tbuckley/cabot-search huggingface dataset:
DIPG-43. PEDIATRIC NON-PONTINE DIFFUSE MIDLINE GLIOMA H3K27M MUTANT: A MONOINSTITUTIONAL EXPERIENCE
Authors: Elisabetta Schiavello, Veronica Biassoni, Emilia Pecori, Barbara Diletto, Manila Antonelli, Piergiorgio Modena, Lorenza Gandola, Maura Massimino
Journal: Neuro-Oncology (2018)

The new entity “diffuse-midline-glioma H3K27M-mutant” has been specified in the 2016 WHO revision. Recent studies have shown this tumor subtype had aggressive clinical behavior and dismal prognosis, sharing the same outcome as DIPG. No prospective studies have been so far published. We report our experience since 2016 in treating patients with radiotherapy and Nimotuzumab/Vinorelbine chemotherapy, as already published for DIPG’s patients (DOI10.1007/s11060-014-1428-z). All patients provided written informed consent for treatment. We treated 6 patients: 5/6 females, median age at diagnosis 9 years, median onset of symptoms 2 months, 3 thalamic, 2 ponto-cerebellar, 1 with two different lesions (brain-stem/cerebellar), no one with spinal cord dissemination. 3/6 were biopsied, the others received partial resection, in all cases a central review of diagnosis was performed: 5 patients had diffuse-midline-glioma H3K27mutated and 1 anaplastic-astrocitoma with loss of trimethylation (ongoing sequencing for mutation). One patient is on treatment two months after diagnosis. Five patients were evaluable for response: median time to progression was 9 months: range 7–12. Three out of 5 died for PD, 1 for an acute event of unknown origin, 1 is alive at 12 months SD after reirradiation. Median observation time from diagnosis was 11 months (range 2–12). The phenotypically/molecularly defined setting and severe outcome of this orphan population provides a rationale for therapies directed against the effects of the H3K27 mutations that are by now not yet proved and suggests inclusion of these entities in DIPG treatment registry and protocols.
HGG-45. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF PEDIATRIC TREATMENT-INDUCED HIGH-GRADE GLIOMA: GERMLINE DNA REPAIR DEFECTS AS A POTENTIAL ETIOLOGY
Authors: John DeSisto, John Lucas, Andrew Donson, Bridget Sanford, Gang Wu, Gregory Armstrong, Michael Arnold, Smita Bhatia, Patrick Flannery, Rakeb Lemma, Lakotah Hardie, Lindsey Hoffman, Kathleen Dorris, Arthur Liu, Nicholas Foreman, Rajeev Vibhakar, Kenneth Jones, Sariah Allen, Suzanne Baker, Thomas Merchant, Brent Orr, Adam Green
Journal: Neuro-Oncology (2018)

Pediatric treatment-induced high-grade glioma (TIHGG) is an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy. Previously, we showed TIHGG gene expression differs from spontaneous pediatric HGG and defined two TIHGG groups (A & B) by transcriptomic profiling. We now report copy-number analysis, whole genome sequencing (WGS), and methylation profiling for an expanded TIHGG cohort. Illumina Infinium 450/850K methylation analysis was performed on 34 TIHGG samples from a multi-institutional/Childhood Cancer Survivors Study Group cohort. WGS was performed on tumor and matched germline DNA from 15 TIHGGs. On methylation profiling, 19/27 TIGs, including all expression group A and B cases (6 each), clustered into a subclass of IDH-wt midline GBM. Recurrent copy number alterations included 1p loss (13/34), 1q gain (13/34), ch13 loss (13/34), PDGFRA gain/amplification (17/34), and CDKN2A loss (14/34). WGS identified a mean germline mutation load of 1.50 mut/Mb. Mean somatic mutation load, excluding one hypermutator sample, was 0.12 and 1.08 mut/Mb for TIHGG expression groups A and B, respectively (p<0.002). All TIHGG group B cases had pathogenic germline alterations in BARD1 or BRCA1, which repair DNA damage from ionizing radiation. TIHGG expression group A samples lacked pathogenic DNA repair mutations, except the hypermutator sample, which had distinct germline DNA repair defects including BRCA2 and ATR. TIHGGs are enriched for distinctive chromosomal aberrations and cluster into a defined epigenetic subgroup. A subset of TIHGGs have a high somatic mutational load, likely from germline defects in homologous recombination, which could predict TIHGG risk before treatment.
