tbuckley/cabot-search huggingface dataset:
Transcatheter Repair or Surgery for Functional Mitral Regurgitation
Authors: Joanna Chikwe, Michelle M Kittleson
Journal: New England Journal of Medicine (2024)

Functional mitral regurgitation is a disease of the left heart as opposed to the valve leaflets themselves. Two thirds of patients with heart failure have moderate or severe functional mitral regurgitation.1 In these patients, left ventricular dysfunction and remodeling cause papillary muscle displacement and mitral annular dilatation; these defects prevent effective leaflet coaptation, which drives a progressive cycle of myocardial and valvular dysfunction, despite normal valve leaflets. Severe functional mitral regurgitation is associated with excess hospitalizations and mortality approaching 55% by 8 years after diagnosis.1 However, the presence and severity of regurgitation are highly dependent on ventricular function, ventricular loading, . . .
Out of Breath
Authors: Meron Teklu, Anand Vaidya, Merve Yonar, June-Ho Kim, Edy Y. Kim
Journal: New England Journal of Medicine (2024)

A 44-year-old woman presented to the primary care clinic with a 2-year history of shortness of breath with minimal exertion, cough productive of clear sputum, generalized fatigue, and an unintentional weight loss of 9 kg ….
Tirzepatide for Obesity Treatment and Diabetes Prevention
Authors: Ania M Jastreboff, Carel W le Roux, Adam Stefanski, Louis J Aronne, Bruno Halpern, Sean Wharton, John P H Wilding, Leigh Perreault, Shuyu Zhang, Ramakrishna Battula, Mathijs C Bunck, Nadia N Ahmad, Irina Jouravskaya
Journal: New England Journal of Medicine (2024)

BackgroundObesity is chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes.MethodsWe performed a phase 3, double-blind, randomized, controlled trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods.ResultsAt 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was −12.3% with the 5-mg dose, −18.7% with the 10-mg dose, and −19.7% with the 15-mg dose, as compared with −1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified.ConclusionsThree years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo. (Funded by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.)
Toward Curing More Patients with Bladder Cancer — A New Perioperative Strategy
Authors: Matthew I Milowsky
Journal: New England Journal of Medicine (2024)

Over the past decade, the use of immune checkpoint inhibitors and antibody–drug conjugates has led to longer survival in patients with metastatic bladder cancer. Platinum-based chemotherapy had been the standard of care for decades. The combination of enfortumab vedotin, an antibody–drug conjugate directed against nectin-4, and pembrolizumab, a programmed death 1 (PD-1) inhibitor, has dramatically improved survival as compared with platinum-based chemotherapy.1 The integration of platinum-based chemotherapy with immune checkpoint inhibitors has been evaluated in several trials, including CheckMate 901, wherein nivolumab, a PD-1 inhibitor, plus gemcitabine–cisplatin led to longer survival than chemotherapy alone, despite negative findings of earlier trials . . .
Therapeutics for Nipah virus disease: a systematic review to support prioritisation of drug candidates for clinical trials
Authors: Xin Hui S Chan, Ilsa L Haeusler, Bennett J K Choy, Md Zakiul Hassan, Junko Takata, Tara P Hurst, Luke M Jones, Shanghavie Loganathan, Elinor Harriss, Jake Dunning, Joel Tarning, Miles W Carroll, Peter W Horby, Piero L Olliaro
Journal: The Lancet Microbe (2024)

