tbuckley/cabot-search huggingface dataset:
Case 22-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, John W. Stakes, Raymond A. Sobel
Journal: New England Journal of Medicine (1986)

Presentation of Case First admission. A 55-year-old right-handed woman was admitted to the hospital because of blurred vision.She was well until 28 months earlier, when she began to experience blurring of vision in both eyes. An ophthalmologist found no history of a preceding respiratory tract infection and made a diagnosis of "papillitis." Her symptoms resolved in six weeks on prednisone. She was then well until nine months before admission, when numbness developed in the right hand, and she dropped a cup of coffee from that hand. The numbness waxed and waned during several days and then worsened, accompanied . . .
Two cases of intrahepatic cholangiocellular carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade
Authors: Minghao Sui, Yu Li, Hongguang Wang, Ying Luo, Tao Wan, Xun Wang, Bingyang Hu, Yanshuang Cheng, Xianrong Lv, Xianlei Xin, Qiang Xu, Guan Wang, Shichun Lu
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Insertion–deletion mutations (indels) may generate more tumour-specific neoantigens with high affinity to major histocompatibility complex class I. A high indel ratio is also related to a good response to programmed death-1 (PD-1) checkpoint blockade in melanoma and renal cell carcinoma. However, the correlation between a high indel ratio and the immunotherapy response in intrahepatic cholangiocarcinoma (ICC) is unknown. <h3>Case presentation</h3> Two patients with relapsed ICC at stage IIIb were treated with PD-1 blockade combined with chemotherapy. After 7 and 4 months of chemotherapy and PD-1 blockade (3 and 15 cycles, and 5 and 6 cycles, respectively), magnetic resonance imaging and positron emission tomography with computed tomography imaging showed that both patients achieved a complete response (CR), which has lasted up to nearly 16 and 13 months to date, respectively. Whole-exome sequencing and immunohistochemistry analysis showed that both patients had cancers with microsatellite stability (MSS) and mismatch repair (MMR) proficiency, weak PD-L1 expression, and a tumour mutation burden (TMB) of 2.95 and 7.09 mutations/Mb, respectively. Patient 2 had mutations of <i>TP53</i> and <i>PTEN</i> that are known to confer sensitivity to immunotherapy, and the immunotherapy-resistant mutation <i>JAK2</i>, whereas patient 1 had no known immunotherapy response-related mutations. However, the indel ratios of the two patients (48 and 66.87%) were higher than the median of 12.77% determined in a study of 71 ICC patients. Moreover, comparison to six additional ICC patients who showed a partial response, stable disease, or progressive disease after PD-1 blockade treatment alone or in combination with chemotherapy demonstrated no difference in PD-L1 expression, TMB, MSI, and MMR status from those of the two CR patients, whereas the indel frequency was significantly higher in the CR patients. <h3>Conclusions</h3> These two cases suggest that indels might be a new predictor of PD-1 blockade response for ICC patients beside PD-L1 expression, TMB, MSI, and dMMR, warranting further clinical investigation.
A phase Ib trial of CB-839 (telaglenastat) in combination with radiation therapy and temozolomide in patients with IDH-mutated diffuse astrocytoma and anaplastic astrocytoma (NCT03528642).
