tbuckley/cabot-search huggingface dataset:
A novel dual inhibitor of IDO and TDO, CMG017, potently suppresses the kynurenine pathway and overcomes resistance to immune checkpoint inhibitors.
Authors: Chan Kim, Joo Hoon Kim, Jin Sung Kim, Hong Jae Chon, Joo-Hang Kim
Journal: Journal of Clinical Oncology (2019)

e14228 Background: Kynurenine production by indoleamine 2,3-dioxygenase (IDO) is critical for tumor immune suppression through effector T cell anergy and regulatory T cell proliferation. This has led to the rapid development of IDO inhibitors for cancer immunotherapy. However, results from recent clinical trials have been disappointing and this is partly due to pathway redundancy. Tryptophan 2,3-dioxygenase (TDO), another important enzyme of the kynurenine pathway, plays a compensatory role in the absence of IDO activity. Therefore, we developed a dual inhibitor of IDO and TDO to achieve maximal inhibition of the kynurenine pathway and alleviate tumor immune suppression. Methods: Small-molecule inhibitors of IDO and TDO were synthesized and evaluated using in vitro cell-based assays. Pharmacokinetic and pharmacodynamic profiles were assessed for these inhibitors. Tumor-bearing mice were treated with CMG017 per os, either alone or in combination with immune checkpoint inhibitors (ICIs). The tumor microenvironment (TME) was assessed through histological, flow-cytometric, and Nanostring immune profiling analyses. Results: CMG017 suppressed kynurenine production more effectively than inhibitors targeting either IDO or TDO alone, in various human and murine cancer cell lines. Single administration of CMG017 showed favorable pharmacokinetic profiles compared with an IDO1 selective inhibitor. Repeated once-daily per os administration of CMG017 decreased kynurenine concentration in both tumors and plasma of tumor-bearing mice and delayed tumor growth without significant toxicity. CMG017 induced dramatic changes in immune-related genes in TME and enhanced intratumoral infiltration of CD8 + effector T cells. The anti-tumor activity of CMG017 was almost negated when T cells were depleted, indicating the importance of adaptive immunity for the in vivo efficacy of CMG017. Of note, combination immunotherapy of CMG017 with ICIs (anti-PD-1 and anti-CTLA-4) led to durable tumor regression and long-term overall survival. Mice with complete tumor regression were immune to tumor re-challenge, indicating the establishment of immunological memory. Conclusions: CMG017, a dual inhibitor of IDO and TDO, potently suppressed the kynurenine pathway and showed promising anti-cancer efficacy, with favorable pharmacologic profiles.
Fibrinolytic Therapy to Reduce Microvascular Obstruction After Myocardial Infarction
Authors: Mohammad Alkhalil
Journal: JAMA (2019)

To the Editor The T-TIME trial showed that among patients presenting with ST-segment elevation myocardial infarction (STEMI), adjunctive low-dose intracoronary alteplase administered during primary PCI did not reduce microvascular obstruction.1
AB0518 - JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS RELATED PANCREATITIS: AN UNCOMMON MANIFESTATION OF A COMMON DISEASE
Authors: Anjani Gummadi, Ankita Singh, Rakesh Kumar, Johnson Nameirakpam, Pandiarajan Vignesh, Deepti Suri, Anju Gupta, Ankur Jindal, Amit Rawat, Surjit Singh
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Pancreatitis is a rare but potentially life-threatening complication of juvenile systemic lupus erythematosus (jSLE). <h3>Objectives:</h3> We report 3 children with SLE who presented with acute pancreatitis. <h3>Methods:</h3> We have reviewed the clinical records of 140 children with SLE between period of 1993-2018. Three of them present with acute pancreatitis. <h3>Results:</h3> <b>Case 1</b><b>-</b>12-year-girl presented with fever of 1 month and alopecia. Examination revealed pedal oedema, periorbital puffiness, generalised lymphadenopathy, large joint arthritis and mild hepatomegaly.Investigations were consistent with lupus.Renal biopsy revealed Class 3 lupus nephritis and initiated on intravenous methylprednisolone.Two days after beginning her medication,she developed severe epigastric pain and vomiting which did not respond to antacids and analgesic.Serum amylase and lipase were elevated.Clinical possibilities included steroid induced pancreatitis and lupus pancreatitis.Intravenous methylprednisolone was continued following which she showed a dramatic improvement.<b>Case 2-</b>A-6-year-old presented with pain abdomen and vomiting. Physical examination showed epigastric tenderness.Investigations showed elevated amylase levels.Computerised tomography(CT) abdomen revealed acute necrotising pancreatitis.A ultrasound abdomen revealed a pancreatic pseudocyst.He had a second episode of acute pancreatitis along with anasarca after 3 months.In follow-up,he presented with anasarca. Investigation were consistent with lupus.Following the initiation of steroids,he improved and there has been no recurrence of pancreatitis over the next 4 years.<b>Case 3</b><b>-</b> 9-year-girl presented with generalised rash and alopecia for 5 months.She also had pain abdomen for last 2 months.Investigations showed elevated amylase and ultrasound abdomen revealed acute pancreatitis. She had undergone a laparotomy elsewhere.Examination showed generalised pigmented rash, periorbital edema, alopecia, periorbital puffiness, hard palate ulcer and surgical scar on the abdomen.Urinalysis showed nephrotic range proteinuria.Serum amylase levels were elevated. Ultrasound abdomen revealed a pancreatic pseudocyst.Further investigations were suggestive of lupus.Workup for APLA revealed positive lupus anticoagulant. She was initiated on oral prednisolone and was given pulses of intravenous cyclophosphamide.There has been no recurrence of pancreatitis over 12-years follow-up. <h3>Conclusion:</h3> Pancreatitis can at times, be the presentation of childhood lupus and requires prompt and aggressive management. <h3>Disclosure of Interests:</h3> None declared
Supplemental oxygen during exercise training in COPD: full of hot air?
Authors: Jessica A. Walsh, Matthew Maddocks, William D-C. Man
Journal: European Respiratory Journal (2019)

