tbuckley/cabot-search huggingface dataset:
PD-1 blockade combined with COX inhibitor in patients with MSI-H/dMMR or high TMB, advanced or metastatic colorectal cancer (PCOX study).
Authors: Zehua Wu, Huabin Hu, Jianwei Zhang, Yue Cai, Xiaoyu Xie, Jiayu Ling, Weiwei Li, Yanhong Deng
Journal: Journal of Clinical Oncology (2020)

111 Background: MSI-H/dMMR and POLE mutation had been proven to be predictive of response to PD-1 blockade in metastatic colorectal cancer. However, reported response rates are often &lt; 50%. Several preclinical studies reported COX inhibitor improve antigen presentation and T-cell infiltration in tumors. We investigated the efficacy of PD-1 blockade combined with COX inhibitor in colorectal cancer patients with MSI-H/dMMR or POLE mutation. Methods: PCOX was a prospective, single arm, phase II study. Patients with MSI-H/dMMR or POLE mutation advanced or metastatic colorectal cancer received PD-1 blockade (pembrolizumab 200mg, q3w; or BAT 1306 100mg, q3w; or nivolumab 3mg per kilogram, q2w) plus COX inhibitor (celebrex 400mg or aspirin 200mg, p.o. qd). The primary endpoint was ORR, secondary endpoints included PFS, OS and safety. Results: Totally 24 patients were enrolled. 14(58.3%) patients were female. Median age was 41.5-years-old. Among 24 patients, 5(20.8%) patients were chemotherapy-naïve, 11(45.8%) patients had first line chemotherapy failed and 8(33.3%) patients had at least second lines chemotherapy failed. 22 patients were MSI-H/dMMR and 2 patients were with POLE mutation. At a median follow-up of 14.5 months, the ORR was 83.3% (20/24), including 5 patients achieved CR (3 pCR and 2 cCR). 3 patients achieved SD and 1 patient was PD. Median PFS and OS was not yet reached. One-year PFS rates was 80.7% (95%CI, 63.5%-97.9%). One-year survival rates was 91.3% (95%CI, 79.7%-100%). The reported treatment-related adverse events were listed in table below. Conclusions: The combination of PD-1 blockade plus COX inhibitor was associated with higher response rates in advanced or metastatic colorectal cancer patients with MSI-H/dMMR or POLE mutation than anti-PD-1 alone as historical controls. Clinical trial information: NCT03638297. [Table: see text][Table: see text]
Trends in PRO reporting in clinical trials leading to cancer immunotherapy drug approvals from 2011 to 2019.
Authors: Houssein Safa, Monica Tamil, Adi Diab, Adele Semaan, Jad Chahoud
Journal: Journal of Clinical Oncology (2020)

105 Background: Patient-reported outcomes (PROs) are a primary tool to evaluate the effect of a given drug on the health-related quality of life from a patient’s perspective and to maximize the value of patient-centeredness in drug development and approval. In this study, we aimed to evaluate the current trend in reporting, analysis and interpretation of PRO data. Methods: We conducted a systematic review of the FDA archives, identifying all cancer immunotherapy drug approvals between the years 2011 and 2019. We then retrieved the clinical trials that respectively led to these drug approvals from PubMed and ClinicalTrials.gov. We systematically screened for PROs and assessed their analytic tools and interpretation methods that were collected from the published journal articles and their study protocols. If one FDA approval was supported by more than one clinical trial, we included all studies in our review. An FDA approval was considered to include PROs if they were reported in at least one of the supporting trials. Results: Thirty-seven clinical trials leading to 35 immunotherapy drug approvals were identified. More than half (54%) did not publish any PROs. While PROs were reported in the primary clinical outcomes manuscript of 4 trials (11%) and in a secondary separately published paper for 13 trials (35%). The median time between the primary and secondary papers was 22 months (range: 5 - 40). In the 17 published PROs, the hypothesis was broad in 12 (71%), not reported in 4 (24%) and specific in only 1 (6%). Ten (59%) were reported as exploratory endpoints, five (29%) as secondary endpoints, and two (12%) did not specify the PRO reporting in their endpoints. The most common PRO instruments were EQ-5D (71%) and QLQ-C30 (65%). Control for type I error was needed but not done in 15 (88%). Fourteen (82%) described an approach for dealing with missing PRO assessments. None reported on significant differences based on race and ethnicity of participants. Conclusions: Suboptimal reporting and delays in publication of PROs occur regularly in cancer immunotherapy trials. Increased efforts are needed to enhance standardization and quality reporting of PROs to maximize the value of this data in cancer immunotherapy drug approval.
BET Signaling: A Novel Therapeutic Target for Pulmonary Hypertension?
Authors: Lingdan Chen, Chunli Liu, Wenju Lu, Tao Wang
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

