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Biomedical subjects

T J Kinsella

Publications and source records attributed to T J Kinsella.

At least 163 records · Page 9Linked to original sources
PubMed1987

Treatment of pelvic sarcomas in adolescents and young adults with intensive combined modality therapy.

Adolescent and young adult patients with pelvic sarcomas continue to have a poor prognosis with standard combination chemotherapy and local irradiation. In addition to a significant risk of local failure, these patients are at high risk for systemic relapse. Twenty-three consecutive patients with Ewing's sarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or malignant peripheral neuroepithelioma originating in the pelvis were treated with short, intensive combined modality therapy. This approach integrates 5 cycles of VADRIAC chemotherapy (Vincristine, Adriamycin, Cyclophosphamide) with high dose irradiation to the primary lesion (55-60 Gy) and sites of gross metastatic disease (45-50 Gy). Following achievement of a complete response, intensification therapy consisting of total body irradiation (TBI) (8.0 Gy), high dose VADRIAC chemotherapy, and autologous bone marow transplantation is given. All therapy is completed within 6-7 months. No maintenance chemotherapy is given; no surgery is intended. Of the twenty-three patients with pelvic sarcomas treated on this combined modality protocol, 22 achieved a complete remission. Local control was achieved and maintained in all twenty-three patients. With a median follow-up of 21 months since initiation of treatment, there have been nine relapses (all systemic). Seven relapses occurred among the thirteen patients who presented with overt metastatic disease and the other two relapses were among the ten patients with localized disease at presentation. All seven metastatic patients who relapsed have died, whereas both of the relapsed localized patients remain alive. Acute and late toxicities have been acceptable using this aggressive combined modality approach. Induction chemotherapy had a significant impact on reduction of the typically large (greater than 10 cm diameter) soft tissue mass associated with these pelvic tumors, thus facilitating achievement of local control by high dose irradiation. Of 18 patients with measureable soft tissue tumor, all experienced a partial response (greater than 50% reduction in size) following the initial two cycles of chemotherapy given prior to local irradiation. In conclusion, this short, intensive chemoradiotherapeutic regimen is highly effective in controlling the primary lesion (100% local control) and inducing a complete response in a high proportion (96%) of these high risk pediatric and young adult patients with pelvic sarcomas. The role of TBI as "systemic" adjuvant therapy to control micrometastatic disease is discussed as still under investigation.

Adolescent↗
PubMed1987

Delivery of intraoperative radiation therapy after pneumonectomy: experimental observations and early clinical results.

Intraoperative radiation therapy (IORT) is capable of delivering high doses of radiation to mediastinal structures while sparing lung parenchyma, heart, and other locoregional tissues. A canine model of pulmonary resection and IORT was investigated by performing a pneumonectomy in 15 adult foxhounds followed by 0 cGy, 2,000 cGy, 3,000 cGy, 4,000 cGy. No clinical complications developed in 4 animals in the 2,000-cGy group. However, 2 of the 8 animals given a high dose died of esophageal hemorrhage or carinal necrosis. Esophagitis occurred in 10 of 12 animals, and none of the animals experienced bronchial stump dehiscence. In a limited Phase I protocol, 4 patients with non-small cell lung cancer were treated with resection and 2,500 cGy of IORT to two separate ports encompassing the superior and inferior mediastinum. Two patients experienced life-threatening bronchopleural fistulas, and 2 patients died as a consequence of esophageal problems. One patients had recurrence with brain metastases, and the 1 long-term survivor is free from disease. As opposed to the animal model of thoracic IORT, the clinical study demonstrated major toxicity with respiratory and esophageal morbidity. The therapeutic usefulness of thoracic IORT in the management of lung cancer must be questioned in view of this small but consistent series of patients. Further carefully designed clinical studies using lower doses of IORT are needed.

Adult↗
PubMed1987

Treatment of peripheral neuroepithelioma in children and young adults.

