Chained smoker.
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Head and Neck Neoplasms↗
Biomedical subjects
D S Shimm
Publications and source records attributed to D S Shimm.
Dose profiles in the region of abutting photon and electron fields in the irradiation of head and neck tumors.
In the treatment of head and neck tumors, after excluding the spinal cord from the primary photon beam, en face electron fields are employed to boost the dose to the tissues overlying the spinal cord. The electron fields are "hot-matched" on skin with the posterior edges of the photon fields irradiating the primary tumor. The purpose of this study is to measure the dose distribution in the "hot" matched region between the photon and the en face electron fields. Using film dosimetry, we measured the dose distributions at depths of 1 cm and 3 cm in the junction of the abutting photon (4 MV) and electron (9 MeV) fields for a hot-match setup. Two photon field setups were studied: (1) laterally opposed and, (2) shallow (5 degrees) right and left anterior oblique fields, a configuration sometimes used to avoid treating through the shoulders. To investigate the changes in dose distributions due to setup uncertainties, we also measured dose profiles at the same two depths using a 2 mm overlap and a 2 mm gap between the electron and photon fields. For a perfect hot-match, the dose profile across the junction at 1 cm depth consists of "hot-spots" on both sides of the junction. The minimum and maximum doses across the junction are 15% and 58%, respectively, above the prescribed dose for a parallel opposed setup and 35% and 54%, respectively, for the angled setup. At 3 cm depth, a 10% "cold spot" is observed in the electron field proximal to the junction while a 50% 'hot spot' is observed in the photon field for the opposed lateral setup. With the lateral fields angled 5 degrees anteriorly, hot spots are observed on both sides of the junction. The minimum and maximum doses are 23% and 54%, respectively, above the prescribed dose. With the right and left anterior oblique fields, a 2 mm overlap of the en face electron field with the ipsilateral photon field resulted in a 72% and 65% hot spot at 1 cm and 3 cm depths, respectively, in the photon field adjacent to the junction. A 2 mm gap still resulted in about a 45% hot spot in the same region at both depths. Clinically, if dose to the overlying tissue of the spinal cord is of primary concern, our measurements suggest that 80% normalization in the electron boost, together with a slight angulation of the photon fields would ensure adequate dose to the overlying tissues. If dose inhomogeneity to the superficial tissues is critical in the electron irradiation, 90% dose normalization in the electron boost, together with laterally opposed photon fields would be preferred. The clinical decision can only be made on a patient-by-patient basis.
Electrons↗
Increased frequency of P-glycoprotein gene amplification in colchicine-resistant Rat-1 clones transformed by v-src.
A rat fibroblast cell line (Rat-1) carrying a temperature-sensitive mutation of v-src was used to determine whether inducible cellular transformation altered the ability of cells to amplify the p-glycoprotein gene in response to colchicine selection. Transformed and nontransformed Rat-1 fibroblasts selected under 4 times the LD50 generated the same number of colchicine-resistant colonies. We next examined colchicine-resistant colonies derived from transformed cells and compared them to colchicine-resistant colonies derived from nontransformed cells. When Rat-1 cells were selected at 35 degrees C (transforming temperature), 7 out of 7 clones exhibited a 3- to 5-fold p-glycoprotein gene amplification. These results contrasted to those found at the nontransforming temperature (40 degrees C); none of the 8 colchicine-resistant clones examined had amplified the p-glycoprotein gene. Thus in Rat-1 cells carrying a temperature-sensitive v-src gene, p-glycoprotein gene amplification was observed at a high frequency only in transformed clones selected at the temperature permissive for v-src activity.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
New types of cancer after basal-cell cancer.
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Basal Cell Carcinoma↗
Vulvar carcinoma.
