tbuckley/cabot-search huggingface dataset:
PARP-1 inhibitor MK-4827 in combination with radiation as a treatment strategy for metastatic neuroblastoma.
Authors: S. Bhargava, S. Mueller, L. Wehmeijer, X. Yang, A. Gragg, K. K. Matthay, W. A. Weiss, D. A. Haas-Kogan
Journal: Journal of Clinical Oncology (2011)

9559 Background: Metastatic neuroblastoma continues to carry a dismal prognosis. Radiation is an important part of the treatment for these patients and PARP inhibitors have been shown to radio-sensitize cancer cells. We hypothesize that the PARP inhibitor MK-4827 will radio-sensitize neuroblastoma cells and lead to a survival benefit in an in vivo model of metastatic neuroblastoma. Methods: Clonogenic survival assays were performed in four human neuroblastoma cell lines [Kelly, NB1691, SY5Y, Tet21(Myc-N expressed) and Tet21 (Myc-N suppressed)] with MK-4827 as a single agent and in combination with radiation. PARP activity in the presence of MK-4827 was assessed at varying concentrations and time points by a PARP activity assay (Trevigen, Inc.) as well as by western blot analysis of Poly-ADP-ribose. Phosphorylated H2AX, a marker of DNA strand breaks, was determined by FACS. In vivo activity of MK-4827 as a single agent and in combination with radiation was assessed in a murine metastatic neuroblastoma model using luciferase modified NB1691 cells. Survival benefit was assessed by Kaplan-Meier estimates. Results: Clonogenic survival assays revealed dose-dependent cytotoxic effects in all neuroblastoma cell lines with IC50 values ranging from 13-38 nM, an effect that was significantly enhanced by radiation. Maximal PARP inhibition of approximately 60% was obtained within 1 hour of MK-4827 administration, and was sustained for 48 hours. Phosphorylated H2AX remained elevated for significantly longer time periods in cells treated with MK-4827 and radiation compared to radiation treatment alone. Mice treated with a combination of MK-4827 and radiation showed significantly reduced tumor burden (p<0.01) and longer survival (p<0.01) compared to mice treated with MK-4827 as single agent. Conclusions: The PARP inhibitor MK-4827 cooperates with radiation to enhance cell death of neuroblastoma cells in vitro. Combination of MK-4827 with radiation decreases tumor burden and prolongs survival in a metastatic neuroblastoma model in vivo. MK-4827 in combination with radiation appears to be a promising new therapy for treatment of metastatic neuroblastoma.
Does insurance coverage affect pancreatic cancer survival? The Medicare age threshold.
Authors: J. K. Smith, J. Dimick, E. R. Witkowski, E. Ragulin-Coyne, T. P. McDade, S. C. Ng, Z. Zhou, J. F. Tseng
Journal: Journal of Clinical Oncology (2011)

6124 Background: The independent effect of health insurance on cancer outcomes is controversial. In the US, the rate of insurance coverage increases substantially at age 65 because of access to Medicare. While overall cancer patient survival is expected to diminish with increasing age, we hypothesized that reaching the threshold of 65 years might improve pancreatic cancer survival. Methods: Data from Surveillance, Epidemiology, and End Results (SEER), 2000-2005 was used to identify all patients with pancreatic cancer. The cohort was then restricted to patients aged 60-70 years old to allow for analyses centered around 65, the age of general Medicare eligibility. Overall median survival was calculated by year of age for the entire cohort, as well as for the subset that had undergone cancer-directed surgery. Kaplan-Meier survival analyses were performed. Median survival trend and potential discontinuity were tested using ARIMA modeling. Results: Overall, 6,035 patients aged 60-70 years old at the time of pancreatic cancer diagnosis were identified. Mean age of this cohort was 65.4 years old. On analysis of median survival per year of age, observational trends demonstrated decreasing survival with increasing age until age 64; at age 65, survival time increased, and then slowly decreased again over time (Table). In contrast, analysis of the subset of the cohort that had undergone cancer-directed surgery revealed no significant differences in survival over ages 60-70. Conclusions: In pancreatic cancer, the age of 65 years, when near-universal insurance takes effect, is a positive inflection point for overall survival. Further studies to examine the influence of insurance coverage on cancer outcomes is warranted. Age at diagnosis (years) Median survival (months) % change 60 7 61 7 0 62 6 -14.3% 63 6 0 64 5 -16.7% 65 6 20% increase 66 6 0 67 5 -16.7% 68 5 0 69 4 -20.0% 70 4 0
Association of skin rash severity and overall survival in patients receiving erlotinib for pancreatic cancer in the community setting.
Authors: E. J. Stepanski, C. M. Reyes, M. S. Walker, S. Satram-Hoang, L. Leon, S. Wojtowicz-Praga, P. J. Miller, L. S. Schwartzberg
Journal: Journal of Clinical Oncology (2011)

