bluuebunny/crossref_metadata_2025 huggingface dataset:
Decision support system for treatment selection: Application of a statistical expert advisor to the problem of prostate cancer treatment selection
Authors: Whittington Richard , Altschuler Martin D.
Published: February 2007

For clinical cases with difficult combinations of patient parameter values, treatment selection may be complex or controversial and require considerable time. Treatment selection may be affected by a clinician's experience with a disease and expertise with a treatment, existing protocols, capabilities of local medical facilities, and patient preference. We discuss the concepts and clinical applications of an interactive statistical package (isp) software shell which can create systems that reproduce the judgment of one or more expert clinicians in the management of a patient. An isp system can 1) be taught, verified, updated, and tailored to local facilities quickly and easily by an individual clinician, 2) compute and rank treatment selection probabilities for a presented case in accord with the treatment preferences of its human teacher and explain to a clinician the logical and statistical basis of each step of the decision process, 3) identify sensitive variables of a case for additional verification and to allow questions of the type “what would be the treatment preferences if the value of this variable were changed?”, 4) accumulate statistics for unusual cases (rare combinations of patient parameter values), and 5) continue to learn and achieve further (statistical) insight by recognizing variable combinations (joint variables) whose values are more sensitive to the selection of a particular treatment. An isp system can be used for 1) second opinions, by estimating the treatment preferences of one or more clinical experts for a particular case, 2) allowing patient involvement in the treatment decision in cases for which several treatment options may provide the same outcome, 3) quality assurance, by helping a clinician to identify and review critical patient parameter values and pivotal questions, and to check a treatment decision with his own isp system and those of colleagues, 4) avoiding unnecessary diagnostic tests, by identifying parameters that do not affect the treatment selection for a case, 5) documenting the decision factors of a case, 6) finding the reasons for differences among experts in treatment selection for different types of cases, and 7) teaching residents. The concepts and clinical application of an isp system are discussed. © 1993 Wiley‐Liss, Inc.
Reduction in tumor blood flow in skin flap tumor after hydralazine is not due to a vascular steal phenomenon
Authors: Dewhirst Mark W. , Madwed David , Meyer Robert E. , Ong Edgardo T. , Klitzman Bruce , Rosner Gary L. , Dodge Richard
Published: February 2007

The purpose of this study was to evaluate whether a “vascular steal” mechanism (preferential arteriolar vasodilation in normal vs. tumor tissue concomitant with a reduction in blood pressure) is responsible for tumor blood flow reduction after hydralazine administration. Fischer‐344 rats, fitted with dorsal flap window chambers that allowed visualization of tumor and normal healing subcutaneous tissue vasculature, were the experimental subjects. Intravital microscopy of tumor and normal microvasculature was used to measure microvessel diameters and red cell velocities before and after hydralazine (0.4 mg/kg, i.v.) administration. Hydralazine caused an average drop in mean arterial pressure of 32 mmHg and a concomitant 70% drop in capillary and venous blood flow in central tumor regions in both 9‐ and 14‐day‐old tumors. Intermittent blood flow frequency increased in capillaries and veins from 3% prior to drug to 46% after drug administration. In contrast, capillary and venous flow increased in adjacent normal tissues by 30%. Normal and tumor arterioles showed no significant change in diameter after hydralazine administration. Since the reductions in tumor blood flow were not accompanied by preferential arteriolar dilation in normal arterioles, the hypothesis that a vascular steal phenomenon was responsible for the observed reduction in tumor blood flow in this model system was disproved. A more likely explanation is that the reduction in tumor vessel diameter and concomitant flow reduction are a passive effect related to the relative difference between intravascular pressure and interstitial fluid pressure and/or tissue pressures, the latter of which are known to be increased in tumors. The results suggest that reduction in tumor blood flow might be expected following blood pressure reduction, even when the tumor resides in normal tissue beds that are not actively vasodilated by an antihypertensive agent. © 1994 Wiley‐Liss, Inc.
Oxygen tension measurements in human tumors: The institut gustave‐roussy experience
Authors: Lartigau Lric , Randrianarivelo Harizo , Martin Laurent , Stern Sabine , Thomas Carole D. , Guichard Marcelle , Weeger Pascal , le Ridant Anne‐Marie , Luboinski Bernard , Nguyen Tiem , Ortoli Jean‐Christophe , Grange Florent , Avril Marie‐Françoise , Lusinchi Antoine , Wibault Pierre , Haie‐Meder Christine , Gerbaulet Alain , Eschwege François
Published: February 2007

Tumor hypoxia contributes to the response to radiotherapy and to chemotherapy. The oxygenation status of normal tissues and tumors was evaluated using the KIMOC‐6650 histograph in 35 patients with head and neck tumors, 13 patients with metastatic malignant melanoma (MMM), and 6 patients with uterine cervical carcinoma. Patient compliance was good. The pO2 values measured in tumors were in general lower than those measured in normal tissues of the same patient. The pO2 in the tumors varied along the track and from one track to another. Important pO2 variability was also detected from one tumor to another. Patients with head and neck tumors had a median pO2 of 6.76 kPa (52 mmHg) in normal tissues (subcutaneous) and 1.33 kPa (10 mmHg) in tumors with 25% of the values below 0.26 kPa (2 mmHg). Patients with MMM had a median pO2 of 3.64 kPa (28 mmHg) in normal tissues (subcutaneous tissues and muscles) and pO2 was 0.91 kPa (7 mmHg) in tumors with 18% of the values below 0.26 kPa. Patients with uterine cervical carcinoma had a median pO2 of 6.37 kPa (49 mmHg) in normal tissues (vagina) and 2.73 kPa (21 mmHg) in tumors with 16% of the values below 0.26 kPa. The data for N2 and N3 head and neck nodes showed significantly more values below 0.26 kPa (2 mmHg) as nodal size increased (P < 0.001 by chi‐square test). The best parameters to describe tissue oxygenation are discussed. © 1994 Wiley‐Liss, Inc.
Pilot study evaluating nicotinamide in metastatic brain tumors treated with radiation
Authors: Pisch Julianna , Sood Brij M. , Alfieri Alan , Berson Anthony M. , Chadha Manjeet , Vikram Bhadrasain
Published: February 2007

