Comparing Cyclic Fatigue Resistance and Free Recovery Transformation Temperature of NiTi Endodontic Single-File Systems Using a Novel Testing Setup.

The aim of this study was to assess the effect of body temperature (37 °C) on the cyclic fatigue resistance of three endodontic single-file systems using a new testing setup. One Shape® new generation (OS), WaveOne™ (WO) and WaveOne® GOLD (WOG), which are made from different NiTi alloys and operated in different motions (rotation/reciprocation), were evaluated. The study design included four groups. Each group comprised 30 files, 10 files of each of the three file systems, tested at 20 ± 2 °C (group 1 and 3) and at 37 ± 1 °C (group 2 and 4). All files were tested in a custom-made metal block with artificial canals of 60° angle, and a 5 mm and 3 mm radius of curvature, respectively. A heating element was attached to replicate a temperature of 37 °C. Files were introduced 18 mm into the canals and operated until failure. Transformation temperatures of five samples of each of the tested file systems were determined via the bend and free recovery (BFR) method. With the exception of WOG in canals with a 3 mm radius of curvature (p = 0.075), all the tested file systems showed statistically significantly less time needed to fracture when operated at 37 ± 1 °C compared to at 20 ± 2 °C in canals with a 5 mm and 3 mm radius of curvature using Mann-Whitney U test (p < 0.05). All file systems showed transformation temperatures below the body temperature. We concluded that body temperature directly affects the cyclic fatigue resistance of all tested file systems. Bend and free recovery can be suitable for the determination of austenite finish temperatures (Af) of endodontic instruments as it allows testing a longer portion of the instrument.

Management of Teeth with Grade 3 Endo-Periodontal Lesions by Combined Endodontic and Regenerative Periodontal Therapy.

(1) Background: Severely compromised teeth affected by endo-periodontal lesions are often assigned a "hopeless" prognosis, however, there is only limited evidence available. (2) Methods: In a retrospective study, we evaluated the long-term effectiveness of combined endodontic and regenerative periodontal therapy in teeth with advanced endo-periodontal lesions: 35 patients (age 47-83 years) with a total of 39 teeth diagnosed with grade 3 endo-periodontal lesions were treated by endodontists using an operating microscope followed by regenerative periodontal surgery. (3) Results: Changes in radiographic bone levels (rBl) and probing pocket depths (PPDs) were evaluated after 1 year (T1) and up to 7 years postoperatively (Tfinal). Mean rBL gain was significant with 4.87 ± 3.47 mm after 1 year (T1) and stable results with a mean rBL gain of 4.70 ± 3.37 mm at Tfinal. Mean PPD was significantly reduced from 9.74 ± 2.05 mm at baseline to 5.04 ± 1.61 mm at T1 and to 4.87 ± 2.32 mm at Tfinal. Tooth loss amounted to 10.3% (n = 4) and was due to root fracture. (4) Conclusion: The results suggest that the combined endodontic and regenerative periodontal therapy of endo-periodontal lesions of "hopeless" teeth can lead to favorable long-term results with tooth retention for up to 7 years.

Germline polymorphisms in MGMT associated with temozolomide-related myelotoxicity risk in patients with glioblastoma treated on NRG Oncology/RTOG 0825.

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Resection and Surgically Targeted Radiation Therapy for the Treatment of Larger Recurrent or Newly Diagnosed Brain Metastasis: Results From a Prospective Trial.