Matrix metalloproteinase-1 (MMP-1) expression and biological significance in the progression of prostate cancer
Authors: Sai Murali Pulukuri, Jitendra Patel, Norman Estes, Jasti Rao
Journal: Cancer Research (2007)

3072  Prostate cancer is the most commonly occurring cancer in men and advanced prostate cancer that spreads beyond the gland is incurable. Identifying the factors that drive metastasis may offer insights into how to limit or prevent this deadly aspect of prostate cancer progression. Expression of matrix metalloproteinases (MMPs) and their activation in tumor cells has been implicated in tumor cell invasion and metastasis. Broad spectrum MMP inhibitors have been reported to inhibit prostate tumor growth and metastasis in a variety of in vivo models. However, the expression and biological role of individual MMPs in both the primary tumor and in metastatic microenvironments are not fully understood. The objective of this study was to determine the differential expression of MMPs and understand their specific roles in different stages of metastasis formation. Here, we have developed a bioluminescent orthotopic animal model that mimics the behavior of human metastatic prostate cancer in the lung and other metastatic microenvironments. Using this model, we identified that MMP-1 expression was associated in both the primary prostate tumor and in aggressive lung metastatic behavior; these areas were largely negative for MMP-3 and MMP-7. Analysis of protein expression for these genes confirmed that the difference in mRNA levels translated into significant alterations at the protein levels. In addition, we found that increased MMP-1 expression was associated with advanced stages of human prostate cancer tissue samples. In vitro characterization further revealed that increased levels of secreted MMP-1 were only detected in the highly metastatic prostate cancer cell lines DU145 and PC3, but not in the low metastatic prostate cancer cell line LNCaP. Remarkably, MMP-7 expression was undetectable in these cell lines, whereas MMP-9 and MMP-2 activities were comparable in all three of the prostate cancer cell lines with varying metastatic potentials. Treatment of the PC3 cell culture medium with antibodies directed against MMP-1 significantly inhibited tumor cell invasion. Simultaneous immunodepletion of MMP-9 and MMP-2 resulted in only a slight decrease in tumor cell invasion. No effects were seen upon treatment with anti-MMP-3 or anti-MMP-7 antibodies. Taken together, these results strongly suggest that increased expression of MMP-1 plays a critical role in prostate cancer progression during invasive and metastatic stages of the disease and that inhibition of MMP-1 could have therapeutic benefit in the treatment of metastatic prostate cancer.
