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Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non–small cell lung cancer (NSCLC) patients.Experimental Design: This is a single-arm chemotherapy plus phased ipilimumab phase II study of 24 treatment-naïve patients with stage IB–IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles.Results: Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs.Conclusions: This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies. Clin Cancer Res; 23(24); 7474–82. ©2017 AACR.

Spaghetti plots of MDSC and Tregs by visits; stratified by overall response.

Cancer survivors are often sedentary. Self-monitoring may promote physical activity through self-activation. We conducted a pilot trial to evaluate whether wearable activity tracker with personalized text message feedback would increase physical activity. We enrolled 30 patients with solid tumor cancers into a non-randomized prospective intervention trial (NCT02627079): 15 had completed treatment in the past year and 15 under active treatment. Each participant received an activity tracker and daily text messages personalized to their activity level. We assessed patient-reported outcomes and 6-min walk (6 MW) at baseline and 3 months. Twenty-six participants completed the study. There was substantial variation in baseline activity. Overall, 39% of participants increased their steps taken by at least 20%, and 23% increased their 6 MW distance by 20% or more. More participants who had completed treatment strongly agreed (73%) that the intervention increased their exercise levels than those receiving active treatment (47%). At 3 months, there was a significant improvement in median Beck Depression Inventory-II and Godin Leisure Index composite scores. At 6 months, 72% still wore their activity tracker at least 4 days per week. We found that the intervention was well-accepted with a high completion rate at 3 months and continued self-use at 6 months. In this pilot study of combined activity tracker and motivational messaging, we found a signal for increased physical activity over a 3-month period. Future research is needed to study this technique for its impact on activity and other physical and psychological measures of well-being. Activity tracker with personalized motivational messaging may be useful in promoting physical activity in cancer survivors.

Background Spirituality can impact patients’ attitudes and decisions about treatment and end-of-life care when coping with cancer. Previous studies documented health-related quality of life (HRQoL) and spiritual well-being (SWB) as positively correlated within a general cancer patient population, but little is known about their association in the primary brain tumor population. We sought to measure SWB in primary brain tumor patients and evaluate whether it was associated with HRQoL. Methods Six-hundred and six patients treated at The Preston Robert Tisch Brain Tumor Center at Duke between December 16, 2013 and February 28, 2014 with data in the PRoGREss registry are included in this retrospective analysis. Each patient completed the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 (FACIT-Sp-12) and -Fatigue (FACIT-F), and the Functional Assessment of Cancer Therapy-General and -Brain (FACT-G and FACT-Br). Results Mean age was 49.1 years (SD = 13.5 years), male (N = 328, 54.1%), married (N = 404, 66.7%), at least college-educated (N = 381, 62.9%), and diagnosed with a high-grade glioma (N = 412, 68.0%). Multiple regression analyses were performed on both the FACT-G and the FACT-Br using the FACIT-Sp-12 sub-scales of Meaning/Peace and Faith, FACIT-F, belief in God or a higher power, prayer, gender, tumor grade, and Karnofsky Performance Status (KPS) as predictors. We found that greater SWB (measured by FACIT-Sp-12) was associated with better HRQoL (measured by FACT-G and FACT-Br; p < .0001). Conclusion The association between reported SWB and reported improved HRQoL emphasizes the importance of spirituality in primary brain tumor patients, suggesting SWB must be considered in strategies to improve HRQoL.

CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150–200 mg/m2/day × 5 days every 28 days) were randomized to Arm-A (ondansetron 8 mg days 1–5 with aprepitant day 1: 125 mg, days 2–5: 80 mg) or Arm-B (ondansetron). Randomization was stratified by tumor grade and number of prior chemotherapy regimens. The primary endpoint was the percentage of patients achieving complete control (CC), defined as no emetic episode or antiemetic rescue medication over the 7-day study period. Secondary endpoints included CINV efficacy in the acute phase (≤ 24 h) and delayed phase (days 2–7), as well as safety and quality of life (QoL). Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity. Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV’s effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.

Background and purpose Little is known about complementary and integrative health intervention usage in the primary brain tumor population. We aimed to identify the percentage of patients using these practices and explore the impact on quality of life. Materials and methods Clinical records from patients seen in clinic between December 16, 2013 and February 28, 2014 were reviewed retrospectively. The questionnaires used were a modified version of the International Complementary and Alternative Medicine Questionnaire, the Functional Assessment of Cancer Therapy- Brain Cancer and the Functional Assessment of Chronic Illness Therapy- Fatigue. Results 76% of patients utilized a complementary and integrative health modality. The most frequently reported modalities used were vitamins, massage, and spiritual healing, prayer, diet and meditation. Conclusion These results confirm the usage of complementary and integrative health practices within the primary brain tumor population; however, there was no evidence of association between use and quality of life.

