tbuckley/cabot-search huggingface dataset:
Influence of PIK3CA mutations on breast cancer proliferation, lymphocyte infiltration and clinical outcome: Pooled analysis of 484 patients from three prospective multicentre GBG trials
Authors: P. Jank, S. Loibl, P.A. Fasching, T. Karn, F. Marmé, V. Mueller, C. Schem, E. Stickeler, B. Lederer, C. Denkert
Journal: Annals of Oncology (2019)

Background: The PI3K signaling pathway is frequently dysregulated in breast cancer (BC), effected through mutations in PIK3CA, which encodes for the catalytically subunit p110-alpha. An influence of PIK3CA mutations in therapy response resistance associated with a worse clinical outcome has previously been shown in HER2+ BC. Mutations in exon 9 or 20 may play a role in cell proliferation and therapy response. Methods: We investigated PIK3CA mutation status in 484 BC patients, randomized in three clinical multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880). Classical Sanger sequencing in exon 9 and 20 was performed on formalin-fixed paraffin embedded pretherapeutical core biopsies with a tumor content > =20%. Results: Mutation analysis of exon 9 and 20 were successful in 431 cases: PIK3CA was mutated in 21.6%, exon 9 in 8.8% and exon 20 in 13.9% of cases. Detection of a PIK3CA mutation was not significantly associated with a higher proliferation rate (Ki67 >20%: 76.3% mut. vs. 75.0% WT, p = 0.878). TN tumors were more often Ki67 low (38.5%) when exon 20 was mutated compared to wildtype (6.5%) (p = 0.005). There were no significant differences in proliferation in hormone receptor positive or HER2 positive tumors. Lower stromal lymphocyte infiltration was seen when exon 9 was mutated compared to wildtype in HER2+/HR- (Infiltration >60%: 28.5% mut. vs. 5.6% WT, p = 0.012), but not overall or in other subtypes. Detection of any PIK3CA mutation was significantly associated with lower pathologic complete response (pCR, ypT0ypN0) (24.7% in PIK3CA mutated vs. 38.2% in wildtype; p = 0.020). However, patients with mutation in exon 9 (21.1% mutated vs. 36.6% wildtype; p = 0.074) or 20 (25% mutated vs. 36.9% wildtype; p = 0.081) did not reach statistical significance for pCR. Conclusions: PIK3CA mutation is not linked with a higher tumor proliferation, but in HER2+/HR- tumors associated with a lower stromal lymphocyte infiltration. However, PIK3CA could be used as a biomarker for a worse outcome in terms of a lower rate of pCR after neoadjuvant anthracycline-taxane–based chemotherapy. Clinical trial identification: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880). Legal entity responsible for the study: GBG Forschungs GmbH. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
ENDOSCOPIC SUBEPITHELIAL DISSECTION FOR SUPERFICIAL PHARYNGEAL CANCER: A CASE SERIES OF 44 SUPERFICIAL CANCERS
Authors: S Morita, T Inoue, N Shimeno, T Inokuma, S Takebayashi, S Shinohara
Journal: Endoscopy (2019)

The pharyngeal space is the entrance to any endoscopic examination of the upper gastrointestinal tract. Narrow band imaging (NBI) makes it possible to detect superficial cancers in this region. As a minimally invasive treatment, endoscopic subepithelial dissection (ESD) technique could be indicated.
The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors
Authors: Akiko Nakai, Jun Fujimoto, Haruhiko Miyata, Ralf Stumm, Masashi Narazaki, Stefan Schulz, Yoshihiro Baba, Atsushi Kumanogoh, Kazuhiro Suzuki
Journal: The Journal of Experimental Medicine (2019)

