tbuckley/cabot-search huggingface dataset:
Phase II trial of carfilzomib and irinotecan in relapsed small cell lung cancer (NCT01941316).
Authors: Susanne M. Arnold, Kari Chansky, Maria Quintos Baggstrom, Michael A. Thompson, Rachel E. Sanborn, John Villano, Saiama Naheed Waqar, John Turner Hamm, Mark Leggas, Maurice Willis, Joseph G Rosales, John Crowley
Journal: Journal of Clinical Oncology (2019)

8513 Background: Relapsed small cell lung cancer (SCLC) is incurable with limited therapeutic options. This phase II study evaluated efficacy and tolerability of carfilzomib + irinotecan in SCLC pts who progressed after prior platinum-based therapy, based on expected synergy of proteosome inhibitor carfilzomib and topisomerase 1 inhibitor irinotecan. Methods: SCLC pts who progressed after one platinum-containing regimen (no maintenance therapy allowed) for recurrent/metastatic disease were eligible. Pts were stratified by response to platinum-based therapy: sensitive (progressive disease (PD) &gt; 90 days after chemo) versus refractory (PD 30 to 90 days after chemo). Pts were treated with up to 6 cycles of carfilzomib (20/36 mg.m2 D1, 2, 8, 9, 15, 16 q28D) and irinotecan (125 mg/m2 D1, 8, 15 q28D), imaging was performed every 2 cycles. The primary efficacy endpoint was 6-month overall survival (OS). Results: 62 pts enrolled and were evaluable for efficacy and adverse events. The 6-month OS was 59% in the platinum sensitive stratum and 54% in the platinum refractory stratum. Overall response rate: sensitive stratum 21.6% (1.6% CR + 16.4% PR) and refractory stratum 12.5% (all PR). Disease control (SD+PR+CR) was 68% in platinum sensitive and 56% in refractory patients. Progression free survival and OS were 3.6 months (95% CI 2.6 - 4.6) and 6.9 months (95% CI 4.3 - 12.3) in the sensitive stratum, and 3.3 months (95% CI 1.8 – 3.9) and 6.8 months (95% CI 4.1-11) in the refractory stratum. Twenty-nine pts (47%) experienced at least one grade 3 AE and 8 subjects had grade 4 toxicities: decreased neutrophils, leukocytes, and lymphocytes, diarrhea, vomiting, sepsis, hypokalemia, hypocalcemia, and dehydration. There were three treatment related deaths: myocardial infarction (possible), lung infection (possible), sepsis (probable). Conclusions: In previously treated pts with relapsed SCLC, irinotecan and carfilzomib was effective in platinum-sensitive and, notably, platinum-refractory pts with similar toxicity profile. This combination is a viable option in relapsed SCLC, can be considered following progression on immunotherapy (IO) or in subjects who cannot receive IO, and should be further explored in a randomized phase III trial. Clinical trial information: NCT01941316.
AB0086 BCP AND CPPD CRYSTALS INFLUENCE THE CHONDROCYTE PHENOTYPE IN DIFFERENT WAYS
Authors: Uwe Kornak, Franziska Meyer, Miriam Bollmann, Jessica Bertrand
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Calcification of cartilage with BCP crystals is a common finding during osteoarthritis (OA) and is directly linked to the severity of the disease and hypertrophic differentiation of chondrocytes. In some OA cartilage samples calcium pyrophosphate dihydrate (CPPD) crystals can be found. The mechanism underlying the formation of the CPPD crystals and their effects on the chondrocytes are not completely understood. <h3>Objectives</h3> The aim of this study was to evaluate the effect of CPPD compared to BCP crystals on the chondrocyte phenotype in OA cartilage. <h3>Methods</h3> Cartilage samples of patients with chondrocalcinosis were used and compared with samples of severe OA patients without chondrocalcinosis and healthy cartilage samples served as control. Radiological presence of chondrocalcinosis was evaluated using standard X-ray pictures, as well as macroscopically inspection. The cartilage samples were stained using von Kossa/Safranin-orange staining. These stainings were used for OA severity scoring using the Chambers-Score. Chondrocyte differentiation markers were evaluated using Collagen 2 and X, as well as Sox9 and aggrecan as markers for chondrocyte hypertrophic differentiation in immunohistochemistry and qRT-PCR. TUNEL staining was performed to investigate cell death. In vivo results were validated using qRT-PCR for the expression of the respective genes after stimulation of C28 chondrocytes with CPPD and BCP crystals. <h3>Results</h3> Radiologically detectable cartilage calcifications were evident in chondrocalcinosis patients, but absent in OA patients without chondrocalcinosis. Chondrocalcinosis cartilage exhibited an increased collagen 10 expression compared to healthy cartilage, as well as to severe OA cartilage containing BCP calcification. Interestingly, aggrecan and collagen 2 were not reduced in chondrocalcinosis cartilage, but markedly reduced in OA cartilage. TUNEL positive cells were significantly increased in CPPD cartilage compared to OA cartilage, although the histological OA severity was lower. qRT-PCR indicated no relevant influence of CPPD crystals on hypertrophic marker genes, whereas BCP crystals significantly induced hypertrophic differentiation. <h3>Conclusion</h3> BCP and CPPD crystals seem to trigger differential effects on the chondrocyte phenotype. BCP crystals induce hypertrophic differentiation, which is not induced by CPPD crystals. <h3>Disclosure of Interests</h3> None declared
The “effect” of T classification on colorectal liver metastasis.
Authors: Lunpo Wu, Hongjuan Zheng, Jianfei Fu, Jinlin Du, Shu Zheng, Liangjing Wang
Journal: Journal of Clinical Oncology (2019)