Nicotinamide (NAM) has been shown to be an effective radiosensitizer in animal studies, but to date no clinical studies have substantiated this effect. Twenty‐nine patients with brain metastases were randomized to receive NAM and external radiation therapy (RT) (n = 14) or irradiation alone (n = 15). NAM was started on day 1 at 3 g/day and continued until radiation was completed. The RT dose to the whole brain was 30 Gy in 10 fractions in 12–14 days. To evaluate response, a computed tomographic (CT) scan of the head was repeated 1 month post‐treatment. Toxicity was graded from the skin, liver, and gastrointestinal tract. There were no toxicities observed at 39.0 g total dose of NAM. Median survival for the 29 patients, calculated by the Kaplan‐Meier method, was 3.5 months for the NAM + RT group (14 patients) and 3.9 months for the RT alone group (15 patients). Eighteen patients were evaluable for 1 month tumor response by CT scan. Response rates were compared with Fisher's exact two‐tailed test. There was no difference in complete response (CR) (P = 0.62) or CR + partial response (PR) (P = 1.000) between the two groups. Adjuvant NAM, given in doses of 3.0 g/day (39.0 g total dose) in the treatment of brain metastases, has shown no benefit in survival or response in this preliminary Study. © 1994 Wiley‐Liss, Inc.
Protein expression patterns of radiation‐transformed human epidermal keratinocytes: A two‐dimensional gel electrophoretic approach
Authors: Prasad Sarada , Dritschilo Anatoly , Rhim Johng , Worland Peter , Thraves Peter
Published: February 2007

We have previously reported the radiation‐induced malignant transformation of immortalized human epidermal keratinocytes. Two sets of tumorigenic transformants (treated with either 2 Gy or 4 Gy twice) and their respective clonal derivatives were characterized [Thraves et al.: Proc Natl Acad Sci USA 87:1174–1177, 1990]. We have tested the hypothesis that the multiple changes which take place during cellular transformation are reflected at the level of protein expression. Toward this end, we have compared protein expression in the non‐tumorigenic, parental keratinocytes and their radiationtransformed derivatives during the various stages of progression to tumorigenicity. We employed two‐dimensional gel electrophoresis (2D‐PAGE) coupled with silver staining and computer‐assisted data analyses. Eighteen differentially expressed proteins were identified in the various transformed cultures. Changes in 8 of these proteins exhibited a similar pattern in both the 2 and 4 Gy transformants, while the expression of the other 10 varied. Two of the eight proteins that showed identical changes in both sets of transformed keratinocytes have been identified as tropomyosin and proliferating cell nuclear antigen (PCNA) by their characteristic 2D‐map locations and reactivity with specific antisera. The identification of these differentially expressed polypeptides in the tumorigenic keratinocytes constitutes a preliminary step in the study of the complex process of radiation‐induced transformation and its regulation by specific gene products. © 1994 Wiley‐Liss, Inc.
Combining D,L‐α‐difluoromethylornithine with [3H] thymidine increases killing of rat gliosarcoma cells in vitro
Authors: Boggs Sallie S. , Grudziak Aleksandra G. , Deutsch Melvin , Redgate Edward S.
Published: February 2007

The present studies were done to test the hypothesis that the cytostasis caused by D,L‐α‐difluoromethylornithine (DFMO) would enhance cellular retention of [3H] thymidine and thereby increase the effective internal radiation dose and cell killing. To test this hypothesis, 9L rat brain tumor cells were cultured in the presence of 10 μCi of [3H] thymidine for 4 days (about 5 divisions) with or without 1 mM DMFO. After 4 days the [3H] thymidine was removed from the cultures and both groups of cells were treated with 1 mM DFMO for the remainder of the experiment. After 24 days the untreated control group had 2.5 × 1014 colony‐forming cells (CFC) and the group with [3H] thymidine or DFMO alone had 2 × 109 and 2 × 106 CFC, respectively. The group with sequential treatments (4 days [3H] thymidine followed by DFMO) had only 6 × 103 CFC, but the group with simultaneous treatments (DFMO added on day 0 with the [3H] thymidine) had too few CFC remaining by day 8 to measure accurately. In the group given [3H] thymidine and DFMO sequentially, retention of [3H] thymidine was enhanced, but in the group given DFMO simultaneously there was almost total retention as well as increased initial uptake of [3H] thymidine. These studies suggest that combining DFMO with short‐range radioemitters may be a useful approach to brain tumor therapy. © 1994 Wiley‐Liss, Inc.
Fraction size dependent sparing effects of clinically relevant fractionated radiotherapy protocols on human glioma multicellular spheroids
Authors: Li Derui , Class Reiner , Emrich Jacqueline , Miyamoto Curtis , Brady Luther W.
Published: February 2007