Lymphocyte migration is mediated by G protein–coupled receptors (GPCRs) that respond to chemoattractive molecules. After their activation, GPCRs are phosphorylated by different GPCR kinases (GRKs), which produces distinct functional outcomes through β-arrestins. However, the molecular machinery that targets individual GRKs to activated GPCRs remains elusive. Here, we identified a protein complex consisting of copper metabolism MURR1 domain–containing (COMMD) 3 and COMMD8 (COMMD3/8 complex) as an adaptor that selectively recruits a specific GRK to chemoattractant receptors and promotes lymphocyte chemotaxis. COMMD8, whose stability depended on COMMD3, was recruited to multiple chemoattractant receptors. Deficiency of COMMD8 or COMMD3 impaired B cell migration and humoral immune responses. Using CXC-chemokine receptor 4 (CXCR4) as a model, we demonstrated that the COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of the receptor and activation of β-arrestin–mediated signaling. Thus, the COMMD3/8 complex is a specificity determinant of GRK targeting to GPCRs and represents a point of regulation for immune responses.
Pembrolizumab Exposure–Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance—Letter
Authors: Sander Bins, Stijn L.W. Koolen, Ron H.J. Mathijssen
Journal: Clinical Cancer Research (2019)

Turner and colleagues (1) recently presented a hypothesis that the exposure–response relationship of pembrolizumab is confounded by cancer cachexia, because patients in the lowest quartile of exposure at doses of both 2 and 10 mg/kg have comparably bad overall survival (OS). Although at first sight this seems to eliminate the possibility of a real exposure–response relationship, they subsequently showed that clearance of pembrolizumab at baseline (CL0) influenced the HR for OS, both in melanoma and in patients with non–small cell lung cancer. To further investigate this discrepancy, they added cachexia-related factors such as albumin to a multivariate Cox regression model with CL0, which reduced (but not completely superseded) CL0 HR for OS. The latter was interpreted by the authors as strong evidence that cachexia, at least partly, explains the exposure–response relationship, but we do have our doubts about this ‘evidence'.Primarily, CL0 was calculated using a time-dependent population pharmacokinetic (PPK) model (2), in which several baseline factors served as covariates for clearance, for example, albumin, sum of the longest diameter of the target lesions (BSLD), gender, and performance status. These covariates largely overlapped the factors added to the Cox regression model. Because of this circular reasoning, it is not surprising that CL0 HR for OS is reduced by these factors, because they have been used to improve the estimated CL0. In addition, the factors assessed are not exclusive for cachexia, but for a compromised clinical condition in general. Because the time-dependent factors assessed (i.e., change in albumin and weight) comprised the period from baseline up to week 9 of treatment, these factors may merely indicate which patients are deteriorating during treatment and thus have worse survival. Therefore, this will not differentiate between cachexia or any other explanation for this deterioration. Finally, tumor size was part of both the PPK model and the Cox analysis, but unfortunately measurements were not mentioned in the manuscript. This leaves room for speculation on the impact of tumor size: it might indeed cause worse clinical condition at baseline, but since pembrolizumab clearance also appears to be dependent of BSLD, it could be that the necessary drug concentration is not reached at higher tumor volumes. As a similar exposure–response relationship has been identified for nivolumab (3), the underlying mechanism of this unexpected finding needs to be explored further. Although plausible, the cachexia hypothesis remains highly premature and we should be careful to not exclude other theories yet.No potential conflicts of interest were disclosed.
Longitudinal HER2 amplification tracked in circulating tumor DNA for therapeutic effect monitoring and prognostic evaluation in patients with breast cancer
Authors: X. Guan, Y. Niu, B. Liu, C. Li, L. Li, Z. Yi, X. Sun, H. Chen, F. Ma, S. Lu
Journal: Annals of Oncology (2019)

