tbuckley/cabot-search huggingface dataset:
Risk of Bleomycin-Related Pulmonary Toxicities and Operative Morbidity After Postchemotherapy Retroperitoneal Lymph Node Dissection in Patients With Good-Risk Germ Cell Tumors
Authors: Adam C. Calaway, Richard S. Foster, Nabil Adra, Timothy A. Masterson, Costa Albany, Nassar H. Hanna, Lawrence H. Einhorn, Clint Cary
Journal: Journal of Clinical Oncology (2018)

Three cycles of bleomycin, etoposide, and cisplatin (BEP × 3) or four cycles of etoposide and cisplatin (EP × 4) are first-line chemotherapy regimens for men with International Germ Cell Cancer Collaborative Group (IGCCCG) good-risk germ cell tumors (GCTs). We determined whether inclusion of bleomycin affected pulmonary and operative morbidity after postchemotherapy retroperitoneal lymph node dissection (PC-RPLND).We queried our database to identify IGCCCG good-risk patients who received BEP × 3 or EP × 4 induction chemotherapy before PC-RPLND from 2006 to 2016. Patients who received combination regimens were excluded. The primary outcomes of interest were pulmonary morbidity (prolonged intubation, reintubation, supplemental oxygen use, intensive care unit stay) and operative morbidity (operative time, length of stay, concomitant procedures, estimated blood loss).We analyzed 234 patients (191 BEP × 3 v 43 EP × 4). All patients were extubated immediately after the operation. None were reintubated or discharged on oxygen. Two patients in each cohort required an intensive care unit stay for nonpulmonary reasons. Patients treated with BEP required shorter use of supplemental oxygen (0.99 v 1.63 days; P = .005). No significant differences were found in preoperative mass size ( P = .42) or concomitant surgeries ( P = .58). Operative time was significantly shorter (131 v 170 minutes; P < .01), and estimated blood loss was considerably less (194 v 226 mL; P < .01) in patients treated with BEP. Length of stay was shorter in patients treated with BEP (3.3 v 3.9 days; P < .01).In a modern surgical cohort, the inclusion of bleomycin does not seem to influence pulmonary morbidity, operative difficulty, or nonpulmonary postoperative complications after PC-RPLND in men with IGCCCG good-risk GST.
Targeting STAT5 or STAT5-Regulated Pathways Suppresses Leukemogenesis of Ph+ Acute Lymphoblastic Leukemia
Authors: Valentina Minieri, Marco De Dominici, Patrizia Porazzi, Samanta A. Mariani, Orietta Spinelli, Alessandro Rambaldi, Luke F. Peterson, Pierluigi Porcu, Marja T. Nevalainen, Bruno Calabretta
Journal: Cancer Research (2018)

Combining standard cytotoxic chemotherapy with BCR-ABL1 tyrosine kinase inhibitors (TKI) has greatly improved the upfront treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, due to the development of drug resistance through both BCR-ABL1-dependent and -independent mechanisms, prognosis remains poor. The STAT5 transcription factor is activated by BCR-ABL1 and by JAK2-dependent cytokine signaling; therefore, inhibiting its activity could address both mechanisms of resistance in Ph+ ALL. We show here that genetic and pharmacologic inhibition of STAT5 activity suppresses cell growth, induces apoptosis, and inhibits leukemogenesis of Ph+ cell lines and patient-derived newly diagnosed and relapsed/TKI-resistant Ph+ ALL cells ex vivo and in mouse models. STAT5 silencing decreased expression of the growth-promoting PIM-1 kinase, the apoptosis inhibitors MCL1 and BCL2, and increased expression of proapoptotic BIM protein. The resulting apoptosis of STAT5-silenced Ph+ BV173 cells was rescued by silencing of BIM or restoration of BCL2 expression. Treatment of Ph+ ALL cells, including samples from relapsed/refractory patients, with the PIM kinase inhibitor AZD1208 and/or the BCL2 family antagonist Sabutoclax markedly suppressed cell growth and leukemogenesis ex vivo and in mice. Together, these studies indicate that targeting STAT5 or STAT5-regulated pathways may provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease.Significance: Suppression of STAT5 by BCL2 and PIM kinase inhibitors reduces leukemia burden in mice and constitutes a new potential therapeutic approach against Ph+ ALL, especially in tyrosine kinase inhibitor-resistant disease. Cancer Res; 78(20); 5793-807. ©2018 AACR.
Errors Resulting From Standard Order Sets—In Reply
Authors: Arjun Gupta, Sandeep R. Das, Ambarish Pandey
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 15061: Mode of Death and Predictors of Mortality in Adult Fontan Survivors: A Japanese Multicenter Observational Study
Authors: Hideo Ohuchi, Kei Inai, Makoto Nakamura, Hitomi Boku, Mamie Watanabe, Kison Kim, Hisanori Sakazaki, Kenji Waki, Yoshinori Yamagishi, Hiroshi Ono, Kenichiro Yamamura, Kenji Kuraishi, Koichiro Niwa
Journal: Circulation (2017)