To the Editor:Pulmonary hypertension (PH) is a progressive clinical condition with poor prognosis if the patients do not receive adequate therapy.Recent clinical trials demonstrate that combined therapy with multiple drugs improves pulmonary arterial hypertension outcomes more significantly compared with monotherapy (1, 2).However, there are only three types of drugs targeting PH, including the nitric oxide-cyclic guanosine monophosphate pathway, prostacyclin pathway, and endothelin pathway, in current clinical practice.Thus, introduction of new drugs targeting novel pathways may provide more combination options, especially for patients with pulmonary arterial hypertension who are resistant to or show adverse effects from current drugs.In a recent issue of the Journal, Van der Feen and colleagues (3) report that a clinically available BET (bromodomain and extraterminal motif) inhibitor, RVX-208, shows therapeutic effects on three preclinical PH models, with reduced pulmonary vascular resistance, increased cardiac output, and decreased pulmonary vascular remodeling and inflammation through FoxM1 (forkhead box protein M1) and PLK1 (polo-like kinase) signaling pathways.In cultured cells from patients with PH, RVX-208 suppresses pulmonary artery smooth muscle cell proliferation and endothelial cell inflammation through FoxM1/PLK1 pathways also.Drugs targeting these novel pathways have not been used for patients with PH yet because RVX-208 is now clinically available only for coronary artery disease.The promising in vivo and in vitro data from Van der Feen and colleagues suggest that RVX-208 may bring new hope for patients with PH.It is of note that RVX-208 shows synergistic effects with current PH-target drugs such as tadalafil and macitentan in PH models, which is extremely important because combination therapy has been recommended for patients with PH according to recent guidelines for PH practice.However, there are some pitfalls of this study; most of the PH-target drugs have the side effect of dilating blood vessels in systemic circulation.Given the fact that most patients with PH have relatively low blood pressure, it is very important to monitor the change of blood pressure after administration of PH-target drugs.In clinical practice, plasma level of BNP (B-type natriuretic peptide) and right atrial pressure are used to assess the severity and predict the prognosis of PH.It would be interesting to know the changes of blood pressure, BNP, and right atrial pressure on the PH animals in this study.
Establishment of patient-derived tumor xenograft (PDX) model as artificially-created liver metastasis using cryopreserved pancreatic ductal adenocarcinoma.
Authors: Kenjiro Kimura, Ryota Tanaka, Ryosuke Amano, Shoji Kubo, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira
Journal: Journal of Clinical Oncology (2020)

729 Background: Translational research using patient-derived tumor xenograft (PDX) model is progressing rapidly, and is also becoming widespread in pancreatic cancer research. The purpose of this study was to establish the liver transplant PDX model as artificially-created liver metastasis with cryopreserved primary pancreatic ductal adenocarcinoma(PDAC). Methods: The primary PDAC from 10 patients were cryopreserved and transplanted into NSG mice using liver pocket method. For engraftment and similarity evaluation, H&amp;E staining and immunohistochemical staining such as Ki-67, p53, SMAD4, and MUC1 were performed. Results: Patient-derived xenograft was succeeded in 6 cases (60%), 10 mice (33.3%). Ki-67 index of primary PDAC and the interval of cryopreservation were significantly related to successful engraftment, respectively (p = 0.003, p = 0.007). Conclusions: In this study, we succeeded in establishing a liver transplant PDX mouse model as a preclinical platform. The factors such as Ki-67 index and the interval of cryopreservation would affect the successful establishment.
Reply
Authors: Joanna Wallegren
Journal: British Journal of Dermatology (1991)

