tbuckley/cabot-search huggingface dataset:
NANORAY-1100: A phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with anti-PD-1 therapy.
Authors: Colette J. Shen, Katherine LaRoque Jameson, Jared Weiss, Trevor Hackman, Robert Dixon, Jason A. Akulian, Alexander T. Pearson, Jessica Frakes, Patricia Said, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2020)

TPS86 Background: Most cancer patients present resistance to immune therapy; only approximately 15% of patients respond to immune checkpoint inhibitors (ICI). Strategies able to increase ICI response are thus of great interest. Radiotherapy (RT), by acting as an immunomodulator is a good candidate to increase the proportion of ICI responders. However, RT dose and ultimate efficacy are limited by potential toxicity to healthy tissues. NBTXR3, a first in class radioenhancer administered by intratumoral injection, has been designed at the nanoscale to increase RT energy dose deposition within the tumor. The result is increased radiation-dependent tumor cell killing, without increasing radiation exposure of healthy tissues. Preclinical and early clinical data suggest NBTXR3 activated by RT can increase the anti-tumor response yielding both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect while also producing a systemic effect sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: NANORAY-1100 [NCT03589339] is a multicenter, open-label, phase 1 study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregionally recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases from any primary cancer eligible for anti-PD-1, or (3) Liver metastases from any primary cancer eligible for anti-PD-1. Approximately two-thirds of each cohort will be composed of anti-PD-1 non-responders. NBTXR3 injection volume is based on a percentage of gross tumor volume (GTV) determined by central review. The primary objective is to determine R3/RT/PD-1 RP2D. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR) of R3/RT/PD-1, safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, mRNA and cytokine immune marker profiling. Clinical trial information: NCT03589339.
Tumor Mutational Burden and <i>PTEN</i> Alterations as Molecular Correlates of Response to PD-1/L1 Blockade in Metastatic Triple-Negative Breast Cancer
Authors: Romualdo Barroso-Sousa, Tanya E. Keenan, Sonia Pernas, Pedro Exman, Esha Jain, Ana C. Garrido-Castro, Melissa Hughes, Brittany Bychkovsky, Renato Umeton, Janet L. Files, Neal I. Lindeman, Laura E. MacConaill, F. Stephen Hodi, Ian E. Krop, Deborah Dillon, Eric P. Winer, Nikhil Wagle, Nancy U. Lin, Elizabeth A. Mittendorf, Eliezer M. Van Allen, Sara M. Tolaney
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC. Experimental Design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features. Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169). Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.
A study looking at changes in scores over time when using 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 (2020)

Atopic dermatitis is a common skin disease that causes extreme itching (called pruritus) and which mainly affects children. In the United States (U.S.A.), around 17% of schoolchildren are thought to have experienced atopic dermatitis and in Northern Europe, it is similar at about 16%. The researchers of this study are based in the U.S.A and in Germany. The Childhood Atopic Dermatitis Impact Scale (CADIS) is a questionnaire that measures quality of life in young children affected by atopic dermatitis, and their parents. This study aimed to find out whether the CADIS is able to detect changes over time and how big those changes have to be in order to be beneficial for the patients. Parents of affected children completed the CADIS and rated their child's skin condition on a single question at initial enrolment and four weeks later. Only children whose skin condition improved, showed significantly better CADIS scores after four weeks, i.e. the CADIS was sensitive to change towards improvement. However, change scores must be interpretable to be clinically useful. For this reason, the authors calculated the minimal important change (MIC), which is the smallest change in score which patients perceive as beneficial. An improvement in the CADIS of more than 12% was found to very likely represent a clinically important change. Since the CADIS is able to measure change over time, it is a useful instrument in clinical practice. This summary relates to the study: Evaluation of responsiveness and estimation of smallest detectable change and minimal important change scores for the Childhood Atopic Dermatitis Impact Scale
Pemetrexed plus erlotinib as a salvage treatment in high EGFR-expressing metastatic colorectal cancer patients following failure of standard chemotherapy: A phase II single-arm prospective study.
Authors: Seonggyu Byeon, Seung Tae Kim, Jung Yong Hong, Jeeyun Lee, Joon Oh Park, Ho-Yeong Lim, Won Ki Kang, Young Suk Park
Journal: Journal of Clinical Oncology (2020)

