tbuckley/cabot-search huggingface dataset:
Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.
Authors: Hideaki Bando, Daisuke Kotani, Masahito Kotaka, Akihito Kawazoe, Toshiki Masuishi, Hironaga Satake, Hiroya Taniguchi, Kentaro Yamazaki, Takeharu Yamanaka, Eiji Oki, Takayuki Yoshino, Kei Muro, Yoshito Komatsu, Takeshi Kato, Akihito Tsuji
Journal: Journal of Clinical Oncology (2021)

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m 2 , IRI 200 mg/m 2 , and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m 2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m 2 , OX 100 mg/m 2 ), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m 2 , OX 130 mg/m 2 ), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2 nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m 2 IRI, 130 mg/m 2 OX, 1600 mg/m 2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.
SP0152 Why campaigning is good for arthritis!
Authors: N Betteridge
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> The paper will explain why people with arthritis are beginning to campaign in new ways and how this can benefit themselves as individuals, the community of people with arthritis and society as a whole. It will explore the sometimes fractious, and still evolving, history of how people with arthritis have gradually moved away from seeing themselves in an entirely medical context; but also how the social model of disability has been both a liberation and a limitation. The energies of people with arthritis have been released by developing a vision where we are more than just patients or passive recipients of care. We now know that we can be actively involved in managing our condition and have a right to be actively involved in society. But where is that release of energy taking us? Citing anti-discrimination legislation in both the UK and the USA, the paper will seek to summarise the public policy position for people with arthritis in 2001 but will also be forward looking. Does the advent of new technologies mean that science once more becomes the focus for people with arthritis? Or will the links with the civil rights movement of disabled people strengthen and grow so that medicine will be overshadowed by a political drive based entirely on social issues? The speaker, Neil Betteridge, has personal experience of arthritis and is Head of Public Policy and Campaigning at Arthritis Care in the UK. Whilst working for the Royal Association for Disability and Rehabilitation (RADAR) he was involved in campaigning for, and helping to influence, the Disability Discrimination Act 1995. He is currently actively involved in the European Manifesto for People with Arthritis and Rheumatism in Europe.
Adjuvant therapy in patients with resected pancreatic adenocarcinoma: Analysis of treatment allocation patterns in a Canadian provincial institution.
Authors: Manik Chahal, Jonathan M. Loree, Howard John Lim, Janine Marie Davies, Daniel John Renouf, Sharlene Gill
Journal: Journal of Clinical Oncology (2021)

