tbuckley/cabot-search huggingface dataset:
Molecular analysis of osteopontin and STAT3 in luminal and triple-negative/basal-like immunophenotypes of breast carcinoma.
Authors: F. Ortiz-Martinez, F. J. Gutierrez-Aviño, D. Giner, E. Adrover, D. Ciprian, F. I. Aranda, E. Lerma, G. Peiro
Journal: Journal of Clinical Oncology (2011)

e11079 Background: Osteopontin (OPN) plays a role in the growth, progression and metastasis of cancer. Similarly, deregulation of the signal transducer and activator of transcription (STAT)3, a member of the Jak/STAT pathway, has been associated with neoplastic transformation. Recently, it has been suggested that OPN may regulate STAT3 signaling, leading to tumor progression and inhibition of apoptosis in breast cancer (BC) cells. Therefore, the aim of this study was to analyze OPN and STAT3 mRNA expression in a series of BC of luminal and triple-negative (TN)/basal-like immunophenotypes. Methods: We performed an immunohistochemical study in a series of 440 BC. Then, we selected 248 specimens classified as luminal (ER/PR-positive and HER2-negative) (n= 141; 57%) and TN/basal-like (ER/PR/HER2-negative +/- CK5/6 +/- EGFR) (n= 107; 43%) subtypes. Total RNA was isolated from 2-3 paraffin-embedded cylinders from preselected tumor areas and retrotranscripted to cDNA. RT-qPCR was performed by Syber Green to study the mRNA expression levels of total OPN and STAT3. Primers were tested in triplicate; RT minus and two commercial positive controls (total human and BC RNA) were included. Quantification was normalized to β-actin gene (Spearman rank correlation coefficient: r=0.82; p<0.05). Relative mRNA expression levels were carried out using the ΔΔCT method. We correlated statistically the molecular results and stratified by immunophenotypes (Chi-square and Fisher’s exact tests). Results: OPN and STAT3 mRNA overexpression (>2 fold change) was detected in 58% and 68% BC, respectively. Co-expression was seen in 40% cases with a positive predictive value (PPV) of 70% (p=0.2). However, we found no differences after stratification of the results by immunophenotypes: 33% in luminal and 46% in TN/basal-like (p=0.22). Conclusions: In our series, co-expression of OPN and STAT3 was detected in a subset of BC, supporting the regulatory role of OPN. Moreover, the fact that there was no difference among luminal and TN/basal-like phenotypes suggest that OPN control of the Jak/STAT pathway is independent of the tumor hormone receptor status. Supported by grants FCVI-HGUA/2008-PC and ACOMP/2009/195.
Performance-based physical function in long-term survivors of Hodgkin lymphoma.
Authors: K. K. Ness, M. Metzger, T. T. Huang, G. T. Armstrong, L. L. Robison, M. M. Hudson
Journal: Journal of Clinical Oncology (2011)

