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Background To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). Methods Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. Results Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. Conclusion Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

IntroductionThymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs.MethodsThe International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis.ResultsA total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10-year CIR 17.3% versus 21.2%, respectively [p= 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio= 0.63, 95% confidence interval: 0.54-0.74, p < 0.0001]). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor.DiscussionPreviously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs.

Objective We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms. Background The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones. Methods From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays. Results Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline. Conclusions Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

OBJECTIVES Surgeons at different institutions worldwide choose different types of operations for thymic tumours. It is not known whether these differences affect the outcomes of the patients. METHODS A total of 1430 patients with Masaoka-Koga pathological Stage I-II thymic tumours without myasthenia gravis or pre-treatment were identified from the International Thymic Malignancy Interest Group retrospective database. Outcomes of patients from 3 major continents (Europe, North America and Asia) were compared. RESULTS Patients from the 3 continents were comparable in gender and performance status. More European patients had more paraneoplastic syndromes; North American patients had the smallest tumour sizes and less adjuvant therapy; and Asian patients were younger and had more Stage I disease but higher grade tumours. Partial thymectomy was performed more often in Asian patients (31.7%) than in European (2.4%) and North American (5.4%; P

Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

Objectives The aim of this study was to determine whether postoperative radiation therapy (PORT) is associated with an overall survival (OS) benefit in patients with completely resected Masaoka or Masaoka-Koga stage II and III thymoma. Methods All patients with completely resected (R0) stage II or III thymoma were identified in a large database of the International Thymic Malignancy Interest Group. Clinical, pathologic, treatment, and follow-up information were extracted. OS was the primary end point. A univariate analysis using the log-rank test was performed, and a multivariate Cox model was created to identify factors associated with OS. Results Of 1263 patients meeting the selection criteria, 870 (69%) had stage II thymoma. The WHO histologic subtype was A/AB in 360 patients (30%) and B1/B2/B3 in 827 (70%). PORT was given to 55% of patients (n = 689), 15% (n = 180) received chemotherapy, and 10% (n = 122) received both. The 5- and 10-year OS rates for patients having undergone an operation plus PORT were 95% and 86%, respectively, compared with 90% and 79% for patients receiving an operation alone (p = 0.002). This OS benefit remained significant when patients with stage II (p = 0.02) and stage III thymoma (p = 0.0005) were analyzed separately. On multivariate analysis, earlier stage, younger age, absence of paraneoplastic syndrome, and PORT were significantly associated with improved OS. Conclusions We observed an OS benefit with the use of PORT in completely resected stage II and III thymoma. In the absence of a randomized trial, this represents the most comprehensive analysis of individual patient data and strong evidence in favor of PORT in this patient population.

Summary Background Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). Methods In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. Findings Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7–48) of 18 patients with melanoma and six (33%; 14–59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3–4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1–2 seizures (n=3 [17%]) in the melanoma cohort. Interpretation Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.

Purpose Arthralgia occurs in up to 50% of breast cancer survivors treated with aromatase inhibitors (AIs) and is the most common reason for poor AI adherence. We conducted, in 121 breast cancer survivors receiving an AI and reporting arthralgia, a yearlong randomized trial of the impact of exercise versus usual care on arthralgia severity. Patients and Methods Eligibility criteria included receiving an AI for at least 6 months, reporting ≥ 3 of 10 for worst joint pain on the Brief Pain Inventory (BPI), and reporting < 90 minutes per week of aerobic exercise and no strength training. Participants were randomly assigned to exercise (150 minutes per week of aerobic exercise and supervised strength training twice per week) or usual care. The BPI, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire were completed at baseline and at 3, 6, 9, and 12 months. Intervention effects were evaluated using mixed-model repeated measures analysis, with change at 12 months as the primary end point. Results Over 12 months, women randomly assigned to exercise (n = 61) attended 70% (± standard deviation [SD], 28%) of resistance training sessions and increased their exercise by 159 (± SD, 136) minutes per week. Worst joint pain scores decreased by 1.6 points (29%) at 12 months among women randomly assigned to exercise versus a 0.2-point increase (3%) among those receiving usual care (n = 60; P < .001). Pain severity and interference, as well as DASH and WOMAC pain scores, also decreased significantly at 12 months in women randomly assigned to exercise, compared with increases for those receiving usual care (all P < .001). Conclusion Exercise led to improvement in AI-induced arthralgia in previously inactive breast cancer survivors.

BACKGROUND: Disparities in disease incidence and outcomes are common in genitourinary cancers including renal cell carcinoma (RCC). As limited studies evaluate ethnic disparities, we used data from an equal access healthcare system to investigate differences between Hispanics and non-Hispanic whites with RCC. METHODS: We performed a retrospective cohort study within the Kaiser Permanente healthcare system using records from RCC cases. Ethnicity was identified as Hispanic or non-Hispanic whites. Patient characteristics, comorbidities, tumor characteristics and treatment were compared. Overall survival and disease-specific survival was calculated and a Cox proportion hazard model estimated the association of ethnicity and survival. RESULTS: 2577 patients (2152 non-Hispanic whites, 425 Hispanic) were evaluated. Hispanics were diagnosed at a younger age (59.6 vs 65.3 years). Clear cell RCC was more prevalent while papillary RCC less common among Hispanics. Hispanics had a lower AJCC stage (I/II vs III/IV) than non-Hispanic whites (67.4% vs 62.2%). Hispanics were found to have a greater frequency of comorbidities such as chronic kidney disease and diabetes, but still were more likely to receive surgery. The presence of metastases, nodal involvement, increased tumor size, non-surgical management, increasing age, and Hispanic ethnicity were independent predictors of worse cancer specific outcome. CONCLUSIONS: Within an equal access healthcare system, Hispanics were diagnosed RCC at younger ages, had greater comorbidities, and more frequently had clear cell RCC. Despite lower stage and greater receipt of surgery, Hispanic ethnicity was an independent predictor of mortality. Further work is necessary to confirm these findings perhaps due to differences in disease biology or treatment.

Background Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma. Patients and Methods Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete). Results Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths. Conclusion Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients.

The aim of the study was to compare costs associated with excision of routine cavity shave margins (CSM) versus standard partial mastectomy (PM) in patients with breast cancer.Excision of CSM reduces re-excision rates by more than 50%. The economic implications of this is, however, unclear.Between October 21, 2011 and November 25, 2013, 235 women undergoing PM for Stage 0-III breast cancer were randomized to undergo either standard PM ("no shave", n = 116) or have additional CSM taken ("shave", n = 119). Costs from both a payer and a hospital perspective were measured for index surgery and breast cancer surgery-related care through subsequent 90 days.The 2 groups were well-matched in terms of baseline characteristics. Those in the "shave" group had a longer operative time at the initial surgery (median 76 vs 66 min, P0.01), but a lower re-excision rate for positive margins (13/119 = 10.9% vs 32/116 = 27.6%, P0.01). Actual direct hospital costs associated with operating room time ($1315 vs. $1137, P = 0.03) and pathology costs ($1195 vs $795, P0.01) were greater for the initial surgery in patients in the "shave" group. Taking into account the index surgery and the subsequent 90 days, there was no significant difference in cost from either the payer ($10,476 vs $11,219, P = 0.40) or hospital perspective ($5090 vs $5116, P = 0.37) between the "shave" and "no shave" groups.Overall costs were not significantly different between the "shave" and "no shave" groups due to significantly fewer reoperative surgeries in the former.