Background: Human epidermal growth factor receptor 2 (HER2) status is a crucial predictive factor for prognostic assessment and targeted therapy selection, which may be influenced by intratumor heterogeneity and molecular divergence between the primary site and different metastases. Therefore, we performed a prospective study to confirm the concordance of HER2 amplification in circulating tumor DNA (ctDNA) with primary tumor tissue and verified its clinical implications. Methods: A total of 105 breast cancer patients were enrolled, and dynamic monitoring of HER2 copy numbers in ctDNA was conducted in 31 participants during the treatment. In total, 186 plasma samples were prospectively obtained and blinded to test HER2 copy numbers in ctDNA based on low-coverage whole genome sequencing (WGS) by next-generation sequencing (NGS). Results: Comparing HER2 copy numbers in ctDNA collected before the initiation of the next line of anticancer treatment with primary tumor tissue, the concordant rate of HER2 amplification was 86.5% (χ2= 52.901, p < 0.001), with a positive and negative predictive value of 94.9% and 80.7%, respectively. Histopathologically positive, high-level amplification of HER2 copy numbers in the baseline was significantly correlated with the best objective response during the anticancer therapy (p = 0.010). Moreover, HER2 copy numbers fluctuated with HER2-targeted therapeutic response, and the patients with a constantly positive level after 6 weeks of treatment appeared to suffer from significantly reduced progression free survival (p < 0.001). Conclusions: HER2 amplification in ctDNA, with a concordance rate of over 80% with primary tumors, may be a predictive index for prognostic evaluation and therapeutic response monitoring in a noninvasive, repeatable and practical method for breast cancer patients. Legal entity responsible for the study: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Funding: National Natural Science Foundation of China (81472453, 81874122), and the CAMS Initiative for Innovative Medicine (2017-I2M-3-004). Disclosure: Y. Niu, S. Lu: Employee: Yikon Genomics Co. Ltd.
CMR Fingerprinting for Myocardial T1, T2, and ECV Quantification in Patients With Nonischemic Cardiomyopathy
Authors: Armando Ugo Cavallo, Yuchi Liu, Andrew Patterson, Sadeer Al-Kindi, Jesse Hamilton, Robert Gilkeson, Vikas Gulani, Nicole Seiberlich, Sanjay Rajagopalan
Journal: JACC. Cardiovascular imaging (2019)
Simvastatin nanoliposome induces myocardial and hepatic toxicities due to its absorption enhancement in mice
Authors: Nuerbiye Tuerdi, Gulinigaer Anwaier, Xing Zhang, Shu Liu, Wanli Shen, Wen Liu, Qiang Shen, Rong Qi
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin (SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome (SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.
Comparison of Functional Deficit Zone Defined by FDG PET to the Epileptogenic Zones Described in Stereo-Electroencephalograph in Drug-Resistant Epileptic Patients Treated by Surgery
Authors: Marie-Soline Montaz-Rosset, Julia Scholly, Paul Voulleminot, François Severac, Edouard Hirsch, Maria Paola Valenti-Hirsch, Izzie Jacques Namer
Journal: Clinical Nuclear Medicine (2019)

Introduction The purpose of presurgical assessment is to delimit the epileptogenic zone and the functional deficit zone with a brain MRI, an electroencephalograph or even a stereo-electroencephalograph (SEEG), neuropsychological evaluation, and a cerebral FDG PET. Several studies concur that the hypometabolism of FDG PET seems to be consistent with epileptogenic zones. We compared the functional deficit zone defined by FDG PET with the results of the SEEG, for each cluster electrode contact (CEC) located in the gray matter. Methods The electrode diagram of the 15 patients (486 CECs) operated on for drug-resistant epilepsy was merged with MRI and FDG PET. The metabolisms of FDG PET and SEEG were compared using a logistic regression test. Results The presence of hypometabolism resulted in a significantly higher risk of being in the seizure onset zone and the irritative zone, particularly when it was intense. Of the deeply hypometabolic CECs, 47% were in the seizure onset zone and 76% in the irritative zone. Normal metabolism resulted in a significantly higher probability of being in the healthy zone. Conclusions This study demonstrated an association between the presence of normal metabolism and the location of CECs in the healthy zone, and between the presence of pathological metabolism and the location of CECs in the seizure onset zone and the irritative zone, with metabolism abnormalities progressively more present and more intense near the seizure onset zone.
Hepaticogastrostomie comme accès au calibrage des sténose biliaire bénigne en cas de papille non accessible par voie endoscopique rétrograde
Authors: M Pizzicannella, F Caillol, JP Ratone, E Bories, C Pesenti, J Winkler, A Debourdeau, C Decoster, M Giovannini
Journal: Endoscopy (2019)