PURPOSE: Controversies exist regarding the use of radiation therapy in the treatment of vulvar carcinoma. A retrospective review was performed to evaluate our institution's experience with surgery and radiation for this disease. METHODS AND MATERIALS: The medical records of 47 patients treated for squamous cell carcinoma of the vulva at our institution (1974-1992) were reviewed for TNM stage (AJCC criteria), treatment modality, and associated 5-year local control and survival based on Kaplan-Meier analysis. RESULTS: Twenty-eight patients (60%) presented with Stage I and II disease and their 5-year survival was 69%. Stage III patients accounted for 12 (25%) of the patients and their 5-year survival was 73%. Seven patients presented with Stage IV disease and five died within 13 months of diagnosis after predominantly palliative therapy. The 40 patients with Stages I, II, and III disease were treated aggressively and were further evaluated for treatment-modality-associated survival and local control. Radiation therapy was used as primary treatment in nine patients, of whom seven were treated with radiation alone and two were treated postoperatively after wide excision. Surgery alone was performed in 31 patients consisting of either radical vulvectomy (20 patients) or wide excision (11 patients). When comparing outcomes of radical vulvectomy vs. radiation therapy, we noted that the 5-year actuarial survivals were comparable (74% for either modality), despite the presence of more favorable prognostic factors in the group treated with radical vulvectomy. Patients treated with wide excision alone had a trend for a poorer 5-year actuarial survival (51%) and local control (50%). CONCLUSIONS: Radical vulvectomy offers good locoregional control and survival. This retrospective review further supports the use of radiation therapy with conservative surgery as an alternative treatment option for patients with vulvar carcinoma treated with curative intent. In contrast, the use of wide excision alone should be performed with caution due to a higher locoregional failure rate. The role of appropriately prescribed radiation therapy should be further investigated in prospective clinical trials.
Adult↗
Early-stage glottic carcinomas: effect of tumor location and full-length involvement on local tumor recurrence after radiation therapy.
PURPOSE: To correlate tumor location along the vocal cord with local control in stage I and II glottic carcinoma. MATERIALS AND METHODS: Sixty-five patients with stage I and 18 patients with stage II glottic cancer were irradiated with 4-MV x rays. Most patients received a total of 64-66 Gy, at a dose of 1.8-2.0 Gy/d. RESULTS: In stage I tumors, local-control probability was 96% +/- 2 (standard deviation); in stage II tumors, 67% +/- 15. When stages I and II were considered together, tumors that involved the full length of the vocal cord were more likely to recur (P = .069). In stage I tumors, treatment with < 2.0 Gy/d was statistically significantly (P = .038) associated with local recurrence. CONCLUSION: Poor outcome after irradiation could not be predicted with involvement of either the anterior commissure or posterior third of the vocal cord. Risk of tumor recurrence increased with full-length involvement, and in stage I tumors, with a daily fraction < 2.0 Gy.
Glottis↗
Interstitial thermoradiotherapy with ferromagnetic implants for locally advanced and recurrent neoplasms.
PURPOSE: The University of Arizona, University of California at San Francisco, City of Hope Medical Center, and University of Wisconsin participated in a Phase I/II protocol to assess the heating ability and the toxicity of interstitial thermoradiotherapy using ferromagnetic implantation. METHODS AND MATERIALS: Forty-four patients with advanced primary or recurrent extra-cranial solid malignancies were enrolled in this study. Fourteen gauge catheters were implanted into tumors and, once in the department of Radiation Oncology, loaded with ferromagnetic seeds to deliver a 60 min hyperthermia treatment. Multi-point thermometry was continuously used throughout the heating sessions for all patients, sampling the periphery as well as the core of the tumor. After 192Iridium brachytherapy, 18 patients then had an additional treatment. The mean radiation dose while on protocol was 50.0 Gy, with total doses (including prior radiotherapy) ranging from 20.3-151.8 Gy (median = 88.7 Gy). Response and toxicity were assessed by inspection, palpation, and/or radiologic studies. Forty-one patients were evaluable for response, and there were 55 analyzable hyperthermia treatment sessions. RESULTS: The complete response rate was 61% (25/41). The partial response rate was 31.7% and only 7.3% failed to respond. Median duration of local control has not yet been reached. The mean maximum, minimum, and mean time-averaged temperatures for all in-tissue sensors were 43.7 degrees C, 38.7 degrees C, and 41.0 degrees C, respectively. Tumor size was the only factor significantly correlated with temperatures or with complete response rate; larger tumors attained higher temperatures but smaller tumors had a higher response probability. Nineteen patients (43%) experienced toxicities, however there was only a 7% (3/44) rate of serious complications (Grade 3 or 4). Prior treatment with hyperthermia was the only factor significantly correlated with serious toxicity. CONCLUSION: These results, a 93% total response with only 7% serious toxicity, are encouraging especially in the context of the patient population treated. Phase II/III studies involving ferromagnetic implantation are warranted.