Nipah virus disease is a bat-borne zoonosis with person-to-person transmission, a case-fatality rate of 38-75%, and well recognised potential to cause a pandemic. The first reported outbreak of Nipah virus disease occurred in Malaysia and Singapore in 1998, which has since been followed by multiple outbreaks in Bangladesh and India. To date, no therapeutics or vaccines have been approved to treat Nipah virus disease, and only few such candidates are in development. In this Review, we aim to assess the safety and efficacy of the therapeutic options (monoclonal antibodies and small molecules) for Nipah virus disease and other henipaviral diseases to support prioritisation of drug candidates for further evaluation in clinical trials. At present, sufficient evidence exists to suggest trialling 1F5, m102.4, and remdesivir (alone or in combination) for prophylaxis and early treatment of Nipah virus disease. In addition to well designed clinical efficacy trials, in-vivo pharmacokinetic-pharmacodynamic studies are needed to optimise the selection and dosing of therapeutic candidates in animal challenge and natural human infection.
Setmelanotide in patients aged 2–5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial
Authors: Jesús Argente, Charles F Verge, Uzoma Okorie, Ilene Fennoy, Megan M Kelsey, Casey Cokkinias, Cecilia Scimia, Hak-Myung Lee, I Sadaf Farooqi
Journal: The Lancet Diabetes & Endocrinology (2024)
Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients
Authors: Xiuli Zhang, S Peter Goedegebuure, Michael Y Chen, Rashmi Mishra, Felicia Zhang, Yik Yeung Yu, Kartik Singhal, Lijin Li, Feng Gao, Nancy B Myers, Tammi Vickery, Jasreet Hundal, Michael D McLellan, Mark A Sturmoski, Samuel W Kim, Ina Chen, Jesse T Davidson, Narendra V Sankpal, Stephanie Myles, Rama Suresh, Cynthia X Ma, Ademuyiwa Foluso, Andrea Wang-Gillam, Sherri Davies, Ian S Hagemann, Elaine R Mardis, Obi Griffith, Malachi Griffith, Christopher A Miller, Ted H Hansen, Timothy P Fleming, Robert D Schreiber, William E Gillanders
Journal: Genome Medicine (2024)

Abstract Background Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence. Methods Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing. Results Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4–20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7–100%) in the cohort of vaccinated patients. Conclusion Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses. Clinical trial registration number NCT02348320.
A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones
Authors: Raúl Sánchez-Lanzas, Justin Barclay, Alexandros Hardas, Foteini Kalampalika, Amanda Jiménez-Pompa, Paolo Gallipoli, Miguel Ganuza
Journal: Leukemia (2024)

Abstract Clonal hematopoiesis (CH) is nearly universal in the elderly. The molecular and cellular mechanisms driving CH and the clinical consequences of carrying clonally derived mutant mature blood cells are poorly understood. We recently identified a C223Y mutation in the extracellular domain (ECD) of NOTCH3 as a putative CH driver in mice. Provocatively, germline NOTCH3 ECD mutations perturbing cysteine numbers cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a type of vascular dementia, suggesting an unexpected link between CADASIL and CH. Here, we formally demonstrated that mouse hematopoietic stem and progenitor cells (HSPCs) expressing CADASIL-related NOTCH3 C455R exhibit a proliferative advantage resulting in robust cellular expansion in vivo and in vitro. Co-expression of NOTCH3 C455R and Dnmt3a R878H , homologous to a frequent human CH mutation, increased the fitness of NOTCH3 C455R HSPCs, demonstrating their functional cooperation. Surprisingly, the presence of NOTCH3 C455R hematopoietic cells supported the expansion of Dnmt3a R878H HSPCs in a non-cell autonomous fashion in vivo, strongly suggesting that CADASIL patients and asymptomatic carriers can be highly predisposed to DNMT3A R882H -driven CH. Considering that CADASIL-related NOTCH3 mutations are more frequent in the general population than anticipated (~1 carrier in 400 people), the effect of these NOTCH3 mutations on CH development should be considered.
The Utilization of the Accelerated Approval Pathway in Oncology: A Case Study of Pembrolizumab
Authors: Robert Kester, Sunita Zalani, Scot Ebbinghaus, Eric Rubin
Journal: Drugs (2024)