e14508 Background: Erlotinib (E) with gemcitabine (G) has been shown to improve survival in pancreatic cancer (PC) compared to G alone. Clinical trial results have also shown that PC patients treated with E who experience grade ≥2 rash had longer median survival than patients with grade <2 rash. We examined whether the association of rash with survival in this population extends to patients treated in the community setting. Methods: This was a retrospective study of existing data drawn from the ACORN Data Warehouse. Eligible patients were those diagnosed with PC at any stage, age ≥18, who received E with G, and ≥7 days of E. Demographic, disease and treatment characteristics were extracted from the medical record. Rash status, defined at landmark was assessed through medical record review, with rash severity classified as High (“moderate” or “severe” in the medical record) vs. Low (“mild”, “no evidence”, or not mentioned). Kaplan Meier analysis assessed survival by rash status from a landmark of 42 days after treatment initiation. This landmark was chosen based on the time to objective rash onset, date of typical first response assessment, and patient self-report of rash severity collected as part of routine care. Cox regression assessed the association of rash status as a time varying covariate (before vs. after onset of High severity rash) with survival. Results: Of 174 patients enrolled, 6 died or were lost to follow-up before the 42 day landmark, leaving 168 (34 high severity, 134 low severity) eligible for landmark analysis. Patients were 48.3% female, 71.3% Caucasian, with mean age of 67.2 (SD=10.5), and mean body mass index (BMI) of 25.8 (SD=5.7). High severity rash patients were more likely than Low severity patients to be Caucasian (85.3% vs. 68.7%, p= 0.05), and to have higher BMI (28.7 vs. 25.3, p = 0.002). Landmark analysis showed longer median survival for the High severity group (9.0 vs. 6.4 months from treatment start; Log rank p = 0.0339). Cox regression showed high severity rash status to be significant in predicting survival (HR = 0.67, p = 0.0389). Conclusions: Occurrence of moderate to severe rash among patients treated with E in the community is associated with longer survival in patients with PC.
Bridging therapy effectiveness in the treatment of hepatocellular carcinoma prior to orthotopic liver transplantation.
Authors: Maria M Zlobinsky Rubinstein, Andreas Kaubisch, Milan Kinkhabwala, John Reinus, Qiang Liu, Jennifer W. Chuy
Journal: Journal of Clinical Oncology (2016)

401 Background: Orthotopic liver transplantation (OLT) is the only curative intervention for both hepatocellular carcinoma (HCC) and underlying cirrhosis. OLT is limited by both donor organ shortages and long waitlists for transplant. In order to halt tumor progression, various bridging therapies (BT) have been utilized. Despite complete radiologic responses following BT, viable tumor is often present on explant analysis. We present an update of our experience and include novel bridging modalities. Methods: 35 patients were retrospectively evaluated in a transplant center prior to OLT for HCC. A total of 68 locoregional therapies were utilized. Success of BT was assessed by radiologic response and histopathological examination of the explanted livers. Results: 61 nodules were studied in liver explants. Pre-transplant treatments included: TACE, alcohol ablation (ETOH), radiofrequency ablation (RFA), microwave ablation, selective internal radiation therapy (SIRT) and stereotactic body radiation therapy (SBRT). Radiologically, 36 nodules (59 %) achieved complete response compared to 20 nodules (33%) on explant analysis. Approximately 1/3 of treated nodules with complete tumor necrosis (CTN) were treated with TACE + RFA. 60% of nodules (12/20) with CTN were treated with more than one bridging modality. 75% of nodules (3/4) treated with SIRT alone showed CTN. Patients underwent a mean of 2.2 BT. Four out of 35 (11%) patients had no residual HCC on explant analysis. Conclusions: Although favorable radiologic responses are seen following BT, viable HCC is often seen in liver explants. Newer strategies like SIRT may enhance locoregional control and should be explored as part of an aggressive approach for patients awaiting transplant. [Table: see text]
Dose calculation and tolerability of adjuvant AUC 7 carboplatin in 100 patients with stage I seminoma.
Authors: Umberto Basso, Alberto Diminutto, Franco Morelli, Ugo De Giorgi, Alessandra Perin, Anna Paola Fraccon, Giovanni Lo Re, Anna Rizzi, Teodoro Sava, Francesca Valcamonico, Fable Zustovich, Francesco Massari, Marco Maruzzo, Elisa Zanardi, Filiberto Zattoni, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2014)

