tbuckley/cabot-search huggingface dataset:
Outcomes of minimal invasive three stage esophagectomy from a cancer centre in Pakistan
Authors: H. Ali, I.U.I. Nasir, A.W. Anwer
Journal: Annals of Oncology (2018)

Introduction: Management of esophageal cancer has evolved over the last two decades with esophagectomy staying as the main treatment modality for early stage or post neoadjuvant resectable esophageal cancer. Minimal invasive three stage esophagectomy is becoming the routine procedure for resectable mid and lower esophageal cancer in our institution. The aim of this study is to evaluate the surgical and initial oncological outcomes after curative minimal invasive threes stage esophagectomy at our institution and to compare our results with current literature. Management of esophageal cancer has evolved over the last two decades with esophagectomy staying as the main treatment modality for early stage or post neoadjuvant resectable esophageal cancer. Minimal invasive three stage esophagectomy is becoming the routine procedure for resectable mid and lower esophageal cancer in our institution. The aim of this study is to evaluate the surgical and initial oncological outcomes after curative minimal invasive threes stage esophagectomy at our institution and to compare our results with current literature. Methods: All adult patients with a diagnosis of oesophageal cancer who underwent minimal invasive three stage esophagectomy at our institute from 2005 to 2015 were included in this retrospective study. Patients' demographic and clinical characteristics were recorded through our hospital information system. Operative findings and histopathological reports were also recorded on a preformed data sheet. The short-term outcome measures were operative time in minutes, length of hospital and Intensive Care Unit (ICU) stay in days, post-operative complications and 30 days in-hospital mortality. Long-term outcomes were long-term procedure related complications over a minimum follow-up of 1 year and tumor recurrence. Results: Total of 91 patients were included in our study with mean age of 52.7(10.2). Eighty-nine patients had neo-adjuvant chemo-radiation. Sixty patients presented with T3 disease and 48 of 91 patients were reported to have pathological complete response (pCR) at time of surgery. Mean number of lymph nodes dissected were 14. Nineteen patients had recurrence; with 7 loco-regional and 12 distant metastases. There were 2 mortalities. Forty-six patients had minor complications and 14 had major complications. Mean operative time was 345 minutes. Mean length of stay was 9 days with first post-op day in ICU. Conclusion: We report our early experience with Minimal invasive three stage esophagectomy as a safe and oncologically feasible surgical option. We attained comparable surgical results with curative intent.
HGG-27. MALIGNANT TRANSFORMATION OF AN OPTIC NERVE GLIOMA: CASE REPORT
Authors: Huseyin Erdemir, Gozde Erdemir, Aimee Carlson, Gary Hsich, Tanya Tekautz
Journal: Neuro-Oncology (2018)

