Modest Increase In Survival Research Articles

A Systematic Review of Nanomedicine in Glioblastoma Treatment: Clinical Efficacy, Safety, and Future Directions.

(1) Background: Glioblastoma (GBM) is categorized as a grade IV astrocytoma by the World Health Organization (WHO), representing the most aggressive and prevalent form of glioma. It presents a significant clinical challenge, with limited treatment options and poor prognosis. This systematic review evaluates the efficacy and safety of various nanotherapy approaches for GBM and explores future directions in tumor management. Nanomedicine, which involves nanoparticles in the 1-100 nm range, shows promise in improving drug delivery and targeting tumor cells. (2) Methods: Following PRISMA guidelines, a systematic search of databases including Google Scholar, NCBI PubMed, Cochrane Library, and ClinicalTrials.gov was conducted to identify clinical trials on GBM and nanomedicine. The primary outcome measures were median overall survival, progression-free survival, and quality of life assessed through Karnofsky performance scores. The safety profile was assessed by adverse events. (3) Results: The analysis included 225 GBM patients, divided into primary and recurrent sub-populations. Primary GBM patients had a median overall survival of 6.75 months, while recurrent GBM patients had a median overall survival of 9.7 months. The mean PFS period was 2.3 months and 3.92 months in primary GBM and recurrent GBM patients, respectively. Nanotherapy showed an improvement in quality of life, with KPS scores increasing after treatment in recurrent GBM patients. Adverse events were observed in 14.2% of patients. Notably, Bevacizumab therapy exhibited better survival outcomes but with a higher incidence of adverse events. (4) Conclusions: Nanotherapy offers a modest increase in survival with fewer severe side effects. It shows promise in improving the quality of life, especially in recurrent GBM patients. However, it falls short in terms of overall survival compared to Bevacizumab. The heterogeneous nature of treatment protocols and reporting methods highlights the need for standardized multicenter trials to further evaluate the potential of nanomedicine in GBM management.

Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer.

To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Delivery of enzalutamide via nanoparticles for effectively inhibiting prostate cancer progression.

Androgen deprivation therapy has been used as a standard clinical treatment for prostate cancer, but the disease generally progresses to castration-resistant prostate cancer in a very short time. Enzalutamide (ENZ) is an emerging second-generation androgen receptor (AR) antagonist used for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC). However, due to the rapid onset of drug resistance, it provides only a modest increase in survival. Here, we propose a convenient and effective androgen receptor antagonist drug delivery strategy, that is, the use of a biocompatible nanoparticle (NP) drug delivery system for drug delivery to improve its bioavailability and therapeutic performance. Although the particle size of the phenylpropyl polymer (8P4) nanoparticles is small, it has a high drug-carrying capacity. ENZ-8P4 NPs can increase drug delivery efficiency, enhance drug cytotoxicity, and reduce the half-inhibitory concentration (IC50) of the drug. In addition, in vivo experiments confirmed that ENZ-8P4 preferentially accumulates in the tumor and significantly inhibits tumor growth. Hence, the 8P4 drug delivery system loaded with enzalutamide has excellent potential for the treatment of prostate cancer.

A very long-acting IL-15: implications for the immunotherapy of cancer

BackgroundInterleukin-15 (IL-15) is an important cytokine necessary for proliferation and maintenance of natural killer (NK) and CD8+ T cells, and with great promise as an immuno-oncology therapeutic. However, IL-15 has...

NKG2A inhibits the anti-tumor CD8 T cell immune response elicited by radiotherapy

Abstract More than half of patients with solid tumor malignancies undergo treatment with radiotherapy (RT). In addition to causing direct tumor cell death, RT results in release of tumor antigen and damage associated molecular patterns that elicit a CD8 T cell and IFN-g dependent anti-tumor immune response. To further bolster this response, RT has been combined with immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4. Despite a modest increase in survival when these therapies are used alone or together in conjunction with RT, many patients fail to respond to treatment, suggesting other mechanisms of immune suppression exist in the tumor microenvironment (TME). Using syngeneic B16 F10 melanoma and C38 colorectal adenocarcinoma models, we have studied the role of the inhibitory receptor NKG2A. We have observed that NKG2A is expressed only on tumor infiltrating lymphocytes (TILs) and expression of this receptor does not change with RT. Furthermore, RT increases intratumoral expression of the ligand for NKG2A, Qa-1b, as does IFN-g stimulation in vitro. Blockade of NKG2A alone through use of B16 F10 cells lacking Qa-1b expression or blocking antibodies did not significantly increase survival of mice treated with RT. Further analysis revealed that among CD8 TILs, only a minority of cells express NKG2A alone, with most TILs co-expressing NKG2A and PD-1 or PD-1 alone. Thus, we combined anti-NKG2A and anti-PD-1 blockade and observed increased survival in mice treated with RT, whereas either therapy alone was ineffective. These results suggest that NKG2A blockade could be combined with RT and existing immunotherapies clinically to improve patient response. Supported by awards T32AI007285 from the NIAID and R01CA028332 from the NCI.