Background: The number of adult patients after Fontan operation has been steadily increasing and the mortality is higher than that in the other types of congenital heart disease with biventricular ...
Impact of Preeclampsia on the Relationship between Maternal Asthma and Offspring Asthma. An Observation from the VDAART Clinical Trial
Authors: Hooman Mirzakhani, Vincent J. Carey, Thomas F. McElrath, Weiliang Qiu, Bruce W. Hollis, George T. O’Connor, Robert S. Zeiger, Leonard Bacharier, Augusto A. Litonjua, Scott T. Weiss
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Maternal asthma and preeclampsia have independently been reported to be associated with increased asthma incidence in children of affected mothers. Maternal asthma is also associated with increased risk of preeclampsia development. However, the joint effect of these maternal conditions on child asthma risk is unknown.
Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug
Authors: Sofia-Iris Bibli, Andreas Papapetropoulos, Efstathios K Iliodromitis, Andreas Daiber, Voahanginirina Randriamboavonjy, Sebastian Steven, Peter Brouckaert, Athanasia Chatzianastasiou, Kyriakos E Kypreos, Derek J Hausenloy, Ingrid Fleming, Ioanna Andreadou
Journal: Cardiovascular Research (2018)

Nitroglycerine (NTG) given prior to an ischaemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischaemic episode limits infarct size, has not yet been explored.Adult mice were subjected to acute myocardial infarction in vivo and then treated with vehicle or low-dose NTG prior to reperfusion. This treatment regimen minimized myocardial infarct size without affecting haemodynamic parameters but the protective effect was absent in mice rendered tolerant to the drug. Mechanistically, NTG was shown to nitrosate and inhibit cyclophilin D (CypD), and NTG administration failed to limit infarct size in CypD knockout mice. Additional experiments revealed lack of the NTG protective effect following genetic (knockout mice) or pharmacological inhibition (L-NAME treatment) of the endothelial nitric oxide synthase (eNOS). The protective effect of NTG was attributed to preservation of the eNOS dimer. Moreover, NTG retained its cardioprotective effects in a model of endothelial dysfunction (ApoE knockout) by preserving CypD nitrosation. Human ischaemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation.Low-dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of CypD, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results.
Targeting XRCC1 (X-ray repair cross-complementing gene 1) deficiency in tumors for personalized cancer therapy.
Authors: Srinivasan Madhusudan, Tarek M. A. Abdel-Fatah, Rebeka Sultana, Rachel Abbotts, Claire Hawkes, Claire Seedhouse, Andrew R. Green, Stephen Chan, Ian O. Ellis
Journal: Journal of Clinical Oncology (2012)

1014 Background: XRCC1 is essential for DNA base excision repair, single strand break repair and nucleotide excision repair. XRCC1 deficiency promotes genomic instability and may increase cancer risk. Methods: We evaluated XRCC1 immunohistochemically in early stage breast (n=2046), ovarian (n=157), gastric (n=140), colorectal (n=250) and pancreaticobiliary cancers (n=240). Pre-clinically, we evaluated a panel of XRCC1 deficient and proficient Chinese hamster ovary and human cancer cell lines. Double strand break repair (DSB) inhibitors targeting ATM (KU55933), DNA-PKcs (NU7441) and ATR (NU6027) were evaluated for synthetic lethality and cisplatin alone or in combination with DSB inhibitors for chemopotentiation. Results: In breast cancer,XRCC1 loss (16%) was associated with higher grade (p&lt;0.0001), loss of hormone receptors (p&lt;0.0001), presence of triple negative (p&lt;0.0001) and basal like phenotypes (p=0.001). Loss of XRCC1 was associated with a 2-fold increase in risk of death and metastasis (p&lt;0.0001) and independently with poor outcome (p&lt;0.0001). In ovarian cancer, XRCC1 was positive in 44% of tumour and was significantly associated with higher stage (p=0.001), clear/endometroid type (p=0.015) and sub-optimal debulking (p=0.004). XRCC1 positive tumours were more resistant to platinum chemotherapy (p=0.0001). XRCC1 positivity conferred a 2 fold increase of risk of death (p=0.002) and independently associated with poor survival (p=0.002). In gastric cancers, XRCC1 was positive in 37% of tumours. This was significantly associated with high stage disease (p=0.001) and poor survival (p=0.001). Pre-clinically, KU55933, NU7441 and NU6027 were synthetically lethal in XRCC1 deficient compared to proficient cells as evidenced by DSB accumulation, G2/M cell cycle arrest and apoptosis. XRCC1 deficient cells were hypersensitive to cisplatin which was enhanced by DSB repair inhibitors compared to in proficient cells. Conclusions: This is the largest study to confirm the clinical significance of XRCC1 expression in solid tumours. XRCC1 deficiency in human tumours may be suitable for synthetic lethality application and exploited for cisplatin chemotherapy potentiation.
Abstract 24: Changes in Generalized and Central Adiposity are Dynamically Associated with Left Ventricular Remodeling
Authors: Bryan R Wilner, Sonia Garg, Colby R Ayers, Satyam Sarma, Anand Rohatgi, Sandeep R Das, Darren K McGuire, James A de Lemos, Mark H Drazner, Ian J Neeland
Journal: Circulation (2016)