Optic pathway tumors are rare neoplasms of childhood with a 4-6% incidence of pediatric brain tumors. Optic pathway gliomas (OPG) consists of 65% of this small percentage. OPG is usually considered a low-grade lesions (WHO Grade I). In pediatric patients, malignant gliomas such as anaplastic astrocytoma or glioblastoma (GBM) of optic pathway are an exceedingly rare entity and present with aggressive clinical course. Malignant transformation from low-grade astrocytoma to anaplastic astrocytoma or GBM has been described in case series attributed to radiation therapy. Herein we report a fourteen-year old male patient with diagnosis of OPG which progressed to GBM nine years after the completion therapy. He was diagnosed at six-months of age and subsequently underwent four separate courses of chemotherapy initially with vincristine/carboplatin then vinblastine monotherapy, followed by vincristine/actinomycin-D and lastly vincristine/carboplatin via desensitization. Serial imaging studies did not demonstrate tumor progression for nine years after completing therapy. Almost fourteen years after the initial diagnosis, symptom-directed imaging studies showed progressive optic glioma. Bevacizumab monotherapy was started. The course complicated by thromboembolic stroke after the first dose of bevacizumab. Unfortunately he succumbed to the disease 5 weeks after initial hospitalization. Information obtained through autopsy reported disseminated GBM (WHO Grade IV) with extensive leptomeningeal spread. In this case-report, we review the patient’s clinical course with imaging studies and molecular mechanism of malignant transformation. To our knowledge, this is the second case reporting malignant transformation of low grade OPG without any exposure to radiation therapy or underlying tumor predisposition.
ATRT-05. USING DROSOPHILA TO EXPLORE THE FUNCTIONAL RELEVANCE OF GENES AFFECTED BY EPIGENETIC ALTERATIONS IN ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT)
Authors: Isabel Tegeder, Katharina Thiel, Johannes Berlandi, Pascal Johann, Serap Erkek, Marcel Kool, Astrid Jeibmann, Martin Hasselblatt
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant brain tumors arising in young children. The majority of AT/RT is characterized by inactivation of one single gene, the chromatin remodeling complex member SMARCB1 (INI1/hSNF5). However, AT/RTs are epigenetically heterogeneous and can be divided into molecular subgroups based on gene expression, DNA methylation profiles and enhancer landscapes (H3K27ac). Biostatistical analysis of ChIP-seq data resulted in a large set of genes predicted to be affected by differential histone modifications, but little is known on the functional role of these genes in the detrimental effects of SMARCB1 deficiency. We thus explored the functional relevance of 1083 candidate genes using shRNA modifier screens in a Drosophila melanogaster model of SMARCB1 deficiency in vivo. The lethal phenotype caused by glial-specific knockdown of Snr1, the fly orthologue of SMARCB1 was shifted to later stages of development upon additional knockdown of 89 out of 1083 candidate genes. These included CG10348, the fly orthologue of transcriptional regulator PRDM16. We found PRDM16 to be highly expressed in AT/RT. Knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells caused a significant reduction in cell viability. These results demonstrate that fly models can be employed for the identification of functionally relevant genes in the biology of AT/RT. Supported by IZKF Münster (Ha3/019/15).
lncRNA PFAR Promotes Lung Fibroblast Activation and Fibrosis by Targeting miR-138 to Regulate the YAP1-Twist Axis
Authors: Xiaoguang Zhao, Jian Sun, Yingzhun Chen, Wei Su, Huitong Shan, Yue Li, Yining Wang, Nan Zheng, Hongli Shan, Haihai Liang
Journal: Molecular Therapy (2018)

Long non-coding RNAs (lncRNAs) have been reported to be involved in various pathophysiological processes in many diseases. However, the role and mechanism of lncRNAs in idiopathic pulmonary fibrosis (IPF) have not been explicitly delineated. In the present study, we reported that lncRNA NONMMUT065582, designated pulmonary fibrosis-associated RNA (PFAR), is upregulated in the lungs of mice with lung fibrosis as well as in fibrotic lung fibroblasts. Overexpression of PFAR promoted fibrogenesis through modulation of miR-138, whereas knockdown of PFAR attenuated TGF-β1-induced fibrogenesis in lung fibroblasts. In addition, knockdown of miR-138 promoted fibrogenesis by targeting regulation of yes-associated protein 1 (YAP1), whereas enhanced expression of miR-138 attenuated fibrogenesis in lung fibroblasts. Mechanistically, PFAR acted as competing endogenous RNA (ceRNA) of miR-138: forced expression of PFAR reduced the expression and activity of miR-138 to activate YAP1 and promote fibrogenesis in lung fibroblasts, whereas loss of YAP1 abrogated the pro-fibrotic effect of PFAR. More importantly, PFAR silencing alleviated BLM-induced lung fibrosis in mice. Taken together, the results of our study identified lncRNA PFAR as a new pro-fibrotic molecule that acts as a ceRNA of miR-138 during lung fibrosis and demonstrated PFAR as a novel therapeutic target for the prevention and treatment of lung fibrosis.
The cost of relapse in Hodgkin lymphoma.
Authors: Ryan N. Hansen, Scott David Ramsey, Julia Slejko, Josh John Carlson
Journal: Journal of Clinical Oncology (2014)

