Purpose/ObjectiveWe previously found that whole pelvis (WP) IMRT including both the prostate and the pelvic nodes (PN) followed by a conformal boost offers superior dosimetric coverage of PTVs and sparing of bladder/rectum compared to standard 4-field box technique with the same boost. Here we report the acute toxicity data collected in 45 consecutive patients treated with such approach.Materials/MethodsFrom May 02 to January 04, 45 patients with prostate-confined carcinoma and Roach risk of positive PN ≥15% were treated with 3DCRT boost (6-field) delivering 16 Gy in 8 fractions to the isodose covering the prostate followed by IMRT (sMLC) delivering 1.8 Gy, daily to pelvic nodes and seminal vesicles and 2 Gy to the prostate. The total dose to the PN and seminal vesicles (SV) was 54 Gy in 30 fxs and to the prostate 76 Gy in 38 fxs in 7.9 weeks.Patients were seen weekly during treatment and acute toxicity prospectively scored according to RTOG criteria. Acute GI toxicity was further divided into high/diarrhea and low/proctitis. GI toxicity was compared to the one observed within the control arm of a previous randomized study (G Sanguineti et al, Strahlenther Onkol, 2003). In that trial, 76 Gy (ICRU point) had been administered with conformal RT (3-field) to the prostate ± SV only (PO-3DCRT). 33 events, grade 2+ acute GI, all involving the rectum, had been recorded in 63 patients in the control arm.ResultsAcute toxicity rates are shown in the table. Breakdown of patients with grade 2 GI toxicity into high/diarrhea and low/proctitis showed that 13 (28.9%), 8 (17.8%) and 5 (11.1%) patients had high, low or both toxicities. Cumulative incidence of acute grade 2+ GI toxicity with PO-3DCRT (previous study) or WP-IMRT is reported in the figure. Interestingly, overall, PO-3DCRT and WP-IMRT had similar toxicity profiles (PO-3DCRT vs. WP-IMRT/all-GI, p = 0.8). However, if only proctitis is selected as event (disregarding diarrhea), the difference between PO-3DCRT and WP-IMRT is highly significant (PO-3DCRT vs. WP-IMRT/proctitis, p < 0.01).ConclusionsView Large Image Figure ViewerDownload (PPT) Purpose/ObjectiveWe previously found that whole pelvis (WP) IMRT including both the prostate and the pelvic nodes (PN) followed by a conformal boost offers superior dosimetric coverage of PTVs and sparing of bladder/rectum compared to standard 4-field box technique with the same boost. Here we report the acute toxicity data collected in 45 consecutive patients treated with such approach. We previously found that whole pelvis (WP) IMRT including both the prostate and the pelvic nodes (PN) followed by a conformal boost offers superior dosimetric coverage of PTVs and sparing of bladder/rectum compared to standard 4-field box technique with the same boost. Here we report the acute toxicity data collected in 45 consecutive patients treated with such approach. Materials/MethodsFrom May 02 to January 04, 45 patients with prostate-confined carcinoma and Roach risk of positive PN ≥15% were treated with 3DCRT boost (6-field) delivering 16 Gy in 8 fractions to the isodose covering the prostate followed by IMRT (sMLC) delivering 1.8 Gy, daily to pelvic nodes and seminal vesicles and 2 Gy to the prostate. The total dose to the PN and seminal vesicles (SV) was 54 Gy in 30 fxs and to the prostate 76 Gy in 38 fxs in 7.9 weeks.Patients were seen weekly during treatment and acute toxicity prospectively scored according to RTOG criteria. Acute GI toxicity was further divided into high/diarrhea and low/proctitis. GI toxicity was compared to the one observed within the control arm of a previous randomized study (G Sanguineti et al, Strahlenther Onkol, 2003). In that trial, 76 Gy (ICRU point) had been administered with conformal RT (3-field) to the prostate ± SV only (PO-3DCRT). 33 events, grade 2+ acute GI, all involving the rectum, had been recorded in 63 patients in the control arm. From May 02 to January 04, 45 patients with prostate-confined carcinoma and Roach risk of positive PN ≥15% were treated with 3DCRT boost (6-field) delivering 16 Gy in 8 fractions to the isodose covering the prostate followed by IMRT (sMLC) delivering 1.8 Gy, daily to pelvic nodes and seminal vesicles and 2 Gy to the prostate. The total dose to the PN and seminal vesicles (SV) was 54 Gy in 30 fxs and to the prostate 76 Gy in 38 fxs in 7.9 weeks. Patients were seen weekly during treatment and acute toxicity prospectively scored according to RTOG criteria. Acute GI toxicity was further divided into high/diarrhea and low/proctitis. GI toxicity was compared to the one observed within the control arm of a previous randomized study (G Sanguineti et al, Strahlenther Onkol, 2003). In that trial, 76 Gy (ICRU point) had been administered with conformal RT (3-field) to the prostate ± SV only (PO-3DCRT). 33 events, grade 2+ acute GI, all involving the rectum, had been recorded in 63 patients in the control arm. ResultsAcute toxicity rates are shown in the table. Breakdown of patients with grade 2 GI toxicity into high/diarrhea and low/proctitis showed that 13 (28.9%), 8 (17.8%) and 5 (11.1%) patients had high, low or both toxicities. Cumulative incidence of acute grade 2+ GI toxicity with PO-3DCRT (previous study) or WP-IMRT is reported in the figure. Interestingly, overall, PO-3DCRT and WP-IMRT had similar toxicity profiles (PO-3DCRT vs. WP-IMRT/all-GI, p = 0.8). However, if only proctitis is selected as event (disregarding diarrhea), the difference between PO-3DCRT and WP-IMRT is highly significant (PO-3DCRT vs. WP-IMRT/proctitis, p < 0.01). Acute toxicity rates are shown in the table. Breakdown of patients with grade 2 GI toxicity into high/diarrhea and low/proctitis showed that 13 (28.9%), 8 (17.8%) and 5 (11.1%) patients had high, low or both toxicities. Cumulative incidence of acute grade 2+ GI toxicity with PO-3DCRT (previous study) or WP-IMRT is reported in the figure. Interestingly, overall, PO-3DCRT and WP-IMRT had similar toxicity profiles (PO-3DCRT vs. WP-IMRT/all-GI, p = 0.8). However, if only proctitis is selected as event (disregarding diarrhea), the difference between PO-3DCRT and WP-IMRT is highly significant (PO-3DCRT vs. WP-IMRT/proctitis, p < 0.01). Conclusions

