tbuckley/cabot-search huggingface dataset:
Redefining the role of adjuvant versus salvage radiation therapy for prostate cancer after radical prostatectomy for T3 disease and/or positive margins.
Authors: Barry W. Goy, In-Lu Amy Liu
Journal: Journal of Clinical Oncology (2020)

367 Background: SWOG 8794 recommends adjuvant radiation therapy (ART) after radical prostatectomy (RP) for T3 and/or positive margins. Our purpose was to assess 12-year outcomes on 862 RP patients who had either T3 and/or positive margins who underwent surveillance, salvage radiation therapy (SRT), or hormonal therapy (HT), while categorizing these patients into very low risk (VLR), low risk (LR), high risk (HR), and ultra high risk (UHR) groups. Methods: From 2004 - 2007, 862 RP patients had adverse factors of extracapsular penetration (T3a), seminal vesicle invasion (T3b), positive margins, and/or detectable post-operative PSA. Management included surveillance (54.8%), SRT (36.8%), and HT (8.5%) as first salvage therapy, and 21.5% eventually received hormonal therapy. Twenty patients underwent ART, and were excluded from this analysis. We assessed prognostic factors using multivariable analysis, and 12-year estimates of freedom from biochemical failure (FFBF), freedom from salvage therapy (FFST), distant metastases-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS). VLR were those with Gleason Score (GS) of 6. LR were GS 3+4 with only T3a or positive margins, but an undetectable postoperative PSA &lt;0.1. HR were T3b with GS 7-10, any GS 7-10 with T3a/b and positive margins, but an undetectable PSA. UHR were those with a detectable PSA with a GS 7-10. Results: Median follow-up was 12.1 years. Median age was 61.6 years. Median time to first salvage treatment for VLR, LR, HR, and UHR were 10.8, 11.1, 5.3, and 0.6 years, p&lt;0.001. 12-year estimates of FFBF for VLR, LR, HR, and UHR were 60.2%, 52.9%, 28.4%, and 0%, p&lt;0.0001. For FFST, 70.9%, 68.6%, 40.5%, and 0%, p&lt;0.0001. For DMFS, 99.1%, 97.8%, 88.6%, and 63.6%, p&lt;0.0001. For PCSS, 99.4%, 99.5%, 93.5%, and 78.9%, p&lt;0.0001. For OS, 91.8%, 91.8%, 81.0%, and 69.9%, p&lt;0.0001. Conclusions: Outcomes of T3 and/or positive margins using surveillance or SRT as initial management yields excellent outcomes for VLR and LR groups, in which ART should be avoided. For HR, ART can be considered reasonable, since FFBF is only 28.4%. For VHR, these patients may benefit from combined hormonal therapy and ART.
Evaluation of stool melting curve analysis of methylated CpG island promoters as an alternative for early noninvasive diagnosis of colorectal tumors
Authors: D. Azuara, F. Rodriguez-Moranta, A. Soriano-Izquierdo, J. Guardiola, J. de Oca, S. Biondo, I. Blanco, M. Esteller, G. Capella
Journal: Journal of Clinical Oncology (2009)

e15036 Background: Previous studies have shown that assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify all colorectal tumors analyzed. The aim of the present study was to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the diagnosis of colorectal tumors using Methylation Curve (MC) analyses, a technique that simultaneously analyze all CpG residues within a promoter. Methods: Promoter methylation status of 5 tumor-related genes (RARB2, p16 INK4a , MGMT, p14 ARF and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 newly diagnosed patients with primary colorectal carcinomas and 20 with colorectal adenomas using Methylation-specific PCR (MSP). Results were validated in a set of 88 patients (20 healthy subjects, 17 inflammatory bowel disease, 23 adenomas, 28 carcinomas) using MC analyses. Median age for every group was 63, 51, 66 and 67 y respectively. Results: In the initial set, the majority [10 of 12 (83%) carcinomas and 18 of 20 (90%) adenomas] of biopsies were positive for at least one marker. In stool DNA prevalence was 75% for carcinomas (9 of 12) and 60% for adenomas (12 of 20) with no false positive in stools. In the validation set MC was used. Analytical sensitivity of MC was 5% of methylated alleles for p16 INK4a , p14 ARF , RARB2 and APC and 10% for MGMT. In the validation set MC analyses of biopsies showed that at least one marker was positive in 22 of 28 (79%) carcinomas and 16 of 23 (70%) adenomas. In stool DNA, these percentages were 64% (18 of 28) for carcinomas and 42% (9 of 23) for adenomas. No aberrant methylation was observed in healthy subjects and in 2 of 15 (13%) of IBD patients aberrant RARB2 methylation was detected. Conclusions: Melting Curve analysis of a panel of methylation markers in stool DNA is a good alternative for the early non-invasive diagnosis of colorectal tumors. [Table: see text]
Outcomes of systemic therapy in relapsed renal cell carcinoma (RCC) treated with adjuvant sunitinib (AS).