e17537 Background: Hodgkin's lymphoma (HL) currently affects approximately 9,000 people in the US. Relapsed HL frequently carries an unfavorable prognosis and is accompanied by chemotherapies and stem cell transplantations. We sought to investigate the cost of relapsed HL after initial diagnosis and treatment. Methods: We used healthcare claims data from the Truven MarketScan Commercial Databases to conduct a retrospective cohort study comparing the economic impact of relapsed HL in the US. We selected people ages 18 and higher diagnosed with HL between 2007- 2012 that received initial treatment consistent with guidelines. Relapses were identified after a period of at least 30 days following discontinuation of initial chemotherapy by the presence of claims indicating new chemotherapy regimens or a stem cell transplant. Incremental total healthcare costs of relapsed patients (hospitalizations, outpatient services, emergency department visits, chemotherapy and other medications) from the initial time of (re)treatment were estimated using reimbursements and compared to non-relapse patients using the Kaplan-Meier Sample Average (KMSA) estimator. Generalized linear models were then used to determine if age, gender, Charlson comorbidity index, or US region were associated with higher or lower total costs among those with a relapse. Results: Among the 4,529 HL patients identified, the average age was 38 years (S.D. 14.2); 53.7% were male. Over 60 months of follow-up, 127 patients were identified as experiencing relapses. Mean total unadjusted costs for relapsed patients were $401,529 (S.D. 262,385) versus $89,709 (S.D. 105,799) for non-relapse patients. KMSA adjusted total costs for relapsed patients exceeded non-relapsed patients by $120,374 (95% CI: 87,794 to 140,649), $244,164 (95% CI: 220,901 to 299,320), and $269,427 (95% CI: 224,550 to 337,052) at years 1, 2 and 5 respectively. Among relapsed patients, costs varied by region and those with lower age had significantly higher total costs. Conclusions: Relapse of HL represents a high cost burden to the health care system. Novel agents that both reduce the risk of progression or the need for salvage therapy offer the potential to be both clinically effective and cost-effective.
DIPG-49. STAT3 AS A THERAPEUTIC TARGET IN DIPG
Authors: Nagore G Olaciregui, Diana Carvalho, Alan Mackay, Guillem Pascual-Pasto, Matthew Clarke, Valeria Molinari, Elisa Izquierdo, Jordan Goncalves, Yann Courbebaisse, Andres Morales La Madrid, Mariona Suñol, Ofelia Cruz, Jaume Mora, Chris Jones, Angel M Carcaboso
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is characterized by the infiltration and migration of tumor cells within the brain parenchyma. The signal transduction protein STAT3, activated by phosphorylation to phospho-STAT3 (p-STAT3), promotes tumor migration and invasion in many cancer types including gliomas. Thus, we hypothesized that the STAT3 pathway might be involved in the pathogenesis of DIPG. Re-analyzing publicly available gene expression data from 220 pediatric high grade gliomas of which 65 were DIPG, we found that STAT3 upregulation correlated with worse overall survival (p= 0.0099, log-rank test). Using immunohistochemistry and immunoblotting we showed that p-STAT3 was positive in DIPG necropsies and patient-derived cells. Treatment with the STAT3 inhibitor WP1066 led to the inhibition of cell proliferation in DIPG cultures, with IC50 values ranging 0.66–5.5 µM. Sub-cytotoxic concentrations of WP1066 downregulated p-STAT3 and inhibited cell migration in HSJD-DIPG-007 cells (H3F3A K27M, ACVR1 R206H). Treatment of HSJD-DIPG-007 tumor-bearing mice with WP1066 (40 mg/kg every two days for a total of 8 days) extended the median survival of the animals when compared to vehicle (73 versus 82 days, p= 0.045, log-rank test). Upon completion of the therapy treated mice showed less tumor burden and decreased p-STAT3 levels as compared to untreated ones. Drug efficacy could be explained by good CNS penetration since WP1066 reached active concentrations in the tumor (5.8 µM at 0.5 h after one dose of 40 mg/kg). Our results suggest that the STAT3 pathway might be a relevant therapeutic target in DIPG.
HGG-08. BONE METASTASES IN PEDIATRIC HIGH GRADE GLIOMA: A CASE SERIES AND REVIEW OF THE LITERATURE
Authors: Megan Paul, John Crawford, Jennifer Elster
Journal: Neuro-Oncology (2018)

High grade glioma (HGG) has poor outcomes in adults and children. Death usually occurs from progressive intracranial disease. Extraneural metastases are rare in HGG, and poorly characterized with only a few small case series in adults and isolated case reports in pediatrics. No genomic data has previously been published for any children with high grade glioma and extraneural metastasis. We present a case series of two pediatric patients who presented with HGG and developed bony metastases less than six months after initial diagnosis. The first patient was an 11-year-old male with a tumor in the left lateral ventricle invading into the fornices, hypothalamus, and left midbrain, who had subtotal resection, with bony metastasis found at 3.5 months and died 9 months after diagnosis. The second was a 12-year-old female with a tectal/pineal tumor and multiple spinal cord metastases, who had subtotal resection, with bony metastasis at 5.5 months and died at 13 months. Neither had bony metastasis at presentation. Both tumors underwent whole exome sequencing and in both the H3F3A K27M mutation was identified. Both tumors also had additional mutations associated with HGG but no other overlapping mutations. This case series represents the first set of pediatric HGGs with extraneural metastases and whole exome sequencing data. While H3F3A K27M is a common mutation in pediatric midline HGG, especially DIPG, and is associated with more aggressive disease, there has not been an association with extraneural metastasis prior to this series.
Trifluridine/tipiracil vs regorafenib as salvage-line treatment in patients with metastatic colorectal cancer: A multicenter retrospective study
Authors: M. Kotaka, M. Ogata, T. Ogata, Y. Hatachi, H. Yasui, T. Kato, A. Tsuji, H. Satake
Journal: Annals of Oncology (2018)