HGCSG1503: A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer: Analysis of cases of prior regorafenib
Authors: Y. Tsuji, S. Yuki, K. Sawada, T. Muranaka, Y. Kobayashi, H. Okuda, K. Ogawa, S. Minami, T. Honda, M. Dazai, T. Kato, T. Sasaki, Y. Shindo, S. Ota, A. Sato, A. Ueda, S. Saitoh, H. Nagai, Y. Sakata, Y. Komatsu
Journal: Annals of Oncology (2018)
DIPG-65. PRELIMINARY EXPERIENCE OF CHRONIC INTERMITTENT CONVECTION ENHANCED DELIVERY OF CARBOPLATIN AND VALPROIC ACID FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA FOLLOWING RADIATION THERAPY
Authors: Milo Hollingworth, Cornelia Hurter, Max Wooley, Owen Lewis, Steven Gill, Stergios Zacharoulis
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a lethal disease of middle childhood with few treatment options. The failure of chemotherapy is in part due to poor blood-brain barrier penetration. Convection enhanced delivery (CED) uses direct intraparenchymal infusion to distribute drug through target brain volumes. Valproic acid and carboplatin are readily compatible with CED and kill DIPG cells as monotherapies and with synergy when combined. These drugs were combined and translated into a two-day CED treatment schedule for treatment of DIPG on compassionate grounds using a long-term, implantable, drug delivery system (undergoing approval, Renishaw Plc). This device utilises a bone-anchored transcutaneous port for intermittent drug administration without the need for repeated surgery. 9 patients who had previously received radiotherapy were selected for treatment. Surgical implantation of the device was well-tolerated. A total of 27 cycles (54 infusions) of sodium valproate and carboplatin were delivered achieving infusion volumes between 3.6–5.6 mL per infusion. The most common acute infusion-related side-effects included headache and mild limb weakness and all patients were discharged within 24 hours of finishing treatment. We describe our preliminary experience as a prelude to a forthcoming clinical trial.
COPD at work: exposures are different than in the past, but still matter
Authors: Dick Heederik, David M Mannino
Journal: Thorax (2018)

This present common knowledge about the role of occupational exposures in the development of COPD has not been without controversy and is generally accepted only for less than two decades.1 This is because the dominant cause of COPD in high-income countries is cigarette smoking. Despite the biological plausibility of other inhaled agents being causally implicated, only the role of tobacco smoke was accepted as a cause of COPD in the mid-1980s.2 3 At that time, chronic non-malignant lung disease characterised by airflow limitation became more common in occupational population studies as the incidence of TB and pneumoconiosis were decreasing in major heavy industries (mining, foundries). But it was not commonly accepted that occupational dust and fumes exposures could be a cause of this group of diseases, the reasons being that obstructive respiratory disease are multifactorial diseases, strongly associated to non-occupational factors. As a result, a heated discussion existed at that time in the literature on the role of occupational exposures in relation to what we now refer to as COPD. In the case of coal workers, perhaps the best studied occupational group at that time, some argued that airflow limitations were of minor degree and not sufficient to impair lung function and disable the worker unless he was a smoker as well.4–6 Others disagreed and argued that clinically relevant decreased in lung function could result from a lifetime exposure to coalmine dust.2 3 Some suggested that the lung function declines …
Retinoic acid-induced 2 (RAI2) is a potential tumor suppressor and RAI2 promoter methylation is a poor prognostic marker in colorectal cancer
Authors: W. Yan, K. Wu, Y. Yang, M. Guo, G. Dai
Journal: Annals of Oncology (2018)

Introduction: Retinoic acid (RA) plays an important role in development, adult hematopoiesis and cell differentiation. Retinoic acid induced 2 (RAI2) was originally discovered to be induced by retinoic acid in embryonal carcinoma cells. Low retinoic acid induced 2 (RAI2) expression was found in breast cancer as an independent poor prognostic factor, promoting early hematogenous dissemination of human breast cancer cells to bone marrow. The expression of Retinoic acid induced 2 (RAI2) was found reduced in colorectal cancer (CRC) by searching The Cancer Genome Atlas (TCGA) database. The regulation and function of RAI2 in human cancer remain unclear. In this study, we focused on the epigenetic