Introduction Achieving durable local control (LC) for larger (e.g., >2-3 cm) brain metastasis whether newly diagnosed or recurrent remains problematic. Resection (R) alone is typically insufficient and adding radiation therapy (RT) still results in a 12-month recurrence rate of 20% or more in many series. Hypothesizing that R plus immediate radiation utilizing brachytherapy may improve outcomes for this cohort of patients, we designed and prospectively evaluated a permanently implanted surgically targeted radiation therapy (STaRT) device consisting of cesium-131 (Cs-131) seeds positioned within a collagen carrier (GammaTile, GT Medical Technologies, Tempe, AZ). The device was designed to prevent direct source-to-brain contact and maintain inter-source spacing after closure. Methods This was a subgroup analysis of a cohort of patients with either recurrent or previously untreated brain metastases enrolled in a prospective, multi-histology single-arm trial (ClinicalTrials.gov, NCT#03088579), conducted between February 2013 and February 2018, of resection and tumor bed brachytherapy with Cs-131 containing permanently implanted collagen tiles to deliver 60 Gray (Gy) at .5 cm depth. No additional local therapy was given without progression. Results A total of 16 metastases in 11 patients were treated; 12 tumors were recurrent and four were previously untreated. The median preoperative maximum diameter was 3.2 cm (range: 1.9-5.1 cm). Histology was seven breasts, six lungs, and three sarcomas. The median age was 60 years (range: 41-80 years); the Karnofsky Performance Status (KPS) was 70 (range: 70-90). The cohort consisted of seven females and four males. The mean time for implantation completion was five minutes. The median overall survival (OS) was 9.3 months. At a median radiographic follow-up of 9.5 months' treatment, site progression was found in 1/16 (6%) at 10.9 months, and the median treatment site time-to-progression (TTP) has not been reached [95% confidence interval (CI): >10.9 months]. At 12 months, the Kaplan-Meier (K-M) estimates for LC after R+STaRT for all tumors was 83%; for previously untreated tumors, LC at 12 months was 100% and for recurrent tumors, it was 80%. Two tumor beds (12.5%) experienced radiation brain changes: one had grade two and the other grade three. No surgical adverse events occurred. Conclusion In this single-arm precommercial study, R+STaRT demonstrated excellent safety and LC in this cohort. The device has recently received FDA clearance for use in newly diagnosed and recurrent brain metastasis, and randomized clinical trials vs. standard of care treatments in both settings are scheduled to open in 2020.

High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539.

BACKGROUND: Phase 2 cooperative group meningioma trial assessing the safety and efficacy of risk-adaptive management strategies. This is the initial analysis of the high-risk cohort. METHODS AND MATERIALS: High-risk patients were those with a new or recurrent World Health Organization (WHO) grade III meningioma of any resection extent, recurrent WHO grade II of any resection extent, or new WHO grade II after subtotal resection. Patients received intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique (60 Gy high dose and 54 Gy low dose in 30 fractions). Three-year progression-free survival (PFS) was the primary endpoint. Adverse events (AEs) were scored per NCI Common Terminology Criteria for Adverse Events version 3. RESULTS: Of 57 enrolled patients, 53 received protocol treatment. Median follow-up was 4.0 years (4.8 years for living patients). Two patients withdrew without progression before year 3; for the remaining 51 patients, 3-year PFS was 58.8%. Among all 53 protocol-treated patients, 3-year PFS was 59.2%. Three-year local control was 68.9%, and overall survival was 78.6%. Of 51 patients, 1 patient (1.9%) experienced a late grade-5 necrosis-related AE. All other acute (23 of 53 patients) and late (21 of 51 patients) AEs were grades 1 to 3. CONCLUSIONS: Patients with high-risk meningioma treated with IMRT (60 Gy/30) experienced 3-year PFS of 58.8%. Combined acute and late AEs were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. These results support postoperative IMRT for high-risk meningioma and invite ongoing investigations to improve outcomes further.

Somatic mosaicism of androgen receptor CAG repeats in colorectal carcinoma epithelial cells from men.

