Significant Improvement In Median Survival Research Articles

The benefit of complete resection of contrast enhancing tumor in glioblastoma patients: A population-based study.

New treatment modalities have not been widely adopted for patients with glioblastoma (GBM) after the addition of temozolomide to radiotherapy. We hypothesize that increased extent of resection (EOR) has resulted in improved survival for surgically treated patients with glioblastoma at the population level. Retrospective analysis of adult patients operated for glioblastoma in the population of South-Eastern Norway. Patients were stratified into Pre-temozolomide- (2003-2005), temozolomide- (2006-2012), and resection-focused period (2013-2019) and evaluated according to age and EOR. The study included 1657 adult patients operated on for supratentorial glioblastoma. The incidence of histologically confirmed glioblastoma increased from 3.7 in 2003 to 5.3 per 100 000 in 2019. The median survival was 11.4 months. Complete resection of contrast-enhancing tumor (CRCET) was achieved in 386 patients, and this fraction increased from 13% to 32% across the periods. Significant improvement in median survival was found between the first 2 periods and the last (10.5 and 10.6 vs. 12.3 months; P < .01), with a significant increase in 3- and 5-year survival probability to 12% and 6% (P < .01). Patients with CRCET survived longer than patients with non-CRCET (16.1 vs. 10.8 months; P < .001). The median survival doubled in patients ≥70 years and (12.1 months). Survival was similar between the time periods in patients where CRCET was achieved. We demonstrate an improved survival of GBM patients at the population level associated with an increased fraction of patients with CRCET. The data support the importance of CRCET to improve glioblastoma patient outcomes.

Preclinical Validation of EZH2 and HDAC I Dual Inhibition As a Potent Therapy for Refractory Myeloid Leukemia Associated with Down Syndrome

Children with Down Syndrome who are less than 5 years old have approximately 400-fold increased risk of developing myeloid leukemia. Even though children with myeloid leukemia associated with Down syndrome (DS-ML) are more sensitive to chemotherapy than their non-DS-ML counterpart, relapse and treatment-related toxicity needs to be eliminated to achieve better outcome for DS-ML children. Epigenetic alterations including DNA methylation and histone modifications play a key role in the pathogenesis of DS-ML. Enhancer of zeste homolog 2 (EZH2) is one of the epigenetic regulators that harbors high frequency of mutations in DS-ML. EZH2 is a catalytic subunit of PRC2 complex which suppresses gene expression by di- and tri-methylation of lysine27 on histone 3 (H3K27me2/3). EZH2 recruits class I histone deacetylases (HDAC, which remove acetyl groups from histones), on target genes for further suppression of gene expression. Using patient-derived xenograft models of DS-ML, we showed previously that combination of DNA hypomethylating agent azacitidine with HDAC inhibitor panobinostat or BCL2 inhibitor venetoclax showed significant improvement in median survival. Here we aimed to show synergistic effect of EZH2 inhibitor, GSK126, and class I HDAC inhibitor, romidepsin. The viability of CMK, a DS-ML cell line, and NTPL-60 and NTPL-386, in house generated DS-ML PDX lines, was determined by exclusion of propidium iodide-stained cells by flow cytometry. IC50 values for GSK126 and romidepsin were calculated using GraphPad Prism (dose-response curve). The IC50 of GSK126 was 40.5, 18.0, and 17.2 mM, while that of romidepsin was 10.2, 9.2, and 3.0 nM respectively. To determine synergy, the viability of cells exposed to a variety of concentrations of GSK126 and romidepsin alone or in combination was measured. Synergy index was calculated using relative risk ratio (RRR) formula as described previously (Quagliano et al, 56:36, Leuk Res, 2017). All the 3 DS-ML lines showed RRR value of less than 1 indicating synergistic inhibition of cell death by GSK126 and romidepsin treatment in ex vivo culture (Figure 1A). NTPL-386, a refractory DS-ML PDX line, which showed minimal response to chemotherapy (11-day improvement in median survival, Barwe et al., 134:2683, Blood, 2019), was chosen to determine the in vivo efficacy of GSK126 and romidepsin combination. NTPL-386 engrafted mice (n=5 each) were treated with GSK126 (100 mg/Kg) and/or romidepsin (2 mg/Kg) twice weekly for three weeks. Thus, one treatment cycle consisted of six doses. A separate cohort of mice were treated with four cycles of the combination, with two weeks rest between cycles. Disease progression was monitored by percentage of human cells in peripheral blood by flow cytometry. Kaplan-Meier survival estimates were plotted based on the time when mice were euthanized because they met pre-determined experimental endpoints. Compared to untreated mice, GSK126 or romidepsin treatment showed an increase in median survival by 8 days and 11 days respectively (Figure 1B, P <0.005). The combination of these drugs showed a remarkable improvement in survival (41 days). The difference in the median survival of the mice treated with the combination was statistically significant when compared to GSK126 or romidepsin (P <0.005). Further treatment for three additional cycles showed sustained remission upto 150 days post cell injection, when the study was terminated. Prolonged treatment showed a statistically significant improvement in survival compared to one treatment cycle (P <0.05). Further studies to characterize the mechanism of synergy are in progress. In summary, our data show a synergistic effect of EZH2 and HDAC class I inhibition on DS-AML growth and pave the path for clinical evaluation of this combination. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Selinexor Prolongs Survival in Patient-Derived Xenograft Models of Down Syndrome Myeloid Leukemia