Authors: Guillermo de Velasco, Álvaro Ruiz-Granados, Oscar Reig, Francesco Massari, Miguel Angel Climent Duran, Elena Verzoni, Jeffrey Graham, Roberto Llarena, Michele De Tursi, Frede Donskov, Clara Iglesias, Hardev S. Pandha, Xavier Garcia del Muro, Giuseppe Procopio, Stephane Oudard, Daniel Castellano, Laurence Albiges
Journal: Journal of Clinical Oncology (2020)

701 Background: There are no available data on the usefulness of targeted therapy (TT) as the first-line treatment for patients with RCC recurrence after AS. We aim to explore the outcomes of systemic therapy with recurrent RCC after AS including re-exposure to sunitinib. Methods: A multi-institutional retrospective study was conducted on RCC patients who relapsed after AS. The primary end point was progression-free survival (PFS). Secondary end points were overall response rate (ORR) and overall survival (OS). Results: 34 relapses were recorded, 25 patients (73,5%) were male. 25 patients were treated with systemic therapy at first-line after relapse: 65% of patients received Vascular Endothelial Growth Factor (VEGF)-TT (including 7 patients retreated with sunitinib), 21,7% mTOR inhibitors and 13% immunotherapy. The median time to relapse was 20,3 months (IQR 5,2-20,4) from diagnosis, and 7,5 months (IQR 1,0-8,5) months from AS ending. At a median time of follow-up of 23,5 months, 24/25 patients had progressed on first-line systemic therapy. The median PFS was 12,0 months (IC95% 6,6-17,8 months). There was no statistical difference in PFS among the different treatments or the re-exposed to sunitinib. PFS was not statistically different between those relapsing on or after AS ( &lt; 6 or &gt; 6 months after AS). ORR was 20,3%. Median OS was 28,7 months (IC95% 24,4-33,0). Conclusions: This study suggests that TT may still improve PFS and OS in RCC patients who relapsed after AS.
The effect of exposure to cold airflow on skin barrier function and epidermal filaggrin degradation products in children with and without atopic dermatitis
Authors: Jihyun Kim, Min Jung, Insung Kim, Bo Ra Lee, Ji Young Lee, Hyun Mi Kim, Mijeong Kwon, Minjeong Kim, Kyung-Min Lim, Peter Kim, Kangmo Ahn
Journal: Journal of Allergy and Clinical Immunology (2020)
Evaluating Treatment Tolerability in Cancer Clinical Trials Using the Toxicity Index
Authors: Gillian Gresham, Márcio A Diniz, Zahra S Razaee, Michael Luu, Sungjin Kim, Ron D Hays, Steven Piantadosi, Mourad Tighiouart, Greg Yothers, Patricia A Ganz, André Rogatko
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background The National Cancer Institute Moonshot research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project R-04 clinical trial as an example. Methods National Surgical Adjuvant Breast and Bowel Project R-04 was a neoadjuvant chemoradiation trial in stage II–III rectal cancer patients. A 2 x 2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models, where Pr A &amp;lt; B indicates the probability that higher values of TI were observed for A when compared with B. Baseline age, sex, performance status, body mass index, surgery type, and stage were evaluated as independent risk factors. Results A total of 4560 toxicities from 1558 patients were analyzed. Results from adjusted probabilistic index models indicate that oxaliplatin-containing regimens had statistically significant (P &amp;lt; .001) probability (Pr) for higher TI compared with regimens without oxaliplatin (Pr 5FU &amp;lt; 5FU + Oxa = 0.619, 95% confidence interval [CI] = 0.560 to 0.674; Pr 5FU &amp;lt; Cape + Oxa = 0.627, 95% CI = 0.568 to 0.682; Pr Cape &amp;lt; 5FU + Oxa = 0.587, 95% 0.527 to 0.644; and Pr Cape &amp;lt; Cape + Oxa = 0.596, 95% 0.536 to 0.653). When compared with other existing toxicity analysis methods, TI provided greater power to detect differences between treatments. Conclusions This article uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient’s treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs.
