tbuckley/cabot-search huggingface dataset:
Stereotactic body radiotherapy versus lobectomy for operable clinical stage IA pulmonary adenocarcinoma: Comparison of prospective clinical trials with propensity score analysis (JCOG1313-A).
Authors: Junko Eba, Kenichi Nakamura, Junki Mizusawa, Kenji Suzuki, Yasushi Nagata, Teruaki Koike, Masahiro Hiraoka, Shun-ichi Watanabe, Satoshi Ishikura, Hisao Asamura, Haruhiko Fukuda
Journal: Journal of Clinical Oncology (2014)

7543 Background: No randomized controlled trials comparing stereotactic body radiotherapy (SBRT) and lobectomy for operable early-stage non-small cell lung cancer have been successfully conducted. This study compared survival outcomes in two multi-institutional prospective clinical trials for SBRT (Japan Clinical Oncology Group [JCOG] 0403) and lobectomy (JCOG 0201). Methods: Inclusion criteria for this combined analysis consisted of: being operable, cT1N0M0, and adenocarcinoma diagnosed prior to treatment. Forty out of 169 patients enrolled in JCOG 0403 between 2004-2007, and 219 out of 811 patients enrolled in JCOG 0201 between 2002-2004 were included. The primary endpoint was overall survival adjusted with propensity score analysis. The patient selection factors included in the logistic model to estimate the propensity score were age, sex, and two findings on CT: tumor diameter and consolidation/tumor ratio (CTR). Results: The age distribution was quite different, with little overlap: the median was 79 (interquartile range (IQR): 74.5-83.5) in SBRT and 62 (IQR: 55-68) in lobectomy, although other factors were well balanced: males/females were 20/20 in SBRT and 108/111 in lobectomy; the median tumor diameter was 2.36 (IQR: 1.92-2.55) in SBRT and 2.20 (IQR: 1.90-2.70) cm in lobectomy; and the median CTR was 1.00 (IQR: 0.85-1.00) in SBRT and 1.00 (IQR: 0.68-1.00) in lobectomy. In propensity score matching analysis, 21 patients from each group were matched and the hazard ratio (HR) was 9.00 (95% CI: 1.14-71.04), favoring lobectomy. In the inverse probability of treatment weighting (IPTW) analysis, subjects were limited to those aged 75 or younger because JCOG0201 only included those 75 or younger. Thirteen patients for SBRT and 219 for lobectomy were compared and the HR was 1.19 (95% CI: 0.38-3.73), favoring lobectomy. Conclusions: Although all estimates tended to favor lobectomy over SBRT, no confirmatory conclusion was drawn due to the sample size for SBRT being too small. Further investigation with a larger sample size for a younger population with SBRT is needed to facilitate a valid comparison with surgery.
T regulatory cells (Treg) in patients with metastatic renal cell carcinoma (mRCC) decrease during sunitinib treatment: Correlations with clinical responses and T helper 1/T helper 2 (Th1/Th2) bias
Authors: R. Suppiah, J. Finke, B. I. Rini, A. Richmond, L. Wood, P. Elson, P. Shaheen, J. Garcia, R. Dreicer, R. Bukowski
Journal: Journal of Clinical Oncology (2006)

