tbuckley/cabot-search huggingface dataset:
FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy
Authors: Shaoxing Guan, Xi Chen, Youhao Chen, Guohui Wan, Qibiao Su, Heng Liang, Yunpeng Yang, Wenfeng Fang, Yan Huang, Hongyun Zhao, Wei Zhuang, Shu Liu, Fei Wang, Wei Feng, Xiaoxu Zhang, Min Huang, Xueding Wang, Li Zhang
Journal: Acta Pharmaceutica Sinica B (2022)

Hepatotoxicity is a common side effect for patients treated with gefitinib, but the related pathogenesis is unclear and lacks effective predictor and management strategies. A multi-omics approach integrating pharmacometabolomics, pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution. Here, we found that patients with rs4946935 AA, located in Forkhead Box O3 (FOXO3) which is a well-known autophagic regulator, had a higher risk of hepatotoxicity than those with the GA or GG variant (OR = 18.020, 95%CI = 2.473 to 459.1784, P = 0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury. In contrast, erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3. This study reveals that FOXO3 mutation, leading to autophagic imbalance, plays important role in gefitinib-induced hepatotoxicity, especially for patients with high concentration of gefitinib. In conclusion, FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.
The Lumleian Lectures on Inflammation
Authors: J. B. Sanderson
Journal: BMJ (1882)

THE most important of the propositions which I submitted to you in the last lecture was this: that the attribute which distinguishes an infective inflammation (i.e., one which is capable of extending and reproducing itself) from a normal one (which tends to discontinuance on the removal of its cause)-in a word, the property of infectiveness
Lectures on the Relations of Sarcoma to Carcinoma
Authors: H. T. Butlin
Journal: BMJ (1880)

decision after most carefully weighing the evidence on the subject.I cannot but think that the discussion which we shall be privileged to hear on this occasion will tend very greatly to strengthen the hands of the Commriittee, and to expedite in a marked degree the reforms, for which it has so long and earnestly striven.
External beam radiation therapy with or without brachytherapy boost for low PSA, high-grade prostate cancer.
Authors: Benjamin Walker Fischer-Valuck, Brian Christopher Baumann, Vishal Ramesh Dhere, Randall Brenneman, Hiram Alberto Gay, Neal Andruska, Simon A. Brown, Bruce Hershatter, Jeff M. Michalski, Sagar Anil Patel
Journal: Journal of Clinical Oncology (2022)

