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David E Wazer

Publications and source records attributed to David E Wazer.

At least 19 recordsLinked to original sources
PubMed2006

The HBP1 transcriptional repressor participates in RAS-induced premature senescence.

Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Previous work shows that RAS and p38 MAPK participate in premature senescence, but transcriptional effectors have not been identified. Here, we demonstrate that the HBP1 transcriptional repressor participates in RAS- and p38 MAPK-induced premature senescence. In cell lines, we had previously isolated HBP1 as a retinoblastoma (RB) target but have determined that it functions as a proliferation regulator by inhibiting oncogenic pathways as a transcriptional repressor. In primary cells, the results indicate that HBP1 is a necessary component of premature senescence by RAS and p38 MAPK. Similarly, a knockdown of WIP1 (a p38 MAPK phosphatase) induced premature senescence that also required HBP1. Furthermore, HBP1 requires regulation by RB, in which few transcriptional regulators for premature senescence have been shown. Together, the data suggest a model in which RAS and p38 MAPK signaling engage HBP1 and RB to trigger premature senescence. As an initial step toward clinical relevance, a bioinformatics approach shows that the relative expression levels of HBP1 and WIP1 correlated with decreased relapse-free survival in breast cancer patients. Together, these studies highlight p38 MAPK, HBP1, and RB as important components for a premature-senescence pathway with possible clinical relevance to breast cancer.

Binding Sites↗
PubMed2006

Dose-modeling study to compare external beam techniques from protocol NSABP B-39/RTOG 0413 for patients with highly unfavorable cardiac anatomy.

PURPOSE: The aim of this study was to select patients with heart anatomy that is specifically unfavorable for tangential irradiation in whole-breast radiotherapy (WBRT), to be used as an experimental cohort to compare cardiac dosimetric and radiobiological parameters of three-dimensional conformal external beam accelerated partial breast irradiation (3D-CRT APBI) to WBRT with techniques as defined by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 clinical trial. METHODS AND MATERIALS: A dosimetric modeling study that compared WBRT and 3D-CRT APBI was performed on CT planning data from 8 patients with left-sided breast cancer. Highly unfavorable cardiac anatomy was defined by the measured contact of the myocardium with the anterior chest wall in the axial and para-sagittal planes. Treatment plans of WBRT and 3D-CRT APBI were generated for each patient in accordance with NSABP B-39/RTOG 0413 protocol. Dose-volume relationships of the heart, including the V5min (minimum dose delivered to 5% of the cardiac volume), biological effective dose (BED) of the V5min, and normal tissue complication probability (NTCP) were analyzed and compared. RESULTS: Despite expected anatomic variation, significantly large differences were found favoring 3D-CRT APBI in cumulative dose-volume histograms (p < 0.01), dose to the entire heart (mean difference 3.85 Gy, p < 0.01), NTCP (median difference, 1.00 Gy; p < 0.01), V5min (mean difference, 24.53 Gy; p < 0.01), and proportional reduction in radiobiological effect on the V5min (85%, p < 0.01). CONCLUSIONS: Use of 3D-CRT APBI can demonstrate improved sparing of the heart in select patients with highly unfavorable cardiac anatomy for WBRT, and may result in reduced risk of cardiac morbidity and mortality.

Breast Neoplasms↗
PubMed2006

Tumor bed boost omission after negative re-excision in breast-conservation treatment.

BACKGROUND: We evaluated the necessity of a tumor bed boost after whole-breast radiotherapy for early-stage breast cancer after breast-conserving surgery and negative re-excision. METHODS: Of patients treated at the Virginia Commonwealth and Tufts Universities with breast-conservation therapy for early-stage breast cancer between 1983 and 1999, 205 required re-excision of the tumor cavity to obtain clear margins and were found to be without residual disease. Adjuvant conventionally fractionated whole-breast radiotherapy was given to a total dose of 50 Gy in 25 fractions. The tumor bed boost was omitted. RESULTS: The median follow-up was 98 months (range, 6-229 months). The tumor histological diagnosis was primarily infiltrating ductal carcinoma (183 cases; 89%). Nodal involvement was documented in 49 cases (24%). There were four documented recurrences at the tumor bed site. Five in-breast recurrences were documented to be in a location removed from the tumor bed. The overall Kaplan-Meier 15-year in-breast control rate was 92.4%, and the freedom from true recurrence rate was 97.6%. CONCLUSIONS: The findings support the concept that postlumpectomy radiotherapy can be tailored according to the degree of surgical resection. There is an easily identifiable subgroup of patients who can avoid a tumor bed boost, thus resulting in a reduced treatment time and improved cosmesis, while maintaining local control rates that approach 100%. The data suggest that in patients who undergo a negative re-excision, treatment with whole-breast radiotherapy to 50 Gy is a sufficient dose to maximally reduce the risk of local recurrence.