Purpose/Objective: Craniospinal irradiation (CSI) is essential for the treatment of medulloblastoma due to the tendency for subarachnoid dissemination. Achieving a uniform dose throughout the subarachnoid space is technically challenging due to field matching, patient contour, and the utilization of large fields. We have developed a novel delivery technique for CSI that addresses these concerns, and demonstrated superior dose uniformity through the planning target volume (PTV). The purpose of this paper is to provide a description of the novel CSI technique and to compare dose distributions with those created by a conventional CSI plan. Materials/Methods: Two different plans were created using a CT data set obtained from a patient with medulloblastoma, each designed to deliver 36 Gy to the craniospinal axis. The conventional CSI used parallel-opposed lateral fields to the brain with cerrobend blocks to shape the field, and two posterior fields to treat the spinal column. To match the cranial and superior spinal fields, the collimator and couch angle were adjusted. The match lines between the spinal fields, and the upper spine and cranial fields, were moved by 1cm weekly. The novel CSI plan used multiple field segments to obtain dose uniformity within the PTV. A half-beam block was used at the inferior margin of the cranial field and the superior margin of the spinal field, to produce a match at the craniospinal junction. The isocenter of the cranial field was placed posterior and inferior to the eyes, to reduce beam divergence to the contralateral eye. Cerrobend blocks were used to shape the cranial fields. Both the craniospinal and spinal match lines were moved daily using a virtual penumbra generator, obviating the need to move the match line. Thirty field-segments were used to treat the craniospinal axis. Twelve field segments were used to treat the brain, 9 for the superior spinal field, and 9 for the inferior spinal field. The prescribed dose was delivered over an average of 13 minutes, using a multileaf-collimator and auto-sequenced dose delivery for each anatomical region. Dose volume histograms of the brain, spinal cord, and surrounding tissues were calculated to compare the techniques. For the brain and spinal cord, we determined the volumes that received 5% and 10% above the prescribed dose. For the surrounding tissue, excluding the spinal cord and brain we determined the volume that received 100, 110, 120, 130, and 140% above the prescribed dose. Results: With the novel CSI technique, 21 cc of brain received 5% above the prescribed dose, and 0 cc received 10% above, compared to 343 cc and 22 cc for conventional CSI, a reduction of 94% and 100%, respectively. The volume of spinal cord receiving 5% and 10% above the prescribed dose was reduced by 43% (74 cc to 42 cc) and 82% (37 cc to 6 cc) respectively. The volumes of surrounding tissue receiving 100, 110, 120, 130, and 140% of the prescribed dose were reduced respectively from 3881, 1525, 657, 342, and 108 cc, with conventional CSI, to 3318, 1063, 512, 251, and 64 cc, with the novel technique, corresponding to percentage reductions of 14, 30, 22, 27, and 40%, respectively. The dose to the eyes was also reduced by a negligible amount. Conclusions: The novel CSI technique described provided superior dose uniformity within the PTV, compared with conventional CSI, and decreased not only the volume of brain and spinal cord exceeding the prescribed dose, but the surrounding normal tissues. Furthermore, the difficulties of beam divergence and field matching were resolved.