Background: Selinexor, an inhibitor of the nuclear exportin protein XPO1, has been shown to promote cell cycle arrest and induce apoptosis in acute myeloid leukemia (AML) cells. By inhibiting protein export from the nucleus to the cytoplasm, Selinexor causes nuclear accumulation of proteins including tumor suppressors and translation initiation factor eIF4E, resulting in reduced translation of anti-apoptotic proteins BCL2 and MCL1. Venetoclax, a BCL2 inhibitor, has been considered to synergize with Selinexor in preclinical studies of multiple myeloma (Nguyen et a., Blood, 138:2270, 2021), lymphoma and AML (Fischer et al., Blood Adv, 4:586, 2020). A clinical trial evaluating the combination of Selinexor and venetoclax in relapsed/refractory pediatric AML is currently underway (NCT04898894). However, children with Down syndrome, who have a 500-fold increased risk of developing acute leukemia are excluded from this trial. Methods: The viability of mouse passaged Down syndrome myeloid leukemia (DS-ML) samples following exposure to Selinexor and/or venetoclax was evaluated ex vivo by flow cytometry using annexin V and propidium iodide staining. BLISS synergy scores were calculated using SynergyFinder. For the PDX models, 2-3 million cells were injected intravenously in NSG-SGM3 mice. The percentage of human cells in mouse peripheral blood was determined at periodic intervals by flow cytometry. Mice were randomly recruited to treatment groups (n=5 each) when the percentage of human CD45+ cells were first detected in blood. Selinexor (10 mg/Kg) and venetoclax (100 mg/Kg) were administered by oral gavage for 2 weeks and 4 weeks respectively. Mice were carefully monitored and euthanized at the first instance of pre-determined experimental endpoints. Kaplan-Meier survival estimates were generated using GraphPad Prism. Results: We have generated and extensively characterized patient-derived xenograft models of DS-ML, and used for preclinical evaluation of epigenetic drug combination (azacitidine and panobinostat) (Barwe et al., Blood, 134:2683, 2019), and a combination of azacitidine and venetoclax (Barwe et al., Blood, 138:3452, 2021). Ex vivo studies showed a dose-dependent decrease in the viability of mouse passaged DS-ML cells treated with Selinexor or venetoclax. The estimated EC50 concentrations for Selinexor were 0.31 uM (NTPL-60), 0.53 uM (NTPL-386), and 1.01 uM (15384-029). Venetoclax reduced cell viability at EC50 concentrations ranging from 0.37 uM to 1.54 uM. A combination of these drugs was either additive (NTPL-60), mildly synergistic (NTPL-386) or antagonistic (15384-029) (Figure 1A). We tested the efficacy of Selinexor and venetoclax alone or in combination in vivo in three distinct DS-ML PDX models. Selinexor treatment significantly increased median survival in all three models, while venetoclax was effective in two of three models (Figure 1B, *P<0.05, **P<0.01). However, unlike prior reports in multiple myeloma and AML, addition of venetoclax to the treatment regimen did not provide any survival advantage compared to Selinexor alone. This effect was also observed in the percentage of human CD45+ in blood over time, where human CD45+ blood counts were significantly higher in the combination than Selinexor treatment alone, indicating that Selinexor monotherapy was much more efficient in reducing leukemia burden. Conclusion: We evaluated a combination of Selinexor and venetoclax in DS-ML PDX models ex vivo and in vivo. The combination did not show significant synergy in any of the models ex vivo. Selinexor showed significant improvement in median survival in each of the models and performed better than venetoclax alone. Selinexor venetoclax combination was not beneficial than Selinexor alone in DS-ML PDX models. Studies are in progress to identify the determinants of combinatorial response to Selinexor and venetoclax in DS-ML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MMAP-04 CYTOTOXIC, TUMOR-HOMING INDUCED NEURAL STEM CELLS AS AN ADJUVANT TO RADIATION IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER LEPTOMENINGEAL METASTASES