9532 Background: Survivors of pediatric Hodgkin lymphoma (HL) are at increased risk for late effects including loss of physical function, which may interfere with an active lifestyle. The aims of these analyses were to describe the prevalence of physical performance limitations, and to determine associations between treatment exposures and long-term functional loss. Methods: Clinical assessment including measures of ankle flexibility and strength, quadriceps strength, and walking endurance were completed in HL survivors 10+ years from diagnosis. Those with ankle motion < 5 degrees of dorsiflexion (required for foot clearance during walking), and isokinetic strength or distances on the six minute walk in the lowest 10th percentiles of age/sex predicted norms were classified as having severe limitations. The prevalence of severe loss was calculated for each measure. Associations between HL treatment and functional loss were evaluated in regression models. Results: Among the first 196 eligible HL participants randomly recruited to participate in a large cohort study, 188 (median age 40 (26-61) years; median time since diagnosis 26 (11-45) years) completed the performance measures. Severe limitations were present in ankle motion for 29.0%, ankle strength for 22.3%, quadriceps strength for 21.8%, and endurance for 31.9% of survivors. Among those with severe limitations, 53.3% had limitations on 2+ performance measures. Those treated with vinca alkaloids had mean ankle dorsiflexion age/sex specific z-scores of -0.35±1.0 vs. 0.19±1.3 (p=0.007) among those not exposed. Mean quadriceps z-scores were -0.45±1.0 among those exposed to vinca alkaloids vs. -0.29±0.97 (p=0.01) among those not exposed. After adjusting for anthracycline and radiation exposure, those treated were 2.4 (95% CI 1.1-5.2) times more likely than those not treated with glucocorticoids to have poor endurance. Conclusions: Severe physical performance limitations are present in 20-30% of long-term HL survivors. Exposure to vinca alkaloids and glucocorticoids are associated with decreased strength and walking ability, respectively. Losses in lower extremity motion and strength, and in sustained walking ability, may provide targets for intervention.
The use of plasma microRNAs to predict toxicty following liver stereotactic body radiation therapy.
Authors: Kyle Clifford Cuneo, Yilun Sun, Matthew J Schipper, Muneesh Tewari, Theodore Steven Lawrence, Mary Uan-Sian Feng
Journal: Journal of Clinical Oncology (2016)

245 Background: Stereotactic body radiation therapy (SBRT) is an effective treatment for patients with hepatocellular carcinoma or liver metastases. Predictive biomarkers for liver toxicity would allow for careful patient selection and the adaptation of therapy. Prior studies have shown specific miRNAs are elevated prior to clinical signs of toxin induced liver injury. We hypothesized that miRNAs can be used to predict radiation induced liver toxicity prior to clinical manifestations. Methods: As part of an IRB approved clinical trial (NCT01522937) patients with liver tumors underwent a split course of SBRT. All patients underwent liver function testing using indocyanine green clearance (ICG) followed by three SBRT fractions. One month later ICG was reassessed and two more fractions were given if the patient did not have a decline in liver function. Plasma samples were obtained at baseline and 1 month after finishing three of five SBRT fractions for 89 patients. For this exploratory analysis, we selected the 10 patients that had a 2+ point increase in Child-Turcotte-Pugh score within 6 months of completing therapy and 19 additional patients without toxicity. The levels of 752 miRNAs were quantified for each sample using qPCR. We then used a univariate tree based classifier and the elastic net with 10-fold cross validation to calculate the AUC for predicting liver toxicity in individual and small groups of miRNAs, respectively. Results: Several miRNAs were found to be potentially predictive of toxicity on univariate tree based classifier analysis including the liver specific microRNA miR.122.3p, the epithelial specific miR.141.3p and miR.200b.3p, the neuroendocrine related miR.375 and miR.217, and miR.125a.5p which plays a role in hepatitis and regulates ERBB2 and ERBB3 signaling. The elastic net model achieved a conservative AUC estimate of 0.74 +/- 0.04 using 69 baseline miRNAs and 0.76 +/- 0.06 using 11 mid-treatment miRNAs to predict toxicity. Conclusions: Our preliminary analysis of the miRNAome from 29 patients receiving liver SBRT shows promising results for the ability of these markers to select patients at risk for radiation induced liver toxicity. Further validation in a larger patient cohort is needed. Clinical trial information: NCT01522937.
Definitive treatment of localized prostate cancer: Time and geographic trends.
Authors: Jonathan D. Tward, Lindsay Burt, Dennis C. Shrieve
Journal: Journal of Clinical Oncology (2015)

