The importance of incomplete repair, interfraction interval, and fractional dose.
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Brachytherapy↗
Biomedical subjects
R Schmidt-Ullrich
Publications and source records attributed to R Schmidt-Ullrich.
Breast conservation in elderly women for clinically negative axillary lymph nodes without axillary dissection.
BACKGROUND: A prospective study was initiated to explore an approach of limited therapy in elderly patients with early clinical stage breast cancer. METHODS: Between 1982 and 1989, 73 women with American Joint Committee on Cancer Stage I/II, clinically negative axillary lymph nodes aged 65 years or older (median age, 74 years) were enrolled in a treatment program consisting of tumor excision, breast and regional lymph node irradiation, and, in 66 patients, tamoxifen. Patients were assessed for disease outcome and complications. RESULTS: At a median follow-up of 54 months, 8-year rates of local and regional lymph node control were 92.5% and 100%, respectively. Eight-year probabilities of disease free, overall, and breast cancer specific survival were 84%, 52.5%, and 93.8%, respectively. There was minimal morbidity associated with either regional irradiation or tamoxifen. CONCLUSIONS: An approach to early breast cancer in the elderly that seeks to limit the aggressiveness of local and systemic therapies appears to result in a satisfactory disease outcome with few complications.
Age Factors↗
A factor to further reduce late tissue toxicity.
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Carcinoma, Non-Small-Cell Lung↗
Effects of the protein kinase C stimulant bryostatin 1 on the proliferation and colony formation of irradiated human T-lymphocytes.
The protein kinase C stimulant bryostatin 1 (Bryo) was used in examining human peripheral blood T-lymphocyte radiosensitivities in proliferation assays. Bryo was similar to PMA in inducing T-cell proliferation by the CD3, CD28 and CD69 pathways. No difference in radiosensitivities was observed in T-cells stimulated by the three independent surface antigen-mediated activation pathways. CD3 was chosen as the second signal for comparing the potencies of the three different first signals Bryo, phorbol 12-myristate, 13-acetate (PMA), and interleukin 2 (IL-2) in stimulating T-cell proliferation and in maintaining this response after radiation. Though there were radioresponse differences among various individuals, the irradiated lymphocytes consistently showed significantly greater proliferation when treated with Bryo or PMA than with IL-2 (p < 0.05- < 0.005). No difference in proliferative responses was observed in T-cells irradiated between 4 h before and 15 h after the addition of stimulants. Colony forming assays showed higher colony survival for irradiated T-cells stimulated with Bryo than with PMA. These results support the important role of protein kinase C in T-cell radiation responses, and suggest a potential role for Bryo in enhancing T-lymphocyte survival during radiation therapy.
Adjuvants, Immunologic↗
Promoter analysis of the gene encoding the I kappa B-alpha/MAD3 inhibitor of NF-kappa B: positive regulation by members of the rel/NF-kappa B family.
In order to characterize the regulation of the gene encoding the I kappa B-alpha/MAD3 inhibitor of the transcription factor NF-kappa B, we have isolated a human genomic clone and sequenced the promoter of this gene. The MAD3 promoter exhibits a potential TATA element upstream of one of the two major transcription sites, and contains several potential NF-kappa B binding sequences, suggesting that the gene is positively regulated by members of this family. Transfection experiments demonstrate that the MAD3 promoter can be activated by various combinations of members of the rel/NF-kappa B family, as well as by phorbol esters and tumor necrosis factor. Specific deletion of one of the kappa B motifs, located 37 bp upstream of the TATA box, abolishes responses to PMA and TNF. This kappa B motif binds NF-kappa B (p50/relA), p50/c-rel and relA/c-rel heterodimers as well as KBF1 (p50 homodimer). These results help to explain the previously observed transient nature of the NF-kappa B response: following NF-kappa B activation, the expression of the inhibitor is increased, therefore the extent of nuclear translocation of the active complex is reduced, resulting in a decreased activation of its target genes.