e15049 Background: T classification is considered as a detail and credible category of the depth of tumor invasion. Generally, with the increasing T category, the risk of metastases should be continuously rising. However, there is a group of metastatic patients with early T classification, who were supposed to have a low metastatic probability. Our study aims to present the T classification on metastatic liver colorectal cancer (CRLM) in both clinical and biological aspects, and explore preoperative predictions to develop a convenient individual assessment model for clinicians to speculate whether these patients, whose prognosis is extremely poor. Methods: Tissue samples of primary colorectal cancer were obtained at our center. Patients with CRLM during 2010 to 2014 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox models were used to analyze the survival differences. We identified preoperative prognostic factors based on the Cox analysis and constructed a nomogram model. The predictive accuracy and discriminative ability were measured by concordance index (C-index) and calibration curve. Results: The mRNA array from our hospital showed that there is an obvious difference between the T1/2N0M1 subgroup and the T3/4N0M1 subgroup. Patients with early T classification (T1) were more often have tumors located in rectum, with well differentiation, with no lymph node metastasis and a higher CEA level. Further survival analysis indicated that early T classification (T1) was an independent prognostic factor with poorer survival. When the lymph node (N) status was taken into consideration, patients with T1 N+ had an obvious better survival than T1 N0 patients. A clinical nomogram was constructed based on preoperative factors. The calibration curves for probability of 1-, 2-, and 5-year overall survival showed a good agreement between nomogram prediction and actual observation. Conclusions: The prognosis of T1M1 is extremely poorer than T3/4M1. The prognosis of T1N+ is better than T1N0. It is time to pay more attention to the high-risk monitoring and screening of T1 in early colon cancer.
Chemotherapy and trastuzumab-induced cardiotoxicity in geriatric breast cancer patients.
Authors: Christian Agbisit, Alexander Johnson, Kathy Robinson, Kristin Delfino, Meghna R. Desai
Journal: Journal of Clinical Oncology (2019)

e23043 Background: Cardiotoxicity is a known side effect of anthracyclines &amp; trastuzumab. Dilated cardiomyopathy is the most common form of cardiotoxicity associated with this treatment. Cardiovascular disease &amp; cancer are common conditions in the geriatric populations. These comorbidities complicate the treatment of geriatric breast cancer patients. The purpose of this study was to determine the cardiotoxic effects of chemotherapy &amp; trastuzumab in a geriatric population of breast cancer patients. Methods: An institutional database of a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis was reviewed in an IRB approved fashion. Patients were divided in groups depending on the therapy (AC/TAC, CMF, TC and Trastuzumab) they received. Fisher’s exact test was used to calculate overall survival (OS). Results: Of the 269 patients, 72 (26.8%) were offered chemotherapy &amp; 197 (73.2%) were not. Of the patients offered chemotherapy, 58 (21.6%) accepted treatment &amp; 14 (5.2%) declined. 17 (6.7%) had an early termination, AC n = 11,( 4.1%), TAC n = 13, (4.8%), CMF n = 0, (0%), Trastuzumab n = 12, (4.5%), TC n = 11, (4.1%). Cardiovascular risk factors taken into consideration were, CAD n = 30, (13.8%), HLD n = 23, (10.6%), HTN n = 98, (45.2%), HTN/HLD n = 66, (30.4%), DM (N = 45, (16.7%), Smoking n = 121, (46.4%) &amp; BMI &gt; 30, n = 116,( 48.1%). Patients completing chemotherapy had higher OS than patients who had early termination (P = 0.017). Of the 24 patients who received Anthracycline containing regimen, 1 experienced cardiotoxicity. There was no statistically significant difference in OS between AC, TAC &amp; Trastuzumab (P = 0.570, P = 0.547, P = 0.614). A decrease in OS was seen for patient who received TC (P = 0.002). Of the 12 who received trastuzumab, 1 experienced cardiotoxicity. There was a significant association between patients with a high BMI ( &gt; 30) &amp; increased cardiovascular comorbidities (P = 0.0009) but had no impact early on termination of chemotherapy or OS, NS (P = 0.7). Conclusions: The cardiotoxic effect of anthracyclines and trastuzumab are well known, however in our study, only 2 elderly breast cancer patients who received chemotherapy experienced cardiotoxicity. As would be expected, those who completed chemotherapy had improved OS. There were no difference in OS between AC, TAC and Trastuzumab, however TC treatment was associated with a decrease in OS.BMI had an impact on cardiovascular comorbidities but not on early termination of chemotherapy or OS.
Impact of smoke-free ordinance strength on smoking prevalence and lung cancer incidence.
Authors: Ryan Nguyen, Laura Vater, Lava R Timsina, Greg Andrew Durm, Katelin Rupp, Keylee Wright, Miranda Spitznagle, Brandy Paul, Shadia Ibrahim Jalal, Lisa Carter-Harris, Karen S Hudmon, Nasser H. Hanna, Patrick J. Loehrer, DuyKhanh Ceppa
Journal: Journal of Clinical Oncology (2019)