Adult↗
PubMed2006

Persistent seroma after intraoperative placement of MammoSite for accelerated partial breast irradiation: incidence, pathologic anatomy, and contributing factors.

PURPOSE: To investigate the incidence of, and possible factors associated with, seroma formation after intraoperative placement of the MammoSite catheter for accelerated partial breast irradiation. METHODS AND MATERIALS: This study evaluated 38 patients who had undergone intraoperative MammoSite catheter placement at lumpectomy or reexcision followed by accelerated partial breast irradiation with 34 Gy in 10 fractions. Data were collected regarding dosimetric parameters, including the volume of tissue enclosed by the 100%, 150%, and 200% isodose shells, dose homogeneity index, and maximal dose at the surface of the applicator. Clinical and treatment-related factors were analyzed, including patient age, patient weight, history of diabetes and smoking, use of reexcision, interval between surgery and radiotherapy, total duration of catheter placement, total excised specimen volume, and presence or absence of postprocedural infection. Seroma was verified by clinical examination, mammography, and/or ultrasonography. Persistent seroma was defined as seroma that was clinically detectable >6 months after radiotherapy completion. RESULTS: After a median follow-up of 17 months, the overall rate of any detectable seroma was 76.3%. Persistent seroma (>6 months) occurred in 26 (68.4%) of 38 patients, of whom 46% experienced at least modest discomfort at some point during follow-up. Of these symptomatic patients, 3 required biopsy or complete cavity excision, revealing squamous metaplasia, foreign body giant cell reaction, fibroblasts, and active collagen deposition. Of the analyzed dosimetric, clinical, and treatment-related variables, only body weight correlated positively with the risk of seroma formation (p = 0.04). Postprocedural infection correlated significantly (p = 0.05) with a reduced risk of seroma formation. Seroma was associated with a suboptimal cosmetic outcome, because excellent scores were achieved in 61.5% of women with seroma compared with 83% without seroma. CONCLUSION: Intraoperative placement of the MammoSite catheter for accelerated partial breast irradiation is associated with a high rate of clinically detectable seroma that adversely affects the cosmetic outcome. The seroma risk was positively associated with body weight and negatively associated with postprocedural infection.

Adult↗
PubMed2006

Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1.

Genetic and biochemical de-regulation of Wnt signaling is correlated with breast and other cancers. Our goal was to identify compounds that block Wnt signaling as a first step toward investigating new strategies for suppression of invasive and other breast cancers. In a limited phytonutrient screen, EGCG ((-)-epigallocatechin 3-gallate), the major phytochemical in green tea, emerged as an intriguing candidate. Epidemiological studies have associated green tea consumption with reduced recurrence of invasive and other breast cancers. Wnt signaling was inhibited by EGCG in a dose-dependent manner in breast cancer cells. The apparent mechanism targeted the HBP1 transcriptional repressor, which we had previously characterized as a suppressor of Wnt signaling. EGCG treatment induced HBP1 transcriptional repressor levels through an increase in HBP1 mRNA stability, but not transcriptional initiation. To test functionality, DNA-based short hairpin RNA (shRNA) was used to knockdown the endogenous HBP1 gene. Consistently, the HBP1 knockdown lines had reduced sensitivity to EGCG in the suppression of Wnt signaling and of a target gene (c-MYC). Because our ongoing studies clinically link abrogation of HBP1 with invasive breast cancer, we tested if EGCG also regulated biological functions associated with de-regulated Wnt signaling and with invasive breast cancer. EGCG reduced both breast cancer cell tumorigenic proliferation and invasiveness in an HBP1-dependent manner. Together, the emerging mechanism is that EGCG blocks Wnt signaling by inducing the HBP1 transcriptional repressor and inhibits aspects of invasive breast cancer. These studies provide a framework for considering future studies in breast cancer treatment and prevention.

Blotting, Western↗
PubMed2006

Human kallikrein 10, a predictive marker for breast cancer.