BACKGROUND PVSRIPO is a live-attenuated recombinant rhino:poliovirus that mediates antitumor efficacy by engaging antitumor immunity. A subset (~20%) of patients with recurrent GBM (rGBM) survive >24 months after therapy. We previously reported that low tumor mutation burden (TMB) is associated with longer survival after PVSRIPO and immune checkpoint blockade therapy in rGBM, and that low TMB associates with higher inflammatory gene expression signatures in rGBM tumors. METHODS Clinical features were tested for association with survival after PVSRIPO therapy. Whole exome sequencing and RNA-sequencing of tumors were used to correlate mutational landscape, tumor mutation burden (TMB), and gene expression signatures of patient tumors with survival. An in vitro assay that measures inflammatory responses of patient PBMCs to PVSRIPO was performed. An independent cohort of paired primary and recurrent GBM tumors was used to assess longitudinal changes in TMB and gene expression signatures after standard of care treatment. RESULTS A short time to recurrence and low TMB associated with longer survival after PVSRIPO therapy; these features were not prognostic for longer survival in immunotherapy naïve rGBM cohorts. Unexpectedly, higher pre-treatment polio neutralizing antibody titers were also associated with longer survival after PVSRIPO therapy in two independent clinical cohorts. PBMCs from patients surviving longer after PVSRIPO therapy mounted higher TNF, but lower IFN-a responses after in vitro challenge with PVSRIPO. In analysis of paired primary vs recurrent GBM tumors, we discovered that patients with low TMB upon recurrence were more likely to experience increased tumor inflammation and suppression of overall TMB. Low TMB in rGBM tumors was also associated with neoantigen depletion. Collectively, these observations imply that patients with low TMB and/or shorter duration of standard of care therapy may have intact immune surveillance, and that pre-treatment immunological status may dictate survival response to polio virotherapy.

ObjectivesStandard 6-week and hypofractionated 3-week courses of adjuvant radiation therapy (RT) are both options for older patients with glioblastoma (GBM), but deciding the optimal regimen can be challenging. This analysis explores clinical factors associated with selection of RT course, completion of RT, and outcomes following RT.Materials and MethodsThis IRB-approved retrospective analysis identified patients ≥70 years old with GBM who initiated adjuvant RT at our institution between 2004 and 2016. We identified factors associated with standard or hypofractionated RT using the Cochran-Armitage trend test, estimated time-to-event endpoints using the Kaplan-Meier method, and found predictors of overall survival (OS) using Cox proportional hazards models.ResultsSixty-two patients with a median age of 74 (range 70–90) initiated adjuvant RT, with 43 (69%) receiving standard RT and 19 (31%) receiving hypofractionated RT. Selection of short-course RT was associated with older age (p = 0.04) and poor KPS (p = 0.03). Eight (13%) patients did not complete RT, primarily for hospice care due to worsening symptoms. After a median follow-up of 37 months, median OS was 12.3 months (95% CI 9.0–15.1). Increased age (p < 0.05), poor KPS (p < 0.0001), lack of MGMT methylation (p < 0.05), and lack of RT completion (p < 0.0001) were associated with worse OS on multivariate analysis. In this small cohort, GTV size and receipt of standard or hypofractionated RT were not associated with OS.ConclusionsIn this cohort of older patients with GBM, age and KPS was associated with selection of short-course or standard RT. These regimens had similar OS, though a subset of patients experienced worsening symptoms during RT and discontinued treatment. Further investigation into predictors of RT completion and survival may help guide adjuvant therapies and supportive care for older patients.

Background The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. Methods We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase. Results From May 2012 through May 2017, a total o...

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m2 po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2–67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.

Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non–small cell lung cancer (NSCLC) patients. Experimental Design: This is a single-arm chemotherapy plus phased ipilimumab phase II study of 24 treatment-naïve patients with stage IB–IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles. Results: Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs. Conclusions: This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies. Clin Cancer Res; 23(24); 7474–82. ©2017 AACR.

Introduction: Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM. Methods and materials: All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ≥4 BM were included in this institutional review board–approved, retrospective, single-institution study. Patients were treated with linear accelerator–based image guided SRS. Results: A total of 59 patients with ≥4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8 cc (range, 0.7-28.8 cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20 Gy. The median of the mean dose to the total PTV was 19.5 Gy. Although the number of treated lesions (4-5 vs ≥6) did not influence survival, better survival was noted for a total PTV 12 Gy to ≥10 cc of normal brain had worse survival (5.1 vs 8.6 months, respectively; P = .0028). Conclusion: In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12 Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.

Background Stereotactic radiosurgery (SRS) offers excellent local control for brain metastases (BM) with low rates of toxicity. Radiation necrosis (RN) may occur after treatment and is challenging to distinguish from local recurrence (LR). We evaluated enlarging brain lesions following SRS that were subsequently biopsied to differentiate RN versus LR. Methods This study reviewed patients receiving SRS for BM between 2008 and 2012 who underwent a biopsy for suspicion of RN versus LR on MRI. Data collection included demographics, radiation parameters, imaging findings, and post-biopsy pathology. Kaplan-Meier methods determined overall survival. Fisher's exact test assessed for association between lesion biopsy result and variables of interest. Results Thirty-four patients with 35 biopsied BM were included. Lesions were biopsied a median of 8.8 months after SRS. Most patients had primary lung cancer (11; 31.4%). Eleven (31.4%) biopsies were positive for LR and 24 (68.6%) showed RN only. Median overall survival was longer for patients with RN (31.0 mo) than for patients with LR (14.5 mo; P = 0.135). Time from SRS to biopsy was significantly different between RN and LR groups; 10 lesions (52.5%) biopsied ≤9 months after SRS showed LR, whereas 1 lesion (6.3%) biopsied >9 months after SRS showed LR (P = 0.004). For 16 (65.7%) lesions, management was changed or directed by the biopsy results. Conclusions Stereotactic biopsy for accessible enlarging lesions after SRS appears diagnostically valuable in patients with few lesions and changes clinical management. RN should be suspected in patients with an enlarging lesion more than 9 months post-SRS.