258 Background: Radiation dose escalation with the addition of a brachytherapy boost (BT) to external beam radiation therapy (EBRT) may be associated with improved survival in certain men with Gleason grade 5 (GG5) prostate cancer (PCa). However, low PSA, high-grade PCa has much worse outcomes, is associated with neuroendocrine genomic features, and may be more resistant to androgen suppression. It is unclear whether the addition of a BT boost in men with this disease subgroup is associated with a survival benefit and is the subject of this analysis. Methods: Men diagnosed with node-negative, non-metastatic GG5 PCa and treated with (1) EBRT plus ADT or (2) EBRT plus BT plus ADT between 2004 and 2015 were identified in the National Cancer Database (NCDB). The EBRT cohort received conventionally fractionated ≥ 74 Gy or moderately hypofractionated (2.5-3.0 Gy x 20-28 fractions) EBRT. EBRT plus BT cohort received external beam doses of conventionally fractionated ≥45 Gy or moderately hypofractionated (2.5 Gy x 15 – 18 fractions) radiation, and either LDR or HDR BT. Men receiving chemotherapy, immunotherapy, or any form of surgery were excluded. Patients were stratified into two groups based on whether the presenting PSA was above or below the normal threshold (≤4 and &gt; 4 ng/mL). OS was compared using the Kaplan-Meier and log-rank test. Multivariable analysis (MVA) using Cox proportional hazards regression modeling was performed, accounting for age, race, year of diagnosis, Charlson-Deyo comorbidity score, insurance status, treatment facility type, Gleason Score (9 versus 10), and clinical T-stage. Results: 8,260 men met study inclusion criteria of which 658 (8%) presented with PSA ≤4. 572 (87%) patients were treated with EBRT monotherapy and 86 (13%) patients were treated with EBRT + BT. 5-year OS for EBRT versus EBRT plus BT was 79.7 +/- 2.3% versus 86.9 +/- 5.0%, respectively (P = 0.49). On MVA analysis, EBRT plus BT was not associated with improved OS versus EBRT (adjusted HR 0.90, 95% CI 0.52-1.87; P = 0.62). In comparison, for men with PSA &gt; 4 and GG5 disease [EBRT: 6,780 patients (89.2%) &amp; EBRT plus BT: 822 patients (10.8%)], EBRT plus BT was associated with improved OS versus EBRT (adjusted HR 0.85, 95% CI 0.66-0.99; P = 0.044). Conclusions: Receipt of dose-escalated prostate radiation by means of a BT boost was not associated with improved survival in men with PSA ≤4 ng/mL and GG5 prostate cancer. By contrast, an association with improved survival was observed in men with GG5 disease and higher initial PSA. This low PSA, high-grade subgroup may represent a unique risk tier for which current treatment paradigms need further investigation, including study of escalated systemic therapy.
Analysis of the role of PI3K-AKT and DNA damage repair (DDR) genomic biomarkers as predictors of clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Richard Gagnon, Soufiane El Hallani, Richard M. Lee-Ying, Michael Paul Kolinsky, Daniel Joseph Khalaf, Sarah Cook, Catalina Vasquez, Divya Samuel, John D Lewis, Rehan Faridi, Minal Borkar, Daniel Yick Chin Heng, Nimira S. Alimohamed, Joseph D. Ruether, Geoffrey Gotto, Adrian S. Fairey, Tarek A. Bismar, Steven Yip
Journal: Journal of Clinical Oncology (2022)

175 Background: Clinically relevant outcomes in nmCRPC treated with androgen receptor-axis-targeted therapies (ARAT) may be inferior in patients with tumors harboring mutations bypassing androgen receptor signalling. This final update of a retrospective, multicenter analysis explores the association between genomic mutations in the PI3K-AKT and DDR signalling pathways with ARAT treatment outcomes in nmCRPC patients. Methods: Relevant clinical endpoint were collected for high-risk nmCRPC patients treated with an ARAT at APCaRI affiliated cancer centers, including median metastasis-free survival (MFS), overall survival (OS), PSA decline ≥ 50% (PSA50), and second progression free survival (PFS2). Archival tumor tissue was accessed for next generation gene sequencing, examining for genomic alterations in 500 genes, including those involved in the DDR and the PI3K-AKT signalling pathways. Comparison of outcomes of patients with DDR and PI3K-AKT pathway mutations was conducted using Cox proportional hazards regression using wildtype cases as the reference group, adjusting for PSA doubling time and pelvic lymphadenopathy. Results: Of the 37 patients included, 30 (82%) received apalutamide, 5 (13%) received darolutamide, and 2 (6%) received enzalutamide. 10 patients (27%) had PI3K-AKT pathway mutations (4 PTEN, 3 PIK3Ca, 2 PIK3C2G, 1 PIK3C2b), 8 patients (22%) had DDR gene mutations (3 ATM, 2 CHEK1, 1 BRCA2, 1 CDK12, 1 CHEK2, 1 FANCD2, 1 FANCL), and 1 patient (3%) had 2 MLH1 mutations (microsatellite instability). Of those who had subsequent treatment, 1 received enzalutamide and 5 received abiraterone. Patients with PI3K-AKT pathway mutations had significantly shorter MFS (4.8 mo; HR 4.2; 95% CI 1.2 – 15.0; p = 0.025). Those with DDR mutations had a trend towards shorter MFS (23.3 mo HR 3.7; 95% CI 0.71 – 13.4; p = 0.134). OS data remains immature. 4 (11%) patients did not achieve PSA50, including a patient with 2 MLH1 mutations. Conclusions: This final analysis demonstrates that nmCRPC with PI3K and DDR signalling pathway mutations have poor clinical outcomes when treated with ARAT, likely secondary to decreased reliance on the androgen receptor signalling pathway. These results highlight the potential value of exploring targeted therapies, such as PARP or AKT inhibitors in patients with these mutations.
Leads from the MMWR. New recommended schedule for active immunization of normal infants and children
Journal: JAMA (1986)