Journal Article Reply Get access Joanna Wallegren Joanna Wallegren Department of Dermatology, Lund University Hospital. S‐221 85 Lund, Sweden Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 125, Issue 6, 1 December 1991, Pages 605–606, https://doi.org/10.1111/j.1365-2133.1991.tb14810.x Published: 01 December 1991
Incidence and survival patterns of pancreatic neuroendocrine tumors over the last two decades: A SEER database analysis.
Authors: Mohamad Bassam Sonbol, Gina L. Mazza, Jason Scott Starr, Timothy J. Hobday, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2020)

629 Background: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with outcome varying by stage, grade, and clinical presentation. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs over the last two decades using a large population-based database. Methods: Using 2000-2016 data from the SEER 18 registry, we identified pts with PNETs using a combination of ICD-O-3 and histology codes. Age-adjusted incidence rates were calculated using SEER*Stat 8.3.5. Using SAS 9.4, overall survival (OS) was analyzed using the Kaplan–Meier method, and prognostic factors were investigated using a multivariate Cox proportional hazards model. Results: We identified 8,944 pts with PNETs. Annual incidence rates increased over the study period from 0.27 to 1.00 per 100,000. This was largely explained by a significant increase in number of pts diagnosed with localized disease in recent years (2012-2016). Median OS (mOS) for the entire cohort was 68 months (95% CI 64-73) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for pts diagnosed between 2009-2016 (mOS 85 months) compared to those diagnosed between 2000-2008 (mOS 46 months) (HR 0.66; p &lt; .001). In addition, pts with grade I/II metastatic disease who underwent surgery experienced significantly longer OS (mOS 84 months) compared to those who did not undergo surgery (mOS 18 months) (HR 0.31; p &lt; .001). In the multivariate analysis, more recent diagnosis, younger age, female sex, surgery, early stage, and lower grade favorably predicted OS. On the other hand, functional status and race did not predict OS. Conclusions: There has been a steady increase in the incidence of PNETs with notable stage migration as most patients are diagnosed in early stages of disease in recent years. Additionally, this increase in incidence is accompanied by a significant improvement in survival across different disease stages.
The role of circulating tumor DNA (ctDNA), tumor markers (TMs), and patient-reported outcomes (PROs) in predicting treatment response in patients with metastatic gastrointestinal (GI) cancer.
Authors: Aparna Raj Parikh, Madeleine Fish, Emily E. Van Seventer, Kathryn Fosbenner, Katie Kanter, Jill N. Allen, Jeffrey William Clark, Bruce Giantonio, Colin D. Weekes, Samuel J. Klempner, Joseph Wang Franses, Eric Roeland, Lipika Goyal, Jennifer Yon-Li Wo, Theodore S. Hong, Isobel Fetter, Giulia Siravegna, Nora K. Horick, Ryan Bruce Corcoran, Ryan David Nipp
Journal: Journal of Clinical Oncology (2020)