BACKGROUND The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We have previously reported that deep sequencing of biopsy material obtained prior to PVSRIPO infusion confirmed that a very low mutational load is associated with longer survival. METHODS Patient tumor material from both phase I and 2 clinical trials was collected pre PVSRIPO. When available, post-treatment tissue from longitudinal samples were also collected. Tissue was subjected to RNA sequencing, histological analysis, and flow cytometry analysis. RNAseq analyses were performed comparing pre- and post- treatment expression profiles and computational predictions of tumor immune composition deciphered changes after PVSRIPO therapy. Histology and flow cytometry quantitated myeloid, CD8/4/regulatory T cell densities, and other immune cell types after treatment and compared to baseline tissue similarly analyzed to detect changes. RESULTS To date, analysis of phase 1 trial data has demonstrated a correlation between low TMB and increased markers of immunological gene expression profiles. This trend was not observed in TCGA samples that were almost exclusively primary GBM suggesting and interplay with prior therapy or evolution with recurrence. CONCLUSION Our findings presented here suggest that response to PVSRIPO therapy, and possibly that of other modalities engaging innate antiviral signatures in situ, may be dependent upon prevailing tumor microenvironment composition/status at the time of treatment.

Background Overall survival (OS) in glioblastoma (GBM) is poor at an average of 14 to 18 months, and long-term survivors (LTS) of GBM are rare. LTS of GBM, defined as surviving >5 years postdiagnosis, represent only 2% to 10% of all GBM patients. LTS of cancer are at high risk of developing second primary neoplasms. This study looks at occurrences of second primary neoplasms in LTS of GBM. Methods Records from adult patients newly diagnosed with GBM between January 1, 1998 and February 8, 2010, were retrospectively reviewed to identify LTS, defined as patients who survived ≥5 years. We focused on the identification of a new diagnosis of cancer occurring at least 2 years after the initial GBM diagnosis. Results We identified 155 LTS of GBM, with a median OS of 11.0 years (95% CI: 9.0 to 13.1 years) and a median follow-up of 9.6 years (95% CI: 8.7 to 10.7 years). In this cohort of patients, 13 (8.4%) LTS of GBM developed 17 secondary cancers. Eight could potentially be attributed to previous radiation and chemotherapy (skin cancer in radiation field [n = 4], leukemia [n = 2], low-grade glioma [n = 1], and sarcoma of the scalp [n = 1]). The other 9 cases included melanoma (n = 2), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1). Conclusions Although second primary cancers are rare in GBM LTS, providers should continue close monitoring with appropriate oncologic care. Moreover, this highlights the need for survivorship care of patients with GBM.

Mary Lou Affronti,1–3 Sarah Woodring,1,2 Katherine B Peters,1,4 James E Herndon II,5 Frances McSherry,5 Patrick N Healy,5 Annick Desjardins,1,4 James J Vredenburgh,6 Henry S Friedman1,2 1The Preston Robert TischBrain Tumor Center at Duke, South Hospital, Duke University Medical Center, 2Department of Neurosurgery, Duke University Health System, 3Duke University School of Nursing, 4Department of Neurology, 5Department of Biostatistics and Bioinformatics, Duke University Health System, Durham, NC, 6Saint Francis Cancer Center, Hartford, CT, USA Purpose: Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan–bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2–5), overall CINV CR (days 1–5), and QoL, fatigue, and toxicity.Materials and methods: A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL–DEX. Validated surveys assessed fatigue and QoL.Results: A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL–DEX dose administrations 1–3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade≥3 PAL–DEX treatment-related toxicities.Conclusion: Data suggest that PAL–DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma. Keywords: chemotherapy, nausea, chemotherapy-induced nausea and vomiting, antiemetic guidelines, evidence-based practice, glioma

In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control. We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54–60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m2/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67–79 %. Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.

INTRODUCTION: Meningiomas, the most common CNS neoplasm, are often deemed less threatening than their glial counterparts. Unfortunately, these tumors recur and necessitate surgery, radiation, and/or systemic treatment. We explored the psychosocial distress of patients with recurrent meningioma using The National Comprehensive Cancer Network Distress Thermometer (NCCN-DT) and Problem List. METHODS: This was a retrospective analysis of patients with recurrent meningioma seen at the Preston Robert Tisch Brain Tumor Center between 12/31/2004–10/10/2018 who completed a NCCN-DT and Problem List. The first or only NCCN-DT assessment after initial recurrence was used for analysis with a score of 4 indicating moderate to severe distress. RESULTS: 45 patients were identified, 56% female, median age was 61 years and 58% had unifocal disease. 60% were Grade 1, 33% Grade II, 4% Grade III, and 2% indeterminate recurrent meningioma. The median NCCN-DT score was 3, and 49% had a NCCN-DT score 4 indicating moderate to severe distress. 64% of females vs 30% of males reported distress scores 4 (p=0.04). 65% of patients with unifocal disease reported 4 scores compared to 26% with multifocal disease (p=0.02). Fatigue (N=24), Worry (N=23), Nervousness (N=22), Depression (N=19) and Memory/Concentration (N=19) were the most commonly reported problems. A higher incidence of worry among females (64%) than males (35%) was the only problem showing a trend towards significance (p=0.08). Between initial recurrence and NCCN assessment, the type and number of treatments patients received included: surgery (median=1, range 0–5), radiation (median=2, range 0–5), systemic treatment (median=2, range 0–12). There was no association between distress and the number of surgeries (p=0.99), radiation treatments (p=0.49) or systemic therapies (p=0.87). CONCLUSIONS: In our study population, nearly half of recurrent meningioma patients reported moderate to severe distress. Therefore, even in this benign tumor population, the NCCN-DT and problem list should be administered at every clinic visit.

