tbuckley/cabot-search huggingface dataset:
Poly(ADP ribose) polymerase (PARP) inhibition in peripheral blood lymphocytes (PBLs): Does it reflect PARP inhibition in tumor?
Authors: D. R. Shalinsky, D. D. Wang, K. A. Kern, P. English, N. J. Curtin, R. Plummer
Journal: Journal of Clinical Oncology (2011)

3054 Background: PARP activity in PBLs or PBMs, measured as poly(ADP-ribose) (PAR) levels, has been used as a biomarker in the development of PARP inhibitors for dose selection. Results of a phase II study of olaparib in pts with BRCA-deficient ovarian or breast cancer showed that PARP inhibition in peripheral-blood mononuclear cells (PBMCs) plateaued at 100 mg given bid, but better antitumor activity was achieved with 400 mg bid dosing. The goal of this study was to compare PARP inhibition by PF-01367338 (formerly AG014699) in PBLs and tumor using data from a previous Pfizer study. Methods: In a phase I melanoma study, PF-01367338 IV infusion (1 to 18 mg/m2) was given daily with temozolomide for 5 days. For this analysis, PAR in PBLs was measured on Cycle 1 Days 1 or 4 at baseline pretreatment and 4-6 hrs after dosing (cohorts 6-9). Tumor biopsy samples were collected before dosing on Day -7 and 4-6 hrs after dosing on Days 1, 4 or 5 from patients dosed with 12 or 18 mg/ m2. Samples were analysed using a validated immunoblot assay for determination of PAR formation. PARP inhibition was calculated as percent change of PAR level from baseline. Results: Patients provided PBL and tumor biopsy samples for paired analyses to assess PARP inhibition by PF-01367338. Data are summarized in the table below. Conclusions: Similar percent reductions in PAR formation in PBLs and tumor tissue indicate that PARP inhibition by PF-01367338 in PBLs reflects that seen in melanoma tumors. Further investigation is needed to determine whether additional dose escalation would produce additional anti-tumor activity. PF-01367338 dose Median (range)PARP inhibition in PBLs (%) Median (range)PARP inhibition in tumor (%) Wilcoxon Rank-Sum 12 mg/m2 (n = 7) 87.5 (82.1 – 96.0) 90.6 (78.1 – 99.1) z=-1.086, p=0.2774 18 mg/m2 (n = 4) 85.7 (79.1 – 95.6) 91.3 (85.9 – 97.0) z=-0.866, p=0.193 * Wilcoxon rank-sum analysis for pooled data: z = -1.215, one-sided p=0.112.
Long-Term Follow-up in Very Elderly Patients with Chronic Myeloid Leukemia Treated with Imatinib Frontline
Authors: Roberto Latagliata, Massimo Breccia, Dario Ferrero, Francesco Cavazzini, Malgorzata Monika Trawinska, Fausto Castagnetti, Mario Annunziata, Fabio Stagno, Mario Tiribelli, Gianni Binotto, Carmen Fava, Elena Crisà, Giovanna Mansueto, Antonella Gozzini, Franca Falzetti, Enrico Montefusco, Alessandra Iurlo, Russo Sabina, Michele Cedrone, Antonella Russo Rossi, Gabriele Gugliotta, Patrizia Pregno, Alessandro Isidori, Paolo Avanzini, Mauro Endri, Atelda Romano, Gianfranco Giglio, Francesca Celesti, Federica Sorà, Sergio Storti, Ada D'Addosio, Sara Galimberti, Ester Maria Orlandi, Elisabetta Calistri, Monica Bocchia, Monica Crugnola, Giovanna Rege Cambrin, Paolo Vigneri, Luigiana Luciano, Elisabetta Abruzzese, Giuliana Alimena
Journal: Blood (2015)
Molecular subtyping of colorectal cancer to identify a mesenchymal tumor type that might benefit from TGF-beta pathway inhibition.
Authors: Ramon Salazar, Paul Roepman, Stefan M. Willems, Diede Brunen, Udo Kellner, Rachel A Midgley, Rene Bernards, Iris M. Simon
Journal: Journal of Clinical Oncology (2014)

