tbuckley/cabot-search huggingface dataset:
Unconventional T Cells in the Pancreatic Tumor Microenvironment: Thinking Outside the Box
Authors: Sulagna Banerjee, Vikas Dudeja, Ashok Saluja
Journal: Cancer Discovery (2019)

Unlike conventional MHC-reactive T cells, unconventional T cells have emerged as an abundant component of the human immune system because of their role in tumor immunology. In this issue of Cancer Discovery, Hundeyin and colleagues have identified a population of unconventional T cells in pancreatic tumors that can reprogram the immune evasive components of the tumor to promote immunogenicity and thus are critical for the development of novel cell-based therapy in pancreatic cancer.See related article by Hundeyin et al., p. 1288.
Combination trial of duvelisib (IPI‐145) with rituximab or bendamustine/rituximab in patients with non‐Hodgkin lymphoma or chronic lymphocytic leukemia
Authors: Ian W. Flinn, Mohamad A. Cherry, Michael B. Maris, Jeffrey V. Matous, Jesus G. Berdeja, Manish Patel
Journal: American Journal of Hematology (2019)

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m2 IV weekly for two 4-week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m2 IV Day one, bendamustine 90 mg/m2 IV (NHL patients) or 70 mg/m2 IV (CLL patients) Days one-two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty-six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI-145-02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression-free survival was 13.7 months. Median overall survival has not been reached, but 30-month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.
P14.76 Characteristics of anaplastic oligodendrogliomas short-term survivors: a POLA network study
Authors: L Garnier, C Dehais, E Curtit, E Tabouret, C Ramirez, E Vauleon, V Bourg, M Boone, D Figarella-Branger, F Ducray
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Although patients with 1p/19q codeleted anaplastic oligodendrogliomas (AO) usually have a prolonged survival, some patients have a poorer outcome. The aim of the present study was to analyze their characteristics. MATERIAL AND METHODS The characteristics of AO patients with a survival &lt; 5 years included in the POLA network were analyzed and compared to those of AO patients with a survival &gt; 5 years. RESULTS In January 2019, among the 519 patients AO patients included in the POLA network, 55 patients were short-term survivors and 146 patients had a survival &gt; 5 years. Among the 55 AO short-term survivors, 44 patients (80%) died from tumor progression and 11 patients (20%) from another cause (suicide n=2, toxicity n=2, intercurrent disease n=6, other n=1). Compared to &gt; 5 years survivors, short-term survivors were older (57 years vs 48 years, p&lt;0.001) and less frequently presented with isolated seizures (9% vs 33%, p=0.0017). They presented with tumors that more frequently involved multiple lobes (66% vs 47%, p=0.03), had a higher rate of nuclear atypia (80% vs 48%, p&lt;0.001), a higher proliferative index (Ki67, 26% vs 18%, p&lt;0.001), a higher level of p53 expression (10.8% vs 3.9% p&lt;0.001), and had a higher rate of chromosomal abnormalities (91% vs 71% p=0.008). Compared to &gt; 5 years survivors, short-term survivors less frequently underwent a surgical resection (64% vs 89% p&lt;0.001) and their initial treatment more frequently consisted in temozolomide chemotherapy alone (41% vs 20% p=0.008). CONCLUSION AO short-term survivors are associated with distinct clinical, radiological, histological and molecular characteristics at diagnosis.