Ovarian cancer screening: Current status and future directions.

Ovarian cancer is the third most common gynaecological malignancy and the most lethal worldwide. Most patients are diagnosed with advanced disease which carries significant mortality. Improvements in treatment have only resulted in modest increases in survival. This has driven efforts to reduce mortality through screening. Multimodal ovarian cancer screening using a longitudinal CA125 algorithm has resulted in diagnosis at an earlier stage, both in average and high risk women in two large UK trials. However, no randomised controlled trial has demonstrated a definitive mortality benefit. Extended follow up is underway in the largest trial to date, UKCTOCS, to explore the delayed reduction in mortality that was noted. Meanwhile, screening is not currently recommended in the general population Some countries offer surveillance of high risk women. Novel screening modalities and longitudinal biomarker algorithms offer potential improvements to future screening strategies as does the development of better risk stratification tools.

Pathogenesis, diagnosis and treatment of premalignant and malignant stages of cholangiocarcinoma in primary sclerosing cholangitis.

Patients with primary sclerosing cholangitis (PSC) confer a high risk of cholangiocarcinoma (CCA). The molecular mechanisms of CCA development in PSC are incompletely understood, but pro-oncogenic processes resulting from chronic biliary inflammation are presumably of central importance. Distinguishing benign from malignant biliary strictures in PSC patients is challenging and accurately diagnosing CCA in PSC often requires a multifaceted approach involving imaging, serological testing, biliary brush cytology and fluorescence in situ hybridization (FISH). Lack of early detection tools leads to a late diagnosis in the majority of cases. Surgical resection or liver transplantation represent the only curative intent treatments in PSC-CCA, but is only an option for the small subset of patients where CCA is detected at an early stage. Current palliative treatment modalities result in only a modest increase in survival. Overall, PSC-CCA carries a dismal prognosis with a 5-year survival less than 20%. Advances aiming at improving strategies for early detection, treatment and surveillance of CCA will be essential to provide better future patient care for PSC patients. Herein, we review the pathogenetic mechanisms for PSC-CCA as well as strategies for diagnosing and managing premalignant and malignant stages of CCA in PSC.

EP1.01-36 Quality of Life in Advanced Lung Cancer Patients in a Dutch Population

In advanced lung cancer chemotherapy is associated with a statistically significant improvement in overall survival (OS) compared to best-supportive care (BSC) alone, by improving survival with 9% at 12 months and median survival by 1.5 months. However, discussion remains whether adverse events of chemotherapy outweigh the relatively modest increase in survival. We aimed to investigate the quality of life (QoL) of patients with uncurable lung cancer treated with systemic therapy or best-supportive care (BSC) alone. The European Organisation for Research and Treatment of Cancer (EORTC) QOL questionnaire (QLQ-C30) and the EORTC QLQ-LC13 were used to assess patients reported outcome measures (PROMs) at baseline, 3, 6 and 12 months in 235 patients with stage IIIb and IV NSCLC or SCLC diagnosed and treated between 2013 and 2017 in 4 large teaching hospitals in the Netherlands. Comparison between systemic therapy and BSC alone were assessed by using change in SS14 score from inclusion to 12 months. The analysis method used for this correlated longitudinal data was linear mixed modelling. Out of 58 of 235 patients who received no systemic therapy, the vast majority did not receive any treatment because of patients refusal of treatment (58.6%), followed by poor performance status (20.7%), comorbidities (5.2%) and rapid deterioration (15.5%). Systemically treated patients had a significantly prolonged OS compared to BSC (median OS of 691 vs 219 days (p<0.0001)) and a higher number of patients in the best supportive care arm died during the observation period (62.1% vs 44.6%, p=0.02). Over time there was no significant time-treatment interaction in global health, functional or symptom scores between systemic therapy and BSC (p>0.05). Although, systemic therapy in advanced lung cancer patients led to significantly longer OS compared to best supportive care, the quality of life decreased in both groups non-differently over time.