Introduction: Obesity is linked to an adverse cardiac structural phenotype in cross-sectional studies. However, the effects of longitudinal changes in generalized and central adiposity on left ventricular (LV) remodeling are unknown. Methods: Participants without baseline cardiovascular disease or LV dysfunction in the Dallas Heart Study underwent assessment of body composition and cardiac structure by MRI at baseline and then 7 years later. Associations between change in weight and waist circumference with alterations in structure and function were assessed using multivariable linear regression. Results: The study cohort (n=1262) had a mean age of 44 years and was 43% (545 of 1262) male, 44% (556 of 1262) African-American, and 36% (460 of 1262) obese at baseline. At 7 years follow-up, 7% (85 of 1262) had &gt;10% weight loss, 8% (108 of 1262) had 5-10% weight loss, 44% (551 of 1262) had &lt;5% weight change, 20% (248 of 1262) had 5-10% weight gain, and 21% (270 of 1262) had &gt;10% weight gain. Those who gained &gt;10% weight were younger, had lower BMI and LV mass at baseline, and had greater increases in blood pressure, glucose, triglycerides, LDL cholesterol, and hs-CRP over follow-up. In multivariable models adjusted for age, sex, race, and baseline and interim development of comorbidities, 1-standard deviation increases in body weight and waist circumference over follow-up were significantly associated with higher LV mass, LV wall thickness, and concentricity; but minimally or not significantly associated with LV end-diastolic volume or ejection fraction (EF) (Table). Conclusion: Increases in generalized and central adiposity are characterized primarily by concentric remodeling, with a more modest impact on LV volume and EF. These results support the notion that the development of specific obesity patterns may impact cardiac remodeling with potential implications for the development of cardiac hypertrophy and heart failure.
Abstract 12796: Plaque Surface Irregularity and Calcification Length Within Carotid Plaque Predict Secondary Events in Patients With Coronary Artery Disease
Authors: Shinichi Nonin, Shinichi Iwata, Kenichi Sugioka, Yu Kawai, Suwako Fujita, Sera Ishikawa, Naoki Norioka, Asahiro Ito, Masashi Nakagawa, Minoru Yoshiyama
Journal: Circulation (2016)

Introduction: Although comprehensive risk factor modification is recommended, a uniform management strategy does not necessarily prevent secondary events in patients with coronary artery disease (CAD). Therefore, identification of high-risk patients who may benefit from more intensive interventions may improve prognosis. Carotid ultrasound can reliably identify systemic atherosclerosis, and carotid plaque and intima-media thickness (IMT) are known independent risk factors for CAD. However, it is unclear whether findings on carotid ultrasound can improve prediction of secondary CAD events. Methods: The study population comprised 146 consecutive patients with CAD (mean age, 66 ± 9 years; 126 with angina pectoris, 20 with myocardial infarction). IMT, plaque score, plaque area, plaque surface irregularity, and calcification length (calculated by summing the calcified lesions within each plaque accompanied by acoustic shadow) were measured at baseline. Patients were followed for 10 years to ascertain secondary CAD events. Results: Of 146 patients, secondary CAD events occurred in 63 after a median follow-up of 10 years. In univariate analysis, calcification length (P &lt; 0.05) and plaque surface irregularity (P &lt; 0.01) were associated with secondary CAD events, whereas IMT, plaque score, and plaque area were not. Multiple regression analysis demonstrated that calcification length (odds ratio, 1.06; P &lt; 0.05) and plaque surface irregularity (odds ratio, 3.85; P &lt; 0.01) remained independently associated with secondary CAD events after adjustment for age, sex, diabetes mellitus, dyslipidemia, hypertension, chronic kidney disease, and smoking. Moreover, when patients were divided into 4 groups according to calcification length and presence or absence of plaque surface irregularity, the group with longer calcification and plaque surface irregularity had greater risk of secondary CAD events (relative risk, 3.82; P &lt; 0.05). Conclusions: These findings suggest that the combination of calcification length and plaque surface irregularity has additional value beyond traditional risk classification. Intensive intervention for these high-risk patients may avoid or delay progression of atherosclerosis towards secondary CAD events.
Cell circuits between B cell progenitors and IL-7+ mesenchymal progenitor cells control B cell development
Authors: Chris Fistonich, Sandra Zehentmeier, Jeffrey J. Bednarski, Runfeng Miao, Hilde Schjerven, Barry P. Sleckman, João P. Pereira
Journal: The Journal of Experimental Medicine (2018)