P14.118 Carboxypeptidase G2 (CPG2) rescue after high dose methotrexate (hdMTX) chemotherapy for Primary CNS Lymphoma (PCNSL). A French LOC network study
Authors: Y J Garcilazo, C Soussain, E Tabouret, G Ahle, A Schimitt, A Waultier, M Blonski, A Liou-Schischmanoff, K Hoang-Xuan, C Houillier
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND CPG2 is an efficient rescue recombinant bacterial enzyme that cleaves MTX into inactive metabolites. As hdMTX is the key agent in PCNSL, delayed MTX excretion (DME), and/or MTX induced nephrotoxicity (MIN) may expose the patients to severe toxicities and prevent the further use of the drug. Little is known on the use of CPG2 and its impact on patient outcome.Objective: To describe the clinical characteristics, indications, risk factors, outcomes of PCNSL patients treated with CPG2. MATERIAL AND METHODS Retrospective analysis of patients from the LOC network database with histologically proven PCNSL, aged &gt;18, who received CPG2 following hdMTX. RESULTS From 2011 to 2018, 41(3%) of 1236 patients treated with hdMTX used CPG2. Median age: 70 years [46–86], sex ratio M/F 3.6, median KPS 70. Indications of CPG2 were DME (12%), MIN (34%), both (49%). 37/41 (90%) of the patients had either a cardiovascular history (CVH) (76%) or a preexisting chronic kidney disease (CKD) (56%) and 59% had at least one additional risk factor: delayed MTX elimination or renal toxicity in prior cycles (20%), other grade III-IV toxicity (20%), concomitant drugs interfering with MTX excretion (29%), active infection (22%), hypoalbuminemia (59%). Median hdMTX dose was 3 g/m2 [1–3.5], median number of MTX injection received at the time of CPG2: 2[1–6]. At time of the CPG2 administration, median serum creatinine was 185 μmol/l [108–410] and median serum MTX: 25 μmol/l [1–240]. 24% of patients underwent hemodialysis, 76% return to baseline creatinine, in a median of 30 days; no MTX related deaths were reported. Extrarenal grade III-IV toxicities: lymphopenia (46%), neutropenia (22%), mucocutaneous toxicity (15%), thrombopenia (12%), hepatotoxicity (12%), sepsis (12%). Median time to chemotherapy resumption: 26 days (cytarabine-based or hdMTX rechallenge). HdMTX was reintroduced safely in 14 patients (34%) but one. The outcome (ORR, PFS OS) was similar with that expected of patients who would not have had toxicity to MTX. CONCLUSION In our study, a small number of patients have received CPG2 regarding the incidence of MIN and DME, probably due to treatment cost. The high frequency of risk factors points out the need of careful attention of this issue and for adapted hdMTX protocol for this vulnerable population. CPG2 treated patients do not have a worse prognosis than expected. A controlled study is warranted to compare the cost/benefit of the management of MIN /DME with or without CPG2.
Feasibility of implementing a resident oncology video curriculum.
Authors: Sam Brondfield, Nicholas Iverson, Lakshmi Subbaraj, Jennifer Babik
Journal: Journal of Clinical Oncology (2019)

10500 Background: ACGME survey results consistently show that 40% of University of California, San Francisco (UCSF) internal medicine (IM) residents are dissatisfied with their oncology education—higher than the oncology national average and highest among UCSF IM subspecialties. A needs assessment revealed that UCSF residents desire online oncology resources for asynchronous learning. To address this need, we sought online oncology videos targeted to residents but found none. We thus used cognitive theory of multimedia learning principles to develop an oncology video curriculum and evaluated three feasibility components: demand (frequency of use), efficacy, and acceptability. Methods: We chose common cancers from the ABIM blueprint and filmed five 10-minute videos of UCSF oncologists discussing content they chose for residents. We created modules with pre/post tests derived from video content. After a pilot, we sent links to all IM residents on required oncology clinic rotations over four months (n = 25) and offered protected clinic time for optional completion. We compared pre/post test scores with a paired t test and surveyed residents. Results: Demand: 72% (18 of 25) completed ≥1 module; 32% completed all 5. Efficacy: The mean pre- vs. post-test score improved (50% vs. 87%, p = 0.002). Acceptability: 64% completed the survey. Of those who completed ≥1 module, 93% (13 of 14) felt strongly that the videos contributed to their knowledge. 93% recommended the videos to others. Residents praised the length, key points, and pre/post tests. Finding time for the modules was difficult; most did them at home. Suggestions included focusing on fundamentals and creating videos for all common cancers. Conclusions: We present demand, efficacy, and acceptability evidence supporting the feasibility of a resident oncology video curriculum. Formal protected time for module use is critical. We will focus on fundamentals for generalists as we make more videos. We will track ACGME survey results, examination scores, and clinical performance to study impact. We aim to publish the modules online for broader use and as a model solution to address similar needs across specialties and institutions, as complex resident schedules increasingly require asynchronous learning.
