tbuckley/cabot-search huggingface dataset:
A phase 1 study of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors.
Authors: David Michael Hyman, Irene Brana, Anna Spreafico, Alison M. Schram, Naimish B. Pandya, Kimberly Hoffman, Robin Hallet, Patricia Giblin, Judit Anido, Isabel Huber Ruano, Robert Wasserman, Jeanne Magram, Lillian L. Siu, Josep Tabernero, Joan Seoane, Jose Baselga
Journal: Journal of Clinical Oncology (2018)

TPS2602 Background: Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine involved in many physiological and pathological processes. LIF is highly expressed in a subset of tumors across multiple tumor types and shown to correlate with poor prognosis. LIF is hypothesized to contribute to tumor growth and progression by acting on multiple aspects of cancer biology, including immunosuppression of the tumor microenvironment (TME), and is a key regulator of cancer initiating cells (CICs), which are thought to underpin tumor growth, metastasis, and resistance to therapy. MSC-1, a first-in-class humanized IgG1 monoclonal antibody, is a potent and selective inhibitor of LIF. MSC-1 leads to robust STAT3 inhibition by disrupting the LIF signaling through the LIF receptor (LIFR). Blocking LIF with MSC-1 decreased tumor growth in multiple mouse tumor models and drove reprogramming of the TME through differentiation of immunosuppressive macrophages and modulation of several immune cell types. These findings form the basis of a robust therapeutic hypothesis, whereby MSC-1 treatment may lead to clinical activity in multiple cancer indications. Methods: The Phase 1 study of MSC-1 will enroll patients with advanced relapsed/refractory solid tumors. The study will employ an accelerated 3+3 escalation design to explore the safety, PK, immuno-regulatory activity and preliminary anti-tumor activity of MSC-1. Patients will receive treatment with MSC-1 intravenously once every three-weeks until confirmed disease progression or intolerable toxicity. Four tumor specific expansion cohorts will be initiated once dose and schedule are established from dose escalation and include NSCLC, ovarian cancer, pancreatic cancer and a basket of advanced solid tumors; enrollment will be restricted to patients with LIF-High expression in their tumors using a diagnostic selection assay. Response will be assessed every 6 weeks per RECIST v1.1.
Clinical manifestation and prognostic features of extramedullary plasmacytomas.
Authors: Hyun Ae Jung, Chi Hoon Maeng, Jun Ho Jang, Chul Won Jung, Kihyun Kim
Journal: Journal of Clinical Oncology (2017)

e19516 Background: Extramedullary plasmacytomas (EMPs) is a rare presentation of plasma cell neoplasm and accounts for 7 to 15% of all plasma cell neoplasm. Fluorescence in-situ hybridization (FISH)-detected abnormalities, including del(17p), del(13q), and t(4;14), have been associated with inferior prognosis. However, there are few data about the prognostic significance of cytogenetic abnormalities in multiple myeloma (MM) patients with EMPs. This study aimed the clinical features, FISH data and outcome of patients with EMPs Methods: The data were collected from multiple myeloma patients with EMPs, retrospectively. We excluded skeletal plasmacytomas. The clinic-pathologic variables and treatment outcome retrospectively reviewed. Results: Seventeen patients had solitary EMPs. Most common site of solitary EMP was nasal cavity and most patients received radiotherapy (n=7) and surgery (n=6). A total of 905 patients with newly diagnosed MM were included, and 53 patients (8.7 %) had EMPs at diagnosis. Thirty three patients had conventional FISH data. By conventional cytogenetic analysis and FISH, 35.8% (19/53) and 54.5% (18/33) patients were identified genetic abnormalities, respectively. By comprehensive cytogenetic/FISH approach, the most common genetic aberration was 1q21 amplification and/or 1p32 deletion (42.4%, 14/33), followed by -13 or del (13q) (24.3%, 8/33), del (17p) (15.2%, 5/33), IGH/FGFR3 rearrangement (15%, 2/33) and IGH/CCND1 rearrangement (12%, 2/33). Patients with initial EMPs had significantly worse overall survival compared to those without initial EMPs. Del(13q), and t(4;14), have been associated with inferior prognosis. Conclusions: In the current study, del(13q), and t(4;14) were associated with worse survival in MM patients with EMP.
Whole genome and RNA sequencing reveal the distinct genomic landscape of acral melanoma.
Authors: Yan Kong, Zhihong Chi, Lu Si, Xinan Sheng, Chuanliang Cui, Jie Dai, Meng Ma, Xiaowen Wu, Huan Tang, Jiayi Yu, Junya Yan, Huan Yu, Tianxiao Xu, Jun Guo
Journal: Journal of Clinical Oncology (2017)