Clinically relevant X‐ray irradiation protocols were chosen to evaluate the radiation response of human glioma cell lines, A1207 and U‐373 MG, grown as multicellular spheroids. The protocols included single‐dose fraction (SF), conventional fractionation (CF; 2 Gy per fraction, 24 hr interval), hyperfractionation (HF; 1.0 Gy per fraction, 12 hr interval), and accelerated hyperfractionation (AHF; 1.5 Gy per fraction, 6 hr interval). Spheroids from both cell lines are clearly more refractory to the cytotoxic effects of multifractionated irradiation than the single‐dose irradiation. Dose‐sparing effects of CF or HF were comparable in the two cell ilnes. More detailed studies of A1207 spheroids showing sparing effects are fraction size dependent. The smaller the dose size per fraction, the larger the sparing effect. In order to achieve the same biological effect using multifractionated irradiation, compared to single dose, a higher dose is needed to compensate for sublethal damage repair which occurred in the fraction intervals. The relative doses required for achieving isoeffect as SF were 145%, 160%, and 169% for CF, AHF, and HF, respectively, when a total dose of 10 Gy was administered. The isoeffective doses for AHF and HF compared to CF were 113% and 126%, respectively. There was also an increase in sparing effect with increasing total dose administered as multifraction. Our results suggest that in the design of multifractionated radiotherapy regimens, fraction size dependent sparing effects related to dose per fraction and total dose on human gliomas should be taken into consideration to optimize therapeutic outcome. © 1994 Wiley‐Liss, Inc.
Graphic analysis of isobiological effectiveness for twice‐a‐day radiotherapy regimens and its application
Authors: Huang David T. , Schmidt‐Ullrich Rupert , Lin Peck‐Sun
Published: February 2007

The effectiveness of twice‐a‐day (BID) hyperfractionated radiotherapy (RT) schedules has been demonstrated for carcinomas of the head and neck, the lung, and advanced stage breast cancers. Fractionation choices include identical or different doses of the two daily treatments referred to as equally split or unequally split BID doses, respectively. The choices of equally split, unequally split, or a mixture of both are based on the consideration of maximal tumor control or minimal late tissue effect. The comparison of biological effectiveness of different regimens is commonly done by computing the individual biological effective doses (BED) to tumor and late tissue. For this purpose, a different theoretical approach which adopts the concept of isobiological effectiveness may be more general and analytic than point dose computation. Taking advantage of the quadratic nature, a graphic analysis of isobiological effectiveness (GAIBE) was developed to analyze how to optimize the regimens for tumor killing effect and late tissue sparing effect. In this analysis, a Cartesian plot of two dose axes representing the two daily doses is used. The loci of isobiological effective dose (isoBED) regimens are circular on this plot. Thus, the effects of many regimens on tumor and late reacting tissue may be observed simultaneously by comparing the isoBED loci. Graphically, with GAIBE analysis and, mathematically, for a given isoBED to tumor, we have demonstrated that equally split hyperfractionation schedules will deliver the lowest biological effectiveness to late reacting tissues among all isoBED regimens to tumor. Situations when unequally split regimens are beneficial are also discussed. Another variable of clinical importance is the repopulation phenomenon which may counteract the biological effectiveness with increasing length of treatment course. The additive nature of BED from daily treatments allows GAIBE analysis to compensate for the repopulation phenomenon and aid the determination of the course length. Our analysis can also be used for the design of concomitant boost BID regimens. A subroutine in BASIC language has been developed and is available upon request. As a corollary of GAIBE analysis, for a chosen total dose, once‐daily treatment (QD) will result in the most tumor killing and the BID half‐dose exposures will have the least tumor killing. Other combinations of BID exposures with the sum of doses equal to QD exposure will have varying degrees of tumor killing which fall in between these two extremes. This concept from GAIBE analysis may be applied to determine α/β values for tumor cell lines using equally split exposures. © 1994 Wiley‐Liss, Inc.
Complications following radiosurgery: A review
Authors: Marks Lawrence B.
Published: February 2007

The complication rates following radiosurgery (RS) for a variety of intracranial lesions are reviewed. While complications are generally uncommon, increased rates are seen with larger doses and treatment volumes. The deep portions of the brain (e.g., brain stem) and the optic structures are particularly sensitive. The risks of RS need to be considered as RS gains popularity and is used to treat a wider variety of intracranial lesions. © 1994 Wiley‐Liss, Inc.
Increased formation of diacylglycerol in tumor cells that are resistant to ionizing radiations
Authors: Pacini Stefania , Santucci Maria A. , Milano Franco , Casamassima Franco , Greenberger Joel S. , Pierce Jacalyn H. , Ruggiero Marco
Published: February 2007

In order to study the biochemical mechanisms underlying resistance to ionizing radiations we developed tumorigenic 32D hematopoietic cell lines that were resistant to gamma irradiation at clinical low dose rate. In these autonomously growing cultures, we studied alterations of mitogenic signaling. The cultures did not secrete autocrine growth factors and their conditioned medium could not sustain survival or growth of normal factor‐dependent cells. The pattern of protein tyrosine phosphorylation did not change after stimulation with the growth factor interleukin‐3. Transformed cultures showed an increased level of the intracellular second messenger diacylglycerol without a corresponding increase of inositol phosphates. These data suggest that aberrant diacylglycerol accumulation and protein kinase C activation might be involved in the development of resistance to the killing effects of ionizing radiations in spontaneous transformants. © Wiley‐Liss, Inc.
Proliferative activity measured by flow cytometry and Ki‐67 of nodal negative breast cancer as a prognostic parameter for local recurrences and distant metastases ‐first results
Authors: Fietkau R. , Tulusan A. H. , Dressel V. , Günther P. , Wolter Ch. , Lang N. , Meyer M. , Sauer R.
Published: February 2007

