Search

Background and Aim: The standard of care for patients with gliomas should follow established guidelines. In real-world management, however, the management sometimes deviates from these guidelines. We organized a discussion of real-world clinical cases and summarized different considerations from Chinese and European specialists.Case Presentation: A multidisciplinary team comprising experts from Europe and China discussed two patients with glioma treated at Sun Yat-sen University Cancer Center and Liaoning Cancer Hospital and Institute, China. Patient 1 was a 43-year-old man with a recurrent oligodendroglioma in the left frontal lobe diagnosed based on histology alone. He had undergone a biopsy and was diagnosed with an oligodendroglioma 3 years previously. He underwent chemoradiotherapy followed by 12 cycles of chemotherapy with temozolomide (TMZ), and complete remission was achieved. However, the tumor recurred within a short period of time and was resected by a second surgery. The pathologic diagnosis of the recurrent tumor was a glioblastoma because 1p/19q was intact when detected by sequencing. Pathologic consultation from another hospital still considered an anaplastic oligodendroglioma based on the positive result of 1p19q loss of heterozygosity (LOH) determined by fluorescence in situ hybridization. Patient 2 was a 50-year-old man with a left temporal glioblastoma. He underwent tumor resection but no radiotherapy. After seven cycles of TMZ (5/28-day regimen), his symptoms deteriorated, and his treatment was changed to a TMZ dose-dense regimen (7 days on/7 days off) and bevacizumab (7.5 mg/kg every 2 weeks), plus tumor-treating field therapy. Consultation Results: The pathological diagnosis based on biopsy for Patient 1 was an oligodendroglioma (World Health Organization Grade II), whereas the result of the second surgical sample was glioblastoma or anaplastic oligodendroglioma (questionable). Although the accuracy of fluorescence in situ hybridization for the detection of 1p/19q LOH requires improvement, 1p/19q LOH is typically not reconstituted in oligodendroglioma. More likely, it was due to sampling; a positive observation field may be missed with consequent negative results, and both oligodendroglioma (with 1p/19q co-deletion and isocitrate dehydrogenase mutation) and astrocytoma (without 1p/19q co-deletion) may exist. With respect to further treatment for cases such as Patient 1, both Chinese and European experts agree that procarbazine + lomustine chemotherapy is appropriate, while re-irradiation is suggested only if the tumor recurs outside the original radiotherapy field or within the radiotherapy field in the future. Considering the medical history, the rapid tumor regrowth without postoperative radiotherapy in Patient 2 was not surprising. After application of a rescue treatment regimen, the general condition of the patient improved, which may have resulted from the bevacizumab. A consensus was reached between the Chinese and European experts regarding subsequent treatment of Patient 2. Continuation of TMZ and bevacizumab was suggested until further deterioration. Whether tumor-treating field therapy should play a role in this patient could not be evaluated. However, some other molecular targeted agents (e.g. vascular endothelial growth factor receptor tyrosine kinase inhibitors such as regorafenib or apatinib) after bevacizumab failure, the effectiveness of these drugs remains unclear. Conclusion: In clinical practice, although we should follow established guidelines, the final treatment regimen requires informed consent from the patient. Thus, some real-world cases may deviate from the established guidelines. When patients reach end-stage disease with a marked decrease in their performance status and no standard treatment options, active antitumor treatment might be more likely to be attempted in China, while symptomatic treatment is more frequently performed in Europe. Although treatment philosophies for patients with glioma are slightly different between Eastern and Western medical experts, any treatment strategies should satisfy these patients.

Purpose Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone administered every 3 weeks (R-CHOP-21) is the standard care for diffuse large B-cell lymphoma (DLBCL). It is unknown whether the dose-dense R-CHOP (R-CHOP-14) could improve the outcome of the disease in Asian population. Materials and Methods Newly diagnosed DLBCL patients were centrally, randomly assigned (1:1) to receive R-CHOP- 14 or R-CHOP-21. R-CHOP-14 was administered every 2 weeks, and R-CHOP-21 was administered every 3 weeks. Primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), progression-free survival (PFS), response rate and toxicities. Results Seven hundred and two patients were randomly assigned to receive R-CHOP-14 (n=349) or R-CHOP-21 (n=353). With a median follow-up of 45.6 months, the two groups did not differ significantly in 3-year DFS (79.6% for R-CHOP-14 vs. 83.2% for R-CHOP-21, p=0.311), 3-year OS (77.5% for R-CHOP-14 vs. 77.6% for R-CHOP-21, p=0.903), or 3-year PFS (63.2% for R-CHOP-14 vs. 66.1% for R-CHOP-21, p=0.447). Patients with an International Prognostic Index (IPI) score ≥ 2 had a poorer prognosis compared to those with an IPI score < 2. Grade 3/4 hematologic and non-hematologic toxicities were manageable and similar between R-CHOP-14 and R-CHOP-21. Conclusion R-CHOP-14 did not improve the outcome of DLBCL compared to R-CHOP-21 in Asian population. With manageable and similar toxicities, both of the two regimens were suitable for Asian DLBCL patients. For high-risk patients with IPI ≥ 2, new combination regimens based on R-CHOP deserve further investigation to improve efficacy.

Background and Aim: Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in a lower survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA-targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. Subjects and Methods: The study has two parts: part 1 is a dose–escalation and induction format to enroll up to ten patients in which they received VAL-083 at 20, 30, or 40 mg/m2 per day for 3 days every 21 days concurrently with standard radiation treatment and VAL-083 for up to eight additional cycles. Part 2 comprises an expansion phase to enroll up to twenty additional patients. This study was performed with approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017. Results: After completion of dose escalation, VAL-083, 30 mg/m2 per day, in combination with radiation therapy, was generally safe and well tolerated. At the cutoff date, 23 patients had been enrolled, 14 of whom had been treated in the expansion phase. Consistent with prior studies, myelosuppression was the most common adverse event. Pharmacokinetic assessment indicated that the levels of VAL-083 were as high in the cerebrospinal fluid as in plasma, 2 h postinfusion. Of the 22 patients who had reached their four precycle magnetic resonance imaging assessments, 12 were assessed with disease progression, with a median progression-free survival of 9.9 (95% confidence interval 7.3–12.0) months for all the patients studied. Conclusion: These preliminary data support VAL-083 as a potentially valuable treatment option for newly diagnosed GBM.

Background and Aim: Guidelines recommend adjuvant treatment for patients with high-grade gliomas and low-grade gliomas with high risk of progression. In clinical practice, however, treatments may not conform to these suggested guidelines. In this study, we reviewed the treatments and outcomes in patients with gliomas at Sun Yat-Sen University Cancer Center (SYSUCC), China. Materials and Methods: Medical records and radiologic images of 1215 glioma patients who underwent surgery at the center from 2000 to 2017 were retrospectively reviewed, and their clinicopathological characteristics, treatment method, and overall survival (OS) were analyzed. The study was approved by the Ethics Committee of SYSUCC on February 20, 2019 (approval No. GZR2019-219). Results: A total of 1001 patients diagnosed with glioma (initially World Health Organization 2007 criteria, then 2016 criteria) were enrolled, including 90 patients with Grade I, 307 Grade II, 239 Grade III, and 365 Grade IV gliomas. A total of 331 of 604 patients with high-grade glioma (54.8%) and 159 of 397 with low-grade glioma (40.1%) received postsurgical radiotherapy, and 285 patients with high-grade tumors (47.1%) and 80 with low-grade tumors (20.2%) received adjuvant chemotherapy. The median OS was 17.5 months for Grade IV and 43.1 months for Grade III gliomas. The median OS of patients with low-grade glioma was not reached. The 5-year survival rates of patients with Grades I, II, III, and IV gliomas were 94.7%, 73.7%, 45.7%, and 18.6%, respectively. Multivariate analysis identified onset age, preoperative seizure, tumor location, pathological subtype, resection extent, and postsurgical treatment as independent predictors of OS in patients with high-grade gliomas. Patients with high-grade glioma who received postsurgical treatment had better survival than those without adjuvant therapy (Grade III: 52.6 vs. 20.3 months, P = 0.012; Grade IV: 22.6 vs. 12.1 months, P < 0.001). Among patients with diffuse low-grade gliomas, age, performance status, preoperative seizure, Ki-67 index, tumor subtype, and resection extent were associated with clinical outcomes. Conclusion: Glioma patients are not always treated according to guidelines. Although standard care may lead to favorable prognoses, individualized treatments may be more acceptable and result in better outcomes and should thus be considered in routine clinical practice.

Background Differential diagnosis of tumour recurrence (TuR) from treatment effects (TrE), mostly induced by radiotherapy and chemotherapy, is still difficult by using conventional computed tomography (CT) or magnetic resonance (MR) imaging. We have investigated the diagnostic performance of PET/CT with 3 tracers, 13N-NH3, 18F-FDOPA, and 18F-FDG, to identify TuR and TrE in glioma patients following treatment. Methods Forty-three patients with MR-suspected recurrent glioma were included. The maximum and mean standardized uptake values (SUVmax and SUVmean) of the lesion and the lesion-to-normal grey-matter cortex uptake (L/G) ratio were obtained from each tracer PET/CT. TuR or TrE was determined by histopathology or clinical MR follow-up for at least 6 months. Results In this cohort, 34 patients were confirmed to have TuR, and 9 patients met the diagnostic standard of TrE. The SUVmax and SUVmean of 13N-NH3 and 18F-FDOPA PET/CT at TuR lesions were significantly higher compared with normal brain tissue (13N-NH3 0.696 ± 0.558, 0.625 ± 0.507 vs 0.486 ± 0.413; 18F-FDOPA 0.455 ± 0.518, 0.415 ± 0.477 vs 0.194 ± 0.203; both P 18F-FDG (6.918 ± 3.190, 6.016 ± 2.807 vs 6.356 ± 3.104, P = 0.290 and 0.493). L/G ratios of 13N-NH3 and 18F-FDOPA were significantly higher in TuR than in TrE group (13N-NH3, 1.573 ± 0.099 vs 1.025 ± 0.128, P = 0.008; 18F-FDOPA, 2.729 ± 0.131 vs 1.514 ± 0.141, P 13N-NH3; 84.6%, 100% and 0.938, for 18F-FDOPA; and 80.8%, 100%, and 0.952, for the combination, respectively. Conclusion Our results suggest that although multiple tracer PET/CT may improve differential diagnosis efficacy, for glioma TuR from TrE, 18F-FDOPA PET-CT is the most reliable. The combination of 18F-FDOPA and 13N-NH3 does not increase the diagnostic efficiency, while 18F-FDG is not worthy for differential diagnosis of glioma TuR and TrE.