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
MB-35 * VERY ENCOURAGING LONG-TERM SURVIVAL AND NEUROCOGNITIVE OUTCOME OF YOUNG CHILDREN TREATED FOR MEDULLOBLASTOMA WITH SEQUENTIAL HIGH DOSE CHEMOTHERAPY
Authors: L. Lafay-Cousin, S. Chi, A. Smith, E. Wells, J. Madden, A. Margol, V. Ramaswamy, E. Owen, D. Strother, G. Dhall, N. Foreman, R. Packer, E. Bouffet
Journal: Neuro-Oncology (2015)
Annals Graphic Medicine - Her Rounds
Authors: Michelle Lundholm
Journal: Annals of Internal Medicine (2020)

Web Exclusives17 November 2020Annals Graphic Medicine - Her RoundsFREEMichelle Lundholm, MDMichelle Lundholm, MDLoyola University Medical Center, Maywood, Illinois (M.L.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0015 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Loyola University Medical Center, Maywood, Illinois (M.L.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G20-0015.Author/Illustrator Information: Michelle Lundholm, MD (e-mail, [email protected]com). PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 17 November 2020Volume 173, Issue 10Page: W149 ePublished: 17 November 2020 Issue Published: 17 November 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Molecular analysis of primary testicular germ cell tumor and matched metastatic teratomas.
Authors: Anna Savelyeva, Feng Wang, Lei Guo, John T. Lafin, Liwei Jia, Kirill Medvedev, Cheryl Lewis, Payal Kapur, Vitaly Margulis, Solomon L. Woldu, Xiaosong Meng, Nick Grishin, James F. Amatruda, Lin Xu, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2022)

425 Background: Metastastic teratoma (MT) is a unique germ cell tumor (GCT) subhistology characterized by resistance to platinum-based chemotherapy. Metastatic teratoma requires complete surgical excision, usually via retroperitoneal lymph node dissection (RPLND), following chemotherapy as a part of multidisciplinary GCT care. Molecular characterization of post-chemotherapy metastatic teratoma along with companion pre-chemotherapy testicular primary tumors could inform 1) the origin and differentiation site of metastatic teratomas, 2) mechanisms of platinum-resistance, 3) novel therapeutic options for patients with unresectable teratomas. Methods: We performed integrated molecular analysis for 16 primary germ cell tumors and 18 metastatic teratomas, 11 were matched tumor/metastasis pairs. All teratomas in our cohort were collected after induction platinum-based chemotherapy. In addition to SNV analysis, we conducted a chromosomal copy number gain and loss analysis for selected teratomas, matched primary tumors and primary teratomas from the TCGA. Results: Metastatic teratomas as well as their tumors of origin had low tumor mutation burden (0.65 and 0.47 accordingly). Amongst 583 SNVs detected in the study cohort, only two (KRAS p.Gly12Asp and KRAS p.Gly12Val) were previously described as oncogenic. Analysis of SNVs in proteins playing key roles in oncogenic signaling [1] showed that TP53 and Ras pathways were the most affected in metastatic teratomas. The majority of metastatic teratomas possess gain of 3p11.1 and loss of 10q26.3, 16p11.2, 19p13.2, 19q12 and 22q12.3 loci. Within 3p11.1 we did not identify any previously described oncodrivers. However, 5 chromosomal loci with lost heterozygosity contained 16 previously annotated tumor suppressor genes (15 protein coding and 1 microRNA, MIR199A1). Amongst those, GADD45GIP1 inhibition (growth arrest and DNA-damage-inducible, gamma interacting protein 1) is known for playing a role in cisplatin resistance through mechanism of cellular senescence [2]. Conclusions: Metastatic teratoma in our cohort is characterized by low tumor mutational burden, recurring copy number changes, and lack of recurring SNVs. Molecular insight of teratoma may inform disease biology and treatment. References: Sanchez-Vega, Francisco et al. “Oncogenic Signaling Pathways in The Cancer Genome Atlas.” Cell vol. 173,2 (2018): 321-337.e10. Nakayama, Kentaro et al. “Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer.” Oncology letters vol. 13,6 (2017): 4713-4719.
Residual Prostatitis
Authors: W. E. Coutts, E. Silva-Inzunza
Journal: BMJ (1948)