6578 Background: Smoke-free ordinances (SFO) have been shown to decrease the prevalence of cardiovascular and pulmonary disease, but there is limited data on the impact of such policies on lung cancer incidence. We investigated the relationship between strength of county-level SFO with smoking prevalence and lung cancer incidence in Indiana. Methods: Following IRB approval, we queried the Indiana State Cancer Registry and Indiana Tobacco Prevention and Cessation Commission’s policy database between 1995 and 2016. County-level characteristics included population, income, poverty, education, race/ethnicity, sex, and rurality. Lung cancer diagnosis and stage were also collected. Using generalized estimating equations (GEE) with robust standard errors and accounting for the clustering effect at county level, we performed multivariable analyses of smoking prevalence and age-adjusted lung cancer rates with respect to the strength of smoke-free ordinances at the county level over time. Results: Indiana consists of 92 counties, 24 of which had SFO by 2011. In 2012, Indiana enacted a law mandating at least a moderate state-wide SFO. From 1995 to 2016, 110,935 Indiana residents were diagnosed with lung cancer. Indiana also had an average age-adjusted yearly lung cancer incidence of 76.8 per 100,000 population and average yearly smoking prevalence of 25% during this time. Smoking prevalence was 1.2% (95% CI [-1.88, -0.52]) lower in counties with comprehensive or moderate SFO compared with those with weak or no SFO. Counties that had comprehensive or moderate SFO had an 8.36 (95% CI [-11.45, -5.27]) decrease in new lung cancer diagnosis per 100,000 population per year compared with counties that had weak or no SFO. Conclusions: Stronger municipal smoke-free air ordinances are associated with decreased smoking prevalence and fewer new lung cancer cases. Strengthening smoke-free ordinances is paramount to decreasing lung cancer incidence.
Effect of cyclin E overexpression on resistance to trastuzumab and phosphorylation of SMAD3 in HER2+ breast cancer.
Authors: Pridvi Kandagatla, Joseph Decker, Lei Wan, Regan Bernstein, Lonnie Shea, Jacqueline Sara Jeruss
Journal: Journal of Clinical Oncology (2019)

