tbuckley/cabot-search huggingface dataset:
Antitumor T-cell Homeostatic Activation Is Uncoupled from Homeostatic Inhibition by Checkpoint Blockade
Authors: Netonia Marshall, Keino Hutchinson, Thomas U. Marron, Mark Aleynick, Linda Hammerich, Ranjan Upadhyay, Judit Svensson-Arvelund, Brian D. Brown, Miriam Merad, Joshua D. Brody
Journal: Cancer Discovery (2019)

T-cell transfer into lymphodepleted recipients induces homeostatic activation and potentiates antitumor efficacy. In contrast to canonical T-cell receptor-induced activation, homeostatic activation yields a distinct phenotype and memory state whose regulatory mechanisms are poorly understood. Here, we show in patients and murine models that, following transfer into lymphodepleted bone marrow transplant (BMT) recipients, CD8+ T cells undergo activation but also simultaneous homeostatic inhibition manifested by upregulation of immune-checkpoint molecules and functional suppression. T cells transferred into BMT recipients were protected from homeostatic inhibition by PD-1/CTLA4 dual checkpoint blockade (dCB). This combination of dCB and BMT-"immunotransplant"-increased T-cell homeostatic activation and antitumor T-cell responses by an order of magnitude. Like homeostatic activation, homeostatic inhibition is IL7/IL15-dependent, revealing mechanistic coupling of these two processes. Marked similarity in ex vivo modulation of post-BMT T cells in mice and patients is promising for the clinical translation of immunotransplant (NCT03305445) and for addressing homeostatic inhibition in T-cell therapies. SIGNIFICANCE: For optimal anticancer effect, T-cell therapies including chimeric antigen receptor T-cell, tumor-infiltrating lymphocyte, and transgenic T-cell therapies require transfer into lymphodepleted recipients and homeostatic activation; however, concomitant homeostatic inhibition mitigates T-cell therapies' efficacy. Checkpoint blockade uncouples homeostatic inhibition from activation, amplifying T-cell responses. Conversely, tumors nonresponsive to checkpoint blockade or BMT are treatable with immunotransplant.See related commentary by Ansell, p. 1487.This article is highlighted in the In This Issue feature, p. 1469.
Development of an automated RNA-based nuclease protection assay for the detection of expressed EML-ALK fusions, EGFR, and KRAS mutations in NSCLC.
Authors: Matthew Rounseville, Krishna Maddula, Bruce Seligmann, Ihab Botros, Vijay Modur
Journal: Journal of Clinical Oncology (2013)

e22185 Background: The management of patients for NSCLC requires appropriate molecular pathology assessment to determine treatment. However current methods require the use of more than one technology including sequencing for EGFR and KRAS mutation and in situ hybridization for EML-ALK fusion, resulting in slow turnaround, and technical as well as logistical complexities. Here, we report the development of an automated microarray based quantitative nuclease protection assay that determines gene fusions, deletions and point mutations in target genes such as EML4/ALK, EGFR and KRAS from expressed mRNA directly from FFPE tissue without prior RNA extraction. Methods: We designed mutation and fusion specific probes for nuclease protection and measured the sensitivity, specificity, and reproducibility of gene mutations and fusions using in vitro transcribed RNA and cell lysates known to contain the target mutations. In addition to synthetic samples, we also screened 88 lung cancer specimen for EML-ALK fusions. Results: Mutations in KRAS (G12D, G12C, G12V); EGFR (D761Y, T790M, L858R); EML-ALK fusions (v1 v2, v3a, v3b-3, v4, v5a, v5b-3 and v6) were detected at concentrations of 3 copies/cell in 15,000 cells even when present as low as 5% of wild type IVT RNA. The sensitivity corresponds to an amount of FFPE sample ranging from 0.3 to 0.6 square cm of a 5mm FFPE section per replicate assay making it suitable for needle biopsy specimen. Six samples with probable EML4-ALK fusions were identified in the 88 adenomatous NSCLC samples and will be subjected to further confirmation. Additional clinical validation of all the assays will be presented in our poster. Conclusions: An automated, multiplexed, EGFR and KRAS mutation and EML-ALK gene fusion from expressed mRNA is feasible. The assay can be run directly on FFPE sections, does not require RNA extraction or amplification, and is completed within 24 hours.
Multimodality therapeutic approach in anaplastic thyroid cancer (ATC): Study of 56 patients
Authors: H. Koussis, A. Scola, S. Tonello, B. Busnardo, M. Donach, M. Pelizzo, A. Toniato, E. Mazzarotto, E. Mazzarotto, P. Karahontzitis, S. Monfardini
Journal: Journal of Clinical Oncology (2006)

