tbuckley/cabot-search huggingface dataset:
Prognostic Value of Maximum Standardized Uptake Value in 68Ga-Somatostatin Receptor Positron Emission Tomography for Neuroendocrine Tumors
Authors: Dong Yun Lee, Yong-il Kim
Journal: Clinical Nuclear Medicine (2019)

Purpose Somatostatin receptor (SSTR) PET has become a mainstay in the diagnosis of neuroendocrine tumors (NETs) and for selecting patients for SSTR-based therapy; however, no consensus has yet been reached in terms of prognosis. A systematic review and meta-analysis was performed on the prognostic value of the maximum standardized uptake value (SUVmax) for 68 Ga-SSTR PET in patients with NETs. Patients and Methods We performed a systematic search using the following keywords: PET, SSTR, NET, and prognosis. The inclusion criteria were the use of 68 Ga-SSTR PET as an imaging tool, studies limited to NETs, studies that reported progression-free survival (PFS) and/or overall survival (OS), and studies that included SUVmax as a prognostic parameter. The effect of SUVmax on PFS and OS was measured in terms of the hazard ratio (HR). Results Eight eligible studies with 474 patients were finally included and analyzed. The combined HR of SUVmax on PFS was 2.31 with significance (95% confidence interval [CI], 1.34–4.00; P = 0.003). The trim and fill adjusted analysis for SUVmax on PFS demonstrated the combined HR as 1.81 with significance (95% CI, 1.11–2.95; P = 0.017), as the publication bias was found (Egger P = 0.004). The combined HR of SUVmax on OS was 2.97 with significance (95% CI, 1.71–5.15; P = 0.0001), without publication bias (Egger P = 0.929). The subgroup analysis revealed that well-differentiated NETs (grade 1 or 2) on PFS showed significance ( P = 0.03); however, all grades of NETs (including grade 3) on PFS did not reach significance ( P = 0.11). Tumor site and type of radiotracer did not affect the prognostic value of SUVmax. Conclusions Low SUVmax of 68 Ga-SSTR PET was associated with a worse prognosis for PFS and OS in patients with NETs. Well-differentiated NETs had more prognostic value compared with all grades of NETs. The SUVmax of 68 Ga-SSTR PET could be used as an objective prognosis predictor.
Prediction of early death among patients (pts) enrolled in phase I trials: Development and validation of a new model based on platelet count and albumin level.
Authors: Anne Ploquin, David Olmos, Denis A. Lacombe, Roger A'Hern, Alain Duhamel, Christopher Twelves, Silvia Marsoni, Rafael Morales, Jean-Charles Soria, Jaap Verweij, Emile E. Voest, Patrick Schoffski, Jan H. M. Schellens, Andrew Kramar, Hendrik-Tobias Arkenau, Stanley B. Kaye, Nicolas Penel
Journal: Journal of Clinical Oncology (2012)

2540 Background: Selecting pts with “sufficient life expectancy” for phase I oncology trials remains challenging. The Royal Marsden Model (RMM; Arkenau, JCO 2009) identified high-risk pts as those with ≥2 of: albumin (ALB) &lt;35g/l; LDH &gt;ULN; more than 2 metastatic sites. The RMM was assessed in 1845 pts treated in phase I trials by members of the European New Drug Development Network (ENDDN). The present study aimed to develop an alternative prognostic model using a different methodology and to compare its performance with the RMM. Methods: The primary endpoint was 90-day mortality rate (90-DMR). The new model was developed from the ENDDN database using CHAID, an exploratory non-parametric data analysis method evaluating the relationship between a dependent variable (90-DMR) and possible predictive variables through a decision-tree analysis. The ROC characteristics and calibration of both methods were then validated in the independent EORTC Database (n=341 pts). Results: The CHAID method identified low and high-risk groups with 90-DMR of 9.5% vs 37.5%. High-risk pts had ALB&lt;33g/L or ALB≥33g/L but platelet count ≥400.000/mm 3 . Applying both models to the validation dataset; the rates of correctly-classified pts were 0.86 [CI-95% 0.82-0.90] vs. 0.67 [CI-95% 0.60-0.74], with the CHAID model and RMM respectively. The CHAID model had higher specificity (0.90 vs. 0.65), but lower sensitivity (0.36 vs. 0.93) than the RMM. Discriminative slopes were similar for the CHAID model and RMM (19.4% and 19.3%, respectively). The negative predictive value (NPV; correct identification of pts surviving 90 days) was similar for the CHAID model and RMM (0.94 [0.91-0.97] and 0.99 [0.94-1.00] respectively). Calibration, assessed by the Brier score, was slightly better with the CHAID model (0.001 and 0.098, respectively). Conclusions: In selecting pts for phase I trials arguably an important criterion is NPV; the CHAID model and RMM provided a similar high level of NPV but the CHAID model gave a better rate of correctly-classified patients. Both models improved the screening process and reduce the attrition rate in phase I trials.
Targeting NFE2L2/KEAP1 mutations in advanced NSCLC with the TORC1/2 inhibitor TAK-228.
Authors: Paul K. Paik, Linda Su Hyun Ahn, Michelle S. Ginsberg, Andrew J. Plodkowski, Rachel Kim, L. Austin Doyle, Charles M. Rudin
Journal: Journal of Clinical Oncology (2019)