132 Background: Numerous definitive treatment options exist for localized prostate cancer. We evaluated how the distribution of treatments varied by geographic location and over time in a contemporary US population database. Methods: All subjects with NCCN clinical risk-stratifiable localized prostate cancer between the years 2004 and 2011 were identified in the Surveillance Epidemiology and End-Results Database. Descriptive statistics evaluating the relative distribution of therapies by geographic region and over time were performed. Results: There were 290,631 evaluable subjects identified. The Table shows trends in treatment over time for combined low, intermediate, high, and very high risk prostate cancer. The use of brachytherapy has been significantly declining between 2004 and 2011, and no definitive therapy has been increasing. In 2010-2011, regional prostatectomy use varied from a low of 18% (Rural Georgia) to a high of 57% (Iowa). No definitive therapy rates varied between 12% (Hawaii) and 35% (Rural Georgia). Analyses of regional variation at the State County level reveals significant variability in the ratio of subjects receiving surgery to radiation (e.g., State of Utah surgery:radiation ratio 0.25 (Beaver County) versus 3.06 (Toole County). Conclusions: There is marked regional variation of practice at both the county and state levels for localized prostate cancer definitive therapy. The use of radiotherapy has been declining between the years 2004 and 2011, and appears to be offset by increases in no definitive therapy. Prostatectomy rates remained stable. [Table: see text]
Telehealth for oncology genetic counseling: An Idaho experience.
Authors: Jennifer N. Eichmeyer, Dan Sayam Zuckerman, Thomas M. Beck, Nicolas Camilo, Kevin Mark, James Barbera, Nicole Bradshaw, Brett Greenburg, Devan Johnson
Journal: Journal of Clinical Oncology (2012)

288 Background: Access to qualified genetics specialists continues to be a barrier for patients in rural settings. Our institution aimed to develop a proof-of-concept telehealth program that supports the vision of transforming the way healthcare is delivered specific to Idaho. Methods: Based on a needs assessment with 40 direct caregivers the program was designed to eliminate inconsistency and variation through the system and expand the specialty care footprint from the tertiary care hospital. To gain traction, specific areas (genetic counseling and nutritional counseling) were identified that could move forward with telehealth. This small-scale implementation could be rapidly executed using few system resources while providing feedback for future refinement and expansion. Technology needs included, Microsoft Lync, a HD web camera, USB speaker/microphone, dual monitors, and a document camera to be added to workstations for the provider. A transportable cart with computer and dual monitor workstation was assembled for the outreach site with the same technology components. The metrics chosen to track the benefits of this service included: provider travel time and costs, elapsed time from referral to first scheduled appointment, comparison of patient volumes, and patient satisfaction. Satisfaction measures were collected by written questionnaires and interviews with the patient. Results: During a 3-month period 23 genetic counseling appointments were conducted by telehealth. This resulted in a savings of $1050.63 in mileage and travel wages and 13.5 travel hours. Wait times for appointments dropped from 23 days to 16 days, and appointment volumes increased from 6/month to 8/month. Access to services increased from 8 hours per month to 16 variable hours per month with the availability of immediate needs appointments. Patient scores (N=12) demonstrated “Excellent” ratings (5/5) in the following: 83% satisfaction using the telehealth cart, 83% likelihood to use telehealth again, and 92% recommend telehealth to a friend. Conclusions: Improved convenience, access, and cost savings while providing high quality care were maintained using telehealth. Expansion of the program to another outreach site has already been approved by leadership.
Phase I study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase inhibitor, entinostat, in patients with metastatic renal cell carcinoma: Safety and tolerability results.
Authors: Roberto Pili, Li Shen, Saby George, Hans J. Hammers, Anita Sandecki, Connie Collins, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2013)