Our laboratory is involved in identifying genes that can be used as early diagnostic or prognostic markers in breast cancer. We previously identified a gene (NES1) that is expressed in normal but not in transformed mammary epithelial cells (MECs). NES1 is located on chromosome 19q13.4 within the kallikrein locus and thus was designated as human kallikrein 10 (hK10), although we have been unable to detect any protease activity. Importantly, hK10 expression is decreased in a majority of breast cancer cell lines. Transfection of hK10 into hK10-negative breast cancer cells reduces the tumorigenicity. Using methylation-specific PCR and subsequent sequencing, we demonstrate a strong correlation between hypermethylation of hK10 and loss of mRNA expression. Further analysis showed that essentially 100% of normal breast specimens had hK10 expression, whereas 46% of ductal carcinoma in situ (DCIS) and the majority of infiltrating ductal carcinoma (IDC) samples lacked the hK10 mRNA. Importantly, hK10-negative DCIS diagnosed at the time of biopsy were subsequently diagnosed as IDC at the time of definitive surgery. It has been shown that hK10 protein expression is regulated by steroids. In addition to breast cancers, hK10 is downregulated in cervical cancer, prostate cancer and acute lymphocytic leukemia, whereas it is upregulated in ovarian cancers. These results point to the paradoxical role of hK10 in human cancers and underscore the importance of further studies of this kallikrein.

Biomarkers, Tumor↗
PubMed2006

The human kallikrein 10 promoter contains a functional retinoid response element.

Human kallikrein 10 (hK10) protein is expressed in normal breast but is significantly downregulated in a majority of invasive breast cancers. Thus, understanding how hK10 expression is regulated is of substantial significance. In this study, we analyzed the promoter region of hK10 using a website software (TRANSFAC 3.0), which predicted three possible retinoic acid response elements (RAREs), RARE1 at -1041 (TGACCTCGTGATCC), RARE2 at -859 (TGACCTCCTATGA) and RARE3 at -765 (TGACCTCCTGTGA), each with a half-site of a canonical sequence (TGACCT; reverse complement AGGTCA). Using electrophoretic mobility shift assays and nucleotide competition analysis, as well as chromatin immunoprecipitation of the native hK10 promoter, we demonstrated specific binding of RXR only to RARE1. The functional importance of RARE in the hK10 promoter was demonstrated by retinoid induction of hk10 promoter-reporters; furthermore, mutation of RARE1 but not of RARE2 or RARE3 abolished the induction of the reporter. Finally, we demonstrated the induction of hK10 mRNA and protein expression upon retinoid treatment of cells. In view of the correlation of the downregulation of hK10 mRNA and protein with breast cancer progression, these findings suggest a potential approach to restore hK10 expression in cancer patients.

Gene Expression Regulation, Neoplastic↗
PubMed2005

Centrobin: a novel daughter centriole-associated protein that is required for centriole duplication.

In mammalian cells, the centrosome consists of a pair of centrioles and amorphous pericentriolar material. The pair of centrioles, which are the core components of the centrosome, duplicate once per cell cycle. Centrosomes play a pivotal role in orchestrating the formation of the bipolar spindle during mitosis. Recent studies have linked centrosomal activity on centrioles or centriole-associated structures to cytokinesis and cell cycle progression through G1 into the S phase. In this study, we have identified centrobin as a centriole-associated protein that asymmetrically localizes to the daughter centriole. The silencing of centrobin expression by small interfering RNA inhibited centriole duplication and resulted in centrosomes with one or no centriole, demonstrating that centrobin is required for centriole duplication. Furthermore, inhibition of centriole duplication by centrobin depletion led to impaired cytokinesis.

Amino Acid Sequence↗
PubMed2005

Accelerated partial breast irradiation: an analysis of variables associated with late toxicity and long-term cosmetic outcome after high-dose-rate interstitial brachytherapy.