383 Background: In recent years adjuvant therapy (AT) for pancreatic cancer has evolved. Improved overall survival (OS) was demonstrated first in 2017 with gemcitabine and capecitabine (GemCap), and then further improved in 2018 with FOLFIRINOX compared to gemcitabine (gem) alone. Given these options, we retrospectively reviewed the patterns of AT allocation in the province of British Columbia (BC) during these periods of adoption of newer AT regimens. Methods: Patients (pts) treated at BC Cancer centers between January 2017 to June 2018 (the GemCap era), and July 2018 to July 2019 (the FOLFIRINOX era), who had undergone curative intent resection and received at least one cycle of AT were included for chart review. Patient and disease characteristics, treatment details, and stated rationale for choice of AT regimen were collected. Analyses were performed with one-way ANOVA for comparison of means between regimens, and Chi-squared or Fisher Exact tests to determine correlation between clinicopathologic factors and likelihood of undergoing a given AT regimen. Results: 122 pts were identified: 67 treated in the GemCap era (gem: 25, 37%, and GemCap: 42, 63%) and 55 treated in the FOLFIRINOX era (gem: 18, 33%, GemCap: 18, 33%, FOLFIRINOX: 19, 34%). Examined variables included age, gender, ECOG, T and N stage, margins, lymphovascular invasion and post-operative CA19-9. In the GemCap era, use of GemCap vs Gem was associated with younger average age (p = 0.001) and positive lymph node status (91% vs. 60%, p = 0.005). In the FOLFIRINOX era, use of gem AT was associated with a delayed time from surgery to consultation. (p = 0.036) AT assignment was not influenced by high volume vs low volume centre in the GemCap era; however, pts were more likely to receive GemCap in low-volume centres during the mFOLFIRINOX era (p = 0.045). The most common stated reasons for choice of a less intense AT regimen were pt comorbidities or functional status (GemCap era: 24% and FOLFIRINOX era: 31%). Conclusions: Despite improvements in survival with newer AT regimens, the majority of pts in our real-world setting were assigned a less intense AT regimen. Within the limits of a small sample size, significant pt or disease factors predictive of AT assignment were not identified aside from age and lymph node positivity in the GemCap era, and time from surgery to consultation in the FOLFIRINOX era. Efforts to improve adoption of newer AT regimens and optimize pt eligibility for FOLFIRINOX are warranted.
Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β
Authors: Demi Brownlie, Dahlia Doughty-Shenton, Daniel YH Soong, Colin Nixon, Neil O Carragher, Leo M Carlin, Takanori Kitamura
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Metastatic breast cancer is a leading cause of cancer-related death in women worldwide. Infusion of natural killer (NK) cells is an emerging immunotherapy for such malignant tumors, although elimination of the immunosuppressive tumor environment is required to improve its efficacy. The effects of this “metastatic” tumor environment on NK cells, however, remain largely unknown. Previous studies, including our own, have demonstrated that metastasis-associated macrophages (MAMs) are one of the most abundant immune cell types in the metastatic tumor niche in mouse models of metastatic breast cancer. We thus investigated the effects of MAMs on antitumor functions of NK cells in the metastatic tumor microenvironment. Methods MAMs were isolated from the tumor-bearing lung of C57BL/6 mice intravenously injected with E0771-LG mouse mammary tumor cells. The effects of MAMs on NK cell cytotoxicity towards E0771-LG cells were evaluated in vitro by real-time fluorescence microscopy. The effects of MAM depletion on NK cell activation, maturation, and accumulation in the metastatic lung were evaluated by flow cytometry (CD69, CD11b, CD27) and in situ hybridization ( Ncr1 ) using colony-stimulating factor 1 (CSF-1) receptor conditional knockout ( Csf1r -cKO) mice. Finally, metastatic tumor loads in the chest region of mice were determined by bioluminescence imaging in order to evaluate the effect of MAM depletion on therapeutic efficacy of endogenous and adoptively transferred NK cells in suppressing metastatic tumor growth. Results MAMs isolated from the metastatic lung suppressed NK cell-induced tumor cell apoptosis in vitro via membrane-bound transforming growth factor β (TGF-β) dependent mechanisms. In the tumor-challenged mice, depletion of MAMs increased the percentage of activated (CD69 + ) and mature (CD11b + CD27 – ) NK cells and the number of Ncr1 + NK cells as well as NK cell-mediated tumor rejection in the metastatic site. Moreover, MAM depletion or TGF-β receptor antagonist treatment significantly enhanced the therapeutic efficacy of NK cell infusion in suppressing early metastatic tumor outgrowth. Conclusion This study demonstrates that MAMs are a main negative regulator of NK cell function within the metastatic tumor niche, and MAM targeting is an attractive strategy to improve NK cell-based immunotherapy for metastatic breast cancer.
The evolution of the <i>European Respiratory Journal</i>: weathering the publishing pandemic
Authors: Martin Kolb, James D. Chalmers, Marc Humbert
Journal: European Respiratory Journal (2021)