Long-term oxygen therapy is widely accepted as a treatment for severe hypoxaemia in patients with chronic respiratory disorders, based on survival findings from the UK Medical Research Council study [1] and the US Nocturnal Oxygen Therapy Trial [2]. The data from these landmark studies have driven the underlying rationale that correcting hypoxaemia is beneficial, and have led to the prescription of oxygen for other indications, including ambulatory oxygen for patients with exercise-induced oxygen desaturation (EID), nocturnal oxygen therapy for patients with nocturnal hypoxaemia and short burst oxygen for palliation of dyspnoea. This is despite a lack of supporting evidence from randomised clinical trials to support these indications [3–5]. The majority of patients with COPD and exercise induced desaturation safely benefit from exercise training without the need for supplemental oxygen <http://bit.ly/2Yof9xJ>
EMERALD: A randomized, open label, phase III trial to evaluate the efficacy and safety of elacestrant (RAD1901) versus investigator’s choice (IC) of endocrine therapy (ET) for ER+/HER2- advanced breast cancer (BC) following CDK4/6 inhibitor (CDK4/6i) therapy.
Authors: Aditya Bardia, Philippe Georges Aftimos, Hai Jiang, Teeru Bihani, Alfred T Anderson-Villaluz, Maureen G. Conlan, Virginia G. Kaklamani
Journal: Journal of Clinical Oncology (2019)

TPS1104 Background: Estrogen receptor-positive (ER+) BC comprises ~70% of all BC and advanced/metastatic ER+ disease (mBC) remains a major clinical challenge. The addition of CDK4/6i to ET has improved progression-free survival (PFS); however, novel treatments are needed after progression. Putative mechanisms of endocrine resistance, such as ESR1 mutations (mESR1), also indicate the need for additional therapies. Elacestrant, an oral selective estrogen receptor degrader (SERD), demonstrated anti-tumor activity in preclinical models of ER+ BC, including models resistant to CDK4/6i and models with mESR1. An interim evaluation of a phase 1 trial ( NCT02338349 ) of elacestrant in heavily pretreated patients (pts) with mBC, demonstrated an overall response rate (ORR) of 27% with a PFS of 5.4 mo (Bardia, SABCS, 2017). Responses were seen in pts with prior CDK4/6i and with wild-type (WT) or mESR1. Methods: This is a multicenter, international, randomized, open-label, active-controlled phase 3 trial for post-menopausal women or men with mBC. Pts must have received 1-2 prior lines of ET, ≤1 line of chemotherapy for mBC, and have documented progression on a CDK4/6i. Pts with measurable disease (RECIST v1.1) or bone-only disease are eligible. Pts are randomized 1:1 to elacestrant (400 mg orally daily) or IC of fulvestrant or an aromatase inhibitor. Stratification factors include ESR1 mutation status (detected by ctDNA), prior fulvestrant treatment and presence of visceral disease. The primary endpoints are PFS by blinded independent review committee (IRC) in pts with mESR1 and in all pts (WT or mESR1). Secondary endpoints include: overall survival; PFS by IRC in WT, PFS by investigator review; ORR, duration of response, and clinical benefit rate; safety; pharmacokinetics; and quality of life. Approximately 466 pts will be enrolled to detect 340 PFS events in all pts (power ≥90%, hazard ratio (HR) = 0.667) and 160 PFS events in the mESR1 subset (power ≥80%, HR = 0.610), overall α level at 2-sided 5% using the Hochberg procedure. The EMERALD study is open for enrollment. Clinical trial information: NCT03778931.
#earlydetection: Leveraging social media to recruit individuals at increased-risk of pancreas cancer for an early detection study.
Authors: Kelsey Klute, Christina Hoy, Luann Larson, Fang Yu, Michael A. Hollingsworth, Kirsten Eberle, Terri Blase, Brian Boerner, Vijay Shivaswamy, Shailender Singh
Journal: Journal of Clinical Oncology (2019)