Introduction: Trifluridine/tipiracil (TAS-102) and Regorafenib (REG) have shown promising activity in patients with heavily pretreated metastatic colorectal cancer (mCRC). The aim of this study was to compare the efficacy and safety of TAS-102 and REG alone in patients with mCRC refractory to standard chemotherapies. Methods: From May 2014 to December 2017, 135 patients with mCRC were treated with TAS-102 or REG as salvage-line therapy. Efficacy, safety and clinical outcomes were retrospectively evaluated. Inclusion criteria were histologically confirmed colorectal adenocarcinoma; refractory or intolerant to fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF therapy and anti-EGFR antibody (for tumours with wild-type RAS); measurable or evaluable lesion; age ≥ 20 years; Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2; and written informed consent. The clinical outcomes were evaluated using the Cox's proportional hazard models. Results: Among 135 patients, 77 received TAS-102 (median age 77 y, male 49%, ECOG PS 0 62%, RAS wt 43%) and the other 58 received REG (median age 66 y, male 53%, ECOG PS0 64%, RAS wt 51%). With a median follow-up of 5.8 months (range, 1.5 to 19.0), median progression-free survival was statistically longer in the TAS-102 group than in the REG group (TAS-102 2.9 vs REG 2.0 months; HR = 0.591, p = 0.0035). No significant difference in overall survival between TAS-102 and REG (TAS-102 10.4 vs REG 9.2 months; HR = 1.14, p = 0.57) was observed. Conclusion: TAS-102 and REG showed equivalent survival benefit in the treatment of mCRC which had progressed after standard therapies.
CRAN-38. CLINICOPATHOLOGIC FEATURES OF SUPRASELLAR AND LATERAL CEREBRAL DESMOPLASTIC INFANTILE ASTROCYTOMA AND GANGLIOGLIOMA
Authors: Cody Nesvick, Ryan Naylor, Anton Wohl, Aditya Raghunathan, Laurence Eckel, Gesina Keating, David Daniels
Journal: Neuro-Oncology (2018)

Desmoplastic infantile ganglioglioma (DIG; also known as desmoplastic infantile astrocytoma, DIA) is a rare, World Health Organization (WHO) grade-I central nervous system tumor that most often arises in very young children, often with rapidly enlarging head circumference. We reviewed the records of all infants diagnosed with pathology-confirmed DIG/DIA at Mayo Clinic from 1997 to 2016. Immunohistochemical staining was performed on tumor specimens to assess expression of IDH1 R132H, BRAF V600E, H3K27me3 and INI1. Seven patients were included in this study: age range was 2 - 9 months, and four were male. Six patients presented with rapidly enlarging head circumference, and one presented with isolated seizures. On immunohistochemical analysis, all tumors were negative for R132H-mutant IDH1. INI1 expression was retained in all specimens, and BRAF V600E expression was negative or only very focally positive. H3K27me3 expression was partly lost in four tumors. Three tumors were located in the suprasellar region, and four were located in the lateral cerebral hemispheres. All patients underwent surgery for tumor resection; a gross total resection was achieved in the lateral cerebral tumors, and a subtotal resection was achieved in the suprasellar tumors. At 2-year follow-up, none of the patients with a hemispheric tumor developed long-term sequelae from their surgery, but each patient with a supresellar tumor had a neurologic or endocrinologic deficit from tumor progression or surgery, including visual impairment, panhypopituitarism and/or hemiparesis. These results highlight the importance of tumor location in prognosticating these challenging tumors, suggesting that suprasellar location is associated with a poorer prognosis.
CRAN-19. LONG-TERM VISION IMPAIRMENT IS HIGHLY PREVALENT IN PEDIATRIC CRANIOPHARYNGIOMA PATIENTS
Authors: M Fatih Okcu, Murtaza Saifee, William Whitehead, Jane Edmond
Journal: Neuro-Oncology (2018)