Base Sequence↗
Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation.
The in vivo effects on hemoglobin (Hb)-O2 affinity and tissue PO2 were investigated after intraperitoneal administration of 2-[4-(((dichloroanilino)-carbonyl)methyl)phenoxyl]-2-methyl propionic acid (RSR4; 150 mg/kg) or its 3,5-dimethyl derivative (RSR13; 300 mg/kg) in C3Hf/Sed mice. The Hb-O2 dissociation curve was plotted from tail vein blood samples using an O2 dissociation analyzer before and up to 160 min after compound administration. Twenty to 40 min after injection, the PO2 at 50% saturation of hemoglobin (Hb P50) increased by a mean of 25% (range 18-31%) after RSR4 and 53% (range 36-76%) after RSR13. Tissue PO2 was continuously measured using an O2 microelectrode in thigh muscle before and up to 40 min after RSR4 or RSR13 injection. Twenty to 40 min after administration, tissue PO2 increased by a mean of 78% (range 30-127%) after RSR4 and 66% (range 39-97%) after RSR13 administration in anesthetized mice. No change in tissue PO2 was seen in anesthetized controls.
Aniline Compounds↗
Reirradiation of head and neck neoplasms using twice-a-day scheduling.
Between 1985 and 1988, we have explored the value of twice-a-day (BID) irradiation for the retreatment of head and neck neoplasms. In this pilot study of ten patients we used a schedule of BID irradiation at fraction sizes between 1.4 and 1.6 Gy separated by at least 6 h. Of the four patients were treated with curative intent, three patients received 30 Gy in 20 fractions over twelve days followed within ten days by an interstitial/intracavitary Ir-192 implant boost to doses of 30 to 40 Gy and one patient was treated with a 32 Gy BID boost. Four patients were reirradiated with aggressive palliation and received 45 Gy in 30 fractions over 26 days including a break in the third week. The remaining two patients were treated with palliative intent to 30 Gy in 20 fractions over twelve days. Eight patients were treated for recurrent/persistent or second carcinomas, one for a recurrent glomus jugulare tumor. At a median follow-up of 36 months, ranging from six to 61 months, nine of ten patients experienced excellent symptomatic relief. Five patients are alive and free of tumor, one patient is alive with distant metastases, and two each are dead from local or systemic tumor progression. All four patients retreated for cure are alive with no evidence of local disease. The tolerance and tumor control rate of the BID reirradiation schedule were good with severe late sequelae in only one patient.
Aged↗
Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study.
In head and neck carcinoma, the finding of extracapsular lymph node extension and/or positive resection margins portends poor locoregional control and survival. The effectiveness of postoperative radiotherapy in these patients has been controversial due to insufficient studies comparing resected patients with those also receiving radiation. Between 1982 and 1988, 441 radical head and neck resections were performed at the Medical College of Virginia. Pathologic review of these cases identified 125 with extracapsular lymph node extension and/or positive resection margins. Of these, 43 had extracapsular lymph node extension only, 24 had both positive resection margins and extracapsular lymph node extension, and 58 demonstrated positive resection margins only. Surgery alone was performed in 71 of these patients while 54 cases received surgery and postoperative radiotherapy, (combined modality treatment) CMT. Radiotherapy doses ranged from 50 to 70 Gy. The surgery alone and combined modality treatment groups were comparable with respect to the distribution of positive resection margins and extracapsular lymph node extension. Slightly more CMT patients had clinical T4 disease compared with the surgery alone group (22% vs 14%). Slightly fewer combined modality treatment patients had clinical N0 necks than the surgery alone group (20% vs 29%). Multivariate analysis was performed with the variables T, N stages, radiotherapy, margin status, primary tumor sites, microscopic and macroscopic extracapsular lymph node extension, number of positive lymph nodes, number of nodes with extracapsular lymph node extension. Locoregional control was maintained at 5 years in 59% of the combined modality treatment group and 31% of the surgery alone group (p.0001). Subgroup analysis likewise reveals significant differences favoring the combined modality treatment group for positive resection margins only (49% vs 41%; p = .04), extracapsular lymph node extension only (66% vs 31%; p = .03) and extracapsular lymph node extension+positive resection margins (68% vs 0%; p = .001). Adjusted survival also shows a significant benefit of combined modality treatment vs surgery alone for the entire group (72% vs 41%; p = .001). Multivariate analysis revealed that the use of radiotherapy is a strongly favorable variable for local control and adjusted survival. Macroscopic extracapsular lymph node penetration and positive resection margins are unfavorable independent variables for local control. T-stage is the only variable predicting local control in the combined modality group. Extracapsular extension remains an important negative prognostic variable for survival in both treatment groups. In conclusion, this study demonstrates a locoregional control and survival benefit for postoperative radiotherapy in patients with the high risk pathologic findings of extracapsular lymph node extension and positive resection margins.