456 Background: Currently, most colorectal cancer (CRC) patients receive chemotherapy treatment, even though many patients do not benefit. Therefore, a better understanding of the biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for all other patients. Methods: A molecular subtype classification was developed using full genome expression data of 188 stage I-IV CRC patients and validated in 543 stage II and III patients. Subtypes were correlated to clinical factors, prognosis and treatment benefit (stage III). To determine whether TGF-β signaling is elevated in the tumors, 78 patient biopsies were analyzed for p-SMAD2/3 expression using immunohistochemistry. To analyze the effect of TGF-β activation, we studied the effects of MED12 suppression in SKCO-1 CRC cells under treatment with Cisplatin, Oxaliplatin or 5-FU. Results: We developed a diagnostic test that allows the classification of colorectal cancer tumors into different intrinsic molecular subtypes (A-, B-, C-type). The heterogeneity of these subtypes is largely based on 3 biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes resulting in a high mutation frequency associated with MSI, and cellular proliferation. Especially the C-type (~15% of CRC tumors) is of clinical interest, as C-type patients have the worst outcome, a mesenchymal phenotype and show no benefit from chemotherapy treatment in our patient set or a public dataset. The C-type subgroup has elevated TGF-β signaling, as shown by TGF-beta and TGF-beta receptor over-expression (TGFB1, p=0.0012; TGFBR1, p=0.0005) and increased phopho-SMAD2/3 staining in the tumor cells (1.9-fold, p=0.0002). In cell line experiments, we show that up-regulation of TGF-β signaling by MED12 knockdown resulted in resistance against chemotherapy by preventing apoptosis. Conclusions: The molecular subtypes differ largely in prognosis and response to chemotherapy. A treatment strategy combining standard drugs with agents suppressing TGF-β signaling might benefit C-type patients.
NHS recruitment from Europe is already falling because of Brexit, MPs are told
Authors: Adrian O’Dowd
Journal: BMJ (2017)

Workforce experts have warned of signs that healthcare staff from the European Union who were considering coming to work in the NHS are choosing not to do so because of uncertainty over Brexit.

EU staff seem less keen to come to work in the UK, employers are not launching their usual recruitment drives in the EU, and existing EU staff in the NHS are considering leaving, MPs on the parliamentary health committee were told.

At an evidence session for the committee’s inquiry into Brexit held on 21 February, MPs asked about the impact on recruitment and retention of health and care staff since the referendum last June, in which the public voted for the UK to leave the EU.

Giving evidence, Daniel Mortimer, chief executive of NHS Employers, which represents employers in …
Racial/ethnic disparities in hepatocellular carcinoma treatment and survival: Are we making progress?
Authors: Oxana V. Makarova-Rusher, Katerina A. Erokhina, Austin G. Duffy, Susanna Varkey Ulahannan, Tim F. Greten
Journal: Journal of Clinical Oncology (2015)

e17591 Background: Background: Curative treatments are less frequently used in racial/ethnic minorities with hepatocellular carcinoma (HCC) leading to worse survival. It is unknown if any progress was made in reducing these disparities in the past decade. Methods: Patients with HCC (histology 8170-8175, topography C22.0) were identified in SEER 18 database 2000-2011, analyzed by ethnicity/race (Hispanics and non-Hispanic (NH) whites, Asians, blacks and American Indians/Alaska Natives (AI/AN) and divided into 3 time intervals (2000-2003, 2004-2007, and 2008-2011). Treatment variables included curative (transplantation, resection, and ablation) and palliative. Statistical analysis was performed using Chi-Square and Kaplan-Meier tests. Relative survival (RS) was calculated to adjust for differences in background mortalities. Results: We identified 40148 patients with race/ethnicity as follows: NH whites (N 19584), NH Asians (N 7444), NH blacks (N 5228), NH AI/AN (N 443) and Hispanics (N 7449). The analysis showed that fewer NH AI/AN, NH blacks and Hispanics underwent curative treatments than NH whites. Racial disparities decreased for NH AI/AN but not for NH blacks and Hispanics over time (see Table). Less frequent use of surgery in Hispanics, ablation in NH blacks and transplantation in all minority groups were major contributing factors to treatment differences. The gain in median survival increase was less in NH blacks than in NH whites between 2000-2003 and 2007-2011 (NH blacks: 4 to 8 months, NH whites: 5 to 11 months). The difference (NH blacks vs NH white) in 3-year RS did not change in the same time period (12 (CI 10-14) vs 17% (CI 16-18) in 2000-2003 and 22 (CI 19-24) vs 27 % (CI 26-28) in 2007-2011). Conclusions: Over the last decade, little progress has been made in reducing unequal treatment for non-Hispanic blacks or Hispanics with HCC relative to non-Hispanic whites. Curative treatments were used less frequently in non-Hispanic blacks, AI/AN, and Hispanics. Notably, inferior survival was observed in non-Hispanic blacks with HCC. Race Curative treatment % 2000-2003 2008-2011 NH white (ref) 23 Difference from NH white 25 Difference from NH white NH AI/AN 14* 9 22* 3 NH black 18* 5 19* 6 Hispanic 17* 6 18* 7 *p^0.01 *p^0.01
Acceptance of sphincter-preserving surgery for T3 lower rectal cancer after short-course radiotherapy with delayed surgery.
Authors: Naohito Beppu, Hidenori Yanagi, Naoki Yamanaka, Hiroshi Doi, Norihiko Kamikonya, Masafumi Noda, Naohiro Tomita
Journal: Journal of Clinical Oncology (2014)