<b>The COVID-19 pandemic has led to an unprecedented surge in medical publishing, during which the <i>ERJ</i> has had to weather twice as many manuscript submissions as usual</b>https://bit.ly/38IAidU
SP0149 The mar y sol project
Authors: GH Thorén
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Many rheumatics benefit from sun, warmth and a combination of individual treatment by a physiotherapist and physical training in groups, whereby mobility is improved and pain decreases. Swedes have consequently looked for treatment abroad. At the south of Tenerife in the Canary Islands is the Swedish rehabilitation centre Vintersol. People with a range of chronic diseases can be treated during a period of four weeks, financed by public funds. The number of participants is unfortunately very restricted. The Östergötland area has a population of somewhat over 400 000, of which 3000 are members of the local branch of the Rheumatism organisation. A total of around 50 persons are annually granted funding for treatment abroad, of which about 22 are adult rheumatics and six juvenile rheumatics. There is a wide disparity between supply and demand. Patients with rheumatoid arthritis and ankylosing spondylitis are those usually given climate-care. Many diagnoses are consequently not included, but age and general health can also be decisive in the selection process. The Rheumatism organisation in the region of Oestergötland has together with the County Council (Landstinget) in charge of health care in the region carried out a project where 37 rheumatics participated in a 14 -day rehabilitation programme at Marysol in Tenerife, when health professionals from Vintersol were available. The County Council subsidised the project with 115 00 swedish crowns (c. 1 300 Euro), a sum which also enabled a specialised rheumatology nurse to travel with the group of patients. The National Health Service also decided that the "season ticket system", where a ceiling for medical care is reached after a total annual cost of 1800 swedish crowns, should apply. The participants all had letters of referral from their doctors. The purpose has been to determine whether two weeks in a warm climate combined with treatment gives a good and prolonged effect. The results have also been compared regarding different diagnoses. The project has aimed to further cooperation by encouraging the County Council to annually subsidise travel for a number of rheumatics who for various diagnostical, economical, health or other reasons are not allowed or do not have the possibility of climate-care. Good results were noted even after 14 days. All the participants had increased mobility, less pain and reduced need of analgesics. The social aspect was seen to be particularly important for the single or lonely rheumatics. Financial benefit was noted in the comparison of four weeks at Vintersol at a cost of 40 000 Swedish crowns and two weeks at Mar y sol for 10 000 Swedish crowns. The relatively low cost was ensured by local volunteer-work, and the participants paid both privately and with help from various funds.
Liver disease and poor outcomes of COVID-19 hospitalizations-a meta-analysis
Authors: A. Sharma, D. Mehta, P. Jaiswal, H. Upadhyay, S. Nagaraj, A. Zergham, Z. Murtaza, Y. Kerakhan, A. Deol, B. Francis, A. Akbar, L. Saravanan, R. Jaiswal, P. Malik
Journal: Hepatology (2020)

Background: COVID-19 pandemic has been a challenge with globally 12,567,457 coronavirus cases reported and 561,879 deaths as of July 11, 2020 Isolated small studies have reported the prevalence of comorbid chronic liver disease (CM-CLD) and COVID-19 associated acute liver injury (COVID-19-ALI) in hospitalized patients In this metaanalysis, we assessed the association of comorbid liver disease and acute liver injury and outcomes in COVID-19 hospitalized patients Methods: Observational studies describing the CM-CLD and COVID-19-ALI and outcomes of COVID-19 hospitalized patients from December 1, 2019, to June 30, 2020, were identified  Data was extracted following MOOSE guidelines with a consensus of four independent reviewers  Adverse outcomes were defined as admission to intensive care unit (ICU), oxygen saturation <90%, invasive mechanical ventilation (IMV), severe disease and in-hospital mortality Data was analysed using Review Manager 5 4 The odds ratio (OR) and 95% confidence interval (95%CI) were obtained and forest plots were created using randomeffects models The p value <0 05 was considered statistically significant  Results: 12 studies with 7564 confirmed COVID-19 patients were included Out of these, 12 studies (7564 patients) and 3 studies (146 patients) provided data on CM-CLD and COVID-19-ALI, respectively The pooled prevalence of CM-CLD was 2 67% [(202/7564)∗d COVID-19-ALI was 22 6% [(33/146)∗ patients with poor outcomes, the prevalence of CM-CLD was 2 4%(54/2233) and COVID-19-ALI was 32% (18/56) In meta-analysis, CM-CLD had no significant association with poor outcomes (OR:0 89;95%CI:0 65-1 22;p=0 47) with no heterogeneity in the data (p=0 93;I2=0%) COVID-19-ALI had higher odds of poor outcomes with OR of 2 49 (95%CI:1 09-5 69;p=0 03) and without any significant heterogeneity between studies (p=0 67;I2=0%) Conclusion: Our meta-analysis suggests that acute liver injury was significantly associated with COVID-19 severity and poor outcomes Future studies should evaluate changing levels of biomarkers amongst liver disease patients to predict poor outcomes of COVID-19
Abstract 13850: The Role of Mitral Regurgitation of Either Primary and Secondary Origin on Left Atrial Dynamics During Exercise: Insights From Exercise Echocardiography Combined With Gas Exchange Analysis
Authors: Tadafumi Sugimoto, Francesco Bandera, Greta Generati, Eleonora Alfonzetti, Vincenzo Tufaro, Marco Guazzi
Journal: Circulation (2017)

