tbuckley/cabot-search huggingface dataset:
European recommendations and quality assurance for cytogenomic analysis of haematological neoplasms: reponse to the comments from the Francophone Group of Hematological Cytogenetics (GFCH)
Authors: K. A. Rack, E. van den Berg, C. Haferlach, H. B. Beverloo, D. Costa, B. Espinet, N. Foot, S. Jeffries, K. Martin, S. O’Connor, J. Schoumans, P. Talley, N. Telford, S. Stioui, Z. Zemanova, R. J. Hastings
Journal: Leukemia (2020)
DKN-01 in combination with pembrolizumab in patients with advanced gastroesophageal adenocarcinoma (GEA): Tumoral DKK1 expression as a predictor of response and survival.
Authors: Samuel J. Klempner, Johanna C. Bendell, Victoria Meucci Villaflor, Laura LaNiel Tenner, Stacey Stein, Girish S. Naik, Cynthia A. Sirard, Michael Kagey, Marya F. Chaney, John H. Strickler
Journal: Journal of Clinical Oncology (2020)

357 Background: Dickkopf-1 (DKK1) modulates Wnt signaling and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody + pembrolizumab (P) has demonstrated safety and clinical activity in advanced GEA. We report response and survival outcomes in anti-PD-1/anti-PD-L1 naïve GEA patients by high/low tumoral DKK1 expression. Methods: We enrolled advanced anti-PD-1/PD-L1 naïve GEA patients (pts) in a Phase 1b/2a study of D + P (NCT02013154). Tumoral DKK1 mRNA expression was assessed by an in situ hybridization RNAscope assay. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) were compared between DKK1 high and low groups. Kaplan-Meier method and Cox-PH model was used for survival analysis and logistic regression was used for clinical benefit/response outcome. Results: 34 GEA pts were enrolled to receive 300 mg D + P. 31 GEA pts had DKK1 expression available (25 response-evaluable/RE) and 27 had both DKK1 and PD-L1 expression available (22 RE). In RE pts, DKK1 high (H-score ≥ upper-tertile [≥35]) had an ORR of 50% (5 PR/10), DCR of 80% (8/10) while DKK1 low ( &lt; upper-tertile) had an ORR of 0% (0/15) and DCR of 20% (3/15); DKK1 high (vs. low) had an OR of 16 (95%CI: 2.2, 118.3; n = 25) and adjusted (for PD-L1 CPS ≥10 vs. &lt; 10) OR of 17.6 (95%CI:1.6, 194.4; n = 22) for clinical benefit/response (PR/SD vs. PD). Median PFS was 22.1 weeks in DKK1 high (n = 11) vs. 5.9 weeks in DKK1 low (n = 20); HR of 0.23 (95%CI: 0.082, 0.66; n = 31). Adjusted (for PD-L1 expression) HR for DKK1 high was 0.20 (95%CI: 0.061,0.68; n = 27) for PFS. DKK1 high (n = 11) had a median OS of 31.6 weeks vs. 17.4 weeks in DKK1 low (n = 20); HR of 0.45 (95%CI: 0.16, 1.3; n = 31) and adjusted HR of 0.62 (95%CI: 0.2,1.9; n = 27). Conclusions: High levels of tumoral DKK1 expression identify advanced anti-PD-1/PD-L1 naïve GEA pts with the greatest benefit from D + P. Improvements in response/clinical benefit and PFS were observed independent of PD-L1 expression. Tumoral DKK1 as a potential predictive biomarker for DKN-01 treated GEA pts will be evaluated in future studies. Overall survival follow-up is ongoing. Clinical trial information: NCT02013154.
MMTV-NeuマウスにおけるTip30欠失は,EGFRシグナル伝達の強化とエストロゲン受容体陽性かつプロゲステロン受容体陰性の乳房腫瘍の発達をもたらす
Authors: Zhang Chengliang, Mori Mikito, Gao Shenglan, LI Aimin, Hoshino Isamu, D Aupperlee Mark, Z Haslam Sandra, Xiao Hua
Journal: Cancer Research (2010)
Receipt and survival outcomes by age following second-line therapy for metastatic CRC (mCRC): Analysis of 5,289 patients from the ARCAD Clinical Trials Program.
Authors: Nadine Jackson McCleary, William S. Harmsen, Eric VanCutsem, Alberto F. Sobrero, Richard M. Goldberg, Josep Tabernero, Matt Seymour, Leonard B. Saltz, Bruce J. Giantonio, Arnold Dirk, Mace L. Rothenberg, Miriam Koopman, Hans-Joachim hans-joachim Schmoll, Henry C. Pitot, Paulo Marcelo Hoff, Alfredo Falcone, Aimery De Gramont, Qian Shi, Stuart M. Lichtman
Journal: Journal of Clinical Oncology (2020)