104 Background: We conducted a single-arm, phase II study to evaluate the combination of pemetrexed and erlotinib as a salvage treatment in high EGFR-expressing (2+ or 3 on immunohistochemistry (IHC)) metastatic colorectal cancer (CRC) patients who failed to show a benefit after standard chemotherapy. Methods: We investigated pemetrexed and erlotinib (pemetrexed 500 mg/m 2 on Day 1 and erlotinib 100 mg/m 2 on Days 1–21) as a salvage treatment, given every three weeks, until disease progression or intolerable toxicity. The primary outcome was overall response rate (RR). Results: From May 2017 to April 2018, 29 metastatic CRC patients with high EGFR expression who previously received the standard therapies were enrolled into this trial. The regimen was well tolerated. Skin rash, vomiting, fatigue, and anorexia were common toxic effects but were mostly manageable and controllable side effects of only grades 1 or 2. In intent-to-treat analysis, three partial responses (PRs) were observed in enrolled patients, revealing an overall RR of 10.3%. This value supported the statistical hypothesis of this study. Fifteen patients had stable disease and the disease control rate (DCR) was 62.1%. All three patients who achieved a PR had an expression of EGFR 3+ in a tumor. Among eight patients with a tumor expressing an EGFR value of 3+, the RR and DCR were 37.5% and 75.0%, respectively. Conclusions: This phase II trial using pemetrexed and erlotinib in metastatic CRC with high EGFR expression met the primary endpoint of tumor response. Clinical trial information: NCT03086538.
Prospective DPYD testing and dose adjustment in colorectal cancer patients prior to fluoropyrimidine-based chemotherapy: Experience in a regional cancer center.
Authors: Janet Shirley Graham, Jocelyn Saunders, Gregory Naylor, Christine Crearie, Wendy Campbell, Tareq Abdullah, Mary G. Dunn, Nicholas James MacLeod, Alec McDonald, Gillian McGaffin, Anne Jane McKillop, Laura Miller, Nazia Mohammed, Aqilah Othman, Liz Radford, Karen Smith, Dawn Jane Storey, Nicola Williams, Paul Westwood, Richard H. Wilson
Journal: Journal of Clinical Oncology (2020)

93 Background: The fluoropyrimidines (FP), 5-Fluorouracil (5-FU) and capecitabine are a mainstay of colorectal cancer (CRC) treatment. Dihydropyrimidine dehydrogenase (DPYD), an enzyme encoded by the DPYD gene, is the initial and rate-limiting step in pyrimidine catabolism, deactivating over 80% of 5-FU. Approximately 5% of the population are deficient in DPYD and can develop severe or fatal FP toxicities. Currently, few national guidelines recommend routine prospective DPYD testing. In July 2019, we commenced a 6 month prospective pilot, testing DPYD status of all CRC patients undergoing first FP treatment in a large regional cancer centre. Methods: All CRC patients eligible for first exposure to FP are tested using a rapid molecular assay screening for five SNPs (detects 70% of DPYD mutations) and we will present data on prevalence of each. We will use electronic chemotherapy prescribing records (July 19-Jan 20) to collect information on dose modifications and toxicities. Once the pilot is completed we will perform a cost-effectiveness analysis. Results: Data from the first 3 months of this pilot have been reviewed and 201 patients have been tested with 15 heterozygotes identified, of which 2 had more than one mutation. No homozygotes were found. All heterozygote patients are started with a dose reduction (or have alternative therapy). One patient treated at 50% dose was hospitalised with several grade 3 toxicities despite dose reduction. Two patients have had subsequent dose escalation (by 25%). Nine patients have received one dose reduced cycle without complication. Three patients are due to start dose-reduced treatment. Conclusions: Routine prospective testing of DPYD status in a large regional cancer centre is feasible and with a sufficiently swift result turnaround to permit up-front dose modification. Detailed toxicity analysis and cost-effectiveness data will be presented.
経食道心エコーに対する心臓内科医が投与したプロポフォール鎮静の安全性 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Mahara Keitaro, Sasaki Shunsuke, Ota Mitsuhiko, Kishiki Kanako, Umemura Jun, Sumiyoshi Tetsuya, Tomoike Hitonobu
Journal: Circulation (2013)
Cytoreductive surgery in selected patients with metastatic gastric cancer treated with systemic chemotherapy.
Authors: Yaniv Berger, Darryl Schuitevoerder, Charles Christian Vining, Mihai Giurcanu, Mitchell C. Posner, Kevin K. Roggin, Blase N. Polite, Chih-Yi Liao, Oliver Eng, Daniel V.T. Catenacci, Kiran Turaga
Journal: Journal of Clinical Oncology (2020)