The accelerated approval (AA) pathway was established by the United States Food and Drug Administration (FDA) to provide earlier access to therapies for patients with serious medical conditions and unmet medical needs. Since its inception, the AA pathway has been used for novel treatments across different therapeutic areas, but most prominently in oncology, including the immune checkpoint inhibitor class. This review article describes the history of regulatory approvals for pembrolizumab, an immunotherapy agent targeting programmed death receptor-1 (PD-1), and use of the AA pathway and the corresponding regulatory decisions made by the FDA. From its first AA in September 2014 to February 2024, pembrolizumab has used the accelerated pathway for roughly 40% of the approved indications listed in the US Prescribing Information and was the first oncology therapy to receive an AA for an alternate dosing regimen and a tissue-agnostic indication. As of February 2024, 14 of the 18 indication-specific AAs and 1 post-marketing requirement (PMR) for the alternate dosing regimen AA were converted to traditional approvals. Accelerated approvals for two indications were withdrawn, and the remaining ongoing PMRs are not due until later in 2024 or 2025. The median conversion time from AA to traditional approval was 2.6 years, which is roughly 6 months earlier than the median time reported for oncology AAs. While FDA was the first agency to establish an expedited approval pathway, regulators from other countries have established similar pathways. For pembrolizumab, approximately half of the datasets that supported US AAs also supported expedited approval, or sometimes full approval, in Canada, EU, Australia or Japan. Ultimately, the AA pathway balances the provision of earlier access to therapies with overcoming uncertainty about potential effectiveness, and therefore it is important to confirm treatment benefit and withdraw indications that do not confirm benefit in a timely manner. The regulatory strategy and use of this expedited program for pembrolizumab highlights the importance of the AA pathway in providing oncology patients with earlier access to life-saving medications.
A multimodal endoscopic approach for esophageal fistula closure
Authors: Andrea Telese, Benjamin Norton, Apostolis Papaefthymiou, Alberto Murino, Charles Murray, Rehan Haidry
Journal: Endoscopy (2024)

Several endoscopic options are available for the treatment of post-surgical fistulae including clipping, stenting, vacuum therapy, and endoscopic suturing. Choosing between these depends on multiple factors including defect size and site, etiology, and presence of associated cavity [1] [2] [3]. We present the case of a 59-year-old man with recurrent chest infections secondary to an esophago-jejunal anastomotic fistula. He had previously undergone a total gastrectomy and chemotherapy for gastric adenocarcinoma (T4aN1M1), followed by distal pancreatectomy, hepatic resection, and jejunal repair for primary pancreatic adenocarcinoma (T4aNxMx; R1) that left him with an esophago-jejunal anastomosis. He continued adjuvant chemo-immunotherapy; two years later he had evidence of progressive disease and developed respiratory symptoms.
Suprapapillary trisectoral deployment of slim fully covered metal stents with ultra-stiff high-sliding guidewires for malignant hilar biliary obstruction
Authors: Tadahisa Inoue, Rena Kitano, Tomoya Kitada, Kazumasa Sakamoto, Satoshi Kimoto, Jun Arai, Kiyoaki Ito
Journal: Endoscopy (2024)

Placement of bilateral suprapapillary uncovered metal stents is recommended for unresectable malignant hilar biliary obstruction (MHBO) owing to superior patency compared with plastic stents, unilateral placement, and positioning across the papilla [1] [2] [3]. Recent studies also suggest that bilateral trisectoral placement further improves survival, especially in patients undergoing chemotherapy [4]. However, stent occlusion still affects approximately half of all cases, and reintervention for occlusion is technically demanding after bilateral placement of uncovered metal stents. Therefore, we proposed a novel approach, suprapapillary trisectoral placement of a slim, fully covered metal stent, which reduces the risk of side-branch occlusion and is easily removable, facilitating straightforward reintervention. Although insertion of the second and third stents becomes primarily challenging with this method, utilizing an ultra-stiff, high-sliding guidewire can circumvent this issue ([Fig. 1]).
Endoscopic intermuscular dissection: insights from China on minimally invasive treatment for early rectal cancer
Authors: Dejun Fan, Tao Yang, Jingwen Qi, Qiuning Wu, Xutao Lin, Chujun Li, Xianhe Kong
Journal: Endoscopy (2024)