The prognostic value of proliferative activity [percentage of S‐phase cells = S‐phase fraction (SPF) and Ki‐67] was determined in nodal negative breast carcinomas and correlated with no evidence of disease (NED) survival and analysis of recurrence. Overall 193 breast carcinomas were investigated. SPF of 183 breast carcinomas was determined by one‐dimensional flow cytometry. Histochemically the percentage of Ki‐67‐positive cells was measured in 188 patients. Slowly proliferating tumors determined by SPF (SPF < median) had a better 5‐year NED survival (91%), a lower rate of distant metastases (1%), and a lower rate of loco‐regional recurrences (4.5%) compared to fast proliferating tumors (SPF > median; NED survival 63%; distant metastases 15.7%; loco‐regional recurrences 21%). Slowly proliferating tumors determined by Ki‐67 (Ki‐67 < 20%) had a better 5‐year NED survival (77%) and a lower rate of distant metastases (6.1%) compared to fast proliferating tumors (percentage of Ki‐67‐positive cells > 20%; NED survival 63%; distant metastases 17.9%). However, there was no significant difference in loco‐regional control. Stepwise multivariate analysis showed that SPF (P= 0.002) was the only independent prognostic factor for NED survival: SPF in interaction with grading (P= 0.001) and family history (P= 0.044) for distant metastases; and SPF (P= 0.0039), method of surgical treatment (P =0.071), and grading (P =0.0956) for loco‐regional recurrences. In conclusion, proliferative activity is a relevant prognostic parameter for nodal negative breast Cancer. © Wiley‐Liss, Inc.
Total lymphoid irradiation prior to bone marrow transplantation for severe aplastic anemia:Analysis of 20 cases
Authors: Zapatero Almudena , Cerro Elia Del , Pinar Beatriz , Cerezo Laura , Domínguez Pedro , Torrubia Armando Pérez
Published: February 2007

Twenty patients with severe aplastic anemia were treated with allogeneic bone marrow transplantation (BMT) between June 1986 and August 1992. The conditioning regimen included high‐dose cyclophosphamide, 50 mg/kg over 4 consecutive days, followed by 7 Gy total lymphoid irradiation (TLI) in 2 fractions the day before BMT. A combination of methotrexate and cyclosporine was used for prophylaxis of graft vs. host disease (GVHD). All recipients were previously transfused. Fourteen of the 20 transplanted patients are alive with a median follow‐up of 42 months. Actuarial survival was 70 ± 15% for the entire group and 83 ± 20% for the 6 patients ≤18 years. There was not any case of graft rejection following BMT. The incidence of moderate and severe acute GVHD was 29% and of chronic GVHD was 14%. Our findings indicate that the combination of cyclophosphamide and 7 Gy TLI prior to BMT provides excellent transfusion free survival and is extremely effective in decreasing rejection rates in previously transfused patients with severe aplastic anemia. © Wiley‐Liss, Inc.
Value of surgery and radiotherapy in the treatment of brain metastases
Authors: Nieder C. , Niewald M. , Schnabel K. , Berberich W.
Published: February 2007

In this study the results of surgery and radiotherapy (RT) in 26 patients, compared with those of 42 patients who had only RT are analyzed. The most frequent sites of primary tumors were the lung and breast. In the first years 20 × 2 Gy was given; later on 10 × 3 Gy was administered. Sixteen non‐operated patients received 20 × 2 Gy followed by a local boost of 10–20 Gy. Because a matched cohort pair method was chosen for this analysis, all prognostic factors were equally distributed between the operation (OP) + whole‐brain irradiation (WBI) and the WBI only group. The local remission rate after OP + WBI was 81% vs. 38.5% after WBI only and 69% after WBI + boost. Median survival after surgery (17 months) was significantly longer, but the dose of RT had no influence on survival (7 vs. 8 months). The distribution of prognostic factors was significantly different between the WBI + boost group and the other groups, and therefore a prospective randomized trial will become necessary to verify the superiority of surgical treatment compared to “high‐dose” RT. When compared to “standard” RT equivalent to the 10 × 3 Gy schedule, surgery + RT is significantly superior. © Wiley‐Liss, Inc.
Treatment of arteriovenous malformations with stereotactic radiosurgery: A review
Authors: Wilder Richard B.
Published: February 2007