Adult↗
Radiation therapy for the palliation of multiple myeloma.
PURPOSE: This reviews the experience at the University of Arizona in an effort to define the minimum effective radiation dose for durable pain relief in the majority of patients with symptomatic multiple myeloma. METHODS AND MATERIALS: The records of 101 patients with multiple myeloma irradiated for palliation at the University of Arizona between 1975 and 1990 were reviewed. Three hundred sixteen sites were treated. Ten sites were asymptomatic, including six hemibody fields with advanced disease unresponsive to chemotherapy and four local fields with impending pathological fractures. Three hundred six evaluable symptomatic sites remained. The most common symptom was bone pain. Other symptoms included neurological impairment and a palpable mass. RESULTS: Total tumor dose ranged from 3.0 to 60 Gy, with a mean of 25 Gy. Symptom relief was obtained in 297 of 306 evaluable symptomatic sites (97%). Complete relief of symptoms was obtained in 26% and partial relief in 71%. Symptom relief was obtained in 92% of sites receiving a total dose less than 10 Gy (n = 13) and 98% of sites receiving 10 Gy or more (n = 293). No dose-response could be demonstrated. The likelihood of symptom relief was not influenced by the location of the lesion or the use of concurrent chemotherapy. Of the 297 responding sites, 6% (n = 19) relapsed after a median symptom-free interval of 16 months. Neither the probability of relapse nor the time to relapse was related to the radiation dose. Retreatment of relapsing sites provided effective palliation in all cases. CONCLUSION: Radiation therapy is effective in palliating local symptoms in multiple myeloma. A total dose of 10 Gy should provide durable symptom relief in the majority of patients.
Adult↗
A phase I study of the toxicity of regional hyperthermia with systemic warming.
This study examines the consequences of allowing moderate systemic hyperthermia during regional heating of the abdomen and pelvis in 29 patients participating in Phase I studies of hyperthermia combined with chemotherapy or radiation therapy. In Group 1 (20 patients, 42 treatments), systemic temperatures were limited by employing surface cooling, while in Group 2 (9 patients, 24 treatments), surface warming and insulation were used so that systemic temperature would rise. Mean time-averaged oral temperatures were 38.4 degrees C and 39.9 degrees C for Groups 1 and 2, respectively. Time-averaged mean regional temperatures were 40.2 +/- 0.7 degrees C and 41.5 +/- 0.2 degrees C for Groups 1 and 2, respectively (p < .001). Regional temperatures > or = 41.0 degrees C were achieved by 64% of Group 1 and all Group 2 patients. The mean time-averaged power required was significantly lower for Group 2 (453 W vs 740 W; p = .032), as was the incidence of pain. Mean maximum pulse rate was significantly higher in Group 2, although this was not associated with symptoms. Allowing systemic temperature to rise decreased power requirements and treatment-related pain, at the cost of an asymptomatic increase in heart rate. The results suggest that regional heating may be more readily achieved in the setting of elevated systemic temperature.
Adolescent↗
Ethical issues and clinical trials.
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Capital Financing↗
Pterygium treated with excision and postoperative beta irradiation.