Pediatric patients with craniopharyngioma have a high rate of survival but are at risk for vision loss. The epidemiology of long term vision impairment has not been well-described in the literature in patients diagnosed in the recent decades. We reviewed medical records and abstracted information on clinical presentation, treatment and sequential vision function in 44 patients diagnosed and treated between 1997 and 2014 at a large tertiary children’s hospital. We assessed visual impairment using a combined metric of visual acuity and visual fields using an adapted version of the International Statistical Classification of Diseases standards for vision. Sixteen patients underwent a gross total resection (GTR, 6 received radiotherapy) and 22 were treated with radiation therapy at diagnosis or recurrence in addition to subtotal resection, biopsy or cyst-directed therapy. Eighteen (41%) had a recurrence and with a median follow up time of 59 months overall survival rate was 93%. At diagnosis 18 (51%) patients were classified as having normal vision, 9 (26%) impaired and 8 (23%) blind (9 uncooperative), whereas at latest follow-up 15 (35%) had normal vision, 9 (21%) were impaired and 19 (44%) were blind (1 uncooperative) (p = 0.13). Upfront treatment modality (GTR vs any XRT) and recurrence were not associated with visual impairment. Substantial number of patients with craniopharyngioma have poor vision at long-term follow up. Larger multicenter studies are needed to determine whether upfront treatment modality has an impact on vision in long term survivors.
MBCL-34. STRUCTURAL CONNECTIVITY ABNORMALITY IN CHILDREN TREATED FOR MEDULLOBLASTOMA
Authors: Adeoye Oyefiade, Kiran Beera, Jovanka Skocic, Cynthia De Medeiros, Donald Mabbott
Journal: Neuro-Oncology (2018)

Curative treatments for medulloblastoma impart significant toxicity on the developing brain. Though treatment-related changes to the white matter connections have been described, there remains a limited understanding of treatment effect on the structural connectome: the dense, integrative network of white matter connections present in the brain. The connectome is thought to subserve complex and dynamic behaviors, therefore identifying areas of compromise within the connectome may help elucidate the mechanisms of toxicity common among medulloblastoma survivors. METHODS AND Magnetic resonance images were acquired for 12 medulloblastoma survivors and 13 age and gender-matched children using a Siemens 3-Tesla scanner at the Hospital for Sick Children in Toronto. Post-processing of MR images was completed using FreeSurfer and MRtrix3 software. Probabilistic streamlines were generated and used to estimate whole-brain structural connectivity matrices based on the length of white matter connections. Mass univariate testing of all white matter connections (FDR = 0.05) showed significantly shorter connections in survivors (p < 0.0001). Global connectivity metrics were also analyzed; we observed significantly longer path lengths in patients (p = 0.02) but no significant differences in clustering (p = 0.99) or small-worldness (p = 0.98). These results suggest perturbed inter-regional connectivity but spared local connectivity in medulloblastoma survivors. Treatment of medulloblastoma may disrupt inter-regional connectivity between distant brain regions. Future work will aim to identify the regions most affected by perturbed inter-regional connectivity, and to relate pertuberance along those connections to neuropsychological outcome in medulloblastoma survivors.
Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy
Authors: Federico Rossari, Filippo Minutolo, Enrico Orciuolo
Journal: Journal of Hematology & Oncology (2018)

Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein resulting from t(9, 22)-derived Philadelphia chromosome. Although the specific targeting of that oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of resistance to imatinib arose after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment.Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances. Imatinib fine mechanisms of action had been elucidated to rationally develop those second- and third-generation inhibitors. Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future.Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.
Response to: ‘Antinuclear antibody as entry criterion for classification of systemic lupus erythematosus: pitfalls and opportunities’ by Bossuyt <i>et al</i>
Authors: David S Pisetsky, Diane M Spencer, Peter E Lipsky, Brad H Rovin
Journal: Annals of the Rheumatic Diseases (2018)

We very much appreciate the comments of Willems et al 1 on our article on the variability of antinuclear antibody (ANA) testing for patients with established systemic lupus erythematosus (SLE).2 Others have provided their perspective on test variability.3–6 In their letter, Willems et al discuss the importance of antibody titre especially in the context of patient classification. In the new classification criteria under development, a positive ANA at a titre of 1:80 or higher is required.7 In …