tbuckley/cabot-search huggingface dataset:
Association of <i>HER2</i> alterations and <i>ESR1</i> mutations in cell-free DNA (cfDNA) with circulating tumor cells (CTCs), multiple metastasis, and prognosis in stage III/IV breast cancer (BCa).
Authors: Qiang Zhang, Lorenzo Gerratana, Ami N. Shah, Andrew A. Davis, Lisa E. Flaum, Youbin Zhang, Wenan Qiang, Amir Behdad, William John Gradishar, Leonidas C. Platanias, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2019)

1036 Background: The monitoring of CTCs and cfDNA in metastatic BCa showed ability to predict treatment resistance and survival. Here we report a highly significant correlation between HER2 alterations and ESR1 mutations of cfDNA with CTCs and prognosis of BCa, which may help to predict disease recurrence and treatment benefit. Methods: A total of 85 blood samples (7.5ml/each) were collected from 85 patients with stage III/IV BCa who received treatments at Northwestern RHLCCC. CTC enumeration was performed in FDA approved CELLTRACKS ANALYZERII System (Menarini). Plasma cfDNA was analyzed using Guardant360 NGS-based assay including a 73-gene panel for genomic alterations or mutations. We previously reported cut-off of 5.7% (2018 ASCO) was used to dichotomize the prognostic value of cfDNA percentage. Kruskal-Wallis test was used for statistics. Results: Of the 85 whole samples analyzed, there were 72 samples and 67 samples without ESR1 mutations (ESR1 - ) and HER2 alterations ( HER2 - ) respectively, and there are 13 samples and 18 samples that had ESR1 mutations ( ESR1 + ) and HER2 alterations ( HER2 + , 10 amplified, 7 mutated, 1 for both) respectively. CTC positive (≥5) were detected in 13/57 ESR1 - HER2 - samples (Group 1) and 5/15 ESR1 - HER2 + samples (Group 2), 7 /10 ESR1 + HER2 - samples (Group 3), 3/3 ESR1 + HER2 + samples (Group 4). The median CTCs number/sample in Group 3 (15 CTCs) and Group 4 (12 CTCs) were significantly higher than Group 1 (0 CTC) and Group 2 (2 CTCs) (P = 0.0020). There were a significant higher average metastasis sites in Group 3 (3 sites) and Group 4 (3 sites) in compared to Group 1 (2 sites) and Group 2 (1 site) (P = 0.0035). Furthermore, patients in Group 4 ( ESR1 + HER2 + ) has the worst prognosis in compared to other groups (P = 0.0151) on overall survival. Conclusions: Both ESR1 mutations and HER2 alterations in cfDNA contribute to CTCs detection and disease metastasis sites independently, when ESR1 mutations plays a major role. The synergy of ESR1 mutation and HER2 alteration expands the predictive role of liquid biopsy tests monitoring the metastatic prognosis and endocrine resistance for clinical decision-making.
AB0285 PREDICTORS OF UNACCEPTABLE PAIN, AND UNACCEPTABLE PAIN WITH LOW INFLAMMATION, IN EARLY RHEUMATOID ARTHRITIS
Authors: Anna Eberhard, Tor Olofsson, Lennart T.H. Jacobsson, Carl Turesson
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Pain is a major symptom in many patients with rheumatoid arthritis (RA). In early RA, pain is usually due to active synovitis, but over the disease course some patients experience pain without elevated laboratory markers of inflammation. <h3>Objectives</h3> To investigate predictors of unacceptable pain, and unacceptable pain with low inflammation, in patients with early RA. <h3>Methods</h3> Consecutive patients with early RA (symptom duration &lt;12 months), recruited in 1995-2005 from a defined area, were followed through 5 years. Patients were managed according to usual care, with no pre-specified treatment protocol. Pain was assessed using a visual analogue scale (VAS; 0-100 mm). Unacceptable pain was defined as VAS pain&gt;40 based on the patient acceptable symptom state (PASS) (1), and low inflammation as CRP&lt;10 mg/l (2). Baseline predictors of unacceptable pain, and of unacceptable pain with low inflammation, were evaluated using logistic regression analysis. <h3>Results</h3> A total of 233 patients with early RA (73% female, 57% anti-CCP positive, mean age 60 years, median symptom duration 7 months) were included. Of these, 179 attended the 5-year follow-up. At 5 years, 34% had unacceptable pain, and 23% had unacceptable pain with low inflammation. High VAS scores for pain and patient's global assessment (PGA) at baseline were associated with unacceptable pain at 5 years (Table). There was a negative association between baseline swollen joint count (SJC28) and unacceptable pain at the 5 year follow-up. In multivariate logistic regression analysis including VAS PGA and SJC28, both had an impact on unacceptable pain after 5 years (adjusted odds ratios per standard deviation (SD), with 95% CI 1.78 (1.26-2.52) and 0.61 (0.42-0.89), respectively). Anti-CCP positive patients were significantly less likely to experience unacceptable pain with low inflammation at 5 years (Table). <h3>Conclusion</h3> More than 1/3 of early RA patients experienced unacceptable pain after 5 years. Extensive synovitis in early RA was associated with a reduced risk of unacceptable pain at 5 years, likely due to positive effects of treatment on inflammation related pain. Non-inflammatory pain may be a greater long term problem in anti-CCP negative patients. <h3>References</h3> [1] Tubach, et al. Arthritis Care Res2012; 64: 1699-707 [2] Lourdudoss, et al. Arthritis Care Res2018; 70: 205-12. <h3>Disclosure of Interests</h3> Anna Eberhard: None declared, Tor Olofsson: None declared, Lennart T.H. Jacobsson Consultant for: LJ has received lecture and consulting fees from Pfizer, Abbvie, Novartis, Eli-Lily and Janssen, Carl Turesson: None declared
Swallow screen and test in cancer patients.
Authors: Shiva Shrotriya, Calvin Abro, Fawzi Abu Rous, Rosemary Trimmer, Mukta Sharma, Supratik Rayamajhi, Bassam N. Estfan, Declan Walsh
Journal: Journal of Clinical Oncology (2019)