374 Background: Administration of carboplatin AUC 7 has become a standard adjuvant option to be discussed with pts following orchiectomy for stage I seminoma, as alternative to radiotherapy on retroperitoneal lymphnodes or observation. The toxicity of AUC 7 carboplatin appeared manageable in the pivotal trial by Oliver et al. (Lancet, 2005), but dose ranges were not reported. Oncologists use different methods to estimate GFR and to calculate this unusually high dosage of carboplatin, and fear of toxicity may induce arbitrary dose reductions and potentially compromise the outcome. Methods: In 9 Italian centers we conducted a retrospective review focusing on adjuvant carboplatin administration to stage I seminoma pts. Modality of dose calculation, dose reductions and toxicities were recorded. Results: Since August 2006, 100 pts have been treated, median age 35 years (range 26 to 58). Adverse prognostic factors were either T &gt;4 cm (14% of pts) or rete testis invasion (32), both (36), none or unspecified (18). Glomerular Filtration Rated was estimated mainly by Cockroft-Gault formula (55% of pts), Jeliffe formula (27%), 24-hour urine collection (17%), MDRM (1%): median value was 106 ml/min (range 75 to 209). All Oncologists declared to use Calvert formula to calculate AUC 7 dose, and administered a median of 900 mg of carboplatin (range 690 to 1535). A dose reduction &gt; 10% was prudentially applied to 15% of pts; a second cycle was delivered in 8 pts. Acute toxicities are outlined in table 1. After a median follow-up of 20 months, 6% of patients have relapsed (all in the retroperitoneum), none of whom had been treated with reduced dose. Conclusions: AUC 7 carboplatin dosage peaked 1,535 mg in our cohort of stage I seminoma patients with no infections and nephrotoxicity, moderate nausea-vomiting, but 5% of grade 3-4 thrombocytopenia. Prudential dose reductions appeared unfrequent and should be proscribed. [Table: see text]
A breast analytics dashboard to allow near-real-time visualization of quality assurance data.
Authors: Mia Alyce Levy, Jeremy Warner, Neal Sanders, Pam Carney, Joy Pratt, Jared Cobb, Ariadne Taylor, Michael N. Neuss
Journal: Journal of Clinical Oncology (2014)

186 Background: Quality metrics for internal use (e.g. quality improvement; quality assurance [QA/QI] activities) and external use (e.g. accreditation; national quality reporting) are currently primarily obtained through retrospective manual data abstraction on subsets of patients, at a majority of cancer centers. Real-time QA/QI of all patients is attractive but requires collection of electronic data from disparate clinical systems that are rarely fully interoperable. We developed a dashboard to aggregate relevant clinical information in near real-time for QA/QI visualizations. Methods: Tableau® software was used to visualize data from multiple clinical systems at Vanderbilt University Medical Center (VUMC). Custom extract, transform, and load (ETL) processes were developed to collect radiology, pathology, professional billing, and clinical data on a daily basis. An integrated dashboard was developed through an iterative process involving physicians, nurses, and software engineers. As a pilot project, data from all patients with an image-guided breast biopsy obtained at VUMC from 2009-2013 was visualized. Results: 4177 biopsies were included in the visualized cohort as of June 2014. 3,210 (77%) of the biopsies were preceded by a BiRADS 4 or 5 mammogram. The annual biopsy rate increased by 51% over the time period. Despite this increase in volume, the median number of weekdays from BiRADS 4 or 5 mammogram to image-guided biopsy was stable at 5 days over the time period. Prior diagnosis status, lesion class, procedure type, and imaging exam type were also included in the dashboard. Conclusions: This pilot project demonstrates the ability to visualize near real-time clinical data for QA/QI purposes. Tableau® is interactive, so that certain patterns (e.g. the distribution of number of days from screening mammogram to biopsy) can be explored at a granular level. This functionality also allows the user to investigate why 23% of patients had no apparent imaging before biopsy. Based on a perceived pattern of delayed biopsy in certain outliers, QI efforts at VUMC are underway to ensure timely biopsy. Interactive visual dashboards such as the one described present opportunities to rapidly cycle QA findings into QI actions.
The role of post-cystectomy radiation in treatment of squamous cell carcinoma of the bladder: A combined retrospective analysis.
Authors: Baoqing Li, Alexander Michael Stessin, Dattatreyudu Nori
Journal: Journal of Clinical Oncology (2013)