Carcinoma, Squamous Cell↗
Late effects after radiotherapy in head and neck malignancies: overall treatment time, number of fractions and the linear-quadratic model.
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Carcinoma, Squamous Cell↗
Human monoclonal antibodies against Plasmodium falciparum: production, stabilization and characterization.
Nine human monoclonal antibodies (MoAbs) recognizing 7 different antigenic structures of blood-stages of the human malarial parasite P. falciparum (Pf) were produced by Epstein-Barr virus transformed B-cell lines (EBV-TCL) with or without fusion to the lymphoblastoid cell line KR4. The peripheral blood B-lymphocytes were obtained from 8 Gambian donors immune to Pf malaria. Two of the EBV-TCL could be expanded and maintained for more than 6 months but neither one could be cloned. Six additional EBV-TCL were stabilized after fusion with the KR4 lymphoblastoid cell line. All resulting hybridomas permitted easy cloning. Some of the MoAbs produced distinct fluorescent staining patterns of asexual Pf blood-stage parasites when using high-resolution digitized video-intensified fluorescence microscopy. Antigens on 195 kD and 155 kD proteins were recognized by 3 and 1 MoAb, respectively, using Western blotting and immunoprecipitation techniques.
Animals↗
Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma.
PURPOSE: The study was undertaken to assess the relationship among cosmesis and complications to factors related to disease presentation, surgical and radiotherapeutic technique, and adjuvant systemic therapy in conservative treatment for early-stage breast carcinoma. PATIENTS AND METHODS: Between 1982 and 1988, 234 women with stage I/II breast carcinoma were treated with conservation therapy by a highly standardized protocol of limited excision and radiotherapy. Radiation boost and/or reexcision were determined by careful quantitation of the normal tissue margin around the primary tumor. Boosts to 20 Gy were preferentially performed with interstitial iridium-192 (192Ir) implants. Axillary node dissections were performed in all patients aged less than 70 years. Adjuvant therapy consisted of cyclophosphamide, methotrexate, (doxorubicin), and fluorouracil (CM[A]F) six to eight times for node-positive premenopausal women and tamoxifen for node-positive or -negative postmenopausal women. Median follow-up was 50 months (range, 20 to 80 months). Cosmesis was graded by defined criteria, and complications were individually scored. RESULTS: Factors found to impact cosmesis adversely were palpable tumors (P = .046), volume of breast tissue resected (P = .027), reexcision of the tumor bed (P = .01), number of radiation fields (P = .03), radiation boost (P = .01), and chest wall separation (P = .01). There was a trend toward worse cosmesis (P = .062) in patients receiving tamoxifen. Cosmesis was not adversely affected by interstitial implant in spite of a higher prescribed dose. Factors influencing complication risk were axillary node dissection (P = .02), number of lymph nodes harvested (P = .05), and chemotherapy (P = .03). CONCLUSIONS: Optimal cosmesis and minimal complication risk require careful attention to the technical details of surgery and radiotherapy. The impact of systemic therapies needs to be more thoroughly examined.
