tbuckley/cabot-search huggingface dataset:
Predictive phosphoproteomic signatures for midostaurin plus chemotherapy response in FLT3 mutant positive acute myeloid leukaemia.
Authors: Arran David Dokal, Andrea Arruda, Ryan Smith, Calum Greenhalgh, Francesca Patella, Pedro Maria Casado-Izquierdo, Bela Wrench, Jane Theaker, Andrew Thompson, Mark D. Minden, John G. Gribben, David James Britton, Pedro Rodriguez Cutillas
Journal: Journal of Clinical Oncology (2021)

7019 Background: Midostaurin is approved for FLT3 mutant-positive (FLT3+) acute myeloid leukemia (AML), however efficacy has also been observed in a subpopulation of FLT3 mutant-negative AML, suggesting that FLT3 mutation is not the only determinant in conferring midostaurin sensitivity. We previously described a phosphoproteomic signature significantly elevated in primary AML blasts that responded to midostaurin ex vivo (Casado et al Leukaemia 2018). This signature includes phosphorylation sites on protein kinase C delta (a midostaurin off-target) and its substrate GSK3A. In this study, we tested whether these phospho-signatures could group FLT3+ patients based on clinical responses to midostaurin plus chemotherapy. Methods: We obtained FLT3+ bone marrow (BM) and peripheral blood (PB) diagnosis specimens (n=56 cases) from the Leukemia Tissue Bank at Princess Margaret Cancer Centre. These patients were treated with standard chemotherapy plus midostaurin. Phospho-signatures quantified using mass spectrometry were analysed with a classification machine learning algorithm to group patients based on response to treatment as a function of phospho-signature status. Other features (e.g. genetic mutations, HSC-transplant) were also analysed. Differential survival analysis was carried out with Kaplan-Meier and Log Rank test methods. Phospho-signatures for BM and PB samples were analysed independently. Results: A first ML model was developed based on the signature described in the Casado et al study. Patients positive for this signature exhibited a survival probability of 243 weeks, compared to 126 weeks in signature negative patients (averages by geometric mean, Log Rank p = 9.88e-05). As the patients in the current study received chemotherapy, in addition to midostaurin, we also identified a new signature consisting of 26 phospho-sites (model 2), which partially overlapped with the first model. Patients positive for model 2 signature showed a markedly longer survival time than negative patients (269 vs 76 weeks, Log Rank p = 1.30e-05 for PB and 241 vs 56, Log Rank p = 2.13e-09 for BM specimens, Table). No other features separated survival as clearly as model 2. Conclusions: We have identified phospho-signatures with the potential to further stratify FLT3+ AML for midostaurin treatment. The presence of PRKCD signalling components in signatures provides a rationale for midostaurin activity in sensitive cases. Analysis will also be performed on FLT3 mutant-negative cases to validate the signature in this group.[Table: see text]
A multicenter, prospective evaluation of a urine-based assay for bladder cancer diagnosis.