BACKGROUND: The X-linked human androgen receptor gene (AR) contains an exonic polymorphic trinucleotide CAG. The length of this encoded CAG tract inversely affects AR transcriptional activity. Colorectal carcinoma is known to express the androgen receptor, but data on somatic CAG repeat lengths variations in malignant and normal epithelial cells are still sporadic. MATERIALS AND METHODS: Using laser capture microdissection (LCM), epithelial cells from colorectal carcinoma and normal-appearing mucosa were collected from the fresh tissue of eight consecutive male patients undergoing surgery (mean age, 70 y; range, 54-82). DNA isolated from each LCM sample underwent subsequent PCR and DNA sequencing to precisely determine AR CAG repeat lengths and the presence of microsatellite instability (MSI). RESULTS: Different AR CAG repeat lengths were observed in colorectal carcinoma (ranging from 0 to 36 CAG repeats), mainly in the form of multiple shorter repeat lengths. This genetic heterogeneity (somatic mosaicism) was also found in normal-appearing colorectal mucosa. Half of the carcinoma cases examined tended to have a higher number of AR CAG repeat lengths with a wider range of repeat size variation compared to normal mucosa. MSI carcinomas tended to have longer median AR CAG repeat lengths (n = 17) compared to microsatellite stable carcinomas (n = 14), although the difference was not significant (P = 0.31, Mann-Whitney test). CONCLUSIONS: Multiple unique somatic mutations of the AR CAG repeats occur in colorectal mucosa and in carcinoma, predominantly resulting in shorter alleles. Colorectal epithelial cells carrying AR alleles with shorter CAG repeat lengths may be more androgen-sensitive and therefore have a growth advantage.

Long-term outcome data from 121 patients treated with Gamma Knife stereotactic radiosurgery as salvage therapy for focally recurrent high-grade gliomas.

INTRODUCTION: We examined patient outcomes after Gamma Knife stereotactic radiosurgery (GKSRS) salvage therapy for recurrent high-grade gliomas (HGGs) to determine whether tumor grade or lesion size affected overall survival (OS) and progression-free survival (PFS). METHODS: This single-center retrospective study assessed radiographic response and clinical outcomes following GKSRS salvage treatment of recurrent malignant gliomas (January 2005-March 2014). RESULTS: A total of 121 patients (67 female) with 132 tumors were treated. Median (range) PFS was 4.7 (3.9-5.4) months for the cohort, 6.8 (4.6-8.9) months for initial grade 2 tumors, 4.2 (1.9-6.5) months for initial grade 3 tumors, and 4.3 (3.7-4.9) months for initial grade 4 tumors. Patients with small lesions (≤6.7 cm3; n = 53) had significantly longer median (range) PFS (6.8 [4.8-8.8], P=0.02). CONCLUSIONS: GKSRS offers meaningful salvage therapy with minimal morbidity in appropriately selected patients with focally recurrent HGGs.

The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525.

BACKGROUND: Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m2 may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m2 was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed. METHODS: The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. Obesity was defined as a BMI ≥30. RESULTS: There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, P < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) P = .009 in spite of the lack of association between gender and BSA or BMI. CONCLUSION: TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.

Resection and permanent intracranial brachytherapy using modular, biocompatible cesium-131 implants: results in 20 recurrent, previously irradiated meningiomas.

OBJECTIVE: Effective treatments for recurrent, previously irradiated intracranial meningiomas are limited, and resection alone is not usually curative. Thus, the authors studied the combination of maximum safe resection and adjuvant radiation using permanent intracranial brachytherapy (R+BT) in patients with recurrent, previously irradiated aggressive meningiomas. METHODS: Patients with recurrent, previously irradiated meningiomas were treated between June 2013 and October 2016 in a prospective single-arm trial of R+BT. Cesium-131 (Cs-131) radiation sources were embedded in modular collagen carriers positioned in the operative bed on completion of resection. The Cox proportional hazards model with this treatment as a predictive term was used to model its effect on time to local tumor progression. RESULTS: Nineteen patients (median age 64.5 years, range 50-78 years) with 20 recurrent, previously irradiated tumors were treated. The WHO grade at R+BT was I in 4 (20%), II in 14 (70%), and III in 2 (10%) cases. The median number of prior same-site radiation courses and same-site surgeries were 1 (range 1-3) and 2 (range 1-4), respectively; the median preoperative tumor volume was 11.3 cm3 (range 0.9-92.0 cm3). The median radiation dose from BT was 63 Gy (range 54-80 Gy). At a median radiographic follow-up of 15.4 months (range 0.03-47.5 months), local failure (within 1.5 cm of the implant bed) occurred in 2 cases (10%). The median treatment-site time to progression after R+BT has not been reached; that after the most recent prior therapy was 18.3 months (range 3.9-321.9 months; HR 0.17, p = 0.02, log-rank test). The median overall survival after R+BT was 26 months, with 9 patient deaths (47% of patients). Treatment was well tolerated; 2 patients required surgery for complications, and 2 experienced radiation necrosis, which was managed medically. CONCLUSIONS: R+BT utilizing Cs-131 sources in modular carriers represents a potentially safe and effective treatment option for recurrent, previously irradiated aggressive meningiomas.