OBJECTIVE This study was designed to retrospectively analyze the dynamic changes of peripheral blood lymphocyte subsets and prognosis among patients with intracranial germ cell tumors. METHODS A total of 150 intracranial germ cell tumors patients diagnosed between June 2011 till November 2019 were retrospectively investigated. Peripheral blood total T lymphocytes (CD3+) percentage, T helper/inducible lymphocytes(CD3+CD4+)percentage, T inhibitory/toxic lymphocytes (CD3+CD8+) percentage, B lymphocyte (CD19+) percentage, NK lymphocyte (CD3/CD16+CD56+) percentage, regulatory T cells (CD4+CD25+,CD8+CD25+), and T helper/toxic lymphocyte ratio (CD4+/CD8+ ratio) were quantified by flow cytometry analysis. Clinical information was extracted from the database in Sun Yat-sen University Cancer Center and survival data was confirmed through outpatient visits and telephone follow-up. RESULTS T lymphocytes population was increased after anti-tumor treatment, with significant difference of total T lymphocytes (CD3+), inhibitory/toxic T cells (CD3+CD8+) and regulatory T cells (CD4+CD25+ and CD8+CD25+), (p=0.008, p=0.000, p=0.008 and p=0.001 respectively), while B lymphocytes(CD19+) decreased after chemotherapy(p=0.003). The dynamic levels of T lymphocyte and B lymphocyte subpopulation after chemotherapy did not present significant differences between gender, age, and locations of tumors (p >0.05), except CD4+CD25+ T cells in younger children (age< 16 years older) increased significantly than the elder (age >16), p=0.04. Patients with increased CD19+ B cells presented significant suboptimal outcomes compared with the no increased (p=0.024). Similarly, increased CD3+ T cells, CD3+CD8+ T cells, CD4+CD25+ T cells reduced the risk of death (p=0.006, p=0.019, p=0.042 respectively). Multivariate Cox Regression analysis showed: increased CD19+ B cells, p=0.04, HR=1.688, 95%CI=1.025-2.779. CONCLUSION After anti-tumor treatment, cell-mediated immunity activated, enhanced, and dominated in anti-tumor response. An increased level of CD19+ subsets was an independent predictor for inferior overall survival. Systemic circulating T cells immunity played an important role and mediating antitumor responses may pave the road for new immunity strategies.

BackgroundProteins containing the caspase recruitment domain (CARD) play critical roles in cell apoptosis and immunity. However, the impact of CARD genes in tumor immune cell infiltration, responsiveness to checkpoint immunotherapy, and clinical outcomes of gliomas remains unclear. Here, we explore using CARD genes to depict the immune microenvironment and predict the responsiveness of gliomas to anti-PD-1 therapy.MethodsThe genome and transcriptome data of 231 patients with isocitrate dehydrogenase wild-type (IDH-wt) gliomas were retrieved from The Cancer Genome Atlas (TCGA) database to screen CARD genes associated with T lymphocyte infiltration in gliomas. Weighted co-expression network and LASSO penalized regression were employed to generate a CARD-associated risk score (CARS). Two independent and publicly available datasets were used to validate the effectiveness of CARS.ResultsThe CARS divided the 231 glioma patients into high- and low-risk subgroups with distinct immune microenvironment and molecular features. The high-risk group had high CARS and was characterized by enrichment of dysfunctional T lymphocytes in a profound immunosuppressive microenvironment, whereas the low-risk group had low CARS and exhibited an immune exclusion genotype. Moreover, signaling aberrations including upregulation of PI3K/Akt/mTOR, NF-κB, and TGF-β were found in the high-risk group. In contrast, the activated WNT pathway was more evident in the low-risk group. Furthermore, we found that an elevated CARS indicated a decreased overall survival for IDH-wt gliomas under standard care but a clinical benefit from checkpoint immunotherapy.ConclusionThis study developed an immune- and prognosis-relevant risk score, which could be used to enhance our understanding of the heterogeneity of immune microenvironment of gliomas and facilitate to identify patients who will benefit from checkpoint immunotherapy.

Background: Medulloblastoma (MB) is one of the most malignant neuroepithelial tumors in the central nervous system. This study aimed to establish an effective prognostic nomogram and risk grouping system for predicting overall survival (OS) of patients with MB.Materials and Methods: The nomogram was constructed based on data from the database of Surveillance, Epidemiology, and End Results (SEER). This database consisted of 2,824 patients with medulloblastoma and was used as the training cohort. The data of another additional 161 patients treated at the Sun Yat-sen University Cancer Center (SYSUCC) were used as the external validation cohort. Cox regression analysis was used to select independent prognostic factors. Concordance index (C-index) and calibration curve were used to predict the prognostic effect of the nomogram for overall survival.Results: In the training cohort, Cox regression analyses showed that the prognostic factors included histopathology, surgery, radiotherapy, chemotherapy, tumor size, dissemination, and age at diagnosis. The internal and external validated C-indexes were 0.681 and 0.644, respectively. Calibration curves showed that the nomogram was able to predict 1-, 3-, and 5-year OS for patients with MB precisely. Using the training cohort, a risk grouping system was built, which could perfectly classify patients into four risk nomogroups with a 5-year survival rate of 83.9%, 76.5%, 64.5%, and 46.8%, respectively.Conclusion: We built and validated a nomogram and risk grouping system that can provide individual prediction of OS and distinguish MB patients from different risk groups. This nomogram and risk grouping system could help clinicians making better treatment plan and prognostic assessment.

OBJECTIVES: To observe the improvement effect and its mechanism of chlorogenic acid (CGA) on the glucose tolerance and its curve characteristics in high fat diet-induced obesity (DIO) rats. METHODS: Eight of 56 male SD rats were randomly selected as the normal diet group (CON), and the rest were fed with high-fat diet. After 4 weeks, 24 DIO rats were screened and then randomly divided into high fat diet group (HFD group), 50% CGA group and 98% CGA group. The CGA groups received intragastric administrations of 50% CGA and 98% CGA (80 mg/kg/d) once a day for 8 weeks, respectively, while the CON and HFD groups received a carrier solution PBS. Body weight was measured weekly and OGTT was performed every 4 weeks. Fasting insulin and insulin release were measured, HOMA-IR was calculated. Histopathological examination by hematoxylin and eosin staining method were evaluated in the pancreatic tissues. Non-targeted metabolomics analysis of rat serum was performed using UHPLC-Q-Orbitrap MS. RESULTS: Before the intervention of CGA, blood glucose levels at 120 min after glucose loading (P

Glioma, especially glioblastoma (GBM), is the most aggressive malignant brain tumor and its standard therapy is often ineffective because of temozolomide (TMZ) resistance. Reversal of the TMZ resistance might improve the prognosis of glioma patients. We previously found that interferon-α (IFN-α) and anti-epileptic drug levetiracetam (LEV) could sensitize glioma to TMZ, respectively. In this study, we further investigated the efficiency of combining of LEV and IFN-α for improving the efficacy of TMZ. We evaluated whether LEV and IFN-α could increase TMZ efficacy using colony formation assay and cell viability assay with MGMT-positive and MGMT-negative glioma cell lines in vitro. Subcutaneous xenografts and orthotopic xenografts mice models were used in vivo to observe the tumor growth and mice survival upon treatments with TMZ, TMZ + IFN-α, TMZ + LEV, or TMZ + LEV + IFN-α. The expression levels of MGMT, markers of pro-apoptotic and anti-apoptotic in tumor samples were analyzed by Western blotting. The combinational use of IFN-α, LEV, and TMZ showed the best anti-tumor activity in MGMT-positive cell lines (U138, GSC-1, U118, and T98 G). TMZ + LEV + IFN-α further obviously increased TMZ + LEV or TMZ + IFN-α efficiency in MGMT-positive cell lines, while not in negative cell lines (SKMG-4, U87, U373, and U251) in vitro, which were also observed in subcutaneous mice models (U138, GSC-1 compared to SKMG-4, U87) and orthotopic models (GSC-1) in vivo. Strikingly, the combination of LEV and IFN-α together with TMZ significantly prolonged the survival of mice with orthotopic GSC-1 glioma. Furthermore, we confirmed that the combination of LEV and IFN-α enhanced the inhibition of MGMT and the activation of apoptosis in U138 tumor on the basis of TMZ treatment. The combination use of LEV and IFN-α could be an optimal method to overcome TMZ resistance through obvious MGMT inhibition in MGMT-positive glioma.