9085 Background: Despite efforts over the past decade, no targeted therapy options exist for SQCLC pts. We have identified a heretofore untargeted oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~20% of patients with SQCLC. NFE2L2 encodes Nrf2, a transcription factor involved in the oxidative stress response which is targeted for degradation by Keap1. NFE2L2 mutations occur exclusively in an exon 2 hotspot that encodes the Neh2 domain (aa.1-86), which is the binding site for Keap1. Mutations in this region disrupt Keap1 binding, leading to Nrf2 nuclear translocation and increased mTOR signaling through RagD (Shibata Cancer Res 2010). We report translational studies and results from an ongoing phase 2 trial of the oral TORC1/2 inhibitor TAK-228. Methods: Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells (NFE2L2 E79K mut) treated with TAK-228, everolimus, rapamycin, or deforolimus. Pts with stage IV SQCLC harboring NFE2L2 or KEAP1 mutations and NSCLC harboring KRAS + NFE2L2 or KEAP1 co-mutations are treated on an NCI CTEP phase 2 study of TAK228 3mg po qd (continuous 28 day cycles; NCT02417701). Primary endpoint: ORR. Secondary endpoints: PFS. The study utilizes a Simon 2-stage design for each cohort with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK-228 exhibited increased anti-tumor activity over TORC1 rapalogs in LK-2 cells. TAK-228 alone was cytotoxic at sub-[μM] (IC50 68nM); all other rapalogs exhibited IC50s &gt; 10μM. This was associated with marked decrease in pS6, pAKT, and pERK. Tumor response (-55%) was seen in an LK-2 xenograft treated with TAK228. No anti-tumor/growth inhibitory response was seen with any other rapalog. N = 15 evaluable pts have been treated on study (7 NFE2L2, 3 KEAP1, 5 KRAS + NFE2L2 or KEAP1). 2 related-SAEs (G3 hyperglycemia, G3 confusion) were seen; there were no unexpected AEs. Within SQCLC NFE2L2 pts ORR = 29% (2/7 PR) and DCR = 100%. Prolonged duration of response is present, with PFS = 10.5mo, 11.4mo (18.2mo tx beyond PD), 6mo (8mo tx beyond PD), 5.5mo+, 4.5mo, and 1.5mo+. Within SQCLC KEAP1 pts DCR = 66% (2SD, 1PD) with PFS = 7.4mo+, 3mo+, 1mo. Data for the KRAS + NFE2L2/KEAP1 arm will be presented. Conclusions: TAK228 is tolerable with evidence of pre-clinical activity, radiographic responses, and prolonged DOR in biomarker-selected NSCLC pts. Accrual is ongoing. Clinical trial information: NCT02417701.
NHS pensions: government must change rules, or waiting times will keep rising, trusts warn
Authors: Abi Rimmer
Journal: BMJ (2019)

The government’s recently announced proposal to rectify doctors’ pension problems is inadequate, NHS Providers has said, and more must be done now or the care of patients will be affected.

In June the government announced a plan that would allow senior clinicians such as GPs and consultants to halve their pension contributions to avoid big tax bills.1 Currently, the NHS scheme does not offer any flexibility in the rate at which pensions build, with the highest earning consultants contributing 14.5% of their pensionable pay each month.