PURPOSE: To perform a detailed analysis of variables associated with late tissue effects of high-dose-rate (HDR) interstitial brachytherapy accelerated partial breast irradiation (APBI) in a large cohort of patients with prolonged follow-up. METHODS AND MATERIALS: Beginning in 1995, 75 women with Stage I/II breast cancer were enrolled in identical institutional trials evaluating APBI as monotherapy after lumpectomy. Patients eligible included those with T1-2, N0-1 (<or=3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular nodal extension, and negative results on postexcision mammogram. All patients underwent surgical excision and postoperative irradiation with HDR interstitial brachytherapy. The planning target volume was defined as the excision cavity plus a 2-cm margin. Treatment was delivered with a high-activity Ir-192 source at 3.4 Gy per fraction twice daily for 5 days to a total dose of 34 Gy. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. All patients were evaluated at 3-6-month intervals and assessed with a standardized cosmetic rating scale and according to Radiation Therapy Oncology Group late normal tissue toxicity scoring criteria. Clinical and therapy-related features were analyzed for their relationship to cosmetic outcome and toxicity rating. Clinical features analyzed included age, volume of resection, history of diabetes or hypertension, extent of axillary surgery, and systemic therapies. Therapy-related features analyzed included volume of tissue encompassed by the 100%, 150%, and 200% isodose lines (V100, V150, and V200, respectively), the dose homogeneity index (DHI), number of source dwell positions, and planar separation. RESULTS: The median follow-up of all patients was 73 months (range, 43-118 months). The cosmetic outcome at last follow-up was rated as excellent, good, and fair/poor in 67%, 24%, and 9% of patients, respectively. Suboptimal cosmetic outcome was significantly associated with the number of source dwell positions, V150, and V200 and inversely associated with DHI (0.77 vs. 0.73; p=0.05). Late skin toxicity was rated as Grade 0, 1, or 2 in 77%, 19%, and 4% of patients, respectively. The risk of Grade 1/2 skin toxicity was significantly associated with V150 and V200 and inversely associated with DHI (0.77 vs. 0.71; p=0.009). Late subcutaneous toxicity was rated as Grade 0, 1, 2, 3, or 4 in 55%, 15%, 12%, 5%, and 13% of patients, respectively. The risk of Grade 0/1 vs. Grade 2-4 subcutaneous toxicity was significantly associated only with a lower value of DHI (0.77 vs. 0.73; p=0.02). To further explore factors that might contribute to the risk of fat necrosis (symptomatic or asymptomatic), a separate analysis showed that only dose hotspots as reflected in V150 and V200 were significantly associated with elevated risk. The use of adriamycin-based chemotherapy after APBI was found to be associated with a significant increase in the incidence of higher-grade skin toxicity and a higher risk of fat necrosis and suboptimal cosmetic outcome. Patient age, volume of resection, extent of axillary surgery, a history of diabetes or hypertension, and the use of tamoxifen were not found to be significantly associated with cosmetic outcome or late normal tissue complications. CONCLUSIONS: Long-term cosmetic results and the risk of late skin and subcutaneous toxicity after APBI with interstitial HDR brachytherapy can be correlated with specific treatment-related variables. These data provide dosimetric parameters that might be used to minimize the risk of normal tissue injury after APBI interstitial brachytherapy.

Adipose Tissue↗
PubMed2005

MammoSite excision volume as a predictor for residual disease.

BACKGROUND: The MammoSite catheter is a brachytherapy device used for accelerated partial breast irradiation. Currently, it is available as 2 spherically shaped balloons meant to fill 70-cc and 120-cc cavity volumes. This study was designed to define the relation of these excision volumes to the likelihood of microscopically detectable, residual disease based on tumor size, margin status, patient age, and histology. METHODS: The study data base was comprised of 531 patients with Stage 0, I, and II breast carcinoma (using American Joint Committee on Cancer staging criteria) who received breast-conserving therapy and underwent surgical reexcision. Patients in the data base were stratified based on the volume of their initial excision: < or = 70 cc versus > 70 cc and < or = 120 cc versus > 120 cc. RESULTS: Surgical margin size was found to be a strong predictor of residual disease both for patients with smaller excision volumes (P = 0.0014) and patients with larger excision volumes (P = 0.0003); histology (extensive intraductal component [EIC] or pure ductal carcinoma in situ [DCIS]) also was a strong predictor. Tumor size was significant only for the larger volume group (P = 0.029). On multivariate analysis, only histology and initial margin status were significant correlates with residual disease. The adjusted odds ratio for residual disease with pure DCIS was 0.79, and the adjusted odds ratio for invasive ductal or lobular carcinoma (IDC/ILC) without EIC was 0.44 relative to IDC/ILC with EIC (P = 0.008). The adjusted odds ratio for residual disease with a positive initial margin versus a negative initial margin was 2.65 (P < or = 0.0001). CONCLUSIONS: For excisions amenable to use of the MammoSite catheter, a margin > or = 1.0 mm appeared to afford at most a 35% risk of microscopically detectable residual tumor. Evidence of EIC on excision of IDC/ILC connoted a significantly higher risk. Age did not appear to be predictive for residual disease.

