tbuckley/cabot-search huggingface dataset:
The impact of a routine late third trimester growth scan on the incidence, diagnosis, and management of breech presentation in Oxfordshire, UK: A cohort study
Authors: Ibtisam Salim, Eleonora Staines-Urias, Sam Mathewlynn, Lior Drukker, Manu Vatish, Lawrence Impey
Journal: PLoS Medicine (2021)

Background Breech presentation at term contributes significantly to cesarean section (CS) rates worldwide. External cephalic version (ECV) is a safe procedure that reduces term breech presentation and associated CS. A principal barrier to ECV is failure to diagnose breech presentation. Failure to diagnose breech presentation also leads to emergency CS or unplanned vaginal breech birth. Recent evidence suggests that undiagnosed breech might be eliminated using a third trimester scan. Our aim was to evaluate the impact of introducing a routine 36-week scan on the incidence of breech presentation and of undiagnosed breech presentation. Methods and findings We carried out a population-based cohort study of pregnant women in a single unit covering Oxfordshire, United Kingdom. All women delivering between 37+0 and 42+6 weeks gestational age, with a singleton, nonanomalous fetus over a 4-year period (01 October 2014 to 30 September 2018) were included. The mean maternal age was 31 years, mean BMI 26, 44% were nulliparous, and 21% were of non-white ethnicity. Comparisons between the 2 years before and after introduction of routine 36-week scan were made for 2 primary outcomes of (1) the incidence of breech presentation and (2) undiagnosed breech presentation. Secondary outcomes related to ECV, mode of birth, and perinatal outcomes. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. A total of 27,825 pregnancies were analysed (14,444 before and 13,381 after). A scan after 35+0 weeks was performed in 5,578 (38.6%) before, and 13,251 (99.0%) after ( p &lt; 0.001). The incidence of breech presentation at birth did not change significantly (2.6% and 2.7%) (RR 1.02; 95% CI 0.89, 1.18; p = 0.76). The rate of undiagnosed breech before labour reduced, from 22.3% to 4.7% (RR 0.21; 95% CI 0.12, 0.36; p &lt; 0.001). Vaginal breech birth rates fell from 10.3% to 5.3% (RR 0.51; 95% CI 0.30, 0.87; p = 0.01); nonsignificant increases in elective CS rates and decreases in emergency CS rates for breech babies were seen. Neonatal outcomes were not significantly altered. Study limitations include insufficient numbers to detect serious adverse outcomes, that we cannot exclude secular changes over time which may have influenced our results, and that these findings are most applicable where a comprehensive ECV service exists. Conclusions In this study, a universal 36-week scan policy was associated with a reduction in the incidence but not elimination of undiagnosed term breech presentation. There was no reduction in the incidence of breech presentation at birth, despite a comprehensive ECV service.
Real-world study of treatment patterns and outcomes among patients with metastatic pancreatic ductal adenocarcinoma (PDAC) in Europe.
Authors: Julien Taieb, Pascal Hammel, Michele Reni, Daniel H. Palmer, John A. Bridgewater, Antonio Cubillo, Gerald W. Prager, Alice Vermeire, Nathalie D'Esquermes, Fabienne Biville-Hedouin, Zhaoyang Teng, Thomas Seufferlein, Teresa Macarulla
Journal: Journal of Clinical Oncology (2021)

391 Background: Few data are available regarding real-world treatment patterns and outcomes for metastatic PDAC (mPDAC) in Europe. Methods: This retrospective, observational, chart-review study involved medical oncologists and gastroenterologists from France, Germany, Italy, Spain, and the UK. Physicians completed online patient (pt) reports for 20 consecutive pts diagnosed with PDAC between 01 and 10/2016. Here, the analysis is focused on treated pts diagnosed with mPDAC. Reports provided information on general disease and pt characteristics, diagnosis, and treatment of metastatic disease. Outcomes included median PFS and OS according to each line of metastatic therapy. In addition, how baseline performance status (PS) and treatment sequence affected OS and PFS were assessed. Results: 304 physicians (France [n=62], Germany [n=60], Italy [n=63], Spain [n=66], UK [n=53]) participated and enrolled 6,000 pts with PAC, of whom 3827 had mPDAC. Of the 3827, 3432 were treated for their metastatic disease. The most common first-line therapies were modified FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%), while the most common second-line therapies were gemcitabine monotherapy (25.0%), 5-FU + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). The longest median PFS and OS were obtained when using mFOLFIRINOX as first-line therapy, with gemcitabine-based combinations as second-line therapy. However, pt characteristics were more favorable with FOLFIRINOX compared with the other regimens used in first line. The most common treatment in first line for patients with a worse baseline PS (PS &gt;1) was gemcitabine monotherapy (571 patients [46%]); in addition, having a worse baseline PS was predictive of shorter survival in second line. The most common reason for discontinuation of either line was disease progression. The study showed that the choice of first- and second-line treatment among European physicians is in accordance with current ESMO guidelines; in contrast, the choice of subsequent line was more heterogeneous, according to local practices. Additional data concerning first and second line OS and PFS per treatment regimen will be presented at the meeting. Conclusions: This large real-life study highlights a clear picture of treatment patterns in European real-world clinical practice and outcomes for metastatic PDAC, which may help in more effectively managing such patients in the future. Further univariate and multivariate analysis will complete this first description.
Survival outcomes of adjuvant chemotherapy in elderly patients with stage III colon cancer.
Authors: Walid Labib Shaib, Lana Khalil, Mehmet Akce, Jeffrey M. Switchenko, Xingyu Gao, Maria Diab, Christina Wu, Olatunji B. Alese, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2021)