Background Differentiating glioma recurrence from treatment-related changes can be challenging on conventional imaging. We evaluated the efficacy of quantitative parameters measured by dual-energy spectral computed tomographic (CT) for this differentiation. Methods Twenty-eight patients were examined by dual-energy spectral CT. The effective and normalized atomic number (Zeff and Zeff-N, respectively); spectral Hounsfield unit curve (λHU) slope; and iodine and normalized iodine concentration (IC and ICN, respectively) in the post-treatment enhanced areas were calculated. Pathological results or clinicoradiologic follow-up of ≥2 months were used for final diagnosis. Nonparametric and t-tests were used to compare quantitative parameters between glioma recurrence and treatment-related changes. Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), and accuracy were calculated using receiver operating characteristic (ROC) curves. Predictive probabilities were used to generate ROC curves to determine the diagnostic value. Results Examination of pre-contrast λHU, Zeff, Zeff-N, IC, ICN, and venous phase ICN showed no significant differences in quantitative parameters (P > 0.05). Venous phase λHU, Zeff, Zeff-N, and IC in glioma recurrence were higher than in treatment-related changes (P 3, achieving 66.7, 91.7, 83.3, and 91.7% sensitivity; 100.0, 77.8, 88.9, and 77.8% specificity; 100.0, 73.3, 83.3, and 73.3% PPV; 81.8, 93.3, 88.9, and 93.3% NPV; and 86.7, 83.3, 86.7, and 83.3% accuracy, respectively. The respective areas under the curve (AUCs) were 0.912, 0.912, 0.931, and 0.910 in glioma recurrence and treatment-related changes. Conclusions Glioma recurrence could be potentially differentiated from treatment-related changes based on quantitative values measured by dual-energy spectral CT imaging.

Twist is a transcription factor involved in the process of epithelial to mesenchymal transition (EMT) of carcinoma cells, and the promotion of invasion of gliomas through the mesenchymal adjusting process. However, its clinical significance in human glioma has not yet to be understood. To delineate the clinical-pathological significance and prognostic value of Twist, the expression of Twist was evaluated by Immunohistochemistry for 187 glioma samples. We found that Twist demonstrated frequent nuclear expression in the glioma samples and its expression levels were associated with tumor grade (P

Purpose This study aimed to analyze the preferred locations of secondary brain tumors of breast carcinoma according to different biological characteristics. Method 161 Breast cancer brain metastasis (BCBM) patients diagnosed between January 2007 and February 2018 were retrospectively analyzed. MR images when brain metastases occurred were collected, registered, segmented. The frequency and p-value heatmaps were constructed to compare two biological phenotypes using two-tailed Fisher’s exact test. Age, treatments, the status of ER, PR, and HER2, luminal subtype, tumor marker levels in peripheral blood including CEA, CA19-9, and CA15-3 were statistically analyzed. Survival data were analyzed by Kaplan–Meier method, log-rank test, and multivariate logistic regression. Result The frequency heat map shows lesions of patients with BCBM are more inclined to the cerebellar hemisphere. Older patients(>49 years old, median age) mainly occur in the left frontal lobe, the right parietal lobe, and adjacent meninges comparing with white matter of the left parietal lobe, cerebellar vermis, and areas around the fourth ventricle among younger patients and the difference is significant. Patients with tumors located on the surface of the brain are more likely to undergo surgical treatment, however, conservative treatment was considered if metastases are located at the midline structure. ER and PR-positive and HER-2 enriched patients have more significance in metastases, at the left parieto-occipital junction area, frontal lobe, parietal lobe, cerebellar hemisphere, and adjacent meninges. Metastases with high levels of CEA are found significantly at areas around the central anterior gyrus. Lesions with an elevated level of CA19-9 and CA15-3 tend to be frontal, parietal, and occipital. Besides, HER-2 enriched in primary sites and a normal level of CA15-3 in peripheral blood were two independent protective factors in determining prognostic outcomes. Conclusion The preferred locations of BCBM could be clues of further study and helpful for clinical strategies.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. The majority of glioblastoma multiforme (GBM) patients have an unmethylated MGMT promoter status, leading to limited response to TMZ and decreased survival. Current standard-of-care includes surgery followed by chemoradiation and TMZ. An unmethylated promoter for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is strongly correlated with poor outcomes. VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated drug-resistance and has demonstrated cytotoxicity in MGMT-unmethylated GBM cell lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. A Phase 2, open-label, biomarker-driven, study is being conducted to evaluate the tolerability and efficacy of VAL-083 in combination with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 given IV at 20, 30, or 40 mg/m2/day x 3 days every 21 days and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study has 2 stages: Stage 1, dose-escalation, has identified a recommended dose of 30 mg/m2/day of VAL-083 in combination with RT as generally safe and well-tolerated. Stage 2, an expansion stage, has enrolled 20 additional patients at 30 mg/m2/day IV infusion on days 1, 2, and 3 of 21-day cycles. As of January 11, 2021, all 29 subjects in the study have been enrolled and completed the treatment stage of the study. Tumor response are assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. The trial is continuing as planned and an update on primary results on safety and efficacy, and pharmacokinetics will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736. Citation Format: Zhong-ping Chen, Cheng-cheng Guo, Qun-ying Yang, Jia-wei Li, Shao-xiong Wu, John Langlands, Gregory Johnson, Claire Kwan, Sarath Kanekal, Richard Schwartz, Jeffrey Bacha, Anne Steino, Dennis Brown. Phase 2 clinical trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT172.

Ependymomas are glial brain tumors accounting for approximately 2~3% of all primary tumors of the central nervous system (CNS), and 12% of all pediatric intracranial tumors. To better understand the evolution process of ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. This girl was diagnosed as ependymoma at age of 9 years old, and experienced 7 times tumor relapse and received 9 times surgeries but finally ceased at 19 years old with multiregional recurrences. The pathological characteristics, radiographic images and therapeutic strategies of the patient were all retrieved. Molecular markers confirmed the diagnosis of anaplastic ependymoma based on the updated WHO guideline for CNS tumors. Whole-genome sequencing (WGS) was performed to elucidate the landscape of mutation signatures and to identify potential driver mutations along the tumor progression. The seven tumor specimens showed a highly branched evolutionary pattern. There were six gene mutations found in 5 of the 7 specimens (PCDHA4, PCDHA8, SEC14L6, SETD2, RIOK2, and SLCO2A1) and three in 6 of 7 the samples (RYR1, SNX25, DSC2). Strikingly, there was one gene, ADGRL3, which was found to be consistently mutated in the entire disease progression process. Our findings therefore suggest that ADGRL3 might play roles in the disease progression of ependymoma patient.

BACKGROUND Glioma often recurs and the imaging evaluation whether the tumor has returned after glioma treatment is still challenging. PET/CT is one of the most important techniques to assess the post-treatment of glioma. However, differentiating tumor recurrence (TuR) from treatment effects (TrE) remains difficult. In this study, we aim to retrospectively compare the diagnostic performance of three PET tracers 13N-NH3, 18F-DOPA, and 18F-FDG on PET/CT in differentiating between TuR and TrE in post-treatment glioma patients. METHODS Forty-three patients with MRI-suspected recurrent glioma were included. The maximum and mean standardized uptake value (SUVmax and SUVmean) of the lesion and the lesion-to-normal Gray-matter cortex uptake (L/G) ratio were recorded and the reference standard was verified by surgical histopathology or more than 6 months of follow-up with clinical/radiological. The diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. RESULTS 34 patients were confirmed as glioma TuR and 9 patients met the standard of TrE. The median time interval from primary diagnosis surgery to PET/CT was 14.83 months (range, 4.10-62.77 months). The SUVmax of 13N-NH3 and 18F-DOPA PET/CT at the lesions was significantly higher than normal brain tissue (13N-NH3 0.696±0.095 vs 0.486±0.071, 18F-DOPA 0.455±0.079 vs 0.194±0.031, both P< 0.001), while 18F-FDG was not (6.918±0.525 vs 6.356±0.510, P=0.290). TuR showed significantly higher L/G ratios than TrE both in 13N-NH3 and 18F-DOPA PET/CT (13N-NH3, 1.573±0.099 vs 1.025±0.128, P=0.008; 18F-DOPA, 2.729±0.131 vs 1.514±0.141, P< 0.001). The sensitivity, specificity and the area under the curve (AUC) by ROC analysis were 57.7, 100% and 0.803 for 13N-NH3, and 84.6, 100% and 0.938 for 18F-DOPA respectively. CONCLUSIONS PET/CT is a powerful tool to distinguish glioma TuR from TrE, and 18F-DOPA PET/CT has remarkably better differential diagnosis efficacy than 13N-NH3 and 18F-FDG.

BACKGROUND: The present study explored the predictive value of systemic inflammatory indexes in diagnosing grade III gliomas of oligodendroglial origin. METHODS: A retrospective study of 154 patients with grade III gliomas was conducted. Systemic inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), albumin-to-gamma-glutamyl transferase ratio (AGR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, prognostic nutritional index, and fibrinogen-to-albumin ratio, were reviewed. The resulting predictive model was externally validated using a demographic-matched cohort of 49 grade III glioma patients. RESULTS: In the training set, gliomas of oligodendroglial origin tended to have a lower NLR (P=0.018) and a higher AGR (P=0.036) than those with tumors of astrocytic origin. Moreover, both NLR and AGR had predictive value for oligodendroglial tumors, when compared with astrocytic tumors. The best diagnostic value was obtained using NLR + AGR (AUC =64.9%, 95% CI: 55.5–74.3%, P=0.005). In the validation set, NLR + AGR satisfactorily predicted the presence of oligodendroglial tumors (AUC =66.5%, 95% CI: 50.6–82.4%, P

OBJECTIVE Brain metastases are the most common malignant tumors of the central nervous system. In patients with brain metastases with surgical indications, total surgical resection is the most effective treatment for prolonging patient survival and relieving neurological symptoms. In this study, the clinical data of 147 patients in a single group underwent microsurgery of brain metastases were retrospectively analyzed to investigate the therapeutic value of microsurgery in patients with brain metastases. METHODS From January 2000 to December 2017, patients who underwent microsurgical removal of brain metastases from the Department of Neurosurgery in Sun Yat-sen University Cancer Center were retrospectively analyzed. The clinical and pathological features and prognosis of the patients were collected and analyzed. The characteristics of brain metastases were analyzed through surgical recording and videos. RESULTS A total of 147 patients were enrolled, including 86 males and 61 females. The average age was 54.4 years, of which 125 were younger than 65 years old. 137 people with KPS ≥ 70. 95.9% (141 patients) had an RPA grade of I-II, of which 51 (34.7%) were RPA class I and 90 (61.2%) were RPA class II. 90.5% (133 patients) were single brain metastases. 71.5% (105 cases) of patients with metastases are located in the cerebral area. The distribution of primary lesions suggested that the lung cancer was the most, reaching 62.6%; followed by breast source (10.9%). The surgical video analysis suggest that most brain metastatic lesions have obvious supplying vessels, relatively clear boundaries with a pseudo-capsule structure. The 5-year OS of all patients reached 15% with a median survival of 42.3 months. CONCLUSION The brain metastases have clear blood supplying vessels and relatively clear boundaries that favors gross total resection. Surgical treatment is associated with better prognosis in patients with brain metastases.

Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT gene, which confers a limited response to standard of care treatment with temozolomide (TMZ) resulting in a lower survival. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation and induction format to confirm the recommended dose of VAL-083 when administered concurrently with radiation therapy (RT) based on safety and tolerability. The subjects received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment. Stage 2 comprises an expansion phase to enroll up to 30 patients. The dose escalation stage is complete and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. As of 17 May, 2019, 18 patients have been enrolled. Fifteen patients have completed their prospectively planned MRI scans and had their initial assessment for tumor progression. Of these 15 patients, seven were assessed as a complete response (CR), and eight patients as having stable disease (SD). Of the remaining three patients, one died prior to their post-cycle 3 MRI and two have not been on study long enough to reach their planned post-cycle 3 MRI. As of the data cutoff, 14 of the 18 patients were still alive. Consistent with our prior experience, myelosuppression was the most common adverse event. Three dose-limiting toxicities have been reported - one at the 40 mg/m2/day and two at the 30 mg/m2/day dose. Further enrollment, safety & study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

e14019 Background: High-grade glioma (HGG) is the most common malignant brain tumor and lacks effective treatment regimen. Anlotinib is a multikinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. This study was performed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide (TMZ) in the treatment of recurrent HGG. Methods: This is a single-center, retrospective study. Eligible patients (pts) were diagnosed with pathologically confirmed high grades (WHO III/IV) glioma and had recurrent or progressive disease on or after prior treatment. Other key eligibility criteria included Karnofsky Performance Status (KPS) ≥ 40, aged 16 ̃75 years and having at least one measurable lesion (RANO criteria). Pts were administrated with anlotinib once daily for 14 days every 3 weeks till disease progression, intolerable toxicities or death. The initial dose was 12mg for younger pts ( < 40 years old) with KPS ≥ 60 and 10 mg for others. Combination treatment was allowed if previous TMZ was effective and tolerable. TMZ was administered on dose-dense schedule (150mg/m2, QD, d1-d7 and d15-d21 every 28 days) or metronomic schedule (25-50mg/m2 QD). The primary endpoint was progression-free survival at 6 months (PFS6m) accessed according to RANO criteria. The second endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Between August 2019 and June 2020, 23 pts with HGG (15 grade IV; 8 grade III; 12 males, 11 females) were enrolled. The median age and median KPS was 42 years and 60. 16 pts have multifocal or disseminated disease. 18 pts received ≥2 lines previous treatment. At the data cutoff date on September 2020, the median duration of treatment was 9 weeks (range: 3-33). The PFS6m was 39.1% and the median PFS was 4.2 months (95% CI: 2.8, 5.6). The median OS was not reached (95% CI: NE, NE) and the OS at 12 months (OS12m) was 54.8%. 8 pts observed tumor response and 9 pts had stable disease. The ORR and DCR were 34.8% and 73.9% respectively. The results of survival analysis for subgroups were summarized in table below. Grade 1 or 2 treatment-related adverse events (TRAEs) occurred in 65.2% pts. No ≥ grade 3 TRAE was found. All hematological TRAEs occurred in patients received combination regimen. No TRAE-induced treatment termination occurred. The lower incidence of TRAE may partly attributed to that most pts (18/23) received lower initial dose (10mg) of anlotinib and the relatively shorter treatment duration. Conclusions: This study showed treatment with anlotinib alone or in combination with TMZ had promising efficacy and favorable tolerability in patients with recurrent HGG.[Table: see text]

BACKGROUND AND OBJECTIVE Primary intracranial germ cell tumors (PIGCTs) are a group of heterogeneous tumors. It is very difficult to treat those patients without pathological diagnosis. This study retrospectively analyzed the clinical data and outcomes of patients with clinically diagnosed (without histologically confirmed) PIGCTs in SunYat-sen University Cancer Center. METHODS Patients who were clinically diagnosed as PIGCTs without histological diagnosis through surgical resection or biopsy were included in this study. Patients were analyzed for clinical characteristics, treatment patterns, outcomes and adverse effects. RESULTS From May 2002 to July 2014, 74 patients clinically diagnosed with PIGCTs received chemotherapy and/or radiotherapy at the Sun Yat-sen University Cancer Center. The median age was 16.5 years old (4–45 years old, majority was teenagers). The most of tumors were found in male, and located in the pineal and suprasellar regions. When the patients were grouped into diagnostic chemotherapy group (57 cases), diagnostic radiotherapy group (5 cases) and gamma knife radiosurgery group (12 cases) based on their initial anti-tumor therapy. The 5-year survival rates were 84.3%, 75.0% and 75.0%, respectively. There was a trend that the chemotherapy group got a better survival. Patients were allocated to secretory tumor group (49 cases) and non-secretory tumor group (25 cases) based on their levels of tumor makers (α-FP and β-hCG). The 5- year survival rates were 80% and 77.8% (P value = 0.966), respectively. CONCLUSION Clinical diagnosed PIGCT (without histological confirmation) patients may obtain good responses when receiving comprehensive treatments of chemotherapy combined with radiotherapy.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemoirradiation and temozolomide (TMZ). An unmethylated promoter for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is strongly correlated with poor outcomes. The majority of glioblastoma multiforme (GBM) patients have an unmethylated MGMT promoter status, leading to limited response to TMZ and decreased survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated drug-resistance and has demonstrated cytotoxicity in MGMT-unmethylated GBM cell lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. A Phase 2, open-label, biomarker-driven, study has been initiated to evaluate the tolerability and efficacy of VAL-083 in combination with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 given IV at 20, 30, or 40 mg/m2/day x 3 days every 21 days and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study has 2 stages: Stage 1 is a dose-escalation and induction format to establish a recommended dose of VAL-083 when administered concurrently with RT based on safety and tolerability. The dose escalation stage has been completed and we identified a recommended dose of 30 mg/m2/day of VAL-083 in combination with RT as generally safe and well-tolerated. Stage 2 comprises an expansion stage to enroll up to 20 additional patients at 30 mg/m2/day IV infusion on days 1, 2, and 3 of 21-day cycles and is currently ongoing. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. As of 21st January 2020, 19 subjects have initiated treatment in stage 2. The enrollment, safety data and primary results update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736. Citation Format: Zhong-ping Chen, Cheng-cheng Guo, Qun-ying Yang, Jia-Wei Lei, Shao-xiong Wu, Gregory Johnson, John Langlands, Claire Kwan, Sarath Kanekal, Richard Schwartz, Jeffrey A. Bacha, Anne Steino, Dennis M. Brown. Phase 2 trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT273.

Due to the variable overlap of multiple symptoms, accurate early diagnosis of NK/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS) is difficult, making the prognosis extremely poor. Hemophagocytic syndrome (HPS) is now diagnosed primarily based on the hemophagocytic lymphohistiocytosis (HLH)-2004 diagnostic criteria, and platelet count is one of the baseline evaluations. However, in our study, the data showed that decreased platelets were not only a clinical feature of HPS but also the key cells that regulate inflammation by releasing α-granules containing upregulated platelet factor 4 (PF4) and downregulated platelet-derived growth factors (PDGFs). Furthermore, we found that angiopoietin-4 (ANG-4), which has significant differential expression, has been less reported, that may affect hematopoiesis and proinflammatory responses and can be used as diagnostic biomarkers together with PF4 and PDGFs.

Primary CNS germ cell tumors (CNS-GCTs) are a group of heterogeneous tumors, and comparative higher incidence in Asian countries. Here we present our institutional experience for CNS-GCTs treatment. There are 209 CNS-GCTs cases treated at Sun Yat-sen University Cancer Center during last 15 years. The median age of patients was 16 years old (4-69 y-old). The tumors were classified as Germinoma and Nongerminoma germ cell tumors(NG-GCTs), and also secretory sub-type(AFP≥10 ng/dL and/or β-HCG)≥50 IU/L) or non-secretory sub-type(normal level of tumor marker). There were 60 cases received Ventricle-peritoneal shunt (V-P shunt) or endoscopic third ventricle colostomy due to obstructive hydrocephalus. Treatment modality including: comprehensive treatment 84cases (40.2%), ie chemotherapy plus radiation therapy (some cases with chemo-Radio-chemo Sandwich Therapy) with or without surgical intervention; Monotherapy, ie Chemotherapy only:37 (17.7%), Radiotherapy Only:13 (6.2%). Surgery for tumor removal or biopsy:55cases (25.4%), in which 4 cases were failed from initial diagnostic chemotherapy. There were also some patients(about 6%) received Gamma knife radiosurgery. The 5 years overall survival(OS) rate was better for those with comprehensive treatment, compared those with monotherapy cases: 86.5% vs 66.7%. The 5 ys OS rate according tumor markers was also different: Non Secretory Subtype:79.8%,HCG increased Subtype: 92.9%, AFP increased Subtype: 64.8%, and AFP+HCG coincreased Subtype: 75.0%. Conclusion from our institutional experience: Although smaller number of patients need surgical tumor removal, clinical diagnosed CNS-GCT (without histological confirmation) patients may obtain good responses when receiving comprehensive treatments of chemotherapy combined with radiotherapy.