409 Background: Cytoreductive surgery (CRS – gastrectomy combined with metastasectomy) for non-palliative indications is controversial for patients with metastatic gastric adenocarcinoma (MGA). We hypothesized that CRS in addition to systemic chemotherapy is associated with an improved survival when compared to patients with MGA receiving chemotherapy alone. Methods: Patients with MGA who received systemic chemotherapy between 2004-2016 were identified using the National Cancer Database (NCDB). Nearest neighbor 1:1 propensity score matching of demographic, tumor-related and treatment-related factors was used to create comparable groups. Overall survival (OS) was compared between subgroups using Kaplan-Meier analyses. Immortal bias analysis was performed among those that survived at least 90 days. Results: We identified 29,728 chemotherapy-treated patients who were divided into 4 subgroups: No surgery (NS, n = 25,690), metastasectomy alone (n = 1170), gastrectomy alone (n = 2248) and CRS (n = 620) with a median OS of 8.6, 10.9, 14.8 and 16.3 months, respectively (p &lt; 0.001). Compared to patients who underwent no surgery, patients who underwent CRS were younger (58.9±13.4 vs. 62.0±13.1 years), had lower proportion of disease involving multiple sites (5.0% vs. 26.2%), and were more likely to have clinically occult disease (cM0 58.9% vs. 7.3%) - all p &lt; 0.001. OS for propensity matched patients who underwent CRS (n = 490) was longer than NS (16.3 vs. 8.8 months, p &lt; 0.001), including those with clinical M1 stage (n = 203) in both unmatched and propensity matched (median OS 19.7 vs. 8.6 months, p &lt; 0.001) cohorts. On Cox regression model using the matched data, the hazard ratio for CRS vs. NS was 0.80 (95%CI 0.76-0.84). In the immortal matched cohort, the corresponding median OS was 16.7 vs. 9.7 months, p &lt; 0.001. Conclusions: CRS in addition to systemic chemotherapy may be associated with an OS benefit in a selected group of patients with metastatic gastric adenocarcinoma. Suboptimal matching for tumor burden is our major limitation. In contrast to studies that focus on gastrectomy alone in the setting of MGA, this study highlights the role of CRS among patients receiving systemic chemotherapy.
More Meta-analytical Explorations on Adolescent Sexual Health Interventions Are Needed
Authors: Yuan Yuan, Wenquan Niu
Journal: JAMA Pediatrics (2020)

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Abstract 18107: Systolic Stretch Improves Prediction of Response to Cardiac Resynchronization Therapy in Patients With QRS Width 120-149ms or Non-Left Bundle Branch Block: An Adaptive CRT Trial Substudy
Authors: John Gorcsan, Christopher P Anderson, Bhupendar Tayal, Masataka Sugahara, John Walmsley, Randall C Starling, Joost Lumens
Journal: Circulation (2017)

Background: Guidelines favor cardiac resynchronization therapy (CRT) for patients with left bundle branch block (LBBB) and QRS width ≥150ms. CRT is less clear for those with QRS width 120-149ms or ...
Abstract 9759: Mechanism of the Protective Effects of L-carnitine on Left Ventricular Dysfunction after Short-term Oral Alcohol Administration in Rats
Authors: Zhi Zhang, Che Ping Cheng, Satoshi Masutani, Tiankai Li, Heng-Jie Cheng
Journal: Circulation (2019)

Background: Recent studies indicate that alcohol exposure induces cardiac injury through the induction of oxidative stress. L-carnitine (LC), a natural-occurring amino acid and an essential cofacto...
102P Phase 3 Study Of Nktr-102 Versus Treatment of Physician's Choice (Tpc) in Patients (Pts) with Locally Recurrent or Metastatic Breast Cancer (Mbc) Previously Treated with an Anthracycline, a Taxane, and Capecitabine (Atc)
Authors: J. Cortes, E. Perez
Journal: Annals of Oncology (2012)
Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial
Authors: Robert H Jones, Angela Casbard, Margherita Carucci, Catrin Cox, Rachel Butler, Fouad Alchami, Tracie-Ann Madden, Catherine Bale, Pavel Bezecny, Johnathan Joffe, Sarah Moon, Chris Twelves, Ramachandran Venkitaraman, Simon Waters, Andrew Foxley, Sacha J Howell
Journal: The Lancet Oncology (2020)

Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer.
中枢神経系疾患:電位依存性カリウムチャネル遺伝子KCNH1の変異がテンプル・バライスター症候群およびてんかんを引き起こす | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Simons Cas, Rash Lachlan D, Crawford Joanna, MA Linlin, Cristofori-Armstrong Ben, Miller David, RU Kelin, Baillie Gregory J, Grimmond Sean M, King Glenn F, Taft Ryan J, Alanay Yasemin, Jacquinet Adeline, Debray Francois-Guillaume, Verloes Alain, Shen Joseph, Yesil Goezde, Guler Serhat, Yuksel Adnan, Cleary John G, Mcgaughran Julie, Gabbett Michael T
Journal: Nature Genetics (2015)
Detection of microbial DNA in the blood of colorectal cancer patients for the diagnosis of microbial translocation.
Authors: Ioannis Sougklakos, Ippokratis Messaritakis, Konstantinos Vogiatzoglou, Konstantina Tsantaki, Agapi Dretaki, Asimina Koulouridi, Maria Sfakianaki, Andreas Vasileios Koulouris, Maria Tzardi, Dimitrios Mavroudis, Ioannis Boukovinas
Journal: Journal of Clinical Oncology (2020)