620 Background: One of the reasons for avoiding sphincter-preserving surgery for lower rectal cancer is difficulty in obtaining a sufficient distal margin. Short-course radiotherapy (SRT) with immediate surgery is not expected to reduce tumor volume, and currently available evidence suggests that it does not increase the sphincter-preservation rate. However, SRT with delayed surgery has been linked to downsizing of the primary tumor during the waiting period. We evaluated the feasibility of sphincter-preserving surgery for T3 lower rectal cancer after SRT with delayed surgery and examined whether a distal margin of ≤ 5 mm has an impact on oncologic outcomes. Methods: We retrospectively studied 161 consecutive patients with lower rectal cancer located below the peritoneum reflection who underwent radical surgery with total mesorectum resection (TME) 3 to 4 weeks after the completion of SRT. The median follow-up was 53.5 months. Results: Sphincter-preserving surgery was performed in 149 (92.5%) of the 161 patients. The procedures were as follows: double-stapling technique, 58 patients; intersphincteric resection, 91; abdominoperineal resection, 10; and Hartmann operation, 2. Among the patients who underwent sphincter-preserving surgery, the distal margin was ≤ 5 mm in 41 patients and &gt; 5 mm in 108. The local recurrence rate was respectively 5.8% vs. 10.4% (p = 0.606), the recurrence-free survival 83.4% vs. 82.8% (p = 0.682), and the overall survival at 5 years 82.3% vs. 87.6% (p = 0.418). Our results suggested that there is no difference in long-term outcomes between a distal margin of ≤ 5 mm and &gt; 5 mm. Conclusions: Sphincter-preserving surgery was performed in 92.5% of patients with T3 lower rectal cancer who received SRT with delayed surgery. Our results confirmed the long-term oncologic feasibility of sphincter-preserving surgery with a distal margin of ≤ 5 mm; there was no negative impact on long-term outcomes such as local recurrence, recurrence-free survival, and overall survival.
Effect of adjuvant treatments on quality of life in elderly patients with colorectal cancer: A population-based study
Authors: A. Bouvier, F. Bonnetain, V. Jooste, J. Faivre
Journal: Journal of Clinical Oncology (2008)

4051 Background: Quality of life (QoL) could be determinant to refute the misconception that the elderly are more prone to side effects and that advanced age limits the potential benefit of receiving adjuvant chemotherapy or radiotherapy. The aim of this study was to longitudinally assess the impact of adjuvant treatments on the QoL of colon and rectal cancer elderly survivors. Methods: The population-based Burgundy Digestive Cancer registry was used to select all patients older than 74 years with colorectal cancer from 2003 to 2005. Two hundred nine patients were asked to complete four QoL questionnaires over the first year after diagnosis (Q0: inclusion, Q3: at 3 months, Q6: 6 months and Q12: 12 months) using EORTC QLQ-C30. Then 125 (60%) responded. Mixed model analyses of variance for repeated measurement were used to compare QoL scores according to therapeutic schemes and interactions between time of follow-up and treatment were tested. A p value lesser than 0.05 was significant. Results: Sex, age at diagnosis, location of cancer and stage at diagnosis did not significantly differed between responders and none responders. Global health and emotional functioning increased for colon cancers between Q0 and Q12 and between Q3 and Q12 for rectal cancers. According to French adjuvant treatments recommendations, patients who received chemotherapy for stage III colon cancer (p=.176) or radiotherapy for rectal cancer (p=.959) unexpectedly reported no significant different global health than those not receiving adjuvant therapies. Patients treated with chemotherapy declared higher physical functioning than patients not treated (p=.0113) whatever follow-up. Physical functioning increased for patients who received radiotherapy between Q3 and Q6 (p=.021). Conclusions: This report is the first dealing with trends over time on the influence on QoL of adjuvant chemotherapy and radiotherapy for colon and rectal cancers in a general population of patients aged 75 and over. Providing evidence that colonic adjuvant chemotherapy have no negative impact on the QoL of elderly patients is of great importance to reinforce clinicians to treat this population. No significant financial relationships to disclose.
Diffuse large B-cell lymphoma: A single-institution experience of patient outcomes.
Authors: Ryan James Chan, Rasna Gupta, Sindu Mary Kanjeekal, Mohammed Jarrar, Amin Kay, John Mathews, Indryas Lemma Woldie, Caroline M. Hamm
Journal: Journal of Clinical Oncology (2016)