OBJECTIVE Temozolomide (TMZ), is the first line chemotherapeutic drug for glioma. Previous studies have suggested that interferon (IFN) and levetiracetam (LEV) could respectively reverse the resistance of TMZ by down-regulating MGMT expression. This study, we aim to investigate the therapeutic effect of a cocktail chemotherapy regimen combining TMZ, LEV, IFN in vivo. METHODS Glioma cell lines U251 and SKMG-4 (MGMT protein expression positive), U138 and GSC-1(MGMT protein expression negative) were used for producing xenograft tumors. The xenograft tumors were established by subcutaneously injecting 1×106 glioma cells into female BALB/C nude mice and divided into 5 treatment groups: Control, TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN. The treatment with TMZ (50 mg/kg, i.p.), IFN (2×105 IU, s.c.), LEV (150 mg/kg, i.p.) once a day for five consecutive days and xenograft tumors were measured every two days. RESULTS We identified that U138, U251, SKMG-4 tumor growth among TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN were all significantly inhibited (P< 0.05), compared with the control. As for U251 and SKMG-4, tumor killing effect of all 4 treatment groups were not different (P > 0.05). In the treatment of mice bearing U138 glioma, the tumor weight of TMZ+LEV+IFN (0.2688±0.1169 g) group was the lowest and significantly lower than that of TMZ+LEV (0.6574±0.08174g, P=0.0261), TMZ+IFN(0.6108±0.07317 g, P=0.0381), and TMZ (0.9054±0.07154 g, P=0.0017) group. Glioma stem cells GSC-1 was highly resistant to TMZ, tumor volume of TMZ group was not different from control group (P >0.05). While compared with TMZ (1.993±0.1274 g) group, in TMZ+IFN (1.506±0.1223g, P=0.0203), TMZ+LEV (1.178±0.1807g, P=0.0042), and TMZ+LEV+IFN (1.049±0.2171 g, P=0.0038) groups, GSC-1 tumor growth were significantly inhibited(P< 0.05). CONCLUSION Our data demonstrate that both IFN and LEV can sensitize TMZ effect on glioma in vivo, even for MGMT(+) tumors, and TMZ-LEV-IFN cocktail regimen seems the best. Key words: glioma, TMZ, LEV, IFN

// Chengcheng Guo 1,5 , Chuncheng Hao 1,6 , RuPing Shao 1 , Bingliang Fang 1 , Arlene M. Correa 1 , Wayne L. Hofstetter 1 , Jack A. Roth 1 , Carmen Behrens 2 , Neda Kalhor 3 , Ignacio I. Wistuba 4 , Stephen G. Swisher 1 and Apar Pataer 1 1 Departments of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Current address: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China 6 Current address: Department of Oncology Radiotherapy, The Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China Correspondence to: Apar Pataer, email: // Keywords : PKR, AMPK, nutrient depletion, lung cancer Received : February 05, 2015 Accepted : February 22, 2015 Published : March 14, 2015 Abstract We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2α are independent prognostic markers for overall survival in lung cancer. In the current study, we further investigate the interaction between PKR and AMPK in lung tumor tissue and cancer cell lines. We examined PKR protein expression in 55 frozen primary lung tumor tissues by Western blotting and analyzed the association between PKR expression and expresson of 139 proteins on tissue samples examined previously by Reverse Phase Protein Array (RPPA) from the same 55 patients. We observed that biomarkers were either positively (phosphorylated AMP-activated kinase T172 [p-AMPK]) or negatively (insulin receptor substrate 1, meiotic recombination 11, ATR interacting protein, telomerase, checkpoint kinase 1, and cyclin E1) correlated with PKR. We further confirmed that induction of PKR with expression vectors in lung cancer cells causes activation of the AMPK protein independent of the LKB1, TAK1, and CaMKKβ pathway. We found that PKR causes nutrient depletion, which increases AMP levels and decreases ATP levels, causing AMPK phosphorylation. We further demonstrated that inhibiting AMPK expression with compound C or siRNA enhanced PKR-mediated cell death. We next explored the combination of PKR and p-AMPK expression in NSCLC patients and observed that expression of p-AMPK predicted a poor outcome for adenocarcinoma patients with high PKR expression and a better prognosis for those with low PKR expression. These findings were consistent with our in vitro results. AMPK might rescue cells facing metabolic stresses, such as ATP depletion caused by PKR. Our data indicate that PKR causes nutrient depletion, which induces the phosphorylation of AMPK. AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemo-radiation and temozolomide. An unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance and is strongly correlated with poor outcomes. Unmethylated MGMT represents the majority of newly diagnosed GBM tumors. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as single agent and in combination with radiotherapy. VAL-083 induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083’s unique mechanism-of-action circumvents MGMT-mediated chemoresistance, and it has demonstrated cytotoxicity in MGMT-unmethylated GBM cell-lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. We completed a dose-escalation trial of VAL-083 in recurrent GBM, and a generally well-tolerated dosing regimen was selected for further clinical development. The present trial is an ongoing open-label, biomarker-driven, Phase I/II study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study is being conducted in two parts. The dose-confirmation part (20, 30, and 40 mg/m2/day IV infusion on days 1-3 of a 21-day cycle) has been completed, and the expansion part has been initiated in up to 20 additional patients at 30 mg/m2/day IV infusion on days 1-3 of a 21-day cycle. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. Trial design, enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736. Citation Format: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, John Langlands, Anne Steino, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis Brown. Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed, MGMT-unmethylated glioblastoma [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 CT116.

7537 Background: Radiotherapy is extremely important in extranodal natural killer/T-cell lymphoma (ENKTL). [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a routine pretreatment imaging technique used in ENKTL, while magnetic resonance imaging (MRI) plays a key role in head and neck (HN) cancer. The purpose of this study was to investigate the value of pretreatment HN-MRI and PET/CT-guided therapy in improving survival in upper aerodigestive tract ENKTL (UADT-ENKTL). Methods: We prospectively conducted a single center study on untreated patients with pathologically diagnosed UADT-ENKTL. Patients undergoing PET/CT with/without HN-MRI were decided by clinicians for staging and restaging. The patients were treated with L-asparaginase/Pegaspargase and non-anthracycline-based chemotherapy with intensity-modulated radiation therapy (IMRT). Results: We enrolled 171 patients (median age, 44 years; range, 18-75 years; 118 (69%) males) from April 2011 to March 2018. Overall, 71 patients underwent PET/CT and HN-MRI (PET/CT-MRI) and 100 patients underwent PET/CT alone. HN-MRI upgraded the clinical stages in 8 patients (8/71) undergoing PET/CT based on the Ann Arbor staging system and in 10 patients (10/71) based on the TNM staging system by detecting additional local lesions ( P=0.011 and P=0.019, respectively). With a median follow-up of 54 months, the 5-year overall survival (OS), local recurrence-free survival (LRFS) and progression-free survival (PFS) rates were 72.7%, 68.6% and 68.2%, respectively, for all patients. The 5-year LRFS rate was 100% in the PET/CT-MRI group and 64.3% in the PET/CT group ( P

e13518 Background: The use of rituximab(RTX)for the treatment of primary central nervous system lymphoma(PCNSL) is controversial, and whether the RTX permeability of the blood-brain barrier can be improved by craniotomy is unknown. Methods: ImmunocompetentPCNSL patients newly diagnosed via craniotomy or stereotactic biopsy were enrolled and received RTX (375 mg/m2, Q3w) treatment. Systemicnon-Hodgkin's B cell lymphoma (systemic-B-NHL)patients without CNS involvement served as the control group. The trough concentrations of RTX (CRTX) and CD19 levels in cerebrospinal fluid (CSF) and plasma were analyzed by ELISA and flow cytometry methods during each treatment cycle.The efficacy and adverse effects were recorded. Results: From December 2016 to February 2018, 21 PCNSL and 32 systemic-B-NHL patientswere enrolled. The CSF CRTXin the craniotomy-PCNSL group (0.2198±0.1866μg/ml) was significantly higher than those in the stereotactic-PCNSLgroup (0.0613±0.0408 μg/ml, P = 0.031) and the systemic-B-NHLgroup (0.0799±0.0614μg/ml, P = 0.046). The BBB penetrabilityof RTX in the craniotomy-PCNSL group (1.52±1.05%) was nearly four times that in the stereotactic-PCNSL group (0.41±0.19%, P = 0.048) and nearly three timesthat in the systemic-B-NHL group (0.54±0.61%, P = 0.012). No significant differences in the CRTXor BBB penetrability of RTX were observedbetween the stereotactic-PCNSL and systemic-B-NHL groups. CD19 levels in plasma fell below 0.1% in all patients before the second cycle of chemotherapy, and the time required for CSF CD19cell clearance in craniotomy-PCNSL patients tended to be reduced compared with that required by stereotactic-PCNSL patients. The CR and ORR rates of craniotomy-PCNSL patientswere 30% higher than those of stereotactic-PCNSL patients. Conclusions: The BBB penetrability of RTXand the CSF CRTXare significantly improved in PCNSL patients diagnosed via craniotomy.Rituximab could be recommended for routine use in craniotomy PCNSL patients. Clinical trial information: ChiCTR-TRC-11001687.