Association of neuroendocrine (NE) mRNA expression profiling in hormone-sensitive tumors samples with adverse clinical outcome in castration-resistant prostate cancer (CRPC) patients.
Authors: Mayra Orrillo, Natalia Jimenez, Oscar Reig, Giancarlo Castellano, Albert Font, Montserrat Domenech, Alejo Rodriguez-Vida, Joan Carles, Cristina Suarez, Laura Ferrer, Nuria Gonzalez, Nuria Sala, Leonardo Rodriguez-Carunchio, Sherley Diaz, Aleix Prat, Mercedes Marin, Begona Mellado
Journal: Journal of Clinical Oncology (2020)

165 Background: NE dedifferentiation is associated to clinical aggressiveness and resistance to androgen receptor inhibition in prostate cancer. We investigated impact of a NE expression signature in the clinical outcome of mCRPC patients treated with taxanes. Methods: This is a multicenter retrospective study. A customized panel of 45 NE-related gene signature was tested in total RNA from formalin-fixed paraffin-embedded hormone-sensitive tumor samples, by the nCounter platform (Nanostring Technologies). Patients were grouped according to their molecular profile by unsupervised clustering. Expression levels were correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Eighty seven patients were included in the study, 79 were treated with docetaxel and 8 with cabazitaxel. Median age was 64.8 (44-88.3) years and median follow-up was 20.7 (1.17-74.4) months. High expression of the NE signature was associated with a shorter time of CRPC development (N=60, median 12.8 vs 21.6, HR 2.4, 95%CI 1.3-4.3, P=0.003) and shorter OS from CRPC diagnosis (median 24.1 vs 41.33, HR 2.3, 95%CI 1.4-3.8, P=0.001). Moreover, according to the outcome to taxanes, high NE signature correlated with lower PSA-PFS (median 6.6 vs 10.1 mo P=0.047, HR 1.6, 95%CI 1-2.7, P=0.05) and OS (median 19 vs 22 mo, HR 1.8, 95%CI 1.1-2.8, P=0.014), and it was independently associated to a lower OS (HR 1.9, 95%CI 1.1-3.2, P=0.016). Conclusions: NE-related gene expression in hormone-sensitive tumor samples is associated with adverse clinical outcome and lower taxane benefit in metastatic CRPC patients. Thus, molecular characterization of primary tumors may be useful to guide treatment strategies in metastatic prostate cancer.
Validation of 3-factor clinical-genomic model to predict response to atezolizumab as first-line or post-platinum therapy for advanced urothelial carcinoma.
Authors: Guru Sonpavde, Romain Banchereau, Daren Tayama, Xiaodong Shen, Amin Nassar, David J. Kwiatkowski, Richard Price, Sanjeev Mariathasan
Journal: Journal of Clinical Oncology (2020)

552 Background: Previously, we reported a 3-factor model including tumor mutation burden (TMB), peripheral blood neutrophil/lymphocyte ratio (NLR) and visceral metastasis status to predict tumor regression (c-statistic=0.90) when using ICIs for mUC regardless of line of therapy. We conducted an external validation of this model to determine its ability to predict response. Methods: We utilized data from a phase II trial, IMvigor210, which evaluated atezolizumab (atezo) for post-platinum pts or as first-line therapy for cisplatin-ineligible pts with mUC. Pts with TMB, NLR, visceral metastasis and RECIST1.1 response status available were evaluable. Tumor genomic analysis was performed using FoundationOne, which sequences 324 cancer-related genes. Multivariable regression studied the association of TMB (&lt;10 vs. ≥10 mutations/megabase), NLR (&lt;5 vs. ≥5) and visceral metastasis status (yes vs.no) with RECIST 1.1 response status (≥partial response [PR] vs no PR). Model discrimination performance was assessed using the concordance (c)-index. Results: A total of 234 pts were evaluable for analysis, of whom 185 (79%) were men. 164 (70.1%) pts received post-platinum therapy and 70 (29.9%) received first-line therapy with atezo. 60 pts exhibited RECIST 1.1 ≥PR. On multivariate analysis, all 3 factors were independently and significantly associated with ≥PR: TMB ≥10 mutations/megabase (HR -4.254, p=2.1 x 10 −5 ), low NLR (HR=2.591, p=0.00958) and absence of visceral metastasis status (HR=4.105, p=4.04 x 10 −5 ). The c-index of this 3-factor model to predict ≥PR was 0.77. Presence of all 3 favorable factors (TMB high , NLR low , no visceral metastases) was associated with ≥PR in 15/21 pts (71.4%), while the absence of all 3 factors (TMB low , NLR high , visceral metastases) was associated with ≥PR in 2/37 pts (5.4%). Conclusions: A 3-factor model combining readily available clinical and genomic variables including TMB, NLR and visceral metastasis status was validated to robustly predict RECIST 1.1 response in pts with mUC receiving atezo as first-line or post-platinum therapy. This model may improve the therapeutic index and cost efficacy of atezo.