Investigating the Effect of Reirradiation or Systemic Therapy in Patients With Glioblastoma After Tumor Progression: A Secondary Analysis of NRG Oncology/Radiation Therapy Oncology Group Trial 0525.

PURPOSE: To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. METHODS AND MATERIALS: This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. RESULTS: The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). CONCLUSIONS: Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

Atypical Teratoid Rhabdoid Tumor: Two Case Reports and an Analysis of Adult Cases with Implications for Pathophysiology and Treatment.

We present the first quantitative analysis of atypical teratoid rhabdoid tumors (ATRT) in adults, including two patients from our own institutions. These are of interest as one occurred during pregnancy and one is a long-term survivor. Our review of pathological findings of 50 reported cases of adult ATRT leads us to propose a solely ectodermal origin for the tumor and that epithelial-mesenchymal transition (EMT) is a defining feature. Thus, the term ATRT may be misleading. Our review of clinical findings shows that ATRT tends to originate in mid-line structures adjacent to the CSF, leading to a high rate of leptomeningeal dissemination. Thus, we hypothesize that residual undifferentiated ectoderm in the circumventricular organs, particularly the pituitary and pineal glands, is the most common origin for these tumors. We note that if growth is not arrested soon after diagnosis, or after the first relapse/progression, death is almost universal. While typically rapidly fatal (as in our first case), long-term remission is possible (as in our second). Significant predictors of prognosis were the extent of resection and the use of chemotherapy. Glial differentiation (GFAP staining) was strongly associated with leptomeningeal metastases (chi-squared p = 0.02) and both predicted markedly worse outcomes. Clinical trials including adults are rare. ATRT is primarily a disease of infancy and radiotherapy is generally avoided in those aged less than 3 years old. Treatment options in adults differ from infants in that cranio-spinal irradiation is a viable adjunct to systemic chemotherapy in the adult population. Given the grave prognosis, this combined approach appears reasonable. As effective chemotherapy is likely to cause myelosuppression, we recommend that stem-cell rescue be available locally.

An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor. Nomograms are often used for individualized estimation of prognosis. This study aimed to build and independently validate a nomogram to estimate individualized survival probabilities for patients with newly diagnosed GBM, using data from 2 independent NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials. Methods: This analysis included information on 799 (RTOG 0525) and 555 (RTOG 0825) eligible and randomized patients with newly diagnosed GBM and contained the following variables: age at diagnosis, race, gender, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) methylation status, and survival (in months). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using the 0525 data and were independently validated using the 0825 data. Models were internally validated using 10-fold cross-validation, and individually predicted 6-, 12-, and 24-month survival probabilities were generated to measure the predictive accuracy and calibration against the actual survival status. Results: A final nomogram was built using the Cox proportional hazards model. Factors that increased the probability of shorter survival included greater age at diagnosis, male gender, lower KPS, not having total resection, and unmethylated MGMT status. Conclusions: A nomogram that assesses individualized survival probabilities (6-, 12-, and 24-mo) for patients with newly diagnosed GBM could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free software for implementing this nomogram is provided: http://cancer4.case.edu/rCalculator/rCalculator.html.

Feasibility of cranio-spinal axis radiation with the Hi-Art tomotherapy system.

BACKGROUND AND PURPOSE: Helical tomotherapy can eliminate the need for junction lines. The goal of this study is to evaluate tomotherapy in the delivery of CSA radiation and measurement of plan quality using physical parameters in comparing conventional (CSA-RT) and helical tomotherapy (CSA-TOMO) plans. PATIENTS AND METHODS: CSA-TOMO and CSA-RT plans were created for dosimetric comparison. Integral dose values were calculated. The ratios D50% (dose received by 50% of the organ at risk's volume) and D10% (dose received by 10% of the organ at risk's volume) were calculated representing large volumes and small volumes of organs at risk receiving significant dose. RESULTS: When considering D50% and D10%, CSA-TOMO has a dosimetric advantage over CSA-RT for most organs at risk. The body integral dose was higher for the CSA-TOMO plan by approximately 6.5%. CONCLUSIONS: Tomotherapy is a feasible alternative for treatment of CSA. Analysis shows that tomotherapy improves dose ratios over conventional radiation for most organs at risk. The impact of a small increase in whole body integral dose is unknown. Long-term follow-up will be needed to answer this question as others have argued of the possibility of increased risk of secondary malignancies due to delivery of radiotherapy with IMRT.

Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627).

BACKGROUND: We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM). METHODS: Eligibility requirements were Karnofsky performance status ≥ 60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥ 2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%. RESULTS: A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n = 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2. CONCLUSIONS: Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).

Long-term outcome of combined modality therapy in retroperitoneal and deep-trunk soft-tissue sarcoma: analysis of prognostic factors.

PURPOSE: To evaluate the long-term outcome of surgery and postoperative radiotherapy (RT) in retroperitoneal and deep-trunk soft-tissue sarcoma, and to identify the prognostic factors for local control, disease-free survival, and overall survival. METHODS AND MATERIALS: Between January 1980 and December 1998, 60 patients with nonmetastatic retroperitoneal and deep-trunk soft-tissue sarcoma were treated at Wayne State University using combined surgery and RT. The location was retroperitoneal in 38 patients (63%) and deep trunk in 22 (27%). Forty-six patients (76%) were treated for primary disease and 14 (24%) for recurrent disease. The resection margins were negative in 24 patients (40%), close in 3 (5%), and positive in 33 (55%; 18 microscopic and 15 macroscopic). The median tumor size was 8.6 cm (range 2-55). External beam RT (EBRT; median dose 5220 cGy) was given to 44 patients (73%) and combined EBRT (median dose 4200 cGy) and brachytherapy (median dose 1600 cGy) to 16 patients (27%). Univariate and multivariate Cox regression analyses were conducted to identify the possible associations between patient age, race, gender, tumor site, histologic features, grade, size, stage, surgical margin, RT dose, modality (EBRT vs. EBRT plus brachytherapy), and presentation (primary vs. recurrent) and disease control. RESULTS: The actuarial 5- and 10-year disease-free survival rate was 53% and 44%, respectively. Disease-free survival was significantly associated with female gender on univariate analysis (67% for female patients and 37% for male patients at 5 years, p = 0.05). On multivariate analysis, both gender and surgical margin had borderline significance (p = 0.06). The actuarial local control rate was 71% and 54% at 5 and 10 years, respectively. The median time to local relapse was 10.2 months, with 75% of all failures occurring within 29 months. The surgical margin status was significantly associated with local control (78% for patients with negative or close margins vs. 52% for patients with positive margins at 5 years, p = 0.04). Gender was borderline significant (85% for female patients vs. 54% for male patients at 5 years, p = 0.06). On multivariate analysis, only surgical margin status remained significant (p = 0.032). The distant metastasis-free survival rate at 5 and 10 years was 58% and 54%, respectively. The median time to distant metastases was 15.6 months. The lungs were the most common site of metastases. The only significant factor associated with distant metastasis-free survival was local control (73% for patients with locally controlled tumors vs. 19% for patients with local recurrence at 5 years, p = 0.0013). The actuarial 5- and 10-year overall survival rate was 56% and 47%, respectively. Gender (74% for female patients vs. 37% for male patients at 5 years), surgical margin status (66% for patients with negative or close margins vs. 48% for patients with positive margins at 5 years), and local control (64% for patients with locally controlled tumors vs. 21% for patients with uncontrolled primary tumors at 5 years) were significant predictors on both univariate and multivariate analyses (p <0.05). CONCLUSION: The results of this study demonstrate the paramount importance of local control and complete surgical resection in the management of soft-tissue sarcoma of the retroperitoneum and deep trunk.

Therapeutic postprostatectomy irradiation.