This has led to doctors taking early retirement or cutting clinical hours, as they are unable to control their contributions and thus end up exceeding …
Neurotropic enteroviruses co-opt “fair-weather-friend” commensal gut microbiota to drive host infection and central nervous system disturbances
Authors: Kevin B. Clark
Journal: Behavioral and Brain Sciences (2019)

Abstract Some neurotropic enteroviruses hijack Trojan horse/raft commensal gut bacteria to render devastating biomimicking cryptic attacks on human/animal hosts. Such virus-microbe interactions manipulate hosts’ gut-brain axes with accompanying infection-cycle-optimizing central nervous system (CNS) disturbances, including severe neurodevelopmental, neuromotor, and neuropsychiatric conditions. Co-opted bacteria thus indirectly influence host health, development, behavior, and mind as possible “fair-weather-friend” symbionts, switching from commensal to context-dependent pathogen-like strategies benefiting gut-bacteria fitness.
Grading immunohistochemical markers p16 <sup>INK4a</sup> and HPV E4 identifies productive and transforming lesions caused by low‐ and high‐risk HPV within high‐grade anal squamous intraepithelial lesions
Authors: A. Leeman, D. Jenkins, E. Marra, M. Zummeren, E.C. Pirog, M.M. Sandt, A. Eeden, M.F. Schim van der Loeff, J. Doorbar, H.J.C. Vries, F.J. Kemenade, C.J.L.M. Meijer, W.G.V. Quint
Journal: British Journal of Dermatology (2019)

Because current guidelines recognise high-grade anal squamous intraepithelial lesions (HSILs) and low-grade SILs (LSILs), and recommend treatment of all HSILs although not all progress to cancer, this study aims to distinguish transforming and productive HSILs by grading immunohistochemical (IHC) biomarkers p16
Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage
Authors: Payel Chatterjee, Michael T. Schweizer, Jared M. Lucas, Ilsa Coleman, Michael D. Nyquist, Sander B. Frank, Robin Tharakan, Elahe Mostaghel, Jun Luo, Colin C. Pritchard, Hung-Ming Lam, Eva Corey, Emmanuel S. Antonarakis, Samuel R. Denmeade, Peter S. Nelson
Journal: Journal of Clinical Investigation (2019)

Prostate cancer (PC) is initially dependent on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with anti-tumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks (DSBs), G0/G1 cell cycle arrest and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA which was augmented by PARP1 inhibition. SPA-induced DSBs were accentuated in BRCA2-deficient PCs, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from PC patients receiving SPA as part of ongoing Phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition.
Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2–IL-6 cascade
Authors: Yong-Qiang Chen, Peng-Cheng Li, Ning Pan, Rong Gao, Zhi-Fa Wen, Tian-Yu Zhang, Fang Huang, Fang-Yuan Wu, Xi-Long Ou, Jin-Ping Zhang, Xue-Jun Zhu, Hong-Ming Hu, Kang Chen, Yun-Lang Cai, Li-Xin Wang
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> CD4<sup>+</sup> T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4<sup>+</sup> T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4<sup>+</sup> T cells in the tumor microenvironment. <h3>Methods</h3> TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4<sup>+</sup> T cells to examine the function and mechanism of TRAPs in CD4<sup>+</sup> T cell differentiation and function. TRAPs-elicited CD4<sup>+</sup> T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model. <h3>Results</h3> Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4<sup>+</sup> T cell production of IL-6 via a TLR2–MyD88–NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4<sup>+</sup> T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4<sup>+</sup> T cells inhibited CD4<sup>+</sup> and CD8<sup>+</sup> effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4<sup>+</sup> T cells markedly retarded tumor growth. Furthermore, B cell or CD4<sup>+</sup> T cell depletion impeded tumor growth by increasing effector T cell function. <h3>Conclusions</h3> HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4<sup>+</sup> T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.
Trehalase Gene as a Molecular Signature of Dietary Diversification in Mammals
Authors: Hengwu Jiao, Libiao Zhang, Huan-Wang Xie, Nancy B Simmons, Hui Liu, Huabin Zhao
Journal: Molecular Biology and Evolution (2019)

