tbuckley/cabot-search huggingface dataset:
Gene expression and genetic variants in Parkinson's disease (PD) genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3 phase III trial.
Authors: Francesca Battaglin, Shu Cao, Alberto Puccini, Ryuma Tokunaga, Madiha Naseem, Hiroyuki Arai, Martin D. Berger, Tricia Ning, Shivani Soni, Jae Ho Lo, Afsaneh Barzi, Joshua Millstein, Wu Zhang, Volker Heinemann, Sebastian Stintzing, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

3595 Background: PD is one of the most common age-related neurodegenerative disorders. Large epidemiological studies have consistently reported a reduced risk of CRC in PD patients (pts), but the biology behind this evidence is unclear. The methylation status of SNCA, one of the causal PD genes, has been identified as a tool for CRC screening and early diagnosis when detected in stool samples, and alterations in core PD genes are prevalent across human malignancies including CRC. Methods: The impact on outcome of 13 SNPs within 6 core PD genes ( SNCA, PRKN, UCHL1, PINK1, DJ-1, LRRK2) was analyzed in pts enrolled in the randomized FIRE-3 trial. Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the cet cohort, pts carrying the G/G variants of SNCA rs356165 and rs2736990 had significantly shorter mOS (30 vs 41.1 mo) compared to any A genotype in both uni- and multivariable analysis (adjusted P[ P adj ] = .047 and .042, respectively). LRKK2 rs3761863 T/T allele carriers showed shorter mPFS (9.5 vs 13.3 mo, P adj = .01), while rs11564148 any A carriers had longer mPFS (14.2 vs 10.2 mo, P adj = .01) compared to reference genotypes. LRKK2 rs11564148 any A carriers also showed longer mOS in multivariable analysis (43.7 vs 33.2 mo, P adj = .044). Any C allele carriers of PINK1 rs1043424 showed longer mPFS in uni- and multivariable analysis ( P adj &lt; .001). No significant interaction was found with gender, tumor location and RAS status. These associations were not observed in bev arm. High SNCA expression was associated with worse mPFS (log2 &gt; 7.89, 5.9 vs 11.2 mo) and mOS (log2 &gt; 7.68, 17.9 vs 31.1 mo) in FIRE-3 cet arm ( P &lt; .05). Conclusions: We provide the first evidence that gene expression and genetic variants in PD genes may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment. Our findings open new perspectives on the role of PD genes in CRC biology warranting further investigation.
Chronic cigarette exposure and lung inflammatory changes in rats
Authors: L. Bizeto, O. Nascimento, A. Mayer, A. Camelier, F. Rosa, F. Lopes, P. Sannomyia, M. P. Nunes, Mílton de Arruda Martins, Paulo Hilário Nascimento Saldiva
Journal: American Journal of Respiratory and Critical Care Medicine (2004)
Characteristics of patients receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ.
Authors: Wendy S. Rubinstein, Li Chen, George Anthony Komatsoulis, Edward Stepanski, Monika Jun, Jizu Zhi, Denise Lau, Jeremy Roberts, Robert S. Miller, Mark S. Walker, Ryan Fukushima, Brigham Hyde, Sean Khozin
Journal: Journal of Clinical Oncology (2019)

2566 Background: ICI’s have demonstrated significant clinical benefit since the first FDA approval in 2011 of ipilimumab for metastatic melanoma. Five additional ICI therapies have since been approved across several indications. The objectives of this study were to describe the clinical and demographic features of patients receiving ICI treatment along with utilization patterns in real-world settings. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database, which now contains EHR data from 49 diverse oncology practices in the U.S. Adult patients diagnosed with any cancer type who received ≥1 dose of an ICI (see Table) and had ≥2 clinical visits were eligible for inclusion. Patients were excluded if they received an ICI prior to its first FDA approval date to avoid inclusion of clinical trial patients. Descriptive statistics were used to examine treatment patterns and clinical characteristics of patients receiving ICIs. Results: This analysis included 12,712 patients who received an ICI. Median patient age was 67.4 years [IQR 59.3, 75.3]; 58% were male. White race made up the highest percent (83%) of ICI patients, followed by Black race (9%) and Other (8%). The most common primary cancers at the start of treatment were lung cancer (36%), melanoma (8%), urothelial cancer (2%) and renal cell carcinoma (2%). Of the 8,444 patients with known disease stage, 5,446 (64%) had Stage IV cancer. Breakdown of ICI treatment patterns can be found in the accompanying table. Uptake of ICIs was the most rapid for nivolumab, which had the highest use (49%), followed by pembrolizumab for rapid adoption and use (30%). Conclusions: This analysis gives insights into patient characteristics and real-world treatment patterns for ICIs. ICIs were used most widely in males, lung cancer patients and patients with advanced disease. These baseline characteristics inform our analyses of ICI use in patients with autoimmune disease, also reported herein.[Table: see text]