Authors: Sani Haider Kizilbash, Samuel McBrayer, John Port, Joel M. Reid, Ian Lanza, Jacob B Allred, Arnab Chakravarti, Charles Kunos, Alex A. Adjei
Journal: Journal of Clinical Oncology (2019)

TPS2075 Background: IDH mutant astrocytomas express high levels of 2-hydroxyglutarate (2-HG), an oncogenic metabolite which drives gliomagenesis. Excess 2-HG inhibits branched chain amino acid transaminase, which catalyzes glutamate synthesis from branched chain amino acids. This defect causes these tumors to become more reliant on glutaminase for glutamate biosynthesis from glutamine. CB-839 (telaglenastat) is a novel glutaminase inhibitor which is well tolerated in humans. McBrayer et al have recently demonstrated that CB-839 further depletes intracellular glutamate and glutathione in IDH mutant glioma cells, and enhances RT (radiation therapy) efficacy in an orthotopic glioma model. Methods: NCI #10218 is a CTEP supported phase I clinical trial investigating the safety and tolerability of CB-839 when combined with RT/TMZ (temozolomide) in patients with previously untreated IDH mutant grade II/III astrocytoma. Patients with grade II and III astrocytomas will be treated with 50.4 and 59.4 Gy of RT, respectively, with standard doses of concurrent TMZ. CB-839 will also be administered orally concurrently with RT, with doses escalated in cohorts based on a standard 3+3 design. After defining the maximum tolerated dose (MTD) of CB-839, an expansion cohort will evaluate the pre- and post-CB-839 therapy metabolome of patients with IDH mutant astrocytoma. Enrollment to this cohort will require measurable disease and patients will additionally be treated with a 7 day run-in of CB-839 at MTD prior to RT. The effect of CB-839 on the metabolome will be studied in both plasma (LC/MS/MS) and tumor (magnetic resonance spectroscopy), along with PK to confirm adequacy of systemic exposure. Preliminary data on neurocognitive endpoints will also be acquired. NCI #10218 is currently activated for enrollment to cohort 1. Clinical trial information: NCT03528642.
A phase I, first-in-human, dose-escalation and dose-expansion study of the multitarget kinase inhibitor TT-00420 in patients with advanced solid tumors.
Authors: Sarina Anne Piha-Paul, Qunfang Wan, Wendy Xiong, Peng Peng, Xiaoju Yang, Henry Wu, Brenda Ngo, Frank Wu
Journal: Journal of Clinical Oncology (2019)

TPS3168 Background: Multi-target kinase inhibitors have gained increasing attention in the past few years due to their capabilities of simultaneously targeting several hallmarks of cancer. Triple negative breast cancer (TNBC), the most aggressive type of breast cancer, is a highly heterogeneous disease composed of several subtypes with distinct genomic profiles and activating pathways. TT-00420 is a multi-target kinase inhibitor that targets Aurora A/B, receptor tyrosine kinases (RTKs) involved in angiogenesis, and other kinases involved in tumor-associated inflammation and immune escape. Preclinical studies have established signs of efficacy for TT-00420 in TNBC. Targets inhibited by TT-00420 are among the key dysregulated pathways directly involved in the tumorigenesis of TNBC. TT-00420 is efficacious against most subtypes of TNBC cell lines. This anti-TNBC activity is confirmed in both cell line derived xenograft (CDX) and patient derived xenograft (PDX) TNBC model in vivo, in which TT-00420 is active both as first-line and second-line treatment. TT-00420 demonstrated good oral bioavailability and pharmacokinetic properties in mice, rats and dogs, and revealed mechanism-related but manageable toxicities. The IND approval of TT-00420 was granted by the FDA on Sept. 27, 2018. Methods: TT420X2101 is an open-label, first-in-human, multicenter, phase I study including a dose escalation portion in adult patients with advanced solid tumors, followed by dose expansion in two parallel cohorts, TNBC cohort (N=22) and selected advanced tumor (SAT) cohort (N=22). Adverse events will be evaluated per CTCAE v5.0 criteria, and tumor responses will be evaluated per RECIST v1.1 criteria. Patients aged 18-75 with measurable target lesion(s) at baseline and ECOG status of 0 or 1 will be enrolled. Patients are treated with a single daily oral administration of TT-00420 continuously for a 28-day cycle. Dose escalation is driven by Bayesian modeling with over-dose control. Approximately 66 patients are expected to be enrolled and treated in this study. Primary endpoint is to evaluate dose limiting toxicity (DLT) and identify maximum tolerate dose (MTD), if feasible, or establish recommended dose for Dose Expansion. Preliminary efficacy and PK profile will be evaluated as well. Enrollment is currently ongoing. Clinical trial information: NCT03654547.
A prognostic nomogram to predict the benefit of adjuvant radiotherapy for resected inﬂammatory breast cancer patients.