Molecular determinants for enzalutamide-induced transcription in prostate cancer.

Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 globally directs enzalutamide-induced transcription by facilitating AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.

BSCI-23. TISSUE FACTOR SIGNALING ENHANCES METASTATIC BRAIN CANCER MALIGNANCY

Brain metastases are on the rise and remain one of the most refractory malignancies worldwide. Currently, the standard approach for therapy involves surgery and radiation. However, this approach usually produces only a modest increase in survival. We recently discovered that Tissue Factor (TF) strongly enhances the malignancy of gliomas via protease-activated receptor 2 (PAR2) signaling, though its role in brain metastases is not as well understood. In this study, we further explored the significance of TF in lung cancer brain metastases, showing that genetic and pharmacological targeting of TF-PAR2 signaling may decrease malignancy and increase the efficacy of radiotherapy. Studies were performed using patient-derived brain metastases coming from lung carcinoma. Markers of malignancy were measured by BrdU incorporation for cell proliferation, Matrigel-coated transwell migration, soft agar colony formation for anchorage-independent growth, limiting dilution assay for tumor initiation capacity, and clonogenic cell survival assay to measure radiation sensitivity. Low transcription of the TF gene is a favorable prognostic marker for overall survival in TCGA lung cancer patients (54.7 vs 41.9 months, P=0.0053), with 74% longer progression-free survival (102.7 vs 59.1 months, P=0.0012). TF knockdown significantly reduced tumor malignancy as determined by cell proliferation, invasion, colony formation, and in vivo growth. Conversely, TF overexpression increased tumor malignancy and promoted cancer stem-like behavior, as indicated by CD44 and CD133 expression, extreme limiting dilution assay, and anchorage-independent growth. A PAR2 antagonist, I-191, inhibited TF-mediated signaling and reduced cell proliferation by 51.3% (P< 0.001). TF knockdown and I-191 increased radiation sensitivity. Exogenous treatment of lung cancer cells with recombinant TF suppressed radiation-induced apoptosis, and this effect was blocked with I-191. These data show that TF-PAR2 signaling may represent a novel therapeutic strategy to reduce the malignancy of brain metastasis and increase the efficacy of radiation.

Abstract 4958: Alterations in the immune microenvironment during progression from Barrett's esophagus to esophageal adenocarcinoma

Abstract The incidence of esophageal adenocarcinoma (EAC) has increased 500 fold over the past 30 years and is now a top ten leading cause of cancer death. Systemic chemotherapy and targeted radiation have led to modest increases in survival, however 5-year survival is still less than 20%. Immunotherapy has emerged as a promising approach for the treatment of various solid tumors, however very little is known about the EAC tumor immune microenvironment and how it changes during the progression from Barrett’s metaplasia to carcinoma. The goal of the current study was to identify key changes in the immune microenvironment during progression from Barrett’s Esophagus (BE) metaplasia to the formation of EAC. Tissue samples from 52 patients with various levels of dysplasia (BE, BE w/ low grade dysplasia, BE w/ high grade dysplasia, and EAC) were subject to RNA-Seq analysis and investigated for changes in gene expression of a variety of cytokines and chemokines. Gene expression analysis revealed more than 5-fold increases in expression of multiple cytokines, such as IL8, IL6, CXCR1, and CXCR2, which have been implicated in both immunosuppression and tumor survival. Increases in the expression of immune checkpoint markers, such as PD-L1, TIGIT and CTLA4, were also seen suggesting a worsening immunosuppressive microenvironment during progression from BE to EAC. To further investigate specific changes in the infiltration of CD8 T-cell and T-regulatory cell populations during EAC progression, we performed standard immunohistochemical staining on tissue microarrays from 122 direct-to-surgery EAC patients. Staining for T-cell markers CD3, CD4, CD8, and FoxP3 revealed that only CD8 positive T-cells were increased around tumor cells during progression. Further characterization of individual immune cells was performed through multiplex immunohistochemistry, allowing for the evaluation of multiple immune cell markers within the same tissue section. Multiplex staining for surface expressed markers (CD3, CD8, FoxP3, PD-L1, PanCK, CD163, DAPI), allowed for the quantification and localization of a variety of immune cell types within the EAC microenvironment. In general, the immune cell populations (T-regs, CD8 T cells, and macrophages) increase during progression from BE to BE w/ High Grade Dysplasia. In contrast, EAC tumor sections were relatively immune poor, indicating that the immune microenvironment may often be compromised in cancer. These data collectively demonstrate the EAC microenvironment is characterized by poor infiltration of cytotoxic effector cells, increased expression of immune inhibitory signals from T-regs, inhibitory immune checkpoints and cytokines such as IL-8 and IL-6. These findings suggest an immune suppressive microenvironment which highlights the need for further studies to explore the potential of immune modulating therapy in EAC. Citation Format: Dyke P. McEwen, Derek J. Nancarrow, Jules Lin, Rishindra M. Reddy, Andrew C. Chang, David G. Beer, Kiran H. Lagisetty. Alterations in the immune microenvironment during progression from Barrett's esophagus to esophageal adenocarcinoma [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 4958.