Purpose: Non–small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes. Experimental Design: Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments. Results: In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment. Conclusions: This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC. Clin Cancer Res; 19(19); 5523–32. ©2013 AACR.

The embryonic self-renewal factor SALL4 has been implicated in the development of human acute myeloid leukemia (AML). Transgenic mice expressing the human SALL4B allele develop AML, which indicates that this molecule contributes to leukemia development and maintenance. However, the underlying mechanism of SALL4-dependent AML progression is unknown. Using SALL4B transgenic mice, we observed that HoxA9 was significantly upregulated in SALL4B leukemic cells compared with wild-type controls. Downregulation of HoxA9 in SALL4B leukemic cells led to decreased replating capacity in vitro and delayed AML development in recipient mice. In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells. Furthermore, we observed that SALL4 interacted with mixed-lineage leukemia (MLL) and co-occupied the HOXA9 promoter region with MLL in AML leukemic cells, which suggests that a SALL4/MLL pathway may control HOXA9 expression. In summary, our findings revealed a molecular mechanism for SALL4 function in leukemogenesis and suggest that targeting of the SALL4/MLL/HOXA9 pathway would be an innovative approach in treating AML.

Objectives The latest World Health Organization (WHO) histological classification divides thymic epithelial tumours in thymomas and thymic carcinomas (TCs), the latter also including the neuroendocrine thymic tumours (NETTs). NETTs and other TC histotypes have been described to have a significantly lower survival than thymomas, but these two groups of tumours have rarely been compared directly. Using the European Society of Thoracic Surgeons and the International Thymic Malignancy Interest Group datasets, we wanted to study this issue. Methods This is a retrospective multicentre cohort study of patients operated for TC. Outcome measures were overall survival (OS) and recurrence-free survival (RFS). OS was analysed using the Kaplan-Meier method and RFS was assessed using competing risk analysis. The association with clinical and prognostic factors for OS and RFS was evaluated with log-rank test and Gray's test, respectively. Results A total of 1247 tumours (1042 TCs) were collected between 1984 and 2012. A R0 resection was performed in 363 TCs and in 52 NETTs. The median follow-up was 4.4 years for TCs and 4.1 years for NETTs. Owing to the missing values for survival information, a total of 728 TC patients and 132 NETTs were included in the OS analysis. Among them, 262 TC and 39 NETT patients died. The median OS was 6.6 years for TC and 7.5 years for NETTs. The overall 5-year survival rates were 60% for TC and 68% for NETTs; 10-year survival rates were 40% for TCs and 39% for NETTs (P = 0.19). Five-year RFS was 0.35 and 0.34 for TCs and NETTs (P = 0.36). On multivariate analysis, histology did not influence either OS (P = 0.79) or RFS (P = 0.59). Conclusions This represents the largest clinical series of TCs and NETTs collected. Despite the biological aggressiveness of these rare neoplasms, the 5-year survival rate after resection is over 60% and TCs and NETT showed a similar rate of survival and recurrences after surgery.

Significant racial disparities in survival for renal cell carcinoma (RCC) exist between white and black patients. Differences in access to care and comorbidities are possible contributors. To investigate if racial disparities persist when controlling for access to care, we analyzed data from a single‐payer healthcare system. As part of a case–control study within the Kaiser Permanente Northern California system, pathologic and clinical records were obtained for RCC cases (2152 white, 293 black) diagnosed from 1998 to 2008. Patient demographics, comorbidities, tumor characteristics, and treatment status were compared. Overall survival and disease‐specific survival (DSS) were calculated by the Kaplan–Meier method. A Cox proportion hazards model estimated the independent associations of race, comorbidity, and clinicopathologic variables with DSS. We found that compared to white patients, black patients were diagnosed at a younger age (median 62 vs. 66 years, P

Background In high-risk neuroblastoma patients, response to induction chemotherapy is emerging as an important determinant of overall survival. We sought to determine whether histological changes in the primary tumor following induction therapy could be used as a marker of response. Procedure Second-look primary tumor specimens from 43 patients were reviewed according to specific morphological features. Results In the majority, induction therapy resulted in a shift from an intermediate/high to low mitosis-karyorrhexis index (MKI) (P = 0.0009) and from undifferentiated/poorly differentiated to differentiating tumors (P

Introduction: Venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) and pulmonary embolism (PE), is a cause of significant morbidity and mortality worldwide, with an overall incidence of about 10,000,000 cases per year. The majority of VTEs are believed to be attributable to genetic factors. Yet, the five established heritable thrombophilias of factor V Leiden (FVL), prothrombin (PT) gene mutation, antithrombin (AT) deficiency, protein C (PC) deficiency, and protein S (PS) deficiency comprise only a small portion of VTEs, suggesting that further genetic factors contributing to VTE risk are unrecognized. In our previously published study, we performed whole exome sequencing (WES) in 64 patients with VTE and developed a 55-gene extended thrombophilia panel which identified 40 pathogenic or likely pathogenic variants or variants of uncertain significance (VUS) involving 22 different genes. Here, we present updated data from an expanded patient cohort. Methods: Blood was obtained from 101 patients with VTE. Genomic DNA was extracted and WES performed; mean coverage of the exome was 100x with 98% of the exome covered >/= 20 times. Variants were filtered for an allele frequency of 7% in the GnomAD database. A targeted analysis of the 55 genes in the extended thrombophilia panel was then performed. Variants in these genes were classified according to ACGM criteria as pathogenic, likely pathogenic, VUS, benign or likely benign. The number of patients with pathogenic or likely pathogenic variants and VUS in VTE patients was compared to a control population of 237 patients who had WES performed for reason other than VTE. The results of WES were also compared to those of traditional laboratory-based thrombophilia testing. Further, 17 VUS underwent in silico protein modeling to evaluate structural modifications. Results: Of the 101-patient study population, 46 were men and 55 women; 62% were Caucasian, 22% African American and 5% Hispanic; 15% had unprovoked VTE, 71% had provoked, 12% had both; and 55% had first degree family members with VTE. WES and extended thrombophilia testing identified a pathogenic or likely pathogenic variant or VUS in 69/101 (68%) VTE patients compared to 6/237 (2.5%) controls, a statistically significant difference (p-value A total of 72 genetic variants (26 previously published and 46 novel) were identified in 30 genes in the extended thrombophilia panel. 18 variants were categorized as pathogenic or likely pathogenic and 54 as VUS. 32 patients had pathogenic or likely pathogenic variants in one or more of the major thrombophilia genes, with FVL being the most common, and AT and PS deficiency being more common than PT gene mutation (FVL, n=15; PT gene mutation, n=3; AT deficiency, n=5; PC deficiency, n=3; PS deficiency, n=6). Of pathogenic variants in major thrombophilia genes, 15 were previously reported in literature, while 13 were novel. Of the 52 VUS, 17 were subjected to in silico analysis, including protein modeling, which suggested impaired protein folding in 14 variants. Conclusions: WES and extended thrombophilia testing reveal a high frequency of pathogenic or likely pathogenic variants or VUS in VTE patients compared to controls. These variants demonstrate good concordance with traditional laboratory-based thrombophilia testing. Several novel pathogenic or likely pathogenic variants were identified. In silico studies and protein modeling suggest that many VUS identified by this approach are likely to be deleterious to protein function. The results may underlie a strong genetic component to VTE. Next steps include further characterization of VUS using protein modeling, biochemical analysis, and epidemiological and familial studies to understand potential roles these variants may play in thrombosis. Table. Table. Disclosures Camire: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy.