B cell progenitors require paracrine signals such as interleukin-7 (IL-7) provided by bone marrow stromal cells for proliferation and survival. Yet, how B cells regulate access to these signals in vivo remains unclear. Here we show that proB and IL-7+ cells form a cell circuit wired by IL-7R signaling, which controls CXCR4 and focal adhesion kinase (FAK) expression and restricts proB cell movement due to increased adhesion to IL-7+CXCL12Hi cells. PreBCR signaling breaks this circuit by switching the preB cell behavior into a fast-moving and lower-adhesion state via increased CXCR4 and reduced FAK/α4β1 expression. This behavioral change reduces preB cell exposure to IL-7, thereby attenuating IL-7R signaling in vivo. Remarkably, IL-7 production is downregulated by signals provided by preB cells with unrepaired double-stranded DNA breaks and by preB acute lymphoblastic leukemic cells. Combined, these studies revealed that distinct cell circuits control the quality and homeostasis of B cell progenitors.
Human Papilloma Virus Specific Immunogenicity and Dysfunction of CD8+ T Cells in Head and Neck Cancer
Authors: Sri Krishna, Peaches Ulrich, Eric Wilson, Falguni Parikh, Pooja Narang, Shanshan Yang, Amelia K. Read, Seunghee Kim-Schulze, Jin G. Park, Marshall Posner, Melissa A. Wilson Sayres, Andrew Sikora, Karen S. Anderson
Journal: Cancer Research (2018)

Abstract Human papillomavirus subtype 16 (HPV16) is the primary cause of an increasing number of head and neck squamous cell carcinomas (HNSCC), providing strong rationale for T-cell immune therapies against HPV+ HNSCC. Here we assess immunogenicity of HPV16-specific CD8+ T cells (CTL) and characterize HPV-specific mechanisms of T-cell dysfunction. We identified 16 strong and 29 moderately immunogenic CTL-epitopes from HPV16 E2, E6, and E7 antigens restricted by 12 common HLA class I alleles. E2-specific CTL-reactivity was higher in patients with HPV+ HNSCC than in healthy controls (&amp;gt;3-fold; P = 0.026). Patient-derived E2, E6, and E7 peripheral CTLs exhibited heterogeneity in dysfunctional phenotypes. Immunogenomic analyses of 119 HNSCC transcriptomes revealed high T-cell infiltration and dysfunction in HPV+ HNSCC and correlation of HPV antigen expression with T-cell exhaustion gene signatures. Indoleamine 2,3-dioxygenase (IDO-1) was strongly expressed in HPV+ HNSCC versus HPV− HNSCC (P = 0.001) and correlated with E7 expression (R2 = 0.84; P = 0.033). Combination treatment with PD-1 blockade and IDO-1 inhibition overcame profound CTL-dysfunction, enhancing HPV+ HNSCC sensitivity to CTL-cytotoxicity in vitro (up to 10-fold in E7-CTLs, P = 0.011). Our findings implicate mechanisms of T-cell escape in HPV+ HNSCC, wherein high tumoral HPV-antigen load results in high expression of immune dysfunction genes on tumor cells (e.g., IDO-1), and dysfunction of HPV-specific CTLs (e.g., E7, E2-CTLs). The HPV16 CTL-epitopes identified in this study, in combination with blockade of HPV+ HNSCC-specific PD-1/IDO-1 checkpoints, may be useful for targeted immunotherapy. Significance: This study evaluates the HPV antigen T-cell immunogenicity role of inhibitory receptors and other exhaustion markers in the cytotoxic function of HPV antigen-specific CTLs and identifies combined inhibition of PD-1/IDO-1 as a strategy to enhance CTL targeting of HPV+ HNSCC. Cancer Res; 78(21); 6159–70. ©2018 AACR.
Heterogeneous mutation pattern in tumor tissue and circulating tumor DNA warrants parallel NGS panel testing
Authors: Qiaomei Guo, Junlei Wang, Jianfeng Xiao, Lin Wang, Xiaomeng Hu, Wenjun Yu, Gang Song, Jiatao Lou, JianFeng Chen
Journal: Molecular Cancer (2018)