Background: The hemodynamic impact of left atrial (LA) dynamics in dynamic mitral regurgitation (MR) on cardiopulmonary function has never been studied. Methods: 47 primary MR, 85 secondary MR, and...
Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist
Authors: Punit Upadhyaya, Johanna Lahdenranta, Kristen Hurov, Sailaja Battula, Rachel Dods, Eric Haines, Marianna Kleyman, Julia Kristensson, Jessica Kublin, Rachid Lani, Jun Ma, Gemma Mudd, Elizabeth Repash, Katerine Van Rietschoten, Tom Stephen, Fanglei You, Helen Harrison, Liuhong Chen, Kevin McDonnell, Philip Brandish, Nicholas Keen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background In contrast to immune checkpoint inhibitors, the use of antibodies as agonists of immune costimulatory receptors as cancer therapeutics has largely failed. We sought to address this problem using a new class of modular synthetic drugs, termed tumor-targeted immune cell agonists (TICAs), based on constrained bicyclic peptides ( Bicycles ). Methods Phage libraries displaying Bicycles were panned for binders against tumor necrosis factor (TNF) superfamily receptors CD137 and OX40, and tumor antigens EphA2, Nectin-4 and programmed death ligand 1. The CD137 and OX40 Bicycles were chemically conjugated to tumor antigen Bicycles with different linkers and stoichiometric ratios of binders to obtain a library of low molecular weight TICAs (MW &lt;8 kDa). The TICAs were evaluated in a suite of in vitro and in vivo assays to characterize their pharmacology and mechanism of action. Results Linking Bicycles against costimulatory receptors (e.g., CD137) to Bicycles against tumor antigens (e.g., EphA2) created potent agonists that activated the receptors selectively in the presence of tumor cells expressing these antigens. An EphA2/CD137 TICA (BCY12491) efficiently costimulated human peripheral blood mononuclear cells in vitro in the presence of EphA2 expressing tumor cell lines as measured by the increased secretion of interferon γ and interleukin-2. Treatment of C57/Bl6 mice transgenic for the human CD137 extracellular domain (huCD137) bearing EphA2-expressing MC38 tumors with BCY12491 resulted in the infiltration of CD8+ T cells, elimination of tumors and generation of immunological memory. BCY12491 was cleared quickly from the circulation (plasma t 1/2 in mice of 1–2 hr), yet intermittent dosing proved effective. Conclusion Tumor target-dependent CD137 agonism using a novel chemical approach (TICAs) afforded elimination of tumors with only intermittent dosing suggesting potential for a wide therapeutic index in humans. This work unlocks a new path to effective cancer immunotherapy via agonism of TNF superfamily receptors.
Correspondence on ‘Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome’
Authors: Tomoyuki Kawada
Journal: Annals of the Rheumatic Diseases (2021)

I read with great interest the paper by Scarsi et al. 1 The authors examined the effect of colchicine (1 mg/day) in patients with COVID-19 by setting standard of care (hydroxychloroquine, and/or intravenous dexamethasone, and/or lopinavir/ritonavir).1 The adjusted HR (95% CI) of colchicine for mortality was 0.151 (0.062–0.368). In contrast, older age, worse PaO2/FiO2 and higher serum levels of ferritin at entry were no risk factors of mortality. The authors recommended controlled clinical trials to verify efficacy and safety, and I …
Sintilimab plus oxaliplatin/capecitabine (CapeOx) as neoadjuvant therapy in patients with locally advanced, resectable gastric (G)/esophagogastric junction (GEJ) adenocarcinoma.
Authors: Haiping Jiang, Xiongfei Yu, Mei Kong, Zhiming Ma, Donghui Zhou, Weibing Wang, Haohao Wang, Ning Li, Haiyong Wang, Kuifeng He, Zhongqi Li, Yiming Lu, Jing Zhang, Kui Zhao, Yafei Zhang, Nong Xu, Lisong Teng
Journal: Journal of Clinical Oncology (2021)