P02.01 Analysis of Multimodal Intraoperative Monitoring During Intramedullary Spinal Ependymoma Surgery
Authors: J Park, J Kim, M Shin, D Choi
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND To evaluate the validity of intraoperative somatosensory-evoked potential (SSEP) and motor-evoked potential (MEP) monitoring according to two different warning criteria for 6 months after intramedullary spinal ependymoma (IMSE) surgery. MATERIAL AND METHODS To evaluate the validity of intraoperative somatosensory-evoked potential (SSEP) and motor-evoked potential (MEP) monitoring according to two different warning criteria for 6 months after intramedullary spinal ependymoma (IMSE) surgery. RESULTS The success rates of SSEP and MEP monitoring were 84.9% and 83.7%, respectively. There was one indeterminate case in SSEP and six in MEP. All-or-none criterion in SSEP and MEP monitoring showed higher specificity, PPV, and DOR than 50% decline criterion during 6 months. During the follow up, 37 of 38 extremities (97.4%) and 21 of 29 extremities (72.4%) were observed the improvement of sensory and motor deficit, respectively. Seven indeterminate cases also showed good clinical outcomes. However, most patients remained some degree of neurologic deficit. CONCLUSION Many false positive and false negative results of SSEP and MEP monitoring occurred immediately postoperative period. All-or-none criterion was more beneficial for IMSE surgery than 50% decline criterion. This trend was maintained until 6 months after surgery.
P03.01 Secondary central nervous system lymphoma (SCNSL) in patient with non Hodgkin lymphoma (NHL): a case report
Authors: E Susanti, N Suci Rahayu, M Fuad
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND non Hodgkin lymphoma (NHL) is a systemic cancer that originates from lymphocites. Central nervous system lymphoma is a rare form of non Hodgkin lymphoma that involve brain parenchym and spinal cord. The most common type of nervous system involvement is a leptomeningeal metastases. Whereas brain metastases is an extremely rare finding in NHL. We present a case report of NHL patient which metastasized to brain parenchym. MATERIAL AND METHODS Case report: a fourty two year old male patient suffered from seizure in September 2018, 7 days prior to hospitalized. severe headache and weakness on the left extremities were found in addition to seizure. A single nodule on the right frontal and another nodules on the right neck region were also found since 7 months ago. Patient was diagnosed with NHL in 2017 after a confirmed biopsy of NHL and underwent a chemotherapy procedure, but uncompleted. After head ct scan procedure in September 2018, which depicted a round mass in frontal lobe, patient underwent a complete chemotherapy procedure with CHOP regimen in September 2018. Another head ct scan was performed in January 2019 after a completed chemotherapy cycle which showed significant decrease in tumour size. RESULTS before and after head ct scan showed significant decrease in tumour size, from 4cmx2cm before chemotherapy and 2.5cmx1.3cm after chemotherapy CONCLUSION central nervous system involvement in NHL is a rare condition that carries a poor prognosis. Prophylaxis therapy still on debate about it’s efficacy to prevent this disease from spreading or relapse. Awareness of the possibility central nervous system involvement should always remain in a physician’s mind when dealing with NHL patients.