Adult↗
PubMed2005

The MammoSite balloon brachytherapy catheter for accelerated partial breast irradiation.

Whole-breast irradiation after lumpectomy for early-stage breast cancer appears to prevent relapse only at the site of initial involvement, and therefore it is likely that radiation can safely be limited to tissues immediately surrounding the excision cavity. Accelerated partial-breast irradiation (APBI) with the MammoSite catheter (Proxima Therapeutics, Alpharetta, GA) has been proposed as a means through which APBI can be offered to a wide range of patients. Although sufficient follow-up is not yet available regarding local control, survival, late toxicity, and long-term cosmetic results, early results are promising. This article reviews the current literature reflecting treatment, dose optimization, outcomes, and toxicity of APBI with the MammoSite brachytherapy catheter.

Brachytherapy↗
PubMed2005

A radiobiological model for the relative biological effectiveness of high-dose-rate 252Cf brachytherapy.

While there is significant clinical experience using both low- and high-dose-rate 252Cf brachytherapy, there are minimal data regarding values for the neutron relative biological effectiveness (RBE) with both modalities. The aim of this research was to derive a radiobiological model for 252Cf neutron RBE and to compare these results with neutron RBE values used clinically in Russia. The linear-quadratic (LQ) model was used as the basis to characterize cell survival after irradiation, with identical cell killing rates (S(N) = S(gamma)) between 252Cf neutrons and photons used for derivation of RBE. Using this equality, a relationship among neutron dose and LQ radiobiological parameter (i.e., alpha(N), beta(N), alpha(gamma), beta(gamma)) was obtained without the need to specify the photon dose. These results were used to derive the 252Cf neutron RBE, which was then compared with Russian neutron RBE values. The 252Cf neutron RBE was determined after incorporating the LQ radiobiological parameters obtained from cell survival studies with fast neutrons and teletherapy photons. For single-fraction high-dose-rate neutron doses of 0.5, 1.0, 1.5 and 2.0 Gy, the total biologically equivalent doses were 1.8, 3.4, 4.7 and 6.0 RBE Gy with 252Cf neutron RBE values of 3.2, 2.9, 2.7 and 2.5, respectively. Using clinical data for late-responding reactions from 252Cf, Russian investigators created an empirical model that predicted high-dose-rate 252Cf neutron RBE values ranging from 3.6 to 2.9 for similar doses and fractionation schemes and observed that 252Cf neutron RBE increases with the number of treatment fractions. Using these relationships, our results were in general concordance with high-dose-rate 252Cf RBE values obtained from Russian clinical experience.

Animals↗
PubMed2004

Human ADA3 binds to estrogen receptor (ER) and functions as a coactivator for ER-mediated transactivation.

We have recently identified the hADA3 protein, the human homologue of yeast transcriptional coactivator yADA3, as a novel HPV16 E6 target. Using ectopic expression approaches, we further demonstrated that hADA3 directly binds to the 9-cis retinoic acid receptors alpha and beta, and functions as a coactivator for retinoid receptor-mediated transcriptional activation. Here, we examined the role of endogenous hADA3 as a coactivator for estrogen receptor (ER), an important member of the nuclear hormone receptor superfamily. We show that ADA3 directly interacts with ER alpha and ER beta. Using the chromatin immunoprecipitation assay, we also show that hADA3 is a component of the activator complexes bound to the native ER response element within the promoter of the estrogen-responsive gene pS2. Furthermore, using an ER response element-luciferase reporter, we show that overexpression of ADA3 enhances the ER alpha- and ER beta-mediated sequence-specific transactivation. Reverse transcription-PCR analysis showed an ADA3-mediated increase in estrogen-induced expression of the endogenous pS2 gene. More importantly, using RNA interference against hADA3, we demonstrate that inhibition of endogenous hADA3 inhibited ER-mediated transactivation and the estrogen-induced increase in the expression of pS2, cathepsin D, and progesterone receptor, three widely known ER-responsive genes. The HPV E6 protein, by targeting hADA3 for degradation, inhibited the ER alpha-mediated transactivation and the protein expression of ER target genes. Thus, our results demonstrate that ADA3 directly binds to human estrogen receptor and enhances the transcription of ER-responsive genes, suggesting a broader role of mammalian hADA3 as a coactivator of nuclear hormone receptors and the potential role of these pathways in HPV oncogenesis.