Outcomes of Care in Birth Centers
Authors: Judith P. Rooks, Norman L. Weatherby, Eunice K.M. Ernst, Susan Stapleton, David Rosen, Allan Rosenfield
Journal: New England Journal of Medicine (1989)

Abstract We studied 11,814 women admitted for labor and delivery to 84 free-standing birth centers in the United States and followed their course and that of their infants through delivery or transfer to a hospital and for at least four weeks thereafter. The women were at lower-than-average risk of a poor outcome of pregnancy, according to many but not all of the recognized demographic and behavioral risk factors. Among the women, 70.7 percent had only minor complications or none; 7.9 percent had serious emergency complications during labor and delivery or soon thereafter, such as thick meconium or severe shoulder dystocia. One woman in six (15.8 percent) was transferred to a hospital; 2.4 percent had emergency transfers. Twenty-nine percent of nulliparous women and only 7 percent of parous women were transferred, but the frequency of emergency transfers was the same. The rate of cesarean section was 4.4 percent. There were no maternal deaths. The overall intrapartum and neonatal mortality rate was 1.3 per 1000 births. The rates of infant mortality and low Apgar scores were similar to those reported in large studies of low-risk hospital births. We conclude that birth centers offer a safe and acceptable alternative to hospital confinement for selected pregnant women, particularly those who have previously had children, and that such care leads to relatively few cesarean sections. (N Engl J Med 1989; 321:1804–11.)
Comparison between whole exome sequencing (WES) and single nucleotide polymorphism (SNP)-based tumor mutation burden analysis.
Authors: Kirsten Timms, Andrey Zharkikh, Michael Perry, Nicolai Birkbak, Zoltan Szallasi, Alexander Gutin, Andrea Richardson, Jerry Lanchbury
Journal: Journal of Clinical Oncology (2019)

2634 Background: Immune checkpoint inhibitors (ICI) block proteins which enable cancer cells to evade the immune system. Recent studies have shown that the higher the tumor mutation burden (TMB) the greater the likelihood of response to ICI therapy. Analysis of TMB has focused on WES of paired tumor and normal samples. This study tests the feasibility of measuring TMB from a SNP-based resequencing assay (myChoice HRD Plus). Methods: WES and myChoice HRD Plus were performed on matched tumor and normal DNA from 44 breast and 12 colon tumors. myChoice HRD Plus combines homologous recombination deficiency analysis with resequencing of 108 genes and microsatellite instability analysis. WES-based TMB was calculated by identifying all variants in paired samples, and subtracting germline variants. Two SNP-based TMB (SbTMB) methods were utilized to calculate TMB. The first used germline subtraction similar to the WES-based method. The second utilized an algorithm which removed background germline variants. Median sequence length to calculate TMB was 9.7 Mb for WES, 4.6 Mb for SbTMB (germline subtraction), and 1.9 Mb for SbTMB (algorithm). Results: Correlation coefficients for WES vs. SbTMB (germline subtraction) and SbTMB (algorithm) were 0.895 and 0.908, respectively. The two SbTMB methods had a correlation coefficient of 0.834. SbTMB measures of TMB were generally higher than WES-based TMB with a mean increase in score of 1.6 variants/Mb for SbTMB (germline subtraction; p = 4.6x10 -6 ) and 1.5 variants/MB for SbTMB (algorithm; p = 1.2x10 -5 ). No significant difference in magnitude of TMB score between the SbTMB measures was observed (0.04 variants/Mb; p = 0.88). Conclusions: SNP-based methods for calculating TMB produced highly concordant scores compared to WES-based methods. SbTMB assays produced elevated TMB scores, consistent with selective pressure against mutations in coding regions of genes, necessitating a higher score threshold for when using a SbTMB assay. This SbTMB analysis expands the utility of myChoice HRD Plus, and provides a method for calculation of TMB without sequencing a germline comparator.