e14577 Background: Social media (SM) could transform how individuals learn of clinical trials. In an ongoing, single-center cohort study to collect serial biospecimens and clinical data from high-risk individuals (HRIs) for pancreatic cancer (PC), we explored how HRIs learned of the study, surveyed relevant SM posts and compared those referred by SM vs. other means. Methods: Initial recruitment focused on HRIs with familial risk for PC. Referral method was self-reported. We identified relevant SM posts and compared those referred via SM vs. other means by ANOVA and t-test. Investigators did not create SM content but were featured in a relevant local news clip, institutional blog post and Project Purple podcast; study-related media was IRB-approved. Results: We enrolled 91 HRIs between Aug 2018 and Jan 2019. Over half self-referred; 55.0% of self-referrals came from SM. We identified 16 unique SM posts, all to Facebook. Authors were 2 administrators for local hereditary cancer organizations, Project Purple, UNMC and 2 study subjects (9,4, 3 and 2 posts). Content included links to a podcast, clinicaltrials.gov, local news story, blog post, live chat and anecdotes from subjects. Nine posts shared study contact information or clinicaltrials.gov link. The mean age of those referred via SM was younger than for other methods (mean 49.2 vs. 53.4y) but was not statistically significant (p = 0.19). SM was more likely to recruit HRIs with familial risk than other methods (100.0% vs. 76.3%; p &lt; 0.01) Conclusions: SM effectively recruited HRIs with familial risk for PC; this group may be more likely to seek information online. Individuals may find studies via SM without investigator involvement. SM may be an effective tool to recruit HRIs to early detection research in PC and other conditions. Clinical trial information: NCT03568630. [Table: see text]
Analysis of early mortality in randomized clinical trials evaluating anti-PD-1/PD-L1 antibodies: A systematic analysis by the United States Food and Drug Administration (FDA).
Authors: Flora Mulkey, Kunthel By, Marc Robert Theoret, Virginia Ellen Maher, Richard Pazdur, Rajeshwari Sridhara
Journal: Journal of Clinical Oncology (2019)

2516 Background: Many studies exhibit what seems to be dis-proportionately higher early mortality (EM) in anti-PD-1/PD-L1 containing arms (IO) when compared to active control arms (AC), resulting in early crossing of the Kaplan-Meier overall survival curves. We examine if EM with the use of IO is specific to certain demographic and disease characteristics. Methods: Data from 16 randomized AC trials submitted to FDA containing 6055 IO and 3604 AC patients in HNSCC, Melanoma, NSCLC, RCC, and Urothelial Carcinoma were evaluated for signs of EM. Study-specific and pooled piecewise hazard ratios (HRs) were used to quantify EM from 0 to 60 and &gt; 60 days. Additionally, HRs up to 60 days were used to assess the extent specific subgroups account for EM. Results: Piecewise HRs comparing OS between IO and AC changed direction, &gt; 1 to &lt; 1 in 11 trials; melanoma (5/6), NSCLC (3/7), HNSCC (1/1), RCC (1/1), and urothelial cancer (1/1). When pooled, NSCLC studies retained this EM pattern, although attenuated, with HR (95% CI) of 1.12 (0.91, 1.38) ≤60 days and 0.66 (0.61, 0.72) after 60 days. This was not observed in the pooled melanoma studies: 0.88 (0.63, 1.24) ≤ 60 days and 0.59 (0.53, 0.67) after 60 days. EM in both arms was associated with poor ECOG performance status (PS), increased LDH, and high tumor burden. Comparing EM patients in the IO and AC arms, a larger proportion were female in the melanoma trials (41% vs. 28%), a smaller proportion had squamous histology in the NSCLC trials (32% vs. 41%), and a larger proportion were PD-L1 negative (56% vs. 36% melanoma; 60% vs. 43% NSCLC). Analysis of the pooled melanoma studies suggests PD-L1 negative melanoma patients with high baseline tumor burden and PS played a role in EM with HR before 60 days of 1.49 (0.75, 2.97). However, these results were not reproducible in NSCLC. Conclusions: Potential risk factors for EM were assessed in individual and pooled trials. While several factors—negative PD-1/PD-L1 status and high ECOG, LDH and tumor burden—seem to play a role in EM, these high-risk subgroups do not fully explain the EM patterns observed in the IO treated patients.
AGO-OVAR 2.29 (ENGOT-ov34): Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer (ROC).
Authors: Frederik Marme, Patricia Pautier, Els Van Nieuwenhuysen, Alexander Reuss, Andres Redondo, Kristina Lindemann, Christian Kurzeder, Christian Marth, Alexander Burges, Klaus Pietzner, Pauline Wimberger, Nikolaus De Gregorio, Philipp Harter
Journal: Journal of Clinical Oncology (2019)