A retrospective study was done of 338 patients with pterygia treated between October 1974 and May 1990. These patients resided in the desert of the southwestern United States, where the hot, dry, dusty climate is thought to predispose to pterygium formation and subsequent recurrence. The pterygia were excised, and the administration of beta irradiation was initiated within 24 hr of surgery. Sixteen percent of the pterygia were recurrent. Ninety-five percent of the beta irradiation prescriptions consisted of 3 weekly 800 cGy fractions. For patients with a minimum of 6 months follow-up, the crude local control rate was 225/258 (88%). The Kaplan-Meier estimate of the 5-year local control rate was 84% (95% confidence interval: 79-89%). Ten of 33 recurrences were diagnosed within 6 months, and 32/33 recurrences were diagnosed within 5 years of treatment. Previously untreated pterygia were controlled more easily than were recurrent pterygia (p = 0.005). In 86% of the cases, patients judged the cosmetic results to be satisfactory. No severe complications developed. This study and others, when compared with studies involving excision alone, suggest that postoperative beta irradiation reduces the likelihood for pterygium recurrence. When the beta irradiation is fractionated, satisfactory cosmetic results can be achieved with low morbidity.
Adult↗
Low-dose radiation therapy for benign salivary disorders.
Two patients, one with a persistent salivary fistula after surgery for a skin tumor overlying the parotid region, and the other with a ranula recurrent after surgery, were treated with low-dose irradiation. Both problems resolved after a total dose of less than 30 Gy, and neither patient experienced xerostomia. In selected patients, low-dose radiation therapy offers a solution to persistent salivary flow refractory to surgical management.
Adult↗
Radiation resistance in a doxorubicin-resistant human fibrosarcoma cell line.
In clinical practice, cancers refractory to chemotherapy can appear relatively radioresistant. Recent work in multidrug-resistant cell lines has yielded conflicting results concerning the relationship between drug resistance and radiation resistance. The current study examines the radiation response of a human fibrosarcoma (HT1080) and a doxorubicin-resistant subline (HT1080/DR4). Using soft-agar colony formation after graded doses of x-rays as an endpoint, HT1080/DR4 had an increased D0 (D0 = 2.1 Gy) and a broader initial shoulder (n = 2.7, Dq = 2.1 Gy) than the parental HT1080 line (D0 = 0.7, Gy, n = 1.2, Dq = 0.3 Gy), suggesting that HT1080/DR4 has an increased capacity to repair radiation-induced DNA damage. This possibility was tested by comparing the cell lines' ability to accumulate sublethal damage. In split-dose recovery experiments, HT1080/DR4 demonstrated increased ability to repair sublethal radiation damage following fractionated irradiation, compared with the HT1080 parental line. The mechanism for this radiation resistance is not clear, but a variety of cellular alterations seen in drug-resistant cell lines are discussed with reference to areas of further study.
Cell Cycle↗
Intraoperative radiotherapy.
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Combined Modality Therapy↗
Effects of v-src oncogene activation on radiation sensitivity in drug-sensitive and in multidrug-resistant rat fibroblasts.
Recent work has implicated the activated ras oncogene, whose gene product is a G-protein located in the plasma membrane, as well as the activated raf oncogene, whose gene product is a membrane-associated protein kinase, in contributing to radioresistance. Another transforming oncogene whose gene product is localized to the plasma membrane is v-src. We have examined a rat fibroblast line (RAT-1) infected with an avian sarcoma virus carrying a temperature-sensitive mutation in the v-src tyrosine kinase domain (LA-24). At 40 degrees C, LA-24 cells have a flat morphology and grow as a contact-inhibited monolayer, while at 35 degrees C, LA-24 cells have a transformed morphology, lose contact inhibition, grow in soft agar, and exhibit 3.5-fold higher tyrosine kinase activity. The parental RAT-1 line, not infected by the virus, grows at both temperatures as a contact-inhibited monolayer. This well-characterized system represents a good model for examining the effect of v-src transformation on radiosensitivity. RAT-1 and LA-24 cells grown at 35 and 40 degrees C were irradiated with graded doses of radiation, and clonogenic survival was assayed. For LA-24 cells grown at 35 and 40 degrees C, and for RAT-1 cells grown at 35 and 40 degrees C, calculated D0, n, alpha, and beta values did not differ significantly. To determine whether there might be differences in radiation damage repair capacity too subtle to detect by comparing radiation survival curves, sublethal damage repair capacity was assessed. There was no difference in sublethal damage repair capacity for LA-24 cells grown at 35 or 40 degrees C. Other studies have associated multidrug resistance with radioresistance. We have examined the radiation sensitivity of two colchicine-resistant LA-24 clones with four- to fivefold amplification of the P-glycoprotein gene, which are four-to fivefold more resistant to colchicine than the parental LA-24 line. In these multidrug-resistant clones, v-src activation does appear to increase radiation resistance. This did not appear to be due to alteration in cell cycle kinetics. We conclude that oncogene activation, or even protein kinase activity per se, does not necessarily lead to radiation resistance. Rather, radiation resistance following oncogene activation depends upon the oncogene and cell line studied, and perhaps upon specific protein phosphorylation.