A 73-year-old woman presented with a history of increased bowel movements and intermittent rectal bleeding for 1 month. A colonoscopy revealed tumors in the rectum, which were confirmed through biopsy as adenoma and intraepithelial neoplasia. Staging with computed tomography and magnetic resonance imaging indicated T2N0–1aM0 disease. Endoscopic intermuscular dissection (EID) was subsequently performed ([Video 1]).
The “line-band closure” technique: a new endoscopic traction method for closure of a large defect
Authors: Fei Liu, Zhenyun Gong, Duanmin Hu
Journal: Endoscopy (2024)

We describe the case of a 55-year-old woman with a solitary, yellow, subepithelial mass found in the large curvature of the stomach body on upper gastrointestinal endoscopy ([Fig. 1] a). The lesion had a size of 8 × 6 mm and was considered a neuroendocrine tumor. Endoscopic submucosal dissection (ESD) was performed to achieve complete resection of the lesion. After the lesion was removed, a 20 × 15 mm defect was left ([Fig. 1] b). In order to prevent delayed perforation and bleeding, the defect was closed.
Early gastric adenocarcinoma with enteroblastic differentiation diagnosed synchronously with a conventional gastric adenocarcinoma
Authors: Xiaonan Shen, Heng Zhang, Zhengting Wang, Xi Chen, Aihua Qian
Journal: Endoscopy (2024)

A 59-year old man underwent an esophagogastroduodenoscopy (EGD) for upper abdominal discomfort, which showed two different lesions: lesion 1 was a 0-IIa, slightly reddish, 15×8-mm lesion in the gastric angle; lesion 2 was a 0-IIc, reddish, 8×8-mm lesion in the cardia ([Fig. 1]). On narrow-band imaging (NBI), the 0-IIa lesion appeared slightly brownish, whereas the 0-IIc lesion appeared dark brownish. The demarcation line of 0-IIa lesion was less clear than that of the 0-IIc lesion. On magnifying NBI, the 0-IIa lesion presented an irregular microvascular pattern with loop-like structure. Within the irregular microsurface pattern, the intervening part was wide and elongated ([Fig. 2]). The irregular microvascular and microsurface patterns of the 0-IIc lesion presented loop and irregular mesh patterns with fused glands, an unclear white zone, and white globe appearance ([Fig. 3]). In brief, the 0-IIa lesion seemed to be behaving with a higher degree of differentiation than the 0-IIc lesion.
Successful endoscopic closure using novel clips for a duodenal perforation caused by an endoscopic ultrasound scope
Authors: Haruka Nakamura, Noboru Kawata, Junya Sato, Hiroki Sakamoto, Hiroyuki Ono
Journal: Endoscopy (2024)

Iatrogenic duodenal perforation is a serious complication of endoscopic procedures. Surgical intervention is commonly used to manage such perforations, with endoscopic intervention only recommended immediately post-perforation [1]. Conventional endoclips are usually inadequate to completely close large perforations [2]. The over-the-scope (OTS) clip system (Ovesco Endoscopy AG, Tübingen, Germany) has limited availability and is technically complex and expensive.
A new method with commonly available devices for treating buried bumper syndrome
Authors: Xiaoxiong Guo, Miao Liu, Canmei Zhong, Sihan Zhang, Liying Lin, Mingkai Zhuang, Fenglin Chen
Journal: Endoscopy (2024)

Buried bumper syndrome (BBS) is a rare yet significant complication following percutaneous endoscopic gastrostomy (PEG) that necessitates prompt intervention following diagnosis [1] [2]. There are many methods available for treating BBS, each requiring distinct devices, some of which may need to be specifically dedicated, along with complex endoscopic techniques to guarantee effective treatment [3]. Therefore, we explored the use of commonly available devices, namely hot biopsy forceps and a polypectomy snare, to successfully and efficiently manage a case of BBS ([Video 1]).
Transnasal endoscopic closure of persistent gastrocutaneous fistula via percutaneous suturing in altered oropharyngeal anatomy
Authors: Agnieszka Maniak, Kanika Garg, Gaurav Kakked, Ajaypal Singh, Irving Waxman, Christopher G. Chapman, Neal A. Mehta
Journal: Endoscopy (2024)