Authors: Yang Jun Ping, Qian Chao Nan
Journal: Journal of Clinical Oncology (2019)

e12007 Background: A nomogram is a convenient and reliable tool for individualizing cancer prognosis. Therefore, the purpose of this study was to construct a clinical nomogram for predicting overall mortality (OM) to help clinicians to make individualized estimates of the potential benefit of adjuvant radiotherapy (RT) for resected inﬂammatory breast cancer (IBC) patients. Methods: We used the Surveillance, Epidemiology, and End Results database to identify 4030 IBS patients treated with surgery between 2004 and 2012, and randomly classified the patients into the discovery (n = 2417) and validation (n = 1613) cohorts. A Cox regression hazards model was used to build a nomogram by determining the prognostic factors for OM in the discovery cohort. The overall accuracy and discriminative ability was measured by Brier score and Harrell's concordance index (c-index). Results: In multivariate analysis, age, race, number of primaries, N stage, estrogen receptor, progesterone receptor status, and marital status, were the independent predictive factors of OM. These variables were selected to generate the nomogram. The calibration curves for 2-, and 5-year OM rate showed excellent agreement between prediction and actual observation. The Brier score and c-index demonstrated the nomogram performed better than the 7th edition TNM staging system for predicting OM possibility. In addition, the nomogram predicted that the magnitude of benefit from adjuvant RT for an individual IBS patient could vary, the certain subgroup of patients (prognostic score: 0-25) would not gain benefit from adjuvant RT, while RT had more pronounced effects in participants with higher prognostic score (prognostic score: ≥25). Conclusions: This nomogram is a reliable prognostic method for predicting OM in IBC patients after surgical resection, which could be used to predict which IBC patients may benefit from adjuvant RT after surgery.
Radiologic imaging utilization of small cell lung cancer staging and treatment.
Authors: Elias Kikano, Thomas Bomberger, Atul B. Shinagare, Kai Laukamp, Afshin Dowlati, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2019)

e20079 Background: Over the past several decades, first line therapy recommendations for small cell lung cancer (SCLC) have remained relatively unchanged. Additionally, the National Comprehensive Cancer Network (NCCN) guidelines regarding initial evaluation, staging, response assessment, and surveillance of SCLC have also remained relatively static. To evaluate radiologic imaging utilization for SCLC, we reviewed patients imaging data and assessed their association with staging, metastatic sites at presentation, overall survival, and other clinical factors. Methods: Retrospective analysis of patients with a diagnosis of SCLC that received treatment and follow up from 2003 through 2018 was completed. Cross-sectional radiology imaging data including computed tomography of the chest abdomen and pelvis (CT CAP), magnetic resonance imaging (MRI), and positron-emission tomography (PET) was obtained from the picture archiving and communication system (PACS) and clinical data including age, sex, race, smoking history, extensive/limited stage, and metastatic sites at presentation was obtained from the electronic medical record. Results: The average age at diagnosis for all SCLC patients (n = 518) from 2003 to 2018 was 66 with a male to female ratio of 0.89. The mean overall survival of all SCLC patients was 410.2 days with extensive (n = 371) stage = 312.5 days and limited (n = 147) stage = 718.8 days. We found a significantly increased number of patients less than age 66 presented with brain metastasis compared to those greater than age 66 ( P&lt; 0.01). The absolute total number of CT CAP and PET studies was significantly increased in limited stage patients compared to extensive stage ( P&lt; 0.001). However, when accounting for mean overall survival, extensive stage patients received a significantly increased number of CT Brain ( P&lt; 0.05), PET ( P&lt; 0.01), CT CAP, and MRI Brain ( P&lt; 0.001) studies compared to limited stage per year. Conclusions: Overall radiology imaging utilization is significantly different between limited and extensive stage SCLC patients over the past 15 years.
Effect on anti-tumor immunity and long-term memory CD8+ T-cell generation with a novel, allogeneic cell-based, Gp96-Ig/OX40L cancer vaccine.