Docetaxel (DOC) versus new androgen receptor-targeted agent (ART) in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) having received abiraterone (ABI) or enzalutamide (ENZA) as first-line (L1).
Authors: Antonin Broyelle, André-Michel Bimbai, Aurelien Carnot, Diane Pannier, Samira Makhloufi, Thomas Ryckewaert, Nicolas Penel, Stephane Oudard
Journal: Journal of Clinical Oncology (2020)

109 Background: The main treatments for mCRPC are 2 new ART (ABI, ENZA) and 2 taxanes [doctaxel (DOC) and Cabazitaxel]. The optimal sequence is currently not defined. An increasing number of pts are first treated with one of ART. In this population, data about efficacy of 2nd line (L2) are spare. We designed a retrospective study to evaluate activity of DOC vs ART in mCRPC pts treated with ART as L1 therapy. Methods: In this observational cohort study, we included all consecutive pts with ENZA or ABI as L1 for chemo-naïve mCRPC. We measured PFS and OS during both L1 &amp; L2. To compare the efficacy of DOC versus ART as L2, we measured Growth Modulation Index (GMI=Time To progression with L2/TTP with L1) and we used Cox model to compare PFS/OS in both arm, in both univariate &amp; multivariate analysis using propensity score. Results: We included 175 pts, including 75 treated ENZA and 100 with ABI as L1. 69 (39%) pts received DOC and 30 (17%) pts received ART as L2; 76 (43%) did not receive L2. Median follow-up was 36 months (CI95%: 30.4 - 40). From the starting of L1, PFS was 13.0 months (CI95% 11.0 – 15.0), OS was 34.5 months (CI95%: 28.7 – 38.6). There was no difference between ENZA and ABI in PFS and OS (p=0.684). From the start of L2, the median PFS was 6.0 months (CI95%: 5.0 – 6.6) and the median OS was 18.0 months (CI95%: 13.9 – 21.4). We found a significant benefit in PFS for DOC vs ART in L2 (6.7 months vs 4.0 months, HR 0.60 [CI95%: 0.31 – 0.96], p=0.03). This benefit did not reach the level of significance in OS (19.5 months vs 12.0 months, HR 0.60 [CI95%: 0.35 – 1.03], p=0.1). ECOG-PS and time of castration resistance were associated with OS in multivariable analysis and then used in propensity score. After adjustment to both parameters, we found no difference in PFS (p=0.2) and OS (p=0.1) in pts receiving DOC vs ART as L2. Only 56% of pts received L2. Probability for GMI being &gt;1.33 was not significantly different between DOC (19%) and ART (13%), p=0.099. Conclusions: ABI and ENZA are similarly active in L1 mCRPC. In univariate analysis, L2 with DOC seemed more active than ART. However this benefit was not retained after adjustment to propensity score.