INTRODUCTIONNon-small cell lung cancer (NSCLC) is the most common cancer to spread to the brain, and spread to the leptomeninges is particularly devastating, with a median survival of only months. While radiation may offer symptomatic relief, new adjuvant therapies are needed for more durable tumor kill. Spheroidal, human induced neural stem cells (hiNeuroS) transdifferentiated from fibroblasts are inherently tumoritropic. When engineered to secrete the cytotoxic protein TRAIL, they provide the potential for a personalized, targeted approach to NSCLC leptomeningeal metastases. METHODShiNeuroS-TRAIL in vivo efficacy was determined by tracking the progression and survival of mice with NSCLC leptomeningeal tumors treated with intracerebroventricular hiNeuroS, radiation, or both. To determine the impact of radiation on the tumor tropism of hiNeuroS, we performed 2-dimensional motion assays on hiNeuroS with and without the presence of NSCLC pre- and post-radiation. Migrational capacity in vivo was determined by infusing hiNeuroS into the lateral ventricles of mice with established NSCLC tumors and monitoring hiNeuroS accumulation using post-mortem fluorescent analysis. RESULTS/CONCLUSIONMice treated with the combination of hiNeuroS-TRAIL and 2 Gy showed a significantly reduced mean tumor signal (2.7%) compared to controls (100%) or 2 Gy-only (54.9%). Mice treated with 2 Gy alone showed no significant survival difference compared to controls. Both combination and hiNeuroS-TRAIL-only-treated mice showed a significant improvement in median survival compared to controls (36.6% and 46.3% improvement, respectively). hiNeuroS showed enhanced directionality and displacement in the presence of NSCLC in 2-dimensional motion assays, indicating directional migration, and they maintained this ability following exposure to radiation. Co-localization of hiNeuroS with NSCLC was also observed in vivo. These results suggest the potential of hiNeuroS-TRAIL as a powerful adjuvant to radiation in the treatment of leptomeningeal NSCLC.

Improved survival of patients with myelofibrosis in the last decade: Single‐center experience

The management of myelofibrosis (MF) has changed over the last several years and could have an impact on patient outcome. This study evaluates the survival of patients with MF at the authors' institution to determine whether it changed in the last decade. This retrospective study consists of 844 patients (64% male; median age, 66 years; range, 20-90 years) who were examined between 2000 and 2020 with a new diagnosis of MF. Only patients with available marrow biopsy who had reticulin fibrosis of grade 2 or higher were included. Patients were compared by year of presentation: 2000-2010 (n = 373) and 2011-2020 (n = 471). A statistically significant improvement in median survival in the last decade was noted: from 48 months (95% CI, 42-54 months) to 63 months (95% CI, 55-71 months) (P < .001; HR, 0.78 [95% CI, 0.64-0.95]). Improved survival was observed also in patients 65 years old or older and those having intermediate 2 or high-risk Dynamic International Prognostic Scoring System (DIPSS) or DIPSS-Plus risk scores. Among 532 patients treated with MF-directed therapy, patients exposed to JAK inhibitor ruxolitinib had superior outcomes with median overall survival of 84 months (95% CI, 70-94 months). The results demonstrate that survival of patients with MF has improved in the last decade. This improvement is likely due to increased disease awareness, advances in supportive care, and the development of effective treatments.

Does time to completion of radiation treatment in locally advanced vulvar cancer impact survival?