regulation and function of RAI2 in colorectal cancer (CRC). Methods: Eight CRC cell lines, 237 cases of primary colorectal cancer samples and 15 cases of normal colorectal mucosa were analyzed in this study. Semi-quantitative RT-PCR, methylation specific PCR (MSP), Immunohistochemistry, Western Blot, flow cytometry, cell viability detection assay, trans-well migration assay and invasion assay and xenograft mouse model technique were employed to study the epigenetic regulation and the function of RAI2 in CRC. Results: The promoter region of RAI2 was completely methylated in RKO, LoVo and HCT116 cells, partially methylated in HT29 cells and unmethylated in SW480, SW620, DLD1 and DKO cells. The expression of RAI2 was regulated by promoter region methylation. RAI2 was methylated in 53.6% (127/237) of primary colorectal cancer samples. Methylation of RAI2 was significantly associated with gender (P < 0.001), TNM stage (P < 0.001) and lymph node metastasis (P < 0.001). Analysis using the Kaplan–Meier method demonstrated that methylation of RAI2 was significantly associated with poor 5-years overall survival (OS) (p = 0.0035) and 5-years relapse-free survival (RFS) (p = 0.0062). According to Cox proportional hazards model analysis, RAI2 methylation was an independent prognostic marker for poor 5-years OS after adjusting for TNM stage, tumor differentiation and lymph node metastasis (p = 0.029). RAI2 suppressed cell proliferation, migration and invasion and induced cell apoptosis in CRC. In addition, RAI2 inhibited AKT signaling in CRC cells and suppressed human CRC cell xenograft growth in mice. Conclusion: RAI2 is frequently methylated in human CRC, and the expression of RAI2 is regulated by promoter region methylation. Methylation of RAI2 is an independent poor prognostic marker of CRC. RAI2 suppresses CRC cell growth both in vitro and in vivo. RAI2 may serve as a tumor suppressor by inhibiting AKT signaling in CRC.RAI2 is frequently methylated in human CRC, and the expression of RAI2 is regulated by promoter region methylation. Methylation of RAI2 is an independent poor prognostic marker of CRC. RAI2 suppresses CRC cell growth both in vitro and in vivo. RAI2 may serve as a tumor suppressor by inhibiting AKT signaling in CRC.
Dose finding phase Ib study of triplet plus cetuximab for patients with wild-type RAS gene metastatic colorectal cancer (TRICETSU study)
Authors: H. Satake, T. Kotake, Y. Okita, Y. Hatachi, H. Yasui, M. Kotaka, T. Kato, A. Tsuji
Journal: Annals of Oncology (2018)

Introduction: The aim of this study was to determine the recommended dose of FOLFOXIRI plus cetuximab (Cmab) as first-line treatment for patients (pts) with RAS wild-type metastatic colorectal cancer. Methods: The eligibility criteria included pts with unresectable colorectal adenocarcinoma, age 18 years or more, ECOG PS 0 or 1, wild-type or heterozygous UGT1A1 *28 or *6, no history of prior chemotherapy, and adequate organ function. Patients received the combination of Cmab (initiation dose of 400 mg/m2, followed by weekly infusion of 250 mg/m2 on day 1) with FOLFOXIRI (irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m2, and folinate (LV) 200 mg/m2 on day 1, followed by fluorouracil (5-FU) 3200 mg/m2 infused as a 46-hour continuous infusion starting on day 1) repeated every 2 weeks. Three dose levels of CPT-11 were planned as follows: Level 1: CPT-11 165 mg/m2, Level 0 as starting dose: CPT-11 125 mg/m2, and Level -1: CPT-11 95 mg/m2. The dose-limiting toxicity (DLT) was evaluated in the first cycle. This trial was registered with the University Hospital Medical Information Network (number UMIN000016009). Results: From May 2014 to June 2017, we enrolled a total of 8 pts (4 pts in the Level 0 and 4 pts in the Level 1). The pts characteristics were as follows: median age, 50.4 (range, 38-64); male, 3; ECOG PS 0, 6; and all left sided primary. All were assessed for safety and seven were assessed for efficacy. No treatment related death was observed. The grade 3 or 4 toxicities were neutropenia (n = 2). Among 7 pts who had at least once tumor evaluation, three (43%) were converted to the surgical resection. With a median follow-up period of 33.1 months, the time to protocol treatment failure, the medina progression-free and median overall survival was 7.8 months, 8.0months and not reached, respectively. Conclusion: The recommended phase II dose was determined to be standard dose of Cmab with FOLFOXIRI (CPT-11 165 mg/m2, L-OHP 85 mg/m2, and LV 200 mg/m2 on day 1, followed by 5-FU 3200 mg/m2 infused as a 46-hour continuous infusion).