Le traitement endoscopique des stenoses bénignes sur anastomoses hépatico-jejunales se fait classiquement par voie percutanée. Récemment l'accès aux voies biliaires par hépaticogastrostmie (EUS-HGS) a été décrit dans la pathologie lithiasique (1) et comme moyen de calibrage dans ces sténoses anstomotiques (2). Cependant peu de données restent disponibles sur la possibilité de traitement de ces sténoses anastomotiques par EUS-HGS.
Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Metastases (CYTO-CHIP study): A Propensity Score Analysis
Authors: Pierre-Emmanuel Bonnot, Guillaume Piessen, Vahan Kepenekian, Evelyne Decullier, Marc Pocard, Bernard Meunier, Jean-Marc Bereder, Karine Abboud, Frédéric Marchal, François Quenet, Diane Goere, Simon Msika, Catherine Arvieux, Nicolas Pirro, Romuald Wernert, Patrick Rat, Johan Gagnière, Jeremie H. Lefevre, Thomas Courvoisier, Reza Kianmanesh, Delphine Vaudoyer, Michel Rivoire, Pierre Meeus, Guillaume Passot, Olivier Glehen
Journal: Journal of Clinical Oncology (2019)

Gastric cancer (GC) with peritoneal metastases (PMs) is a poor prognostic evolution. Cytoreductive surgery (CRS) yields promising results, but the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial. Here we aimed to compare outcomes between CRS-HIPEC versus CRS alone (CRSa) among patients with PMs from GC. From prospective databases, we identified 277 patients with PMs from GC who were treated with complete CRS with curative intent (no residual nodules > 2.5 mm) at 19 French centers from 1989 to 2014. Of these patients, 180 underwent CRS-HIPEC and 97 CRSa. Tumor burden was assessed using the peritoneal cancer index. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of HIPEC and account for confounding factors. After IPTW adjustment, the groups were similar, except that median peritoneal cancer index remained higher in the CRS-HIPEC group (6 v 2; P = .003). CRS-HIPEC improved overall survival (OS) in both crude and IPTW models. Upon IPTW analysis, in CRS-HIPEC and CRSa groups, median OS was 18.8 versus 12.1 months, 3- and 5-year OS rates were 26.21% and 19.87% versus 10.82% and 6.43% (adjusted hazard ratio, 0.60; 95% CI, 0.42 to 0.86; P = .005), and 3- and 5-year recurrence-free survival rates were 20.40% and 17.05% versus 5.87% and 3.76% (P = .001), respectively; the groups did not differ regarding 90-day mortality (7.4% v 10.1%, respectively; P = .820) or major complication rate (53.7% v 55.3%, respectively; P = .496). Compared with CRSa, CRS-HIPEC improved OS and recurrence-free survival, without additional morbidity or mortality. When complete CRS is possible, CRS-HIPEC may be considered a valuable therapy for strictly selected patients with limited PMs from GC.
Un tableau mixant des critères diagnostiques validés améliore la caractérisation des lésions colorectales: le tableau CONECCT
Authors: M Fabritius, J Jacques, JM Gonzalez, R Gérard, J Rivory, J Branche, C Lepage, P Bonniaud, E Coron, I Lienhart, L Poincloux, V Lepilliez, X Dray, JC Saurin, T Ponchon, M Pioche
Journal: Endoscopy (2019)