Two of our previous clinical trials targeting Cytomegalovirus (CMV) protein pp65 in newly diagnosed glioblastoma (GBM) using pp65-specific dendritic cell (DC) vaccines have yielded long term survival rates greatly exceeding those predicted with standard of care. In the ATTAC trial (IND 12839), patients received sequential DC vaccination throughout monthly cycles of standard temozolomide (STD-TMZ) 200mg/m(2)/d for 5d and were randomized to one of two vaccine site preconditioning regimens. Significantly higher rates of DC migration (p=0.04) and survival (p=0.013) were observed in patients randomized to tetanus preconditioning, with half of the cohort living to nearly five years after diagnosis. In the ATTAC-GM trial, we treated a subsequent cohort with dose-intensified TMZ (DI-TMZ) 100mg/m(2)/d for 21d prior to and throughout vaccination with GM-CSF-containing DC vaccines and observed extraordinarily prolonged progression-free survival (PFS) and overall survival (OS) (median 25.3 and 41.1 months, respectively). In this trial, DI-TMZ-induced lymphopenia facilitated homeostatic expansion of pp65 responses after an initial DI-TMZ cycle but later ablated T cell responses when monthly cycles were reintroduced. The benefit of DI-TMZ thus warrants further study in a larger series of patients. Here we describe the initiation of a validation trial, “I-ATTAC: Improved Anti-Tumor Immunotherapy Targeted Against Cytomegalovirus in Patients with Newly-Diagnosed WHO Grade IV Unmethylated Glioma” (IND-16301). This prospective single arm Phase 2 trial of 48 patients will validate our findings that tetanus preconditioning and GM-CSF in conjunction with pp65-DCs extends OS in patients with newly diagnosed, unmethylated GBM. By withholding additional TMZ cycles in this patient population, we hypothesize that CMV immune responses will not be abrogated as previously observed, and that this greater expansion will translate into further prolonged survival (primary objective). A series of secondary objectives will be evaluated for the association between increased DC migration, systemic mediators of tetanus preconditioning, and T cell polyfunctionality with survival.

BACKGROUND: Prognosis of recurrent World Health Organization (WHO) grade IV malignant glioma (GBM) in children is dismal with no effective therapy. We have recently performed a dose-finding and toxicity study within adults with GBM, evaluating the recombinant non-pathogenic polio/rhinovirus chimera (PVSRIPO) by intratumoral convection-enhanced delivery (CED). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of tumor stroma. We have commenced a Phase Ib study to evaluate feasibility, safety, and preliminary evidence of efficacy of the optimal adult dose in a pediatric population. METHODS: Patients with a recurrent supratentorial WHO Grade III malignant glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, anaplastic pleomorphic xanthoastrocytoma, ependymoma) or WHO Grade IV malignant glioma (glioblastoma, gliosarcoma) based on imaging studies with measurable disease (≥ 1 cm and ≤ 5.5 cm of contrast-enhancing tumor) will be enrolled. A stereotactic biopsy will be performed prior to virus administration. Immediately following the stereotactically-guided tumor biopsy, a catheter will be implanted in the operating room. PVSRIPO will then be delivered intratumorally by CED, using the catheter placed within the enhancing portion of the tumor, at a dose of 5 x 10(7) TCID over 6.5 hours. CONCLUSION: We will confirm the activity of intratumoral PVSRIPO infusion in recurrent WHO grade III or IV malignant glioma in the absence of neurovirulent potential in children.

Lessons Learned Due to evolving imaging criteria in brain tumors and variation in magnetic resonance imaging evaluation, it is not ideal to use response rate as a primary objective. Future studies involving antiangiogenic agents should use overall survival. Disease-expected toxicities should be considered when defining the clinical significance of an adverse event. For example, vascular thromboembolic events are common in brain tumor patients and should not be attributed to the study drug in the safety analysis. Background Recurrent malignant glioma (rMG) prognosis is poor, with a median patient survival of 3–11 months with bevacizumab (BEV)-containing regimens. BEV in rMG has 6-month progression free survival (PFS-6) of ∼40% and an objective response rate of 21.2%. BEV-containing regimens improve PFS-6 to 42.6%–50.3%, indicating that BEV combination therapies may be superior to single agent. Rilotumumab, a hepatocyte growth factor (HGF) antibody, inhibits angiogenesis and expression of angiogenic autocrine factors (e.g., vascular endothelial growth factor [VEGF]) by c-Met inhibition. Combination of rilotumumab with BEV to block vascular invasion and tumor proliferation may synergistically inhibit tumor growth. Methods Thirty-six BEV-naïve rMG subjects received rilotumumab (20 mg/kg and BEV (10 mg/kg) every 2 weeks. Endpoints included objective response rate (using Response Assessment in Neuro-Oncology [RANO] criteria), PFS-6, overall survival (OS), and toxicity. Results Median patient follow-up was 65.0 months. Objective response rate was 27.8% (95% confidence interval [CI]: 15.7%–44.1%). Median OS was 11.2 months (95% CI: 7–17.5). PFS-6 was 41.7% (95% CI: 25.6%–57.0%). Most frequent treatment-related grade ≤2 events included weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥3 events included venous thromboembolism (four patients), including one death from pulmonary embolism. Conclusion Rilotumumab with BEV did not significantly improve objective response compared with BEV alone, and toxicity may preclude the use of rilotumumab in combination BEV regimens.