JOURNAinfection in a number of children selected for operation.As Mr. Walker suggests in his final comments, this resolves in the vast majority of cases after removal of the diseased tonsils and adenoids.He considers that the unsatisfactory results following tonsillectomy and adenoidectomy are due to sinusitis: we con- sider that they are more likely to be due to an incorrect selection of children for operation.-Weare, etc., M. R. SHERIDAN.Truro, Cornwall.T. M. BANHAM.Residual Prostatitis SIR,-We have read with great interest Dr. F. C. Bourgault DLI Coudray's excellent article on residual prostatitis (Oct.25, 1947, p. 651).Such a condition has been observed by us in a large number of cases, and assuredly also by many others, after sulphonamide or penicillin treatment of the urethral-process gonorrhoea.Some cases were treated for months and even years with massage, diathermy, and high supplementary doses of antibiotics notwithstanding the fact that repeated cultures of prostatic fluid and of semen were sterile or showed some diph- theroids or Gram-positive cocci or bacilli.Streptomycin was used without success in 2 cases.The persistence of pus cells in the prostatic fluid indicated the existence of an infection whose true nature we have cleared
Errors in Results and Discussion Sections
Authors: Yongling Ji, Xianghui Du, Ming Chen
Journal: JAMA Oncology (2022)

Mitchell S. Anscher, MD; Shaily Arora, PharmD; Chana Weinstock, MD; Anup Amatya, PhD; Pradeep Bandaru, PhD; Chad Tang, MD; Andrew T. Girvin, PhD; Mallorie H. Fiero, PhD; Shenghui Tang, PhD; Rachael Lubitz, BA; Laleh Amiri-Kordestani, MD; Marc R. Theoret, MD; Richard Pazdur, MD; Julia A. Beaver, MD
Maintenance Capecitabine in Recurrent or Metastatic Nasopharyngeal Carcinoma—Magic Bullet or Pandora’s Box?
Authors: Wai-Tong Ng, Melvin L. K. Chua, Anne W. M. Lee
Journal: JAMA Oncology (2022)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Oncology journal
Phase 1b study of tarlatamab, a half-life extended bispecific T-cell engager (HLE BiTEimmune therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).
Authors: Rahul Raj Aggarwal, Sylvie Rottey, Ana Aparicio, Richard Greil, Melissa Andrea Reimers, Shahneen Kaur Sandhu, Yiran Zhang, Mark Salvati, Nooshin Hashemi Sadraei
Journal: Journal of Clinical Oncology (2022)

TPS197 Background: NEPC is an aggressive cancer with no standard treatment approach and poor prognosis. It is usually treatment-emergent, occurring in 15%–20% of patients (pts) with metastatic castration-resistant prostate cancer following treatment with androgen signaling inhibitors (ASI) and is characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor. 1 The tumor associated antigen delta-like ligand 3 (DLL3) has been identified as a promising target in both NEPC and small cell lung cancer (SCLC), as it is highly expressed in these tumors and minimally expressed on normal tissue. Tarlatamab is a DLL3-targeting HLE BiTE ® immune therapy designed to bind DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In preclinical studies, tarlatamab induced T-cell dependent lysis of DLL3-expressing neuroendocrine tumor cell lines, including NEPC cells. 2 Interim results of an ongoing first-in-human study in pts with SCLC (NCT03319940) show evidence for tarlatamab efficacy with an acceptable safety profile. 3 Together, these findings support a clinical study of tarlatamab in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating tarlatamab infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with metastatic NEPC whose disease progressed/recurred after ≥1 prior line of systemic therapy (platinum-based regimen for de novo NEPC or an ASI if treatment-emergent), measurable disease per RECIST 1.1 with Prostate Cancer Working Group 3 modifications, and ECOG performance status ≤2. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of tarlatamab. Secondary objectives are to evaluate antitumor activity (as assessed by objective response, duration of response, progression-free survival, overall survival, and disease control rate) and characterize pharmacokinetics. Four US and international study sites have been activated with two enrolled pts. References: Aggarwal R, et al. J Clin Oncol. 2018;36:2492-2503. Cooke K, et al. Abstract 627. Presented at: SITC Annual Meeting, Nov 9–14, 2020; Virtual. Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4–8, 2021; Virtual. Clinical trial information: NCT04702737.
Long-term safety of darolutamide in patients with metastatic castration-resistant prostate cancer.
Authors: Egils Vjaters, Karim Fizazi, Nicholas D. James, Teuvo Tammela, Nobuaki Matsubara, Frank Priou, Thierry Lesimple, Petri Bono, Vesa V Kataja, Jorge A. Garcia, Andrew Protheroe, John Aspegren, Heikki Joensuu, Iris Kuss, Silke Thiele, Sabine Fiala-Buskies, Robert Hugh Jones
Journal: Journal of Clinical Oncology (2022)