Liquid biopsy by genotyping circulating tumor DNA (ctDNA) has provided a non-invasive approach in assessing tumor genomic alterations in clinical oncology. However, emerging evidence in clinical settings has shown significant discordance in the genomic alterations between matched tumor tissue and blood ctDNA samples, and even between the same set of blood samples analyzed on different testing platforms. Thus, it is necessary to study underlying causes of discrepancies in these studies by genotyping tumor tissue and ctDNA in parallel using next generation sequencing (NGS) panels based on the same technology. Here we enrolled 56 non-small-cell lung cancer (NSCLC) patients and evaluated tumor tissue genotyping and ctDNA based liquid biopsy by parallel NGS panel testing and compared different sample preparation conditions. Somatic mutations in plasma cell-free DNA (cfDNA) were detected in 63.6% patients with early-stage NSCLC and 60% patients with advanced-stage NSCLC. The overall concordance between matched formalin-fixed paraffin-embedded sample and cfDNA was 54.6% in early-stage NSCLC patients and 80% in advanced-stage NSCLC patients. The positive concordance rate was 44.4% and 71.4% in early-stage and advanced-stage patients, respectively. Using fresh frozen tumor samples did not improve the overall concordance rate between matched tumor tissue and cfDNA. Processing blood samples beyond 4 h after blood draw significantly decreased the detection rate of somatic mutations in cfDNA. Thus, the concordance rate between tumor tissue-based and ctDNA-based genotyping in clinical samples can be affected by multiple pre-analytical, analytical and biologic factors. Parallel NGS panel testing on both sample types for each patient may be warranted for effective guidance of cancer targeted therapies and possible early detection of cancer.
Abstract 11245: Normal Findings in Late Gestation Fetal Echocardiography
Authors: Lauren Tague, Mary T Donofrio, Amanda Fulgium, Robert McCarter, Catherine Limperopoulos, David Schidlow
Journal: Circulation (2016)

Introduction: Fetal echocardiography (FE) provides detailed information about cardiac structure and function in-utero. Limited information is available regarding normal findings late in pregnancy. We sought to identify and describe common FE findings in late gestation. Methods: Fetuses with structurally normal hearts at mid-gestation were identified within a subset of pregnant women in a prospective study. Atrioventricular (AV) valves, right and left atrium (RA/LA), aortic isthmus (AoI) and ductal arch (DA) diameters and flow abnormalities, septum primum aneurysm (SPA), and presence/grade of tricuspid regurgitation (TR) were assessed. Linear and logistic regression analyses were used to characterize change in quantitative and qualitative FE parameters. Results: 40 fetuses were studied. Each had a FE completed before and after 34 weeks gestation. Studies were compared. RA/LA and tricuspid/mitral valve (TV/MV) ratios increased with GA (p&lt;0.001). Increased AoI and DA diastolic flow, and trivial/mild TR were more frequently identified after 34 weeks gestation. Increased AoI diastolic flow, DA narrowing, DA diastolic flow, TR, and SPA increased linearly with GA (p&lt;0.001). Conclusion: Mild RA/LA and AV valve disproportion, trivial/mild TR, isolated AoI diastolic flow, mild DA narrowing, and SPA are frequently seen after 34 weeks GA. This suggests these FE findings in isolation are likely normal as physiologic changes occur in late gestation. Figure 1: RA/LA disproportion and AV disproportion increase with gestational age. P&lt;0.001.
A novel galactose-PEG-conjugated biodegradable copolymer is an efficient gene delivery vector for immunotherapy of hepatocellular carcinoma
Authors: Ling Liu, Zhi-Min Zong, Qian Liu, Shuang-Shuang Jiang, Qian Zhang, Lan-Qi Cen, Jian Gao, Xiao-Ge Gao, Jian-Dong Huang, Yi Liu, Hong Yao
Journal: Biomaterials (2018)