P14.81 Importance of early spectral variations during a longitudinal 60-month follow-up MRI and 1H-MRS in 135 treated glioblastoma patients
Authors: S Boussida, A Heintz, Z Saidak, M Lefranc, A Galmiche, J Chombar, J Peltier, B Chauffert, M Boone, J Constans
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND To better understand glioblastomas tumor metabolism and metabolic responses to chemotherapy, radiotherapy and antiangiogenic treatments during a longitudinal 60-month follow-up MRI and 1H-MRS in 135 treated glioblastoma patients. MATERIAL AND METHODS 135 patients all biopsied and treated by surgery and STUPP protocol underwent MRI (Sagittal T1, FLAIR, T2*, Diffusion, Perfusion, CoronalT2 and 3DT1 post-Gadolinium) and 1H-MRS (PRESS with multiple TEs: 35ms, 144ms and 288ms on a 6 to 12cm3 volume) exams on 1.5T and 3T GEMS. 92/135 patients underwent resection. MRS data were processed under jMRUI yielding amplitudes, areas under curves and ratios of tCho/tCr, tNAA/tCr, Lip+Lact/tCr, Lact/tCr, Glc/tCr, Glx/tCr and Gln/tCr. Statistical analysis of longitudinal MRI perfusion and spectroscopic data (every 2–3 months above 30 months and 6–9 months over). RESULTS Spectroscopic proﬁles and ratios improve under STUPP protocol and then worsen depending on the percentage of resection. Biopsied patients: a progressive decrease in ratios of tCho/tCr (0–24 months), Lact/tCr (0–18 months) and Glc/tCr (0–18 months) and Glx/tCr (0–12 months) and then increase at respectively 24, 18, 28 and18 months. Resected patients: a progressive decrease in ratios of tCho/tCr (0–9 months), Lact/tCr (0–15 months) and Glc/tCr (0–15 months) and Glx/tCr (0 and 18 months) and then increase at respectively 32, 20, 18 and 24 months. MRI Gadolinium enhancing tumor and necrosis volumes, Diffusion and FLAIR volumes changed less compared to spectroscopic profiles and ratios which do change more. CONCLUSION 1H-MRS allows non-invasive follow-up of treated glioblastomas tumors. Despite inter-subjects variability, spectroscopic and metabolic changes often come well before clinical deterioration and sometimes before clinical improvement. Therefore, 1H-MRS could be more sensitive and could detect changes earlier than MRI and sometimes is predictive of survival and response to treatment. The analysis of spectral proﬁles of long survivors is interesting and could help to better understand tumor metabolism and therapeutic responses.
dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice
Authors: Gaia Colasante, Gabriele Lignani, Simone Brusco, Claudia Di Berardino, Jenna Carpenter, Serena Giannelli, Nicholas Valassina, Simone Bido, Raffaele Ricci, Valerio Castoldi, Silvia Marenna, Timothy Church, Luca Massimino, Giuseppe Morabito, Fabio Benfenati, Stephanie Schorge, Letizia Leocani, Dimitri M. Kullmann, Vania Broccoli
Journal: Molecular Therapy (2019)
Partial Leptin Reduction as an Insulin Sensitization and Weight Loss Strategy
Authors: Shangang Zhao, Yi Zhu, Robbie D. Schultz, Na Li, Zhenyan He, Zhuzhen Zhang, Alexandre Caron, Qingzhang Zhu, Kai Sun, Wei Xiong, Hui Deng, Jia Sun, Yingfeng Deng, Min Kim, Charlotte E. Lee, Ruth Gordillo, Tiemin Liu, Angela K. Odle, Gwen V. Childs, Ningyan Zhang, Christine M. Kusminski, Joel K. Elmquist, Kevin W. Williams, Zhiqiang An, Philipp E. Scherer
Journal: Cell Metabolism (2019)
Wnt/β‐Catenin Signaling Plays a Protective Role in the Mdr2 Knockout Murine Model of Cholestatic Liver Disease
Authors: Tirthadipa Pradhan‐Sundd, Karis Kosar, Harvinder Saggi, Rong Zhang, Ravi Vats, Pamela Cornuet, Sydney Green, Sucha Singh, Gang Zeng, Prithu Sundd, Kari Nejak‐Bowen
Journal: Hepatology (2019)

The Wnt/β-catenin signaling pathway has a well-described role in liver pathobiology. Its suppression was recently shown to decrease bile acid (BA) synthesis, thus preventing the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL).To generalize these observations, we suppressed β-catenin in Mdr2 knockout (KO) mice, which develop sclerosing cholangitis due to regurgitation of BA from leaky ducts. When β-catenin was knocked down (KD) in KO for 2 weeks, hepatic and biliary injury were exacerbated in comparison to KO given placebo, as shown by serum biochemistry, ductular reaction, inflammation, and fibrosis. Simultaneously, KO/KD livers displayed increased oxidative stress and senescence and an impaired regenerative response. Although the total liver BA levels were similar between KO/KD and KO, there was significant dysregulation of BA transporters and BA detoxification/synthesis enzymes in KO/KD compared with KO alone. Multiphoton intravital microscopy revealed a mixing of blood and bile in the sinusoids, and validated the presence of increased serum BA in KO/KD mice. Although hepatocyte junctions were intact, KO/KD livers had significant canalicular defects, which resulted from loss of hepatocyte polarity. Thus, in contrast to the protective effect of β-catenin KD in BDL model, β-catenin KD in Mdr2 KO aggravated rather than alleviated injury by interfering with expression of BA transporters, hepatocyte polarity, canalicular structure, and the regenerative response.The resulting imbalance between ongoing injury and restitution led to worsening of the Mdr2 KO phenotype, suggesting caution in targeting β-catenin globally for all cholestatic conditions.