A phase II study for prostate cancer monitoring using <sup>18</sup>F-DCFPyL and blood-based biomarkers.
Authors: Emerson A. Lim, Akiva Mintz, Mark N. Stein, Alex J. Rai, Mahesh M. Mansukhani, David Henry Aggen, Matthew Dallos, Jessica Hawley, Hiram A Shaish, Lawrence Howard Schwartz, Charles G. Drake
Journal: Journal of Clinical Oncology (2019)

TPS3154 Background: Assessing treatment response in castrate resistant prostate cancer (CRPC), remains a challenge due to the limited sensitivity and specificity of existing imaging modalities. Understanding prostate cancer biology with tumor biopsies does not address the issue of tumor heterogeneity or cellular degradation during the decalcification process of bone biopsies. Next generation positron emission tomography (PET) imaging and circulating biomarkers might provide additional insights on treatment responses and inform clinical decision-making earlier in therapy. 18 F-DCFPyL (PyL) is a second-generation fluorinated PSMA PET tracer that has superior sensitivity and specificity to detect prostate cancer compared to standard imaging. Its role in assessing tumor response to therapy has not been evaluated. Circulating tumor DNA (ctDNA) in blood can provide tumor genomic information, while exosomes in serum and urine may provide data on the proteomic landscape of tumors. Methods: We are conducting a prospective study of 15 men with metastatic CRPC who are scheduled to start a new systemic therapy for their disease. Upon enrollment, subjects will have baseline assessments with standard cross-sectional imaging, 99m Tc bone scan, and blood work. Standard scans will be performed every 8-12 weeks until progression of disease. PyL PET/CT scans and liquid biopsies (ctDNA and exosomes) will occur at baseline, 6 weeks after starting their new therapy, and at disease progression. Lesions seen on PET/CT images will be identified by a certified reader. The maximum standardized uptake value (SUV max ) will be measured and recorded in up to the five hottest lesions and normalized to a background SUV mean measured in the liver, spleen, kidney, mediastinum, and parotid glands. Changes in the normalized SUV from baseline to the 6-week PyL PET scan will be correlated to PSA response by the Pearson’s correlation coefficient. The Kaplan-Meier method will be used to evaluate progression free survival and overall survival dichotomized by the median value of SUV change. Blood for ctDNA and exosomes will be stored for future analysis. The study is open with two patients enrolled at the time of submission. One patient has completed his initial PyL PET/CT scan. Clinical trial information: NCT03585114.
Chronic adverse effects after axillary lymphadenectomy in breast cancer patients after weaker and stronger postoperative analgesia: Results of a prospective double-blind randomized study.
Authors: Nikola Besic, Jaka Smrekar, Branka Strazisar
Journal: Journal of Clinical Oncology (2019)

e23066 Background: Tramadol is commonly used for pain treatment, but it is not known if stronger postoperative analgesia has an effect on chronic adverse effects in breast cancer patients. The aim of this study was to compare the rate of chronic adverse effects after weaker and stronger postoperative analgesia. Methods: A prospective double-blind randomized study included 118 breast cancer patients receiving tramadol for pain relief after axillary lymphadenectomy from 2015 to 2018 (Study EUDRA CT: 2015-000992-28). All patients used one of two analgesic regimens for 4 weeks after lymphadenectomy. Patients with larger dose received 75/650 mg of tramadol with paracetamol every 8 hours and a group with lower dose received 37.5/325 mg of tramadol with paracetamol every 8 hours. All patients received for four weeks twice daily naproxen sodium 550 mg and once a day pantoprazole 20 mg. One year after surgery patients were evaluated for the presence of neuropathic pain, chronic pain, arm symptoms and lymphedema. The association between dose of tramadol and chronic postoperative adverse effects was evaluated using asymptotic z-test and chi-square test. Results: Neuropathic pain was more common one year in comparison to one month after lymphadenectomy (p = 0.0001). There was a trend for lower rate of neuropathic pain after stronger analgesia in comparison to weaker analgesia (p = 0.058). Chronic pain was present in 18% of patients one year after lymphadenectomy. There was no difference in rate of chronic pain after stronger and weaker postoperative analgesia. Patients had less arm symptoms after stronger analgesia than after weaker analgesia (p = 0.02). Furthermore, there was a trend for lower rate of lymphedema of forearm after stronger analgesia than after lower analgesia (p = 0.078). Conclusions: The patients who received stronger postoperative analgesia had a statistical trend for less often neuropathic pain in comparison to patients who received weaker analgesia. The patients who received stronger postoperative analgesia had less arm symptoms and better quality of life in comparison to patients who received weaker analgesia. Clinical trial information: EudraCT 2015-000992-28.