Authors: Liang Wang, Yiming Liang, Min Shi, Tonghui Ma, Jianhua Deng, Degang Ding
Journal: Journal of Clinical Oncology (2021)

e16509 Background: At present, bladder cancer is diagnosed mainly through cystoscopy as the "gold standard" method, which is invasive, costly, and painful for patients. Meanwhile, the current non-invasive liquid biopsy approaches, such as FISH or cytology, still do not show adequate performance in the diagnosis of bladder cancer because of the unsatisfactory sensitivity. Therefore, developing a novel method that performs higher sensitivity and specificity, especially negative predictive value(NPV) is an urgent issue to be addressed and will be very helpful for the clinical application. Methods: From October 2019 to October 2020, we designed a multicenter, prospective study, in which 321 hematuria patients were enrolled, including 218 males and 103 females, and their average age was 56. Based on the final pathological diagnosis, 121 patients were confirmed as bladder cancer and 200 samples were benign urinary diseases. 100ml urine samples were collected from each patient before the endoscopy examination. The Genetron Uro-18 assay, which included a 17 gene mutation panel and the methylation test on ONECUT2, was used in this study. The regions in the panel were selected based on the TCGA database, as well as previous publications. 321 urine DNA libraries were generated using multiplex PCR methods and then sequenced on the Ion S5 System. The CpG-sites on the ONECUT2 gene were detected by bisulfite-specific real-time PCR. Results: In these samples, a total of 205 oncogenic mutations were found in 13 genes in the panel. Mutations on TERT, PIK3CA, FGFR3, and TP53 genes showed significantly higher occurrence. 103 samples were found to be mutation-positive, 92 of which were pathologically confirmed as bladder cancers. When only gene mutations were considered, the sensitivity and specificity of this assay were 76.0% and 94.5%, respectively. The methylation of ONECUT2 had a performance in the test with a sensitivity of 74.4% and specificity of 93.0%. Combining the mutation panel with the ONECUT2 methylation test will improve the sensitivity (86.0%) of this assay, but slightly hampered the specificity (91.0%). The positive predictive value(PPV) and negative predictive value(NPV) of the combination were 85.2% and 91.5%. The sensitivity was as high as 91.5% when low-grade bladder cancer samples were excluded. In contrast, the sensitivity of cytology and FISH tests were only 48.4% and 62.0%. Conclusions: The novel urine-based liquid biopsy assay has excellent performances in the diagnosis of bladder cancer, with sensitivity and NPV reaching 86.0% and 91.5%, which improved significantly than cytology and FISH tests. Thus this assay will be more beneficial for patients with urinary diseases which significantly reduces the current burden of repeat cystoscopies and cytology tests.
Clinical behavior of advanced giant cell tumor: 15 years observation study in N.N. Blokhin National Medical Research Center of Oncology.
Authors: Anastasia Alekseevna Tararykova, Alexander A. Fedenko, Elmar R. Musaev
Journal: Journal of Clinical Oncology (2021)

e23501 Background: Giant cell tumor of bone (GCT) is a relatively rare, benign but locally aggressive osteolytic skeletal neoplasm of young adults, most frequently occurs at the epiphysis of long bones. Distant metastases occur approximately 2-6% of cases most often to the lungs. However, pulmonary metastases do not carry the same connotation as metastases associated with malignant tumors, such as lung cancer or sarcoma. Rarely, GCT undergoes true malignant transformation. The aim of this study is to analyze the clinical behavior of advanced GCT during long-term observer in N.N. Blokhin National Medical Research Center of Oncology. Methods: We observed 51 advanced cases among 298 GCT from 2005 till 2020 in N.N. Blokhin National Medical Research Center of Oncology. Disease was histologically confirmed by a sarcoma pathologist. Patients underwent CT/MRI every 2 or 3 months of treatment and every 3, 6 or 12 months of follow up period. Treatment options were included atypical pulmonary resection, palliative surgery, chemotherapy with CAP or AI combination, interferon alfa or observation until progression. After 2013 prefer treatment option for advanced GCT was denosumab with once in 3 month’s regimen after 2 years monthly therapy. All patients received daily calcium and vitamin D supplement. Logistic regression was using for statistic analyzes. Results: Median follow-up was 45 months. The average age of patients was 34,8 years, and the women and men ratio was about 1,8:1. The most commonly affected sites were tibia (23,5%, 12/21), sacrum (17,6%), radius (13,7%) and femur (9,8%). According Campanacci classification G3 was the most commonly grade (90%). 46 (56%) cases were anatomically compounded due to tumor localization and 19 (37%) cases were primary disease. 18/298 (6%) cases were with pulmonary metastases. Surgery in history (p &lt; 0,001) and tumor localization in extremity (p &lt; 0,001) were significant for metastasis development. The primary malignant GCT observed in 1% (3/298) cases and 1 % cases of malignant transformation GCT into sarcoma. Only 1/51 (1,9%) death was observed in advanced GCT group. Complications ≥3 grade were observed only in pre-denosumab era. Conclusions: In this study we showed long-term observation of advanced GCT and evaluated significant factors for metastasis development. Surgeries in history and tumor localization were associated with higher risk of metastasis. Denosumab for advanced GCT is a choice of treatment, we wasn’t observed any cases of GCT malignant transformation during denosumab treatment. Quality of live was better in compare with pre-denosumab era. Further investigation of long term denosumab complications is awaited.