e18288 Background: Swallowing is a complex process with four phases. It initiates digestion and is essential for proper nutrition. Difficulty swallowing independently correlated with cancer survival. We retrospectively evaluated the prevalence and incidence of difficulty swallowing in an acute care palliative medicine unit. BMI and survival were also examined. Methods: Electronic Medical Records (EMR) 2010-2012 was reviewed. Assessment comprised of 3 steps: nurse survey on patient condition (coma, intubation, PEG/feeing tube, respiratory distress), screening questionnaire and clinical swallowing test. Change in BMI from the day of admission to discharge calculated. Survival calculated from EMR and Social Security Death Index. Results: N = 261 with cancer identified; 47% known metastases. The mean age (± SD) was 68 ± 13 years. 55% females. 71% Caucasians and 25% African Americans. It was common in lung, gastrointestinal (GI) and genitourinary (GU) cancers. Clinical swallowing test was indicated in 94%. Prevalence of difficulty swallowing = 6%. Incidence of difficulty swallowing = 21%. Change in Body Mass Index (BMI) from 26 ± 7 (Mean ± SD) to 26 ± 6 on admission to discharge respectively. Median (25 th , 75 th percentile) survival: 25(13, 62) days. Conclusions: Difficulty swallowing was common in lung, GI and GU cancers. The incidence of difficulty swallowing in acute care palliative medicine unit was 21% and prevalence 6%. 75% with difficulty swallowing identified by nurse’s initial survey, 19% through screening questionnaires and 6% clinical swallowing test. Pneumonia/respiratory and GI problems were common. Swallowing evaluation critical for comprehensive cancer care.
Evaluation of responsiveness and estimation of smallest detectable change and minimal important change scores for the Childhood Atopic Dermatitis Impact Scale
Authors: M. Gabes, S.L. Chamlin, J.‐S. Lai, D. Cella, A.J. Mancini, C.J. Apfelbacher
Journal: British Journal of Dermatology (2019)