Survival outcomes after whole brain radiotherapy for brain metastases in older adults with newly diagnosed metastatic small cell carcinoma: A national cancer database (NCDB) analysis.

Small cell lung cancer (SCLC) is an aggressive malignancy with a tendency to affect older adults and also metastasize to the brain. Older adults tolerate whole brain radiotherapy (WBRT) poorly with marginal survival benefit. We utilized the national cancer database (NCDB) to evaluate the survival outcomes following WBRT in older adults with SCLC and brain metastases. We identified 1615 patients ≥75 years old diagnosed with SCLC and brain metastases. Patients were categorized by type of therapy: chemotherapy + WBRT (n = 576), chemotherapy alone (n = 238), WBRT alone (n = 360) and no chemotherapy or WBRT (n = 441). Clinical and demographic characteristics were reported for each treatment cohort with a subsequent multivariable regression analysis for survival. Median patient age was 79 years. WBRT median dose was 30 Gy. At time of analysis, 1530 of the cohort had died, yielding a median OS of 2.9 months and 6 month survival of 31% for patients that received chemotherapy. For patients treated without chemotherapy, median OS with WBRT was 1.9 months compared to 1.2 months without (p < .0001). For patients receiving chemotherapy with, and without WBRT, median OS was 5.6 months and 6.4 months, respectively (p = .43). Multivariable cox regression revealed age > 80, extracranial disease, male sex, and rural location as predictors of increased risk of death. In older adult patients with SCLC brain metastasis, WBRT was associated with a modest increase in survival in patients not fit for chemotherapy, and there was no association with increased survival over chemotherapy alone.

The Persistent Survival of MPN Cells to JAK2 Inhibition Is Dependent on SHP2 Activity, Which May Provide a Therapeutic Target to Enhance Current Anti-MPN Therapies