The purpose of this study was to determine the outcome of patients receiving external beam radiation for an elevated postprostatectomy prostate-specific antigen (PSA) level. Between December 1991 and September 1998, 108 patients received definitive radiation therapy for elevated postprostatectomy PSA levels. The median dose of irradiation was 68 Gy (range, 48-74 Gy). During treatment, the PSA levels were checked an average of 5 times (range, 3-7 times). Prostate-specific antigen values were judged to decline or increase during treatment if they changed by more than 0.2 ng/mL. After treatment, biochemical failure was defined as a measurable or rising PSA > 0.2 ng/mL. Median follow-up was 51 months (range, 3-112 months). Fifty-eight patients (54%) had evidence of biochemical failure. The 3- and 5-year actuarial biochemical relapse-free (bNED) survivals for all patients were 55% and 39%, respectively. Upon univariate analysis, intratreatment PSA and preradiation PSA were significant predictors of bNED survival. Patients with a PSA level that decreased during treatment had a 5-year bNED survival of 43% compared to 10% in patients with an increasing PSA level (P = 0.0002). Using the preradiation therapy PSA value as a continuous variable, higher preradiation therapy PSA levels were associated with an increased risk of failure (P = 0.004). Cut points of pretreatment PSA were derived at 0.9 ng/mL and 4.2 ng/mL using the Michael Leblanc recursive partitioning algorithm. The 5-year bNED rate for patients with a preradiation therapy PSA < 0.9 ng/mL was 45% versus 42% for patients with preradiation therapy PSA between 0.9 and 4.2 ng/mL and 21% for patients > or = 4.2 ng/mL (P = 0.0003). Patients with a Gleason score of < or = 7 had a 5-year bNED rate of 38% compared to 37% for patients with a Gleason score > 7 (P = 0.27). Other factors examined individually that did not reach statistical significance included time from surgery to radiation therapy, race, seminal vesicle involvement, pathological stage, surgical margin, and perineural invasion. Upon multivariate analysis, only preradiation therapy PSA (P < 0.001) and the PSA trend during radiation therapy (P < 0.001) were significant factors. The results of therapeutic radiation for patients with elevated postprostatectomy PSA levels are sufficiently poor; other strategies should be explored as alternatives, including early adjuvant postprostatectomy irradiation or the use of combined hormonal and radiation therapy in the salvage situation.

Gamma knife radiosurgery in patients with advanced breast cancer undergoing bone marrow transplant.

OBJECT: Recent studies have suggested a high incidence of cognitive deficits in patients undergoing high-dose chemotherapy, which appears to be dose related. Whole-brain radiotherapy (WBRT) has previously been associated with cognitive impairment. The authors attempted to use gamma knife radiosurgery (GKS) to delay or avoid WBRT in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow transplantation (HDC/ABMT) in whom brain metastases were diagnosed. METHODS: A retrospective review of our experience from 1996 to 2001 was performed to identify patients who underwent HDC/ABMT for advanced breast cancer and brain metastasis. They were able to conduct GKS as initial management to avoid or delay WBRT in 12 patients following HDC/ABMT. All patients were women. The median age was 48 years (range 30-58 years). The Karnofsky Performance Scale score was 70 (range 60-90). All lesions were treated with a median prescription dose of 17 Gy (range 15-18 Gy) prescribed to the 50% isodose. Median survival was 11.5 months. Five patients (42%) had no evidence of central nervous system disease progression and no further treatment was given. Four patients were retreated with GKS and three of them eventually received WBRT as well. Two patients were treated with WBRT as the primary salvage therapy. The median time to retreatment with WBRT was 8 months after the initial GKS. CONCLUSIONS: Gamma knife radiosurgery can be effectively used for the initial management of brain metastases to avoid or delay WBRT in patients treated previously with HDC, with acceptable survival and preserved cognitive function.

Gamma Knife radiosurgery for sellar and parasellar meningiomas: a multicenter study.