5571 Background: To investigate the role of multimodality treatment in patients with ATC. Methods: From 1992 to 2005, 56 patients with a histologically or cytologically proven ATC were referred to the Thyroid Centre of Padua University General Hospital. There were 36 females and 20 males, median age 69 years (range 27–90). About one-third of patients had a history of prior nodular goitre. Aggressive local disease was present in 30 patients, distant metastases, mainly to the lung, were present in 32 at diagnosis or quickly developed during the observation period in all but one patient. Patients from our series can be subdivided into 3 groups: Group A: consisted of 19 patients in good general condition which were treated by radiotherapy (RT), total thyroidectomy (TT) and chemotherapy (CHT). All were treated with Cisplatin once a week and by RT 36 Gy in 18 fractions over 3 weeks, followed by TT and by further CHT with Adriamycin and Bleomycin. Additionally, five patients received weekly Docetaxel. Group B: consisted of 19 patients with distant metastasis at diagnosis, who received CHT (Platinum based combination). Group C: consisted of 18 elderly patients in poor general condition; 6 received local RT, while 12 did not receive any treatment. Results: Five complete responses were seen in patients from group A. Four patients had long-term survival (14, 15, 24 and 41 months) with a disease free survival interval of 6, 8, 11 and 32 months. From Group B one patient with a complete remission following antiblastic therapy was later treated by TT and metastasectomia and is still alive without disease after 74 months. Median survival rates for Groups A, B and C were 12, 5.7 and 4 months respectively. Conclusions: In some patients multimodality treatment is associated with increased survival. The best results were obtained in younger patients with less advanced disease. Early diagnosis is mandatory. Only a few patients responded to CHT confirming that anaplastic thyroid carcinoma is often resistant to anticancer drugs. Our experience with combination modalities suggests that aggressive and appropriate combinations of RT, TT and CHT may provide some benefit in patients with ATC. Preoperative RT and CHT may enhance surgical resectability of the primary tumor. No significant financial relationships to disclose.
The Continuing Relevance of Leprosy
Authors: M. Ramam
Journal: JAMA Dermatology (2019)

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 Dermatology 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 Dermatology journal
Outcome of rapid disease progression in the treatment break following cytoreductive nephrectomy (CN) after presurgical sunitinib in patients with primary metastatic renal cell carcinoma (RCC).
Authors: Axel Bex, Thomas Powles, Christian U. Blank, Simon Chowdhury, Simon Horenblas, John Peters, Ekaterini Boleti, John B. A. G. Haanen
Journal: Journal of Clinical Oncology (2012)