e12006 Background: Trastuzumab, an effective treatment for HER2+ breast cancer, can be limited by development of resistance. Cyclin E (CCNE) overexpression was implicated in trastuzumab resistance, though the association is not well understood. We sought to explore a potential mechanism focusing on altered phosphorylation of the TGFβ signaling protein, SMAD3, in CCNE overexpressing HER2+ breast cancer cells, leading to trastuzumab resistance. Methods: A transcriptional activity cell array (TRACER) was used to examine the relationship between specific transcription factors and trastuzumab resistance in BT474 HER2+ human breast cancer cells. Immunoblotting examined phosphorylation patterns of SMAD3 in trastuzumab sensitive and resistant conditions. Effects of blocking CCNE overexpression with a CDK2 inhibitor were measured. To test the relative influence of SMAD3 and SMAD3 linker region phosphorylation on cell proliferation, BT474R2 cell lines were created overexpressing SMAD3 (BT474R2-SMAD3), a mutant construct blocking CCNE-mediated SMAD3 linker region phosphorylation (BT474R2-5M), and a control (BT474R2-Blank). In vitro and in vivo studies measured response to trastuzumab. Results: Resistance to trastuzumab was confirmed for BT474R2 cells, showing a markedly increased resistance to treatment when compared to the parental line. Network analysis of TRACER data identified decreased SMAD3 activity was central to resistance. Immunoblotting showed SMAD3 expression was significantly downregulated in BT474R2 cells (p &lt; 0.01). Noncanonical phosphorylation of SMAD3 was increased in CCNE-overexpressing cells. Blocking CCNE mediated noncanonical phosphorylation of SMAD3 with CDK2 inhibition resulted in decreased proliferation of BT474R2 cells. In vitro studies examining response to trastuzumab showed an increased sensitivity for BT474R2-5M cells. Findings were validated in NSG mice inoculated with BT474R2-5M cells that developed significantly lower tumor volumes (p &lt; 0.001) when treated with trastuzumab. Conclusions: These results identified a mechanism of CCNE-mediated trastuzumab resistance, regulated through noncanonical SMAD3 phosphorylation, which may be effectively treated with CDK2 inhibition to help enhance the efficacy of trastuzumab for patients with HER2+ breast cancer.
Genomic markers of early progression on fulvestrant with or without palbociclib for ER+ advanced breast cancer in the PALOMA-3 trial.
Authors: Ben O'Leary, Ros Cutts, Xin Huang, Sarah Hrebien, Yuan Liu, Isaac Garcia-Murillas, Fabrice Andre, Sherene Loi, Sibylle Loibl, Massimo Cristofanilli, Cynthia Huang Bartlett, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2019)

1010 Background: Markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited despite the key role of these combinations in treating of ER+ advanced breast cancer (ABC). We investigated genomic aberrations in patients treated with fulvestrant, with and without palbociclib, with a circulating tumor DNA analysis of baseline plasma in the PALOMA-3 trial. Methods: PALOMA-3 was a phase III trial that randomized 521 patients with ER+/HER2- ABC 2:1 to palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F). Using baseline plasma samples, somatic mutations were assessed with a 17 gene panel. Copy number aberrations (CNA) were characterized with a 14 gene panel including ~800 SNPs in 8 commonly altered regions for estimation of tumor purity, the percentage of plasma DNA that was derived from tumor cells. Results for mutations and CNAs were available in 310 pts (203 P+F, 107 F) and were associated with clinical characteristics and progression free survival (PFS) using univariable and multivariable Cox proportional hazards models, including tumor purity and treatment as variables. Results: In the multivariable analysis of the whole cohort, higher baseline tumor purity in plasma was associated with worse PFS (HR 1.20, 95% CI 1.09 – 1.32, p = 0.0001, HR per 10% increase in purity). Baseline TP53 mutation was also associated with shorter PFS (HR 1.84, 95%CI 1.27 – 2.65, p = 0.0011), as was baseline FGFR1 amplification (HR 2.91, 95%CI 1.61 – 5.25, p = 0.0004). PIK3CA and ESR1 mutations had no significant association with PFS in the multivariable model. Palbociclib treatment effect was comparable with the overall trial result (HR 0.43, 95%CI 0.32 - 0.57, p &lt; 0.0001). TP53 mutations were significantly associated with visceral (q = 0.046) and soft tissue/LN metastases (q = 0.042) and the number of disease sites (q = 0.0086) after correction for multiple testing. Conclusions: TP53 mutation, FGFR1 amplification , and tumor purity in plasma identified patients at risk of early progression In PALOMA-3. If validated these results could inform future clinical trials of CDK4/6 inhibitors combinations.
FRI0036 EFFECTS OF DISEASE ACTIVITY, ILLNESS PERCEPTION, SOCIAL SUPPORT AND COPING METHODS ON QUALITY OF LIFE IN THE PATIENTS WITH RHEUMATOID ARTHRITIS AND FIBROMYALGIA SYNDROME
Authors: Hakan Kesmen, ahmet kıvanç cengiz, Ayhan Bilgici
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> In chronic diseases, social support, illness perception and coping methods have important effect on quality of life. <h3>Objectives:</h3> In the present study, we aimed to compare the quality of life (QOL) of the patients with rheumatoid arthritis (RA) with fibromyalgia (FMS) patients and healthy controls and to assess the relationship between QOL and illness perception, social support, disease coping methods in the patients with RA and FMS. <h3>Methods:</h3> Fifty-eight patients with RA, 50 patients with FMS and 50 healthy controls were enrolled in the study. Pain (Visual Analogue Scale, VAS), QOL (Short Form SF-36), illness perception (Revised Illness Perception Scale, IPQ-R), social support (Multidimensional Perceived Social Support Scale, MSPSS) were assessed in the patients. In RA patients, disease activity was evaluated with DAS 28 and Clinical Disease Activity (CDAI), and functional status was evaluated with Health Assessment Questionnaire (HAQ). Fibromyalgia Impact Questionnaire (FIQ) scale was used in the clinical assessment of FMS patients. <h3>Results:</h3> While RA and FMS patients had higher COPE-emotional and COPE–problem scores than the healthy controls (p&lt;0.05), there was no significant difference between the patients with RA and FMS (p&gt;0.05). Regarding the all MSPSS scores, there was no significant difference between the three groups (p&gt;0.05). FMS patients had lower scores than the RA patients and healthy controls regarding the physical function, pain, social functioning and mental health subscales of SF-36 (p&lt;0.05). In RA patients, MSPSS-friend and MSPSS-special one scores were positively correlated with all subscales of SF-36. IPQ-R consecuences scores were negatively associated with all subscales of SF-36 (p&lt;0.01). There were positive correlations between IPQ-R treatment control and SF-36 physical function and social function subscales (p&lt;0.05). In FMS patients, IPQ-R-timeline acute\chronic score was negatively correlated with physical function, pain and social function subscales (p &lt;0.05). While IPQ-R timeline cyclical was negative correlated with SF-36 mental health subscale, COPE-emotional was negatively correlated with SF-36 general health <h3>Conclusion:</h3> In RA and FMS patients, QOL and physical functions were found to be related with illness perception, social support and coping methods as much as disease activity. <h3>Disclosure of Interestss:</h3> None declared
Case 10-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, J.M. Rappeport, N.L. Harris
Journal: New England Journal of Medicine (1987)