The Childhood Atopic Dermatitis Impact Scale (CADIS) is an instrument to measure quality of life in young children affected by atopic dermatitis, and their parents. To evaluate the responsiveness (sensitivity to change), smallest detectable change (SDC) and minimal important change (MIC) of the CADIS. Parents and primary caregivers of 300 young children completed the CADIS and a global rating of their child's skin condition at baseline and a 4‐week follow‐up. Kruskal–Wallis tests, Wilcoxon tests and effect sizes were used to assess responsiveness. The SDC can be seen as a change beyond measurement error. Anchor‐based and distribution‐based methods, and an integration of both methods were used to estimate the MIC. In total, 270 families provided data at baseline and 228 at follow‐up. The CADIS total change score and most of the domain scores had moderate‐to‐strong correlations with the skin change score. Patients were grouped according to the skin change score, which served as an anchor. Children whose parents noted an improvement of the skin showed lower CADIS scores at follow‐up (P < 0·001). For the SDC we obtained score changes of 1·34 points on the total score and < 1·0 points on each domain score. All detected MIC values passed the SDC cut‐off. The CADIS is sensitive to change towards improvement of quality of life. A change > 12% on the total score or each domain score very likely represents a clinically important change. What's already known about this topic? Atopic dermatitis reduces the quality of life of affected children and their parents. The Childhood Atopic Dermatitis Impact Scale (CADIS) has been evaluated and translated into two further languages. What does this study add? Further validation of the responsiveness of the CADIS, and whether it is sensitive to change in patients whose condition had changed. Calculation of the smallest detectable change. What are the clinical implications of this work? Estimation of the minimal important change in CADIS provides benchmarks for clinical practice.
CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in <i>KRAS</i> wild-type metastatic colorectal cancer patients: promising findings from a prospective, open-label, randomized, phase III trial
Authors: Yuankai Shi, Jin Li, Jianming Xu, Yan Sun, Liwei Wang, Ying Cheng, Wei Liu, Guoping Sun, Yigui Chen, Li Bai, Yiping Zhang, Xiaohui He, Yi Luo, Zhehai Wang, Yunpeng Liu, Qiang Yao, Yuhong Li, Shukui Qin, Xiaohua Hu, Feng Bi, Rongsheng Zheng, Xuenong Ouyang
Journal: Cancer Communications (2019)

Abstract Background The 5 ‐ fluorouracil/leucovorin plus oxaliplatin (FOLFOX) regimen is the standard first‐line treatment for metastatic colorectal cancer (mCRC), however, the optimal second‐line regimen for KRAS wild‐type mCRC patients is still investigational. In this study, we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan‐only as a second‐line regimen for treating KRAS wild‐type mCRC patients. Methods Patients with KRAS wild‐type mCRC who had previously failed to respond to FOLFOX treatment were randomly assigned in a 2:1 ratio, to receive CMAB009 plus irinotecan or irinotecan‐only. Patients receiving irinotecan‐only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential‐CMAB009 arm. The primary endpoints were overall response rate (ORR) and median progression‐free survival (PFS). The secondary endpoints were median overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). Results The CMAB009 plus irinotecan arm demonstrated significantly improved ORR (33.2% vs. 12.8%; P &lt; 0.001) and longer median PFS (169 days vs. 95 days; P &lt; 0.001) as compared to the irinotecan‐only arm. Patients receiving CMAB009 plus irinotecan also demonstrated improved DCR (80.1% vs. 65.2%, P &lt; 0.001), CBR (30.0% vs. 14.6%, P &lt; 0.001), and DOR (210 days vs. 109 days; P &lt; 0.001) as compared to irinotecan‐only. However, patients treated with CMAB009 had an increased risk of skin rash (66.9% vs. 5.5%, P &lt; 0.001) and paronychia (9.8% vs. 0.0%, P &lt; 0.001). Anti‐drug antibodies (ADA) were detected in 3.6% of patients, and only 0.9% of patients who received CMAB009 experienced hypersensitivity reactions. In patients receiving sequential‐CMAB009 therapy after failure with irinotecan, their median PFS was 84 days (95% CI 65 to 113 days). The median OS was 425 days for patients receiving CMAB009 plus irinotecan and 401 days for those with sequential‐CMAB009 ( P = 0.940). Conclusions Treatment with CMAB009 plus irinotecan was found to be a superior second‐line regimen in comparison to irinotecan‐only in KRAS wild‐type mCRC patients. Further, switching to CMAB009 can be considered as an efficient third‐line of treatment after treatment failure with second‐line irinotecan‐only. Trial registration ClinicalTrials.gov : NCT01550055, retrospectively registered on March 9, 2012.
Case 7-1964
Authors: Kenneth T. Bird, Austin L. Vickery
Journal: New England Journal of Medicine (1964)