IntroductionRNA-dependent protein kinase (PKR) is an independent prognostic variable in patients with non–small-cell lung cancer (NSCLC). In the current study, we investigated the correlation between PKR and 25 other biomarkers for NSCLC, identified the markers that could further improve the prognostic significance of PKR and elucidated the mechanisms of interaction between these markers and PKR.MethodsTissue microarray samples obtained from 218 patients with lung cancer were stained with an anti-PKR antibody and antibodies against 25 biomarkers. Immunohistochemical expression was scored and used for Kaplan–Meier survival analysis. The interaction between PKR and EphA2 in NSCLC cell lines was examined.ResultsWe found that PKR was associated with EphA2 and that the prognostic information regarding NSCLC provided by the combination of PKR and EphA2 (P/E) was significantly more accurate than that provided by either marker alone. The 5-year overall survival rate in patients with PKRlow/EphA2high (20%) was significantly lower than that of patients with PKRhigh/EphA2low (74%), patients with PKRhigh/EphA2high (55%), and patients with PKRlow/EphA2low (55%) (p < 0.0001). We also found that the PKR:EphA2 (P/E) ratio was significantly associated with prognosis (p < 0.0001). Univariate and multivariate Cox analyses revealed that this P/E combination or ratio was an independent predictor of overall survival. In addition, induction of PKR expression reduced EphA2 protein expression levels in NSCLC cell lines.ConclusionsPKR/EphA2 is a significant predictor of prognosis for NSCLC. PKR/EphA2 may be a promising approach to improving screening efficiency and predicting prognosis in patients with NSCLC.

Objective To investigate whether sustained abdominal aorta compression (SAAC) can improve coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR) and improve resuscitation outcomes without causing liver laceration. Design and Setting Animal study. Methods Cardiac arrest was induced by asphyxia in 28 New Zealand rabbits and maintained for 2 minutes before resuscitation. Animals were resuscitated using either standard CPR (STD-CPR group) or standard CPR and SAAC (SAAC-CPR group). Restoration of spontaneous circulation (ROSC), restoration of spontaneous breathing (ROSB) and cerebral performance category score were determined. CPP, mean arterial pressure (MAP) and ROSC were compared in the two groups. Results MAP and CPP in the SAAC-CPR group were significantly higher than in the STD-CPR group. However, MAP and blood gas results showed no significant difference between the two groups during ROSC. ROSC was achieved in seven of fourteen animals in the STD-CPR group and in eleven of fourteen animals in the SAAC-CPR group. Five animals in the STD-CPR group and nine in the SAAC-CPR group survived 24 hours after ROSC. No liver injury occurred in the two groups. Conclusions SAAC-CPR produces an increased CPP and MAP than traditional CPR and it does not lead to liver laceration/injury.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by concomitant chemo-radiation and adjuvant temozolomide (TMZ). Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT), a validated biomarker for TMZ-resistance, is strongly correlated with TMZ-resistance. In addition, defective DNA mismatch repair (MMR) has been identified as a secondary mechanism of TMZ resistance. MGMT-unmethylated tumors represent a majority of newly diagnosed GBM patients demonstrating significantly inferior progression free and overall survival compared to MGMT-methylated GBM patients. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as a single agent and in combination with radiotherapy. VAL-083 rapidly induces interstrand DNA cross-links at N7-guanine, leading to persistent DNA double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells (CSCs). VAL-083's unique cytotoxic mechanism circumvents MGMT-mediated chemoresistance and maintains cytotoxic activity in cancer cells deficient in MMR. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs, in vitro. We completed a 3:3 dose-escalation trial of VAL-083 in temozolomide- and bevacizumab-refractory rGBM. 40mg/m2/day given on days 1, 2, and 3 of a 21-day cycle was well-tolerated with 6% grade 3 or 4 thrombocytopenia. This dose was selected for further clinical development in a pivotal Phase 3 study in bevacizumab refractory rGBM. The present trial is an ongoing open-label, biomarker-driven, Phase 1/2 study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy given daily, 5 days/week) followed by up to 24 weeks of adjuvant maintenance therapy with single-agent VAL-083, is being evaluated as an alternative to standard-of-care in MGMT-unmethylated GBM. The study is being conducted in two parts: 1) a dose-escalation part (20, 30, and 40 mg/m2/day IV infusion on days 1, 2, and 3 of a 21-day cycle) in up to 10 patients, to assess safety and activity of VAL-083 when administered concurrently with radiation therapy; 2) an expansion phase, in which VAL-083 will be studied in up to 20 additional patients at the determined well-tolerated dose. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples (when available). Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736. Citation Format: Zhong-ping Chen, Chengcheng Guo, Jeffrey Bacha, Anne Steino, John Langlands, Claire Kwan, Sarath Kanekal, Richard Schwartz, Lorena Lopez, Dennis M. Brown. Phase I/II study of dianhydrogalactitol (VAL-083) with radiation therapy in patients with newly diagnosed glioblastoma, MGMT-unmethylated [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT168.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare and severe malignancy. ENKTL is primarily located in the upper aerodigestive tract; the nasal/nasopharyngeal localization represents 75% of cases, and other sites involved include the skin, gastrointestinal (GI) tract, testis, bone marrow and spleen [1]. Patients with NK/T-cell lymphoma outside the upper aerodigestive tract tend to present with more aggressive clinical features and have a more unfavorable prognosis. To date, little information regarding primary GI NK/T-cell lymphomas (GINKTLs) is available. Previous studies have reported that the incidence of GINKTL is less than 0.1 cases per 100 000 persons per year [2,3]. Treatment strategies for nodal non-Hodgkin lymphoma (NHL) are well established; however, much debate and controversy remain regarding the optimal approach in GINKTL. Due to the rarity of primary GINKTL, empirical standards in the treatment of GINKTL, consisting of surgical resection of the primary tumor mass followed by chemotherapy or radiotherapy (or both), have not been evaluated prospectively. Hence we initiated a retrospective study to investigate the clinical features of GINKTL, analyze the impact of surgical resection on outcome and delineate its major prognostic factors.

Background We recently showed that IGFBP2 is overexpressed in primary lung cancer tissues. This study aims to determine whether IGFBP2 is elevated in blood samples of lung cancer patients and whether its level is associated with clinical outcomes. Methodology/Principal Findings Plasma IGFBP2 levels were determined blindly by enzyme-linked immunosorbent assay in 80 lung cancer patients and 80 case-matched healthy controls for comparison. We analyzed blood samples for IGFBP2 levels from an additional 84 patients with lung cancer and then tested for associations between blood IGFBP2 levels and clinical parameters in all 164 lung cancer patients. All statistical tests were two-sided and differences with p160.9 ng/ml is 15.1 months; whereas median survival time was 128.2 months for the patients whose blood IGFBP2 was ≤160.9 ng/ml (p =0.0002). Conclusions/Significance Blood IGFBP2 is significantly increased in lung cancer patients. A high circulating level of IGFBP2 is significantly associated with poor survival, suggesting that blood IGFBP2 levels could be a prognostic biomarker for lung cancer.

e13520Background: The reprogrammed cancer cell metabolism is instrumental and may allow for discovery of novel cancer biomarkers and therapeutic targets in glioma. Our previous study showed that RN...

Background Because cell signaling and cell metabolic pathways are executed through proteins, protein signatures in primary tumors are useful for identifying key nodes in signaling networks whose alteration is associated with malignancy and/or clinical outcomes. This study aimed to determine protein signatures in primary lung cancer tissues. Methodology/ Principal Findings We analyzed 126 proteins and/or protein phosphorylation sites in case-matched normal and tumor samples from 101 lung cancer patients with reverse-phase protein array (RPPA) assay. The results showed that 18 molecules were significantly different (p

Pirarubicin is an analog of doxorubicin. Few studies have compared the long-term outcomes of patients receiving pirarubicin-based THP-COP and doxorubicin-based CHOP in the treatment of non-Hodgkin's lymphoma (NHL). We retrospectively compared the efficacy and safety of these two regimens in 459 previously untreated aggressive NHL patients admitted to Sun Yat-Sen University Cancer Center from 1987 to 2003. For initial treatment, 205 patients received the THP-COP regimen, and 254 patients received the CHOP regimen. The patients' characteristics were well balanced. The groups did not differ in the complete remission rate (THP-COP, 57.1% vs. CHOP, 57.0%; P = 0.998) or response rate (THP-COP, 82.9% vs. CHOP, 81.5%; P = 0.691). At a median follow-up of 95.7 months, the 8-year survival rates were also similar (overall survival: THP-COP, 55.8% vs. CHOP, 56.7%; progression-free survival: THP-COP, 47.3% vs. CHOP, 43.5%; lymphoma-specific survival: THP-COP, 51.2% vs. CHOP, 48.5%). The THP-COP group had fewer cases of alopecia (P < 0.001) and gastrointestinal toxicities (P = 0.015). A tendency toward decreased arrhythmia (P = 0.075), especially in elderly patients (P = 0.030), was found. In combination chemotherapy for aggressive NHL, pirarubicin has comparable efficacy to doxorubicin and has a lower incidence of alopecia, gastrointestinal toxicities, and arrhythmia. Further studies are warranted to confirm these results.