2526 Background: High numbers of regulatory T cells (Treg) and high expression of forkhead box transcription factor (FoxP3) in Treg are associated with decreased survival in various malignancies, likely via immunosuppression. Studies demonstrate Th1 suppression (IFN-γ) and Th2 (Il-4) promotion in metastatic renal cell carcinoma (mRCC) patients (pts). The aim of the present study was to determine the profile of Th1, Th2, and Treg at baseline and after 28 days of therapy with the multi-targeted tyrosine kinase inhibitor, sunitinib malate (SU11248). Further, correlation of changes in these parameters and tumor shrinkage (TS) was examined. Methods: Blood was obtained from cytokine-refractory, clear cell mRCC pts on day 1 (pre-treatment) and after 28 days of sunitinib 50mg daily. T cell cytokine expression (IL-4, IFN-γ), percentage in peripheral blood mononuclear cells of CD3+/CD4+/CD25hi+/FoxP3+ cells, and percentage of Treg that were FoxP3+ were evaluated using flow cytometry. Tumor measurements were performed after 2 cycles of therapy. Correlations between immune parameters and TS were assessed with Spearman rank correlations. Results: Ten pts were evaluable for Th1/Th2 responses; 9 for Treg. At baseline 7/10 had Th2 bias and 3/10 had Th1 bias. On day 28, pts maintained Th1 bias (n=3), switched to Th1 bias (n=3), or had decrease in magnitude of Th2 response (n=4). Additionally, a median 74.5% decrease occurred after 28 days of sunitinib in the percentage of CD3/CD4/CD25hi+/FoxP3+ in peripheral blood mononuclear cells, with a median 68.0% decrease of FoxP3+ Treg (CD3/CD4/CD25hi+) cells. Decrease in number of Treg correlated with relative change in Th1 response and Th2 bias (p&lt;.05 for all correlations). All pts had TS including 2 pts with partial response. Degree of TS correlated with relative change in Th1 response (p=.03), and Th2 bias (p=.06), as well as the relative change in FoxP3+ Treg (p=.06). Conclusions: Our results suggest that sunitinib promotes an immunostimulatory Th1 bias and reduces Treg. This immunostimulatory mechanism may contribute to the anti-tumor effect in mRCC. Further studies are on-going. [Table: see text]
A prospective observational study of metastatic renal cell carcinoma (mRCC) prior to initiation of systemic therapy.
Authors: Brian I. Rini, Tanya B. Dorff, Paul Elson, Cristina Suarez, Jordi Humbert, Linda Pyle, James M. G. Larkin, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2014)

4520 Background: The biology of mRCC includes a subpopulation of patients (pts) with indolent growth. Because of the toxicity and non-curative nature of current systemic therapy, select pts may be better served with initial surveillance. A prospective phase II observation trial was conducted in pts with mRCC prior to initial systemic treatment. Methods: Pts with treatment-naïve, asymptomatic, histologically-confirmed mRCC and metastases were enrolled. Local therapy prior to and during the study was permitted. Radiographic assessment was performed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months. The primary objective was to characterize time to initiation of systemic treatment. Secondary endpoints included assessment of depression/anxiety using standardized questionnaires (FKSI-DRS and HADS) and peripheral blood immune repertoire (TH1/TH2, MDSC, Tregs). Target accrual of 50 pts provided adequate power for the primary descriptive endpoint and 80% power to detect changes in correlate endpoints based on a two-sided Wilcoxon signed rank test. Results: 52 pts were accrued; median age 67 (range, 47-88); 75% male; 94% ECOG 0; 96% clear cell; 8% prior metastasectomy and Heng risk group favorable/intermediate 26%/74%. Baseline tumor burden (per RECIST 1.0) was 3.2cm (0.8-19.6cm). Median time on observation until systemic therapy was started was 14.1 months (95% C.I. 10.6-19.3), with estimated 12 month and 24 month rates of continued surveillance of 58% and 33%, respectively. Median change in tumor burden on study was 0.8cm (0-6.5cm); relative change +34% (0-311%) and median growth rate 0.14 cm/month (0-1.75). 31 pts have come off observation (61% for PD), and 25 pts have received systemic therapy. Pts with baseline tumor burden ≤1.5 cm vs. >1.5 cm had a median observation period of 31.6 months vs. 13.8 months (p=0.06). Neither location nor number of metastatic sites impacted the length of observation. Anxiety/depression were not prevalent at baseline, and scores did not worsen over time. There were no significant changes in immunologic parameters. Conclusions: A subset of mRCC pts can be safely observed for a period of time before starting systemic therapy.
NSABP FB-6: Phase II trial of weekly paclitaxel (WP) and pazopanib following doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for HER2-negative locally advanced breast cancer (LABC).
Authors: Antoinette R. Tan, Marc E. Buyse, Priya Rastogi, Samuel A. Jacobs, Andre Robidoux, Patrick J. Flynn, Michael P. Thirlwell, Louis Fehrenbacher, Philip J. Stella, Rakesh Goel, Thomas B. Julian, Louise Provencher, Martin Joseph Bury, Soonmyung Paik, Charles E. Geyer, Sandra M. Swain, Eleftherios P Mamounas, Norman Wolmark
Journal: Journal of Clinical Oncology (2012)