Background The objective of this study was to evaluate the safety and feasibility of using neoadjuvant chemotherapy plus ipilimumab followed by surgery as a treatment strategy for stage II-IIIA non-small cell lung cancer. Methods From 2013 to 2017, postoperative data from patients who underwent surgery after neoadjuvant chemotherapy plus ipilimumab in the TOP1201 trial, an open label phase II trial (NCT01820754), were prospectively collected. The surgical outcomes from TOP1201 were compared with outcomes in a historical cohort of patients receiving standard preoperative chemotherapy followed by surgery identified from our institution's prospectively collected thoracic surgery database. Results In the TOP1201 trial, 13 patients were treated with preoperative chemotherapy and ipilimumab followed by surgery. In the historical cohort, 42 patients received preoperative chemotherapy by a platinum doublet regimen preoperative chemotherapy by a platinum doublet regimen without ipilimumab followed by lobectomy or pneumonectomy. The 30-day mortality in both groups was 0%. The most frequently occurring perioperative complications in the TOP1201 group were prolonged air leak (n = 2, 15%) and urinary tract infection (n = 2, 15%). The most common perioperative complication in the preoperative chemotherapy alone group was atrial fibrillation (n = 6, 14%). One patient (8%) had atrial fibrillation in the TOP1201 group. There was no apparent increased occurrence of adverse surgical outcomes for patients in the TOP1201 group compared with patients receiving standard of care neoadjuvant chemotherapy alone before surgery for stage II–IIIA non-small cell lung cancer. Conclusions This report is the first to demonstrate the safety and feasibility of surgical resection after treatment with ipilimumab and chemotherapy in stage II–IIIA non-small-cell lung cancer.

Primary brain tumor patients experience high levels of distress. The purpose of this cross-sectional, retrospective study is to evaluate the level and different sources of psychosocial distress and how these pertain to health-related quality of life (HRQoL). The Primary and Recurrent Glioma registry at Duke’s The Preston Robert Tisch Brain Tumor Center was queried retrospectively for demographic and clinical information on patients seen between December 2013 and February 2014. Data also included the National Comprehensive Cancer Network’s Distress Thermometer (NCCN-DT), Functional Assessment of Cancer Therapy-Brain Cancer (FACT-Br), and Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). 829 subjects completed questionnaires. 54% were male; 96% completed the NCCN-DT; 33.3% had a DT score ≥4 (moderate/severe distress). Women reported DT ≥ 4 more often than men (38.6 vs 29.0%; p = 0.005). Patients within 1 year of diagnosis reported DT ≥ 4 more often than those 1+ years after diagnosis (38.8 vs 30.9%; p = 0.034). 73.0% reported physical problems; the most frequent being fatigue (43.2%) and memory/concentration (40.9%). 42.0% complained of emotional problems with worry (29.4%) and nervousness (22.4%) being the most common. Patients who reported at least one practical, family, emotional or physical problem had significantly lower HRQoL scores (p

Quality of life (QoL) impairment and fatigue are frequently experienced during treatment for recurrent high-grade glioma (HGG). Fatigue and QoL impairments can be due to primary neurological dysfunction, cytotoxic treatments, mood disturbances, and supportive medications. We now seek to understand how QoL and fatigue impacts survival in recurrent HGG. Using a prospective observational design, 237 patients with recurrent HGG and KPS ≥70 completed a self-administered questionnaire that evaluated QoL and fatigue. QoL was assessed with Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Brain (FACT-Br) scales while fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT-F) scale. Cox proportional hazard models were utilized to evaluate the association between QoL and fatigue and survival. Seventy-three (31 %) subjects had recurrent WHO grade III gliomas and 164 (69 %) had recurrent WHO grade IV gliomas. Median follow-up analysis was 27.60 months. In univariate Cox analyses, the FACT-Br specific subscale (HR 0.88; CI 95 %, 0.77-1; p = 0.048) and FACIT-F (HR 0.82; CI 95 %, 0.68-0.99; p = 0.045) were both significant predictors of survival. Fatigue added prognostic information beyond that provided by KPS, age, sex, tumor grade, and number of prior progressions (HR 0.80; CI 95 %, 0.68-0.9; p = 0.031). A greater degree of fatigue was associated with poorer survival in recurrent HGG patients. In multivariable analyses, FACT-G and FACT-Br are not independent predictors of prognosis. Fatigue is a strong independent predictor of survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent HGG. Pharmacological or non-pharmacological strategies to treat fatigue warrant investigation.

The purpose of this study was to examine the relationship between self-reported exercise behavior, cardiorespiratory fitness (CRF), and cognitive function in early breast cancer patients. Thirty-seven breast cancer patients following completion of chemotherapy (median 16 months) and 14 controls were studied. Cognitive function was assessed using the Central Nervous System (CNS) Vital Signs software (CNS Vital Signs, LLC, Morrisville, N.C., USA), a computerized test battery consisting of 9 cognitive subtests. Exercise behavior was evaluated using the Godin Leisure Time Exercise Questionnaire, and CRF was assessed via a cardiopulmonary exercise test to assess peak oxygen consumption. Patients’ mean total exercise was 184 ± 141 min·week−1 compared with 442 ± 315 min·week−1 in controls (p < 0.001). Significantly fewer patients (32%) were meeting exercise guidelines (i.e., ≥150 min of moderate-intensity or vigorous exercise per week) compared with 57% of controls (p = 0.014). Patients’ peak oxygen consumption averaged 23.5 ± 6.3 mL·kg–1·min−1 compared with 30.6 ± 7.0 mL·kg–1·min−1 in controls (p < 0.01). Scores on the cognitive subdomains were generally lower in patients compared with controls, although only the difference in verbal memory was significant (unadjusted p = 0.041). In patients, weak to moderate correlations were indicated between exercise, peak oxygen consumption, and the majority of cognitive subdomain scores; however, there was a significant positive correlation between exercise and visual memory (r = 0.47, p = 0.004). In conclusion, breast cancer patients following the completion of primary adjuvant chemotherapy exhibit, in general, worse cognitive performance than healthy women from the general population, and such performance may be related to their level of exercise behavior.