271 Background: The Windsor Regional Cancer Program (WRCP) was determined to have consistently been a top performer in time to treatment of diffuse large B cell lymphoma in this Canadian province (http://www.csqi.on.ca/by_type_of_cancer/lymphoma/lymphoma_treatment/). We endeavored to determine whether faster time to diagnosis and treatment for diffuse large B-cell lymphoma (DLBCL) influenced the IPI score (International Prognostic Score), thereby predicting an improved clinical outcome in these presenting patients. Methods: The WRCP services a catchment area of 650,000 people. A retrospective chart review was conducted for patients diagnosed with DLBCL at the Windsor Regional Cancer Program (WRCP) between 2006-2012. Information collected included the five factors for scoring by the International Prognostic Index (IPI) – age, performance status, LDH, stage, and number of extranodal sites – chemotherapy regimen, relapses, existence of second malignancies, cause of death, and dates of diagnosis, last follow-up, and death. We analyzed the relationship between prognostic factors and these clinical outcomes, and also compared the IPI scores for this cohort of patients against a similar population in another Canadian province, British Columbia. Results: It is established that compared to other cancer centres in Ontario, the WRCP is consistently reporting a shorter diagnosis to treatment metric when compared to their counterparts in Ontario, Canada. When compared to historical Canadian data, presenting IPI scores for DLBCL patients were lower on average for patients treated at the WRCP than those reported in British Columbia, Canada by Sehn et al. [Sehn, L. H., et al. (2007). The revised International Prognostic Index is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood, 109(5), 1857-1861.]. Conclusions: A lower presenting IPI score is known to be correlated improved lymphoma related outcome. With attention to the metric of diagnosis to treatment &lt; 30 days for diffuse large B cell lymphoma, we expect an improved lymphoma related outcome for our patients. We recommend ongoing attention to this metric, in order to improve outcomes for our patients.
Role of presurgery circulating cancer cells (CTCs) as a potential pronostic factor in patients (pts) with liver surgery (LS) of colorectal cancer (CRC) metastases (M).
Authors: Lucia Teijeira, Antonio Viúdez, Maria L. Antelo, Antonio Tarifa, Cruz Zazpe, Javier Herrera, Irene Hernandez, Ruth Vera
Journal: Journal of Clinical Oncology (2012)

518 Background: Kinetic behavior of perioperative CTCs in pts with liver CRC M has been little explored. The aim of this study was to quantified CTCs performance before, just performed and 3 months after radical LS in pts with CRC M and analyzed the surrogate role of CTCs determinations in DFS and OS. Methods: 7.5 ml of blood were drawn in CellSave tubes. CTCs were enumerated before, just performed and 3 months after radical LS. CTCs were immunomagnetically separated and fluorescently labeled using the CellSearch System (Veridex/Immunicon Corp.) Results: From February 2009 to August 2011, 30 pts with LS of CRC M were included. Median age was 59 (45-75); 63.3 % men. Kras status: 63.2% wild-type and 36.8% mutated; 46.7% with synchronous disease. Fong-Criteria (FC) distribution: 30% pts with 1 FC, 36.7% pts with 2 FC and 33.3% pts with 3 FC, of whom 56.7% received neoadjuvant (76.4% fluoropirimidines-based; 29% cetuximab-based; 47% bevacizumab-based) and 73.3% adjuvant treatment. PR and SD were observed in 68.8% and 31.3% of pts, respectively (100% DCR). In 83% of cases, limited LS were done (79.3% R0, median M resected: 2), 20% of pts with synchronous surgery of primary tumour. Of the 15 pts analysed, pCR were observed in 2 (13.3%) with 6 other pts (40%) with major pathological response. With a median of follow-up of 21 months, progression disease occurred in 9 pts (55.6% with liver progression), and 4 pts died. Median CTCs was 0 before (0-2: 85%; ≥3: 14.8%), just performed (0-2: 78%; ≥3: 21%) and 3 months after surgery (0-2: 94.1%; ≥3: 5.9%). DFS for pts with pre-surgery CTCs ≥3 was 10 months, and not reached for 0-2 CTCs group. OS has not been achieved in any CTCs group. In the multivariate analysis, with FC and pre-surgery CTCs, pre-surgery CTCs ≥3 tends to be an independent predictor of outcome (HR: 2.83; CI:0.53-15). Conclusions: Independently of neoadjuvant treatment, pre-surgery CTCs levels ≥3 could be a surrogate of short DFS in pts with LS of CRC M. Our study shown a slight increase in CTCs quantification after LS, instead a significant CTCs decrease was observed after adjuvant therapy. Role of radical LS in kinetic of CTCs should continue to be analysed in future studies.
Tumor marker expression is predictive of survival in patient with esophageal squamous cell cancer treated with definitive chemoradiotherapy
Authors: T. Kii, H. Takiuchi, S. Kawabe, M. Gotoh, S. Ohta, K.-I. Katsu
Journal: Journal of Clinical Oncology (2005)