Presentation of CaseA 59-year-old woman was admitted to the hospital because of polyneuropathy and weight loss.She was well until seven years earlier, when she began to notice gradual weight loss. During the three years before admission chronic anemia was noted; slowly worsening ascending peripheral neuropathy developed and did not respond to injections of vitamin B12. A persistent hyperchloremic acidosis was found, with potassium levels that ranged as high as 6.4 mmol per liter. Medical evaluation elsewhere showed increased pigmentation and orthostatic hypotension. The fasting serum cortisol was normal, as were the results of an adrenocorticotropic hormone . . .
Characterization of OASEP1 as a biomarker and therapeutic target for oral cancer.
Authors: Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yataro Daigo
Journal: Journal of Clinical Oncology (2019)

e14627 Background: The improved understanding of cancer-specific oncoproteins could lead to the development of new biomarkers or therapeutic strategies for oral cancers. Methods: We conducted this study as follows: i) Identification of up-regulated genes in oral cancers by means of cDNA microarray, ii) Validation of clinicopathological significance of their protein expression by tissue microarray, iii) Examination of the growth on cancer cells by siRNA, iv) Elucidation of their biological effects on tumor growth. Results: We selected a secreted protein, OASEP1 (oral cancer-associated serum protein 1) as a candidate. Immunohistochemical staining showed that OASEP1 protein expression in cytoplasm was observed in 73 (74.4%) of 98 oral cancers that had undergone curative surgery. In addition, high level of OASEP1 expression was associated with poor prognosis for oral cancer patients ( P = 0.0158, by log-rank test). Suppression of OASEP1 expression by siRNA for OASEP1 significantly suppressed the growth of oral cancer cell lines partly through apoptosis as detected by flow cytometric analysis, apoptosis assays, and time lapse imaging. In addition, siRNAs for a candidate receptor of OASEP1 also significantly inhibited its expression and the growth of oral cancer cells, indicating that the functional interaction between OASEP1 and its receptor could regulate the growth of oral cancer cells. Conclusions: Our data suggest that OASEP1 is a possible prognostic biomarker and therapeutic target for oral cancer.
EU citizens must have legal rights or more doctors will be lost, warns BMA
Authors: Zosia Kmietowicz
Journal: BMJ (2019)

More doctors could be lost to the UK if the government fails to guarantee in law the rights of EU citizens living here, the chair of the BMA has warned.

Chaand Nagpaul was responding to a report from the Home Affairs Committee,1 which raised serious concerns about the current EU Settlement Scheme.

The scheme is supposed to grant eligible EU citizens the right to legal residence in the UK when it leaves the EU. But the committee said that problems with the scheme and uncertainty over the future rights of …