2060 Background: We completed a study evaluating a single intratumoral delivery of PVSRIPO in recurrent WHO grade IV MG patients (N Engl J Med. 2018 Jul 12;379(2):150-161). Some patients who originally benefitted from the infusion of PVSRIPO demonstrated tumor recurrence, and we hypothesized that retreatment could trigger an immune recall effect, further extending their survival. We now report the impact of second and third intratumoral reinfusion of PVSRIPO in patients treated in the original dose finding study. Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG who were experiencing disease recurrence after having benefitted from the first infusion of PVSRIPO. Additional eligibility criteria included: solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. One patient each was retreated at 1 x 107 TCID50 and 1 x 1010 TCID50, and three patients were retreated on the identified phase 2 dose of 5 x 107 TCID50. Results: As of 2/09/2019, five patients have received a second intratumoral dose of PVSRIPO on study, one of which received a total of 3 doses. The patients who received two infusions of PVSRIPO were retreated 72 months, 43 months, 34 months, and 6 months after the first infusion. One additional patient received a second infusion of PVSRIPO 60 months after the first infusion and a third infusion of PVSRIPO 78 months after the first infusion. All patients demonstrated soap bubble degeneration on imaging, and two patients demonstrated tumor contraction. No grade 3 or higher adverse events related to PVSRIPO were observed after retreatment. Three of these patients remain alive more than 81, 80 and 52 months following the first PVSRIPO infusion and more than 9, 20 and 18 months after the second infusion, respectively. Two patients died 63 months and 20 months after the first infusion of PVSRIPO and 19.6 and 14 months after the second, respectively. The patient treated 3 times received the third infusion more than 2 months ago. Conclusions: Intratumoral reinfusion of PVSRIPO via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT01491893.

Background and aims This retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with bevacizumab in a real‐world setting. Methods Adult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan‐Meier estimator was used to describe overall survival (OS), progression‐free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected. Results Seventy‐four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5‐58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval [CI], 7.3‐13.4) and 6.4 months (95% CI, 3.9‐8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8‐∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6‐16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8‐12.5) in those who did (P = 0.0382, log‐rank), while median PFS values were 8.6 months (95% CI, 4.6‐9.7) and 3.7 months (95% CI, 2.7‐6.6), respectively (P = 0.0243, log‐rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab. Conclusions Treatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real‐world setting were comparable with those reported in prospective clinical trials.

Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG.Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status.One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months.Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Background As reported previously, 140 methamphetamine-dependent participants at eight medical centers in the U.S. were assigned randomly to receive topiramate ( N = 69) or placebo ( N = 71) in a 13-week clinical trial. The study found that topiramate did not appear to reduce methamphetamine use significantly for the primary outcome (i.e., weekly abstinence from methamphetamine in weeks 6–12). Given that the treatment responses varied considerably among subjects, the objective of this study was to identify the heterogeneous treatment effect of topiramate and determine whether topiramate could reduce methamphetamine use effectively in a subgroup of subjects. Methods Latent variable analysis was used for the primary and secondary outcomes during weeks 6–12 and 1–12, adjusting for age, sex, and ethnicity. Results Our analysis of the primary outcome identified 30 subjects as responders, who either reduced methamphetamine use consistently over time or achieved abstinence. Moreover, topiramate recipients had a significantly steeper slope in methamphetamine reduction and accelerated to abstinence faster than placebo recipients. For the secondary outcomes in weeks 6–12, we identified 40 subjects as responders (who had significant reductions in methamphetamine use) and 65 as non-responders; topiramate recipients were more than twice as likely as placebo recipients to be responders (odds ratio = 2.67; p = 0.019). Separate analyses of the outcomes during weeks 1–12 yielded similar results. Conclusions Methamphetamine users appear to respond to topiramate treatment differentially. Our findings show an effect of topiramate on the increasing trend of abstinence from methamphetamine, suggesting that a tailored intervention strategy is needed for treating methamphetamine addiction.

Background Patient with neurological disorders and cancer can develop sleep disturbance, in particular insomnia. Etiology of insomnia is multi-factorial in primary brain tumour patients with possible causes including corticosteroids, psychoactive medications, co-morbid psychiatric/medical conditions, and damage to neuronal tissue. Findings To understand better insomnia in recurrent glioma patients, a single-center retrospective analysis was performed looking at recurrent glioma patients from January 2004 to May 2009. Data was extracted and included demographics, clinical factors, psychoactive medications, and co-morbid symptoms. Presence and absence of insomnia complaints was evaluated with other co-morbidities using Chi square and Wilcoxon analyses. Records from 340 recurrent glioma patients were evaluated and 46.8 % (n = 159) indicated presence of insomnia with 20 % (n = 66) actively using medications for sleep. Use of corticosteroids were significantly associated with insomnia (p = 0.0003). Age, gender, tumour location, use of stimulants, antipsychotics, and antidepressants were not significantly associated with insomnia in recurrent glioma patients. There was a trend towards a possible significant association with insomnia to fatigue complaints and use of anti-epileptics, p-values of 0.0501 and 0.0725 respectively. Conclusions In conclusion, insomnia is commonly encountered in patients with recurrent glial tumors. Corticosteroid use is associated with insomnia in this population. In light of the frequency of insomnia and its associations, future analysis is warranted into sleep complaints in recurrent glioma patients and its impact on quality of life.

Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.

Aims Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction. Design Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. Setting The trial was conducted at eight medical centers in the United States. Participants One hundred and forty methamphetamine-dependent adults took part in the trial. Measurements The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. Findings In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated. Conclusions Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.

BACKGROUND: Nausea (N) and vomiting (V) continues to be one of the most feared side effects of individuals undergoing cancer treatment with 10–40% (or 60–90% not) experiencing NV with modern-day antiemetics. Trials establishing antiemetic guidelines excluded glioma patients. OBJECTIVES: To assess overall NV efficacy and safety across multiple glioma trials using palonosetron (PAL), aprepitant plus ondansetron, or ondansetron alone in glioma patients receiving either concomitant radiation therapy and temozolomide, adjuvant temozolomide post-chemoradiation, or irinotecan and bevacizumab in the recurrent setting. METHODS: Review of 270 patients enrolled in four Phase II glioma antiemetic trials was conducted to evaluate complete response (CR) rate defined as no vomiting or use of rescue anti-emetic on day 1 (Acute-CR), days 2–5/7 (Delayed-CR), and overall (Complete Control: CC) during 1 week of treatment. Chemotherapy-induced nausea (CIN) and vomiting (CIV) rates were defined as no nausea or no vomiting during the study period, respectively. RESULTS: Mean age=54.8, 61% male, median KPS 80%, 83% GBM. CC for patients receiving PAL with radiation and temozolomide was 74%; Acute-CR was 87%; Delayed-CR was 82%. CIN rates (6779%) were less than CIV rates (8797%). For 63 recurrent patients receiving irinotecan and bevacizumab, the CC rate was 47%, Acute-CR was 62%, and Delayed-CR was 62%. PAL with 5-day adjuvant temozolomide demonstrated a CC of 88%, Acute-CR of 94%, and Delayed-CR of 88 % in 33 patients. CR rates for the 70 patients in the aprepitant/ondansetron arm receiving adjuvant temozolomide were CC: 58.6%; Acute-CR: 97.1%; Delayed-CR: 58.6% and for the 66 in the ondansetron alone arm were CC: 54.5%; Acute-CR 87.9%; Delayed-CR 57.6%. Main attributable adverse events included constipation, headache, and diarrhea and were all grade 1–2. CONCLUSIONS: Review of NV rates in glioma patients are comparable to other cancers. Meta-analysis and safety results will be presented.

BACKGROUND: The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report results of the dose finding trial evaluating PVSRIPO delivered intratumorally by convection-enhanced delivery (CED). METHODS: Eligible patients were adults with recurrent supratentorial WHO grade IV MG; solitary tumor 1–5.5cm in diameter; 4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS70%; and positive anti-polio titer. RESULTS: A total of 61 pts were treated on study. Only one DLT was observed, a grade 4 intracranial hemorrhage at the time of catheter removal on DL5. Study related adverse events consisted of localized peritumoral inflammation, triggering neurologic symptoms in relation to the location of the infused tumor. Of the 26 patients treated more than 36 months ago, six are alive at 73.6+, 72.5+, 60.6+, 44.0+, 39.3+, and 36.9+ months. Deep sequencing of biopsy material obtained prior to PVSRIPO infusion in 31 samples, confirmed that a very low mutational load is associated with longer survival (p=0.017). Additionally, no patients whose tumors had >0.5 non-synonymous mutations per Mb survived beyond 18 months. CONCLUSION: Infusion of PVSRIPO via CED is safe and encouraging efficacy results were observed in adults along with mutational correlates of response.

92 Background: Cancer survivors have high rates of sedentary behavior leading to obesity and cardiovascular disease. Physical activity improves quality of life (QOL) and reduces morbidity and mortality. However, cancer survivors commonly cite motivation as a barrier to increasing physical activity. We hypothesized that a motivational text-messaging feedback system linked to a Fitbit Flex activity tracker would increase the activity level of survivors and those undergoing cancer treatment. Methods: 29 participants were enrolled in an IRB-approved single-institution study. Eligibility allowed any cancer/stage, ≤2 days of exercise per week, life expectancy of 12+ months, and smartphone access. After baseline fitness/QOL testing, participants were provided a Fitbit Flex activity tracker. A text-messaging program automatically uploaded data from the tracker via an application programming interface and provided personalized text message feedback to subject’s smartphone daily for 3 months. Primary endpoint was change in step count from baseline to 3 months, with additional endpoints of change in 6 minute walk/QOL measures at 3 months, and continued exercise/use of tracker at 6 months. Results: To date, 24 have completed the 3 month program. Both academic and community sites participated, including areas with limited internet access. Most participants were female (71%) and white (63%). Eight cancer types and all stages were represented. Three participants withdrew – one because of lost tracker, one cancer death, and one “disappointed” with tracker function. Median daily steps at baseline were 3773 (IQR 2928) and 4365 at 3 months (IQR 4864). 42% had at least a 20% increase in median step count at 3 months. Improvement was noted in 45% of survivors and 38% of active treatment participants. Participants frequently used research nurses for guidance on use of wearable tracker (e.g. syncing, charging, features). Conclusions: Activity tracker with personalized daily feedback via text message successfully motivates cancer patients to increase daily activity. Patients are interested in health technology, but require technical support and coaching to maintain use. Clinical trial information: NCT02627079.