9589 Background: Acral melanoma is a common subtype of melanoma in Asians with extremely poor prognosis, and therapy strategy has not been clearly established for acral melanoma. The aim of this study is to perform genomic and RNA profiling of acral melanoma to obtain the comprehensive genomic view of this subtype of melanoma. Methods: Genomic DNA was extracted with Qiagen DNeasy Blood or Tissue Kit . DNA libraries were prepared using a CancerPROTM-P88 BOX library Prep kit and sequencing was performed using the Illumina HiSeq X10. RNA was isolated with Qiagen RNeasy mini-spin column. cDNA was synthesized from total RNA using the SuperScript III first-strand synthesis system . RNA libraries were prepared using the NEBNext Ultra II Directional RNA Library Prep Kit and sequencing was performed using the Illumina HiSeq X10. Results: To obtain a comprehensive genomic and functional genomic view of acral melanoma, we sequenced the genomes of 14 acral melanoma and transcriptomes of 11 of these melanoma samples. We found a new mutation in the V28 codon of BRAF in three patients. Furthermore, we identified recurrent non-synonymous single nucleotide variants in previously described oncogene NRAS, as well as in genes encoding keratin associated proteins (KRTAP4-7, KRTAP4-5) and mucin (MUC2, MUC21). Notably, a recurrent noncoding hotspot mutation was discovered in 4 of 11 cases. By analyzing the RNA sequencing data, we found significant divergence on transcriptome between patients with or without ulcer. In total, we identified 201 genes were significantly up-regulated and 386 genes significantly down-regulated in acral melanoma patients with ulcer. Differentially expressed genes were enriched in pathways associated with cancers, melanogenesis, cell death signaling, skin diseases, etc. Conclusions: Our study reveals potentially different driver mutations and distinct transcriptome in acral melanoma patients compared with cutaneous melanoma patients and sheds lights to the further personalized medicine for acral melanoma patients.
Next generation sequencing (NGS) based mutation profiling and heterogeneity of resistance mechanisms to AZD9291.
Authors: Jun Zhao, Rongrong Chen, Gen Lin, Xinghao Ai, Wang Sheng, Youxin Ji, Zaiwen Fan, Liyun Miao, Lingjun Zhu, Qiong Zhao, Renhua Guo, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