Seventeen patients with peripheral neuroepithelioma were treated with an intensive chemotherapy regimen of vincristine, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (VADRIAC) in combination with radiation therapy. Fifteen patients with stage III (seven) or stage IV (eight) at presentation were treated on a more intensive regimen including total body irradiation (TBI) (8 Gy). Two patients with stage I (one) or II (one) disease received a less intensive chemotherapy regimen of VADRIAC. Therapy was completed within 6 to 7 months in all patients. The disease arose in the chest wall in 12 patients, pelvis in three patients, and extremity in two patients. Sixteen of the 17 (94%) patients achieved a complete remission. With a median follow-up of 18 months, ten patients remain in complete remission with an actuarial survival of 68% and an actuarial relapse-free survival of 56% at 12 months. On the basis of our initial experience with this tumor, we believe that peripheral neuroepithelioma is a chemoresponsive and radioresponsive tumor.

Adolescent↗
PubMed1987

Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults.

One hundred twenty-four children and young adults with recurrent tumors, predominantly sarcomas, were treated with the combination of ifosfamide, etoposide, and the uroprotector, mesna (2-mercaptoethane sulphonate), in a phase II trial. The treatment regimen consisted of 12 cycles of therapy administered every 3 weeks. After evaluation of the tumor response to chemotherapy alone, radiation or surgery was used to eradicate residual sites of metastatic disease where possible. At the present time, 77 patients are evaluable for response to the chemotherapy; 43 of the patients have experienced a significant reduction in the tumor size in response to the chemotherapy alone (39 partial responses [PR] and four complete responses [CR]). Sixteen of 17 patients with Ewing's sarcoma, nine of 13 with rhabdomyosarcoma, four of eight with peripheral neuroepithelioma, three of eight with osteosarcoma, and 11 of 31 with other tumors have responded with a PR or CR. The toxicity of the regimen was acceptable. Moderate or severe toxicity evaluated on a per cycle basis included: neutropenia, 97%; thrombocytopenia, 32%; nephrotoxicity, less than 1%; mucositis, 1%; neurologic toxicity, 2%; nausea and vomiting, 13%; hemorrhagic cystitis, less than 1%. Fever was present after 33% of cycles and sepsis following 7%. One patient died due to sepsis and pancytopenia. At the present time, only seven of the 43 patients who responded to the chemotherapy regimen have relapsed, with a median follow-up of 10 weeks after the response. This drug combination is highly active in the treatment of recurrent sarcomas and other tumors in children and young adults.

Adolescent↗
PubMed1986

Potentiation of chemotherapy cytotoxicity following iododeoxyuridine incorporation in Chinese hamster cells.

This study reports on the potentiation of selected chemotherapy drugs following halogenated pyrimidine incorporation into cellular DNA. Exponentially growing cultures of Chinese hamster V79 cells were exposed to 10(-5) M IdUrd or BrdUrd for 17 hr (approximately 2 cell doublings). This exposure resulted in approximately 16% replacement of thymidine by IdUrd or BrdUrd in the cellular DNA. Following the IdUrd exposure, dose response curves were determined for a 1 hr exposure to the various drugs. IdUrd pre-treatment was shown to enhance the cytotoxicity of melphalan, adriamycin, cisplatin, and neocarzinostatin with enhancement ratios at 1% survival of 1.5, 1.8, 1.5, and 1.4 respectively. BrdUrd pre-treatment also enhanced cisplatin cytotoxicity. A combination of BrdUrd pretreatment, cisplatin, and X rays was shown to yield additive survival effects. These findings are discussed in the context of possible clinical application of local drug perfusion of tumor-containing organs.

Animals↗
PubMed1986

The use of non-hypoxic cell sensitizers in radiobiology and radiotherapy.