89 Background: The survival impact of multi-agent (MAC) as compared to single-agent (SAC) adjuvant chemotherapy (AC) in elderly patients with stage III colon cancer (CC) remains controversial. The aim of this study is to evaluate the survival outcome comparing MAC to SAC in this population utilizing the National Cancer DataBase (NCDB). Methods: Patients 70 years and older with pathological stage III CC were identified between 2004 and 2015 from the NCDB using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490, and C18.0-18.8 (without C18.1). Univariate and multivariable analyses were conducted and Kaplan-Meier analysis and Cox proportional hazard models were used to identify the association between MAC vs. SAC and overall survival (OS). Results: A total of 41,707 elderly patients (≥70 years old) with stage III CC were identified. Around half of the patients (n = 20,257; 48.5%) received AC; the majority of whom (n = 12,923, 63.8%) received MAC. The median age was 79 (range 70-90). Of the patients who received AC, the majority were female (n = 11,201, 55.3 %), Caucasians (87.4%) and had a moderately differentiated tumor grade (n = 12,619, 62.3%). Tumor size more than 4 cm was identified in 11,785 (58.2%) patients and 18,496 (91.3%) had negative surgical margins. Low-risk stage III CC constituted 50.6% (n = 10,264) of the study population. High-risk stage III CC was associated with worse OS compared to low-risk disease (p &lt; 0.001). MAC was associated with better 5-year OS compared to SAC (p &lt; 0.001). High-risk stage III patients who received MAC had an OS of 4.2 v. 3.4 years in SAC (p &lt; 0.001). In low risk stage III, patients who received MAC had median OS of 8.5 v. 7 years in SAC (p &lt; 0.001). In Univariate, male sex, positive surgical margin, insurance and facility types, age, year of diagnosistumor size, and Charlson-Deyo Score of &gt; 2 were associated with worse OS (p &lt; 0.05). Conclusions: Multi-agent AC is associated with better survival in stage III CC patients 70 years and older compared to SAC. Enhanced benefit of MAC was shown for both low risk and high risk stage III CC.
When the Human Voice Speaks Volumes About Lung Function
Authors: Kristin Walter
Journal: JAMA (2021)

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OP0056 Tnf-alpha blockade with infliximab in patients with active spondyloarthropathy: follow-up of one year maintenance regimen
Authors: E Kruithof, F Van den Bosch, D Baeten, F De Keyser, H Mielants, EM Veys
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In an open pilot study, the anti-TNF-alpha monoclonal antibody, infliximab, induced a rapid and significant improvement in global, peripheral and axial disease manifestations of patients (pts) with active spondyloarthropathy (SpA), without major side effects.<sup>1</sup> <h3>Objectives</h3> The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the observed effect. <h3>Methods</h3> The safety and efficacy of a maintenance regimen (5 mg/kg IV infliximab every 14 weeks) was evaluated using the same measurements reported in the open label study.<sup>1</sup> Of the initial 21 pts 19 completed the 1 year follow-up for efficacy. Two pts (1 psoriatic arthritis, 1 undifferentiated SpA) changed to another dosing regimen of infliximab after week 12 due to partial lack of efficacy. However, these pts are still in follow-up and are included in the safety analysis. <h3>Results</h3> Efficacy: After every retreatment (at week 20, 34 and 48) a sustained significant decrease of global, peripheral and axial disease manifestations was observed (p &lt; 0,05 compared to baseline). Before retreatment, recurrence of symptoms was observed in 3 pts (16%) at week 20, 13 pts (68%) at week 34 and 15 pts (79%) at week 48. Safety: No withdrawals due to adverse events occurred. No significant laboratory abnormalities were detected. No major peri-infusional allergic reactions were observed. Three infectious episodes (pyelonephritis, otitis media, and tooth abscess) were observed. During the 1 year follow-up 12 pts (57%) developed on at least 2 occasions antinuclear antibodies; in 4 of these pts (19%) antibodies to dsDNA were detected. However, no lupus-like syndromes occurred. <h3>Conclusion</h3> In this open follow-up study of infliximab in pts with active SpA, the significant improvement of all disease manifestations was maintained over a 1 year follow-up period without major adverse events. Since recurrence of symptoms was observed in a rising number of patients with every retreatment, the maintenance regimen (5 mg/kg every 14 weeks) probably needs adjustment (shorter interval or higher dose). <h3>Reference</h3> Ann Rheum Dis. 2000;59:428–33
Covid-19—a rehearsal to build a greener and healthier society
Authors: Maria Nilsson, Kristie L Ebi, Diarmid Campbell-Lendrum, Brama Kone, Peter Friberg
Journal: BMJ (2021)