9068 Background: AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is active against patients with EGFR T790M-mutant non–small cell lung cancer (NSCLC) who failed prior treatment with EGFR TKIs. However, acquired resistance to AZD9291 is inevitable. In this study, we retrospectively analyzed mechanisms of acquired resistance to AZD9291 in advanced NSCLC. Methods: A total of 293 advanced lung adenocarcinoma patients with signs of AZD9291 resistance were enrolled in the study from January to October 2017. Tissue biopsy was the first choice for mutation profiling, and ctDNA testing was used as an alternative. All samples were analyzed using next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across at least 59 genes (59-1021). Results: At resistance, 3 molecular subtypes emerged: 66 cases (22.5%) lost original EGFR activating mutation and T790M mutation; 130 cases (44.4%) lost the T790M mutation despite detecting of the underlying EGFR activating mutation; 97 cases (33.1%) maintained both EGFR activating mutation and T790M mutation. Known resistance mechanisms detected in 11/66 (16.7%), 56/130 (43.1%), 62/97 (63.9%) cases respectively for all the 3 subtypes. The most frequently known mechanism was EGFR C797S which was identified in 60 cases, while EGFR L792H/V, G796S, L718Q/V, G719A, and E709K were in 27 cases. Activating mutations of PI3K-AKT-mTOR signaling, amplification of the MET, activating mutation / amplification of ERBB2, ALK/ROS1/RET fusion, activating mutation of BRAF, or KRAS were identified in 37, 16, 14, 9, 8, 5 patients respectively. Moreover, 24 cases had Rb1 loss of function mutation. Co-occurrence of resistance mechanisms were observed in 31 patients. Conclusions: There was a high frequency of inter and intra-patient heterogeneity of resistance mechanisms after AZD9291 therapy. Comprehensive NGS analysis may facilitate the broad exploration of potential resistance mechanisms.
A man with fever and haemoglobinuria after blood transfusion
Authors: Ammaarah Said, Efthymia Vlachaki, Jibril Abukar, Dimitris A Tsitsikas
Journal: BMJ (2018)

A 32 year old Afro-Caribbean man with HbSS homozygous sickle disease was admitted with vaso-occlusive crisis affecting his chest wall. Over 24 hours, he developed acute chest syndrome with worsening chest pain, hypoxia, tachypnoea, and new bibasal infiltrates on radiography. He was managed with oxygen, intravenous antibiotics, and automated red cell exchange transfusion. He was transfused with 12 units of red blood cells.

The man’s respiratory symptoms improved, but four days after the transfusion he developed intermittent fevers, jaundice, and haemoglobinuria (table 1).

View this table:

Table 1 
Progression of haemoglobin



On day 5 he underwent a simple transfusion with a further 2 units of red blood cells, but there was no improvement in his symptoms. His haemodynamic parameters remained stable, however, and there were no new radiological changes.

Peripheral blood smears before the exchange transfusion showed sickle cells, polychromatophilic red blood cells, and target cells, which is consistent with sickle cell anaemia (fig 1).



Fig 1 

Peripheral blood smears were repeated on day 6 after the exchange transfusion and showed spherocytes and erythroblasts (fig 2).



Fig 2 



### 1. What is the diagnosis?

The progressive drop in haemoglobin to below pre-transfusion levels suggests a diagnosis of hyperhaemolysis—a well recognised but rare transfusion reaction predominantly encountered in patients with homozygous sickle disease. Haemolysis of donor and recipient red blood cells is a key characteristic of the condition; the spherocytes …
Prognostic significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio in gastric cancer patients who underwent palliative chemotherapy.
Authors: Seok Yun Kang, Yong Won Choi, Mi Sun Ahn, Hyun Woo Lee, Jin-Hyuk Choi
Journal: Journal of Clinical Oncology (2018)