TPS5601 Background: A standard non-platinum based treatment option in patients with relapsed ovarian cancer is bevacizumab in combination with paclitaxel or pegylated liposomal doxorubicin, but responses are still short-lived. Checkpoint-inhibitors as single agent have limited activity in ovarian cancer. However, the role of the checkpoint-inhibitor like atezolizumab, in addition to chemotherapy and bevacizumab in ovarian cancer is so far undefined. Methods: AGO-OVAR 2.29 is a randomized (1:1), double blinded, phase III trial evaluating the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy (weekly paclitaxel or pegylated liposomal doxorubicin) compared with placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian-, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after platinum-based chemotherapy or 3rd relapse. A tumor biopsy available at study entry for PD-L1 testing is mandatory. Patients are treated with chemotherapy plus bevacizumab +/- atezolizumab/placebo until progression or prohibitive toxicity. Co-primary endpoints are overall survival and progression-free survival. It is planned to randomize 664 patients. A safety interim analysis will be done when 24 patients have been randomized and completed at least cycle 1. As of 1 st February 2019, 24 patients have been randomized. Clinical trial information: NCT03353831.
Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy: A Breast International Group (BIG) 1-98 sub-analyses.
Authors: Jose Pablo Leone, Bernard F. Cole, Meredith M. Regan, Beat J. K. Thurlimann, Alan S. Coates, Aron Goldhirsch, Angelo Di Leo, Marco Colleoni, Ines Maria Vaz Duarte Luis, Nancy U. Lin
Journal: Journal of Clinical Oncology (2019)

538 Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in HR+ breast cancer. Currently, no data exists evaluating differences in clinical behavior after DR between patients (pts) treated in the adjuvant setting with different endocrine therapy regimens. The aim of this study was to analyze post-DR survival of pts treated on BIG 1-98. Methods: BIG 1-98 compared 5 years of adjuvant treatment between 4 arms: tamoxifen (T), letrozole (L), T followed by L (TL) and L followed by T (LT). After 8.1 years median follow-up (follow-up through 2010), 911 (T n = 302, L n = 285, TL n = 170, LT n = 154) of 8010 pts had DR as site of first recurrence. Univariate and multivariable Cox analyses were performed to determine features associated with post-DR survival. With 661 total observed deaths, statistical power was 0.8 to detect a hazard ratio (HaR) &gt; 1.24 at the 2-sided 0.05 level of significance. Results: Median follow up time after DR was 59 months (IQR: 29-88). Among all pts with DR, 38.1% were ≥ 65 years at study enrollment, 61.9% had tumor size &gt; 2 cm, 69.7% were node positive. Neo/adjuvant chemotherapy was administered to 35.6% of pts. There was no difference in post-DR survival by treatment arm (median survival: T 20.8, L 17.9, TL 17.3, LT 20.8 months; p = 0.21). In multivariable analysis, older pts (HaR 1.36; p = 0.0002), tumors &gt; 2cm (HaR 1.2; p = 0.04), ≥ 4 positive nodes (HaR 1.32; p = 0.05) and PR- tumors (HaR 1.28; p = 0.001) had significantly worse post-DR survival. Endocrine treatment arm, type of surgery, radiotherapy and neo/adjuvant chemotherapy were not associated with post-DR survival in the multivariate model. Conclusions: Treatment with adjuvant T, L or their sequence were not associated with differences in survival after DR. We observed significant differences in survival by primary tumor size, nodal and PR status, which suggest that traditional high-risk features remain prognostic in the metastatic setting. Clinical trial information: NCT00004205.
Risk of colorectal cancer and endoscopic screening in families of patients with hereditary nonpolyposis syndrome of colorectal cancer.
Authors: Nicodim F. Belev, Rodica Mindruta-Stratan, Diana Iarovoi, Tatiana Kazubskaya, Diana Brega
Journal: Journal of Clinical Oncology (2013)

