 post-WBH (100 mg/m2) for adult patients with refractory sarcoma. 12 patients entered this trial; all were evaluable. 8 patients had a history of prior chemotherapy associated with disease progression. Following WBH/ICE, 7 partial remissions were observed (58%); 3 patients experienced disease stabilisation; the aforementioned 10 patients each received four cycles of therapy. 2 patients exhibited progressive disease. Episodes of WHO graded (grade 3; grade 4) toxicity observed included: anaemia (2;2); leucopenia (5;7); thrombocytopenia (1;6); renal (0;1). Other toxicities (grade 1 and 2) included: anasarca, diarrhoea, ventricular arrhythmias, pressure sores, and perioral herpes simplex.

Adolescent↗
PubMed1996

Hematological effects of radiant heat-induced whole body hyperthermia on dogs.

The effects on hematological parameters of radiant heat-induced whole body hyperthermia (WBH) at 40.5 degrees C and 41.8 degrees C were determined in 6 normal dogs. Complete blood counts determined prior to WBH, immediately post WBH plateau, and at 1, 2, 7, and 14 days posttreatment did not change significantly following WBH at 40.5 degrees C or 41.8 degrees C. Similarly, no significant changes were detected in platelet counts measured following 40.5 degrees C WBH. In contrast, platelet counts 11 days following 41.8 degrees C WBH increased significantly (P < 0.05) consistent with the hypothesis of induction of putative WBH-induced platelet stimulating factors.

Animals↗
PubMed1995

Cytokine induction by 41.8 degrees C whole body hyperthermia.

The potential for 41.8 degrees C whole body hyperthermia (WBH) to enhance ionizing irradiation and cytotoxic chemotherapy without a commensurate increase in normal tissue toxicity is currently receiving renewed clinical interest. Additionally, WBH may have other biological sequela which may be clinically exploited. In this paper, data are summarized revealing the ability of WBH to induce elevated plasma levels of granulocyte-colony stimulating factor (G-CSF), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) within hours of WBH. Data regarding TNF-alpha shows induction in only a proportion of patients. No induction of C-reactive protein (CRP) or the following cytokines was observed: granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), interleukin-1 alpha (IL-1 alpha), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-7 (IL-7), interleukin-11 (IL-11), interleukin-12 (IL-12), macrophage-colony stimulating factor (M-CSF), and macrophage inflammatory protein-1 alpha (MIP-1 alpha). Data regarding interleukin-3 (IL-3) and transforming growth factor-beta 1 (TGF-beta 1) were variable and inconclusive. The implications of these results to past and future clinical trials are discussed.

Cytokines↗
PubMed1995

Cytotoxic interactions of tumor necrosis factor, melphalan and 41.8 degrees C hyperthermia.

Experience with limb perfusion-hyperthermia, TNF, and L-PAM suggests dramatic clinical responses in sarcoma and malignant melanoma. To extrapolate these results to clinical 41.8 degrees C whole-body hyperthermia (WBH) and systemic therapy, we studied the cytotoxic interactions of TNF, L-PAM and hyperthermia in L929 cells. The optimal sequence was TNF preceding 41.8 degrees C hyperthermia by 48 h, and L-PAM given simultaneously with heat. Trimodality synergism between TNF, hyperthermia and L-PAM was demonstrated. Non-cytotoxic doses of TNF had a super-additive interaction with L-PAM/heat. Conversely, non-cytotoxic doses of L-PAM had super-additive interactions with TNF followed by hyperthermia. Relative to therapeutic index, we studied WBH, L-PAM and TNF in non-tumor bearing mice. The optimal trimodality sequence did not result in increased normal tissue toxicity compared to L-PAM alone. The concentrations and sequencing of TNF and L-PAM studied are consistent with clinical application to WBH.

Animals↗
PubMed1994

A new technological approach to radiant heat whole body hyperthermia.

A new methodology for administering radiant heat whole body hyperthermia (WBH) in humans is described. The technology utilized circulates hot water in a cylinder constructed from copper tubing; the design incorporates a counter current distribution system to maintain thermal constancy. The tubing is coated with a temperature resistant high emissivity finish. Other features include a humidification system to eliminate evaporative heat losses. Data accrued from initial evaluation of this apparatus with a canine model shows that there was no detectable WBH-related hematological, biochemical or physiological toxicity. The perceived advantages of this WBH-system are discussed.

Animals↗
PubMed1994

Step down heating and melphalan: cytotoxic interactions and clinical implications.

Step down heating from 41.8 degrees C (10, 15 and 20 min) to 40.5 degrees C (55, 50 and 45 min respectively) was studied in vitro in L929 sarcoma cells in the presence and absence of increasing doses of melphalan. Results for heat killing alone demonstrated that step down heating for 20 min (but not 10 or 15 min) at 41.8 degrees C was equivalent to 41.8 degrees C x 65 min. Heat enhancement of melphalan, however, was observed at 10, 15 and 20 min with thermal enhancement ratios of 8.3, 10.3 and 8.5 respectively (p < or = 0.01), consistent with the enhancement of 41.8 degrees C x 65 min. The relevance of these data to hyperthermic limb perfusions for the treatment of malignant melanoma and sarcoma are discussed.

Animals↗
PubMed1993

Deoxyribonucleoside triphosphate pools and thymidine chemosensitization in human T-cell leukemia.

Thymidine kills cells by depleting dCTP stores. The present experiments tested whether deoxycytidine, by replenishing dCTP pools, could prevent thymidine cytotoxicity and thymidine's enhancement of carboplatin killing in two human T-cell acute leukemia cell lines. MOLT3 and JM cells were exposed to combinations of thymidine, deoxycytidine, and carboplatin and then assessed for survival, the magnitude of thymidine-carboplatin chemosensitization, and changes in deoxyribonucleoside triphosphate pools. For both cell lines, deoxycytidine (up to 144.5 micrograms/ml x 24 h) completely restored dCTP pools but only partially protected against thymidine cytotoxicity (100-1000 micrograms/ml x 24 h) and thymidine-carboplatin sensitization (up to 60 micrograms carboplatin/ml during the last hour of thymidine). This contrasts with complete protection in prior studies using other cell types. Thymidine alone markedly increased dTTP and dGTP pools and decreased dCTP; dATP pools underwent a sharp decline which has not been observed before in any cell line. In subsequent studies 0.0336-137.3 micrograms deoxyadenosine/ml partially prevented cytotoxicity and carboplatin sensitization by 300 micrograms thymidine/ml. Together, deoxycytidine and deoxyadenosine completely prevented thymidine-carboplatin sensitization even though dATP and dCTP pools were not entirely returned to normal. These findings are discussed in regard to the unusual sensitivity of T-cell malignancies to thymidine toxicity, mechanisms of cytotoxicity and chemosensitization by thymidine, and the possibility of thymidine selectively sensitizing T-cell malignancies to killing by alkylating agents.

Carboplatin↗