833 Background: Changes in ctDNA and serum TMs (CEA and CA19-9) can serve as predictors of response to systemic therapy in GI cancer patients (pts). Similarly, PROs correlate with survival and treatment response. We present a preliminary analysis of ctDNA, TMs, and PROs in predicting treatment response. Methods: We are enrolling 200 pts in a prospective study with metastatic pancreatic (PDAC), colorectal (CRC), gastroesophageal (GE), and biliary cancers. We are collecting ctDNA, TMs (CEA for all tumor types; CA19-9 for PDAC, GE, biliary), and PROs (FACT-G for QOL [higher scores indicate better QOL]; ESAS-r and PRO-CTCAE for symptoms; and PHQ-4 [consists of GAD-2 and PHQ-2 for anxiety and depression]; higher ESAS-r, PRO-CTCAE, and PHQ-4 scores reflect greater symptom burden) at baseline and 4 weeks. ctDNA is benchmarked against somatic tissue alterations, and serially assessed by digital droplet PCR. We correlated median percent change from baseline to 4 weeks for ctDNA, TMs, and PROs with treatment response (clinical benefit [CB], progressive disease [PD]). Results: From April to August 2019, we have enrolled 38/45 (84.4%) eligible pts (median age = 64 years; 36.8% female). Among these 38 pts, tumor types are PDAC (36.8%), CRC (31.6%), GE (28.9%), and biliary (2.6%). 18/38 pts were evaluable for ctDNA. Change in ctDNA was -94.5% in pts with CB (n = 10) and -19.5% in pts with PD (n = 8; p = 0.025). No correlation was observed between CEA and treatment response (p = 0.367). Change in CA19-9 was -1.5% for pts with CB and +47% for pts with PD (p = 0.019). Changes in PRO-CTCAE (p = 0.345), GAD-2 (p = 0.697), and ESAS scores (p = 0.743) did not differ between pts with CB and PD. However, changes in PHQ-2 (CB 0% v. PD +22.5%; p &lt; 0.001), PHQ-4 (CB -8.5% v. PD +5%; p = 0.015), and FACT-G (CB +30% v. PD +5%; p = 0.049) were significant. Conclusions: Preliminary analysis suggests that ctDNA and PROs demonstrate promising utility for early prediction of treatment response, with favorable performance relative to standard TMs. Further analyses of larger pt numbers in this ongoing study may clarify the use and integration of these measures to better predict pt outcomes.
Association of an RNA signature (RS) with emergence of ICOS hi CD4 T cells and efficacy outcomes for the ICOS agonist vopratelimab (vopra) and nivolumab (nivo) in patients (pts) on the ICONIC trial.
Authors: Timothy A Yap, Justin F. Gainor, Howard A. Burris, Shivaani Kummar, Russell Kent Pachynski, Margaret K. Callahan, Patricia LoRusso, Scott S. Tykodi, Geoffrey Thomas Gibney, Gerald Steven Falchook, Osama E. Rahma, Tanguy Y. Seiwert, Kyriakos P. Papadopoulos, James Walter Mier, Yasmin Hashambhoy-Ramsay, Daniel Felitsky, David Y. Lee, Lara McGrath, Christopher Harvey, Ellen Hooper
Journal: Journal of Clinical Oncology (2020)