6 Background: Rates and survival outcomes for second-line therapy for mCRC for OA vs. YA are poorly understood. Methods: Pts with available subsequent treatment data after progression from 10 1st line trials were included. Associations between key clinical/disease characteristics, time to initial progression (TTiP) and rate of receipt of second-line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA who were enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: OA comprised 16.4% of first-line trials. OA and ECOG PS &gt;0 were less likely to receive second-line therapy than YA. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p=0.0117). OA enrolled in second-line trials experience similar mTTP and mOS as YA (5.1 vs. 5.2mos; 11.6 vs 12.4mos, respectively). Conclusions: OA are less likely to receive 2nd line therapy for mCRC. We did not observe a statistical difference in survival outcomes for OA vs. YA following second-line therapy. Further study is needed to examine unmeasured factors, including comorbidity and functional status given observed inferior outcomes among adults with ECOG PS &gt;0, and consideration given to inclusion of geriatric assessment to select OA likely to benefit from 2nd line therapy for mCRC. [Table: see text]
Abstract 16760: Frequency and Spectrum of Treatment Associated Side Effects and Complications in Patients With Long QT Syndrome
Authors: Ram K Rohatgi, Johan M Bos, Michael J Ackerman
Journal: Circulation (2017)

Introduction: Beta-blockers (BB), left cardiac sympathetic denervation (LCSD), and implantable cardioverter defibrillators (ICDs) are the primary therapeutic modalities to prevent or reduce long QT...
Abstract 02: Brain Regions Activation During Stress and Accelerated Biological Aging
Authors: Zakaria Almuwaqqat, Matt Wittbrodt, Jonathan Nye, Kasra Moazzami, Bruno B Lima, Amit J Shah, Elizabeth Blackburn, Jinying Zhao, Jue Lin, Yan Sun, Arshed A Quyyumi, Viola Vaccarino, J Douglas Bremner
Journal: Circulation (2020)

Background: Psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease (CAD). Accelerated biological aging, as indicated by telomere shortening, is a recognized pathway by which stress may lead to cardiovascular disease incidence and mortality. We sought to investigate brain correlates of acute psychological stress and short telomeres in men and women with CAD. Methods: Individuals with CAD (N = 170) underwent a validated mental stress protocol including public speaking and mental arithmetic. Imaging of the brain with [O-15] water positron emission tomography (PET) was performed during mental stress and control conditions. Telomere length in peripheral leucocytes was measured by quantitative PCR and expressed as T/S-units. Voxel-wise regression models were constructed to assess the association between brain areas and activity during rest and mental stress after adjustments for demographic factors and clinical characteristics. Methods: The mean (SD) age was 62 (8) years, and 69% were men. The median telomere length was 0.84 T/S-units. Increased activation with mental stress in the lingual gyrus, cerebellum and superior and inferior gyrus in the frontal lobe were associated with reduced telomere length; 1.6 higher voxel activation of the inferior frontal gyrus was associated with 0.1 T/S-units reduction in telomere length (P &lt; 0.005). Additionally, higher resting activities of the precentral, middle and superior frontal gyri and middle temporal gyri were associated with short telomeres. Results remained consistent after adjustment for demographic and clinical risk factors. Conclusion: Increased resting brain activity and reactivity to mental stress within the frontal lobe is associated with short telomeres. These frontal areas may regulate biological aging at rest and in connection with stress, which may contribute to cardiovascular vulnerability.
Pilot study of the safety and feasibility of immediate adjuvant chemotherapy (IAC) in nonmetastatic colonic adenocarcinoma (nmCC).
Authors: Mehraneh D. Jafari, Sarath Sujatha-Bhaskar, Mathew Brady, Steven D. Mills, Joseph C. Carmichael, Farshid Dayyani, Fa Chyi Lee, Jason A. Zell, Alessio Pigazzi
Journal: Journal of Clinical Oncology (2020)