Nomogram based on multivariable regression model estimates the overall survival of patients with nivolumab who were previously treated for advanced non-small cell lung cancer.
Authors: Motohiro Tamiya, Akihiro Tamiya, Hirofumi Go, Takako Inoue, Madoka Kimura, Kei Kunimasa, Kenji Nakahama, Yoshihiko Taniguchi, Takayuki Shiroyama, Shun-Ichi Isa, Kazumi Nishino, Toru Kumagai, Hidekazu Suzuki, Tomonori Hirashima, Shinji Atagi, Ayumi Shintani, Fumio Imamura
Journal: Journal of Clinical Oncology (2019)

e20683 Background: Nivolumab (Nivo) has demonstrated with its efficacy against metastatic non-small cell lung cancer (NSCLC). However, it has been also reported that Nivo does not show beneficial effects in approximately 80% of patients. The predictive ability of biomarkers still is yet unclear; thus identifying biomarkers which better predict overall survival (OS) of such patients treated with Nivo is crucial. In this study, we conducted multivariable cox regression analysis including biomarkers and clinical factors measured at the time of initiating treatment with Nivo to assess predictive ability of OS of patients. Results of the multivariable analysis were elucidated with a nomogram which estimates the OS of Nivo in previously treated patients with advanced NSCLC. Methods: In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement, and we evaluated two programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems (22C3 and 28-8). Results: The median age at the time of administration nivolumab was 68 years, 135 patients were male, 157 patients had a smoking history, and 152 patients had a performance status (PS) score of 0–1. 39 patients had EGFR (37) or ALK (2) mutation positive. For 22C3 and 28-8, 36.3% and 36.8% of patients were negative, 17.4% and 14.4% had PD-L1 status of 1-49%, and 11.9% and 14.9% had PD-L1 status of ≥50%, 34.3% and 33.8% had PD-L1 status of missing, respectively. Kendall’s rank correlation coefficient between 22C3 and 28-8 was 0.8414. The median OS of all patients was 333 (95% confidence interval (CI): 116-520) days. In the multivariate analysis, PS score ≥2 (hazard ratio (HR): 2.23; 95%CI: 1.36-3.66 p &lt; 0.001), high LDH level at baseline (HR: 1.13 95%CI: 1.03-1.24; p = 0.008, and progression disease (PD) of pre-treatment response (HR: 3.64 95%CI: 2.29-5.79 p &lt; 0.001) were significantly associated with poor OS. There was not significant distance between PD-L1 status and OS of Nivo. Based on these analyses, we created the nomogram to estimate the OS of Nivo in previously treated patients with advanced NSCLC. Conclusions: PS score ≥2, high LDH levels at baseline, and PD of pre-treatment response were predictive of poor OS of Nivo, moreover the nomogram might be useful to estimate the OS of Nivo in previously treated patients with advanced NSCLC.
Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC).