14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an investigational ICOS agonist antibody that results in activation and proliferation of primed CD4 T effector cells. Vopra was assessed in heavily pretreated patients with advanced solid tumors as monotherapy (mono) or in combination with nivolumab (nivo) in the Phase 1/2 ICONIC trial (NCT02904226). Emergence of a distinct ICOS high (hi) population of peripheral CD4 T effector cells, not seen with PD-1 inhibitors alone, was associated with improved ORR, PFS and OS with vopra mono and combo therapy (AACR 2019). Baseline tumor and blood biomarkers were assessed for ability to predict ICOS hi CD4 T cell emergence and clinical outcomes. Methods: Fresh pre-treatment tumor biopsies were assessed by RS, a gene signature describing immune cell infiltration, and other biomarkers, including PD-L1 TPS by IHC. Pts were classified as RS1 and RS2 based on medium and high cutoffs. Associations between potential predictive biomarkers, ICOS hi CD4 T cell emergence and clinical outcomes were evaluated. Results: Baseline RS is significantly higher in patients with emergence of ICOS hi CD4 T cells. High RS was associated with increased emergence of ICOS hi CD4 T cells, accompanied by improved RECIST response, PFS, and OS. In contrast, no association was noted with PD-L1 IHC. Clinical trial information: NCT02904226. Conclusions: In this retrospective subset analysis, the RS score, but not PD-L1, in baseline tumor biopsies was predictive of emergence of an ICOS hi CD4 T cell population and improved RECIST response, PFS, and OS in patients treated with vopra alone and in combination with nivo. Clinical evaluation of vopra and investigational PD-1 inhibitor JTX-4014 in cancer patients with RS selection is planned. [Table: see text]
Cabazitaxel Early Access Program (EAP) - Canadian Interim Results: Safety, QOL, and Utility Values in Metastatic Castration Resistant Prostate Cancer (MCRPC)
Authors: S.S. Sridhar, E. Winquist, S. Hubay, C. St.-Laurent Thibault, H. Assi, S. Berry, E. Levesque, N. Aucoin, P. Czaykowski, F. Saad
Journal: Annals of Oncology (2012)
Effects of early discontinuation of adjuvant chemotherapy (EDAC) and the timing of treatment on outcomes in patients with early-stage pancreatic cancer (ESPC): Result from a population-based retrospective cohort study.
Authors: Javeria Muhammadzai, Michael Moser, Kamal Haider, John Shaw, Haji I. Chalchal, Donald Gardiner, Adnan Zaidi, Osama Ahmed, Yigang Luo, Bryan Brunet, Dueck Dorie-Anna, mussawar iqbal, Gavin Beck, Shahid Ahmed
Journal: Journal of Clinical Oncology (2020)

694 Background: Although evidence suggests that a delay in initiation of adjuvant chemotherapy (AC) results in inferior outcomes in some cancers, little is known about its detrimental effects in patients with ESPC. Moreover, it is not known if EDAC has been associated with high risk of recurrence and poor survival. The current study aims to determine association between timing and completion of AC and outcomes in ESPC. Methods: Patients with ESPC who were diagnosed from Jan 2007 to Dec 2017 and underwent complete resection in the province of Saskatchewan were examined. Kaplan Meier methods and log rank tests were performed for survival analyses. Cox proportional multivariate analyses were performed for correlation with recurrence and survival. Results: A total 168 patients with ESPC were identified. 97 (57%) patients were excluded as they did not receive AC, were found to have metastatic disease, did not have curative surgery or had received preoperative chemotherapy. Of 71 eligible patients with median age of 69 years (IQR: 57-73), 52% were male, 31% had WHO performance status of 0 and 92% had a comorbid illness. 78% had pancreatic head tumor, 66% had T3 tumor and 63% had node-positive disease. Median time to start of AC from surgery was 73 days (IQR: 59-89). 32% were started AC within 60 days of surgery. 89% received single-agent chemotherapy and 25% received adjuvant radiation. 69% completed planned treatment. Median time to recurrence in group which completed treatment was 22 months (95%CI:15.8-28.2) vs. 9 months (3.3-14.7) if treatment was discontinued early (P &lt; 0.001). Median overall survival of the group that completed treatment was 33 months (17.5-48.5) vs. 16 months (17.5-48.5) if it was stopped early (P &lt; 0.001). On multivariate analysis, EDAC was significantly correlated with recurrent disease (HR = 3.0; 1.6-5.5), P = 0.0001 and inferior survival (HR = 3.2; 1.68-6.12), P &lt; 0.001. No correlation between AC timing and survival was noted. Conclusions: Although timing of AC does not correlate with inferior outcomes, EDAC has been associated with high risk of recurrence and inferior survival in ESPC.
Abstract 15581: Effect of Dapagliflozin on Atrial Fibrillation/Flutter in Patients With Type 2 Diabetes Mellitus: Insights From the DECLARE-TIMI 58 Trial
Authors: Thomas A Zelniker, Marc P Bonaca, Ofri Mosenzon, Julia F Kuder, Sabina A Murphy, Remo H Furtado, Deepak L Bhatt, Lawrence A Leiter, Darren K McGuire, John P Wilding, Andrzej Budaj, Robert Gabor Kiss, Francisco Padilla, Ingrid A Gause-Nilsson, Anna Maria Langkilde, Itamar Raz, Marc S Sabatine, Stephen D Wiviott
Journal: Circulation (2019)