Purpose To review our institution's experience with treatment of craniopharyngioma in children, and to report long-term treatment outcomes stratified by treatment era to assess whether modern treatment techniques result in improvements in local control and survival. Materials and Methods We retrospectively reviewed the records of 100 children who underwent surgery for craniopharygioma at Children's Hospital Boston (CHB) from August 1976 to March 2003. Of these, 79 children (median age 8.5 years) had initial treatment at CHB and sufficient follow-up data to be included in this analysis. We report their treatment course, recurrence rates, and treatment-related morbidity. We compared the results in two different treatment eras based on changes in surgical approach at CHB. Results Thirty-six patients underwent initial treatment with surgery alone; 63% treated prior to 1988 recurred and 36% treated after 1988 recurred. Recurrence rates following combined modality therapy (CMT) with limited surgery followed by radiation were 21 and 5% in the pre- and post-1988 eras, respectively. Accounting for treatment era, patients treated with surgery alone were 7.7 times as likely to recur as those treated with CMT (95%CI: 2.0, 28.7). In the Cox regression model, there was no significant difference in local control or overall survival based on treatment era; initial treatment remained the only statistically significant variable (P = 0.02). Conclusions Advancements in treatment techniques have improved local control in children diagnosed with craniopharyngioma. The excellent survival rates necessitate long-term patient follow-up to identify and manage any treatment-related effects, including second tumors, vascular abnormalities, and endocrinopathies. Pediatr Blood Cancer 2011;56:1120–1126. © 2010 Wiley-Liss, Inc.

In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival.In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival.In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months.In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)

Background Surgical resection is often the only treatment necessary for pediatric low-grade gliomas (LGGs) and is thought to define a population with an excellent long-term prognosis. The goal of this study was to describe the multidimensional late-effects of pediatric LGG survivors treated exclusively with surgery. Methods A retrospective chart review of “surgery-only” LGG survivors followed at Dana-Farber/Children's Hospital Cancer Care was undertaken. Patients had to be diagnosed with an LGG before the age of 22 years, treated with “surgery-only” and be at least 2 years from diagnosis. Results Sixty survivors were eligible with a median age at the time of review of 16.3 years and the median time since diagnosis of 8.4 years. Tumor locations were predominantly posterior fossa (47%) or cortical (33%). Eighty-five percent of patients had at least one ongoing late-effect, and 28% had three or more. The most common late-effects consisted of motor dysfunction (43%), visual problems (32%), anxiety (19%), social difficulties (19%), seizure disorders (17%), depression (15%), poor coordination/ataxia (14%), behavioral problems (13%), and endocrinopathies (10%). Nine patients had a history of suicidal ideation; two with suicide attempts. The mean full-scale IQ was normal, however, the number of survivors scoring one standard deviation below the mean was twice the expected number. Special education services were utilized by more than half of the survivors. Conclusions “Surgery-only” LGG survivors may be more affected by their tumor and its resection than previously appreciated. A prospective study is needed to address this survivor population. Pediatr Blood Cancer 2009;53:417–423. © 2009 Wiley-Liss, Inc.

Purpose Atypical teratoid rhabdoid tumor (ATRT) of the CNS is a highly malignant neoplasm primarily affecting young children, with a historic median survival ranging from 6 to 11 months. Based on a previous pilot series, a prospective multi-institutional trial was conducted for patients with newly diagnosed CNS ATRT. Patients and Methods Treatment was divided into five phases: preirradiation, chemoradiation, consolidation, maintenance, and continuation therapy. Intrathecal chemotherapy was administered, alternating intralumbar and intraventricular routes. Radiation therapy (RT) was prescribed, either focal (54 Gy) or craniospinal (36 Gy, plus primary boost), depending on age and extent of disease at diagnosis. Results Between 2004 and 2006, 25 patients were enrolled; 20 were eligible for evaluation. Median age at diagnosis was 26 months (range, 2.4 months to 19.5 years). Gross total resection of the primary tumor was achieved in 11 patients. Fourteen patients had M0 disease at diagnosis, one patient had M2 disease, and five patients had M3 disease. Fifteen patients received radiation therapy: 11 focal and four craniospinal. Significant toxicities, in addition to the expected, included radiation recall (n = 2) and transverse myelitis (n = 1). There was one toxic death. Of the 12 patients who were assessable for chemotherapeutic response (pre-RT), the objective response rate was 58%. The objective response rate observed after RT was 38%. The 2-year progression-free and overall survival rates are 53% ± 13% and 70% ± 10%, respectively. Median overall survival has not yet been reached. Conclusion This intensive multimodality regimen has resulted in a significant improvement in time to progression and overall survival for patients with this previously poor-prognosis tumor.

The survival of untreated non-small cell lung cancer (NSCLC), or the natural history, is an important perspective for patients considering resection for NSCLC. The National Cancer Database (NCDB) allows untreated NSCLC patients who were recommended to undergo surgical resection (ie, "operable") to be identified. The survival of untreated NSCLC patients in the NCDB was studied to determine the natural history of operable NSCLC.The NCDB was queried for untreated clinical stage I to IIIA NSCLC patients diagnosed between 2003 and 2009. The natural history cohort was defined as patients who were recommended to undergo resection but went untreated.We identified 1,693 untreated patients with operable NSCLC. The median survival for clinical stage I, II, and IIIA was 16.6, 9.4, and 8.4 months, respectively. The 5-year Kaplan-Meier estimates of survival for clinical stage I, II, and IIIA NSCLC were 10.1%, 7.3%, and 4.9%, respectively. At each stage (I to IIIA), the survival of untreated operable NSCLC patients was superior to that of untreated NSCLC patients not recommended to undergo resection (nonoperable, p 0.001). A multivariable Cox regression model identified increasing age, male gender, white (vs black) race, increasing comorbidity, squamous cell or large cell histology, and increasing stage as predictors of decreased survival.The natural history of operable NSCLC, although poor, varies with clinical stage and is superior to that of nonoperable NSCLC.

In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events. Both cohorts experienced similar event-free and overall survival. Both regimens led to a distinct pattern but similar degree of mid-cycle immune activation, manifested as increased expression of cytokines and lytic genes in T and natural killer (NK) cells. Pomalidomide induced poly-functional T-cell activation, with increased proportion of coinhibitory receptor BTLA(+) T cells and Tim-3(+) NK cells. Baseline levels of ikaros and aiolos protein in tumor cells did not correlate with response or survival. Pomalidomide led to rapid decline in Ikaros in T and NK cells in vivo, and therapy-induced activation of CD8(+) T cells correlated with clinical response. These data demonstrate that pomalidomide leads to strong and rapid immunomodulatory effects involving both innate and adaptive immunity, even in heavily pretreated multiple myeloma, which correlates with clinical antitumor effects. This trial was registered at www.clinicaltrials.gov as #NCT01319422.