171 Background: Dysbiosis has been associated with diseases and is of a major public health importance. Can lead to the passage of viable bacteria, their products or their fragments from the intestinal lumen through the mesenteric lymph nodes and other sites, known as bacterial translocation. The aim of the study was to determine whether microbial translocation occurs in stage II/III-IV colorectal cancer (CRC) patients and evaluate the usefulness of blood PCR for diagnosis of such translocation. Also to correlate the presence of Toll-Like Receptor and Vitamin D Receptor polymorphisms with the detection of microbial DNA fragments in the blood of CRC patients. Methods: Peripheral blood was obtained from 397 CRC patients (adjuvant n = 202 and metastatic n = 195) and 32 healthy individuals. DNA from all subjects was analyzed using PCR for amplification of genomic DNA encoding 16S rRNA, β-galactosidase gene of E. coli, Glutamine synthase gene of B. fragilis and 5.8S rRNA found in C. albicans. Results: Significantly higher rates of 16S rRNA, β-galactosidase, Glutamine synthase and 5.8S rRNA detection was observed in the pool of CRC patients than the controls ( p&lt; 0.001). All microbial DNA fragments detected were also significantly associated with the metastatic disease ( p&lt; 0.001) leading to shorter survival rates ( p&lt; 0.001). Moreover, individuals with the homozygous mutant alleles of either TLR or VDR gene polymorphisms had significantly higher detection rates of microbial DNA fragments. Conclusions: The detection of microbial DNA fragments in patients with CRC highlights the role of these microbes in cancer development, progression and therefore in patients’ survival.
Analysis of Hepsin mRNA expression by real time PCR and in situ hybridization in normal tissues and tumors of human colon, lung and bladder
Authors: Vun-Sin Lim, Neville Young, Beryl Cronin, Sandie Martin, Paul Loadman, Jason Gill, Roger Phillips
Journal: Cancer Research (2007)

1486  Hepsin is a serine protease that has been implicated in the metastatic process and is overexpressed in prostate cancer. Little is known about the expression of hepsin in other tumors and therefore the aim of the study was to characterise hepsin expression in more clinical tumor specimens. Using beta-actin as an internal standard, analysis of hepsin expression by real time PCR in tumor tissues shows that non-small cell lung cancer (NSCLC, n = 39) expressed the highest hepsin mRNA level (mean expression ratio 3692 x 10-5) followed by colon tumors (mean expression ratio 1681 x 10-5, n = 38) and bladder tumors (mean expression ratio 273.2 x 10-5, n = 46). Inter-patient heterogeneity was low in colon (ranging from 7.36 to 13947 x 10-5 ) and NSCLC tumors (ranging from 2.83 to 13112.4 x 10-5 ) but considerably high in bladder tumors (ranging from 0.5 to 3386.6 x 10-5 ). However, there is evidence from the bladder tumor study that hepsin expression was almost 4-fold higher in invasive disease (T2) compared to the superficial tumors (Ta/T1) with median expression ratios of 48.4 x 10-5 and 12.5 x 10-5 respectively. In normal tissues, colon (n = 13) expressed the highest hepsin mRNA level (mean expression ratio 28650 x 10-5), followed by NSCLC (mean expression ratio 9486 x 10-5, n= 14) and bladder (mean expression ratio of 63.7 x 10-5, n = 18). When comparing normal tissues and tumors, considerable inter-patient heterogeneity exists within both superficial and invasive bladder tumours with some tumours having significantly elevated levels of hepsin (> 100 fold) compared to normal tissues. In these cases, therapeutic strategies designed to inhibit or use hepsin to activate pro-drugs may be useful in the treatment of invasive bladder cancer. In contrast, normal tissues of colon and lungs showed significantly higher hepsin mRNA levels than those in the respective tumors. These expression profiles were further confirmed by in situ hybridisation (probe generated from pCR4-TOPO/Hepsin provided by Genentech, USA); hepsin was mainly localised in the epithelial cells of the normal colon and lung tissues at high level but distributed in the stroma of tumors (including lymphocytes and capillaries) at low levels. In conclusion, this study has demonstrated that the expression of Hepsin mRNA is high in normal colon and lung tissues and provides an early indication that toxicity to these organs may occur following treatment with inhibitors of Hepsin.