La caractérisation endoscopique des polypes colorectaux est un point essentiel au cours de la coloscopie pour choisir l'option thérapeutique adaptée à chaque lésion. Actuellement elle est basée sur 7 classifications différentes (Paris, LST, WASP, SANO, JNET, Kudo, NICE) qui ont fait leurs preuves mais qui peuvent paraître fastidieuses pour les non experts. Dans ce contexte, nous avons regroupé ces différentes classifications dans un seul tableau appelé CONECCT. Toutes les lésions colorectales y sont randomisées en 5 types histologiques (CONECCT IH pour les polypes hyperplasiques, CONECCT IS pour les lésions festonnées sessiles, CONECCT IIA pour les adénomes à très faible risque d'adénocarcinome non visible, CONECCT IIC pour les adénomes à haut risque d'adénocarcinome non visible ou les adénocarcinomes superficiels et CONECCT III pour les adénocarcinomes profonds. Chaque type histologique nécessite une prise en charge spécifique (pas de résection pour CONECCT IH, résection sans viser RO pour CONECCT IS et IIA, résection avec marges de résection saines pour CONECCT IIC et prise en charge chirurgicale pour CONECCT III). Notre étude avait pour objectif d'évaluer le bénéfice d'une session de formation à ce tableau CONECCT chez les internes et seniors de Gastro-Entérologie pour la prédiction histologique et le choix thérapeutique des polypes colorectaux à court et long terme.
Le rendement diagnostique de la vidéocapsule endoscopique dans la maladie de Crohn suspectée
Authors: AM Singeap, O Petrea, A Trifan, C Stanciu
Journal: Endoscopy (2019)

Le rôle de la vidéocapsule endoscopique (VCE) pour l'intestin grêle, une technique d'imagerie non-invasive relativement nouvelle, dans le diagnostic de la maladie de Crohn (MC), s'est élargi avec les progrès de la technologie, la meilleure compréhension de la pathologie de la maladie et la préférence pour les méthodes non invasives. Il n'existe pas un seul test diagnostique unique et de référence pour la MC. Même si la VCE est l'investigation de première ligne pour la pathologie de l'intestin grêle, le processus de diagnostic implique à la fois un jugement clinique complexe et une approche dédiée multidisciplinaire.
Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver
Authors: Hong‐Min Ni, Xiaojuan Chao, Hua Yang, Fengyan Deng, Shaogui Wang, Qingyun Bai, Hui Qian, Yue Cui, Wei Cui, Yinghong Shi, Wei‐Xing Zong, Zhengtao Wang, Li Yang, Wen‐Xing Ding
Journal: Hepatology (2019)

Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis; however, the mechanisms behind why a lack of autophagy induces these complications are not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy‐induced liver pathogenesis and tumorigenesis was investigated by using liver‐specific autophagy related 5 knockout (L‐ATG5 KO) mice, L‐ATG5/mTOR, and L‐ATG5/Raptor double knockout (DKO) mice. We found that deletion of mTOR or Raptor in L‐ATG5 KO mice at 2 months of age attenuated hepatomegaly, cell death, and inflammation but not fibrosis. Surprisingly, at 6 months of age, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L‐ATG5 KO mice. Moreover, more than 50% of L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice already developed spontaneous tumors, but none of the L‐ATG5 KO mice had developed any tumors at 6 months of age. At 9 months of age, all L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO had developed liver tumors. Mechanistically, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice had decreased levels of hepatic ubiquitinated proteins and persistent nuclear erythroid 2 p45‐related factor 2 activation but had increased Akt activation compared with L‐ATG5 KO mice. Conclusion: Loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy.
Évaluation de la sécurité et de l'efficacité de l'Hemospray comme traitement hémostatique des saignements diffus modérés au cours d'une nécrosectomie endoscopique
Authors: N Grieve, O Rouquette, M Riquelme, M Jabaudon-Gandet, A Abergel, L Poincloux
Journal: Endoscopy (2019)

La nécrosectomie endoscopique est devenue la technique de 1ère intention dans le traitement de l'infection de nécrose au cours de la pancréatite aiguë. Cependant la survenue d'un saignement de la cavité de nécrose est une complication fréquente et augmente la morbi-mortalité du geste. Plusieurs études publiées sur l'Hemospray ont montré son efficacité et sa sécurité dans les hémorragies digestives. Nous avons évalué son application comme traitement hémostatique des saignements diffus modérés survenant au cours d'une nécrosectomie endoscopique.