OBJECT: Parasellar and sellar meningiomas are challenging tumors owing in part to their proximity to important neurovascular and endocrine structures. Complete resection can be associated with significant morbidity, and incomplete resections are common. In this study, the authors evaluated the outcomes of parasellar and sellar meningiomas managed with Gamma Knife radiosurgery (GKRS) both as an adjunct to microsurgical removal or conventional radiation therapy and as a primary treatment modality. METHODS: A multicenter study of patients with benign sellar and parasellar meningiomas was conducted through the North American Gamma Knife Consortium. For the period spanning 1988 to 2011 at 10 centers, the authors identified all patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were also required to have a minimum of 6 months of imaging and clinical follow-up after GKRS. Factors predictive of new neurological deficits following GKRS were assessed via univariate and multivariate analyses. Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression. RESULTS: The authors identified 763 patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were assessed clinically and with neuroimaging at routine intervals following GKRS. There were 567 females (74.3%) and 196 males (25.7%) with a median age of 56 years (range 8-90 years). Three hundred fifty-five patients (50.7%) had undergone at least one resection before GKRS, and 3.8% had undergone prior radiation therapy. The median follow-up after GKRS was 66.7 months (range 6-216 months). At the last follow-up, tumor volumes remained stable or decreased in 90.2% of patients. Actuarial progression-free survival rates at 3, 5, 8, and 10 years were 98%, 95%, 88%, and 82%, respectively. More than one prior surgery, prior radiation therapy, or a tumor margin dose < 13 Gy significantly increased the likelihood of tumor progression after GKRS. At the last clinical follow-up, 86.2% of patients demonstrated no change or improvement in their neurological condition, whereas 13.8% of patients experienced symptom progression. New or worsening cranial nerve deficits were seen in 9.6% of patients, with cranial nerve (CN) V being the most adversely affected nerve. Functional improvements in CNs, especially in CNs V and VI, were observed in 34% of patients with preexisting deficits. New or worsened endocrinopathies were demonstrated in 1.6% of patients; hypothyroidism was the most frequent deficiency. Unfavorable outcome with tumor growth and accompanying neurological decline was statistically more likely in patients with larger tumor volumes (p = 0.022) and more than 1 prior surgery (p = 0.021). CONCLUSIONS: Gamma Knife radiosurgery provides a high rate of tumor control for patients with parasellar or sellar meningiomas, and tumor control is accompanied by neurological preservation or improvement in most patients.

The impact of adjuvant stereotactic radiosurgery on atypical meningioma recurrence following aggressive microsurgical resection.

OBJECT: Patients with atypical meningioma often undergo gross-total resection (GTR) at initial presentation, but the role of adjuvant radiation therapy remains unclear. The increasing prevalence of stereotactic radiosurgery (SRS) in the modern neurosurgical era has led to the use of routine postoperative radiation therapy in the absence of evidence-based guidelines. This study sought to define the long-term recurrence rate of atypical meningiomas and identify the value of SRS in affecting outcome. METHODS: The authors identified 228 patients with microsurgically treated atypical meningiomas who underwent a total of 257 resections at the Barrow Neurological Institute over the last 20 years. Atypical meningiomas were diagnosed according to current WHO criteria. Clinical and radiographic data were collected retrospectively. RESULTS: Median clinical and radiographic follow-up was 52 months. Gross-total resection, defined as Simpson Grade I or II resection, was achieved in 149 patients (58%). The median proliferative index was 6.9% (range 0.4%-20.6%). Overall 51 patients (22%) demonstrated tumor recurrence at a median of 20.2 months postoperatively. Seventy-one patients (31%) underwent adjuvant radiation postoperatively, with 32 patients (14%) receiving adjuvant SRS and 39 patients (17%) receiving adjuvant intensity modulated radiation therapy (IMRT). The recurrence rate for patients receiving SRS was 25% (8/32) and for IMRT was 18% (7/39), which was not significantly different from the overall group. Gross-total resection was predictive of progression-free survival (PFS; relative risk 0.255, p < 0.0001), but postoperative SRS was not associated with improved PFS in all patients or in only those with subtotal resections. CONCLUSIONS: Atypical meningiomas are increasingly irradiated, even after complete or near-complete microsurgical resection. This analysis of the largest patient series to date suggests that close observation remains reasonable in the setting of aggressive microsurgical resection. Although postoperative adjuvant SRS did not significantly affect tumor recurrence rates in this experience, a larger cohort study with longer follow-up may reveal a therapeutic benefit in the future.