150 Background: The optimal timing of adjuvant chemotherapy (AC) in nmCC is poorly defined. Delays in AC result in decreased survivalbut fear of postoperative complications often causes long intervals between surgery and AC initiation. Given the transient immune suppression, inflammatory changes and increase in circulating tumor cells occurring in the perioperative period, effective cytotoxic treatments should be considered at this time to limit metastatic spread. The immediate adjuvant chemotherapy concept intends to capitalize on the therapeutic benefits that can be achieved in the perioperative period (intraoperative and early postoperative). We aim to demonstrate that IAC is safe and tolerable for patients with nmCC. Methods: Patients with nmCC microsatellite stable invasive adenocarcinomas were treated with intravenous Leucovorin 20mg/m2 followed by a single dose of 5-Flurouracil 400mg/m2 at the time of minimally invasive surgical resection. High risk stage II and stage III received the first dose of standard AC at 14 days after surgery. Serial measurements of blood-based biomarkers (circulating tumor cells, cell free DNA, and neutrophil lymphocyte ratio were measured. Quality of life (QOL) was measured using EORTC QLQ-C30. Results: Of the 20 patients recruited, 40% had final pathology of stage III, 40% stage II and 20% stage I. All patients received intra-operative chemotherapy with no associated morbidity. Median length of stay was 2 days (range of 2-4). Grade 1 complications were reported in 2 (10%) of patients. No grade 2 or higher adverse events were reported. There was no mortality. Early postoperative AC was administered to 65% of patients. The median time to AC was 14 days (range 14-36). Overall quality of life and health scores were similar before surgery and at 30-day postoperatively (p &lt; 0.05). Conclusions: A protocol based on immediate adjuvant chemotherapy starting at the time of surgical resection was found to be safe and feasible in nmCC with no adverse effects on surgical morbidity or quality of life. Further prospective studies are needed to explore the oncologic benefit of this novel systemic treatment approach.
First-line drug selection versus sequential treatment in advanced pancreatic cancer: Does it really matter? Multi-institutional Canadian perspective.
Authors: Ivan Barrera, Neha Papneja, Jill Ranger, Abhishek Papneja, Petr Novotny, Shahid Ahmed, Gerald Batist, Petr Kavan
Journal: Journal of Clinical Oncology (2020)

673 Background: Folfirinox (FFX) and Gemcitabine with nab-Paclitaxel (GN) are both proven to be superior to Gemcitabine (G) in the first line treatment (1LTx) for advanced pancreatic cancer (APC). Yet, the optimal 1LTx selection nor sequential Tx (ST) has not been fully established. Therefore, the best choice for 1LTx is a matter of debate often influenced by access to drugs. This analysis was conducted to compare outcomes based on 1Ltx selection and ST in APC. Methods: We assessed patients (pts) with APC who received either FFX or GN as 1LTx during 2010-2019 at three Canadian institutions. As well as the ST used. The main objective was to assess survival. Kaplan method and log-rank test were used for survival curves. Results: This retrospective study included 231 pts; 1LTx included 143 pts on FFX and 88 pts on GN. FFX pts were predominantly male; 89(62.2%) vs 46(52.3%) and slightly younger (median age 62 vs 66) than GN. WHO performance status (PS) of 0 were 38 (28.4%) vs 14 (16.5%) and 1 were 90 (67.2%) vs 65 (76.5%) respectively. There were more grade 3-4 toxicity in FFX vs GN group: GI 55 (38.5%) vs 15 (17%) and hematologic 51 (35.4%) vs 20 (22.7%) respectively. Grade 3-4 neutropenia rates were similar in both regimens. The median PFS of FFX was 5.5 months (95% CI: 5.0-6.7) vs 5.1 (95% CI: 3.8-7.1) with GN (p=0.37). The median OS with FFX was 9.3 months (95% CI: 7.5-11.1) vs 10.2 (95% CI: 6.8-11.3) with GN (p=0.81). There were not statically significant. Table shows Tx frequency across 4LTx. 2LTx and beyond regimens included G, GN, FFX, Capecitabine, Irinotecan liposome plus 5-FU, Irinotecan and clinical trials. Conclusions: Our results revealed that pts who received 1LTx FFX or GN had similar PFS and OS even though 1LTx FFX group was younger with better PS, allowing to continue 2-4LTx more frequently when compare with 1LTx GN group. Therefore, 1LTx selection appear to have more impact in our pts rather than ST, whereas GN is less toxic and seems a preferable 1LTx choice for most pts. FFX could be reserved for young high-performance pts. [Table: see text]
Association of Visceral Adiposity With Pain but Not Structural Osteoarthritis
Authors: Shanshan Li, Ann V. Schwartz, Michael P. LaValley, Na Wang, Nancy Desai, Xianbang Sun, Tuhina Neogi, Michael Nevitt, Cora E. Lewis, Ali Guermazi, Frank Roemer, Neil Segal, David Felson
Journal: Arthritis & Rheumatology (2020)