e16008 Background: Several systemic inflammatory markers in blood, such as neutrophil lymphocyte ratio (NLR) or platelet lymphocyte ratio (PLR), have been suggested as predictive and prognostic factors in various cancers. We investigated the prognostic significance of NLR and PLR in patients (pts) with recurrent or metastatic gastric cancer who underwent chemotherapy. Methods: A retrospective review was conducted on 687 pts who received palliative chemotherapy for recurrent (n = 304) or primary metastatic (n = 383) gastric cancer. Overall survival (OS) of pts with high NLR or PLR ( > median value) before first-line chemotherapy was compared to that of pts with low NLR or PLR (≤median value). Results: High NLR was observed in pts with ECOG PS 2 or 3 (p = 0.02), primary metastatic disease (p < 0.0001), peritoneal metastasis (p = 0.039), and no palliative surgery (p < 0.0001). High PLR was associated with primary metastatic disease (p < 0.0001), peritoneal metastasis (p < 0.0001), and absence of liver metastasis (p = 0.004). The median OS of pts with low NLR or PLR was significantly longer than that of pts with high NLR or PLR (13 vs. 8 months, p < 0.0001; 12 vs. 9 months, p < 0.0001). In multivariate analysis, high NLR and PNR were independently associated with poor OS (hazard ratio = 1.36, p = 0.001; hazard ratio = 1.21, p = 0.031) along with ECOG PS 2 or 3 (p = 0.005), signet ring cell histology (p < 0.0001), and peritoneal metastasis (p = 0.038), whereas ≥second-line chemotherapy (p < 0.0001), and palliative surgical resection (p < 0.0001) were independent prognostic factors of favorable OS. Conclusions: The present study suggests that both high NLR and PLR before palliative chemotherapy are independent prognostic factors for poor OS in in recurrent or metastatic gastric cancer pts who received palliative chemotherapy.
Post- progression treatment patterns in advanced lung cancer patients treated with nivolumab.
Authors: Aparna Madhukeshwar Hegde, Cynthia R. Cherry, Chipman Robert Geoffrey Stroud, Nitika Sharma, Sulochana Devi Cherukuri, Mark Bowling, Andrew Wenhua Ju, Hyder Husain Arastu, Paul R. Walker
Journal: Journal of Clinical Oncology (2018)

e21070 Background: In lung cancer patients receiving immunotherapy, radiographic disease progression (PD) has poor correlation with overall survival (OS) due to unconventional response patterns. Therefore, radiographic assessment may not be reliable for determining treatment strategies. Evidence from the OAK trial indicated survival benefit with continued atezolizumab beyond PD. We evaluated OS with different post- PD treatment strategies in lung cancer patients receiving the anti- PD-1 agent, nivolumab at our institution. Methods: Advanced lung cancer patients who initiated nivolumab between April 2015 and May 2017 were identified by retrospective chart review. Patients who had radiologist reported PD that was either confirmed on subsequent imaging or was followed by documented death due to PD were included in the analysis. Type of treatment received at PD was ascertained. Follow- up cut- off was December 31, 3017. Kaplan- Meier analysis was used to estimate post- PD OS. Results: Out of 110 patients who received nivolumab, 77 (70%) had PD by a median of 4.2 months after nivolumab initiation. Post- PD, 22 (28.6%) got chemotherapy, 8 (10.4%) got nivolumab monotherapy, 9 (11.7%) got palliative radiation (RT) and 38 (49.4%) got best supportive care (BSC). Seven out of 22 patients who got chemotherapy and 3 out of 9 patients who got RT, continued nivolumab. There was no significant difference in the incidence of grade 3-4 adverse events between different groups [χ2 (3) = 0.07, p = 1.0]. Median follow up was 10.6 months. Survival estimates are as follows- Conclusions: This is the first report of treatment patterns post- PD in lung cancer patients receiving nivolumab in a non- clinical trial setting. Post- PD, there is a significant survival benefit when nivolumab is continued in combination with chemotherapy or RT. Group 1-year OS (%) mOS (95% CI) (months) Log rank p = 0.03 Chemo or RT w nivolumab 46.7 7.0 (3.6- 7.0) Nivolumab monotherapy 22.5 3.9 (1.6- 12.4) Chemo or RT w/o nivolumab 19.0 3.6 (2.3- 4.5) BSC 10.9 1.5 (0.7- 2.7)
Integrative oncology consultations at a comprehensive cancer center: Analysis of patient reported outcomes.
Authors: Gabriel Lopez, Jennifer Leigh McQuade, Richard T. Lee, Bryan Fellman, Yisheng Li, Amy Spelman, Eduardo Bruera, Lorenzo Cohen
Journal: Journal of Clinical Oncology (2016)