Patient Characteristics and Adenoma Detection Rates—Reply
Authors: Shashank Sarvepalli, Maged K. Rizk
Journal: JAMA Surgery (2019)

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Angiosarcoma of bone: A European Muscoloskeletal Oncology Society (EMSOS) multicenter, retrospective study.
Authors: Emanuela Palmerini, Andreas Leithner, Reinhard Windhager, Georg Gosheger, Kjetil Boye, Minna Laitinen, Jendrik Hardes, Frank Traub, Paul Jutte, Madeleine Willegger, Jose' Casanova, Elisabetta Setola, Alberto Righi, Piero Picci, Davide Maria Donati, Stefano Ferrari
Journal: Journal of Clinical Oncology (2019)

11046 Background: Angiosarcoma of bone (B-AS) is an exceedingly rare malignant tumor of vascular origin. The aim of this EMSOS retrospective study is to report on natural history, type of treatment and prognosis of B-AS. Methods: Patient data were collected according to the national rules for observational studies through electronic dataset available on EMSOS WEBsite. Results: 80 patients (51 male and 29 female, median age 54 years, range 17 to 92 years, 56% with localized disease, 44% metastatic) from 8 EMSOS Centers were collected. Surgery of the primary tumor was performed in 76% of patients (amputation in 30%), with intralesional margins in 26%. A surgical complete remission status (SCR) was achieved in 47% of the patients. Radiotherapy (RT) was delivered in 41% of the patients (in 15 patients as definitive local treatment), chemotherapy (CT) in 47% (56% in metastatic and 41% in localized cases). With a median follow-up of 31 months (range 40 to 309 months), 68% of patients died, 16% were disease-free, 12% were alive with disease and 4% dead for other causes. The 5-year overall survival (OS) was 27% (95%CI 16-30): 41% (95%CI 25-56) for localized patients (45% SCR, 17% no SCR, p = 0.03) and 8% (95%CI 0-20) for metastatic patients (p = 0.002). Among metastatic patients, 29/35 have died, with a median time to death of 6 months (1-45), while 6 patients were alive with a median follow-up of 22 months (8-106). Improved survival was observed for male patients (30% vs 8%, p = 0.04), while type of treatment (surgery, chemotherapy, radiation), pattern of metastases and age did not affect outcome. In 18 metastatic patients who underwent chemotherapy partial respo nse (PR) was documented in 1/3 patients after paclitaxel (RR 33%), and stable disease (SD) in 5 patients (2/2 with gemcitabine, 2/8 with doxorubicin/ifosfamide, and 1/4 with osteosarcoma-like chemotherapy). In localized patients, the 5-year OS was significantly better for age ≤ 50 years (68% vs 34%, p = 0.02) and extremity and central tumor as compared with pelvis/sacral location (50% vs 58% vs 0%, p = 0.008), with improved disease-free survival (DFS) after chemotherapy (49% vs 33%, p = 0.04). Conclusions: Metastatic B-AS is a fatal disease and inclusion in experimental trials is warranted. In localized patients, a better probability of survival is expected in younger and surgically treated patients. The use of chemotherapy was associated with improved DFS.