Objective Osteoarthritis ( OA ) and pain are both made more severe by low‐grade inflammation. This study was undertaken to examine whether visceral fat, a major source of inflammatory cytokines and adipokines, is associated with an increased risk of knee OA or musculoskeletal pain. Methods Subjects in the Multicenter Osteoarthritis Study cohort, who were age 50–79 years and had or were at high risk of knee OA , underwent whole‐body dual x‐ray absorptiometry ( DXA ) at baseline. At baseline, 30 months, and 60 months radiographs and magnetic resonance images ( MRI s) of the knees were obtained, and patients were asked to score the severity of their knee pain and to identify sites of joint pain using a body homunculus. Baseline DXA scans were used to measure total body fat and visceral and subcutaneous fat in the torso. The association of fat depot size with structural outcomes (incident radiographic OA and cartilage loss and synovitis on MRI ) and with pain outcomes (worsening knee pain, number of painful joints, and widespread pain) was assessed. Regression analyses were adjusted for age, sex, race, education level, smoking status, physical activity, body mass index ( BMI ), and depressive symptoms. Results Of the 2,961 participants at baseline, 60.7% were women. The mean age was 62.5 years and mean BMI was 30.5 kg/m 2 . After adjustment for covariates, no fat measures were associated with any structural outcomes. However, total and visceral, but not subcutaneous, fat were positively associated with worsening knee pain ( P = 0.0005 for total fat and P = 0.007 for visceral fat) and widespread pain ( P = 0.001 for total fat and P = 0.02 for visceral fat), and the amount of visceral fat was associated with the number of painful joints ( P = 0.07). Conclusion Our findings indicate that visceral fat is associated with an increased risk of musculoskeletal and widespread pain.
Renoprotective and Immunomodulatory Effects of GDF15 following AKI Invoked by Ischemia-Reperfusion Injury
Authors: Jing Liu, Sanjeev Kumar, Andreas Heinzel, Michael Gao, Jinjin Guo, Gregory F. Alvarado, Roman Reindl-Schwaighofer, A. Michaela Krautzberger, Pietro E. Cippà, Jill McMahon, Rainer Oberbauer, Andrew P. McMahon
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Gdf15 , which encodes a signaling factor activated by oxidative stress, DNA damage, and proinflammatory cytokines, is upregulated in the human and mouse kidney within a few hours of ischemia-reperfusion injury. Using novel mouse strains, the authors mapped cellular sites of Gdf15 expression in normal and injured kidney and examined Gdf15 ’s role in ischemia-reperfusion injury. They showed that Gdf15 is expressed within hypoxic regions of the kidney and is predominantly activated within tubular epithelial cells at injury repair sites; loss of Gdf15 exacerbated injury, enhancing the inflammatory response. In an analysis of clinical data, they demonstrated that single nucleotide polymorphisms linked to lower circulating GDF15 levels associate with an increased incidence of biopsy-proven acute rejection. These findings point to modulating GDF15 levels in patients receiving kidney transplant as a possible therapeutic strategy. Background Gdf15 encodes a TGF- β superfamily member that is rapidly activated in response to stress in multiple organ systems, including the kidney. However, there has been a lack of information about Gdf15 activity and effects in normal kidney and in AKI. Methods We used genome editing to generate a Gdf15 nuGFP-CE mouse line, removing Gdf15 at the targeted allele, and enabling direct visualization and genetic modification of Gdf15 -expressing cells. We extensively mapped Gdf15 expression in the normal kidney and following bilateral ischemia-reperfusion injury, and quantified and compared renal responses to ischemia-reperfusion injury in the presence and absence of GDF15. In addition, we analyzed single nucleotide polymorphism association data for GDF15 for associations with patient kidney transplant outcomes. Results Gdf15 is normally expressed within aquaporin 1–positive cells of the S3 segment of the proximal tubule, aquaporin 1–negative cells of the thin descending limb of the loop of Henle, and principal cells of the collecting system. Gdf15 is rapidly upregulated within a few hours of bilateral ischemia-reperfusion injury at these sites and new sites of proximal tubule injury. Deficiency of Gdf15 exacerbated acute tubular injury and enhanced inflammatory responses. Analysis of clinical transplantation data linked low circulating levels of GDF15 to an increased incidence of biopsy-proven acute rejection. Conclusions Gdf15 contributes to an early acting, renoprotective injury response, modifying immune cell actions. The data support further investigation in clinical model systems of the potential benefit from GDF15 administration in situations in which some level of tubular injury is inevitable, such as following a kidney transplant.
Myeloid-derived suppressor cells—new and exciting players in lung cancer
Authors: Zhenzhen Yang, Jiacheng Guo, Lanling Weng, Wenxue Tang, Shuiling Jin, Wang Ma
Journal: Journal of Hematology & Oncology (2020)