Diet is a key factor in determining and structuring animal diversity and adaptive radiations. The mammalian fossil record preserves phenotypic evidence of many dietary shifts, whereas genetic changes followed by dietary diversification in mammals remain largely unknown. To test whether living mammals preserve molecular evidence of dietary shifts, we examined the trehalase gene (Treh), which encodes an enzyme capable of digesting trehalose from insect blood, in bats and other mammals with diverse diets. Bats represent the largest dietary radiation among all mammalian orders, with independent origins of frugivory, nectarivory, carnivory, omnivory, and even sanguivory in an otherwise insectivorous clade. We found that Treh has been inactivated in unrelated bat lineages that independently radiated into noninsectivorous niches. Consistently, purifying selection has been markedly relaxed in noninsectivorous bats compared with their insectivorous relatives. Enzymatic assays of intestinal trehalase in bats suggest that trehalase activity tends to be lost or markedly reduced in noninsectivorous bats compared with their insectivorous relatives. Furthermore, our survey of Treh in 119 mammal species, which represent a deeper evolutionary timeframe, additionally identified a number of other independent losses of Treh in noninsectivorous species, recapitulating the evolutionary pattern that we found in bats. These results document a molecular record of dietary diversification in mammals, and suggest that such molecular signatures of dietary shifts would help us understand both historical and modern changes of animal diets.
Mental health research in the Arab region: challenges and call for action
Authors: Fadi T Maalouf, Bibi Alamiri, Samir Atweh, Anne E Becker, Majda Cheour, Hala Darwish, Lilian A Ghandour, Suhaila Ghuloum, Mouin Hamze, Elie Karam, Brigitte Khoury, Samia J Khoury, Ali Mokdad, Lokman I Meho, Tarek Okasha, Geoffrey M Reed, Eman Sbaity, Pia Zeinoun, Elie A Akl
Journal: The Lancet Psychiatry (2019)
Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: Analysis of the CASSIOPEIA trial.
Authors: Herve Avet-Loiseau, Philippe Moreau, Michel Attal, Cyrille Hulin, Bertrand Arnulf, Jill Corre, Laurent Garderet, Lionel Karlin, Jérôme Lambert, Margaret Macro, Aurore Perrot, Pieter Sonneveld, Mark-David Levin, Saskia Klein, Christopher Chiu, Lixia Pei, Carla De Boer, Tobias Kampfenkel, Soraya Wuilleme, Marie-Christine Béné
Journal: Journal of Clinical Oncology (2019)

8017 Background: In TE NDMM patients (pts), the CD38 monoclonal antibody DARA significantly reduced the risk of progression/death and improved stringent CR, ≥CR, and MRD-negative rates when added to VTd in the phase 3 CASSIOPEIA study. MRD status and its association with progression-free survival (PFS) was evaluated in TE NDMM pts receiving D-VTd vs VTd as pre-transplant induction/post-transplant consolidation in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts were randomized 1:1 to 4 cycles of pre-ASCT induction and 2 cycles of post-ASCT consolidation with DARA + VTd or VTd. Landmark analyses of MRD were performed on bone marrow aspirates after induction by multiparametric flow cytometry (MFC; 10 –5 sensitivity threshold) and after consolidation (at Day 100 post-ASCT) by MFC (10 –5 ) and next-generation sequencing (NGS; 10 –6 ) for all pts, regardless of response. Results: A cohort of 1085 pts was randomized (D-VTd, n = 543; VTd, n = 542). Post-induction and post-consolidation MRD-negative rates were significantly higher for D-VTd vs VTd (Table). Post-consolidation MRD-negative rates (MFC) were consistent across pt subgroups, including ISS stage III or high-risk cytogenetics. Multivariate analyses accounting for treatment arm and MRD negativity (MFC) showed a PFS benefit in pts reaching MRD negativity (HR, 0.31; 95% CI, 0.20-0.50; P &lt;0.0001). Based on these analyses, D-VTd showed additional PFS benefit vs VTd (HR, 0.48; 95% CI, 0.30-0.78; P = 0.0028). Analysis of MRD based on response (per IMWG criteria) will be presented. Conclusions: Adding DARA to VTd induction and consolidation deepened responses, as demonstrated by significant increases in MRD-negative rates. MRD negativity was associated with a PFS benefit regardless of treatment group. However, deepened responses with D-VTd led to improved outcomes, with MRD negativity associated with prolonged PFS, versus VTd in pts with TE NDMM. Clinical trial information: NCT02541383. [Table: see text]
Validation of a novel staging system for breast cancer patients treated with neoadjuvant chemotherapy
Authors: E. A. Mittendorf, S. L. Tucker, J. S. Jeruss, A. M. Gonzalez-Angulo, T. A. Buchholz, A. A. Sahin, J. N. Cormier, A. U. Buzdar, G. N. Hortobagyi, K. K. Hunt
Journal: Journal of Clinical Oncology (2009)