Background and objectives: Methotrexate (MTX) is a folic acid reductase inhibitor widely used. Peripheral infusion of high dose MTX (HD-MTX) could prevent the central nervous system recurrence of leukemia and NHL. Due to the blood brain barrier, only 1-3% of MTX in the peripheral blood can enter the cerebrospinal fluid. Improving the peripheral MTX drug dosage helps to improve MTX concentration in the cerebrospinal fluid. However, high concentration of MTX has serious side effects to normal organs. Leucovorin (CF) rescue is given to reduce the toxic effect of methotrexate on normal cells. During high dose MTX therapy, monitoring of serum concentration of MTX and timely CF rescue therapy are mandatory so as to maximum the efficacy of MTX and minimize the toxicities. Due to the lack of randomized clinical trials with large sample, the safe dose and most appropriate time of leucovorin rescue treatment are of no consensus. In order to study the effect of different time of leucovorin rescue treatment on the serum concentration of MTX, we carried out this study. Patients and methods: We included patients who had pathological diagnosis of non-Hodgkin's lymphoma and indications to receive HD-MTX as single agent or component in combined regimen consecutively from October 2011 to June 2014 at our hospital. Patients were randomized to receive CF rescue at the sixth hour after MTX infusion in the first course and twelfth hour in the second course or the twelfth hour in the first course and sixth hour in the second course. A dosage of 3.5 g/m2 of MTX was provided. Adequate hydration, alkalization and monitoring of laboratory tests were administered. Intrathecal injection of MTX plus cytarabine and dexamethasone were given after MTX infusion. 100mg of CF was given at the first time, then 30mg of CF were given every 6 hours for a total of 7 times until the plasma concentration of MTX were lower than 1×10-7 mol/L. Blood samples were collected at 2, 12, 18, 24, 28, 72 hours after the beginning of MTX infusion. High performance liquid chromatography was used to test the plasma concentration of MTX. Results: There were 23 male patients and 12 female patients with a mean age of 41 years. Most of patients were diagnosed as diffuse large B cell lymphoma (65.7%). Eleven cases (31.4%) had central nervous system invasion at the time of HD-MTX treatment. Twenty-one patients (51%) had more than one extra-nodal lesion. Sixteen patients were randomly to be rescued at the sixth hour in the first course then the twelfth hour in the second course. Nineteen patients were randomly to be rescued at the twelfth hour in the first course then the sixth hour in the second course. The plasma concentration of MTX of patients rescued at the sixth hour at the time of 2, 12, 18, 24, 48 hours were 5.21±0.36×10-5 mol/L, 8.01±0.635×10-5 mol/L, 4.57±1.67×10-6 mol/L, 1.43±0.83×10-6 mol/L, 0.1±0.1×10-6 mol/L, respectively; The plasma concentration MTX of patients rescued at the twelfth hour at the time of 2, 12, 18, 24, 48 hours were 5.46±0.34×10-5 mol/L, 8.65±0.663×10-5 mol/L, 5.4±0.93×10-6 mol/L, 1.12±0.21×10-6 mol/L, 0.1±0.24×10-6 mol/L, respectively. There was no significant difference of MTX concentration level between patients treated with different CF rescue timing, P >0.05. Most of patients achieved maximal MTX concentration at the twelfth hour, and descended to be lower than the minimal effective concentration at the eighteenth hour. At the forty-eighth hour, majority of patients had MTX concentration being in a safe range. The rate of grade 3 to 4 adverse reactions including neutropenia, anemia, thrombocytopenia and grade 1 to 2 side effects including neutropenia, thrombocytopenia, mucositis, fatigue, and MTX discharge delay were higher when patients were rescued with CF at the twelfth hour, though P >0.05. Conclusion: Most of patients treated with high dose MTX reached the maximum MTX concentration at the twelfth hour after MTX infusion, and descended to be under the minimal effective concentration at the eighteenth hour, then to be in the safe range at the forty eighth hour. No significant difference of MTX concentration was found between patients rescued with CF at the sixth hour or the twelfth hour. However, adverse reactions were lower when patients were treated with CF rescue at the sixth hour. It seems a better choice to give patients CF rescue at the sixth hour after MTX infusion. Disclosures No relevant conflicts of interest to declare.

18 F-PET-CT is clinically recommended for monitoring therapeutic response in DLBCL patients. But the role of interim PET-CT remains controversial, and most of the previous researches were retrospective. We designed this study to prospectively evaluate whether interim PET-CT was a valid prognostic tool for patients with DLBCL treated with R-CHOP regimen and if yes, try to determine the more appropriate time and interpretation method for interim PET-CT. This study was a sub-study of the parental study "A prospective, multicenter randomized phase III clinical trial of intensified chemotherapy in improving the treatment efficacy of patient with diffuse large B-cell lymphoma" (NCT01793844). The sub-study included patients that have already been enrolled in the parent study at Sun Yat-Sen University Cancer Center prospectively. Patients were evaluated with PET-CT scans before treatment and after every 2 cycles of R-CHOP and after the completion of first-line treatment. Regular follow-up starts from the enrollment. Between Jan. 2008 and Aug. 2014, 221 patients in Sun Yat-Sen University Cancer Center were enrolled in this sub-study, among whom 203 patients were included in the analysis and the other 18 were excluded for lacking the necessary raw data of PET-CT scan. PET evaluation would be applying the visual criteria of International Harmonization Project(IHP) and the Deauville 5-point scale(5-PS). The results showed PET positive in 103 patients and negative in 100 patients after 2 cycles of R-CHOP chemotherapy with IHP criteria. Among the 103 patients with positive PET-2, 53 patients turned negative after 4 cycles of chemotherapy and still 50 patients remain positive. At the evaluation of end-of-first-line-treatment, 165 patients achieved CR, while 30 achieved PR and 8 PD . According to 5-PS criteria, 146 patients were PET negative with 57 were positive after 2 cycles of chemotherapy. And 173 patients were negative in PET-4 evaluation, while 30 patients remained positive. With a median follow-up of 25.46 months (range 3.60~77.33 months) and according to IHP criteria, patients with negative PET-2 had superior 3-year PFS (84.7% vs. 63.8%, p < 0.001) and OS (89.8% vs. 80.4%, p = 0.045) than those with positive results. Patients with negative PET-4 also had a better clinical outcome compared with the positive group with 3-year PFS (84.1% vs. 43.8%, p < 0.001) and OS (90.7% vs. 67.8%, p < 0.001). A further analysis showed that patients who achieved PET negative just after 2 cycles of chemotherapy (Early responder, ER) had a similar prognosis comparing with those who achieved PET negative after 4 cycles (Later responder, LR). There were no significant differences in the persistent CR rates (87.00% vs. 86.79%, p = 0.971), 3-year PFS (84.7% vs. 82.2%, p = 0.867) and 3-year OS (89.8% vs. 92.9%, p = 0.638) between the ER group and the LR group. Patients who remained PET positive after 4 cycles of chemotherapy (Interim non-responder, I-NR) had the worst prognosis. Their persistent CR rate (42.00% vs. 87.00%, p < 0.001; 42.00% vs. 86.79%, p < 0.001), 3-year PFS (43.8% vs. 84.7%, p < 0.001; 43.8% vs. 82.2%, p < 0.001) and 3-year OS (67.8% vs. 89.8%, p < 0.001; 67.8% vs. 92.9%, p = 0.002) were significantly lower, comparing with the ER and LR group. And according to 5-PS criteria, the results were similar. Patients with negative PET-2 had superior 3-year PFS (82.9% vs. 51.6%, p < 0.001) and OS (89.7% vs. 72.9%, p = 0.001) than those with positive results. Patients with negative PET-4 also had a better clinical outcome compared with the positive group with 3-year PFS (81.8% vs. 30.0%, p < 0.001) and OS (90.1% vs. 54.2%, p < 0.001). In the multivariate analysis, PET-4 with IHP criteria, PET-4 with 5-PS criteria and IPI score were independent predictive factors for PFS of patients with DLBCL. A further analysis of positive predictive value (NPV) and negative predictive value (PPV) showed PET-4 was superior than PET-2, especially interpretated with 5-PS. The PPV and NPV of PET-4 with 5-PS criteria were 70.00% and 83.82% respectively. These data indicates that Interim 18 F-FDG PET-CT scan could predict the prognosis of DLBCL patients treated with R-CHOP regimen. And it was recommended that interim 18 F-FDG PET-CT scan be done after 4 cycles of chemotherapy, and that 5-PS criteria be applied in the interpretation of interim PET-CT scan rather than IHP criteria. Disclosures No relevant conflicts of interest to declare.