4611 Background: There is concern that interruption of tyrosine kinase inhibitors (TKI) triggers disease progression (PD) and metastasis. This is based on preclinical models and observation of rapid PD in the postsurgical treatment break in patients pretreated with TKI. Little is known about the frequency of PD during postsurgical TKI interruption and its outcome. These data may have implications for neoadjuvant or presurgical treatment concepts. Methods: Of 66 patients from two closed phase II trials investigating 2-3 months presurgical sunitinib for primary metastatic clear-cell RCC, 45 were evaluated in this retrospective analysis because they had absence of PD prior to planned surgery and underwent CN (35 [78%] MSKCC intermediate and 10 [22%] poor risk). Patients had CT scans at the end of pretreatment and at 4 weeks post-nephrectomy before restarting sunitinib. In patients with postsurgical RECIST PD at 4 weeks when compared to the preoperative CT scan overall survival (OS) was measured from the time of nephrectomy and compared to patients without treatment break PD. Results: Median OS of 45 patients from the time of surgery was 22 months (13.0-31.5 months). Overall 14 patients progressed during treatment break (31%), with new sites of disease in 5/14 (35%). Reintroduction of sunitinib resulted in disease stabilisation or better in 13. Patients with poor risk were represented in the progressors (n=4[28%]) and non-progressors (n=6 [19%]) (p=0.7 fishers exact test). The hazard ratio (HR) for death associated with PD during treatment break was 1.90 (95% CI 0.89-4.08). OS for non-progressors was 25 months (15-NA) and 13 months (6-27) for progressors. Conclusions: A significant proportion of patients develop PD upon sunitinib withdrawal in a 4 week recovery period following CN. In view of the small sample size these data suggest a strong trend toward treatment break PD being associated with a poor outcome. It is not clear whether this PD is related to interruption of TKI, surgery or a combination of factors. The EORTC SURTIME trial investigates treatment break PD after immediate CN and CN after sunitinib and may answer this question.
The potential role of lung cancer screening in lung cancer survivors.
Authors: John M. Varlotto, Nengliang Yao, Rickhesvar Mahraj, Abram Recht, John Charles Flickinger, Chandra Prakash Belani, Jennifer Toth, Michael Reed, Chris Sciamanna, Christopher Gilbert, Suhail M. Ali, Malcolm M. DeCamp
Journal: Journal of Clinical Oncology (2013)

7553 Background: The National Lung Screening Trial demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS) in the 55-74-year-old age group, likely due to finding early-stage lung cancer. Patients with a past history of lung cancer were excluded from this trial. The purpose of investigation is to assess whether there is an increasing frequency of second lung cancers and whether the first primary reduces survival in a proposed screening population with Stage I (tumor size &lt;4cm) NSCLC (survivor population, SP) as compared to similar patients presenting with their first lung cancer (new patients, NP). Methods: The SEER databases were used to investigate incidence (1973-2009) and OS/LCSS (1998-2009) of secondary lung cancer. Incidence was examined by frequency analysis and trend analysis. A SP was chosen who was originally treated definitively for Stage I-III NSCLC and survived at least four years after diagnosis (N=515). They were compared to NP who were presenting with their first lung cancer (N = 21,040). OS/LCSS in NP and SP with Stage I NSCLC were analyzed by Kaplan-Meier estimation, log-rank tests, and multivariate proportional hazards modeling. Results: The annual incidence rate/100,000 for secondary lung cancer has increased almost 5-fold in last 36 years (2.5 in 1973; 12 in 2009; p&lt;0.001), more so in male patients. OS was not significantly different between NP and SP after accounting for treatment, tumor, and patient characteristics (male, HR=1.111, p=0.330; female, HR=0.840, p=0.118). Multivariate analyses show that LCSS was significantly better in SP females than for NP females (HR=0.849, p=0.025) but did not differ for males (HR=0.923, p=0.388). In the SP, OS decreased significantly with less aggressive treatment compared to lobectomy as the reference treatment (sub-lobar resection, HR=1.841, p=0.009; radiation, HR=2.351, p=0.002; observation, HR=2.145, p=0.016). Patient and tumor characteristics of the first lung cancer diagnosis were not significantly linked to OS. Conclusions: NP and SP diagnosed at Stage I had similar survival rates. The SP group also benefitted from increasingly aggressive treatment. Screening for lung cancer might be of benefit to lung cancer survivors.
The Role of Medicare Reimbursement in Determining Access to Palliative Radiotherapy During Hospice Care
Authors: Chithra R. Perumalswami, Samyukta Mullangi, Reshma Jagsi
Journal: JAMA Oncology (2019)