The purpose of the study was to investigate the difference in overall survival in patients with localized carcinoma of esophagus treated using chemo-radiation (bi-modality, BM) or chemo-radiation followed by surgery (tri-modality, TM). From 1981 to 1999, 65 patients were identified who had localized carcinoma of the esophagus treated with either concurrent chemo-radiation (BM, n=22) or concurrent chemo-radiation followed by surgery (TM, n=43) at the University of Texas Medical Branch at Galveston. All 65 patients received concurrent chemotherapy and external beam radiation. Radiation was delivered by linear accelerators (greater-than-or-equal 6 MV), except in one patient who had part of his treatment given by a Co-60 machine. Chemotherapy consisted of 5-fluorouracil and cisplatin plus minus vinblastine under different regimens. Median follow-up time was 10 months (range=1-195 months) for all patients. Of the 14 patients still alive, the median follow-up time was 32 months (range=2-192 months). No difference in overall survival was detected between the two treatment groups, BM vs. TM (P=0.394) despite a selection bias favoring the TM group. Five-year survival rates of the BM and TM groups were 17% and 18%, respectively; 10-year survival rates were 17% and 12%, respectively. The presence of significant past medical history (P=0.017) and a complete pathologic response in the TM group (P < 0.001) were significant independent predictors of survival. We did not find any difference in survival between chemo-radiation or chemo-radiation followed by surgery in patients with localized carcinoma of the esophagus. Use of biologic markers and functional imaging should be explored in order to segregate patients with different tumor biology for treatment using different treatment strategies.

Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities. The MLIV gene, ML4 (MCOLN1), has recently been localized to chromosome 19p13.2-13.3 by genetic linkage. Here we report the cloning of a novel transient receptor potential cation channel gene and show that this gene is mutated in patients with the disorder. ML4 encodes a protein, which we propose to call mucolipin, which has six predicted transmembrane domains and is a member of the polycystin II subfamily of the Drosophila transient receptor potential gene family. The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed.

The Ras oncogene products regulate the expression of genes in transformed cells, and members of the Ets family of transcription factors have been implicated in this process. To determine which Ets factors are the targets of Ras signaling pathways, the abilities of several Ets factors to activate Ras-responsive enhancer (RRE) reporters in the presence of oncogenic Ras were examined. In transient transfection assay, reporters containing RREs composed of Ets-AP-1 binding sites could be activated 30-fold in NIH 3T3 fibroblasts and 80-fold in the macrophage-like line RAW264 by the combination of Ets1 or Ets2 and Ras but not by several other Ets factors that were tested in the assay. Ets2 and Ras also superactivated an RRE composed of Ets-Ets binding sites, but the Ets-responsive promoter of the c-fms gene was not superactivated. Mutation of a threonine residue to alanine in the conserved amino-terminal regions of Ets1 and Ets2 (threonine 38 and threonine 72, respectively) abrogated the ability of each of these proteins to superactivate reporter gene expression. Phosphoamino acid analysis of radiolabeled Ets2 revealed that Ras induced normally absent threonine-specific phosphorylation of the protein. The Ras-dependent increase in threonine phosphorylation was not observed in Ets2 proteins that had the conserved threonine 72 residue mutated to alanine or serine. These data indicate that Ets1 and Ets2 are specific nuclear targets of Ras signaling events and that phosphorylation of a conserved threonine residue is a necessary molecular component of Ras-mediated activation of these transcription factors.