Presentation of Case* First admission. A twenty-two-year-old woman entered the hospital because of cold hands and feet.The patient had been well until eight months previously, when she began to experience episodic numbness and blanching of several fingers on exposure to cold and when emotionally upset. During the next few months the remaining fingers and all the toes became involved. For many months she had had dyspnea on climbing more than one flight of stairs and a chronic cough that was occasionally productive of a few drops of blood.Physical examination revealed an obese young woman with cold, wet . . .
Clinical-relevant model of intraductal papillary mucinous neoplasm induced by <i>ARID1A</i> loss.
Authors: Tao Wei, Qi Chen, Tingbo Liang, Xueli Bai
Journal: Journal of Clinical Oncology (2019)

e14696 Background: Intraductal papillary mucinous neoplasm (IPMN) constitutes a precursor lesion for malignancy of pancreas. Genes encoding subunits of SWI/SNF chromatin-remodeling complexes like ARID1A are collectively mutated in a significant proportion of patients with pancreatic neoplasm. In the present study, we characterize the role of ARID1A in pancreatic tumorigenesis using genetic engineering mouse models. Methods: Various mouse strains were interbred to obtain pancreas-specific Arid1a flox , Kras LSL-G12D/+ ; Arid1a flox , Kras LSL-G12D/+ ; Tgfbr2 flox ; Arid1a flox , and various littermate control animals. Tissue microarrays were used to determine the expression of ARID1A in human pancreatic ductal adenocarcinoma and IPMN. Results: Arid1a loss in pancreas of mice incurred pancreatic duct dilation and development of cystic lesions. Concomitant Kras mutation and Arid1a inactivation accelerated formation of cystic neoplasm resembling human IPMN. These lesions were reminiscent of specific subtype of IPMN given their morphology and expression pattern of mucin proteins. Histological examination further revealed the step-wise progression of these neoplasm from low-grade to high-grade dysplasia and even invasive carcinoma. TGFBR2 deletion promoted the malignant transformation of IPMN to invasive carcinoma in the background of Kras and Arid1a alterations. Analysis of human tissues consistently showed negative or low expression of ARID1A in over half of IPMN patients. Moreover, patients with pancreatic adenocarcinoma also exhibited downregulated ARID1A expression, and reduced expression correlated with worse prognosis. Conclusions: We have established a preclinical mouse model of pancreatic cystic tumor closely resembling human IPMN. This is helpful for the further understanding of biology of IPMN and highlight therapeutic niches for patient tailored treatment in those with altered SWI/SNF function.
Case 14-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Howard J. Weinstein, Nancy L. Harris
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 28-month-old boy was seen in consultation at this hospital because of a question of juvenile rheumatoid arthritis.The boy was born of an uncomplicated second pregnancy of 36 weeks' duration of a mother aged 22 years, by a second cesarean section under spinal anesthesia. His birth weight was 2.9 kg. The neonatal course was complicated by jaundice, for which phototherapy was administered, and he was discharged home with his mother on the fifth day of life. He was reported to be "late" in walking and talking. He was well until the age of 25 months, when . . .
Specificity of markers CD44 and S100 for skin melanoma and nevi tissues.
Authors: Irina A. Goroshinskaya, Oleg I. Kit, Elena M. Frantsiyants, Valeria A. Bandovkina, Viktoria V. Pozdnyakova, Alla I. Shikhlyarova, Amira A. Akhmedova, Olga V. Khokhlova, Irina V. Neskubina, Natalia D. Cheryarina
Journal: Journal of Clinical Oncology (2019)