e12543 Background: Relatives of patients with hereditary nonpolyposis colorectal cancer (HNPCC) have an elevated risk of colorectal cancer (CRC) and adenomas. To determine the efficacy of endoscopic screening among relatives of patients with HNPCC syndrome. Methods: 50 relatives of the first and 17 relatives of the second-degree relatives of 127 families of patients with HNPCC syndrome was subjected to endoscopic screening (colonoscopy). Results: The analysis of cancer register database of families, which includes clinical and genealogical information about 1,505 patients with colorectal cancer (CRC) and 407 with the primary multiple malignant neoplasms (PMMN), found 127 (6.6%) families, which are consistent with Amsterdam criteria of HNPCC. Among the 1057 first-degree relatives malignancies were detected in 238 (22.5±2.7%). The CRC among of the first degree relatives of patients with HNPCC syndrome was identified in 118 (11.2±2.9%), which is 20 times the population frequencies (0.56±0.004%) (p&lt;0.001). The frequency of aggregation of PMMN and adenomas of the colon was 1.8±3.1% (19) è 0.6% (6), respectively. Prevalence of PMMN in the general population is 0.009±0.0005%, and adenomas - 4.7±1.4%. From 809 of first degree relatives 50 were available for the survey, and from the 924 second degree relatives - 20. The endoscopic screening of first degree relatives found the presence of different pathology in 35(60.0%±8.3%) surveyed persons, including CRC – at 19(38.0±11.4%) (p&lt;0.01), primary multiple colorectal cancer – at 6(12.0±14.5%), adenomas - at 5(10.0%). Among the surveyed second degree relatives the pathology was identified at 8(40±18.5%), primary multiple colorectal cancer at 3(15.0%), and adenomas of the colon – at 5(25%). Conclusions: Colonoscopy is an effective method for identifying malignant and benign tumors of the colon at relatives in the families of patients with HNPCC syndrome. A high percentage of cancer detected in these families need to refine the survey mode in order to identify early forms of cancer and its secondary prevention.
A survey of cancer patients’ rehabilitation therapy needs in Southwest China.
Authors: Zhou Jin, Fang Li, Peng Xiaodong, Peng Jingjing, Jiang Shasha, He Lang, Wang Xiaoshan, Zhu Jiang, Ye Bin, Du Chi, Xiong Zhujuan, Gao Qian
Journal: Journal of Clinical Oncology (2019)

e18003 Background: Medical advance in the recent decades has turned cancer into a chronic disease. At the same time, quality of life (LoF) during the treatment period has emerged as a new concern of cancer patients. Rehabilitation therapy, which can help patients conquer fear and be more engaged in the process, has gradually attracted more attentions in China. We designed a survey, for both the cancer patients and their families, to understand their view of the rehabilitation therapy. Methods: We sent paper-based surveys to volunteers consisted of cancer patients and their families. Majority of patients are from 10 cancer centers at the southwest region of China. The main cancer types are lung cancer, breast cancer and colon cancer. The survey questions focus on: patients and their families’ engagement of the treatment, their view on rehabilitation therapy, and their method preference for the rehabilitation therapy. Results: We sent 2,000 copies of the survey and received 1,920 valid inputs. Below are the key findings. 1. Their biggest concern: the outcome of the treatment 55.8%, side effects 19.7%, financial burden 12.8% and mental stress 11.5%. 2. The importance of the rehabilitation therapy as compared to traditional medical treatment, such as surgery and chemotherapy: equally important 67.8%, less important 17.7%, more important 10.1%, no preference 4.4%. 3. The necessity of rehabilitation therapy: very necessary 65.7%, somewhat necessary 22.7%, not necessary 11.6%. 4. The first three reasons for participating rehabilitation therapy: it helped go through the treatment 42.8%, it improved quality of life 31.6% and it helped release their mental stress 22.3%. 5. The best form to conduct rehabilitation therapy: face-to-face communicate with the doctors 60.6%, telecommunication 15.8% and combination of both 22.1%. Conclusions: The results of the survey strongly indicate the demands for rehabilitation therapy. Patients started to understand it – more than half of them think it is as important as the traditional medical treatment. Patients’ quality of life and mental health, which is part of the holistic treatment, are gradually recognized. Next, we plan to group our survey results by types of cancers, patients and their families’ genders and age, as well as the local economics, to better understand the data. We hope this study can serve as a data point to help build China’s rehabilitation therapy infrastructure.