A 65-year-old man with a past medical history of oropharyngeal squamous cell carcinoma, status post resection and flap reconstruction, presented with concern for gastrojejunostomy tube malfunction. During the patient's most recent gastrojejunostomy exchange, he was noted to have significant leakage around the tube. On physical examination, there was a 15-mm gastrocutaneous fistula visualized on the abdominal wall with an ulceration lateral to the tract. The gastrojejunostomy was removed at bedside in the hope of healing the ulceration and fistula.
Novel method for retrieving Santorini duct stones from a patient with a rare chymotrypsin C variant combined with pancreas divisum
Authors: Guangchao Li, Rui Ji, Fan Zhang, Ning Zhong, Yan-Qing Li, Peng Wang
Journal: Endoscopy (2024)

An 18-year-old man with chronic pancreatitis presented with recurrent abdominal pain. He had undergone endoscopic retrograde pancreatography (ERP) 3 years earlier, which revealed incomplete pancreas divisum ([Fig. 1]). Despite endoscopic sphincterotomy and stent placement, his abdominal pain persisted. Recent computed tomography showed acute peripancreatic effusion, calcification, and dilation of the Wirsung and Santorini ducts ([Fig. 2]). Endoscopic ultrasound confirmed calcified stones impacted in the pancreatic duct ([Fig. 3]). Subsequent ERP revealed the opaque stone impacted in the Santorini duct. Attempts were made to remove the stone via the major papilla, but the balloon failed to grab the stone ([Fig. 4]). Intubation of the minor papilla was difficult. Pancreatoscopy was then used for further exploration.
Peroral pancreatoscopy-guided lithotripsy via an endoscopic ultrasonography-guided pancreatogastrostomy
Authors: Masatoshi Murakami, Nao Fujimori, Akihiko Suenaga, Yumeka Kawaguchi, Akihisa Ohno, Kazuhide Matsumoto, Keijiro Ueda
Journal: Endoscopy (2024)

A 72-year-old man with autoimmune pancreatitis type 2 presented with acute pancreatitis due to an impacted pancreatic stone ([Fig. 1]). Immediate transpapillary drainage was unsuccessful, leading us to attempt drainage via endoscopic ultrasonography-guided pancreaticogastrostomy (EUS-PGS) ([Video 1]).
Forward-viewing echoendoscope-guided recanalization plus radial incision and cutting technique for rectal anastomotic atresia
Authors: Xiao Li, Qingshan Pei, Shengqiang Zhao, Qian Ding, Zhen Li, Yongjun Shi
Journal: Endoscopy (2024)

Rectal anastomotic atresia is rare in clinical practice and is challenging to manage using traditional approaches [1] [2] [3] [4]. Here, we report successful recanalization utilizing a forward-viewing echoendoscope and endoscopic radial incision and cutting (ERIC) technique.
Epidemiology and Risk Factors for Testicular Cancer: A Systematic Review
Authors: Valentina Tateo, Zachary J Thompson, Scott M Gilbert, Victoria K Cortessis, Siamak Daneshmand, Timothy A Masterson, Darren R Feldman, Phillip M Pierorazio, Gagan Prakash, Axel Heidenreich, Peter Albers, Andrea Necchi, Philippe E Spiess
Journal: European Urology (2024)
Emerging Long-Term Risks of the Use of Proton Pump Inhibitors and Potassium-Competitive Acid Blockers
Authors: Katarina Jankovic, Ian M. Gralnek, Halim Awadie
Journal: Annual Review of Medicine (2024)

Acid-related disorders represent a significant global health burden. Pharmacological treatment of these conditions has at times been challenged and limited by incomplete effectiveness, antibiotic resistance, adverse medication effects and/or interactions, and disease recurrence. Since the early 1990s, the mainstay of treatment has been proton pump inhibitors (PPIs). Recently, the US Food and Drug Administration issued a clearance for vonoprazan, a potassium-competitive acid blocker (PCAB). PCABs are a new class of acid-suppressing agents that may overcome some of these challenges. The aim of this review is to evaluate and compare the emerging long-term risks of PPI and PCAB therapies.