Introduction: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with diabetes and its comorbidities including hypertension, obesity, and heart failure (HF). Sodium-glucose cotranspor...
Impact of high-risk features for stage II adenocarcinoma of the appendix.
Authors: Mehmet Akce, Katerina Mary Zakka, Mckenna Penely, Renjian Jiang, Olatunji B. Alese, Walid Labib Shaib, Christina Wu, Madhusmita Behera, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2020)

795 Background: Clinico-pathological high risk features are frequently utilized in adjuvant chemotherapy (AC) decisions in stage II colorectal cancer and their utility in stage II appendiceal adenocarcinoma (AA) is less established. The aim of this study is to determine the impact of high risk features on clinical outcomes and whether high risk features are predictive of AC benefit in stage II AA. Methods: Patients with pathological stage II AA between 2010 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140, 8480 and C18.1. High risk stage II AA was defined as having at least one of the following clinicopathological features: T4 tumor, &lt; 12 lymph nodes examined, poorly differentiated histology, positive margins, or lymphovascular invasion. Patients with none of these features were defined as low-risk. Results: A total of 1,040 patients were identified. 51.0% males, 84.5% Caucasian; median age 61 (range, 19-90). 46.4% were determined to have high-risk stage II AA. High-risk status was associated with worse OS compared to low-risk in univariate (HR 1.55; 95% CI 1.18-2.02; p = 0.001) and multivariable analyses (HR 1.36; 95% CI 1.03-1.79; p = 0.028). High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients (67.1% vs. 74.5%, p = 0.0013). AC was administered in 34.4% (n = 166) of high-risk patients and in 36.5% (n = 203) of low-risk patients. Among high-risk patients, AC was not associated with better OS in univariate (HR 0.86; 95% CI 0.59-1.26; p = 0.722) and multivariable analyses (HR 1.35; 95% CI 0.90-2.04; p = 0.324) compared to no AC. Similarly, among low-risk patients, AC was not associated with better OS in univariate (HR 0.92; 95% CI 0.60-1.39; p = 0.813) and multivariable analyses (HR 1.27; 95% CI 0.81-2.02; p = 0.334) compared to no AC. For high-risk patients, 5-year OS was 68.3% in patients that received AC vs. 66.5% in patients that did not (p = 0.722). For low-risk patients, 5-year OS was 74.0% in patients that received AC vs. 76.3% in patients that did not (p = 0.813). Conclusions: High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients. AC did not improve survival regardless of high risk features in stage II AA.
Abstract 12779: Effect of Combination of Losartan and Hydrochlorothiazide on Diastolic Heart Failure in Dahl Salt-Sensitive Rats
Authors: Tetsuya Adachi, Kasumi Masuda, Toshihiko Asanuma, Satoshi Nakatani
Journal: Circulation (2012)

Background: Therapeutic strategy for diastolic heart failure (DHF) has not been established. Because angiotensin II receptor blocker (ARB) has cardioprotective effects and hydrochlorothiazide (HCTZ...
Helen Salisbury: Sitting in someone else’s chair
Authors: Helen Salisbury
Journal: BMJ (2020)

This week I took a turn at our front desk while the reception team had a long overdue meeting. I wasn’t very good at it, and at the end of my short shift I had to leave a list of things I’d not been able to sort out. My main learning was the extent of my ignorance about the practical complexities of being a GP receptionist. One of my colleagues asked whether it was good use of a doctor’s time, which was a fair question, so I’ve been thinking about why the answer is probably yes.

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