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis, are hematopoietic stem cell disorders that affect about 300,000 people in the U.S. PV and ET can progress to myelofibrosis where patients are susceptible to bone marrow failure, increased incidence of acute leukemia, and poor survival. MPNs are driven by aberrant JAK2 activity that is a consequence of mutations in JAK2, Mpl, or CalR. The JAK1/2 inhibitor ruxolitinib, which is FDA-approved for a subset of MPN patients, is effective in reducing patient symptomology but fails to induce remission, as it has little effect on the neoplastic cell burden. However, a modest increase in survival and decrease of allele burden has been suggested following long-term ruxolitinib treatment. The quality of life benefit afforded by ruxolitinib suggests it will likely remain a mainstay of future MPN therapies. Identifying the mechanism(s) by which cells persistently survive in the presence of ruxolitinib could prove pivotal to improving JAK2 inhibitor therapies in MPN patients.In order to identify mechanisms by which JAK2-driven MPN cells survive ruxolitinib treatment, we utilized global phospho-tyrosine proteomics to compare ruxolitinib-sensitive and persistent cells, the latter of which are drug persistent by nature due to their reacquisition of JAK2 inhibitor sensitivity upon removal of ruxolitinib. We utilized the JAK2-V617F-driven MPN model cell lines UKE1 and SET2 for this analysis. Pathway analysis from the datasets obtained indicated changes in phosphorylation of proteins involved in growth factor and cytokine signaling. Notably, we identified changes in phosphorylation of several tyrosine phosphatases, including SHP1 and SHP2. The SH2 domain-containing tyrosine phosphatase SHP2 (encoded by PTPN11) plays important roles in relaying signals from cell surface receptors, notably mediating activation of ERKs, and was the first phosphatase identified as leukemogenic. SHP2 regulates JAK2 signaling and is found mutated in ~8% of post-MPN leukemia, suggesting it may play a role in the biology of MPNs. In addition, SHP2 has been identified as a potential mediator of targeted therapy resistance in cancer. Therefore, we hypothesized that SHP2 activity may contribute to the persistent survival of MPN cells in ruxolitinib and provide a therapeutic target in MPNs. To test our hypothesis, we treated ruxolitinib-sensitive (drug naïve) and persistent cells with a specific allosteric inhibitor of SHP2, SHP099. Ruxolitinib-persistent cell growth was more sensitive to SHP2 inhibition, and SHP099 enhanced the growth inhibitory effects of ruxolitinib on ruxolitinib-sensitive cells. Treatment of UKE1 cells with a high concentration (~10X GI50) of ruxolitinib leads to the persistent survival of a small population of cells and this was prevented by SHP099. SHP2 inhibition was also deleterious to the maintenance of an existing drug persistent state in a high concentration of ruxolitinib. Interestingly, signaling pathways in cells persistently growing in ruxolitinib differentially respond to SHP2 inhibition. In both ruxolitinib-sensitive and persistent cells activation of ERK was inhibited by SHP099. However, in ruxolitinib-persistent UKE1 cells, this inhibition was more rapid, suggesting the kinetic regulation of ERK activation by SHP2 is altered in these cells. Also, SHP099 led to an increase in pSTAT3 in both ruxolitinib-sensitive and persistent cells. However, SHP099 led to an increase in pSTAT5 in ruxolitinib sensitive UKE1 cells, but not in cells persistently growing in ruxolitinib. Re-activation of signaling pathways following ruxolitinib treatment likely contributes to cell survival. We observed that ERK becomes re-activated shortly after ruxolitinib treatment, and this re-activation depends on SHP2 activity. Finally, we observed dose-dependent inhibition of the neoplastic growth of primary MPN patient cells by SHP099 and synergistic inhibition with ruxolitinib, suggesting co-targeting SHP2 may improve JAK2-targeted MPN therapies.In conclusion, our data suggest that re-wiring of signaling in cells challenged with ruxolitinib may create greater dependence on SHP2 activity that contributes to cell survival to JAK2 inhibition. Thus, targeting SHP2 may improve the efficacy of ruxolitinib as an anti-MPN therapy. DisclosuresHaura:Incyte Corporation: Research Funding. Reuther:Incyte Corporation: Research Funding.

PC-FACS

PC-FACS

High annual survival in infected wildlife populations may veil a persistent extinction risk from disease

AbstractHost response to emerging pathogens is variable, causing uncertainty about population‐level impacts and challenging effective disease management. White‐nose syndrome (WNS) has caused catastrophic declines in some bat species, while others appear less impacted. Developing predictive models based on observed survival patterns can generate testable hypotheses about mechanisms driving population dynamics and contribute to the development of targeted approaches to disease management. We conducted a mark–recapture study of federally endangered Indiana bats (Myotis sodalis) during 2011–2016. Annual survival decreased from 0.78 (95% CI: 0.59, 0.89) and 0.79 (95% CI: 0.70, 0.86) for females and males, respectively, in 2011 to 0.74 (95% CI: 0.33, 0.94) and 0.75 (95% CI: 0.53, 0.89) for females and males, respectively, in 2015. We then modeled two explanatory mechanisms potentially driving the observed patterns: (1) phased exposure to disease through the spatial spread of the pathogen within the hibernaculum; and (2) cumulative mortality risk from iterative yearly WNS infection. Under a phased exposure scenario, models suggest that infected individuals have an average survival probability of 0.68, and disease prevalence is predicted to reach 100% within 9 yr of disease emergence. Under the cumulative mortality risk hypothesis, survival probability of individuals decreases with each infection cycle. In either case, infected populations are predicted to stabilize at a negative growth rate. Results suggest that Indiana bats tolerate a pathogen load prior to onset of infection, leading to a less pronounced population decline than for other susceptible species. However, the long‐term risk of WNS to Indiana bats may be more severe than current population trends suggest. To inform current conservation management, we performed a vital rate sensitivity analysis, which suggested that modest increases in survival (4–5%) through targeted intervention may return declining populations to stability (λ = 1.0). Demographic modeling approaches coupled with continued population monitoring can highlight important differences in disease response, and ultimately extinction risk, in host species allowing conservation practitioners to tailor intervention actions so that they will be most effective.

Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: real-world analysis of Korean national database

BackgroundA randomized clinical trial has found that the addition of erlotinib to gemcitabine (GEM-E) for pancreatic cancer led to a modest increase in survival. The aim of this national population-based retrospective study was to compare the effectiveness of GEM-E to GEM alone for pancreatic cancer patients in real clinical practice.MethodsPatients with pancreatic cancer (ICD-10: C25) with prescription claims of gemcitabine or erlotinib between Jan 1, 2007 and Dec 31, 2012 were retrospectively identified from the Korean Health Insurance claims database. To be included in the study population, patients were required to have had a histological or cytological diagnosis within one year before chemotherapy. Patients treated with prior radiotherapy, surgery, or chemotherapy were excluded to reduce heterogeneity. Overall survival from the initiation of therapy and the medical costs of GEM-E and GEM were compared.ResultsA total of 4,267 patients were included in the analysis. Overall survival was not significantly longer in patients treated with GEM-E (median 6.77 months for GEM-E vs. 6.68 months for GEM, p = 0.0977). There was also no significant difference in the respective one-year survival rates (27.0 % vs. 27.3 %; p = 0.5988). Multivariate analysis using age, gender, and comorbidities as covariates did not reveal any significant differences in survival. Based on this relative effectiveness, the incremental cost per life year gained over GEM was estimated at USD 70,843.64 for GEM-E.ConclusionsGEM-E for pancreatic cancer is not more effective than GEM in a real-world setting, and it does not provide reasonable cost-effectiveness over GEM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2482-z) contains supplementary material, which is available to authorized users.

56. Intracerebroventricular and Intravenous AAV Gene Therapy in Canine Globoid Cell Leukodystrophy

Globoid cell leukodystrophy (GLD), or Krabbe disease, results from a deficiency in the hydrolytic enzyme galactosylceramidase (GALC), which is responsible for degrading the central and peripheral nervous system (CNS, PNS) myelin lipids galactosylceramide and galactosylsphingosine (psychosine). Symptoms in infants include irritability and stiffness with disease progressing rapidly to a vegetative state and death typically resulting by 2 years of age. GLD is naturally occurring in dogs and signs include ataxia, tremors, pelvic limb paralysis, loss of hearing, and blindness, with disease progression warranting euthanasia at 15.9 ± 4.6 weeks. In GLD dogs, GALC concentrations are decreased in leukocytes, CSF, and tissues and psychosine concentrations are elevated in serum and CSF. Conduction velocities in peripheral nerves of GLD dogs are < 50% of normal and G-ratios of the sciatic nerve are significantly higher than normal. Brain stem auditory evoked response testing exhibits a loss of waveform integrity and increased central conduction time consistent with auditory system demyelination. MRI of the brain shows T2-weighted hyperintensity of the white matter, widened sulci, and enlarged ventricles and MRS identified decreases in N-acetylaspartate and increases in choline. Diffusion tensor imaging established decreased fractional anisotropy and increased radial diffusivity in multiple white matter tracts including the corpus callosum and posterior internal capsule. Histologically, GLD dogs revealed severe loss of myelin, a decrease in oligodendrocytes, astrogliosis, and microgliosis. Combination gene therapy has been evaluated in GLD affected dogs using AAVrh10 encoding canine GALC (AAVrh10-cGALC). Two GLD dogs received a low dose of AAVrh10-cGALC, 1.2E12, by combination intravenous (IV) and intracerebroventricular (ICV) injection routes and displayed a modest increase in survival to 17.9 and 22.1 weeks of age. Two additional GLD dogs were treated with an increased dose of AAVrh10-cGALC, 1.9E13, and survival was further increased to 30.3 and 43.1 weeks of age. Both low and high dose combination IV and ICV therapy delayed the onset of neurological signs and prevented the onset of tremors, one of the debilitating neurologic signs in untreated GLD dogs. High dose AAVrh10-cGALC, but not low dose, resulted in complete normalization of pelvic and thoracic limb NCV and near normal sensory NCV. Combination therapy of either dose had negligible effect on the auditory system, as treated animals showed little to no improvement in distance between waveform peaks or hearing threshold over untreated animals. After high dose treatment with AAVrh10-cGALC, GALC activity reached near normal levels in the cerebellum and sciatic nerve, with levels decreasing in more distal brain regions. GALC levels in the liver and heart were intermediate between affected untreated GLD and normal control dogs. Interestingly, the highest GALC activity was found in the quadriceps muscle. GLD dogs treated with high dose AAV had CSF psychosine concentrations lower than untreated and low dose AAV-treated GLD dogs, despite being substantially older. Efficacy of hematopoietic stem cell transplant (HSCT) alone and in combination with IV AAVrh10-cGALC is currently being evaluated in GLD dogs. Ongoing studies suggest that addition of IV infusion of AAVrh10-cGALC substantially increases survival as compared to HSCT alone.