<b>Maria Nilsson and colleagues</b> argue that reducing the severe health risks from the climate crisis requires political commitment and funding like that mobilised to limit the spread of SARS-CoV-2
Serial cell-free DNA (cfDNA) sampling in advanced pancreatic ductal adenocarcinoma (PDAC) patients may predict therapeutic outcome.
Authors: Gehan Botrus, Yu Fu, Mohamad Bassam Sonbol, Leylah Drusbosky, Daniel H. Ahn, Mitesh J. Borad, Jason S. Starr, Jeremy Clifton Jones, Puneet Raman, Kabir Mody, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2021)

423 Background: Advanced PDAC remains a deadly disease with a 5-year survival rate of less than 10%. cfDNA - based next generation sequencing (NGS) may identify actionable alterations in patients with PDAC. In this study, we aim to determine the feasibility of utilizing serial cfDNA NGS testing and its potential relevance in predicting therapeutics outcomes. Methods: A total of 23 PDAC patients with PDAC cfDNA isolated from plasma collected at diagnosis and upon disease progression to first line SOC therapy and were analyzed on a 73-74 gene NGS panel (Guardant Health). Changes in molecular profiles from baseline to progression were analyzed for overall survival, progression free survival (PFS), and treatment response. PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test was used to compare the survival of different groups of patients. All p-values were two-sided. Analyses were performed using R (version 3.5.1, R Foundation, Vienna, Austria). Results: In this retrospective study, the 1-year probability of survival was 71% (median 473 days) and the 1-year PFS was 14% (median 212 days). TP53 and KRAS were the most frequently mutated genes identified in baseline samples, with 78% prevalence for each. Patients with clearance of TP53 17% (3/18) patients and/or KRAS 33% (6/18) patients clones after first line therapy significantly increases PFS (p=0.0056 and p=0.037, with HR of 0.087 and 0.32, respectively). However, appearance of TP53 or KRAS alterations upon progression does not significantly affect overall survival or PFS. Conclusions: The preliminary results from this study suggest that cfDNA clearance of TP53 and/or KRAS alterations may predict for improved PFS in PDAC. Confirmation of these findings in larger studies is warranted.
Cost-effectiveness of Pembrolizumab as a Second-Line Therapy for Hepatocellular Carcinoma
Authors: Chi-leung Chiang, Sik-kwan Chan, Shing-fung Lee, Irene Oi-ling Wong, Horace Cheuk-wai Choi
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Immune checkpoint inhibitors have been approved for use as a second-line therapy for hepatocellular carcinoma (HCC) in patients who previously received sorafenib. Pembrolizumab has shown substantial antitumor activity and a favorable toxicity profile as a second-line treatment of HCC. However, considering the high cost of pembrolizumab, there is a need to assess its value by considering both the clinical efficacy and cost. <h3>Objective</h3> To evaluate the cost-effectiveness of pembrolizumab vs placebo as second-line therapy in patients with HCC from the US payer perspective. <h3>Design, Setting, and Participants</h3> A Markov model was developed to compare the lifetime cost and efficacy of pembrolizumab as a second-line treatment of HCC with those of placebo using outcome data from the KEYNOTE-240 randomized placebo-controlled trial, which included 413 patients with advanced HCC previously treated with sorafenib and randomized patients to receive pembrolizumab plus best supportive care or placebo plus best supportive care in a 2:1 ratio. <h3>Main Outcomes and Measures</h3> Life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were estimated at a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed to account for the parameter of uncertainty. A cost-threshold analysis was also performed. The study was conducted from January 31 to July 29, 2020. <h3>Results</h3> The base-case model found that treatment with pembrolizumab was associated with increased overall cost by $47 057 and improved effectiveness by 0.138 QALYs compared with placebo, leading to an ICER of $340 409 per QALY. The model was most sensitive to the hazard ratio of overall survival (range, 0.61-1.00), health utility of placebo (range, 0.59-0.93), price of pembrolizumab (range, $5531-$8297), and price of postprogression therapies (range, $5596-$7944 for pembrolizumab and $4770-$7156 for placebo). The ICER of pembrolizumab was larger than $150 000 per QALY in most of the sensitivity and subgroup analyses. The price of pembrolizumab needed to be reduced by 57.7% to $2925 per cycle to achieve cost-effectiveness. <h3>Conclusions and Relevance</h3> The findings of this cost-effectiveness analysis suggest that, at its current price, pembrolizumab is not a cost-effective second-line therapy for HCC in the US, with a willingness-to-pay threshold of $150 000 per QALY.
The Importance of Conduct Disorder in the Treatment of Violence in Schizophrenia: Efficacy of Clozapine Compared With Olanzapine and Haloperidol
Authors: Menahem Krakowski, Umit Tural, Pál Czobor
Journal: American Journal of Psychiatry (2021)