Many different non-hypoxic cell radiosensitizers have been identified over the years. Radiosensitization by these agents is mediated through a variety of mechanisms, including inhibition of repair (both enzymatic and chemical), modification in the DNA molecule, and perturbation and redistribution in the cell cycle. Recent clinical interest in the use of halogenated pyrimidines as radiosensitizers has prompted a number of questions requiring both laboratory and clinical research to maximize this therapeutic approach. Other radiosensitizers that alter cellular redox processes in different ways are discussed in the context of better understanding the cellular biochemical systems that are affected in aerobic radiosensitization. Advancement in the use of non-hypoxic cell sensitizers in radiation cancer treatment will most likely depend on a knowledge of the detailed biochemical mechanisms of these agents and how they might be used to exploit any subtle biochemical differences between tumor and normal tissue.

Animals↗
PubMed1986

Interaction of iododeoxyuridine and its primary metabolite, iodouracil on radiation response.

An in vitro model using Chinese hamster V79 cells was designed to test the interaction of iododeoxyuridine (IdUrd) and its primary metabolite, iodouracil (IU) on growth and radiation response. A recent clinical pharmacology study documented that while steady-state arterial plasma levels of IdUrd remained linear over the dose range of 250-1200 mg/m2/12 hour intravenous infusion, plasma levels of IU rose to greater than 1 log higher (approaching 10(-4) M) at the completion of the 12-hour infusion. Using these clinically relevant doses of IdUrd and IU, we report no apparent effect on radiosensitization of IU alone, or in combination with IdUrd using exponentially growing V79 cells. Similarly, IU does not result in any growth delay. Thus, unlike the recent reports of 5-fluorouracil being incorporated into DNA following phosphorylation to FdUMP, iodouracil does not appear to follow similar metabolic pathways and is unlikely to contribute to the clinical radiosensitizing potential of iododeoxyuridine.

Animals↗
PubMed1986

Modulation of X ray DNA damage by SR-2508 +/- buthionine sulfoximine.

It has been demonstrated that glutathione (GSH) depletion with buthionine sulfoximine (BSO) potentiates SR-2508 radiosensitization in hypoxic cells. We have measured the effect of SR-2508 alone, BSO alone, and combined treatment on radiation-induced DNA strand breaks in hypoxic V79 cells using alkaline and neutral elution. DNA base damage recognized by a damage specific endonuclease from M. luteus was also studied. Hypoxic irradiation markedly reduces the efficiency of single-strand (SSB) and double-strand breaks (DSB) to 10-20% compared to oxic irradiation. Hypoxia had less effect on the efficiency of base damage (ESS). BSO treatment alone, resulting in GSH depletion to less than 5% of controls, had little effect of hypoxic-SSB, DSB, and ESS. SR-2508 (5 mM) treatment alone in hypoxic cells increased the number of SSB, DSB and ESS to approximately half of that resulting from oxic irradiation. However, the combination of BSO and SR-2508 in hypoxic cells resulted in SSB and DSB comparable to oxic irradiation. This combined treatment resulted in less effect on ESS. We conclude that the observed hypoxic radiosensitization, using clonogenic survival assays with combined BSO-SR-2508, correlates with our results assessing DNA strand breaks and base damage.

Animals↗
PubMed1986

Quality control parameters of intraoperative radiation therapy.

We have tried to outline many of the factors which must be considered in the technical delivery of IORT and in subsequent evaluation of these patients. Unless careful attention is given to details of patient selection, surgery, pathology, radiation therapy and follow-up, it is likely that a vast morass of data will be obtained which will be very difficult to interpret. It is the hope of the IORT Working Group that other institutions using IORT will employ our recommendations with regard to dosimetry, follow-up, and the general technical approach. This will likely lead to an earlier understanding of the exact role of this modality in cancer therapy today.

Combined Modality Therapy↗
PubMed1986

Analysis of the effect of DNA alkylation on alkaline elution.