e21690 Background: Patients (pts) receiving cancer care are increasingly interested in complementary health approaches. We report on demographics and patient reported outcomes in an integrative oncology (IO) clinic. Methods: Pts presenting for IO consultation or follow-up completed: Measure Yourself Concerns and Wellbeing (MYCaW), Edmonton Symptom Assessment Scale (ESAS), Short Form 12 (SF-12), and an overall satisfaction questionnaire. Consultations were provided by medical oncologists. Results: For 2,474 consultations from 9/2009 to 12/2013, 26.0% (n = 643) had ≥ 1 follow-up visit (mean 3.2; SD1.8). Most were female (69%) and white (75%); most frequent cancer types were breast (29%) and gastrointestinal (13%); 29% had advanced disease. Most common concerns (MYCaW) were Integrative Approach (34.2%), Herbs/Supplements (33.8%), and Nutrition (21.1%). At baseline, ESAS scores were highest for Sleep (4.2; SD 2.8), Fatigue (4.0; SD 2.8), Well-Being (3.8 SD 2.6) and Anxiety (3.1; SD 2.9). Mean standardized T-scores on the SF-12 (n = 1253) were physical health 35.3 and mental health 46.8 (50 = healthy populations). Older age, living locally, and higher levels of anxiety and psychological distress were predictors of follow up. For ESAS baseline scores ≥ 4 and follow up within 30 days of consultation, we observed overall improvement in symptoms (38-60% of pts with ESAS decrease ≥ 1). Integrative Approach, Herbs/Supplements, and Pain were most likely reasons for follow up. Integrative services accessed following the initial consultation included Acupuncture (n = 215 pts, mean 4.7 visits); Massage (n = 156, mean 4); Physical Therapy ( n = 75, mean 1.3); Meditation (n = 72, mean 1.3); Dietitian (n = 70, mean 1.1); and Music Therapy (n = 36, mean 1.8). Pts were satisfied to very satisfied with how well concern 1 (8, SD 2.2) and concern 2 (9.1, SD 1.8) were addressed. Overall satisfaction was high at both initial encounter (9.4; SD 1.3) and first follow up (9.5; SD 1.2). Conclusions: An IO consultation satisfactorily addressed patient concerns about an integrative approach and herbs/supplements, with significant improvements in symptom distress. Pts seen had a moderate symptom burden with lower than average physical health.
Broad, hybrid capture-based next generation sequencing guided personalized therapy in metastatic colorectal cancer.
Authors: Helei Hou, Chuantao Zhang, Dong Liu, Na Zhou, Xiaomei Xu, Lihua Deng, Jinping Zhang, Hongying Lv, Jingjuan Zhu, Xiaoping Zhang, Xiaonan Yang, Shida Zhu, Zhuokun Li, Hongmei Zhu, Xiaochun Zhang
Journal: Journal of Clinical Oncology (2016)