EPCT-23 PRE-CLINICAL STUDY OF FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING AND PANOBINOSTAT FOR DIFFUSE INTRINSIC PONTINE GLIOMA TREATMENT
Authors: Hong-Jian Wei, Antonios Pouliopoulos, Nina Yoh, Masih Tazhibi, Nicholas McQuillan, Xu Zhang, Luca Szalontay, Robyn Gartrell, Jovana Pavisic, Zhiguo Zhang, Neil Feldstein, Oren Becher, Stergios Zacharoulis, Elisa Konofagou, Cheng-Chia Wu
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is the lethal high-grade brain tumor in children with no effective treatment options to date. Despite excessive clinical trials, the prognosis remains poor, with a median overall survival (mOS) of less than 1 year. Genomic studies of DIPG tissue have identified highly recurrent mutations in genes encoding histone H3 resulting in the substitution of lysine to methionine at position 27 (K27M), which is found in approximately 80% of DIPG. Recent drug screening studies identified the histone deacetylase (HDAC) inhibitors panobinostat as a highly effective drug against DIPG in vitro. However, due to the poor Blood-Brain Barrier (BBB) penetration of systemic administration, to enhance the delivery of panobinostat to improve treatment efficacy is needed. Focused ultrasound (FUS) has been shown to be able to safely and non-invasively open BBB to enhance drug delivery. Hence, in this study, we hypothesize that FUS-mediated BBBO (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG. Herein we established the syngeneic DIPG model by intracranially injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) and used FUS and microbubbles to open BBB and enhance the panobinostat delivery. Magnetic resonance (MR) imaging was utilized to evaluate BBBO and tumor progression. We first demonstrated that FUS-mediated BBB-opening is safe and feasible to mice with DIPG tumors by MR imaging and passive cavitation detection. Moreover, this DIPG cell line is very sensitive to panobinostat in in vitro cytotoxicity assay. The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival. The current results demonstrated FUS could increase the treatment efficacy of panobinostat to DIPG animals may be due to the increase of targeted delivery of systemic panobinostat to DIPG tumors in brainstem.
Identification and Evaluation of Serum Protein Biomarkers That Differentiate Psoriatic Arthritis From Rheumatoid Arthritis
Authors: Angela Mc Ardle, Anna Kwasnik, Agnes Szentpetery, Belinda Hernandez, Andrew Parnell, Wilco de Jager, Sytze de Roock, Oliver FitzGerald, Stephen R. Pennington
Journal: Arthritis & Rheumatology (2021)

Objective To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. Methods The serum proteome of patients with PsA and patients with RA was interrogated using nano–liquid chromatography mass spectrometry (nano‐LC‐MS/MS) (n = 64 patients), an aptamer‐based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). Results Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano‐LC‐MS/MS, 0.69 for bead‐based immunoassay measurements, and 0.73 for aptamer‐based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. Conclusion We present a serum protein biomarker panel that can separate patients with early‐onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making.
A commentary on “Effects of parecoxib after pancreaticoduodenectomy: A single center randomized controlled trial” (Int J Surg 2021; 28: 105962)
Authors: María Manuela Rodríguez-Gutiérrez, Doménica Acevedo-López, Nicole Andrea Acevedo-López, María Carolina Díaz-Rivera
Journal: International Journal of Surgery (2021)
Infections in cancer patients treated with immune checkpoint inhibitors: Data from randomized trials.