BACKGROUND: Prognosis of recurrent MG remains poor with a median survival of 3-11 months for patients on BEV-containing regimens. Few active evidence-based treatments are available & response rates have been

Lessons Learned Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy. Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. Background. Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. Methods. Patients received up to 4 cycles of TMZ at 200 mg/m2 per day on days 1–5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m2 or 340 mg/m2 depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. Results. Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial respons!e, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2–13.5 months). Conclusion. Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.

Objective: Three genetic mutations have been associated with an increased risk of thromboembolic events: factor V Leiden R506Q, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T (MTHFR) mutations. The aim of this study was to determine the effect of these mutations on patency of peripheral bypass procedures and preoperative and postoperative thromboembolic events. Methods: Two hundred forty-four randomly selected volunteers participating in the Veterans Affairs Cooperative Study #362 were tested for factor V Leiden, prothrombin, or MTHFR mutations with polymerase chain reaction. Patients enrolled in the study were randomized to receive aspirin therapy or aspirin and warfarin therapy after a peripheral bypass procedure. The frequencies of preoperative and postoperative thromboembolic events and primary patency (PP), assisted primary patency (APP), and secondary patency (SP) rates were compared among carriers of the various mutations. Results: Fourteen patients (5.7%) were heterozygous for the factor V Leiden mutation, seven (2.9%) were heterozygous for the prothrombin mutation, and 108 (44.6%) were heterozygous and 15 (6.2%) homozygous for the MTHFR mutation. After surgery, patients homozygous for the MTHFR gene mutation had increased graft thrombosis, compared with patients who were heterozygous (33.3% versus 11.1%; P = .01), and lower PP, APP and SP rates (P < .05). Furthermore, patients heterozygous for the MTHFR mutation had fewer graft thromboses (11.1% versus 24.4%; P = .01), fewer below-knee amputations (0.9% versus 7.6%; P = .02), and higher PP, APP, and SP rates (PP, 79.6%; APP, 88.9%; SP, 90.7%; P < .05) compared with wild-type control subjects (PP, 63%; APP, 75.6%; SP, 76.5%; P < .05). Conclusion: Patients with either factor V Leiden or prothrombin mutations were not at an increased risk for postoperative graft occlusion or thromboembolic events. Patients heterozygous for MTHFR mutation had a lower risk of graft thrombosis and higher graft patency rates compared with both homozygous and wild-type control subjects. Patients homozygous for the MTHFR mutation had lower graft patency rates compared with patients who were heterozygous, and a trend was seen toward lower patency rates compared with wild-type control subjects. Therefore, screening for the MTHFR gene mutation before surgery may identify patients at an increased risk of graft thrombosis. (J Vasc Surg 2002;36:1198-206.)

In this study we used the DIG trial database to determine whether clinical variables used in combination could accurately predict left ventricular EF for individual patients with HF. The prediction model was able to identify within 0.05 (± 5 EF U) the correct numerical EF only 45% of the time. Although categorical analysis showed that nearly all of the 38% of patients who had the lowest predicted EF actually had EF ≤0.45, this method was unreliable for the remaining 62% of patients.

Lessons Learned Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma. Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens. Background Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression-free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM. Materials and Methods In this phase II, single-center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28-day cycle. The primary endpoint was 6-month PFS (PFS6). Results Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%–44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6–12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment-related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified. Conclusion Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy.

Complementary and Alternative Medicine (CAM) uses diverse practices and products that are not a part of standard of care while Integrative Medicine combines both CAM and conventional medicine. Given the poor prognosis of glioblastoma (GBM), many patients will explore other options to improve survival or quality of life. We sought to examine the association between CAM modalities and survivorship. In this cross-sectional retrospective analysis, data about CAM treatment and self-help practices were obtained from the modified International Complementary and Alternative Medicine Questionnaire (I-CAM-Q). CAM treatment included modalities such as vitamins/supplements, massage, energy work, or acupuncture, while CAM self-help practices consisted of praying, exercise, visualization, meditation, relaxation, or diet. Survival was defined by date of questionnaire completion to date of death. There were 365 GBM patients (31% censored) with a median overall survival (mOS) of 14.1months, 95% CI: 12.2, 17.0. Those patients who used CAM self-help practices (n=188, mOS =16.2 months, 95% CI: 12.2, 18.1) and CAM treatments (n=237, mOS = 15.5 months, 95% CI: 9.9, 18.1) did not have any association with survival compared to those who did not use self-help (n=65; mOS = 20.9 months, 95% CI: 12.7, 39.1) or CAM treatments (n=74, mOS = 15.5 months, 95% CI: 9.9, 18.1). The most popular modalities used, prayer (n=171, 15.1 vs 22.7 months) and supplements (n=220; 14.7 vs 16.5 months) were also not associated with survival. The use of CAM was not a predictor of survival whereas those who were multifocal, grade IV, older than 55, or had recurrent disease had significantly poorer survival. It is difficult to accurately predict survival benefit because of this study’s cross-sectional design. Due to the increased interest in CAM in the primary brain tumor population, a prospective analysis utilizing some of these self- help practices or treatments may be warranted.