Adult↗
Proliferative inhibition of human breast carcinoma cells by high concentration estradiol does not alter radiosensitivity.
The proliferation of ER+ malignant mammary epithelial cells (MMEC), MCF-7 and T-47D, was markedly inhibited by 10 microM 17 beta-estradiol (E2), while the ER- line, MDA-MB-231, was minimally affected. This concentration of E2 did not alter the proportion of non-viable cells or the plating efficiency. The decrease in proliferation was not associated with any consistent alteration in the cell kinetic profile between lines, though there was clearly no dominant cell cycle re-assortment after a two day incubation. Colony forming ability after exposure to ionizing irradiation was compared for proliferating and confluent MMEC to cells incubated in 10 microM E2 for two days. The presence of E2 resulted in no significant differences for any of the linear quadratic curve fitting parameters or for mean inactivation doses for both subconfluent and confluent cultures. Further, 10 microM E2 had no effect on the ability of cells to recover from split radiation fractions. There were no differences in the amount of DNA single strand break induction with E2, but there was a significant shortening in the repair halftime with E2 for the ER- MDA-MB-231 cells. Though high concentrations of E2 can markedly inhibit the proliferation of ER+ MMEC, this does not alter sensitivity to ionizing irradiation.
Breast Neoplasms↗
Effects of tamoxifen and protein kinase C inhibitors on hyperthermic cell killing.
The effects of the anti-estrogen, tamoxifen, and the protein kinase C inhibitor, 1-(5-isoquinolinylsulfonyl)2-methylpiperazine (H7), on hyperthermic cytotoxicity were studied. Three cell lines were used, a human colon cancer cell line (HT-29), a human mammary carcinoma cell line (MCF-7), and Chinese hamster V79 lung fibroblasts. With all three cell lines, tamoxifen at concentrations greater than 7.5 microM during heating or with a 3-hr exposure prior to heating significantly sensitized cells to heat. When cells were preincubated with 10-20 microM tamoxifen for 1-2 hr at 37 degrees C prior to heat treatment, washed free of extracellular tamoxifen, heated to generate thermoresistance, and examined 18 hr later for thermoresistance, tamoxifen treated HT-29 and MCF-7 cells were significantly more heat sensitive than thermotolerant controls not previously exposed to tamoxifen. In contrast, the degree of induced thermoresistance of V79 cells was unchanged after tamoxifen treatment. H7, but not its structural analogue and low affinity protein kinase C inhibitor, HA1004, also sensitized cells to heat. Neither H7 nor HA1004 had any apparent effect on the degree of heat-induced thermoresistance in the three cell lines tested.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Interstitial IR-192 implants of the oral cavity: the planning and construction of volume implants.
The success of radioactive implant therapy for head and neck carcinomas depends critically on careful planning and execution of the implant procedure. In this paper we discuss our experience with oral tongue and floor of mouth implants, and some innovations introduced to facilitate these procedures. Implants were carried out using standard angiocatheters modified with magnetic caps at the open end and terminated with Teflon spacers and lead shot at the closed end. The importance of accurate source placement and careful determination of the target dose rate is discussed with numerical examples. Differential hot-loading of sources is clearly indicated in cases of extension of the lesion to the dorsal or lateral tongue surface. For dorsal surface extension the use of Teflon spacers at the closed ends of the catheters helps to ensure adequate coverage of the target volume with the higher dose region enclosing the demonstrable tumor. All 10 patients implanted with this technique are controlled without recurrence at a median follow-up of 38 months. The two complications observed appeared to be associated with excessive hot-loading of edge plane sources.
Brachytherapy↗
Transfection of the CD8 alpha gene restores specific target cell lysis: factors that determine the function and the expression of CD8 in a cytotoxic T cell clone.