Treatment of violence in schizophrenia remains a challenging problem, especially in patients with conduct disorder. Previous clinical studies did not select patients on the basis of violence and did not focus on conduct disorder. This study is a head-to-head comparison of clozapine, olanzapine, and haloperidol in the treatment of violent schizophrenia patients with and without conduct disorder.Physically assaultive schizophrenia patients (N=99) were randomly assigned to receive clozapine, olanzapine, or haloperidol in a 12-week double-blind trial. They were characterized on the basis of the presence or absence of conduct disorder before age 15. Assaults were recorded; their frequency and severity were scored on the Modified Overt Aggression Scale. Psychiatric symptoms were evaluated through the Positive and Negative Syndrome Scale.Patients with a history of conduct disorder had more frequent and severe assaults than those without conduct disorder during the 12-week trial. Clozapine was superior to haloperidol and olanzapine in reducing assaults; olanzapine was superior to haloperidol. Clozapine's greater antiaggressive efficacy over haloperidol was substantially more pronounced in patients with conduct disorder than in patients without conduct disorder. In patients with conduct disorder, clozapine was four times more likely than haloperidol to result in lower violence; in patients without conduct disorder, it was three times more likely to do so. Olanzapine's superiority over haloperidol was also more pronounced in patients with conduct disorder.This study is the first to examine the effect of clozapine in violent schizophrenia patients with conduct disorder. When conduct disorder is present, clozapine is the optimal treatment.
Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in persons with pancreatobiliary cancer or other mesothelin expressing solid tumors.
Authors: Guillaume Joe Pegna, Mehwish Iqra Ahmad, Seth M. Steinberg, Cody J. Peer, William Douglas Figg, David JP FitzGerald, Raffit Hassan, Ira Pastan, Christine Alewine
Journal: Journal of Clinical Oncology (2021)

TPS452 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting with a modified Pseudomonas exotoxin A payload. Formation of anti-drug antibodies (ADAs) is thought to contribute significantly to limited clinical efficacy of LMB-100 seen in prior clinical trials. Most patients develop clinically meaningful ADAs after 1-2 cycles of LMB-100, resulting in rapid neutralization of LMB-100 during subsequent cycles and undetectable plasma drug levels. Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the treatment of rheumatoid arthritis and ulcerative colitis. Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs against recombinant immunotoxin (Onda et al. Journal of Immunology 2014), and that co-administration of tofacitinib with LMB-100 increases immunotoxin serum half- life in mice and anti-tumor efficacy (Simon et al. JCI Insight 2019). We hypothesize that co-administration of tofacitinib with LMB-100 will prevent or delay the formation of high titer ADAs to LMB-100, such that 2 effective cycles of immunotoxin can be administered to patients. Methods: This phase I clinical trial consists of a dose escalation phase using 3+3 design to determine the maximum tolerated dose (MTD) of LMB-100 that can be administered with tofacitinib in participants (n = 18 max) with mesothelin-expressing solid tumors, followed by a dose expansion phase at the MTD for participants (n = 15) with pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma. The primary objective of the expansion phase is to determine whether co-administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs for cycle 2 of treatment as measured by LMB-100 plasma drug levels. A positive outcome will be reached if percent of participants achieving threshold LMB-100 drug levels during cycle 2 increases from 50% to 80% (83.6% probability if &gt;10 of 15 evaluable participants meet this milestone). Plasma drug levels during cycle 3 will also be analyzed as a secondary endpoint. Key inclusion criteria include adults with histologically confirmed previously treated solid tumor malignancies. Participants will receive tofacitinib 10 mg twice daily on days 1-10 and LMB-100 at 65, 100, or 140 mcg/kg on days 4, 6 and 8 of a 21-day cycle. The dose escalation phase has been completed and enrollment onto dose expansion phase is ongoing. Clinical trial information: NCT04034238.