Authors: Cinzia Solinas, Anna Maria Morelli, Andrea Luciani, Antonio Ghidini, Fausto Petrelli
Journal: Journal of Clinical Oncology (2021)

2637 Background: Febrile neutropenia and infections are well studied complications of chemotherapy (CT) and some targeted agents employed in oncology. Less is known about the risk of infection associated with the use of immune checkpoint inhibitors (ICIs) in cancer patients. The present systematic review and meta-analysis was performed to address this question in patients diagnosed with solid tumors enrolled in randomized trials employing ICIs as experimental treatment. Methods: The Cochrane Library, EMBASE, and Pubmed databases were searched from inception through December 1 st, 2020. Randomized clinical trials comparing any ICI alone, with CT, or with other agents vs CT, placebo, or other agents in patients with solid tumors were included. Two independent reviewers used a standardized data extraction and quality assessment form. Discordant cases were discussed with a third independent investigator. The following information was extracted: baseline study characteristics, including the primary tumor, author, year of publication, type of trial, type of disease, and the type of therapy (experimental and control arms); and the incidence of any-grade (grades [G] 1–5), low-grade (G1–2), and high-grade (G3–4), fatal event (G5) infections, and type of event. Random or fixed-effect models were used according to the statistical heterogeneity. Results: 36 randomized clinical trials were deemed eligible. The total population reached 21451 patients. In the pooled analysis, the use of ICIs was associated with a similar risk of all-grade infections (relative risk, RR = 1.02; 95% CI 0.84–1.24; P = 0.85) compared to non-ICI treatments (G1-5 events: 9.6 vs. 8.3%). When the ICIs alone arms were compared to CT, the experimental arms were associated with a 42% less risk of all-grade infections (RR = 0.58, 95% CI 0.4–0.85; P = 0.01; N = 18 studies). Compared to CT, the combination of ICIs and CT increased the risk of all-grade infections (RR = 1.37, 95% CI 1.23–1.53; P &lt; 0.01; N = 13 studies) and severe infections (RR = 1.52, 95% CI 1.17–1.96; P &lt; 0.01; N = 12 studies). Fatal infections were similar in the experimental and control arms (0.5%). Conclusions: In patients with advanced solid tumors, when ICIs were administered with CT, the risk of all-grade and G3-5 infections was significantly increased. Compared to CT alone, ICIs were safer and their use should be recommended for frail patients. Further studies are required to identify high-risk patients and evaluate the need for CT dose reduction or prophylactic myeloid growth factors use.
Enhancing Prediction of Psychosis Risk With Cognitive Measures
Authors: James M. Gold, Zachary B. Millman, Dwight Dickinson
Journal: JAMA Psychiatry (2021)

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 Psychiatry 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 Psychiatry journal
Systemic chemotherapy in patients with brain only metastatic breast cancer: A retrospective analysis.
Authors: Akshjot Puri, Charisma Mylavarapu, Joe E. Ensor, Parveen Parveen, Ivo Tremont-Lukats, Jenny Chee Ning Chang, Polly Ann Niravath
Journal: Journal of Clinical Oncology (2021)

1093 Background: The treatment of patients with brain only metastatic breast cancer (BO-MBC) remains very challenging. There is also very limited literature informing on appropriate treatment or natural history of this entity. Systemic chemotherapy in addition to targeted therapy and/or anti-estrogen treatment is often used, but little is known if it adds to the overall or disease free survival. In this retrospective study, we examine this, as well as other factors which may be associated with increased risk of CNS or systemic recurrence in these patients. Methods: A database search at a single institution identified 178 patients with brain metastases (BM) from breast cancer out of which 45 patients had BO-MBC between 2007-2020. We collected demographic, clinical, radiographic and other treatment data. Leptomeningeal disease (LMD) was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. We used the Brookmeyer and Crowley method. Results: The patients were followed for a median of 17.9 months; 36 out of 45 patients (80%) received local treatment for BM (surgery/radiation/both) and HER2 directed antibodies or tyrosine kinase inhibitors and/or anti-estrogen treatment, whereas 9 out of 45 patients (20%) received systemic chemotherapy in addition. There were 22 out of 45 (49%) HER2 +, 5 out of 45 (11%) HR + and 18 out of 45 (40%) triple negative breast cancer (TNBC) patients. There were 17 out of 45 patients (38%) who were deemed to have low burden of BM (defined as one to three BM and largest being ≤3 cm) whereas there were 24 out of 45 patients (53%) who had high burden of BM (defined as four or more BM or largest being &gt; 3 cm). Conclusions: Patients with BO-MBC represent a distinct entity. Despite having better survival than patients with BM and extra CNS disease these patients have a high risk of developing LMD, CNS and systemic recurrences. The addition of chemotherapy to targeted therapy and/or anti-estrogens does not decrease the rates of systemic or CNS recurrence. The ER+ subset have a lower rate of development of systemic disease, as expected due to their relatively indolent biology. The CNS and systemic recurrence seem to be higher in patients with HER2+ cancers and counterintuitively even in those with low burden of BM; albeit these were statistically insignificant.[Table: see text]
Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells
Authors: Hewang Li, Ines Armando, Peiying Yu, Crisanto Escano, Susette C. Mueller, Laureano Asico, Annabelle Pascua, Quansheng Lu, Xiaoyan Wang, Van Anthony M. Villar, John E. Jones, Zheng Wang, Ammasi Periasamy, Yuen-Sum Lau, Patricio Soares-da-Silva, Karen Creswell, Gaétan Guillemette, David R. Sibley, Gilbert Eisner, John J. Gildea, Robin A. Felder, Pedro A. Jose
Journal: Journal of Clinical Investigation (2008)
Timing of postoperative radiation therapy and survival in resected salivary gland cancers: Long-term results from a single institution.
Authors: Perrin Romine, Jenna M. Voutsinas, Vicky Wu, Micah Tratt, Jay Justin Liao, Upendra Parvathaneni, Brittany Barber, Jasjit Dillon, Mari-Alina Timoshchuk, Neal D. Futran, Jeffrey Houlton, George E. Laramore, Renato G. Martins, Keith D. Eaton, Cristina P. Rodriguez
Journal: Journal of Clinical Oncology (2021)

e18052 Background: Timely administration of postoperative radiation therapy (PORT) impacts oncologic outcomes in resected squamous cell carcinomas of the head and neck. Salivary gland cancers (SGCs) are uncommon, and timing of PORT has not been extensively explored. We aimed to determine if the interval between surgery and PORT impacts outcomes in SGCs. Methods: We retrospectively identified patients with SGCs who underwent curative intent surgical resection followed by adjuvant PORT at our tertiary referral center. Demographic, tumor, and treatment data were collected. Patients with non-oncologic resections and/or delay of &gt; 6 months to radiation start were excluded. Locoregional control (LRC), relapse free survival (RFS), and overall survival (OS) were estimated using the Kaplan Meier method. A multivariate analysis explored the association between demographics, tumor characteristics, and PORT timing with oncologic outcomes using a stepwise Cox proportional hazards model. Results: Between 1/1/1997 and 12/31/2017 180 eligible patients were identified. Patient characteristics are described in Table. The median time to PORT start was 61 (range 8-121) days, 169 (93.9%) of patients received neutron beam PORT. With a median follow up of 8.2 years in surviving patients, the 5-year OS and LRC estimates were 73% and 67%, respectively. In a multivariate analysis, only nodal involvement, histologic grade, and age at diagnosis were associated with OS, while nodal involvement, tumor size, and age at time of diagnosis were associated with LCR and RFS. Time to PORT start or completion was not statistically associated with survival outcomes on multivariate analysis. Conclusions: SGC patients who underwent surgery in our tertiary institution received PORT within a median of 61 days after surgery. With long term follow up, PORT timing in this retrospective series was not associated with worse oncologic outcomes, and support timely administration of PORT with 3 months of surgical resection. Further work is necessary to assess generalizability of these results.[Table: see text]