e21036 Background: The high metastatic potential of melanoma and the need for long-term patient monitoring causes the search for tumor markers of this malignant neoplasm. Our aim was a comparative analysis of levels of tumor-specific proteins CD44 and S100 and protein composition in melanocytic lesions of the skin. Methods: We studied 86 samples of cutaneous melanoma and nevus tissues, their perifocal tissues and resection line tissues obtained during tumor excision from 23 patients with cutaneous melanoma pT 1-4 N 0-1 M 0 and 14 patients with nevi. Intact skin samples obtained from non-cancer patients during reconstructive plastic surgery were used as the comparison group. All patients gave their written informed consent. Levels of CD44 (BenderMedSystems, USA) and S100 (Fujirebio, Sweden) were determined by ELISA in 10% homogenates of all tissues; total protein levels were determined by standard spectrometry and fractional composition of proteins were studied by turbidimetric method. Statistical processing of results was performed using the Statistika 6.0 program with Student’s t-test for two independent groups. Results: Melanoma was characterized by a sharp increase in S100B levels, 28 and 7 times exceeding the levels in intact tissues and nevi. The level of CD44 in melanoma tissue was increased only by 2 times, in nevus tissue - by 48%. The ratio of albumin and gamma globulins in the tissue of melanoma and nevi was 79% and 29% lower than in healthy skin. A more than twofold increase in the gamma globulin fraction in the melanoma tumor tissue against a decrease in albumin and the absence of changes in other globulins, as well as a moderate but statistically significant increase in the gamma globulin fraction in nevi tissue, indicates that S100B and CD44 proteins belong to the gamma globulin fraction. Conclusions: A highly specific increase of S100 levels and a less specific increase of CD44 levels in supernatant liquid of melanoma tissue homogenates, together with the predominance of the gamma globulin fraction, allow considering such factors as a prognostically unfavorable sign of tumor progression, which can be important when choosing a personalized treatment strategy.
Clinical models to predict response and survival in metastatic melanoma (MM) patients (pts) treated with anti-PD-1 alone (PD1) or combined with ipilimumab (IPI+PD1).
Authors: Ines Esteves Domingues Pires Da Silva, Tasnia Ahmed, Serigne Lo, Rajat Rai, Jessica Louise Smith, John J. Park, Caroline Nabhan, Richard A. Scolyer, Matteo S. Carlino, Jennifer Leigh McQuade, Douglas Buckner Johnson, Georgina V. Long, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2019)

