tbuckley/cabot-search huggingface dataset:
Characterization of POLE-mutated (POLE+) urothelial carcinoma of the bladder and urinary tract (UC).
Authors: MinYuen Teo, Hikmat Al-Ahmadie, Eugene K. Cha, Guido Dalbagni, Bernard H. Bochner, David B. Solit, Michael F. Berger, Barry S. Taylor, Dean F. Bajorin, Gopa Iyer, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2017)

387 Background: The POLE gene encodes for the catalytic and proofreading unit of DNA polymerase epsilon. Mutations in POLE gene, recently observed in endometrial and colorectal cancers, are associated with unique clinical features and an ultramutated phenotype. We sought to quantify and characterize POLE+ in UC. Methods: POLE+ cases were identified from a database of 532 UC tumors sequenced with the MSK-IMPACT assay (Cheng et al J Mol Diagn 2015). Tumors were classified based on total mutation: hypermutated (20 - 149 mutations) and ultramutated ( ≥ 150 mutations) as previously described in colon cancer (Stadler et al J Clin Oncol 2016). An institutional cohort of patients with metastatic UC was used as historical POLE- control (n = 94). Results: Thirty two POLE+ patients (6%) and 42 mutations were identified. Median age of diagnosis was 65 years (range: 31 - 94) and 81% were male. Seven patients were found to have Lynch’s syndrome, 8 with ERCC2 mutations which were hotspots or within the helicase domains and 1 with germline NBN mutation. These were excluded from further analysis. Of the remaining 16 patients (3%) and 22 mutations, four were found within the proofreading domain (positions 268 – 471), one was a previously reported hotspot (P286R) and one was a truncating mutation (R114*). Four cases were considered hypermutated and two ultramutated based on mutation counts. Clinically, four had non-invasive disease and 4 had metastatic disease at diagnosis. Eight patients had muscle-invasive disease, five of whom received neoadjuvant chemotherapy. All 8 patients developed metastatic disease with a median time interval of 10.3 months (range: 3.3 – 29.6). Nine of the 12 metastatic patients had nodal metastases while only one had visceral metastasis. With median follow-up of 25.4 months, median overall survival from metastatic diagnosis was not reached and 83% remained alive at 2 years, which was superior to survival for POLE- metastatic patients (HR 0.36, p = 0.04) and POLE- nonvisceral, node only metastatic patients (HR 0.33, p = 0.03). Conclusions: POLE+ prevalence is low in UC but might exhibit superior overall survival. It remains to be investigated if this is strictly the effect of POLE+ or other as yet unidentified genomic events.
Consultant productivity drops as result of poor workforce planning
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The productivity of consultants working in NHS acute care hospitals in England has fallen by an average of 2.3% over the past six years, new research has shown.1

The think tank the Health Foundation, which conducted the research, attributed the fall to poor workforce planning. It highlighted a 22% rise in the number of NHS consultants over the past six years, whereas the number of nurses rose by just 1%.

Anita Charlesworth, director of research and economics at the Health Foundation and coauthor of the paper, said, “Consultant productivity has been falling, but not because staff aren’t working incredibly hard. NHS consultants work in a system, and if that system isn’t well designed they can’t be productive.

“Much better workforce planning is critical. Increasing the number of consultants by a fifth …
Survival after pathologic complete response in patients with cancer of the esophagus or gastroesophageal junction.
Authors: Sjoerd M Lagarde, Maarten CJ Anderegg, Wernard A Borstlap, Suzanne S Gisbertz, Sybren L. Meijer, Maarten Hulshof, Jacques Bergman, Hanneke W.M. Van Laarhoven, Mark van Berge Henegouwen
Journal: Journal of Clinical Oncology (2014)