Authors: Jeff Hutchins, Vikas Tahiliani, Jayalakshmi Miriyala, Jason Rose, Patrick Dillon, Matthew M Seavey
Journal: Journal of Clinical Oncology (2019)

e14016 Background: We are focused on developing and optimizing a next generation cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-cell costimulation (OX40L-Ig), into a single tumor cell line overexpressing a host of cancer associated neoantigens. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma cell line, stably transfected to express gp96-Ig, is being tested in a phase 1/2 clinical trial (NCT#02439450) for NSCLC. A similar line was generated that complements HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). Methods: To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines (mHS-110 and mHS-130) to activate and expand adoptively transferred ovalbumin specific T cells (OT-1) responding to tumor challenge with ovalbumin over-expressing, B16F10. To identify the best ratio of mHS-110 to mHS-130; multiple dose ratio and dose escalation studies were performed to measure T cell expansion (peripheral and intratumoral) in the context of tumor challenge. Results: CD8+ T-cell expansion was observed on day-7, post-priming, with greatest expansion seen for the 1 to 0.5 ratio. Animals were subsequently boosted 14-days post-priming; the 1 to 0.5 ratio combination gave the most consistent and robust expansion, peaking on day-21. Animals were then challenged with tumors s.c. and growth delay was monitored. Only the 1 to 0.5 and 1 to 4.5 ratio dose groups showed significant delay in tumor growth and weight. Spleen CD4+ and CD8+ T-cells, and CD8+ TILs all increased significantly, as compared to mHS-110 vaccination alone, for the 1 to 0.5 and 1 to 4.5 ratio dose groups. Conclusions: Only the 1 to 0.5 ratio dose group showed any long-term OT-1 expansion or longevity over all other dose ratios, strongly suggesting this is the best combination of gp96-Ig and OX40L-Ig expression for long-term anti-tumor memory generation. These results support the clinical translation of this approach of combining a T cell activation platform with costimulation.
AB0580 A VISION OF THE CHARACTERISTICS AND COMORBIDITIES OF GIANT CELL ARTERITIS FROM THE HOSPITAL RECORDS OF THE NATIONAL HEALTH SYSTEM
Authors: Carmen de Frutos Fernández, Maria Angeles Martinez Huedo, Irene Monjo, Eugenio de Miguel
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Gigant cell arteritis (GCA) is the most frequent systemic vasculitis in older than 50 years old, with serious repercussions on the quality of life and survival of patients. The low prevalence and heterogeneous presentation make progress in the diagnostic and the knowledge of the disease difficult. <h3>Objectives</h3> The objective of this study has been to gather a large database to analyze the epidemiological characteristics, the comorbidities and the causes of mortality associated with the hospitalizations by ACG in our country. <h3>Methods</h3> Retrospective observational study based on data from the Database of Hospital from the Spanish National Health Service with primary or secondary diagnostic of GCA between January 1<sup>st</sup>, 2005 and December 31th, 2015. The included variables were sex, age, main reason for admission, secondaries diagnostics, time of stay, costs, comorbidities, temporal artery biopsy and mortality. <h3>Results</h3> The study cohort included 29.576 patients with GCA, 18.568 (62,8%) women, and the mean age was 80 ± 8 years. The number of hospital admissions with this diagnostic has increased between 2008 and 2013 with an annual cumulative increase rate of 3%, passing from 2.487 to 2.997 patients/year. We have found a different disease affectation pattern in men and women in terms of distribution by age group and the comorbidities associated. We have found that the mortality risk increases with the age and with the presence of cardiovascular disease OR 1,816 (1,484-2,221), ischemic heart disease OR 1,590 (1,302-1,941), renal disease OR 1,386 (1,225-1,569) and cancer OR 2,428 (2,039-2,891). While, a decrease in the risk of death was observed in patients who associated polymyalgia rheumatica OR 0.682 (0, 5810,801). *Statistically significant differences (P &lt; 0.05) <b>DM2:</b> Diabetes mellitus Type 2 <b>PMR</b>: Polymyalgia rheumatica <b>ICC:</b> Congestive heart failure <b>IHC:</b> ischemic heart disease<b> ECV:</b> Cerebrovascular disease <b>CCI:</b> Charlson Index of Comorbidities <h3>Conclusion</h3> In recent years the number of GCA hospital admissions has increased. The presence of comorbidities is high and greater in men. An increase in deaths for ischemic cause and a reduction of mortality in patients with PMR associated is observed. <h3>Disclosure of Interests</h3> None declared
Large cell neuroendocrine carcinoma of the lung: A population-based study.