9542 Background: Currently there are no robust biomarkers to predict immunotherapy response in MM. Specific clinical and molecular variables have been proposed, but in most cases, these factors have been studied individually. We sought to build a predictive model for response rate (RR), progression-free survival (PFS) and overall survival (OS), by including clinical data available at the point of treatment selection for MM pts treated with PD1 or IPI+PD1. Methods: 786 MM pts were included in 4 cohorts; 447 pts treated with PD1 (discovery, n = 343; validation, n = 104) and 339 pts treated with IPI+PD1 (discovery, n = 229; validation, n = 110). Demographics, disease characteristics and baseline blood parameters were examined. Predictive models were selected using multivariate Cox proportional hazard model, logistic regression and LASSO. ROC curve analyses were performed for each model and validation was measured by discrimination índex (c-statistic). Results: Predictive models for RR and PFS in PD1 pts (AUC = 0.69 and AUC = 0.71, respectively) included mutational status (HR for PFS: BRAF 1; NRAS 0.68; WT 0.57; P = 0.002), primary melanoma site (HR for PFS: occult 1; head and neck 0.67, others 1.04; P = 0.052), elevated LDH (HR for PFS: 1.77, P &lt; 0.0001) and monocyte count &gt; median (HR for PFS: 1.56, P = 0.003). Predictive models for RR and PFS in IPI+PD1 treated pts (AUC = 0.71 and AUC = 0.73, respectively) included AJCC stage M1C/M1D (HR for PFS: 2.12, P = 0.009), elevated LDH (HR for PFS: 2.65, P &lt; 0.0001), liver mets (HR for PFS: 1.63, P = 0.038) and basophil count &gt; median (HR for PFS: 0.50, P = 0.003). ECOG ≥ 1, elevated LDH and brain mets associated with worse OS and were included in predictive models for OS in PD1 (AUC = 0.74) and IPI+PD1 (AUC = 0.85). These models showed consistency with internal and external validation (c-statistic: &lt; 10% difference between the original model and validations for all outcomes). Conclusions: A combination of routinely collected clinical factors are highly predictive of outcome in MM pts treated with PD1 and IPI+PD1. A prognostic index will be presented for each treatment. Such tools may be practical, cheap and valuable for clinical decision making.
Inpatient outcome of solid tumor associated tumor lysis syndrome.
Authors: Zimu Gong, Faisal Ali, Yanting Wang, Sabah Syed, Jessica Lee Garcia
Journal: Journal of Clinical Oncology (2019)

e18185 Background: Tumor lysis syndrome (TLS) is a constellation of metabolic disturbances that can occur in virtually any malignancy, though it is more common in hematological malignancies given their high tumor burden and growth index. While TLS can occur in patients with solid tumors, the clinical behavior and outcome of solid tumor associated-TLS (STA-TLS) is not well characterized. Methods: We used the national inpatient sample to identify patients with STA-TLS (utilizing the ICD10 code E883; and ICD9 code 27788), from year 2010 through year 2016. Patients with both hematological malignancy and solid tumor, and patients without a cancer diagnosis were excluded. Results: A total of 11,733 patients were identified using the above criteria, of which 2117 (18.0%) had STA-TLS. The median age at admission was 63 years and 940 (44.4%) STA-TLS patients were females. The most common primary cancer sites were lung (26.8%), breast (4.2%), and colon (3.7%). Patients with STA-TLS were more likely to receive mechanical ventilation and less likely to receive red blood cell or platelet transfusion compared to those with hematological malignancies ( Table). STA-TLS was also associated with a significantly higher inpatient mortality rate and shorter length of stay than TLS in hematological malignancies ( P &lt; 0.001). No statistically significant difference was found in the requirement of dialysis, transfusion of plasma, and cardiac arrest rates. Conclusions: STA-TLS is rare with an inferior outcome than TLS in hematological malignancies evident by a higher mechanical ventilation and mortality rate. Future studies should identify factors that impact management and outcome of STA-TLS. [Table: see text]
Allow more overseas doctors to work in NHS, immigration committee advises
Authors: Abi Rimmer
Journal: BMJ (2019)

All doctors should be added to the UK’s shortage occupation list—the official list of jobs without enough UK resident workers to fill the vacancies—the Migration Advisory Committee has recommended.1

Doctors in certain grades and specialties are already included on the list, as are all nurses.2

If a post is on the shortage occupation list the employer can bypass the usual requirement to carry out a resident labour market test when employing a doctor from outside the European Economic Area and Switzerland.2 The applicant is also exempt from the requirement to earn a minimum of £35 000 (€39 700; $44 200) to be eligible for a visa.13

The committee, which …