The colony stimulating factor-1 receptor (CSF-1R) affects mitogenic growth and gene expression in NIH 3T3 cells through signaling pathways that require the products of the c-ras and c-myc proto-oncogenes. In this work we tested the hypothesis that there is direct communication between the Ras and Myc pathways. In transient transfection assays Ras increased by 5-fold transcriptional transactivation by chimeric c-Myc-Gal4 proteins. A constitutive active form of the CSF-1R also stimulated this activity and co-expression of a dominant negative ras gene ablated receptor stimulation. Deletion analysis of the c-Myc N-terminal region demonstrated that amino acid residues between positions 92 and 143 are the targets for Ras action. Transactivation by chimeric Myc proteins that were stably expressed could be transiently enhanced by either CSF-1 or serum, with peak activity occurring 2 h after mitogen stimulation. The steady-state levels of the chimeric c-Myc transactivators were increased following stimulation with CSF-1 or serum, but this increase in steady-state protein level did not strictly correlate with the increase in transactivation activity. Thus, Ras signaling may directly affect the activity of the c-Myc N-terminal region.

The mouse urokinase-type plasminogen activator (uPA) gene was used as a model macrophage colony-stimulating factor 1 (CSF-1)-inducible gene to investigate CSF-1 signalling pathways. Nuclear run-on analysis showed that induction of uPA mRNA by CSF-1 and phorbol myristate acetate (PMA) was at the transcriptional level in bone marrow-derived macrophages. CSF-1 and PMA synergized strongly in the induction of uPA mRNA, showing that at least some components of CSF-1 action are mediated independently of protein kinase C. Promoter targets of CSF-1 signalling were investigated with NIH 3T3 cells expressing the human CSF-1 receptor (c-fms). uPA mRNA was induced in these cells by treatment with CSF-1, and a PEA3/AP-1 element at -2.4 kb in the uPA promoter was involved in this response. Ets transcription factors can act through PEA3 sequences, and the involvement of Ets factors in the induction of uPA was confirmed by use of a dominant negative Ets-2 factor. Expression of the DNA binding domain of Ets-2 fused to the lacZ gene product prevented CSF-1-mediated induction of uPA mRNA in NIH 3T3 cells expressing the CSF-1 receptor. Examination of ets-2 mRNA expression in macrophages showed that it was also induced synergistically by CSF-1 and PMA. In the macrophage cell line RAW264, the uPA PEA3/AP-1 element mediated a response to both PMA and cotransfected Ets-2. uPA promoter constructs were induced 60- to 130-fold by Ets-2 expression, and the recombinant Ets-2 DNA binding domain was able to bind to the uPA PEA3/AP-1 element. This work is consistent with a proposed pathway for CSF-1 signalling involving sequential activation of fms, ras, and Ets factors.

HomeRadiologyVol. 190, No. 3 PreviousNext Oncology/radiation therapy.J E Marks, M Colman, R H SagermanJ E Marks, M Colman, R H SagermanJ E MarksM ColmanR H SagermanPublished Online:Mar 1 1994https://doi.org/10.1148/radiology.190.3.8115663MoreSectionsPDF ToolsAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookXLinked In Article HistoryPublished in print: 1994 FiguresReferencesRelatedDetailsRecommended Articles RSNA Education Exhibits RSNA Case Collection Vol. 190, No. 3 Metrics Altmetric Score PDF download

Previous studies have shown, that for log phase cultures, tumorigenic segregants of HeLa x skin fibroblast human hybrid cells are slightly more radiosensitive in terms of cell killing than their nontumorigenic parents (Redpath et al. 1985, Colman et al. 1988). Other studies have shown that these same tumorigenic segregants exhibit a markedly enhanced G2 chromosomal radiosensitivity (Sanford et al. 1986) thus offering a possible explanation for the cell killing data. The present study set out to examine the G2-phase radiosensitivity of these cells in terms of cell killing with the expectation that an enhanced sensitivity in the tumorigenic cells would be seen. No enhanced sensitivity was observed. The G2 chromosomal radiosensitivity was then examined and no differential was seen between the non-tumorigenic and tumorigenic cells. This lack of confirmation of previously reported studies may be due to some technical differences in the experimental protocols.