We performed an analysis to determine the relative contribution of the Oncotype DX (ODX) recurrence score (RS) results in adjuvant therapy delivery compared with traditional pathologic factors.We performed a retrospective review of women with stage I-IIIA breast cancer treated at the Yale Comprehensive Cancer Center from 2006 to 2012 with available ODX results. We constructed separate logistic models with the clinicopathologic factors alone and also integrating RS and compared these models using the likelihood ratio test and c-statistic to determine whether integration of the RS will result in better prediction of chemotherapy (CTx) delivery.We identified 431 women with a median age of 58 years. The RS was low (18), intermediate (18-30), and high (30) in 56%, 37%, and 7%, respectively. CTx was delivered to 30% of the patients. Age, differentiation, lymphovascular invasion, and progesterone receptor (PR) positivity50% were associated with CTx delivery in multivariable logistic regression of clinicopathologic factors alone (P.05). In the model integrating the RS, an intermediate or a high RS was the most influential factor for CTx delivery (odds ratio, 7.87 vs. 265.35, respectively; P.0001). The PR results and grade were no longer significant (P = .74 and P = .06, respectively). The integration of the RS resulted in improved model fit and precision, indicated by the likelihood ratio test (ΔG2, 100.782; df = 2; P.0001) and an improved c-statistic (0.720 vs. 0.856).Gene expression profiling appears to account for a substantial amount of variability in CTx delivery in current practice. Further work is needed to ensure appropriate test usage and cost-effectiveness.

BackgroundRoutine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer. MethodsIn this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; seco...

To examine recall rates from screening mammography and the mammographic findings that caused recall in women who underwent digital breast tomosynthesis with conventional mammography (referred to as two-dimensional [ 2D two-dimensional ] with three-dimensional [ 3D three-dimensional ] imaging [ 2D two-dimensional + 3D three-dimensional ]) and in women who underwent conventional mammography alone (referred to as 2D two-dimensional ).This was an institutional review board-approved, HIPAA-compliant study with waivers of informed consent. A retrospective review of 2D two-dimensional + 3D three-dimensional and 2D two-dimensional screening mammograms from August 1, 2011, to December 31, 2012, was performed. Recall rates and abnormalities that caused recall were compared by controlling for differences in patient age, breast density, and risk factors. Cancer detection rate was assessed from this time period and from 1 year before the introduction of tomosynthesis for a historic control.This study included 17 955 screening mammograms; of the total, there were 8591 (47.8%) 2D two-dimensional + 3D three-dimensional screening examinations and 9364 (52.2%) 2D two-dimensional examinations. The recall rate was 7.8% (671 of 8592) for 2D two-dimensional + 3D three-dimensional and 12.3% (1154 of 9364) for 2D two-dimensional (P.0001); the rate of recall was 36.6% lower in the 2D two-dimensional + 3D three-dimensional group than in the 2D two-dimensional group. Recall rates for the 2D two-dimensional + 3D three-dimensional group were significantly lower for patients with asymmetries, ( 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 3.1% [267 of 8591] vs 7.4% [689 of 9364], respectively; P.0001) and calcifications ( 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 2.4% [205 of 8591] vs 3.2% [297 of 9364], respectively; P = .0014). For patients with masses and architectural distortion, the difference in recall rates was not significant (masses: 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 2.5% [215 of 8591] vs 2.5% [237 of 9364], respectively; P = .90; architectural distortion: 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 0.68% [58 of 8591] vs 0.69% [65 of 9364]; P = .88). Cancer detection was highest in the 2D two-dimensional + 3D three-dimensional group at 5.9 cancers per 1000 examinations, with 5.7 cancers per 1000 examinations in the concurrent 2D two-dimensional group, and 4.4 cancers per 1000 examinations in the historic control.Use of tomosynthesis ( 2D two-dimensional + 3D three-dimensional ) compared with conventional mammography ( 2D two-dimensional ) is associated with a lower recall rate of screening mammography, most often for asymmetries.

The median survival for patients with metastatic gastroesophageal adenocarcinoma is 24 months. Treatment-related grade 3/4 toxicities included neutropenia (33.3%), neuropathy (20.5%), thromboembolism (VTE) (7.7%), thrombocytopenia (7.7%), anemia (2.6%), hypertension (2.6%), and proteinuria (2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. First-line mFOLFOX6 with bevacizumab for metastatic gastroesophageal adenocarcinoma was well tolerated and associated with longer PFS and OS compared with historical data from similar populations treated without bevacizumab. Our results suggest that the addition of bevacizumab to mFOLFOX6 may provide clinical benefit in American patients with metastatic gastroesophageal adenocarcinoma, a finding consistent with previous studies of first-line bevacizumab in combination with chemotherapy for this disease.

Background Preoperative chemotherapy improves the survival of surgically managed stage III non-small cell lung cancer (NSCLC). A proportion of stage III NSCLC patients in the United States have undergone operations primarily and been given chemotherapy postoperatively. It is unclear whether postoperative chemotherapy is as effective as preoperative chemotherapy. Our objective was to determine the survival of resected stage III NSCLC according to the timing of chemotherapy. Methods The National Cancer Database (NCDB) was queried for clinical T1–4N2M0 NSCLC (cstage III–cN2) undergoing lobectomy or pneumonectomy between 2003 and 2006. Results 1,356 patients with surgically managed cstage III–cN2 disease who received preoperative chemotherapy were compared with 649 patients receiving postoperative chemotherapy. In a Cox proportional hazards model with adjustment for demographics, comorbidities, and tumor attributes, the results of postoperative chemotherapy appeared similar to those of preoperative chemotherapy (hazard ratio [HR] = 1.05, 95% confidence interval [CI] 0.93–1.19, p = 0.438). In separate Cox models, the results of postoperative chemotherapy alone were similar to those of preoperative chemotherapy alone (HR = 1.106, 95% CI 0.91–1.344, p = 0.3124). The results of postoperative chemotherapy + radiation were similar to those of preoperative chemotherapy + radiation (HR = 1.125, 95% CI 0.949–1.333, p = -0.175). Conclusions Adjusted comparison of preoperative and postoperative chemotherapy results for cstage III–N2 NSCLC in the NCDB failed to identify a superior chemotherapy approach. This suggests that a more rigorous examination of the widely held view that preoperative chemotherapy is superior may be warranted.

Background: Our knowledge of thymic malignancies has largely been derived from small, single-institution series. Recognition of the need for broad collaboration led to the creation of the International Thymic Malignancy Interest Group (ITMIG) and the development of a large, centralized database to advance knowledge of these rare tumors. Methods: A multidisciplinary Database Committee was convened to define a common set of data elements a priori. Retrospective data were solicited from ITMIG members and collated using standardized fields. Patients with thymoma, thymic carcinoma, or thymic carcinoid were included. Results: Over a 6-month period, 47 institutions spanning 15 countries contributed a total of 6097 cases (mean, 129 [range, 10-1209]). The sex distribution was equal for thymomas, but there was a greater proportion of men with thymic carcinoma and thymic carcinoid (p < 0.0001). Nearly all cases (99%) were treated surgically. WHO type B2 was the most frequent histologic classification among thymomas, whereas squamous was the most common among thymic carcinomas. In total, 38% of patients with thymoma had myasthenia gravis compared with less than or equal to 5% for thymic carcinoma and thymic carcinoid. Median overall survival was 18.9 years (95% confidence interval [CI], 17.4-20.3) for thymoma, 6.8 years (95% CI, 5.5-7.9) for thymic carcinoma, and 7.5 years (95% CI, 6.5-8.5) for thymic carcinoid. Conclusions: The rapid creation of the ITMIG database demonstrates the feasibility of international collaboration for this rare set of malignancies and attests to the engagement of its membership. This database represents the largest collective data set ever assembled and provides an unprecedented resource for research of these tumors.