Animals↗
Basal cell carcinoma treated with radiation therapy.
Between 1974 and 1989, 85 patients with 115 biopsy-proven basal cell carcinomas were treated with radiation therapy at the University Medical Center in Tucson. Either orthovoltage or megavoltage photons were used to deliver doses ranging from 2000 cGy in a single treatment to 7300 cGy in 35 fractions over 62 days. The median length of follow-up was 40 months. Kaplan-Meier estimates of the 5-year local control rates are presented by American Joint Committee on Cancer stage. The difference between the local control rates for both previously untreated and recurrent Stage I and II carcinomas (95% at 5 years) and Stage III and IV carcinomas (56% at 5 years) was statistically significant (P = 0.0001, by Mantel-Haensel test). Although recurrent basal cell carcinomas generally have a worse prognosis, the Kaplan-Meier estimate of the 5-year local control rate for recurrent Stage I and II carcinomas treated with radiation therapy was 95%. These results, along with a review of the literature, suggest two points: (1) high cure rates can be obtained when Stage I and II basal cell carcinomas are treated with radiation therapy and (2) radiation therapy is a relatively effective method for treating recurrent basal cell carcinomas, with cure rates surpassed only by Mohs micrographic surgery.
Adult↗
Merkel cell carcinoma. Improved locoregional control with postoperative radiation therapy.
Between April 1981 and May 1990, 11 patients with Merkel cell carcinoma were treated with radiation therapy in Tucson, Arizona. The length of follow-up time from the time of irradiation ranged from 6 to 64 months. Locoregional control was maintained in seven of eight patients treated with surgery and postoperative radiation therapy for primary or recurrent cancer. The other three patients had bulky metastatic disease at the time of referral. Palliation was achieved in all three patients with radiation therapy. Hyperthermia also appeared to be beneficial in the one patient in which it was used, and chemotherapy achieved responses in two of four patients. These results, combined with a review of the literature, suggest that the administration of radiation therapy postoperatively to both the surgical bed and the draining lymph nodes improves locoregional control and may result in long-term disease-free survival when administered after the initial surgical resection.
Carcinoma, Merkel Cell↗
Industry reimbursement for entering patients into clinical trials: legal and ethical issues.
Pharmaceutical manufacturers commonly contract with clinical investigators for pre-market testing of new products. The per-patient reimbursement offered to the investigator generally exceeds the per-patient costs incurred by the investigator. This excess represents a windfall that can be used to pay for travel, equipment, or supplies, or to fund research for which the investigator cannot obtain funding through peer-reviewed granting channels. This excess raises a potential conflict of interest, because it may lead the investigator to propose experimental treatment for a patient when the patient might be better served by conventional treatment or by no treatment at all. Not only does this situation pose a conflict of interest, it also is a conflict of which few patients are aware and fewer are informed. We propose that all experimental subjects be informed of the source, amount, and mechanism of funding for the experimental treatments they undergo. Further, we propose that payments from pharmaceutical manufacturers for pre-market testing of drugs go to the medical school dean rather than to the individual investigator. With this money, the dean can defray the direct as well as the indirect costs of the clinical study; the remainder, which would otherwise go directly to the investigator, should be placed in a funding pool for which the entire medical school could compete. This solution largely eliminates conflict of interest, addresses informed consent, and reasonably balances the interests of the experimental subject, the clinical investigator, the pharmaceutical manufacturer, and the academic institution.
Biomedical Research↗