Authors: Connor J Kinslow, Michael S. May, Tony J. C. Wang, Simon Cheng
Journal: Journal of Clinical Oncology (2019)

e13122 Background: In 2015, the World Health Organization dissolved the category of non-small cell lung cancer (NSCLC) that was previously known as “large cell carcinoma” into adeno- or squamous cell carcinomas, with the exception of large cell neuroendocrine carcinoma (LCNEC), which is now grouped with other neuroendocrine carcinomas of the lung. There is limited data on the epidemiology and best treatment practices for this malignancy, and studies comparing prognosis with SCLC and NSCLC have been conflicting. Methods: We reviewed the epidemiology of LCNEC using data from the Surveillance, Epidemiology and End Results Program from 2010 – 2015. Demographical features and overall survival were compared with SCLC and NSCLC. Trends in incidence and mortality rates were observed from 2004 – 2015. Results: We analyzed 195,148 cases of lung cancer, including 1,681 (0.9%) cases of LCNEC. Age-adjusted incidence of LCNEC was 0.31 per 100,000 people and had increased by 50% over the period studied. This increased incidence was primarily the result of increased incidence of stage IV disease. LCNEC was more likely to present with brain metastasis at diagnosis (19.2%) than either SCLC (16.7%, p = .01) or NSCLC (13.0%, p &lt; .001). Survival patterns for LCNEC mirrored NSCLC in stage I – III disease and SCLC in stage IV disease. After adjusting for other clinical and demographic variables, survival for LCNEC was not different than SCLC but worse than NSCLC (HR = 0.88 for NSCLC vs. LCNEC, p &lt; .001). Survival rates for LCNEC and SCLC did not significantly change over the time period studied, whereas survival rates for NSCLC significantly improved. Consistent with our findings of increased incidence of LCNEC with no change in survival patterns, age-adjusted incidence-based mortality increased by two-fold over the time period studied. Conclusions: LCNEC generally has a worse prognosis than NSCLC and better than SCLC. LCNEC presents with brain metastases more frequently than SCLC. Incidence of LCNEC is consistently increasing in the U.S. Despite this, it remains poorly studied and prognosis for LCNEC has not improved with time. LCNEC has, therefore, become an increasing cause of lung cancer mortality in the American population.
Effect of gender on the outcome of patients receiving nivolumab for metastatic renal cancer: Results from a large study population.
Authors: Giuseppe Procopio, Serena Di Cosimo, Ugo De Giorgi, Giacomo Cartenì, Enrico Cortesi, Claudia Caserta, Roberto Sabbatini, Alessandra Bearz, Sebastiano Buti, Sandro Pignata, Alfredo Berruti, Enzo Ruggeri, Carmelo Bengala, Lorenzo Livi, Daniele Fagnani, Andrea Bonetti, Manfred Mitterer, Cinzia Ortega, Francesco Cognetti, Massimo A. Di Nicola
Journal: Journal of Clinical Oncology (2019)

e16087 Background: Several studies, the majority on melanoma and lung cancer, have addressed the value of gender with respect to immune check point inhibitors outcome as compared to standard therapy, showing conflicting results. Nevertheless, few focused on gender-related clinical outcome and toxicity in renal cell carcinoma (RCC) patients. Methods: This analysis evaluated the effect of gender on overall survival and adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 in an expanded access programme of nivolumab 3 mg/kg once every 2 weeks in second-line and beyond metastatic RCC. Only patients assuming at least one dose of nivolumab were analyzed. Results: Of 389 patients analyzed, 25.2% were female. On study entry, no differences were found in women as compared to men in terms of age, on average 64 years, p = 0.91; overweight/obesity, 45 versus (vs) 49%, p = 0.47; LDH , mean U/L 391 vs 32, p = 0.17); and neutrophils/lymphocytes ratio&gt; 3 (62 vs 63%, p = 0.87). Disease presentation was similar according to gender, although women tended to present less lung (66% vs 76%, p = 0.06) and bone metastases (42% vs 52%, p = 0.07). Notably, there was no differences in the IDMC prognostic model by gender (p = 0.94). Any drug related AEs (38 vs 30%, p 0.15), grade 3-4 (6% vs 6%) and median number of drug doses 12 (53% vs50%, p = 0.58 ) did not differ between gender. After adjusting for known prognostic variables, multivariate analysis showed that women had similar overall survival as compared to men (hazard ratio 0.81, 95% confidence interval 0.56-1.17, p = 0.26). Conclusions: Women demonstrate similar overall survival than men in metastatic RCC treated with secondal line and beyond nivolumab, with no differences observed in serious AEs and dose administered.