リボソームタンパク質L17,RpL17は,血管平滑筋の成長および頸動脈内膜形成の阻害物質である
Authors: M Smolock Elaine, A Korshunov Vyacheslav, Glazko Galina, Qiu Xing, Gerloff Janice, C Berk Bradford
Journal: Circulation (2012)
Association of Variation in Consultant Use Among Hospitalist Physicians With Outcomes Among Medicare Beneficiaries
Authors: Jennifer P. Stevens, Laura A. Hatfield, David J. Nyweide, Bruce Landon
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Evidence is lacking on the consequences of high rates of inpatient consultation. <h3>Objective</h3> To examine outcomes and resource use of patients cared for by hospitalists who use more inpatient consultation than their colleagues. <h3>Design, Setting, and Participants</h3> A retrospective cohort study of medical admissions to hospitalists among fee-for-service Medicare beneficiaries was conducted. Hospitalist consultation tendency was identified from January 1, 2013, to December 31, 2014; admissions were calculated in 2013; and outcomes were measured in 2014. Data were analyzed from January 31, 2017, to May 9, 2019. A total of 711 654 admissions with patients receiving care from 14 584 hospitalists at 737 hospitals were included. <h3>Exposure</h3> Admission to high-consulting hospitalists, considered to be those who were in the top 25% of the distribution of consulting frequency at their own hospital (adjusted for patient case mix). <h3>Main Outcomes and Measures</h3> Outcomes included length of stay, Medicare Part B inpatient charges, discharge destination, all-cause 7- and 30-day readmissions, 90-day outpatient specialist visits, and 30-day mortality. <h3>Results</h3> The 711 654 hospital admissions included 408 489 women (57.4%); mean (SD) age of the population was 80 (8.5) years. Length of stay of patients cared for by high-consulting hospitalists was longer compared with other hospitalists (adjusted incidence rate ratio, 1.04; 95% CI, 1.03-1.05). The admissions resulted in a mean of $137.91 (95% CI, $118.89-$156.93) more in Medicare Part B charges and were less likely to end with the patient going home (adjusted odds ratio [aOR], 0.96; 95% CI, 0.94-0.98) compared with patients cared for by other hospitalists in the cohort. Patients cared for by high-consulting hospitalists also were 7% more likely than patients cared for by other hospitalists to see an outpatient specialist at 90 days (aOR 1.07; 95% CI, 1.05-1.09), with no significant differences in 30-day mortality (aOR 1.01, 95% CI, 0.98-1.03) or readmissions (7-day readmissions: aOR 1.01; 95% CI, 0.98-1.03; 30-day readmissions: aOR, 1.01; 95% CI, 0.99-1.03). <h3>Conclusions and Relevance</h3> Hospitalists who obtain consultations more than their colleagues at the same institution were associated with greater use of health care resources without apparent mortality benefit. Further investigation should identify whether reducing high rates of consultation can reduce resource use without harming patients.
Relative risk of pneumonitis associated with first-line use of immune checkpoint inhibitors in advanced renal cell carcinoma.
Authors: Nusrat Jahan, Francis Mogollon-Duffo, Srikala Meda, Fred L. Hardwicke, Lukman Aderoju Tijani
Journal: Journal of Clinical Oncology (2020)

676 Background: After approval in 2006, sunitinib remained the standard for the first line treatment of advanced renal cell carcinoma (aRCC) for a decade. Immune checkpoint inhibitors (ICI) have changed the landscape of aRCC management in recent years. Pneumonitis is a significant immune related adverse event (iRAE) associated with ICIs causing morbidity, mortality and treatment interruption. We conducted a meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of pneumonitis associated with first line use of ICIs for aRCCs. Methods: We conducted a systematic search using PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until May 2019. Phase 3 RCTs using ICIs in the intervention arm for the first line treatment of aRCC and reporting the number of pneumonitis for both intervention and control arms were included in the analysis. We used the Mantel-Haenszel (MH) method utilizing random effects model to calculate pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I 2 value. Results: Three phase 3 RCTs, CheckMate 214, IMmotion151 and KEYNOTE-426, randomizing 2833 patients (1427 in the ICI arms and 1406 in the control arms) were included in the analysis. ICI regimens used in the study arms were as follows — CheckMate 214: nivolumab and ipilimumab, IMmotion151: atezolizumab and bevacizumab, and KEYNOTE-426: pembrolizumab and axitinib. Sunitinib was used for all the control arms. Randomization was 1:1 in all three studies. Pneumonitis of any-grade was reported in 56 (3.92%) patients in the ICI arms versus 1 (0.07%) patient in the control arms. The pooled RR of any grade pneumonitis was 22.11 (95% CI: 5.34-91.55, P&lt;0.0001, I 2 =0%). Grade 3 and above pneumonitis was reported in 12 (0.84%) patients in the ICI arms versus 0 (0%) patient in the control arms with pooled RR of 8.39 (95% CI: 1.54-45.80, P=0.01, I 2 =0%). Conclusions: The relative risk of any-grade as well as high-grade pneumonitis are significantly higher with ICI based regimens compared to sunitinib for aRCC. Early detection and prompt intervention are vital to reduce morbidy and mortality associated with this iRAE.
Effect of HIV-infection on QuantiFERON-plus accuracy in patients with active tuberculosis and latent infection
Authors: Elisa Petruccioli, Teresa Chiacchio, Assunta Navarra, Valentina Vanini, Gilda Cuzzi, Claudia Cimaglia, Luigi Ruffo Codecasa, Carmela Pinnetti, Niccolò Riccardi, Fabrizio Palmieri, Andrea Antinori, Delia Goletti
Journal: Journal of Infection (2020)