e15038 Background: Patients with metastatic colorectal cancer are now recommended to profile for RAS and BRAF mutations before receiving cetuximab or panitumumab. However, lots of patients with both RAS and BRAF wild-type tumors determined by non-NGS testing might still not respond due to the presence of additional gene mutation such as PIK3CA or PTEN. Therefore, it’s necessary to screen mutations in genes other than RAS and BRAF on the efficacy of anti-EGFR therapy. Besides, new available agents could potentially be used based on the other targetable alterations discovered. In this study, a broad, hybrid capture-based next generation sequencing (NGS) assay was used to identify RAS, BRAF and additionally targetable genetic alterations from colorectal cancer tissue. Methods: 72 cases of colorectal cancers were enrolled and all the patients signed the informed consent before assay. 7708 exons of 508 tumor related genes and 78 introns of 19 frequently rearranged genes were assessed for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 450×. Results: 50.4% (37/72) of the tumors harbored a KRAS mutation, 4.2% (3/72) harbored a NRAS mutation and 4.2% (3/72) harbored a BRAF mutation. More specifically, 82.5% (33/40) of RAS mutation was located in exon 2. Except for RAS and RAF, 4.2% (3/72) anti-EGFR therapy response genetic mutations were found in PTEN (n = 3). It’s also worth noting that actionable alterations were found in HER2 (n = 5, including 4 amplification and 1 activating mutation), FBXW7 (n = 3) and others (n = 5). Conclusions: Our results implied that 63.9% (46/72) metastatic colorectal cancers with genetic mutations including KRAS, NRAS, BRAF and PTEN might not benefit from anti-EGFR therapy. 26.4% (19/72) of samples harbored at least one actionable genetic alteration rather than RAS identified by NGS testing. Significantly, HER2 defined a unique subpopulation of 6.9% (5/72) of metastatic colorectal cancer and might be a promising driven-gene. These findings suggest that high throughput NGS testing in colorectal cancer tissue was a comprehensive and efficient genomic profiling assay to guide personalized therapy.
Abstract 17101: Vasoprotective Properties of HDL Improve Early Ater Roux-en-y Gastric Bypass but Not After Diet Treatment: The Superior Cardiometabolic Benefits of RYGB
Authors: Elena Osto, Eve McLoughlin, Petia Doytcheva, Marietta Charakida, Nicholas Finer, Luc Van Gaal, John Deanfield, Thomas Luescher
Journal: Circulation (2015)

Introduction: Roux-en-Y gastric bypass (RYGB) reduces cardiometabolic risk through different potential mechanisms. High density lipoprotein cholesterol (HDL-C) changes might explain part of this benefit. Hypothesis: We assessed the effect of RYGB on HDL vasoprotective properties in comparison with a hypocaloric diet-induced weight loss. Methods: HDL was isolated from serum of obese patients (BMI &gt; 35 kg/m2) before and 6 months after RYGB (n=32) or diet (n=32). In endothelial cells stimulated with HDL, we quantified nitric oxide (NO) production by DAF-2 fluorescence and paraoxonase-1 antioxidant activity (PON-1). Total cholesterol, low density lipoprotein (LDL-C), HDL-C, and triglycerides (TG) as well as glucose plasma fasting levels were measured. Results: At baseline there was no significant difference in mean body weight (BW) and BMI between RYGB and diet patients (119.9 Kg; 42kg/m2 vs. 110.9 kg; 37.4 kg/m2, respectively, p=0.06). At 6 months, BW and BMI were not different (RYGB: 94kg; 33 kg/m2; diet: 99kg; 33.4 kg/m2, p=ns). In both groups, mean total cholesterol and TG were reduced; LDL-C decreased only after RYGB. Total HDL-C increased 6 months after both interventions (RYGB: 1.2±0.5 baseline vs 1.3±0.4 after 6months; diet 1.1±0.25 baseline vs 1.3±0.3 after 6months, p&lt;0.05). However, only RYGB improved the vasoprotective HDL-stimulated NO production (RYGB: 234.2±178.0 vs diet 98.8±76.4 arbitrary units, p&lt;0.0001) and HDL-associated PON-1 activity (RYGB: 40% vs diet: 9% increase compared to baseline; p&lt;0.0001). Fasting glucose levels improved in both groups and were not different at 6 months between the two interventions. Conclusions: Our study shows that although HDL concentration increased after RYGB and diet-induced BW loss, only RYGB restored endothelial protective HDL properties even though patients were still obese. This suggests that BW loss is not sufficient or critical to improve the protective properties of HDL, unless accompanied by yet unknown surgery-specific effects.
EXTH-41. EFFECTS OF TUMOR TREATING FIELDS (TTFIELDS) ON BLOOD BRAIN BARRIER (BBB) PERMEABILITY
Authors: Almuth Kessler, Clara Schaeffer, Malgorzata Burek, Ursula Ruschig, Catherine Tempel Brami, Tali Voloshin, Moshe Giladi, Rolf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann
Journal: Neuro-Oncology (2018)