Recently, it has been reported that changes in DNA higher-order structure and DNA-associated protein structure in methylmethane sulfonate (MMS)-treated cells can affect the rate of alkaline elution independent of the DNA single-strand break (SSB) frequency. This conclusion was based on the observation that the rate of elution of alkylated DNA increased when the cell lysates were held at pH 10 for extended periods of time prior to alkaline elution; this increase in elution rate was attributed to changes in nucleoprotein structure rather than additional DNA SSB. We have examined this phenomenon in more detail and find evidence that both DNA SSB and alkaline-labile sites are produced spontaneously in alkylated DNA at pH 10. Alkaline elution of DNA from MMS-treated cells was carried out after incubation of the cell lysates at pH 10 for 48 h; the rate of elution was markedly greater at pH 12.8 compared with pH 12.2 elution. Since this pH effect was not seen in control cell DNA, it was attributed to the production of alkaline-labile sites during the pH 10 incubation. When DNA SSB were measured by alkaline unwinding assay, more SSB were detected in alkylated DNA held at pH 10 for 48 h than for 0.25 h. Double-stranded DNA was treated with MMS in vitro and analyzed by neutral or alkaline gel electrophoresis immediately or after 48 h incubation at pH 10; substantially higher levels of DNA SSB were detected with the pH 10 incubation by either neutral or alkaline gel electrophoresis. In order to determine if changes in DNA structure affect the rate of elution independent of the SSB frequency, we attempted to design an experiment which would severely disrupt DNA higher-order structure but not produce DNA SSB in one of the two complementary DNA strands. V79 cells were grown in bromodeoxyurine (BUdR) under conditions such that all unsubstituted strands were base paired with BUdR-substituted DNA. When this DNA was analyzed by alkaline elution, the unifilar substituted BUdR strand hydrolyzed in alkali and eluted from the filter; this had no effect on the elution rate of the unsubstituted strand. These results indicate that the only known cause for an increase in alkaline elution rate is DNA SSB; severe changes in DNA higher order structure including hydrolysis of one strand by unifilar substitution with an alkaline-labile base analog have no effect on the elution rate of the unsubstituted strand.

Alkalies↗
PubMed1986

Pathological tissue changes following intraoperative radiotherapy.

Ninety patients with a variety of advanced-stage malignancies were treated with surgical resection, when feasible, and with intraoperative radiotherapy. Certain patients received additional external beam radiotherapy. During clinical follow-up, 45 patients died. Twenty-two patients (49% of deaths) underwent detailed autopsies between 1 and 18 months after treatment, with special attention directed towards assessing radiation damage to various tissues. Histological changes related to radiation were generally manifested as fibrosis. Mild fibrotic changes in retroperitoneal soft tissues and mild hypocellularity in vertebral bone marrow were consistently present in patients treated for pancreatic carcinoma, gastric carcinoma, and retroperitoneal or pelvic sarcomas. Fibrosis of the soft tissues of the porta hepatis without narrowing of the bile duct was present in patients treated for pancreatic or gastric cancer. perineural fibrosis was present in retroperitoneal and pelvic nerve trunks in patients treated for abdominal or pelvic sarcomas and in patients treated for unresectable carcinoma of the pancreas. Significant radiation-related changes were generally not observed in major blood vessels, intestine, or ureter. Intact irradiated primary tumors consistently displayed necrosis.

Autopsy↗
PubMed1986

Repair of ionizing radiation DNA base damage in ataxia-telangiectasia cells.

Micrococcus luteus endonuclease sensitive sites were measured by alkaline elution in normal human and ataxia-telangiectasia (AT) fibroblasts after ionizing radiation. Due to the sensitivity of this assay, repair of base damage after 3 to 6 kilorads has been measured after oxic or hypoxic radiation. With 5.5 kilorads of oxic radiation, more than 50% of the base damage was removed after 1.5 h of repair incubation in all cells, including exr+ and exr- AT cells, and approximately 75% was removed by 4 h. After 3 or 4.5 kilorads of hypoxic X-irradiation, repair was equivalent in normal and exr- AT cells. This study included three exr- AT strains which have been reported to be deficient in the removal of gamma-ray base damage at higher doses. Since these strains repaired ionizing radiation base damage normally at lower doses, which are more relevant to survival, it is concluded that the X-ray hypersensitivity of AT cells is probably not related to the repair of base damage.