5593 Background: Although well established in cervical cancer, it is unclear whether time from initiation to completion of radiation therapy for vulvar cancer affects survival outcomes. We seek to assess if completion of radiation, either alone (RT) or as concurrent chemoradiation (CRT), within a planned timeframe in locally advanced squamous cell vulvar cancer impacts overall survival (OS). Methods: Women 18 years or older with FIGO stage II to IVA vulvar cancer who received external beam RT or CRT as part of their initial treatment course were identified from the National Cancer Database from 2004-2017. Patients with non-squamous cell carcinoma histology or who received systemic cytotoxic therapies as primary treatment were excluded. Patients who received less than 20 fractions of radiation were also excluded. Time to radiation completion was the number of days from the initiation to completion of radiation. The delay of radiation completion was calculated as the difference between the actual time to radiation completion and predicted duration of radiation. Types of treatment (RT and CRT) were both stratified into groups based on the delay of radiation completion, less than 7 days or greater than 7 days. Chi-square, Fisher Exact ANOVA and Kruskal-Wallis tests were used for analysis. Kaplan-Meier curves with log-rank tests were fit for univariate time-to-event analysis. Multivariable Cox proportional hazard models were fit to assess effects after controlling for confounding. Results: There were 2378 patients identified for analysis (n = 856 RT and n = 1522 CRT). Median age was 67 (IQR 56-78) and the CRT group was younger (p &lt; 0.0001) than the RT group. The majority were white (88.35%) with advanced FIGO stage III or IVA (72.29 %) disease. Median dose of total radiation was 5720 cGy (IQR 5040-6300) with higher doses observed in the greater than 7 days delay group versus less than 7 days, (p &lt; 0.0001). Median follow up was 27.2 (IQR 11.8-57.9) months. For both cohorts, completion of treatment with delay less than 7 days resulted in significant improvement in median survival when compared to treatment completion delay of more than 7 days: RT (Median OS 34.9 versus 21.6 months, p &lt; 0.01) and CRT (58 versus 41.3 months, p &lt; 0.01). On multivariate subset analysis, both completion of CRT and RT were associated with improved OS when treatment was completed with less than 7 days delay vs greater than 7 days delay, CRT (HR 0.869 [95%CI 0.758-0.997]), RT (HR 0.820 [95%CI 0.698-0.964]). Advanced FIGO stage IVA was associated with the greatest increase in hazard of death, (HR 1.758 [95%CI 1.516-2.039]), compared to FIGO stage II. Conclusions: Completion of radiation with less than 7 days delay is associated with improved overall survival, which is independent of concurrent chemotherapy. These findings suggest that strategies to minimize delays in radiation treatment are crucial in treating locally advanced vulvar cancer.

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.

IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p &amp;lt; 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.

Atypical Teratoid Rhabdoid Tumors (ATRT): King Faisal Specialist Hospital and Research Centre experience.

BackgroundAtypical teratoid rhabdoid tumor is an uncommon aggressive central nervous system tumor. All retrospective series have shown a short mean overall survival rate. Considering the rarity of the disease, few prospective clinical trials addressed treatment recommendations for such aggressive tumors, and consequently no definitive treatment guidelines have been established. In this study, we are reviewing our experience in treating atypical teratoid rhabdoid tumor patients.MethodsWe reviewed the medical charts of 43 patients with atypical teratoid rhabdoid tumor who were treated in King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, between 1996 and 2013. We evaluated the overall survival rate and the influence of different clinical features and treatment protocols on survival.ResultsThe median overall survival time was 16.9 months (95% Confidence Interval, 5.2–32.9 months) with an estimated 2- and 5-year overall survival of 41.9% ± 9.6 and 27.9% ± 9.2, respectively. Patients receiving trimodal treatment (surgery, chemotherapy, and radiotherapy) exhibited significantly better median overall survival time compared to their counterparts (P value < .001).ConclusionsAtypical teratoid rhabdoid tumor is rare and aggressive central nervous system tumor. Despite the limitations of the study, our results support several of clinical practice development. Utilization of postoperative radiotherapy and the adoption of trimodal therapy are associated with significant improvement of median survival. Prompt management with aggressive trimodal therapy should be the standard for future treatment protocols.

Abstract IA06: The Long-Term Ovarian Cancer Survivor Project: A Department of Defense initiative