Objectives: To evaluate the amount of hemophagocytosis in 64 marrow core biopsy specimens and aspirates from 58 patients with clinical suspicion for secondary hemophagocytic lymphohistiocytosis (HLH) or reported findings of hemophagocytosis. Methods: A review of medical records assigned patients to a low-risk (45 patients) or high-risk (13 patients) HLH group, and association with histologic findings was examined using the Fisher exact test. Results: The amount of hemophagocytosis in aspirate or the core biopsy specimen did not correlate with disease probability (P = .17 and P = .63, respectively). Of the clinical/laboratory criteria assessed, the most significant correlations with HLH were highly elevated ferritin (P = .01), cytopenias (P = .02), and fever (P = .009). Conclusions: Our findings indicated that marrow histologic findings alone do not reliably predict the probability of HLH, and an isolated finding of hemophagocytosis, even when present in a high amount, lacks specificity for HLH.

The role of leptin in mediating calcium-related metabolic processes is not well understood.We enrolled patients with hyperparathyroidism undergoing parathyroidectomy in a prospective study to assess postoperative changes to serum leptin and parathyroid hormone levels and to determine the presence of LEPR (leptin receptor) polymorphisms. Patients undergoing hemithyroidectomy under identical surgical conditions were enrolled as controls. Wilcoxon signed-rank test was used to analyze changes in leptin. Pearson correlations and Bland-Altman methods were used to examine the between-subject and within-subject correlations in changes in leptin and parathyroid hormone levels. Five single-nucleotide polymorphisms in the LEPR gene were genotyped, and linear regression analysis was performed for each polymorphism.Among the 71 patients included in the clinical study, after-surgery leptin levels decreased significantly in the parathyroid adenoma (p0.001) and parathyroid hyperplasia subgroups (p = 0.002) and increased in the control group (p = 0.007). On multivariate analysis, parathyroid disease subtype, baseline leptin levels, age, body mass index, and calcium at diagnosis was associated with changes in leptin. Among the 132 patients included in the genotyping analysis, under a recessive model of inheritance, single-nucleotide polymorphism rs1137101 had a significant association with the largest parathyroid gland and total mass of parathyroid tissue removed (p = 0.045 and p = 0.040, respectively). When analyzing obese patients only, rs1137100 and rs1137101 were significantly associated with total parathyroid size (p = 0.0343 and p = 0.0259, respectively).Our results suggest a role for the parathyroid gland in regulating leptin production. Genetic contributions from the leptin pathway might predispose to hyperparathyroidism.

Timeliness of care improves patient satisfaction and might improve outcomes. The CCCP was established in November 2007 to improve timeliness of care of NSCLC at the Veterans Affairs Connecticut Healthcare System (VACHS).We performed a retrospective cohort analysis of patients diagnosed with NSCLC at VACHS between 2005 and 2010. We compared timeliness of care and stage at diagnosis before and after the implementation of the CCCP.Data from 352 patients were analyzed: 163 with initial abnormal imaging between January 1, 2005 and October 31, 2007, and 189 with imaging conducted between November 1, 2007 and December 31, 2010. Variables associated with a longer interval between the initial abnormal image and the initiation of therapy were: (1) earlier stage (mean of 130 days for stages I/II vs. 87 days for stages III/IV; P.0001); (2) lack of cancer-related symptoms (145 vs. 60 days; P.0001); (3) presence of more than 1 medical comorbidity (123 vs. 82; P = .0002); and (4) depression (126 vs. 98 days; P = .029). The percent of patients diagnosed at stages I/II increased from 32% to 48% (P = .006) after establishment of the CCCP. In a multivariate model adjusting for stage, histology, reason for imaging, and presence of primary care provider, implementation of the CCCP resulted in a mean reduction of 25 days between first abnormal image and the initiation of treatment (126 to 101 days; P = .015).A centralized, multidisciplinary, hospital-based CCCP can improve timeliness of NSCLC care, and help ensure that early stage lung cancers are diagnosed and treated.

BACKGROUND: SOX2 is an embryonic developmental transcription factor, which is important in the development of the respiratory tract. SOX2 overexpression is associated with aggressive disease in several tumor types. However, SOX2 overexpression and gene amplification associates with favorable outcome in lung squamous cell carcinomas (SCC) and dissimilar results have been reported in lung adenocarcinomas (ADC). The aim of the present study was to evaluate SOX2 expression in NSCLC and determine the relationship with clinico-pathological variables and outcome. METHODS: SOX2 protein levels were measured in tissue microarrays (TMAs) containing FFPE samples from two independent lung cancer cohorts (n = 340 & 307) using automated quantitative immunofluorescence (QIF). Assay validation was performed using FFPE preparations of cell lines with known SOX2 expression. Associations of SOX2 levels with main clinico-pathological characteristics and with overall survival were studied using uni-and multivariate analysis. RESULTS: SOX2 levels were higher in patients with SCC than in ADC in both cohorts (p value

PET studies are used on a regular basis to stage lymphoma patients pretreatment. Bone marrow uptake (BMu) can be associated with disease involvement, however occasionally uptake is related to benign etiologies (anemia, stimulation, a hypercellular marrow etc…). Uncovering quantitative and qualitative parameters to elucidate the etiology of (BMu) may help the radiologist and oncologist in cases where a BM biopsy (BMb) cannot be performed or interpreted by the pathologist or is unavailable. We looked retrospectively at a group of consecutive lymphoma patients (pts) who had an initial staging PET scan. Out of 121 patients, 36 had a (BMb) report available for review. We attempted to evaluate whether semi quantitative parameters – maximum standardized uptake value (SUVm); Average SUV (SUVav); SUVm/Mediastinal blood pool (MBP) ratio - could discriminate between different bone marrow patterns (normal, hypercellular, positive). We also looked at the type of BMu (none; mild; prominent) and pattern (patchy; diffuse; focal). The average age of our patient population was 52.19. 66.66% were males (24/36). Most of our patient’s had a normal BMb. 25 % (9/36) had a positive BM. In the BM positive group, no pts had patchy uptake and 2 pts were found to have no appreciable uptake. In the BM normal group 71.5 % (15/21) had either mild or prominent uptake and only 28.5% had no uptake. None had focal uptake and 90% of pts had diffuse uptake. The majority of whole cohort had a SUVm> 2.5: 90 % of BM normal; 100% of hypercellular BM and 88.88% of the BM positive group and an SUVm/MBP>2.5: 52.4%; 66.66% and 55.5% respectively. Using a Chi-square test BM Pathology level was overall significantly different across the BMu patterns (p=0.0192). Analysis looking at BM positive versus BM negative groups, shows BM pattern is no longer a significant variable to predict BM pathology (p=0.168). Subsequently, the odds ratio of having only positive BM pathology based on focal vs. patchy pattern is not significant. Conclusion: No qualitative or semi quantitative parameters were found to be statistically significantly associated with BM pathology. Further exploration in a larger cohort is necessary.