CRAN-39. BARIATRIC SURGERY FOR TREATMENT OF HYPOTHALAMIC OBESITY
Authors: Thomas Inge, Megan Kelsey
Journal: Neuro-Oncology (2018)

Craniopharyngiomas (CP) are neoplasms generally found in the area of the pituitary and hypothalamus, and treatment can lead to clinically significant endocrine, neurologic, behavioral and metabolic dysfunction. Severe obesity occurs in a high percentage of patients with CP, leading to metabolic comorbidities, impaired quality of life, and weight-related physical disabilities. This resultant hypothalamic obesity (HyOb) is often refractory to conventional lifestyle interventions and pharmacotherapy. Roux en Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are bariatric operations for which there is an emerging experience in patients with HyOb. Although existing literature is limited, with heterogeneity of outcomes, evidence shows that RYGB can result in long term (≥2 years) weight loss of in excess of 20%, while weight loss after VSG is more modest at >10%. In this presentation, we will review the current evidence pertaining to the use of bariatric surgery in the treatment of CP-HyOb. We will also compare these results to those reported for other populations of HyOb, including Prader-Willi Syndrome and hypothalamic melanocortin signaling defects. While initial reports of bariatric surgery in CP-HyOb are promising, their limited scope makes it difficult to draw any substantial conclusions as to the long term safety and efficacy of bariatric surgery in CP-HyOb, and in particular which bariatric operations are most indicated for these patients. More robust, controlled, prospective studies with long term follow-up are needed to better define the role of bariatric procedures in the treatment of HyOb.
A multicenter, multicohort, phase 2 study of trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing metastatic colorectal cancer - Trial in progress
Authors: T. Yoshino, S. Siena, R. Dalal, Y. Okuda, E. Yamamoto, A. Grothey
Journal: Annals of Oncology (2018)

Introduction: Approximately 1% to 5% of metastatic colorectal cancers (mCRC) are HER2-overexpressing. HER2 is considered to be an important target for mCRC, however no HER2-targeted therapies are approved for mCRC. Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker (deruxtecan), and with a high drug-to-antibody ratio of 7 to 8. In the ongoing phase 1 DS8201-A-J101 trial, DS-8201a provided durable antitumor activity with a manageable safety profile in subjects with HER2-expressing solid tumors, including subjects with mCRC (preliminary objective response rate [ORR] of 20.0% in mCRC) (Tsurutani et al, ESMO 2017). Methods: This multicenter, open-label, 3-cohort, phase 2 study (ClinicalTrial.gov: NCT03384940) will assess the efficacy and safety of DS-8201a in subjects with HER2-expressing mCRC. Cohort A will include approximately 50 subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+) mCRC. At the start of the study, only cohort A will be active. Depending on the risk/benefit assessment after at least 20 subjects in cohort A complete tumor assessments at week 12, cohort B (IHC 2+/ISH-) and cohort C (IHC 1+) will open to enroll approximately 20 subjects each. All enrolled subjects will receive a 6.4 mg/kg dose of DS-8201a once every 3 weeks; study treatment will be continued until disease progression, unacceptable toxicity, or other treatment discontinuation criteria are met. The anticipated duration of the study is at least 24 months. The primary endpoint is ORR (complete response or partial response), as assessed by an independent central review committee, in cohort A. Secondary efficacy endpoints include progression-free survival, duration of response, disease control rate, and overall survival. Safety assessments include serious and treatment-emergent AEs, physical examination findings, and vital sign measurements. The study will enroll subjects in Japan, the US, and Europe. Recruitment began in December 2017.