Arteriovenous malformations (AVMs) are vascular anomalies in which blood is shunted from the arterial to the venous system. In general, the annual risk of hemorrhage from an intracranial AVM is 2–3%. The morbidity and mortality rates associated with an initial hemorrhage are 30% and 10%, respectively. Based on these risks, intervention for unruptured AVMs is commonly recommended. Microneurosurgery is regarded by most physicians to be the treatment of choice for small cortical AVMs in noneloquent areas since resection can result in immediate cure. Stereotactic “radiosurgery” (radiation therapy) is commonly recommended for patients with deep AVMs ≤ 15 cm3 (approximately 3 cm in maximum dimension), where the risks of surgery are excessive. AVMs larger than approximately 15 cm3 may be treated with embolization followed by either microneurosurgery or stereotactic radiosurgery. When AVMs have been managed with stereotactic radiosurgery and the size of the lesion is taken into consideration, gamma knives, linear accelerators, and cyclotrons have produced similar angiographic complete obliteration rates. Gamma knives are expensive to purchase and install but are easy to operate. Linear accelerators are the most economical and versatile machines for stereotactic radiosurgery. Although cyclotrons are very expensive to build and operate, they afford maximal sparing of normal tissue when large lesions are irradiated. The complete obliteration rates 1,2, and 3 years following the management of AVMs ≤ 10 cm3 with stereotactic radiosurgery are 40–50%, 70–90%, and 75–95%, respectively. Following the administration of radiosurgery, 2‐year angiographic complete obliteration rates are 88% for AVMs <4 cm3, 75% for AVMs 4–10 cm3, 67% for AVMs 11–25 cm3, and 39% for AVMs 26–70 cm3. Much lower (0‐45%) long‐term complete obliteration rates have been obtained with fractionated photon and neutron beam radiation therapy, apparently due to the administration of inadequate total doses. The crude incidence of complications following the treatment of AVMs with stereotactic radiosurgery is approximately 3%, with no treatment‐related mortality. Patients with AVMs in the brain stem, thalamus, or basal ganglia are at higher risk for complications. In the future, authors should consider reporting the number of patients who undergo follow‐up MRI or CT scans but not angiography and consider presenting complication rates as a function of time in order to allow one to more accurately assess results. © Wiley‐Liss, Inc.
Definition and manipulation of tumor oxygenation
Authors: Teicher Beverly A. , Dupuis Norman P. , Holden Sylvia A. , Schwartz Gary N. , Lester Susan , Frei Emil
Published: February 2007

Using a computer‐controlled polarographic oxygen electrode system, the oxygen tension profiles of two rat tumors, the 13762 mammary carcinoma and the 9L gliosarcoma, and one murine tumor, the FSall fibrosarcoma, were determined under eight different conditions. The oxygen profiles were characterized by four parameters related to tumor oxygenation and by three parameters related to tumor hypoxia. In the rat 13762 mammary carcinoma tumor median pO2 and the percent of pO2 were correlated with tumor volume under three different conditions. With these tumors the decrease in percent of pO2 readings in the tumor <5 mmHg appeared to correlate with the enhancement in therapeutic response of the rat tumors to single dose radiation therapy and of the mouse tumor to single doses of melphalan or cyclophosphamide. Both the perfluorochemical emulsion (Oxygent(tm) CA) with carbogen breathing and the polymerized bovine hemoglobin with air or carbogen breathing were effective in increasing the oxygenation of these three tumors. Pentoxifylline administration especially along with carbogen breathing increased the oxygenation of the tumors. These studies indicate that the decrease in the percent of the tumor which is most severely hypoxic may be predictive of improved therapeutic response in tumors treated with oxygen‐dependent or oxygen‐responsive therapies and oxygen delivery agents. © Wiley‐Liss, Inc.
Fractionated brain stereotactic irradiation using a non‐invasive frame: Technique and preliminary results
Authors: Delannes Martine , Daly‐Schveitzer Nicolas , Sabatier Jean , Bonnet Jacques
Published: February 2007

In this study we report on the use of two non‐invasive head frames in fractionated stereotactic irradiation for small benign or low grade brain tumors. Sixty‐one patients were treated from April 1988 to December 1992 with external stereotactic irradiation: 12 presented with arteriovenous malformations (AVMs), 32 with benign tumors, and 17 with malignant tumors. Sire of the lesions ranged from 15 to 45 mm in diameter. Two immobilization devices were used: the Laitinen stereoadapter, until December 1992, and then the Beverly frame, specifically designed for radiotherapy. Treatment was given daily, 5 days/week, using 1 or 2 non‐coplanar arcs, the dose per fraction ranging from 2 to 3 Gy. The study of the accuracy of the two frames showed an average discrepancy <1 mm for 25 setups, irrespective of the spatial plane. All the patients tolerated well the immobilization devices. Forty‐one of the 61 patients were followed at least 2 years after the treatment (7 with AVMs, 20 with benign tumors, 14 with malignant tumors). For AVMs, 1 regressed completely, 1 partially decreased in size, and the other 5 remained unchanged. For benign tumors, 14 patients are alive without disease progression, 5 showed a marked tumor decrease, and 1 died of intercurrent disease. For malignant tumors, 3 patients died of their disease, 2 are alive with disease progression, 8 are alive without disease progression, and 1 has a complete tumor regression. From these results we conclude that the Beverly frame is perfectly suited to fractionated stereotactic irradiation. For AVMs, the obliteration rate with fractionated irradiation at low dose is disappointing. These lesions probably require larger single dose treatments to induce vascular sclerosis. For other benign or low grade tumors, the observed results are satisfactory and the progression‐free rate may be as high as that obtained with single fractions with presumably less adverse effects. © Wiley‐Liss, Inc.
Preparations for phase I clinical trials of boron neutron capture therapy at the mit reactor and the New England Medical Center
Authors: Harling Otto K. , Zamenhof Robert G. , Solares Guido R. , Yanch Jacquelyn C. , Wazer David E. , Rogus Ronald D. , Chabeuf Jean‐Michel , Yam Sam C. , Bernard John A. , Cano Guillermo , Dipetrillo Thomas , Madoc‐Jones Hywel
Published: February 2007