ATNT-15. MIBEFRADIL DIHYDROCHORIDE WITH HYPOFRACTIONATED RADIATION FOR RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS OF A PHASE I DOSE EXPANSION TRIAL Nataniel H. Lester-Coll1, Jeannie Kluytenaar1, Kira F. Pavlik2, James B. Yu1, Joseph N. Contessa1, Jennifer Moliterno3, Joseph M. Piepmeier3, Kevin P. Becker4, Joachim M. Baehring4, Anita J. Huttner5, Alexander O. Vortmeyer5, Ramachandran Ramani6, Rachel J. Lampert7, Xiaopan Yao8, and Ranjit S. Bindra1; Departmentof TherapeuticRadiology, YaleUniversity School of Medicine, New Haven, CT, USA; Yale University School of Medicine, New Haven, CT, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA; Department of Cardiology, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT, USA BACKGROUND: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Our group recently performed a high-throughput drug screen for novel DNA repair inhibitors which identified mibefradil dihydrochloride, a T-type calcium channel blocker. Follow-up studies by our group and others subsequently revealed that mibefradil is active as a glioma radiosensitizer. Based on these findings, we sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and hypofractionated radiation (RT), in a Phase I study of patients with recurrent GBM. A subset of patients are enrolled on a molecular biomarker sub-study, in which the drug is administered prior to surgical re-resection, and the tissue is analyzed for tumor penetration and in situ activity. METHODS: The inclusion criteria are histologically proven GBM progressive or recurrent following RT and temozolomide treatment. Patients receive mibefradil, in escalating dose from 150mg/day until the maximum tolerated dose (MTD) or a dose of 350 mg/day is reached using a standard 3 + 3 design. RT consists of 5 fractions of 600 cGy each, delivered over 2 weeks for a total of 3,000 cGy using stereotactic, intensity-modulated RT. RESULTS: To date, eight patients have been enrolled including two patients on the molecular biomarker sub-study, and seven have been successfully treated. The first dose level cohort has completed accrual. Median progression-free survival was 2.5 months. One patient experienced a complete radiographic response on MRI and one had grade 3 or higher drug-related toxicity. CONCLUSIONS: This Phase I dose-escalation study assesses the safety and determines the MTD of mibefradildihydrochlorideas anovel radiosensitizer inpatientswith recurrent GBM. Our preliminary data suggest that mibefradil and RT can be safely co-administered with the potential to improve disease response as a novel radiosensitizer. Neuro-Oncology 17:v10–v17, 2015. doi:10.1093/neuonc/nov205.15 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

e18198Background: Hospitalizations in patients with cancer are common near the end-of-life, associated with poor prognosis and often against patients’ expressed wishes. The Rothman Index (RI) is a ...

Although FOLFIRINOX significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine (Conroy et al. N Engl J Med 364:1817–1825, 2011), toxicities have tempered enthusiasm for its use in full doses. To assess the impact of dose attenuations on toxicity and efficacy, we reviewed our institution’s experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC) and MPC. We performed a retrospective review of dose, toxicity, and efficacy of FOLFIRINOX in all patients with LAPC and MPC treated between June 2010 and July 2011 at Yale. Toxicities in all patients and response rate (RR) and survival in previously untreated MPC were compared to data reported by Conroy. Overall survival (OS) and progression-free survival were estimated by Kaplan–Meier method. Thirty-five patients were treated (16 LAPC; 19 MPC). Twenty-nine patients received dose attenuations with the first cycle. Median relative doses of irinotecan and bolus fluorouracil were less than those reported by Conroy (64 vs. 81 % and 66 vs. 82 %, respectively). RR was 50 % in LAPC and 47 % in MPC, and the latter did not differ significantly from the RR reported by Conroy (p = 0.19). OS at 6 and 12 months in MPC was comparable to OS reported by Conroy. Grade 3/4 toxicities were less than reported by Conroy, including fatigue (p = 0.009) and neutropenia (p

A multicenter Eastern Cooperative Group (ECOG) phase 2 trial assessed whether adding prednisone to lenalidomide would improve previously reported responses in persons with myelofibrosis (MF). Forty-eight subjects with anemia (42 evaluable) received lenalidomide, 10 mg/d, with a 3-month low-dose prednisone taper. Ten subjects received 3 months, and 25 received 6 months of therapy. Myelosuppression was the main toxicity with 88% with ≥ grade 3 hematologic toxicity and 45% ≥ grade 3 nonhematologic toxicity. There were responses in 10 subjects (23%) using the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)–defined clinical improvement of anemia in 8 (19%) and/or decreased spleen size in 4 (10%). Serial bone marrow analysis showed no resolution of disease-related fibrosis or angiogenesis. With a median follow-up of 2.3 years, 23 subjects are alive. Lenali-domide and prednisone for myelofibro-sis evaluated through a multicentered-cooperative group mechanism is only modestly active and myelosuppre-sive. This study was registered at http://clinicaltrials.gov as NCT00227591.

Background Neurofibromatosis type 1 (NF1) is characterized by low-grade tumors of the central and peripheral nervous system. There is also an increased risk of developing malignant tumors. Glioblastoma is an uncommon, malignant tumor of children that is even less frequently observed in children with NF1. Procedure We performed a retrospective review of patients with NF1 and glioblastoma to determine specific clinical and pathologic indicators of overall prognosis. Results Five patients were identified from the CHB/DFCI database for whom pathologic and imaging studies were available. All pathologic specimens demonstrated vascular proliferation and necrosis. All samples stained positively for p53. Chromogenic in situ hybridization (CISH) for epidermal growth factor receptor (EGFR) copy numbers was increased, PTEN copy numbers were normal and the promoter of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene was unmethylated in the one patient evaluated. In the same time period, there were 56 patients without NF1 diagnosed with glioblastoma who were treated at our institution. Although the small sample size precludes formal statistical analysis, the 2-year survival of patients with NF1 is 60% with median overall survival of 9.25 years compared to non-NF1 patients with a 2-year survival of 25% and median overall survival 1.08 years. Conclusions This study provides preliminary evidence that children with NF1 may be at risk for glioblastoma, but that these patients have an increased survival compared to children without NF1. Additional molecular studies will be required to determine if the pathogenesis of these tumors differs from glioblastoma in children without NF1. Pediatr Blood Cancer 2010;54:890–896 © 2010 Wiley-Liss, Inc.

Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer1, 2. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males3. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease., This study was supported by the Fund for Scientific Research (FWO) Flanders (postdoctoral grants to P.V.V. and T.T., PhD grant to J.V.d.M., senior clinical investigator award to B.P. and project grants G.0198.08 and G.0869.10N to F.S.); the GOA-UGent (grant no. 12051203); the IWT-Vlaanderen (SBO grant no. 060848); the Children Cancer Fund Ghent (F.S.); Leukemia Research UK (C.J.H.); the Stichting Kinderen Kankervrij (KiKa; grant no. KiKa 2007-012 to L.Z.); the Belgian Program of Interuniversity Poles of Attraction; the Belgian Foundation against Cancer; the Austrian Ministry of Science and Research (GEN-AU Child, GZ 200.136/1-VI/1/2005 to S.S.), the US National Library of Medicine (1R01LM010140-01 to R.R. and H.K.); the ECOG and DCOG tumor banks; grants from Spain's Plan Nacional (BFU 2007-60990 and PlanE2009-0110 to M.L.T.), Comunidad de Madrid (S-SAL0304-2006 to M.L.T.), Fundación MM (M.L.T.), Instituto de Salud Carlos III (RECAVA RD06/0014/1012 to M.L.T.), an Institutional Grant from the Fundación Ramón Areces (M.L.T.), the Alex's Lemonade Stand Foundation Young Investigator Award (T.P.); a US Northeast Biodefense Center ARRA award (U54-AI057158 to R.R.); the US National Institutes of Health (R01CA120196 and R01CA129382 to A.F.); the Rally across America Foundation (A.F); the Swim across America Foundation (A.F.); the Golfers against Cancer Foundation (A.F.); and a Leukemia and Lymphoma Society Scholar Award (A.F.).