1025 Background: Pazopanib is an oral, small molecule inhibitor of VEGFR-1, -2, and-3, PDGFR-α, and -β, and c-kit tyrosine kinases. The purpose of this trial was to determine the activity and safety profile of pazopanib when added to neoadjuvant WP following AC in LABC. The primary endpoint was pathologic complete response in the breast and nodes (pCR-BN). Methods: Women with HER2-negative stage IIIA-IIIC breast cancer were treated with AC (60 mg/m 2 /600 mg/m 2 ) for 4 cycles every 3 weeks followed by WP 80 mg/m 2 on days 1, 8, and 15 every 28 days for 4 cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Postoperatively, pazopanib was given for 6 months. The regimen would be considered active if ≥14 responses (16% pCR rate in breast and nodes) were observed in 87 evaluable patients. Patients were considered evaluable if they received at least 1 dose of pazopanib. Results: Between July 2009 and March 2011, 101 pts (median age 51 yrs, range 30-71) were enrolled; 56% had stage IIIA, 34% stage IIIB, and 10% stage IIIC disease. 74 pts (73%) had ER-and/or PR-positive tumors and 27 pts (27%) were triple negative. 8 patients did not begin pazopanib. The pCR-BN rate in evaluable patients for whom surgical information was known was 18% (16/89). The pCR-BN rate in ER positive disease was 9% (6/65) and was 42% (10/24) in TNBC. Toxicities observed with WP and pazopanib included diarrhea (gr 2/3, 10%/5%), hand-foot syndrome (gr 2/3, 11%/1%), hypertension (gr 2/3, 12%/3%), neuropathy (gr 2/3, 14%/1%), and neutropenia (gr 3/4, 25%/1%). Liver toxicity during WP and pazopanib included ALT (gr 2/3/4, 13%/7%/1%), AST (gr 2/3, 7%/7%), and total bilirubin (gr 2, 2%). Conclusions: A regimen of WP and pazopanib following AC was active as neoadjuvant therapy in women with LABC and met the pre-specified criteria of interest. The activity in TNBC was notable. The toxicity profile of WP and pazopanib was consistent with previous experience. Support: GlaxoSmithKline.
Pharmacodynamic monitoring of DNA damage biomarkers in circulating tumor cells (CTCs) to assess the mechanism of action of the topoisomerase-1 (Topo1) inhibitor, NKTR-102.
Authors: Sujita Sukumaran, Christopher Neal, Jacky Woo, Vladislava O. Melnikova, Kenna Lynn Anderes, Christine Taylor Brew, Darren W. Davis, Ute Hoch
Journal: Journal of Clinical Oncology (2012)

e13577 Background: Inhibitors of Topo1 abrogate DNA replication and induce apoptosis in tumor cells. Topo1 inhibitors are effective cancer therapeutics however improved pharmacokinetic profiles have been sought. NKTR-102 is a next generation topoisomerase I-inhibitor with a unique pharmacokinetic profile that provides continuous exposure of the active metabolite, SN38. NKTR-102 is in phase III clinical development for patients with metastatic breast cancer. Monitoring DNA damage response markers in CTCs may be an informative, minimally invasive approach to detect drug activity in patients. Objectives of this study are to: 1) develop a multiplex immunofluorescent assay for measuring DNA damage effects of SN38 in CTCs; 2) obtain data to determine whether measuring DNA damage biomarkers in CTCs isolated from blood of cancer patients treated with SN38 ex vivo could be applied clinically to identify the best responders to NKTR-102. Methods: Solid tumor cell lines were treated with SN38 for 24 hr. Expression levels of gH2AX, survivin, BRCA1, BRCA2, RAD51, ATM and TUNEL were measured by quantitative laser scanning cytometry (LSC).Cytotoxcity was confirmed by MTT assay. Blood samples from 3 cancer patients were treated ex vivo with SN38 and CTCs were recovered and analyzed for expression of DNA damage biomarkers by LSC. Results: Treatment of H460 and HCT116 cells with SN38 led to a dose-dependent increase in the level of protein expression and/or frequency of positive cells for all DNA damage markers. Ex vivo treatment of breast cancer patients' blood with SN38 for 24 hr induced a dose-dependent increase in the expression of ATM (7.8-fold) and RAD51(188-fold) in one patients’ blood sample. An increase in the percent TUNEL-positive cells (0-20% in untreated to 44-54% in drug-treated samples) was observed in 2 patients’ samples without affecting the total number of isolated CTCs. Conclusions: Quantitative multiplex immunofluorescent assays for monitoring changes in gH2AX, ATM, RAD51 protein expression and percent TUNEL positive CTCs have been developed using LSC. These assays have been incorporated into an ongoing phase III clinical study of NKTR-102.
The P-2t antagonist AR-C69931MX is a more effective inhibitor of ADP-induced platelet aggregation than clopidogrel.
Authors: Gavin Jarvis, M.A. Nassim, R.G. Humphries, I.P. Kirk, W. Tomlinson, E.A. Cusworth, A. Midha, J.H. Perrett, E.J. Mobbs, M.D. Hammersley, I.S. Watts
Journal: Blood (1999)
Investigating the effectiveness of the cognitive remediation and cognitive behavior therapy skills training program (CRCST).
Authors: Jun Zhao, Puja G Patel, Amy C. Fowler, Thea Norris
Journal: Journal of Clinical Oncology (2014)