In order to precisely define the sequences that constitute the ras-responsive enhancers element present in the murine retrotransposon NVL3, point mutations were introduced into the previously defined minimal transcriptional enhancer DNA. Analyses of the effects of these point mutations in transient transfection experiments, in gel retention assays, and by methylation interference footprinting indicated that the enhancer element was composed of two binding sites for distinct nuclear factors. Both binding sites were required for activation of the enhancer by either ras or v-fms oncogenes, and the distinct nuclear factors were found in extracts from cells that contained either oncogene. UV cross-linking analysis revealed that the AP1-related binding site, TGACTCT, was recognized by a nuclear factor of apparent molecular size of 50 kilodaltons, that is probably c-jun. The other binding site, CAGGATAT, is very similar to sites recognized by the ets-family of transcription factors, and was recognized by the 120-kilodalton ras-responsive factor-1. Activation of the NVL3 element was reconstituted in an in vitro transcription assay. The ets-related binding site was necessary for this in vitro reconstitution of activity. Thus, the NVL3 enhancer is related to the previously described oncogene-responsive enhancer element present in polyoma virus and is also related to elements identified in several cellular genes known to be ras-responsive, including the transforming growth factor-beta 1 gene.

Sixteen patients with advanced epithelial ovarian cancer who were treated with cytoreductive surgery followed by multiagent chemotherapy were found to have residual tumor masses less than 2 cm in greatest diameter at reexploration and were treated with whole-abdominal radiation (19–31 Gy). Thirteen patients also received pelvic boosts to a total pelvic dose of 41–53.7 Gy. Radiotherapy was completed in all but 2 patients after treatment delays in 7 patients. Early treatment complications included myelosuppression in 11 patients, diarrhea in 3, and a self-limited small bowel obstruction in one. Delayed complications were severe and included 9 patients with radiation enterocolitis, 8 of whom required intestinal resection or diversion. One additional patient with radiation cystitis required instillation of formalin to control bleeding. Two patients are without evidence of disease 28 and 30 months following radiotherapy, while the remaining 14 patients have recurred after a median progression-free interval of 9 months (range 1–30 months). All patients who recurred failed within the treatment field and died of cancer after a median interval of 19 months following radiotherapy and 9 months after documentation of progression. These data suggest that few patients with persistent ovarian cancer following surgery and chemotherapy will be salvaged with radiotherapy.

215 patients with stage III Hodgkin's disease (HD) were treated at the Royal Marsden Hospital between 1963 and 1985 (median follow-up 9 years). The actuarial 5- and 10-year survival was 77 and 65%, respectively with 55 and 48% 5 and 10 year disease-free survival. Of 13 variables tested, age was the only independent prognostic indicator for survival on multivariate analysis. Patients aged under 40, 40-59 and over 60 years had a 10-year survival of 76, 41 and 8%, respectively (p much less than 0.001). Ninety-one patients were initially treated with combined chemotherapy and radiotherapy (combined modality therapy, CMT), 73 patients with radiotherapy (RT) and 51 patients with chemotherapy (CT) alone. Patients under 40 years treated with CMT achieved the best disease-free survival (10 year disease-free survival: CMT 68%; RT 38%; CT 45%). The observed survival advantage for CMT was not statistically significant. In patients aged greater than 40 there was no survival or disease-free survival advantage following CMT. Analysis of recurrence pattern confirmed that CMT improves initial disease control both at previously involved and uninvolved sites. Recurrences at previously uninvolved sites continued up to 6 years following CT, up to 8 years following CMT and up to 14 years after RT alone. These results indicate that only long-term follow-up gives the true picture of stage III HD.

The neoplastic transformation of human cell hybrids (HeLa x skin fibroblasts) is accompanied by the expression of a cell surface protein for which monoclonal antibodies have been raised. The gamma-radiation-induced neoplastic transformation of these cells has been studied where the expression of this cell surface protein, as detected by immunoperoxidase staining, has been used as an end point. The yield of foci of positively staining cells has been shown to increase with increasing time postirradiation at which the assay is done and decrease with increasing density of viable cells plated postirradiation. The time of plating postirradiation is also an important parameter with transformation frequencies increasing over the first 6 h of postirradiation holding at confluence, followed by a gradual decrease.