369 Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor activity in different malignancies and to induce immuno-modulatory effects. We have previously reported that a class I selective HDAC inhibitor, entinostat, has synergistic anti-tumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model (Kato Y, et al. Clinical Cancer Res 2007). Our group has also recently shown that low dose entinostat induces STAT3 acetylation, down-regulates Foxp3 expression in Tregs, and blocks Tregs suppressive function without affecting T effector cells (Shen Li, et al. PLoSONE 2012). Methods: Based on these preclinical evidences, we have initiated a Phase I/II clinical study with entinostat and high dose IL-2 in patients (pts) with metastatic renal cell carcinoma. The primary objective of the phase I portion was to evaluate the safety and tolerability of this combination strategy. The main eligibility criteria were clear cell histology, no prior treatments, and being fit to receive high dose IL-2. Results: The phase I portion consisted of two dose levels of entinostat (3 and 5 mg) and a fixed standard dose of IL-2 (600,000 units/kg every 8 hrs) according to a 3+3 design. To date, dose level one and two have been completed without DLTs. No severe adverse events have been observed during the first 45 days of treatment. The most common transient grade 3/4 toxicities were hypophosphatemia and thrombocytopenia (6 pts), neutropenia and lymphopenia (2 pts). The 5 mg dose level has been expanded. To date we have enrolled eight eligible pts and six have completed one cycle (84 days) treatment with four achieving objective responses by RECIST criteria. Decreased Tregs and increased CD8 numbers have been observed in tumor biopsies following treatment. Conclusions: The results from the phase I portion suggest that entinostat can be given safely in combination with high dose IL-2. Preliminary results also show encouraging biological and efficacy data (R21CA137649; U0-1CA70095). Clinical trial information: NCT01038778.
The effect of postoperative morbidity on survival after resection for gastric adenocarcinoma: Results from the U.S. Gastric Cancer Collaborative.
Authors: Linda X. Jin, Lindsey E. Moses, Yan Yan, Malcolm Hart Squires, Sharon M. Weber, Mark Bloomston, George A. Poultsides, Konstantinos I. Votanopoulos, Timothy M. Pawlik, William G. Hawkins, David Linehan, Steven M. Strasberg, Alexandra W. Archer, Aslam Ejaz, David A. Kooby, Carl Richard Schmidt, Doug S. Swords, David J. Worhunsky, Shishir Kumar Maithel, Ryan C. Fields
Journal: Journal of Clinical Oncology (2014)

5 Background: The negative impact of postoperative complications (POCs) on survival is well documented for many cancer types, but has not been well described in gastric cancer. Here, we evaluated the effect of POCs on survival after surgery for gastric cancer in a cohort of patients from a multi-institutional database. Methods: Patients who underwent surgery with curative intent for gastric adenocarcinoma between 2000-2012 from participating institutions of the U.S. Gastric Cancer Collaborative were analyzed. Patients who died within 30 days of surgery were excluded. Ninety-day postoperative complication data were collected. Survival probabilities were estimated by Kaplan-Meier analysis and compared using the log-rank test. Results: A total of 853 patients from seven institutions met inclusion criteria. Median follow-up was 32 months. The overall complication rate was 40% (n=344). The most frequent complications were: infectious (25%, including surgical site infection [8%]), and anastomotic leak (6%). 7% of patients underwent reoperation during the same hospitalization. Five-year overall survival (OS) for patients without perioperative complications was 54%, compared with 39% for patients with POCs (p=0.001). Disease free survival (DFS) at five years was 61% for patients without POCs compared to 49% in patients with POCs (p=0.002). Patients without POCs were significantly more likely to receive adjuvant therapy (55% vs 42%; p&lt;0.001). Conclusions: In a large, multi-institutional cohort, POCs were associated with decreased survival in patients undergoing surgery for gastric adenocarcinoma. This may be due, in part, to the negative impact of complications on the receipt of adjuvant therapy. Efforts aimed at reducing perioperative morbidity are important not only for short-term surgical outcomes, but also for enhancing long-term oncologic outcomes in patients with gastric cancer. [Table: see text]
A model of early integration of palliative care into oncology care for patients with metastatic colorectal cancer.
Authors: Carling Jade Ursem, Laura Cantino, Ingrid Maravilla, Nicole Thompson, Chloe Evelyn Atreya, Kara Bischoff
Journal: Journal of Clinical Oncology (2016)