Acute graft-versus-host disease (aGVHD) is a major complication after hematopoietic stem cell transplantation (HSCT). The pathophysiology of aGVHD involves priming of naïve donor T cells in host secondary lymphoid tissue, followed by migration of effector T cells to target organs. Mediators of lymphocyte trafficking are believed to play a significant role in this migration. In this retrospective case-controlled study, we analyzed the expression of alpha4beta7 integrin and CCR9, 2 surface T cell molecules specific for intestinal trafficking, from blood samples collected previously from 59 patients after HSCT (20 without aGVHD, 20 with skin aGVHD, and 19 with intestinal aGVHD). All samples had been obtained before the onset of aGVHD symptoms (with 1 sample collected on the day of symptom onset). Analysis by flow cytometry demonstrated that alpha4beta7 integrin was significantly increased on both naïve and memory T cells in patients who subsequently developed intestinal aGVHD, with the most significant differences observed in memory subsets. Immunohistochemical staining on rectal biopsy specimens from patients with intestinal aGVHD showed that expression of alpha4beta7 integrin was concentrated on mononuclear cells in blood vessels within the intestinal mucosa. These results suggest that alpha4beta7 integrin likely is involved in lymphocyte trafficking in intestinal aGVHD and may have potential clinical use as a correlative biomarker or as a target for the treatment and prophylaxis of intestinal aGVHD after HSCT.

The molecular mechanisms involved in disease progression and relapse in T-cell acute lymphoblastic leukemia (T-ALL) are poorly understood. We used single nucleotide polymorphism array analysis to analyze paired diagnostic and relapsed T-ALL samples to identify recurrent genetic alterations in T-ALL. This analysis showed that diagnosis and relapsed cases have common genetic alterations, but also that relapsed samples frequently lose chromosomal markers present at diagnosis, suggesting that relapsed T-ALL emerges from an ancestral clone different from the major leukemic population at diagnosis. In addition, we identified deletions and associated mutations in the WT1 tumor suppressor gene in 2 of 9 samples. Subsequent analysis showed WT1 mutations in 28 of 211 (13.2%) of pediatric and 10 of 85 (11.7%) of adult T-ALL cases. WT1 mutations present in T-ALL are predominantly heterozygous frameshift mutations resulting in truncation of the C-terminal zinc finger domains of this transcription factor. WT1 mutations are most prominently found in T-ALL cases with aberrant rearrangements of the oncogenic TLX1, TLX3, and HOXA transcription factor oncogenes. Survival analysis demonstrated that WT1 mutations do not confer adverse prognosis in pediatric and adult T-ALL. Overall, these results identify the presence of WT1 mutations as a recurrent genetic alteration in T-ALL.

Introduction: Venous thromboembolism (VTE) occurs with an incidence of 1-2 per 1000 individuals per year. Approximately 10-20% of patients with VTE have a heritable thrombophilia involving one of five known genes: Factor V, prothrombin (PT), antithrombin (AT), protein C (PC), and protein S (PS). Significant variability of laboratory functional assays as well as fluctuating plasma levels of AT, PC and PS lead not only to delay in initial thrombophilia screening but also to multiple rounds of costly testing. Whole exome sequencing (WES) is a potentially useful diagnostic tool for inherited thrombophilias as it avoids dependence on laboratory and situational variation in protein levels. We compiled a panel of 33 genes involved in thrombosis with a goal of investigating the diagnostic yield and cost of WES in comparison to traditional thrombophilia testing. Methods: Since January of 2014, we have been performing WES in patients with a personal and family history of VTE seen at Yale New Haven Hospital. Thus far, 18 such patients have had a complete WES analysis. Data regarding patient demographics, number and type of VTE events, family/surgical history, medical co-morbidities, and traditional laboratory testing for inherited thrombophilias was recorded. Costs of each test were determined based on the amount billed to insurance. WES focusing on 33 genes involved in thrombosis was performed and analyzed by the DNA Diagnostic Lab at the Yale School of Medicine. Positive WES testing was defined as identification of a pathogenic variant in a gene known to be associated with thrombophilia, found at a frequency consistent with frequency of the disease, and with evidence that the variant predisposes to thrombosis. Positive laboratory testing was defined as any test that led to an unequivocal diagnosis of Factor V Leiden, PT mutation, homozygous MTHFR mutation with hyperhomocysteinemia, or a deficiency in AT, PC, or PS. Results: All 18 patients (7 male, 11 female) were included in the final analysis. Median age at first VTE was 35.5 years (range, 14-78 years); median number of independent VTE events was 2 (range, 1-9). WES with our 33-gene thrombophilia panel was positive in 11 of 18 (61.1%) patients, while traditional laboratory testing was positive in only 2 of 16 (12.5%) cases (Table 1). There were no statistically significant differences in clinical characteristics between those patients with positive findings on WES versus those without. Identified variants included those in genes with well known roles in thrombosis (SERPINC1, PROS1, F5), and in genes with emerging data regarding thrombosis (HABP2, SERPINA10, SERPIND1). Two patients identified on WES as having PS deficiency, one with AT deficiency, and one with a non-Leiden Factor V mutation had laboratory testing that was either normal or uninterpretable. The total cost of WES at our institution was $1935.00; by comparison, among 16 patients who underwent laboratory testing, median cost of laboratory testing was $2892.70 (range, $406.90-$11419.80), and the cost of laboratory testing exceeded WES in 13 patients. Conclusions: WES using our 33-gene thrombophilia panel has higher diagnostic yield and is more cost effective than traditional thrombophilia testing. With increasing availability and declining cost, this thrombophilia gene panel has the potential to truly transform thrombophilia testing. Further investigation of the diagnostic power and phenotypic correlation of identified mutations is in progress. | Gender | Age (yrs) | Lab testing result | WES result | | ------ | --------- | ------------------------- | --------------------------------------------------------- | | M | 40 | Negative | SERPINA10 (Q384R) heterozygous | | M | 67 | Negative | SERPINC1 (S426W) heterozygous | | M | 30 | Negative | PROS1 (Y234C) heterozygous | | F | 34 | Negative | HABP2 (G508E) heterozygous | | F | 56 | APC resistance | F5 (R506Q) heterozygous | | F | 27 | F2 20210 G>A heterozygous | F2 20210G>A heterozygous; vWF P2063S heterozygous | | F | 37 | Negative | SERPIND1 (R468C) heterozygous | | F | 48 | Negative | F5 (T915S) heterozygous | | M | 20 | Negative | PROS1 (P76L) heterozygous | | M | 55 | Negative | SERPINA10 (21_23delCCT ) heterozygous | | F | 78 | Negative | HABP2 (G534E) heterozygous | | F | 49 | Negative | Negative | | F | 41 | Negative | Negative | | M | 32 | Negative | Negative | | F | 64 | Negative | Negative | | M | 42 | Negative | Negative | | F | 51 | Negative | Negative | | F | 28 | Negative | Negative | Table 1. Mutations detected by the 33 gene thrombophilia panel Disclosures No relevant conflicts of interest to declare.