Wearable activity monitors to assess performance status and predict clinical outcomes in advanced cancer patients
Authors: Gillian Gresham, Andrew E. Hendifar, Brennan Spiegel, Elad Neeman, Richard Tuli, B. J. Rimel, Robert A. Figlin, Curtis L. Meinert, Steven Piantadosi, Arvind M. Shinde
Journal: npj Digital Medicine (2018)

An objective evaluation of patient performance status (PS) is difficult because patients spend the majority of their time outside of the clinic, self-report to providers, and undergo dynamic changes throughout their treatment experience. Real-time, objective activity data may allow for a more accurate assessment of PS and physical function, while reducing the subjectivity and bias associated with current assessments. Consenting patients with advanced cancer wore a wearble activity monitor for three consecutive visits in a prospective, single-cohort clinical trial. Provider-assessed PS (ECOG/Karnofsky) and NIH PROMIS® patient-reported outcomes (PROs) were assessed at each visit. Associations between wearable activity monitor metrics (steps, distance, stairs) and PS, clinical outcomes (adverse events, hospitalizations, survival), and PROs were assessed using correlation statistics and in multivariable logistic regression models. Thirty-seven patients were evaluated (54% male, median 62 years). Patients averaged 3700 steps, 1.7 miles, and 3 flights of stairs per day. Highest correlations were observed between average daily steps and ECOG-PS and KPS (r = 0.63 and r = 0.69, respectively p < 0.01). Each 1000 steps/day increase was associated with reduced odds for adverse events (OR: 0.34, 95% CI 0.13, 0.94), hospitalizations (OR: 0.21 95% CI 0.56, 0.79), and hazard for death (HR: 0.48 95% CI 0.28-0.83). Significant correlations were also observed between activity metrics and PROs. Our trial demonstrates the feasibility of using wearable activity monitors to assess PS in advanced cancer patients and suggests their potential use to predict clinical and patient-reported outcomes. These findings should be validated in larger, randomized trials.
ATRT-39. TRANSCRIPTIONAL ANALYSIS OF ATRT SAMPLES FROM LONG-TERM SURVIVORS AND MATCHED PRIMARY/RECURRENT PAIRS
Authors: Patrick Flannery, John DeSisto, Andrew Donson, Rakeb Lemma, Rajeev Vibhakar, Kenneth Jones, Adam Green
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumor (ATRT) comprises 20% of all brain tumors in children less than 3 years old and is incurable at recurrence. The aim of our study is to determine transcriptional differences that may predict recurrence and raise more effective therapeutic strategies at recurrence. We performed microarray RNA expression profiling on three primary ATRT samples from long-term recurrence-free survivors (two from the SHH and one from the MYC epigenetic subgroup) and three sets of matched primary and recurrent patient ATRT samples (two MYC and one SHH). RNA-Seq was also performed on the primary/recurrent sets. We conducted clustering and geneset enrichment analysis (GSEA) on the microarray data. Clustering analysis identified two subgroups, with the first group containing the three non-recurrent tumors and the six samples from the primary/recurrent pairs in the second (coph=1.0). GSEA demonstrated upregulation of the Myc oncogenic pathway (Hallmark Myc geneset, NES=1.53, FDR=0) and upregulated tumor invasion pathways (Hallmark EMT geneset, NES=1.0, FDR=0.09) in primary tumors that recurred compared to those that did not. In recurrent tumors versus their primary pairs, GSEA showed upregulation of Myc pathway genes (Hallmark Myc geneset, NES=3.68, FDR=0), epigenetic regulators (BMI1 geneset, NES=3.15, FDR=0), and neuronal genes (NES=2.93, FDR=0.0), and downregulation of PTEN (NES=2.36, FDR=0.002). CONCLUSIONS/CURRENT Primary ATRTs that will eventually recur show upregulation of genes associated with oncogenesis and tumor invasion as compared to non-recurrent tumors. At recurrence, these tumors show further upregulation of Myc pathway genes. RNA-Seq analysis is currently in process.