Abstract Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.
Profiles of Ganglion Cell-Inner Plexiform Layer Thickness in a Multi-Ethnic Asian Population
Authors: Yih-Chung Tham, Miao Li Chee, Wei Dai, Zhi Wei Lim, Shivani Majithia, Rosalynn Siantar, Sahil Thakur, Tyler Rim, Carol Y. Cheung, Charumathi Sabanayagam, Tin Aung, Tien Yin Wong, Ching-Yu Cheng
Journal: Ophthalmology (2020)
The incidence of peritoneal carcinomatosis and impact on outcomes in relapsed early T4 colorectal cancer.
Authors: Rosemary Habib, Val Gebski, Kenneth Micklethwaite, Duncan McLeod, James Toh, Toufic El-Khoury, Nimalan Pathma-Nathan, Grahame Ctercteko, Kavitha Gowrishankar, Nicholas Wilcken, Mark Wong, Adnan Nagrial
Journal: Journal of Clinical Oncology (2020)

73 Background: There is limited data regarding the association between peritoneal carcinomatosis (PC) and clinical outcomes in colorectal cancer (CRC). We examined the incidence of PC and explored the relationship to survival (RFS &amp; OS) in CRC. Methods: The demographic and clinical details of patients with stage II/III CRC referred to a tertiary centre in Western Sydney between 2009-2016 were obtained. Associations between clinical outcomes and baseline prognostic factors were investigated using proportional hazards regression models. The effect of prognostic factors on outcome were examined by tumour stage. Results: 495 patients were identified, 281 (57%) with stage II and 214 (43%) with stage III. Median follow-up was 38 months. 330 (67%) had T3 and 165 (33%) had T4 disease. Median age at diagnosis was 72 years (19 -94). 104 (21%) patients relapsed, 24 (23%) had PC and of those, 6 had PC as their only site of metastasis. 10% (n = 5) with T3 developed PC compared with 35% (n = 19) with T4 disease (P = 0.02). Compared with non-PC, PC was associated with poorer median OS (28 Vs 46 m; p = 0.03). Median RFS for T3 was 16 months, T4, 14 months (NS). Median OS for T3 was 34 months Vs T4 28 months (P = 0.45). Of those with PC relapse, the diagnosis of PC was highest in the first two years post-operatively (88%). 9 patients (38%) with PC died due to bowel obstruction Vs 4 (5%) patients with non-PC relapse (P &lt; 0.01). Poorer OS was associated with PC (HR 1.74; p = 0.03), right sided primary (HR 1.602; P = 0.05), T4 stage (HR 1.69; P = 0.03), LVI (HR 1.95; p &lt; 0.01), N stage (HR 1.51; P &lt; 0.01), and number of metastases at baseline (HR 1.25; p = 0.04). On multivariable analysis right sided primary and T4 stage remained significant. Conclusions: Patients with PC relapse have an 18 month shorter median OS than those with non-PC relapse. Further, PC recurrence is more common in patients with T4 compared with T3 CRC and was the only site of metastatic disease in 7% of relapsed patients with T4 CRC. Consideration for peritonectomy and/or HIPEC should be given for patients with PC metastases. For patients with resected early stage T4 CRC, consideration should be given for surveillance laparoscopy.