Abstract In 2019 there will be 22,500 new cases of ovarian cancer, resulting in approximately 14,000 deaths. Ovarian cancer remains the highest case fatality rate of any gynecologic cancer. Despite significant improvement in the surgical and chemotherapeutic managements of ovarian cancer patients, the overall survival has not changed in 30 years. However, these new therapies have resulted in a significant improvement in median survival, resulting in increasing numbers of patients surviving greater than 10 years with disease. The clinical and molecular features of these unique patients remain uncharacterized. The Department of Defense Ovarian Cancer Research Program (DOD OCRP) funded the creation of our interdisciplinary Long-term Survivor Consortium (LTSC), composed of 6 research sites including MDACC, UAB, IU, UCI, Ludwig Cancer Research, and University Hospitals of Canton Vaud (CHUV) and INOVA, a bioinformatic center at DFCI, and administrative centers at UCI and UAB. The purpose of the consortium is to identify characteristics and predictors of long-term survival in advanced ovarian cancer patients. The consortium is overseen by both a scientific and advocacy advisory board to guide direction and efforts. 285 specimens of advanced-stage high-grade serous ovarian cancers with full clinical annotation including greater than 12 years of follow-up were analyzed for this project. In addition, 340 early-stage high-grade ovarian cancers were available for one of the AIMs of the project. These latter samples were obtained through the creation of an international consortium funded by the DOD OCRP. All specimens were first reviewed for tumor context by H&amp;E staining to determine percentage of tumor. The scientific platforms include whole transcriptome, microRNAs, global proteomics, immune profiling, and methylation. All specimens were analyzed on each individual platform and the results will be integrated in a global process. In parallel with these efforts, a systematic analysis of quality of life of patients at the time of diagnosis and later during the course of their disease based upon patient-reported outcome surveys has been undertaken. These data will also be integrated with genomic results to produce signatures that can further characterize long-term survivors of ovarian cancer. Citation Format: Michael J. Birrer, Lari Wenzel, Austin Miller, Heather Lankes, Nilsa Ramirez, Giovanni Parmigiani, Samuel Mok, Kenneth Nephew, Thomas Conrads, George Coukos, George L. Maxwell, Giulia Fulci, Mary Scroggins. The Long-Term Ovarian Cancer Survivor Project: A Department of Defense initiative [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA06.

Abstract 2262: Chemotherapy, checkpoint inhibition, and MGMT-modified adoptive gamma-delta (γδ) T cell-based therapy to treat post-resection, primary glioblastomas

Abstract Introduction: Recent evidence supports the crucial contribution of innate immunity to chemotherapy-based cancer treatments. Our previous in vitro modeling shows improved killing of glioblastoma (GBM) cell lines when γδ T cells are combined with alkylating agents such as Temozolomide (TMZ), which cause DNA damage but are also lymphodepleting. We now report findings from combined TMZ therapy with MGMT-modified γδ T cells (Drug Resistant Immunotherapy - DRI) in a xenograft (PDXT) mouse model of primary and recurrent GBM. Methods: Effectorγδ T cells were manufactured from apheresis product in media containing 5mM Zoledronic Acid and 50U/mL rhIL-12. Cultures were transduced with a P140K-MGMT lentivector, maintained for up to 14 days, harvested, and evaluated in vitro for PDXT lysis +PD-1, CTLA-4 and PD-L1 by flow cytometry. Primary (P) and recurrent TMZ-resistant (T) GBM were modeled orthotopically using classical JX12P and mesenchymal JX59P intracranial (IC) xenografts versus JX12T, JX22T and JX59T. After placement of IC xenografts, mice received concurrent intraperitoneal TMZ 60mg/kg and 1 x 106IC DRI γδ T cells on post-tumor days 6, 8,13 and 15. Control mice received either γδ T cells, TMZ, or no therapy. Survival was assessed by Kaplan-Meier analysis.NKG2DL and PD-L1 expression was assessed on FFPE sections of tumor during therapy and at termination. Results: DRI-treated JX12P mice showed significant improvement in median survival (MS) over TMZ alone (p=0.0001) with 80% tumor-free survivors. DRI also improved survival for JX59P-bearing mice with 60% survivors as compared to 30% for mice receiving TMZ alone (p=0.044). TMZ reduced tumor growth in primary but not TMZ-resistant PDXT-bearing mice while γδ T cells alone had no survival benefit over untreated controls for any model. For JX12T, DRI improved MS from 27 to 38 days (+41%) over TMZ alone (p=0.017). JX22T and JX59T tumors were resistant to DRI (p=0.0966 and 0.1390). DRI γδ T cells upregulated PD-1 and CTLA-4 over baseline and showed improved function against TMZ-resistant xenolines after blockade of PD-1 and/or CTLA-4 by as much as 200%. TMZ induced upregulation of NKG2DL (MIC-A/B, ULBP-4), and PD-L1 on both primary and TMZ-resistant PDXT following TMZ injection and for several days thereafter. Conclusions: Primary GBM PDXT are significantly more sensitive to DRI than TMZ-resistant GBM suggesting that DRI would be more effective if administered as adjuvant therapy in the TMZ-maintenance phase following primary resection and chemo/radiotherapy. Additionally, TMZ increases GBM immunogenicity by upregulating NKG2DL expression but also PD-L1. Checkpoint blockade improves γδ T cell function. These findings show the potential to augment the effect of DRI and improve immune effectiveness against more resistant tumors. Citation Format: Sailesh Pillai, George Y. Gillespie, Louis B. Nabors, Samantha Langford, Catherine P. Langford, Lawrence S. Lamb. Chemotherapy, checkpoint inhibition, and MGMT-modified adoptive gamma-delta (γδ) T cell-based therapy to treat post-resection, primary glioblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2262.