4080 Background: This study was designed to determine the prognostic value of immunohistochemical tumor marker expression in a population of patients with esophageal squamous cell cancer (ESCC) treated with definitive chemoradiotherapy (CRT). Methods: Selection criteria for subjects were: 1) no previous treatment; 2) PS < 2; 3) age < 80, 4) UICC stage II or III; 5) no serious complication. Between 1995 and April 2003, 51 pts (Male/Female; 42/9, stage II/III; 18/33, T1–2/T3–4; 11/40, N0/1; 18/33) were treated with CRT (5-FU+CDDP+RT 60Gy). Biological tumor markers (p53, EGFR, VEGF, cyclin D1, PCNA) in a pre-treatment biopsy were investigated immunohistochemically. The Kaplan-Meier product limit estimator and the log rank test were used to describe the relationship between individual study variables and outcome. Variables that achieved statistical significance at p less than or equal to 0.05 in univariable analysis were then placed into multivariable models. Results: The CR rate after CRT was 53% (stage II/III; 61%/49%). Univariable analysis demonstrated a significant relationship between survival and the following variables: low-level VEGF expression (p=0.047), low-level PCNA expression (p=0.005), clinical T1–2 (p=0.012). Cox regression analysis including interaction-terms between survival and clinical and tumor markers showed that both low-level VEGF expression and low-level PCNA expression had large interactions with survival (p=0.007). Conclusions: This study supports the prognostic value of immunohistochemical tumor markers, specifically the expression pattern of VEGF and PCNA in patients with ESCC treated with CRT. No significant financial relationships to disclose.
Engaging managing physicians in clinical staging prior to the initiation of cancer treatment.
Authors: Anne Barry-Weers, Carol Huibregtse, Marija Bjegovich-Weidman, James L. Weese
Journal: Journal of Clinical Oncology (2016)

143 Background: Managing physicians (medical oncologist, radiation oncologist, surgeons) have a responsibility to clinically stage patients prior to the initiation of cancer treatment. Clinical staging not only directs the treatment plan, but identifies appropriate clinical trials and estimates prognosis. We sought to determine whether engagement of managing physicians would result in increased clinical staging for various types of cancer. Methods: Baseline data on clinical staging for breast, colorectal (colon, rectal, anal, rectosigmoid junction)*, thoracic (lung esophageal)†, genitourinary (prostate, penis, testes)‡, and pancreatic primary cancers were obtained. The data were grouped by disease type and sub-specialty of the managing physicians. Based on that data, several performance improvement initiatives were implemented to provide managing physicians the opportunity to clinically stage the cancer patient prior to the initiation of treatment. The initiatives for completing and documenting staging were: a tutorial on use of Problem List in the electronic medical record (EMR); modification of history &amp; physical and consult notes to include a field for staging; sharing among sub-specialties the smart lists within the template to allow for customization of existing templates; and 1:1 review with physicians who had outliers without clinical staging. Results: Clinical staging documented prior to the initiation of cancer treatment significantly increased in all five types of cancers studied (p &lt; .01; Table). Conclusions: Though collaborative efforts by managing physicians continues to evolve, in many cases, use of the electronic medical record through a variety of performance improvement initiatives has facilitated documentation of clinical staging of cancer patients prior to the initiation of treatment. This engagement changed practice patterns, aligned our institution with best practice guidelines and aided in treatment selection for the best possible patient outcomes. [Table: see text]