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
Toxicity and efficacy profiles of intrathecal injection of I-131 NaI via intraventricular (IVent) or intralumbar (Ilumb) route for leptomeningeal metastases (LM) therapy
Authors: F. C. Wong, M. Groves, N. Papadopoulos, S. Kim, C. Conrad, C. Meyers, S. Hsu, A. Kumar, S. Tummala, E. Kim
Journal: Journal of Clinical Oncology (2006)

1549 Background: LM is a fatal complication occurring in up to 30% of cancer patients. Intrathecal chemotherapy of LM is limited by diffusion while external beam irradiation is limited by neurotoxicity. Radioiodine I-131 may serve as a ablating agent because of its radiations transverse the meningeal thinkness but spare distant underlying nervous tissues. Two phase I studies are designed to determine MTD and to evaluate potential toxicity and efficacy of intrathecal I-131 sodium iodide (NaI) injected via IVent or the ILumb route. Methods: The IVent or Ilumb protocols each accured 5 groups of patients with cytology-confirmed LM from solid tumors. An injection of 15, 30, 60, 90 or 120 mCi of I-131 NaI was performed after thyroid blockade (Lugol solution and perchlorate), via an Ommaya reservoir (IVent) or lumbar puncture (ILumb). Patients underwent whole-body scintigraphy for biodistribution and radiation dosimetry. Follow-up studies consisted of serial CSF cytology, neuropsychology, ophthalmology, and serum tests (TSH and CBC) to 6 months. Results: The IVent and Ilumb studies accured 16 and 15 patients respectively with LM from melanoma, lung, breast and other tumors (13, 8, 6 and 4 of 31 patients). Because of re-entry into the protocols, one patient received a total of 407 mCi; the maximum radiation absorbed doses were estimated at 3716 cGy in the ventricular CSF and 54 cGy in the red marrow. No treatment-related NCI-Grade II/III/IV neurologic, hematologic or thyroid toxicity is noted. Transient improvements up to 6 weeks are noted in neuropsychologic tests (5/16 and 5/15), ophthalomologic test (3/16 and 1/15) and CSF cytology conversion (to negative) in 5/16 and 4/15 patients, respectively. Electrophysiology tests of 2 patients demonstrated normalization of P37 waves measured by somatosensory evoked potentials along with neuropsychologic test improvements. Conclusions: The MTD has not been reached up to 120 mCi on either the IVent or Ilumb protocol. Intrathecal I-131 NaI is likely to be efficacious to eradicate tumors in the CSF for LM therapy. Because of the low toxicity and likely efficacy, a phase II study with higher dosages is needed to fully explore therapeutic potentials of intrathecal I-131 NaI. No significant financial relationships to disclose.
Improved Communication in Home Health Care Could Reduce Hospital Readmission Rates
Authors: Christine D. Jones, Cari R. Levy
Journal: JAMA Internal Medicine (2019)

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 Internal Medicine 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 Internal Medicine journal
Integrin β1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH
Authors: Qianqian Guo, Kunimaro Furuta, Fabrice Lucien, Luz Helena Gutierrez Sanchez, Petra Hirsova, Anuradha Krishnan, Ayano Kabashima, Kevin D. Pavelko, Benjamin Madden, Husam Alhuwaish, Yandong Gao, Alexander Revzin, Samar H. Ibrahim
Journal: Journal of Hepatology (2019)
Cost-effectiveness analysis per life-year gained based on predictors of response for first-line metastatic colorectal cancer therapy in Spain.
Authors: Cristobal Belda-Iniesta, Victor Moreno, Brezo Martinez-Amores, Jorge Barriuso, Laura Mezquita, Inmaculada Ibañez de Cáceres, Angel Ayuso Sacido, Jose Maria Peña, Rosario Perona
Journal: Journal of Clinical Oncology (2012)