Evolution of pancreatectomy with en bloc venous resection for pancreatic cancer in Italy. Retrospective cohort study on 425 cases in 10 pancreatic referral units

IntroductionThe aim of this study is to analyze the evolution of pancreatectomy with venous resection in 10 referral Italian centers in the last 25 years. MethodsA multicenter database of 425 patients submitted to pancreatectomy with venous resection between 1991 and 2015 was retrospectively analyzed. Patients were classified in 5 periods: 1 (1991–1995); 2 (1996–2000); 3 (2001–2005); 4 (2006–2010); 5 (2011–2015). Indications and outcomes were compared according to the period of surgery. ResultsNineteen patients were operated in period 1, 28 in period 2, 91 in period 3, 140 in period 4, and 147 in period 5. Use of neoadjuvant therapy increased from 0% in period 1 and 2–12.1% in period 5. Postoperative complications ranged from 46.3% to 67.8%, and mortality from 5.3% to 9.2%. Median survival progressively increased, from 6 months in period 1–16 months in period 2, 24 months in period 3 and 4 and 35 months in period 5 (p = 0.004). Period, venous and nodal invasion were significant prognostic factors for survival. ConclusionManagement and outcomes of pancreatectomy with venous resection have evolved in the last 25 years in Italy. Improvement in patients' multidisciplinary management has lead to significant improvement of median survival.

Metal-Free Cycloaddition Chemistry Driven Pretargeted Radioimmunotherapy Using α-Particle Radiation.

The pretargeted radioimmunotherapy approach (PRIT) decouples the administration of tumor targeting monoclonal antibodies (mAbs) from that of the radiolabeled ligand. This multistep strategy allows delivery of high doses of radiation to tumor cells while minimizing nonspecific normal tissue irradiation. In this study, we evaluated the potential of pretargeted α-particle radioimmunotherapy based on the inverse electron demand Diels-Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine (Tz). Two tetrazine based chelators, DOTA-Tz and TCMC-Tz, were synthesized and compared for their radiolabeling efficiency with 212Pb, radiochemical stability, and in vivo pharmacokinetics. Dosimetry was determined from pretargeted biodistribution studies. The PRIT study was carried out in LS174T tumor bearing mice pretargeted with CC49-TCO mAb. After removing unbound mAbs from the blood using two doses of clearing agent, mice were treated with various doses of (0, 2.78, 4.63, 7.40, and 2 × 2.78 MBq) of 212Pb-DOTA-Tz. 212Pb-DOTA-Tz displayed better in vivo biodistribution than 212Pb-TCMC-Tz and was selected for PRIT study. All the mouse groups receiving treatment displayed a dose dependent reduction in tumor size, while the control groups showed exponential tumor growth. Treatment with 2.78, 4.63, and 2 × 2.78 MBq of 212Pb-DOTA-Tz resulted in statistically significant improvement in median survival (26, 35, and 39 days, respectively). Groups receiving 7.40 MBq of 212Pb-DOTA-Tz and 0.55 MBq of direct labeled CC49 exhibited acute radiation associated toxicity. This study successfully demonstrated that pretargeted 212Pb α-particle therapy resulted in reduced tumor growth rates and improved survival with minimal normal tissue toxicity.

Trends and outcomes of pancreaticoduodenectomy for periampullary tumors: A 25-year single-center study of 1000 consecutive cases.

AIMTo evaluate the evolution, trends in surgical approaches and reconstruction techniques, and important lessons learned from performing 1000 consecutive pancreaticoduodenectomies (PDs) for periampullary tumors.METHODSThis is a retrospective review of the data of all patients who underwent PD for periampullary tumor during the period from January 1993 to April 2017. The data were categorized into three periods, including early period (1993-2002), middle period (2003-2012), and late period (2013-2017).RESULTSThe frequency showed PD was increasingly performed after the year 2000. With time, elderly, cirrhotic and obese patients, as well as patients with uncinate process carcinoma and borderline tumor were increasingly selected for PD. The median operative time and postoperative hospital stay decreased significantly over the periods. Hospital mortality declined significantly, from 6.6% to 3.1%. Postoperative complications significantly decreased, from 40% to 27.9%. There was significant decrease in postoperative pancreatic fistula in the second 10 years, from 15% to 12.7%. There was a significant improvement in median survival and overall survival among the periods.CONCLUSIONSurgical results of PD significantly improved, with mortality rate nearly reaching 3%. Pancreatic reconstruction following PD is still debatable. The survival rate was also improved but the rate of recurrence is still high, at 36.9%.