We investigated the functional role of CD8 and the control of CD8 expression in a constitutively activated murine cytotoxic T cell clone (C196), in CD8 deficient variants of this clone, and in cell lines derived by transfecting such variants with the CD8 alpha (Lyt-2) gene. CD8 deficient variants of C196 are deficient in specific target cell lysis but retain the ability to perform anti-CD3 induced cytolytic function. Following transfection with the Lyt-2 gene, specific target cell lysis was restored in some but not all CD8 positive transfectants whereas no alteration of anti-CD3 induced lysis was observed. All CD8 deficient variants studied lost the surface expression of both Lyt-2 and Lyt-3 polypeptide chains. However, while Lyt-2 mRNA was abolished as well, typical CD8 deficient variants retained wild type levels at Lyt-3 mRNA. Moreover, a low level of cytoplasmic Lyt-3 protein was demonstrable. Following transfection with the Lyt-2 gene, both Lyt-2 and Lyt-3 polypeptide chains reappeared on the membrane. In one atypical CD8 deficient variant that carries a mutated Lyt-3 gene and fails to express Lyt-3 mRNA, Lyt-2 transfection causes membrane-reappearance of Lyt-2 only. These results may reflect the occurrence on normal T cells of Lyt-2/Lyt-3 heterodimers and of Lyt-2/Lyt-2 homodimers, whereas surface expression of Lyt-3 alone has not been observed. In CD8 deficient variant, a particular restriction site 5' at the Lyt-2 gene is methylated which is undermethylated in the wild type C196. Culture of such variants in 5-azacytidine partially restored CD8 expression. This suggests a negative correlation of Lyt-2 transcription with site-specific DNA methylation in the C196 system. However, results on T cells unrelated to C196 suggests that the site whose methylation appears to be critical in C196 is not responsible for Lyt-2 transcription in all T cells.
Animals↗
Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma.
Between 1982 and 1985, 108 women with AJC Stage I and II invasive mammary carcinoma were treated to 115 breasts with conservative surgery and irradiation. The irradiation dose was adjusted to the histopathological normal tissue margin around the carcinoma in the tumor excision specimens. Margins were arbitrarily determined negative, close, and positive with normal tissue margins in the inked tumor excision specimens of greater than 5 mm, 2-5 mm, and less than 2 mm, respectively. Negative, close, and positive tumor margin patients were treated to radiation doses of 60, 65, and 70 Gy, respectively. The boost in excess of 50 Gy was directed to the tumor bearing quadrant of the breast using interstitial Ir-192 implants for doses greater than or equal to 70 Gy. The draining lymphatics were irradiated to 50 Gy except in patients with tumor in the lateral half of the breast and no axillary lymph node metastases. Histopathological evaluation of re-excision specimens revealed the difficulty of obtaining negative margins for tumors greater than 2 cm. By our criteria, 54% of the patients had a positive resection margin. None of the patients experienced a local recurrence at 60 months median follow-up. Three patients failed regionally, two in un-irradiated lymph node areas, one in the skin of the contralateral breast; five patients failed systemically. Overall and disease-free survival for Stages T1/N0, T1/N1, T2/N0 was 100 and 95%, respectively, and for T2/N1, 90 and 80%, respectively. The cosmesis was excellent in 66% of the patients with minimal treatment related complications. Carefully planned standardized irradiation with assessment of resection margins yields both excellent local control rates and cosmetic results.
Axilla↗
Distinct functions of CD8(CD4) are utilized at different stages of T-lymphocyte differentiation.
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Animals↗
Residual breast carcinoma after biopsy: role of mammography in evaluation.
The records of 21 consecutive patients referred for breast-conservation treatment of early-stage mammary carcinoma contained insufficient histopathologic documentation of adequate resection margins after tumor excision at other hospitals. All patients underwent postbiopsy mammography before reexcision of the tumor bed. In 12 of the 21 cases, there was pathologic evidence of macroscopic or microscopic residual tumor. In seven of the 12 cases, there was no clinical or mammographic evidence to suggest residual carcinoma. The findings indicate that mammography is insufficient to evaluate the completeness of tumor excision in the absence of histopathologic documentation.
Biopsy↗