259 Background: Squamous cell carcinoma (SCC) is the most common nonurothelial histology in bladder cancers. Given the high locoregional recurrence as the primary cause of death, radiation therapy (RT) is often recommended in the post-operative setting. Large-scale randomized trials that are dedicated to bladder SCC would be difficult to accrue to adequate numbers. Therefore, we utilized the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The SEER (1998-2007) was queried for patients with muscle-invasive (stage II-IV) squamous cell carcinoma of the urinary bladder who underwent complete cystectomy. Kaplan-Meier survival analysis and Cox regressions were used to assess survival outcomes. Additionally, records were reviewed for patients treated at New York Presbyterian Hospital-Weill Cornell Medical College (NYP-WCMC) between 1991 and 2010. Results: A total of 331 patients from the SEER were included in the analysis; Majority were received cystectomy alone (n=297), while 10% (n=34) received post-operative RT. Factors associated with post-operative RT were younger age (p=0.03) and more advanced stage at diagnosis (p&lt;0.001). Median survival was 40 months for patients treated with surgery alone and 18 months for post-operative RT (p&lt;0.05). In the institutional record review, 17 patients underwent cystectomy; of these, 5 received post-cystectomy RT. Those who underwent post-operative RT had better performance status (80% vs 25%) and a higher rate of positive surgical margins (67% vs 20%). Median survival was 38 months for patients treated with surgery alone and 22 months for post-op RT. Conclusions: RT has been employed as a post-operative treatment for some patients with muscle-invasive SCC of the urinary bladder. Younger age, better performance status, advanced stage, and positive margins may prompt the use of post-operative RT. However, both SEER and single institution retrospective analyses failed to show any survival advantage associated with the use of post-operative therapy. Further studies are needed to identify any subsets of patients with bladder SCC who may benefit from post-cystectomy radiation.
Cancer symptom scale preference: One size to fit all?
Authors: Brenda O'Connor, Kirby Jeter, Siobhan Blackwell, Lucy Burke, Emma Victoria Conway, Catherine Moran, Iseult Cremen, Pauline Ui Dhuibhir, David Joyce, Declan Walsh
Journal: Journal of Clinical Oncology (2015)

69 Background: Systematic assessment in cancer is conducted by a variety of instruments. Such assessment is important as comprehensive instruments detect more symptoms than casual clinical evaluation. In choosing assessment scales for polysymptomatic cancer patients one must consider the burden of assessment to ensure satisfactory completion rates. This study investigated patient preference and clinical utility of symptom assessment scales. Methods: A prospective survey was conducted in an Irish palliative medicine inpatient unit.Consecutive cancer admissions were recruited within 7 days. Patients’ preferences were elicited with regards to 3 symptom assessment scales; categorical response (CRS), numerical rating (NRS), and visual analogue (VAS), across 3 common symptoms; appetite loss, pain, and tiredness. Participants selected their preferred scale per symptom. We determined the clinical utility of each scale, defined by ease of completion as judged by an observer. Results: 100 participants wererecruited,aged 38-93 years (x̅ = 71 years; SD=11.6). Median European Cooperative Oncology Group (ECOG) score was 2 (range 0-4). Participants preferred CRS for appetite loss (48%) and tiredness (40%), and NRS for pain (44%). VAS was consistently the least preferred measure. Scale preference was fully consistent across symptoms for 52% of patients, with just 4% choosing a different scale per symptom. There was moderate agreement between participant scale preference and ease of completion as determined by observer (Pain: K=0.486; Fatigue: K=0.452; Appetite loss K=0.364). Conclusions: (1) Most participants had a specific scale preference which was consistent across symptoms, (2) CRS was preferred overall, (3) Participants did not need to experience a symptom to have a preference, (4) VAS should be used with caution in hospice clinical care or research, (4) Symptom assessment scales should be carefully selected for clinical and research purposes.
Phosphorylation of the estrogen receptor α at serine 305 and prediction of tamoxifen resistance in breast cancer
Authors: M. Kok, C. Holm, R. Michalides, R. Fles, R. H. Koornstra, M. Hauptmann, J. Neefjes, O. Stal, G. Landberg, S. C. Linn
Journal: Journal of Clinical Oncology (2008)