Radium-223 dichloride for metastatic prostate cancer: long-term safety profile and future opportunities

Prostate cancer is the most common new cancer diagnosis and the second leading cause of cancer death in men in the United States. Worldwide, it is the second most common cancer in men (1). As a result of screening, the majority of new cases are diagnosed when the disease is localized and can be cured. For patients who develop metastatic disease, androgen deprivation therapy (ADT) has been the first line of treatment. Unfortunately, the disease eventually becomes castration-resistant [metastatic castration-resistant prostate cancer (mCRPC)], causing significant morbidity and mortality. There had been little progress in systemic therapy for mCRPC until 2004 when two randomized studies demonstrated that docetaxel improved the overall survival of these patients (2,3). In the last decade, five more new agents have been approved by the FDA for the treatment of mCRPC, the most recent one being radium-223 ( 223 Ra) dichloride in 2013. In the ALSYMPCA study, patients with mCRPC were randomized to 223 Ra or placebo (4). There was a significant improvement in median survival in patients receiving 223 Ra for mCRPC as compared to placebo (14.9 vs . 11.3 months).

Survival improvements with adjuvant therapy in patients with glioblastoma.

Evaluate survival of patients diagnosed with glioblastoma multiforme (GBM) managed with adjuvant intensity modulated radiation therapy and temozolomide since the introduction of the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada Clinical Trials Group (EORTC-NCIC) protocol. All patients with GBM managed between May 2007 and December 2014 with EORTC-NCIC protocol were entered into a prospective database. The primary endpoint was the median survival. Univariate predictors of survival were evaluated with respect to tumour resection, age and Eastern Cooperative Oncology Group (ECOG) performance status using log-rank comparisons. Two hundred and thirty-three patients were managed under the protocol and analysed for outcome. The median age was 57 years; the rate of gross total resection, subtotal resection and biopsy were 47.2%, 35.2% and 17.6%, respectively. At progression, 49 patients had re-resection, and in addition to second-line chemotherapy, 86 patients had Bevacizumab including 26 with re-irradiation. Median survival was 17.0 months (95% CI: 15.4-18.6). On univariate evaluation, extent of resection (P = 0.001), age, ECOG performance status and recursive partitioning analysis class III were shown to significantly improve survival (P < 0.0001). The median survival for gross total resection, age <50 years, ECOG 0-1 and recursive partitioning analysis class III were 21, 27, 20 and 47 months, respectively. This study confirms the significant improvement in median survival in GBM that has occurred in recent years since introduction of the EORTC-NCIC protocol. Further improvements have occurred presumably related to subspecialized care, improved resection rates, sophisticated radiotherapy targeting and early systemic salvage therapies. However, the burden of the disease within the community remains high and the median survival improvements over time have plateaued.

Metastatic soft tissue sarcomas (STS) in elderly patients: 18 years of monoinstitutional experience.

e22528 Background: Elderly people represent more than 50% of STS patients, but few data are available in this population and old patients in clinical studies are underrepresented or not included. Aim of this retrospective, monoinstitutional study is to describe the activity and feasibility of first and second line chemotherapy in elderly patients with metastatic STS. Methods: Patients older than 65, with metastatic STS of the scalp, trunk, girdles and extremities, treated and followed from February 1998 to December 2015 in an Italian referral Center for diagnosis and care of STS were included. Median Overall survival (OS) was the principal end point calculated from the start of chemotherapy to the last date of follow up or death. Response rate and toxicities related to type of administered chemotherapy were the secondary end points. Results: 134 patients (79 M, 55F) were considered, (65-70 y) 63%, (71- 75y) 25%, ( &gt; 76 y)11% . STS histologies: mixoid and round cell liposarcomas (34%), leiomyosarcomas (25%), pleomorphic undifferentiated sarcomas (13%), Angiosarcoma (10%), Mixofibrosarcoma (6%), MPNST (4%), synovial sarcoma (2%), other histologies (6%). All the patients received at least one course chemotherapy (1-12). Mono CT was the preferred administered schedule (92%of cases). Median OS was 7.3 months; at the time of this analysis only 14 patients were alive (10%). In the first line therapy we recorded 1 CR, 14 PR and 43 SD. In second line therapy no CR, 4 PR, 23 SD. PR were recorded mainly in 65-70y old patients. Bad PS, low score in Comprehensive Geriatric Assesment (CGA), vulnerability, comorbidities, number of metastasis, were negative prognostic factors. No toxic death were recorded. 12% of the pts were recovered for febrile neutropenia, thrombocitopenia and mucositis . Conclusions: Our study confirms that elderly patients with metastatic STS is a difficult population to be treated. Only patients less aged, good PS, good GCA and 0-1 comorbidities can be treated with full dose of drug, generally with mono CT. Chemotherapy in elderly pts doesn’t produce a significant improvement in Median Survival and benefit observed support the routine use of citotoxic treatment in selected good performance status population.