A team of scientists, engineers and medical researchers from the New England Medical Center (NEMC) and the Massachusetts Institute of Technology's (MIT) Nuclear Reactor Laboratory have been developing Boron Neutron Capture Therapy (BNCT), a binary radiation therapy, for the treatment of refractory tumors such as glioblastoma multiforme and melanoma. After 6 years of effort on several fronts, the interdisciplinary and inter‐institutional research group is planning Phase I clinical trials in the near future. This paper briefly reviews the preparations at NEMC/MIT, including the various technologies and research tasks which are important or necessary for the initiation of clinical trials. © Wiley‐Liss, Inc.
Role of p53 and ras genes in radiation‐induced transformation of immortalized human epidermal keratinocytes
Authors: Varghese S. , Jung M. , Prasad S. , Rhim J. S. , Dritschilo A. , Thraves P. J.
Published: February 2007

The biological effects of exposure to ionizing radiation have particular relevance to radiation protection and risk assessment. Since most cancers are of epithelial origin, it is important to obtain a better understanding of radiation‐induced oncogenic transformation in this cell type. Our previous studies have demonstrated the potential of ionizing radiations to transform human epidermal keratinocytes (RHEK‐1) [Thraves et al.: Proc Natl Acad Sci USA 87:1174–1177, 1990; Thraves et al.: Carcinogenesis (in press)] and have described the cellular characteristics, saturation density, anchorage‐independent growth, and tumorigenicity of these transformed cells, together with a preliminary determination of the role of cellular ras genes. The present study has expanded these molecular studies to conclude a molecular analysis of all the ras genes and the tumor suppressor gene p53. Single‐strand conformational polymorphism (SSCP) analysis and DNA sequencing demonstrated the absence of point mutations, deletions, and rearrangements in codons 12/13 and 61 in the Ha‐ras or N‐ras genes and exons 4–9 of the p53 tumor suppressor gene. These studies demonstrate that mutations in either the cellular p53 or ras genes do not occur in these immortalized human epithelial cells (RHEK‐1) transformed to a malignant phenotype with ionizing radiation. © Wiley‐Liss, Inc.
Influence of the extent of nodal involvement on the outcome in stage D1 prostate cancer
Authors: Wiegel T. , Bressel M.
Published: February 2007

From 1975 to 1991, 82 patients with pathological stage D1 prostate cancer underwent radiation therapy. Twelve patients were excluded from analysis because treatment started when local tumor progression was determined. Of the 70 remaining patients, 30 initially had a radical prostatectomy with orchiectomy and 40 patients had only a biopsy with orchiectomy. All patients had an additional androgen blocking. Sixty‐seven of 70 patients were treated with photons up to a total dose of 4,000–5,000 cGy to the small pelvis and 55 of 67 received an additional boost to the prostatic region to deliver 6,000–7,000 cGy. In 12 cases, 14 MeV fast neutrons were used for the boost. Three patients underwent only irradiation of the prostate. With a median follow up of 58 months (range: 3–183 months), the overall survival rate (OS) for 5 and 10 years was 78% and 45%, respectively. The cause‐specific survival rate was 86% and 69% for 5 and 10 years, respectively. Thirteen patients with one microscopically positive node (group I) had an OS of 90% and 68% (5 and 10 years, respectively) compared to 57 patients with one or more microscopically positive nodes (group II), who had an OS of 75% and 40%, respectively (P > 0.05). A significant advantage for patients with microscopically involved nodes was seen in disease‐free survival: 84% vs. 62% for 5 years and 63% vs. 27% for 10 years (P < 0.05) and in cause specific survival: 100% vs. 82% for 5 years and 100% vs. 59% for 10 years (P < 0.05). Major complications occurred in four patients (6%); all of these were treated following prostatectomy. Prospective randomized clinical trials should compare the results of radiotherapy and hormonal treatment with radical prostatectomy and hormonal treatment and hormonal treatment alone in stage D1 prostate cancer. The treatment of choice remains unclear. © Wiley‐Liss, Inc.
Overexpression of the radiation‐inducible gene, GADD153, in drug‐resistant burkitt lymphoma cells
Authors: Hollander M. Christine , Tan K. B. , Fornace Albert J.
Published: February 2007

A frequent problem in cancer therapy is the emergence of resistant cells. The nitrogen mustard‐resistant cell line Raji‐HN2 was used to investigate the relationship between drug resistance and expression of a variety of genes which are inducible by various types of DNA damage including radiation. It ws found that only GADD153, a member of the CCAAT enhancer binding protein (C/EBP) family of transcription factors, showed increased expression in these drug‐resistant cells. Increased GADD153 expression is intriguing since this gene is induced in non‐resistant cells by HN2, as well as other drugs, certain types of radiation, and growth arrest. Since GADD153 is a transcription factor, its overexpression in resistant cells may modulate the expression of other genes as well. It was also found that a short G‐tract‐containing transcript was also increased in the Raji‐HN2 cells. The nature of this transcript and its relevance to drug resistance in Raji‐HN2 are unknown. © Wiley‐Liss, Inc.
Effect of etanidazole on absolute sensitivity and increased radioresistance in hypoxic cells at low doses
Authors: Skov Kirsten A. , Koch Cameron J. , Marples Brian
Published: February 2007