Ataxia Telangiectasia↗
PubMed1986

Incorporation of iododeoxyuridine into DNA of granulocytes in patients.

Iododeoxyuridine (IdUrd) competes with thymidine for incorporation into DNA. In order to measure the incorporation of the drug in vivo, granulocytes were isolated from peripheral blood of patients at various times during and after 9- to 14-day IdUrd i.v. continuous infusions. DNA was extracted and enzymatically hydrolyzed. Both thymidine and IdUrd were separated and measured by high-performance liquid chromatography. Thymidine substitution by IdUrd was less than 1% prior to the fifth day of infusion and then increased rapidly to achieve a maximal value between 7 and 17% at the end of the infusion. In our protocol, thrombocytopenia was the most frequent dose-limiting systemic toxicity. For our group of patients, there was a clear overall relationship between the extent of substitution by IdUrd and the hematological toxicity. To our knowledge, these data provide the first direct quantitative determination of substitution by a drug into DNA in vivo without the use of radiolabeled compounds. The ability to directly monitor drug incorporation into DNA may provide the basis for monitoring and improving the selectivity of therapy.

DNA↗
PubMed1986

Repair of gamma-ray-induced DNA base damage in xeroderma pigmentosum cells.

The repair of DNA damage produced by 137Cs gamma irradiation was measured with a preparation from Micrococcus luteus containing DNA damage-specific endonucleases in combination with alkaline elution. The frequency of these endonuclease sensitive sites (ESS) was determined after 54 or 110 Gy of oxic irradiation in normal and xeroderma pigmentosum (XP) fibroblasts from complementation groups A, C, D, and G. Repair was rapid in all cell strains with greater than 50% repair after 1.5 h of repair incubation. At later repair times, 12-17 h, more ESS remained in XP than in normal cells. The frequency of excess ESS in XP cells was approximately 0.04 per 10(9) Da of DNA per Gy which was equivalent to 10% of the initial ESS produced. The removal of ESS was comparable in XP cells with normal radiosensitivity and XP3BR cells which have been reported to be moderately radiosensitive.

Cells, Cultured↗
PubMed1985

Hepatic irradiation in the management of metastatic hormone-secreting tumors.

Three patients with extensive liver metastases from hormone-secreting tumors were treated with external beam radiation therapy to palliate signs and symptoms of tumor mass and/or hormone secretion. These patients experienced an objective response of 3, 14, and 24 months duration, respectively, as measured by plasma hormone levels and/or computed tomography (CT) scanning. Using conventional fractionation, a dose of 2400 to 3000 rad was delivered without significant acute or late toxicity. Although these tumors have a long natural history (many years), even after the development of liver metastases, radiation therapy can provide effective palliation and should be considered as a therapeutic option.

Adenoma, Islet Cell↗
PubMed1985

Measurement of DNA polymerase beta in skin fibroblast cell lines from patients with ataxia telangiectasia.

DNA polymerase beta levels were measured in 4 cell lines of normal human skin fibroblasts and in 5 cell lines of skin fibroblasts from patients with ataxia telangiectasia, an autosomal recessive disease exhibiting marked X-ray sensitivity. The enzyme specific activities for the normal lines were similar and the mean value was 2-fold lower than the mean value for the ataxia lines. With both kinds of cells, the enzyme level did not change as the cultures progressed from logarithmic to stationary phase of growth. Thus, this putative DNA repair enzyme appears to be 'constitutive' in human skin fibroblast lines, and a modest elevation of beta-polymerase activity is associated with ataxia telangiectasia. These results are discussed in the context to current views about DNA-repair enzymes in X-ray-sensitive cultured mammalian cells.

Ataxia Telangiectasia↗