11058 Background: Phosphorylation of estrogen receptor α at serine 305 (ERαS305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other anti-endocrine agents, such as fulvestrant. We evaluated ERαS305-P in 377 breast carcinomas from premenopausal participants of a randomized trial (n=248) and patients with advanced disease (n=129). Methods: Immunohistochemistry on formalin-fixed paraffin embedded tumor tissue was performed using a new monoclonal antibody. Results: Among the premenopausal patients, adjuvant tamoxifen improved recurrence-free survival (RFS) for ERαS305-P negative tumors (multivariate HR=0.53, 95%CI 0.32–0.86, p=0.010), but not for ERαS305-P positive tumors (multivariate HR=1.01, 95%CI 0.33–3.05, p=0.99) (interaction p=0.131). Notably, ERαS305-P was not significantly associated with RFS in patients not treated with tamoxifen (multivariate HR=0.64, 95%CI 0.30–1.37, p=0.248), indicating that ERαS305-P is a marker for treatment outcome rather than tumor progression. In advanced disease, the combined expression of phospho-protein kinase A and ERαS305-P, the former known to be involved in phosphorylation of ERαS305, was associated with poor outcome after tamoxifen. Conclusions: Given the direct experimental link between ERαS305-P and tamoxifen resistance, and these first clinical data suggesting that premenopausal patients with ERαS305-P positive breast cancer are resistant to adjuvant tamoxifen, alternative endocrine treatment should be considered for this subgroup. No significant financial relationships to disclose.
The effects of concurrent or sequential administration of trastuzumab on radiation-induced pulmonary fibrosis in rats
Authors: C. Umay, N. S. Bese, S. Serdengecti, N. Kepil, C. Karaca, N. Sut, T. Altug, A. Ober
Journal: Journal of Clinical Oncology (2008)

11554 Background: There is not enough data regarding late effects of combination of T with RT. Lung is the most sensitive tissue to observe late effects of irradiation. We evaluated if concurrent or sequential administration of T has any impact for development of radiation- induced pulmonary fibrosis (RIPF) in rats. Methods: 54 female wistar- albino rats were divided into 6 groups (G). G 1 (concurrent T) had irradiation in two hours of following T administration. G 2 (sequential T-RT) received irradiation, one week after T. G 3 (sequential RT-T) had irradiation first and received T one week after RT. G 4 (T only) had only T. G 5 (RT only) had only irradiation. The rats in G 6 (sham) were only observed. A single dose of 12Gy was given to both lungs with an anterior field at 2 cm depth after simulation. T dose which was equivalent to 6mg/kg adult dose was calculated for each rat, and injected by the tail vein. For sequential administration one week interval was given between T and RT which was shown to be the half life of T in rats. Animals were sacrificed 16 weeks after RT which was shown to be a sufficient period for the development of RIPF in rats. Five-micrometer thick sections were stained with Masson’s trichrome to visualize fibrosis and collagen. As quantitative endpoint the extent of fibrosis for each field was graded on a scale from 0 (normal lung or minimal fibrous thickening of alveolar/bronchial walls) to 4 (total fibrous obliteration). The mean score values were calculated for each group. Normality distribution and linearity were tested, then the One way ANOVA test and Tukey HSD post-hoc test were used to calculate the significance of the differences among groups. Results: The mean value of fibrosis were 1.44, 1.77, 1.75 and 1.62 for G 1, G 2, G 3 and G 5, respectively. There were no significant differences among the comparison of these 4 groups (p>0.05). The mean value of fibrosis score was 0.25 for G 4 and 0.33 for G 6. The difference was not significant (p>0.05). When the mean value of fibrosis scores of the groups which had thoracic irradiation with or without T, compared with observation arm and T only group, differences were significant (p<0.05). Conclusions: This study shows that addition of T to thoracic irradiation either sequentially or concomitantly does not increase the RIPF in rats. No significant financial relationships to disclose.