Background: Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer, second to death caused by cancer itself. Guidelines from the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) support the use of low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) for treatment of VTE in cancer patients. The novel oral anticoagulants (NOACs) are increasingly being used for all types of VTE, but their safety and efficacy in cancer-associated VTE has not been established. In the CLOT trial of LMWH in cancer-associated VTE, the rate of recurrent VTE was 9.0%, compared to 5.1% among the subgroup of cancer patients who received rivaroxaban in the EINSTEIN trial; bleeding rates among cancer patients in the CLOT and EINSTEIN trials were 14% and 15.2%, respectively. Due to a paucity of data, at this point neither the NCCN nor ASCO supports the use of NOACs for treatment of cancer-associated VTE. Objective: Evaluate the efficacy and safety of NOACs in cancer-associated VTE. Methods: We performed a retrospective chart review of all patients with a diagnosis of active malignancy who received a prescription for a NOAC for treatment of VTE at Yale Cancer Center between February 1, 2012, and December 31, 2014. Patients with a heritable thrombophilia or bleeding disorder were excluded. Data collected included patient demographics, body mass index (BMI), cancer type and stage, type of VTE event (deep venous thrombosis (DVT), pulmonary embolism (PE), or both), type of NOAC, compliance with NOAC therapy, appropriate NOAC dose, and potential drug-drug interactions (DDI) with NOACs. Primary outcomes were recurrent VTE, defined as the finding of new or progressive DVT or PE on imaging with or without symptoms, and clinically relevant bleeding (CRB), defined as a decrease in hemoglobin of at least 2 g/dL in a 24-hour period, a requirement for red blood cell transfusion, any critical site bleeding event, or any type of bleeding event requiring increased physician monitoring. Fisher's exact test was used to calculate p-values where appropriate. Results: 75 patients met inclusion criteria; rivaroxaban was the only NOAC used in all cases. The incidence of recurrent VTE and CRB was 7.0% (n = 5) and 25.3% (n = 19), respectively. There were two fatal events, one due to recurrent VTE and one due to major gastrointestinal bleed; in neither case was NOAC compliance, dosing, or DDIs implicated in the fatality. Over half (n = 39) of all study patients were on a concomitant medication with a known DDI with NOAC therapy; the most common such agents were ciprofloxacin, fluconazole, azithromycin and voriconazole. In only one of the 80 DDI cases was anticoagulation therapy changed. NOAC dosing was inappropriate in 20 instances, mostly due to patients not receiving the recommended loading dose prior to beginning maintenance dosing. Among the 19 occurrences of CRB, advanced stage solid tumor emerged as a statistically significant (p = 0.0151) risk factor for bleeding while on rivaroxaban. Conclusion: Treatment of cancer-associated VTE with NOAC therapy is effective, but the risk of bleeding in our cohort was higher than in other published studies. Patients with advanced stage solid tumors may be at a particularly high risk of bleeding. Prescriber practices with NOACs may require modification based on high utilization of concomitant medications with DDIs and failure to prescribe appropriate loading doses of NOACs in treatment of VTE. Disclosures No relevant conflicts of interest to declare.

Background: Patients with plasma cell disorders (PCDs) are among the most susceptible to common infections including influenza and these infections are a major source of morbidity. Although seasonal influenza vaccination is routinely employed in patients with PCDs, the data about its efficacy are limited, as few studies have focused on this population. Based on historical data, PCD patients have a 10 fold increased risk of influenza and an expected yearly flu infection rate of at least 20%. The major surrogates for influenza vaccine response are hemaglutination antibody inhibition (HAI) titers; however rates of achieving protective HAI titers after standard influenza vaccination in PCD patients range from 5-19%. One approach to enhancing the efficacy of influenza vaccination is the use of standard dose boosters, and a recent study in multiple myeloma patients suggested improved seroprotection. Another approach may be increasing the amount of antigen in vaccines. Fluzone® high-dose vaccine was FDA approved in 2009 for adults aged 65 and older based on data regarding higher seroprotection rates but has not been studied specifically in PCD patients. Methods: In order to directly address the significant unmet need of improving vaccination strategies in patients with PCDs, we evaluated a novel vaccine strategy in patients with PCDs over the 2014-15 flu season that involved two doses of Fluzone® High-Dose influenza vaccination 30 days apart, regardless of age. Eligibility criteria allowed any patient with a PCD and no contraindication to trivalent inactivated influenza vaccine. The primary endpoint was laboratory confirmed flu infection rate. Patients were asked to report all flu-like illnesses for viral testing (PCR) and patients were asked about infectious symptoms at all study visits and at the end of the flu season in May 2015. A secondary endpoint is comparing rates of seroprotection with HAI titers and virus neutralization assays. Another secondary endpoint is to explore cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness. Results: 51 total PCD patients were enrolled (41 with disease requiring therapy and 10 with asymptomatic gammopathy) and all patients received two doses of Fluzone High-Dose vaccine. Median age was 75 years (range 36-90). This novel vaccination strategy was safely tolerated in all patients with no ≥ grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% (2/51) of patients developed laboratory confirmed influenza. Preliminary data on a cohort of 30 multiple myeloma patients demonstrates that only 7% (2/30) had baseline protective HAI titers to all three seasonal influenza vaccine strains and after one Fluzone® High-Dose vaccine the seroprotection rate increased to 33% (10/30). Final seroprotection analysis and measurements of cell-mediated immunity are underway. Conclusions: This pilot study demonstrates that the two dose strategy of Fluzone® High-Dose influenza vaccine was safely tolerated in patients with PCD. The observed rate of seroprotective HAI after one dose of high dose vaccine was 33%, approximately double the historically observed rate of 5-19% after standard dose vaccine. The rate of seroconversion after the second dose is currently being analyzed and will be presented. Interestingly the rate of documented flu infections was only 4% compared to an expected 20% and may be due in part to the higher rate of seroconversion. These results suggest that this novel vaccination strategy is safe and may have a clinical benefit in improving HAI seroprotection and reducing documented flu infections in PCD patients. Given these encouraging clinical results, we are planning a randomized trial for the upcoming 2015-2016 influenza season comparing this novel vaccination strategy to standard of care vaccination in patients with plasma cell disorders. Disclosures Off Label Use: In order to directly address the significant unmet need of improving vaccination strategies in patients with plasma cell disorders, we present a pilot study which evaluated a novel vaccine strategy over the 2014-15 flu season. Fluzone® High-Dose influenza vaccine was administered in a booster strategy (two doses 30 days apart)..

BACKGROUND: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Our group recently performed a high-throughput drug screen for novel DNA repair inhibitors which identified mibefradil dihydrochloride, a T-type calcium channel blocker. Follow-up studies by our group and others subsequently revealed that mibefradil is active as a glioma radiosensitizer. Based on these findings, we sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and hypofractionated radiation (RT), in a Phase I study of patients with recurrent GBM. A subset of patients are enrolled on a molecular biomarker sub-study, in which the drug is administered prior to surgical re-resection, and the tissue is analyzed for tumor penetration and in situ activity. METHODS: The inclusion criteria are histologically proven GBM progressive or recurrent following RT and temozolomide treatment. Patients receive mibefradil, in escalating dose from 150mg/day until the maximum tolerated dose (MTD) or a dose of 350 mg/day is reached using a standard 3 + 3 design. RT consists of 5 fractions of 600 cGy each, delivered over 2 weeks for a total of 3,000 cGy using stereotactic, intensity-modulated RT. RESULTS: To date, eight patients have been enrolled including two patients on the molecular biomarker sub-study, and seven have been successfully treated. The first dose level cohort has completed accrual. Median progression-free survival was 2.5 months. One patient experienced a complete radiographic response on MRI and one had grade 3 or higher drug-related toxicity. CONCLUSIONS: This Phase I dose-escalation study assesses the safety and determines the MTD of mibefradil dihydrochloride as a novel radiosensitizer in patients with recurrent GBM. Our preliminary data suggest that mibefradil and RT can be safely co-administered with the potential to improve disease response as a novel radiosensitizer.