It has been known for some time that oxygen and certain electron affinic radiosensitizers exhibit less effective enhancement of cell kill at low clinically relevant X‐ray doses, a behavior which has still not been adequately explained. This is further complicated by more recent findings that at low concentrations of nitroimidazoles there are anomalous results on hypoxic low dose radiosensitization. In the low dose range below 1 Gy, where survival is high, we have reexamined radiosensitization of hypoxic hamster cells by etanidazole at various concentrations (200–2,000 μM) using automated microscopic localization of cells to obtain more precise measurements of survival. As previously observed, etanidazole at low concentrations (200 μM) was found to be more effective at low (∼1 Gy, survival ∼80%) rather than high (survival ∼2%) X‐ray doses. When plotted as absolute sensitivity, data for high concentrations of etanidazole (> 1,000 μM) fall in one area of the D80−1 vs. D2−1 plot, whereas concentrations below 1,000 μM might be suggested to behave “differently,” and several explanations are suggested. One of these involves a structure of the survival curve which has been suggested to reflect induced repair. This structure is modified at the higher concentration of etanidazole, but there is little effect at 200 μM. An alternate proposal considers accessibility of DNA to drug, or type of lesions affected as possible explanations for the apparent differential sensitization by etanidazole at high and low X‐ray doses. In summary, a clinically relevant concentration of etanidazole provides relatively good radiosensitization at low, clinically relevant radiation doses; thus hypoxic sensitizers may affect survival in those cell lines which have a large survival curve shoulder since the extent of the shoulder is purported to reflect the degree of induced radioresistance. © Wiley‐Liss, Inc.
Effect of misonidazole and low‐oxygen treatment on mouse tumors
Authors: Hendrikse A. , Blekkenhorst G.
Published: February 2007

The tumor cytotoxic activity of a bioreductive agent is dependent on the extent of tumor hypoxia. It is to be expected, therefore, that the tumor cytotoxicity of misonidazole will vary depending on whether it was administered to mice exposed only to an air‐breathing environment or whether it was administered either before mice were treated with 8% oxygen for 48 hr (maximal tumor levels of the drug will then coincide with an increase in tumor hypoxia) or after mice completed a 48‐hr 8% oxygen treatment (maximal tumor levels of the drug will now coincide with a reduction in the tumor hypoxic fraction). This was investigated using the 3‐methylcholanthrene‐induced rhabdomyosarcoma in BALB/c mice, the Fib/T tumor in WHT mice, and the CaNT tumor in CBA mice. The response of all three tumor types to the various treatments was determined by assessing post‐treatment tumor growth. An excision and in vitro colony‐forming assay was also used to assess Fib/T tumor response. Results indicated that only the 3‐methylcholanthrene‐induced rhabdomyosarcoma responded to misonidazole and only when the 48‐hr 8% oxygen exposure preceded drug administation. In explaining this result, it is proposed that misonidazole increases reperfusion damage that occurs when animals are returned to an air‐breathing environment following a low‐oxygen exposure. © Wiley‐Liss, Inc.
Intrinsic radiosensitivity of head and neck carcinomas as predictive test for clinical tumor control: Comparative analysis and critical assessment of technical reliability
Authors: Kocagöncü K. O. , Marangoni G. , Cozzi‐Fogliata A. , Griffin S. , Garavaglia G. , Thum P. , Bernier J.
Published: February 2007

Using a cell adhesion matrix monolayer culture system, we assayed the intrinsic radiosensitivity of 108 biopsies or surgical specimens of head and neck, colo‐rectum, or cervix uteri carcinomas. After irradiating single cell suspensions with increasing doses (0–4 Gy), surviving fractions at 2 Gy (SF‐2), initial slope α were estimated after a linear quadratic fitting of the curves. For cultures from biopsies or surgical specimens of head and neck carcinomas, the overall success rate was 65%. The pattern of the causes of failure for mass cultures was similar in other institutions investigating intrinsic radiosensitivity of squamous cell carcinomas. Within the same anatomic site and histological type, rumors were characterized by a wide range of in vitro radiosensitivity. In a series of 28 patients with head and neck cancers, the mean and standard deviation values of SF‐2 were 0.30 ± 0.34. Likewise, α coefficients had an average of 0.61 ± 0.96 Gy−1. Cultures from colo‐rectal cancers seem to have a higher mean level of intrinsic radioresistance (mean SF‐2 = 0.49) than that of cells from head and neck tumors. Papanicolaou (PAP) staining and immuno‐chemistry studies using monoclonal antibodies showed that stromal expression was a major problem for techniques using pre‐coated plates. Nevertheless, the pattern of cumulative distribution of SF‐2 values is not significantly different for cultures characterized by fibroblast overgrowth. In conclusion, notwithstanding variations in fibroblast growth, the comparative analysis of data published so far on intrinsic radiosensitivity shows that similar distributions of individual survival parameter values are yielded in the laboratories involved in this research field. Nevertheless, further studies on culture characterization, using monoclonal antibodies and flow cytometry, should be carried out to quantify better the impact of fibroblast contamination on culture response to irradiation. © Wiley‐Liss, Inc.
Cervical metastases from unknown primaries treated with different radiation techniques
Authors: Schnabel Th. , Wustlich S. , Bier H. , Zamboglou N. , Kolotas C. , Hartmann A. , Schmitt G.
Published: February 2007