Authors: Karim Fizazi, Neal D. Shore, Teuvo Tammela, Iris Kuss, Marie-Aude Le Berre, Ateesha F. Mohamed, Dawn Odom, Jennifer Bartsch, Amir Snapir, Toni Sarapohja, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2019)

5000 Background: DARO is a structurally distinct androgen receptor antagonist for which in vitro and phase 1/2 studies suggest low risk of adverse events (AEs) and drug–drug interaction. In the ARAMIS study of DARO in nmCRPC, metastasis-free survival (MFS) was significantly prolonged vs placebo (PBO) (40.4 vs 18.4 mo; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P &lt; 0.001) and interim overall survival (OS) favored DARO (HR 0.71; 95% CI 0.50–0.99; P = 0.045). Methods: 1509 pts were randomized 2:1 to DARO 600 mg (two 300 mg tablets) twice daily (n = 955) or PBO (n = 554) while continuing androgen deprivation therapy (ADT). Primary endpoint was MFS. Secondary endpoints included OS and time to pain progression (assessed by Brief Pain Inventory Short Form). QoL was assessed by European Organisation for Research and Treatment of Cancer QoL Prostate Cancer module (EORTC-QLQ-PR25) at baseline (BL) and every 16 wks until end of treatment. Analysis of time to deterioration in EORTC-QLQ-PR25 subscales, defined as first occurrence of a minimally important difference (half the standard deviation of BL value), used Kaplan–Meier estimators and stratified Cox proportional hazard models. Results: DARO significantly delayed pain progression vs PBO (40.3 vs 25.4 mo; HR 0.65; 95% CI 0.53–0.79; P &lt; 0.001); this was maintained beyond end of study treatment. Time to deterioration of EORTC-QLQ-PR25 outcomes showed statistically and clinically significant delays with DARO vs PBO for urinary symptoms (25.8 vs 14.8 mo; HR 0.64; 95% CI 0.54–0.76; P &lt; 0.01). Time to deterioration of hormonal treatment-related symptoms was comparable with DARO vs PBO (18.9 vs 18.4 mo; HR 1.06; 95% CI 0.88–1.27; P = 0.52). DARO was well tolerated. Exposure-adjusted incidences (pts per 100 years’ exposure) of AEs of interest were similar/lower with DARO vs PBO (fatigue/asthenic conditions [11.3 vs 11.1], hypertension [4.7 vs 5.1], hot flush [3.7 vs 4.1], fracture [3.0 vs 3.5], falls [2.7 vs 4.1], cognitive disorder [0.3 vs 0.2], and seizure [0.2 vs 0.2]). Conclusions: For nmCRPC pts, DARO prolongs MFS, is well tolerated, maintains QoL, and delays worsening of pain and disease-related symptoms compared with PBO. Clinical trial information: NCT02200614.
AB1245 COMPARATIVE ANALYSIS OF SPONTANEOUS INFECTIOUS SPONDYLITIS: PYOGENIC VERSUS BRUCELLA
Authors: Lobna Ben Ammar, Aicha Ben Tekaya, Rawdha Tekaya, Olfa Saidane, Mohammed Ben Hammamia, Ines Mahmoud, Leila Abdelmoula
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Infectious spondylitis is an infectious disease of the spine or paraspinal structures that can be caused by various microorganisms. Without adequate chemotherapy, the outcome can be fatal or result in severe neurologic damage. Therefore, differentiating the etiology of spondylitis is very important. <h3>Objectives:</h3> To compare the clinical features, laboratory and radiological aspects, treatment and outcome data of patients diagnosed as brucellar spondylitis (BSP) and pyogenic spondylitis (PSP). <h3>Methods:</h3> Retrospective study including 45 (22 BSP and 23 PSP) spondylodiscitis hospitalized in our department between 1999 and 2019. The diagnosis was based on clinical, biological, radiological and bacteriological data. <h3>Results:</h3> The patients' mean age was 54 years. There were 31 men (68.8%) and 14 women (31.2%). There was no difference in mean age and sex between the two groups (p=0.8 and p=0.4; respectively). The pyogenic group had a relatively higher proportion of Predisposing factors especially diabeties (p=0.04). PSD patients suffered an impaired general condition more frequently than BSD patients (p=0.01) while BSD patients complained of night sweats more frequently compared to PSD cases (p=0.026). The peak CRP value was higher in the pyogenic group than in the brucella group (87 mg/L and 37 mg/L, respectively, p=0.027), whereas the ESR was not significantly different between the groups (71 mm/h and 67 mm/h, respectively, p=0.7). We found no statistically significant difference regarding the seat of the spondylitis. Whereas, multifocal involvement was higher in PSD (p=0.049). Radiologically, the frequency of prevertebral, paravertebral, epidural, and psoas abscess formations and spinal cord compression was similar in both groups (p=0.8) Surgical interventions and percutaneous sampling and/or abscess drainage were applied more frequently in PSD but with no significant difference (p&lt;0.23). Favourable clinical outcome rate was 60% in PSD and it was 72% in BSD group (p=0.39). <h3>Conclusion:</h3> The clinical and radiological manifestations of spontaneous spondylitis differ based on the causative organism. Pyogenic spondylitis patients tend to have a more severe clinical course and a higher CRP level. However, there was no significant difference regarding the presence of abscess and epiduritis or the occurrence of complications between brucella and pyogenic spondilitis. <h3> Disclosure of Interests:</h3> None declared