558 Background: We previously described a novel staging system to assess patient prognosis after neoadjuvant chemotherapy based on pretreatment clinical stage (CS), post-treatment pathologic stage (PS), estrogen receptor (E) status and grade (G). This CPS+EG staging system was determined by points assigned for each variable and allowed for better determination of breast cancer specific survival than either CS or PS alone. The current study was undertaken to validate this staging system in a more contemporary cohort of patients. Methods: A prospectively collected database of patients treated with neoadjuvant chemotherapy from 2003 to 2005 identified 804 eligible patients for analysis. Because determination of the CPS+EG staging system predated the use of neoadjuvant trastuzumab therapy, patients receiving neoadjuvant trastuzumab were excluded from the validation cohort. Clinicopathologic characteristics, treatment regimens and patient outcomes were assessed. Patient outcomes were stratified according to their CPS+EG score. Results: Median follow-up time was 3.4 years (range 0.3–5.9 years). The 5-year disease specific survival (DSS) rate for the entire cohort was 77% (95% CI: 72–82). The table summarizes 5-year DSS rates for each CPS+EG score. The pattern of prediction determined in the initial cohort was again seen in the validation cohort. Application of the staging system facilitated separation of patients into more refined subgroups by outcome than the current AJCC staging system applied to either presenting clinical stage or final pathologic stage. Conclusions: This study validates our previously published CPS+EG staging system. We suggest that the AJCC staging system should be revised to incorporate biologic markers and response to treatment for patients receiving neoadjuvant chemotherapy. As targeted agents are being increasingly employed in treatment regimens, future work will focus on further refinement of the staging system with additional biologic markers. [Table: see text] No significant financial relationships to disclose.
The outcome and toxicity profile of checkpoint inhibitor immunotherapy subsequent to high-dose IL-2 in the treatment of metastatic melanoma and renal cell carcinoma.
Authors: Stephanie A. Berg, Joseph I. Clark, Elizabeth Henry, Courtney Regan Wagner, Robert Charles Flanigan, Hanh P. Mai
Journal: Journal of Clinical Oncology (2019)

14 Background: Approved treatments for metastatic melanoma (MM) and metastatic renal cell carcinoma (mRCC) include targeted agents, high dose interleukin-2 (HD IL-2) and checkpoint inhibitors (CI). A subset of responders to HD-IL2 can achieve long term durable remissions (7-10%). Recently, data suggests that durable remissions are possible with CI. Thus, despite increased toxicity, first-line immunotherapy with HD-IL2 is a reasonable consideration in carefully selected patients with clear cell mRCC and MM followed by CI upon relapse. Our study explores the utility and safety of CI subsequent to HD-IL2 in patients (pts) in this population. Methods: We conducted a single institution retrospective analysis of pts with MM or mRCC who received HD-IL2 and subsequent CI from 2008-2017. Pts treated with prior targeted therapy were included. Statistical analysis was performed using Fischer's exact tests, log-rank test for KM analysis and non-parametric Wilcoxon Rank Sum tests to compare the groups. Results: We identified 34 unique pts (19 MM, 15 mRCC) from our pre-specified cohort. Pts were male (73%), Caucasian (88%), and median age=53. mRCC pts received more cancer related treatments than MM prior to CIs after HD-IL2 was given (2 vs. 1, p=0.002), had more total CI cycles administered (12 vs. 7, p=0.10) but less IL-2 doses than MM pts (20 vs. 24, p=0.26). mRCC pts tended to record higher HD-IL2 toxicity grade compared to MM pts (exact =0.04). 26% (9/34) of pts experienced a grade 2 or higher CI toxicity. Pts had higher HD IL-2 toxicities than CI toxicities during therapy but these two measures were not significantly correlated (r=0.07, p=0.73); furthermore, there was no survival difference between pts with reported grade 2 or higher CI toxicity compared to pts without any CI toxicity ( p=0.14). Conclusions: Our study suggests that CI therapy after HD-IL2 is feasible and not associated with more frequent toxicity or less clinical efficacy in pts with MM or mRCC.
Abstract 14930: Role of the Enterocyte Enpp2 Gene in Western Diet-induced Systemic Inflammation
Authors: Pallavi Mukherjee, Greg Hough, Arnab Chattopadhyay, Victor Grijalva, Ellen I O’Connor, Alan Wagner, Susan S Smyth, Wouter H Moolenaar, Mohamad Navab, Srinivasa T Reddy, Alan M Fogelman
Journal: Circulation (2017)

Introduction: We previously reported that adding 1 μg/gram diet of lysophosphatidic acid (LPA) 18:1 in chow-fed LDLR null mice resulted in dyslipidemia, systemic inflammation and increased aortic a...