142 Background: Current NCCN guidelines recommend that “institutions should develop processes for integrating palliative care into cancer care.” However, it is not clear what the best method is for implementing this integrated care. Palliative care needs specific to patients with metastatic colorectal cancer (mCRC) and best practices for integration of outpatient palliative and oncologic care in mCRC are not well understood. Methods: We conducted a pre-post prospective cohort study to evaluate the palliative care needs of mCRC patients and the implementation of an integrated palliative care program. In both the control and implementation phase, we enrolled patients with mCRC within 90 days of diagnosis or establishing care for mCRC at UCSF. Patients were surveyed regarding their symptoms, quality of life, psychosocial concerns, functional status and understanding of prognosis. During the control phase, patients received usual oncologic care. Based on survey results from the control phase, we designed a palliative care program to target the needs identified. In the intervention phase, patients are receiving longitudinal palliative care integrated into their usual cancer care. Results: The 30 patients in the control phase reported anorexia, fatigue and poor quality of life as their most common symptoms. Common psychosocial challenges were transportation, insurance/financial and difficulty with treatment decisions. Patients also had unrealistic expectations of their prognosis. In order to improve these identified issues, we designed and implemented an integrated palliative care program that includes weekly multidisciplinary meetings with oncology and palliative care providers and proactive palliative care visits from the time of diagnosis, which occur within the oncology clinic at a time that coincides with oncology visits. Conclusions: Physical symptoms, psychosocial concerns and poor prognostic awareness are common among patients with mCRC. We have implemented an integrated palliative care program to address these needs. Evaluation of the effectiveness of this intervention is ongoing.
Outcomes in elderly patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.
Authors: Cora N. Sternberg, Johann Sebastian De Bono, Kim N. Chi, Karim Fizazi, Peter Mulders, Mohammad Hirmand, David Forer, Howard I. Scher
Journal: Journal of Clinical Oncology (2013)

16 Background: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway (Tran et al, Science. 2009;324:787). The phase III AFFIRM trial demonstrated that ENZA increased median overall survival (OS) by 4.8 months with a 37% reduction in the risk of death (P &lt;0.001, HR 0.63) vs placebo (PBO) in post-docetaxel mCRPC patients (pts) (Scher et al, NEJM 2012; 367:1187). In a post-hoc analysis, the effect of ENZA on outcomes in elderly (≥ 75 yrs) vs younger (&lt; 75 yrs) pts in the AFFIRM trial was assessed. Methods: The AFFIRM trial was a Phase III multinational, randomized, double-blind study in post-docetaxel mCRPC pts. Randomization was 2:1 to ENZA 160 mg/day or PBO, stratified by baseline ECOG performance status and mean pain score. Statistics are presented by age group (≥75, yrs &lt;75 yrs) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), and time to prostate-specific antigen (PSA) progression. Top line safety results are also presented for both age groups. Results: Elderly pts comprised 25% (199/800) of ENZA pts and 26% (104/399) of PBO pts. Improved outcomes with ENZA treatment were observed in both elderly and younger pts, with similar safety profiles in each age group. Conclusions: ENZA significantly improved outcomes in both elderly (≥ 75yrs) and younger pts (&lt; 75yrs). Safety and tolerability findings were comparable between the two age groups. Clinical trial information: NCT00974311. [Table: see text]
Tumor Associated Macrophage Expression, CD163, Is Associated with Poorer Outcome in Diffuse Large B-Cell Lymphoma
Authors: Olga L. Bohn, Jocelyn C. Maragulia, Hilda Crispin, Camille Gonzalez, Cornelius Miething, Andrew D. Zelenetz, Julie Teruya-Feldstein
Journal: Blood (2012)
NHS trusts face £900m deficit amid winter pressure
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Record levels of demand for hospital treatment this winter have left England’s NHS trusts struggling to meet financial targets and facing a combined end of year deficit of almost £900m (€1bn; $1.1bn).

The regulator NHS Improvement, which published the figures for the third financial quarter of 2016-17,1 said that hospitals had experienced “one of the toughest winters on record.”

The NHS Confederation, which represents most NHS organisations, said that “real suffering for patients and exhausted staff” lay behind the headline figures, and it urged the government to invest more money in social care services in the upcoming budget to help ease pressure on the NHS.

The figures show that NHS trusts are on course …