211 Background: The application of anti-programmed death 1 (PD-1) antibodies in neoadjuvant setting has not been well established. This phase 2 study (NCT04065282) was conducted to evaluate the efficacy and safety of sintilimab plus CapeOx as neoadjuvant therapy for resectable G/GEJ adenocarcinoma. Methods: Patients with histologically confirmed resectable G/GEJ adenocarcinoma (stage cT3-4NxM0) were enrolled to receive neoadjuvant therapy with sintilimab (3mg/kg for wt &lt; 60kg, 200mg for wt ≥60kg, Q3W) plus CapeOx (oxaliplatin 130mg/m 2 iv D1, capecitabine 1000mg/m 2 bid po D1-14, Q3W) for 3 cycles. Gastrectomy was scheduled within 4 weeks after last dose of neoadjuvant treatment. Tumor imaging evaluation was performed at baseline and within 1 week before gastrectomy. The primary endpoint was pathological complete response (pCR) per Becker criteria. Results: As of August 4, 2020, 36 pts were enrolled. Patients who had received gastrectomy after neoadjuvant treatment (n = 26) were included in this analysis. 25 (96.2%) pts completed 3 cycles of neoadjuvant treatment, except one completed 2 cycles due to grade 3 AST increased. All pts received complete resection (R0). 6 (23.1%) pts achieved pCR (TRG1a) and 14 (53.8%) pts achieved major pathologic response (MPR, TRG1a/b). 3 pts had partial response (ORR was 3/5 among pts with target lesions) and no patients progressed per RECIST 1.1 before surgery. Among 18 pts who received PET-CT evaluation per PERCIST, 11 (61.1%) achieved partial metabolic response (PMR). Neoadjuvant treatment-related AEs (neoTRAEs) to any drug were reported in 25 (96.2%) pts. Mostly TRAEs were grade 1-2, and only 6 (23.1%) pts experienced grade 3 TRAEs (Neutropenia in 4 pts, Leukopenia, Thrombocytopenia, AST increased, and GGT increased in 1 pt each). One patient experienced grade 1 hypothyroidism which is considered to be immune-related AE. There is no serious peri-operative complication and mortality. Conclusions: Sintilimab plus oxaliplatin/capecitabine showed promising efficacy with high pCR and MPR rate and well-tolerated safety profile in neoadjuvant settings. This combination regimen might present a new option for patients with locally advanced, resectable G/GEJ adenocarcinoma. Clinical trial information: NCT04065282.
Correspondence on ‘Anti-inflammatory therapy for COVID-19 infection: the case for colchicine’
Authors: Carlo Perricone, Elena Bartoloni, Giacomo Cafaro, Roberto Caporali, Roberto Gerli
Journal: Annals of the Rheumatic Diseases (2021)

It is well recognised that hyperinflammation induced by SARS-CoV-2 is a major cause of disease severity and mortality in infected patients and many of the proposed treatments include agents currently used in rheumatologic clinical practice.1 One critical question, however, is which anti-inflammatory drugs are most appropriate. Among the most traditional non-biological anti-inflammatory therapies, corticosteroids appear to provide some benefit in advanced stages of the disease,2 but concerns may arise from immunosuppression induced during viral replicative phase. On the contrary, no data are available on possible effects of non-steroidal anti-inflammatory drugs (NSAIDs).

In their interesting paper,3 Reyes et al highlighted the potential anti-inflammatory role of colchicine in COVID-19. The primary mechanism of action of colchicine is tubulin disruption leading to down-regulation of multiple inflammatory pathways.4 Among these, colchicine is able to impair platelet aggregation and leucocyte migration through an action on adhesion molecules,5 effect shared with NSAIDs, including salicylates.6 7 However, another important anti-inflammatory effect of colchicine, not described for NSAIDs, derives from its ability to inhibit the NLR family pyrin domain containing 3

(NLRP3) inflammasome with consequent reduction of proinflammatory cytokines.4 It is for this reason that colchicine …