3601 Background: Economic crisis, increasing prevalence and cost of mCRC management endanger availability of biological therapies for public health systems due to budget limitations. We performed a cost-effectiveness analysis based on markers of response/resistance including biological therapies available in Spain for mCRC. Methods: We aimed to calculate incremental cost-effectiveness ratio (ICER) per life-year gained (LYG) and progression-free year gained based on predictive markers for mCRC. Efficacy data include randomized trials (RT) that guided on-label uses of bevacizumab and cetuximab. Control arms from these trials were used as reference to calculate ICERs. Markers of clinical benefit (biological and radiological) were included in this model. Toxicity as predictor of efficacy was excluded for any therapy. Prices for drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs. For 1st line, median duration of therapy reported by RT was used to calculate the final budget. 70kg and 1.7 m were used as reference for patients dose calculations. If accessible, HR for PFS and OS were used instead of medians. Results: K-Ras status and early response measured by CT at 8 weeks were used as predictors of resistance and increased efficacy for cetuximab-based combinations. We have not identified any predictor marker for other drugs from RT. In this regard, FOLFIRI+cetuximab combination obtained an ICER below the widely-proposed Spanish threshold of 30,000 € per LYG if patients harbored wt K-Ras tumors and evidenced an objective response at 8 weeks. Other ICERs for different schedules were too distant from this limit, they will be presented at the meeting. Multivariate analysis confirmed the robustness of results. Conclusions: 1st line FOLFIRI+cetuximab therapy for wt K-Ras patients that get an objective response measured by CT at 8 weeks is the only cost-effective therapy option for mCRC below usual health-economic thresholds for Spain. Our results are critical to design cost-effectiveness based clinical guidelines for mCRC that will contribute to financial sustainability of public health system in Spain.
New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders
Authors: Evangelos Evangelou, He Gao, Congying Chu, Georgios Ntritsos, Paul Blakeley, Andrew R. Butts, Raha Pazoki, Hideaki Suzuki, Fotios Koskeridis, Andrianos M. Yiorkas, Ibrahim Karaman, Joshua Elliott, Qiang Luo, Stefanie Aeschbacher, Traci M. Bartz, Sebastian E. Baumeister, Peter S. Braund, Michael R. Brown, Jennifer A. Brody, Toni-Kim Clarke, Niki Dimou, Jessica D. Faul, Georg Homuth, Anne U. Jackson, Katherine A. Kentistou, Peter K. Joshi, Rozenn N. Lemaitre, Penelope A. Lind, Leo-Pekka Lyytikäinen, Massimo Mangino, Yuri Milaneschi, Christopher P. Nelson, Ilja M. Nolte, Mia-Maria Perälä, Ozren Polasek, David Porteous, Scott M. Ratliff, Jennifer A. Smith, Alena Stančáková, Alexander Teumer, Samuli Tuominen, Sébastien Thériault, Jagadish Vangipurapu, John B. Whitfield, Alexis Wood, Jie Yao, Bing Yu, Wei Zhao, Dan E. Arking, Juha Auvinen, Chunyu Liu, Minna Männikkö, Lorenz Risch, Jerome I. Rotter, Harold Snieder, Juha Veijola, Alexandra I. Blakemore, Michael Boehnke, Harry Campbell, David Conen, Johan G. Eriksson, Hans J. Grabe, Xiuqing Guo, Pim van der Harst, Catharina A. Hartman, Caroline Hayward, Andrew C. Heath, Marjo-Riitta Jarvelin, Mika Kähönen, Sharon L. R. Kardia, Michael Kühne, Johanna Kuusisto, Markku Laakso, Jari Lahti, Terho Lehtimäki, Andrew M. McIntosh, Karen L. Mohlke, Alanna C. Morrison, Nicholas G. Martin, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Bruce M. Psaty, Olli T. Raitakari, Igor Rudan, Nilesh J. Samani, Laura J. Scott, Tim D. Spector, Niek Verweij, David R. Weir, James F. Wilson, Daniel Levy, Ioanna Tzoulaki, Jimmy D. Bell, Paul M. Matthews, Adrian Rothenfluh, Sylvane Desrivières, Gunter Schumann, Paul Elliott
Journal: Nature Human Behaviour (2019)