90 Background: Darolutamide, a structurally distinct and highly potent androgen receptor inhibitor, had a consistently favorable safety and tolerability profile in patients with nonmetastatic castration-resistant prostate cancer in ARAMIS, and discontinuation rates due to adverse events (AEs) remained consistently low after longer follow-up. In previously reported phase 1/2 studies in patients with metastatic castration-resistant prostate cancer (mCRPC), darolutamide was well tolerated for up to 25 months. We report the safety and tolerability of extended treatment with darolutamide in these mCRPC studies. Methods: Data from three phase 1/2 studies (NCT02363855, NCT01317641/NCT01429064, and NCT01784757) in patients with mCRPC were pooled for analysis of long-term safety. Results are summarized descriptively. Results: Of 173 patients with mCRPC evaluable for safety in the 3 studies, 13 patients received &gt; 2 years of darolutamide treatment; median duration of treatment was 38 months (range 24–90). Six patients received &gt; 4 years of darolutamide treatment. Nine of 13 patients with &gt; 2 years of darolutamide therapy initially received 600 mg BID; others received 200 mg (n = 1), 300 mg (n = 1), or 700 mg (n = 2) BID. Median age was 68 years in the &gt; 2-years group, and most patients were white. Patients were enrolled from France (n = 4), Latvia (n = 3), United Kingdom (n = 3), Finland (n = 2), and Japan (n = 1). Most patients had normal renal function (n = 10) and hepatic function (n = 10), 12 patients had Eastern Cooperative Oncology Group performance status of 0, and 9 patients had a Gleason score ≥7. Prior systemic anticancer treatments taken by more than 1 patient were bicalutamide (n = 10); cyproterone (n = 3); and triptorelin and leuprorelin (n = 2 each). No patient received prior chemotherapy. All 13 patients reported AEs, most grade 1 or 2; 6 reported grade 3 AEs. Treatment-related AEs were reported in 5 patients, and all were grade 1 in severity. Serious AEs were reported in 6 patients, and all were judged not related to darolutamide. One patient treated with darolutamide for &gt; 2 years had an AE (new neoplasm; not related to darolutamide) that led to treatment discontinuation. Conclusions: Extended darolutamide treatment &gt; 2 years in this small group of patients with mCRPC was generally well tolerated, with safety and tolerability consistent with that previously reported. Clinical trial information: NCT02363855, NCT01317641/NCT01429064, and NCT01784757.
Independent Association of Lipoprotein(a) and Coronary Artery Calcification With Atherosclerotic Cardiovascular Risk
Authors: Anurag Mehta, Nestor Vasquez, Colby R. Ayers, Jaideep Patel, Ananya Hooda, Amit Khera, Roger S. Blumenthal, Michael D. Shapiro, Carlos J. Rodriguez, Michael Y. Tsai, Laurence S. Sperling, Salim S. Virani, Michael J. Blaha, Parag H. Joshi
Journal: Journal of the American College of Cardiology (2022)