Background: CD20-antibody (rituximab) plus CHOP chemotherapy (R-CHOP) have become the first-line regimen for CD20 positive DLBCL since the introduction of rituximab at the end of 1990s. Our group (Chinese south-west oncology group, CSWOG) planned to evaluate the efficacy and toxicity of biweekly schedule of RCHOP (RCHOP-14) compared to triweekly RCHOP (RCHOP-21) for DLBCL. Purpose: RCHOP-14 vs. RCHOP-21 for untreated diffuse large B-cell lymphoma (DLBCL), compare the 5-year disease-free survival (DFS), overall survival (OS), response rate and the side effects. Patients and methods: Patients older than 18 years, newly diagnosed of CD20-positive DLBCL with adequate organ function were recruited. All patients were randomized into two groups after provided written informed consent, and received RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. The RCHOP-14 group was administered every 2 weeks, patients received prophylactic granulocyte colony-stimulating after each chemotherapy cycle. The control group RCHOP-21 was administered every 3 weeks. The planned cycles of chemotherapy was 6 to 8 cycles. Patients received imaging evaluation at the baseline and every 2 cycles of chemotherapy. Radiotherapy was recommended to treat local residue or bulky tumor. Vital signs, physical examination, and laboratory studies were documented at each follow-up visit. Results: From January 2008 to December 2014, a total of 702 patients with newly diagnosed DLBCL were recruited in 14 cancer centers of CSWOG. There were 407 males (58.0%) , 295 females (42.0%) , and median age of 52 years (range 18-80 years). 353 assigned to the RCHOP-21 group and 349 assigned to the RCHOP-14 group, patients in the two groups totally received 3989 cycles of chemotherapy, an average of 5.70 cycles per patient. There was no significant difference between the RCHOP-21 and RCHOP-14 groups in terms of sex, age, Ann Arbor stage, International Prognostic Index, B symptoms, extranodal involvement and seropositive status for hepatitis-B surface antigen. Overall, 496 (70.7%) achieved CR, 136 (19.4%) PR, 16 (2.3%) SD and 50 (7.1%) PD. For RCHOP-21 group, the incidence of CR, PR and PD was 72.8%, 18.4%, 6.5%, respectively, the response rate was 91.2%, and relapse rate was 22.6%. For RCHOP-14 group, the incidence of CR, PR and PD was 69.1%, 20.9%, 7.7%, respectively, the response rate was 90.0%, relapse rate was 16.8%, and the results were no significant difference. With the median follow-up of 35.95 months, the 5-year DFS, OS, and PFS of RCHOP-21 compared with RCHOP-14 was 72.2% vs.72.8%, p=0.306; 68.9% vs62.3%, p=0.856; and 53.8% vs. 54.4%, p=0.357,respectively. The most common side effect was bone marrow suppression including 83.6% granulopenia and 46.7% grade III/IV granulopenia, Febrile Neutropenia 24.9%; 69.1% anemia and 12.6% grade III/IV anemia; 50.6% thrombocytopenia and 11.5% grade III/IV thrombocytopenia. Other side effects included: 18.6% pneumonia, 6.8% interstitial pneumonia, 17.1% other site of infection, 17.5% ALT/AST increasing, 17.4% peripheral neuritis, 13.1% fatigue, 11.9% nausea, 13.1% vomiting, 4.6% oral ulcer. There were no significant difference between the two groups about the above side effects. There were 32 patients (9.1%) in RCHOP-21 and 40 patients (11.5%) in RCHOP-14 delayed the chemotherapy because of severe side effects. High score of IPI, insufficient chemotherapy cycles and relapse during chemotherapy were independent prognosis factors in multivariate analysis. Conclusion: RCHOP-14 did not showed superior effective than RCHOP-21. The side effects were similar with prophylactic GCSF in RCHOP-14 regimen. Therefore, RCHOP-21 is still the standard treatment for DLBCL. Disclosures No relevant conflicts of interest to declare.

e19508 Background: Ritubximab (RTX) with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) regimen is a gold standard therapy in treatment of diffuse large B-cell lymphoma (DLBCL)...

Predictive value of therapeutic monitoring with plasma Epstein-Barr virus DNA in Extranodal NK/T cell lymphoma, nasal type Background: Predictive tumor markers are essential for extranodal NK/T cell lymphoma, nasal type (ENKTL), which pursues an aggressive clinical course with poorer prognosis. This prospective study was conducted to evaluate the dynamic monitoring value of circulating EBV DNA concentration for the prediction of ENKL during treatment. Method: Patients with untreated, centrally reviewed diagnosis of ENKTL were included in our study. Plasma Epstein-Barr virus (EBV) DNA levels were collected before and/or every 2 cycles of chemotherapies for circulating EBV DNA measurement by a real-time PCR assay. Result: From Jan 2002 to Aug 2012, 113 newly diagnostic ENKTL patients enrolled. The positive rate of circulating EBV DNA is 61.9% (70/113) with a median concentration of 1.21×103copies/ml. Patients who had initial positive circulating EBV-DNA had more lymph nodes invasion, higher IPI and KPI score. The more advance of the stage, the higher rate of the circulating EBV-DNA positive. When divided the positive group as low and high-dose ones by the cut-off value as 2×104copies/ml, the CR rate of the high-dose group is much lower and the 5-year OS is significantly better than the low-dose group and the negative group. After two cycles of chemotherapy, 45 patients were tested circulating EBV-DNA and 53.33% (24/45) patients became negative EBV-DNA candidates. There were 87.5% (21/24) patients obtained complete remission at the end of the treatment, comparing as 42.86% (9/21) in the still positive EBV-DNA groups(P= 0.002). There is a tendency that the patients whose circulating EBV-DNA become negative after two cycles will have better prognosis (5-year OS: 75% vs 46%, P=0.074). The similar situation of CR rate and OS happened in the EBV-DNA detection of completion of total chemotherapy. 7 of 13 relapsed pts of ＞1×103copies/ml EBV-DNA at the time of recurrent, and the survival outcome was dismal for them compared to the other 6 pts of ≤1×103copies/ml（5- year OS: 0% vs 80%, P=0.001） Conclusion: Circulating EBV-DNA level can predict the efficacy of treatment as a dynamic marker of ENKL. Patients with early positive detection of EBV-DNA after 2 cycles of chemotherapy maybe received more aggressive treatments. Disclosures No relevant conflicts of interest to declare.

Purpose 18F-FDG PET-CT has been widely used for pre-treatment staging and post-treatment response assessment in diffuse large B cell lymphoma (DLBCL), but the predictive value of interim PET-CT remained controversial and most of studies were retrospective. Patients and Methods Newly-diagnosed DLBCL patients treated with R-CHOP regimen were included in our prospective study to evaluate the predictive value of interim PET-CT. All patients were evaluated with PET-CT scans before treatment and after every 2 cycles of R-CHOP. PET-CT positivity or negativity was related to survival using Kaplan-Meier analysis. Results From Feb 2008 to Jan 2013, 149 patients were included. After 2 cycles of R-CHOP, the PET-CT evaluation showed CR in 82 patients. Among the remaining 67 non-CR patients, 31 achieved CR after 4 cycles. At the end of treatment, PET-CT evaluation showed CR in 121, PR in 21, SD in 3 and PD in 4 patients. With a median follow-up of 20.6 months (range 1.5-60.5 months), patients with negative PET-2 (PET-CT scan after 2 cycles) had a superior 2-year PFS than those with positive PET-2 (86.6% vs. 67.0%, p=0.019) and a tendency of superior 2-year OS without statistical differences (91.9% vs. 85.2%, p=0.330). The 2-year PFS and OS for negative PET-4 (PET-CT scan after 4 cycles) compared with positive PET-4 group were 84.8% vs. 51.9% (p=0.001) and 93.1% vs. 73.0% (p=0.027) respectively. PET-CT scans were interpreted using the International Harmonization Project (IHP) criteria above. The second analysis applying the Five-Point Scale (5PS) criteria showed that 2-year PFS for score 1-2 (uptake＜mediastinum), score 3 (mediastinum＜uptake≤liver) and score 4-5 (uptake＞liver) group were 86.6%, 75.8% and 71.0% according to PET-2, and 84.9%, 50.0% and 52.7% according to PET-4. PFS of score 3 group was not significant different from the other two groups in PET-2 (both P＞0.05), but significantly inferior to score 1-2 group (p=0.046) and similar to score 4-5 group (p=0.767) in PET-4. In the multivariate analysis, only PET-4 (95%CI, 1.07-5.44) and IPI score (95%CI, 1.53-10.06) remained independent predictive factors for PFS. Conclusion PET-CT after 4 cycles of R-CHOP in patients with DLBCL is highly predictive of PFS and should be considered in clinical practice. (Clinical Trail Registration Number: CTR-TRC-11001687) Disclosures No relevant conflicts of interest to declare.

We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2α are independent prognostic markers for survival in lung cancer. In the current study, we aimed to elucidate PKR's specific role in lung cancer. We examined PKR and p-PKR protein expression in 60 frozen primary lung tumor tissues by Western blot analysis and analyzed the association between PKR/p-PKR expression and expression of 139 proteins examined previously by reverse phase protein array in tissue samples from the same 60 patients. We demonstrated several biomarkers that were either positively (p-AMPK) or negatively (IRS1, p-IGF1R, MRE11, ATRIP, telomerase, CHK1, and cyclin E1) correlated with PKR and p-PKR. We confirmed that induction of PKR or p-PKR with expression vectors in lung cancer cells caused phospholation of the AMP-activated protein kinase (AMPK) protein; phospholation was independent of the LKB1, CaMKKβ, and TAK1 pathways. We observed that AMPK phosphorylation was caused by the elevated levels of AMP and decreased levels of ATP resulting from PKR-mediated nutrient depletion. Inhibition of AMPK expression by compound C or siRNA enhanced PKR-mediated cell death. We next investigated the combination of PKR and p-AMPK expression in non-small cell lung cancer patients; we observed that high expression of p-AMPK predicted worse prognosis in patients with high PKR expression but better prognosis in patients with low PKR expression. The p-AMPK may be required for cancer cell survival in patients with high PKR expression and may inhibit cancer cell growth in patients with low PKR expression. In summary, our data indicate that PKR-mediated nutrient depletion induces phosphorylation of AMPK, which is required for lung cancer cell survival. Citation Format: Apar Pataer, Chengcheng Guo, Ruping Shao, Arlene M. Correa, Carmen Behrens, Bingliang Fang, Jack A. Roth, Ignacio I. Wistuba, Stephen G. Swisher. Nutrient depletion caused by PKR induces phosphorylation of AMPK in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4739. doi:10.1158/1538-7445.AM2014-4739

e19532 Background: High-dose cytarabine treatment of non-Hodgkin lymphoma most likely cause severe thrombocytopenia which may be fatal. Thrombopoietin (TPO) specifically stimulates megakaryopoiesis...

e19551 Background: Patients with high-risk diffuse large B-Cell lymphoma (DLBCL) have a unfavourable clinical outcome even treated with R-CHOP. Thalidomide inhibits angiogenesis and exerts complex ...

8562 Background: Predictive tumor markers are essential for extranodal NK/T cell lymphoma, nasal type (ENKL), which pursues an aggressive clinical course with poorer prognosis. This prospective stu...

8552 Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is a rare and high aggressive disease with poor prognosis. The Ann Arbor staging system had been unable to define ENKTL staging i...