Systemic Chemotherapy in Advanced Pancreatic Cancer

Pancreatic cancer remains one of the most lethal cancers. These patients often have multiple symptoms, and integrated supportive care is critical in helping them remain well for as long as possible. Fluorouracil-based chemotherapy is known to improve overall survival (OS) by approximately 3 months, compared to the best supportive care alone. A 1997 study comparing gemcitabine and fluorouracil treatment of advanced pancreatic cancer patients showed an improvement in OS of 1 month in patients receiving gemcitabine. Over the next 10 years, multiple randomized studies compared single-agent gemcitabine with combination chemotherapy and showed no effective survival improvement. However, the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, was associated with a significant improvement in OS of approximately 2 weeks. However, adoption of this regimen has not been widespread because of its limited effect and added toxicity. Two clinical trials have recently prolonged OS in advanced pancreatic cancer patients by almost 1 year. The first compared FOLFIRINOX with gemcitabine alone, and was associated with a significant improvement in median survival. The second compared gemcitabine and nab-paclitaxel with gemcitabine alone, and was associated with improvements in OS. At present, these regimens are considered standard treatment for patients with good performance statuses.

ATPS-09A MITOCHONDRIAL METABOLISM INHIBITOR RADIO-SENSITIZES GLIOBLASTOMA TUMOURS IN MICE

PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a mitochondrial metabolism inhibitor that is currently in Phase I clinical testing in patients with solid tumors refractory to standard therapy. PENAO is a cysteine mimetic trivalent arsenical that enters cells via an organic ion transporter and accumulates in the mitochondrial matrix where the arsenical moiety cross-links Cys160 and Cys257 on the matrix face of adenine nucleotide translocase (ANT), which inactivates the transporter. ANT inactivation leads to partial uncoupling of oxidative phosphorylation, increase in superoxide production, proliferation arrest and ultimately apoptosis of the cell. PENAO only reacts with ANT when cells are proliferating as Cys160 and Cys257 appear to be disulfide bonded in growth quiescent cells, and so unreactive towards PENAO. PENAO inhibited the proliferation of a panel of 13 glioblastoma cells, including cells from both primary and recurrent tumors, with IC50 values ranging from 0.3-4.5 µM. The IC50 values for proliferation arrest of normal lung fibroblasts and astrocytes are 9 µM and 7 µM, respectively, indicating selectivity for glioblastoma cells. Administration of PENAO (3 mg/kg/day) to mice bearing subcutaneous glioblastoma xenografts resulted in significant inhibition of tumor growth (7 partial and 3 complete responses). Ki67 and TUNEL staining of tumor sections showed that PENAO induced tumor cell growth arrest and death, respectively. Pharmacokinetic analysis demonstrated that PENAO readily crossed the blood-brain-barrier and accumulated specifically in tumor tissue. There were also no signs or symptoms of treatment toxicity. As PENAO induces superoxide production in glioblastoma cells, we hypothesized that PENAO in combination with radiation would synergise. Combining 2 Gy/day radiation (20 Gy total) with intraperitoneal administration of 20 mg/kg/day PENAO, resulted in significant improvement in median survival in an orthotopic glioblastoma murine model. These in-vitro and in-vivo results show that PENAO is a potential new therapeutic for glioblastoma, alone or in combination with radiation therapy

Case–Control Estimation of the Impact of Oncolytic Adenovirus on the Survival of Patients With Refractory Solid Tumors

Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial, an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (from 170 to 208 days, P = 0.0012, N = 148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N = 90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N = 37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.