Cathepsin D↗
PubMed2004

MammoSite and interstitial brachytherapy for accelerated partial breast irradiation: factors that affect toxicity and cosmesis.

BACKGROUND: In interstitial brachytherapy (IB), cosmesis and toxicity correlate with volume of tissue irradiated, dose homogeneity index (DHI), and adjuvant doxorubicin/cyclophosphamide based chemotherapy (ACCT). MammoSite brachytherapy (MSB) irradiates smaller volumes than IB, and lower dose homogeneity does not appear to affect toxicity. However, clinical experience suggests that other factors may also play an important role in cosmesis and toxicity with MSB. We reviewed our prospectively maintained data base of women who underwent accelerated partial breast irradiation (APBI) to assess this issue. METHODS: Beginning in September 1995, 115 women were enrolled in a trial evaluating APBI as monotherapy after lumpectomy. The first 75 eligible patients received IB, and the most recent 28 eligible patients received MSB. All patients received 34 gray (Gy) in 10 twice-daily fractions through high-dose rate iridium-192 brachytherapy; 19% of patients in the IB group and 0% of patients in the MSB group received ACCT. RESULTS: At 1 year after treatment, MSB caused significantly less Grade 2-4 subcutaneous fibrosis (as graded by a radiation oncologist according to the Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group system) compared with IB (10.7% vs. 32%; P = 0.04). However, when only ACCT-naïve patients in the IB group were compared with patients in the MSB group, this finding became nonsignificant. Among the patients who received MSB, significantly smaller volumes were irradiated, and the DHI was lower. CONCLUSIONS: Current studies suggest an improved toxicity profile with MSB compared with IB that is attributed to lower irradiated volumes with MSB. When only chemotherapy-naïve patients were compared, however, toxicity and cosmesis were found to be similar between MSB and IB, suggesting a more complex interplay between irradiated volumes, DHI, and chemotherapy. The relation of ACCT to toxicity in this scenario is intriguing and warrants further investigation.

Aged↗
PubMed2004

Analysis of dose conformity and normal-tissue sparing using two different IMRT prescription methodologies for irregularly shaped CNS lesions irradiated with the Beak and 1-cm MIMiC collimators.

PURPOSE: To determine whether intensity modulated sequential tomotherapy using the NOMOS Beak provides superior dose conformity and organ sparing to the MIMiC "1-cm" mode, and if so, to identify a subset of patients most likely to benefit from Beak intensity modulated sequential tomotherapy. METHODS AND MATERIALS: Twelve patients with irregularly shaped central nervous system tumors were selected for intensity modulated radiation therapy planning. Two treatment plans, one using the Beak collimator and the other using the 1-cm MIMiC collimator, were generated for each patient with identical anatomic contouring, prescriptions, and optimization algorithms. The Beak attaches to the MIMiC collimator and truncates the 1-cm MIMiC mode beamlet size from 1.00 x 0.85 cm(2) to 1.00 x 0.39 cm(2) at isocenter. Conformity indexes were calculated for each lesion using two different prescription methodologies, and mean doses to critical structures were recorded. RESULTS: For the first prescription methodology using uniform prescribed isodose, mean conformity index was 2.19 (range, 1.33-3.90) for the Beak compared to 2.67 (range, 1.64-4.75) for the 1-cm mode (p = 0.0003). Mean doses to the brainstem, right orbit, and left optic nerve were significantly lower with the Beak than with the 1-cm mode (p = 0.0150, 0.0068, and 0.0284, respectively). For the second prescription methodology using uniform target volume coverage prescription, mean conformity index was 2.04 (range, 1.56-2.70) for the Beak compared to 2.73 (range, 1.70-8.58) for the 1-cm mode (p = 0.07). Mean doses to the brain, brainstem, optic chiasm, right optic nerve, left optic nerve, and left orbit were significantly lower with the Beak than with the 1-cm mode (p = <0.0001, <0.0026, <0.0016, <0.0076, <0.0007, and <0.046, respectively). CONCLUSION: Beak intensity modulated sequential tomotherapy is superior to the 1-cm MIMiC mode for irregularly shaped central nervous system tumors, because it provides better conformity and critical organ sparing. These differences may allow for safer dose escalation and retreatment, so the method presents an alternative to gamma knife stereotactic radiosurgery.

Algorithms↗