10087 Background: Improvements in cancer treatments over the past forty years have led to a significant increase in the number of pediatric oncology survivors. With this feat, also emerges the ongoing risk for the development of long-term cognitive impairments and corresponding emotional distress. In particular, neurocognitive late effects from treatment include deficits in attention, memory, and processing speed. Promising research has demonstrated cognitive remediation using a computerized exercise program can produce improvements in this area. Additionally, therapeutic skills from cognitive behavior therapy have shown to effectively reduce emotional vulnerability. The aim of this program was to improve difficulties with working memory, attention, and executive functioning as well as enhance emotional well being using a unique intervention program. Methods: Twenty-four patients, ages 8 to 18 years old, who have undergone radiation and/or chemotherapy treatment and displayed neurocognitive and/or psychological late effects indicated by neuropsychological testing participated. The program consisted of 9 group sessions in clinic and completion of 45 twenty-minute computer training sessions at home. Participants and parents completed self-report measures of the Behavior Rating Inventory of Executive Function and the Behavior Assessment System, 2nd Edition. Results: A paired sample t-test using the SPSS was conducted. A significant improvement was noted from pre-testing to post-testing for working memory [t(23)= 2.6., p<.05], attention [t(23) = 4.7, p<.05], executive functioning [t (23) = 2.1, p<.05], and emotional well being with improvement in internalization [t(23) = 2.6., p <.05]. Conclusions: These results suggest that a combined program with computerized cognitive exercises and cognitive strategies can effectively improve late-effects from treatment.
Policing and Public Health—Strategies for Collaboration
Authors: Jonathan P. Shepherd, Steven A. Sumner
Journal: JAMA (2017)

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In patients receiving palliative care, risperidone or haloperidol increased delirium symptoms vs placebo
Authors: Justin Lee, Anne Holbrook
Journal: Annals of Internal Medicine (2017)

Source Citation Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017;177:34-42. 27918778
Can an integrated pathology process and decision support tool improve diagnosis and treatment of hematologic malignancies?
Authors: Susan K Brenneman, Angela V Belland, Erin M Hulbert, John Leite, Jeff Hall, Mike Nerenberg
Journal: Journal of Clinical Oncology (2014)

e17622 Background: The process of integrating and interpreting information from multiple diagnostic tests, which may have been provided by multiple laboratories, can result in inaccurate diagnoses and treatment delays for patients with hematologic malignancies. A diagnostic process and decision support tool that integrates laboratory results and guides clinical diagnosis may improve diagnostic accuracy and timeliness. The purpose of this investigation is to compare the completeness and actionability of bone marrow procedure (BMP) results provided in integrated and traditional laboratory reports. Methods: Adult patients who had undergone a BMP and had been diagnosed with a hematologic condition between January 2007 and March 2012 were identified from a large US commercial health insurance database affiliated with Optum. Medical charts were obtained from the BMP-referring physician. Independent oncologists and hematologists reviewed patients’ medical charts to determine the impact of BMP pathology reports on diagnosis and disease management. Integrated and traditional reports were compared for completeness (diagnostic work-up in accordance with guidelines and no additional tests recommended) and actionability (enough information provided to make or rule out a diagnosis and to generate treatment recommendations). Results: This analysis included 150 subjects (75 integrated and 75 traditional). As shown in the Table, differences were found in the completeness and actionability of the integrated vs. traditional BMP reports. Conclusions: Comprehensive integrated reports of complete BMP results provide advantages over traditional lab reports by highlighting critical information and ensuring testing is completed according to both guidelines and clinical need. Report type Integrated Traditional P Diagnostic work up in accordance with guidelines 95% 81% 0.01 Additional testing recommended 9% 25% 0.01 Enough information for a definitive diagnosis or to rule out a diagnosis 85% 81% 0.01 Enough information to generate treatment recommendations 83% 68% 0.04
Identification of patients with hormone receptor–positive breast cancer who need adjuvant tamoxifen therapy for more than 5 years.
Authors: Chiao-En Wu, Shin-Cheh Chen, Hsien-Kun Chang, Yung-Feng Lo, Swei Hsueh, Yung-Chang Lin
Journal: Journal of Clinical Oncology (2014)