Cancer of unknown primary (CUP) syndrome presenting as metastatic lymph nodes of unknown primaries in the head and neck is a difficult clinical problem. The optimal treatment policy is not yet defined. A retrospective analysis of the clinical outcome and side effects of 41 patients with CUP syndrome treated with different irradiation techniques is given in this report. Tweny‐eight patients received “involved field” irradiation confined to the involved neck and all the other patients were treated with “extended fields” including the contralateral neck and oro‐ and hypopharynx. The relative risk of recurrence was 30% and 56% after 1 and 3 years for patients irradiated with “involved fields” and 56% for both periods for patients treated with “extended fields.” During follow‐up the primary tumor was detected in 11 patients. In conclusion, after thorough diagnostic workup and surgery, limited radiotherapy to the involved neck is justified. © Wiley‐Liss, Inc.
Simple numerical system for scoring the cosmetic effects of radiation and surgery post‐conservation therapy for breast cancer
Authors: Steeves Richard A. , Stitt Judith A. , Chappell Richard , Wolberg William H. , Kinsella Timothy J.
Published: February 2007

To improve the documentation of cosmetic outcome in women with breast cancer treated by conservative surgery and radiation, we developed a simple numerical scoring system. Cosmetic scores are based on the effects of surgery and radiation and also include a comparison of breast symmetry. The scoring system ranges from a minimum score of 2 to a maximum of 10. Between June 1978 and June 1992, 226 patients were treated at the University of Wisconsin by tumorectomy and breast irradiation. Of these, 209 patients were evaluable after a minimum period of 2 years. Blind tests of interobserver agreement gave a correlation coefficient of 0.74 between faculty and resident scores. Scores tended to be slightly lower for larger or node‐positive cancer, but they were not adversely affected by tumor location or by the type of prior chemotherapy. At 2, 5, and 10 years post‐treatment, mean cosmetic scores were 8.1, 7.3, and 6.2, while local recurrence rates were 2, 8, and 16%, respectively. This numerical system for assessing breast cosmesis is easy to use and is more amenable to statistical analysis than qualitative descriptors such as “excellent, good, fair, or poor.” © Wiley‐Liss, Inc.
Feasibility study of radioimmunoguided iodine‐125 brachytherapy for metastatic colorectal cancer
Authors: Nag Subir , Ellis Rod J. , Martin Edward W. , Stacy Karen , Brown Cheryl , Young Donn
Published: February 2007

The radioimmunoguided brachytherapy (RIGBY) approach was developed to identify and treat occult residual disease after resection. Between September 1989 and March 1992, 30 patients with metastatic recurrent colorectal cancer were implanted with iodine‐125 (125I) seeds using the RIGBY technique. These patients would otherwise have died of disease progression. Patients were injected with 125I radiolabeled antibody. A hand‐held gamma‐detecting probe (GDP) was used to detect and resect areas of high radioactivity representing tumor. Areas which had persistent high probe counts after resection represented areas of occult residual disease which were then implanted with a median dose of 160 Gy 125I. The GDP was used to demarcate the occult tumor volume in 20 of 30 patients (67%). Patients were followed for 7–36 months (median 17 months); local control was 73% by clinical assessment; the median survival was 17.5 months, with 1‐year survival of 73% and 2‐year survival of 27%. There were no intraoperative deaths. Major surgical morbidity was seen in 9 patients (30%), comparable to the high morbidity seen in recurrent colorectal cancer patients undergoing major surgery. The RIGBY procedure did not significantly increase the morbidity. Further close follow‐up and additional accural of patients is warranted to evaluate the efficacy and morbidity of the RIGBY procedure, as well as evaluation of its other possible uses. © 1995 Wiley‐Liss, Inc.
T2‐T3 carcinoma of the supraglottic larynx: A comparison of surgery and radiotherapy
Authors: Fein Douglas A. , Nichols R. Charles , Lee W. Robert , Mendenhall William M. , Parsons James T. , Stringer Scott P. , Cassisi Nicholas J. , Million Rodney R.
Published: February 2007

This paper compares results for T2‐T3 carcinoma of the supraglottic larynx treated with radiotherapy (RT), supraglottic laryngectomy, or total laryngectomy. Two hundred thirty patients with T2‐T3 carcinoma of the supraglottic larynx were treated at the University of Florida between 1964 and 1989. All had a minimum 2‐year follow‐up. Patients were treated with RT alone (160), supraglottic laryngectomy (25), or total laryngectomy (45). The probabilities of local control, local‐regional control, distant metastasis, and survival were calculated by the Kaplan‐Meier product‐limit method and comparisons were made between the three treatment methods. American Joint Committee on Cancer (AJCC) stage, T stage, anatomic suitability for a supraglottic laryngectomy, treatment group, and presence or absence of a pretreatment tracheostomy were evaluated in multivariate analyses for the various end points. The 2‐year local control rates for patients treated with RT alone, supraglottic laryngectomy, and total laryngectomy for T2 lesions were 87%, 82%, and 100%, respectively, and rates for T3 lesions were 70%, 71%, and 81%. In the multivariate analyses, T stage was of independent prognostic significance for the end point of local control, whereas AJCC stage was a significant prognostic factor for control above the clavicles and cause‐specific survival. The incidence of severe complications was as follows: RT (6%), supraglottic laryngectomy (20%), and total laryngectomy (16%). In this analysis of T2‐T3 supraglottic larynx carcinomas, treatment with RT offered equivalent local control rates, local‐regional control rates, and survival rates with fewer severe complications compared with supraglottic laryngectomy. Although total laryngectomy was associated with a modest improvement in local‐regional control, the differences were not statistically significant, and this procedure would rarely be indicated today for T2 lesions and uncommonly for T3 lesions. © 1995 Wiley‐Liss, Inc.