The Role of Glucose Modulation and Dietary Supplementation in Patients With Central Nervous System Tumors.

Central nervous system gliomas are the most common primary brain tumor, and these are most often high-grade gliomas. Standard therapy includes a combination of surgery, radiation, and chemotherapy which provides a modest increase in survival, but virtually, no patients are cured, the overall prognosis remains poor, and new therapies are desperately needed. Tumor metabolism is a well-recognized but understudied therapeutic approach to treating cancers. Dietary and nondietary modulation of glucose homeostasis and the incorporation of dietary supplements and other natural substances are potentially important interventions to affect cancer cell growth, palliate symptoms, reduce treatment-associated side effects, and improve the quality and quantity of life in patients with cancer. These approaches are highly desired by patients. However, they can be financially burdensome, associated with toxicities, and have, on occasion, reduced the efficacy of proven therapies and negatively impacted patient outcomes. The lack of rigorous scientific data evaluating almost all diet and supplement-based therapies currently limits their incorporation into standard oncologic practice. Rigorous studies are needed to document and improve these potentially useful approaches in patients with brain and other malignancies.

Paradoxical effects of the autophagy inhibitor 3-methyladenine on docetaxel-induced toxicity in PC-3 and LNCaP prostate cancer cells.

Docetaxel was the first chemotherapeutic agent to increase survival time in patients with androgen-resistant prostate cancer. However, it provides only a modest increase in survival and is associated with significant toxicity. Therefore, there is an urgent need to identify potential adjunct therapies. Given the key role of autophagy in both tumour survival and chemoresistance, the impact of autophagy modulation on docetaxel toxicity was tested in vitro. PC-3 and LNCaP cells were pre-treated with the autophagy inhibitor 3-methyladenine (5mM) and then exposed to various concentrations (0-100μM) of docetaxel. Cytoxic effects of docetaxel were measured using resazurin reduction to resorufin, whilst autophagy and apoptosis was measured using monodansylcadaverine, annexin V and caspase-3, respectively. Docetaxel produced significant toxicity in PC-3 cells but was not toxic to LNCaP cells. Pre-treatment with the autophagy inhibitor, 3-methyladenine (5mM) significantly protected PC-3 cells against docetaxel-induced cytotoxicity, increased autophagosome formation and apoptosis measured using monodansylcadaverine, annexin V and caspase-3 fluorescence, respectively. In contrast, 3-methyladenine was toxic by itself in LNCaP cells and also increased autophagic vesicle formation and apoptosis but did not influence docetaxel toxicity in these cells. These paradoxical effects of 3-methyladenine were largely independent of reactive oxygen species production. We show here that modulation of autophagy may influence docetaxel-induced toxicity in prostate cancer cells and these effects may differ between cell lines.

197 - Reversal of BRAF Resistance via Re-Establishment of Redox Balance Using a Unique Anti-Oxidant Strategy

197 - Reversal of BRAF Resistance via Re-Establishment of Redox Balance Using a Unique Anti-Oxidant Strategy