539 Background: Extended hormonal therapy with tamoxifen for more than 5 years has improved disease-free survival (DFS) and overall survival (OS) in hormone receptor (HR)-positive breast cancer patients. However, this strategy in patients with a low risk of recurrence is controversial, since the benefits should outweigh the risk of endometrial cancer or thromboembolic disease. Therefore, we attempt to identify risk factors for late recurrence after 5 years of adjuvant tamoxifen therapy. Methods: Between 1990 and 2004, 1,104 HR-positive breast cancer patients who had received tamoxifen treatment at our institution at some point and had been disease free for at least 6 years were included in this analysis. Univariate and multivariate analyses of prognostic factors for late recurrence were performed using the binary logistic regression model. Results: During a median follow-up period of 10.9 years after surgery, 70 patients died and 99 showed recurrence. Patients aged <40 years, those aged >65 years, those with stage T2–4 tumors, those with positive lymph nodes, and those with positive estrogen receptor (ER) status had significantly higher rates of recurrence. In multivariate analysis, age < 40 years (odds ratio [OR] = 4.21, P < 0.001) and lymph node metastasis (OR = 2.67, 3.77, 6.10 for N1, N2, N3 vs. N0, P < 0.001) were associated with higher rates of recurrence. We stratified patients into high-risk (age < 40 years or positive lymph node status, 536 patients) and low-risk (age > 40 years and negative lymph node status, 566 patients) groups. The recurrence rates were 14.6% and 3.5% in the high-risk and low-risk groups, respectively. Patients in the high-risk group had poorer DFS (estimated 15-year DFS rate: 78% vs. 92.3%, P < 0.01) and OS (estimated 15-year OS rate: 83.1% vs. 92.6%, P= 0.01) than those in the low-risk group. Conclusions: Our findings suggest that HR-positive breast cancer patients either aged <40 years or with positive lymph node status were justified in continuing with tamoxifen therapy for more than 5 years.
Monocytosis in polycythemia vera: Clinical and molecular correlates
Authors: Daniela Barraco, Sonia Cerquozzi, Naseema Gangat, Mrinal M. Patnaik, Terra Lasho, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2017)

Monocytosis (absolute monocyte count, AMC ≥ 1 × 109 /L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the current study, we examined the prevalence, laboratory and molecular correlates, and prognostic relevance of monocytosis in polycythemia vera (PV). Among 267 consecutive patients with World Health Organization (WHO)-defined PV, 55 (21%) patients displayed an AMC of ≥1 × 109 /L and 18 (7%) an AMC of ≥1.5 × 109 /L. In general, PV patients with monocytosis were significantly older and displayed higher frequencies of leukocytosis (81% vs. 50% at AMC ≥1 × 109 /L) and TET2/SRSF2 mutations (57%/29% vs. 19%/1% at AMC ≥ 1.5 × 109 /L). In univariate analysis, AMC ≥1.5 × 109 /L adversely affected overall (OS; P = .004; HR 2.6, 95% CI 1.4-4.8) and myelofibrosis-free (MFFS; P = .02; HR 4.4, 95% CI 1.3-15.1) survival; during multivariable analysis, significance was borderline sustained for OS (P = .05) and MFFS (P = .06). Other independent risk factors for OS included unfavorable karyotype (P = .02, HR 3.39, 95% CI 1.17-9.79), older age (P < .0001, HR 3.34 95% CI 1.97-5.65), and leukocytosis ≥15 × 109 /L (P = .004, HR 2.04, 95% CI 1.26-3.29). In conclusion, in the current study, we encountered a higher than expected prevalence of monocytosis in patients with PV and the mutation profile and age distribution of PV patients with monocytosis is akin to those of patients with CMML and might partly contribute to their worse prognosis.