e15084 Background: The preferred curative strategy for esophageal cancer patients with locally advanced cancers, but without distant metastases consists of esophagectomy with preceding chemo(radio)therapy (CRT). In 10-40% of patients, In 10-40% of patients who are neoadjuvantly treated, there is absence of viable tumor at the time of surgery (pathologic complete response (pCR)). Therefore the aim of the present study was to define the outcome of patients with a pCR and identify predictive factors for survival in this group. Methods: Between March 1994 and September 2013 all consecutive patients with cancer of the esophagus or gastroesophageal junction who underwent esophageal resection after neoadjuvant chemo (radio) therapy were included in the present study. Multivariate Cox regression analysis was carried out to identify independent prognostic factors. Results: Of the 463 included patients, 86 (19%) patients had a pCR (pyT0N0M0R0) (54 men, 32 women, median age: 63yrs (range 33-82 years)). 48 (56%) patients had an adenocarcinoma. Eight (9%) patients underwent neoadjuvant chemotherapy and 78 (91%) underwent neoadjuvant chemoradiation therapy. During follow-up, 25 (29%) patients developed recurrent disease. Nineteen (76%) patients developed haematogenous metastasis, 6 developed lymphatic metastases (of which 3 patients distant lymphatic location). 5-year disease free survival was 61%, 5 year overall survival was 58%. Cox regression analysis revealed no prognostic factors for any of the variables tested (sex, age, histologic subtype, tumorlocation, type of neoadjuvant therapy, cTNM stage). Conclusions: Patients with a pathologic complete response have a relative good survival. However one third of the patients developed recurrent disease. Thus far it is unclear how these patients can be identified.
The relationship between body mass index, diabetes, and triple-negative breast cancer prognosis.
Authors: Jose Maria Pacheco, Sarah Tait, Feng Gao, Caroline Bumb, Matthew James Ellis, Cynthia X. Ma
Journal: Journal of Clinical Oncology (2014)

1108 Background: Higher body mass index (BMI) and diabetes are associated with worse breast cancer prognosis. However, information on how these variables relate to survival in triple-negative breast cancer (TNBC) is limited. Methods: We retrospectively reviewed 501 patients with TNBC first seen at the Washington University Breast Oncology Clinic between January 2006 and December 2010. Cox proportional hazards models were used to determine the relationship between BMI at diagnosis and diabetes with overall survival (OS) and disease free survival (DFS). Results: 448 patients had BMI recorded and 71 had diabetes. Of these, 4.50% with BMI available and 2.82% with diabetes presented with stage IV disease. The median age at diagnosis was 53 (23-98) years and follow-up was 40.1 months. There was no significant difference between groups in time from imaging to biopsy, time from biopsy to surgery, receipt of neoadjuvant or adjuvant chemotherapy, pathologic complete response to neoadjuvant chemotherapy, grade, pathological stage or duration of follow-up. Additionally, for BMI groups, there were also no differences in age or menopausal status. Interestingly, baseline BMI and diabetes were not associated with OS or DFS. OS hazard ratios (HRs) for overweight patients (BMI 25.1 to 29.99), those with class I obesity (BMI 30 to 34.99) or BMI ≥ 35 were 0.82 (CI 0.53 – 1.25, p = 0.35), 0.86 (CI 0.56 – 1.33, p = 0.50) and 0.87 (CI 0.54 – 1.40, p = 0.57), respectively. While the HRs for DFS in overweight patients, those with class I obesity or BMI ≥ 35 were 0.83 (CI 0.54 – 1.27, p = 0.39), 0.93 (CI 0.60 – 1.44, p = 0.74) and 0.96 (CI 0.61 – 1.52, p = 0.87), respectively. Similarly, the HRs for diabetics were 1.14 (CI 0.75 – 1.75, p = 0.55) for OS and 0.90 (CI 0.59 – 1.39, p = 0.63) for DFS. Conclusions: We conclude that obesity and diabetes did not significantly affect survival for TNBC patients in this single center cohort study.
Effect of secondary KIT mutations on growth of GIST cells in the absence of selective pressure by imatinib in isogenic models of imatinib resistance.
Authors: Susanne Grunewald, Thomas Mühlenberg, Brian Rubin, Martin H. Schuler, Jonathan A. Fletcher, Sebastian Bauer
Journal: Journal of Clinical Oncology (2014)

10555 Background: Secondary mutations of KIT are commonly found in progressing lesions of imatinib (IM)-resistant GIST and represent a major factor of drug resistance. Development of salvage treatments is complicated by the genomic heterogeneity of secondary mutations. We hypothesize that resistant clones require selective pressure to overgrow sensitive GIST and that mixed sensitive/resistant populations may still display drug sensitivity. Methods: Based on parental IM-sensitive GIST-T1 (KIT Ex11 57bp del) we have developed IM-resistant isogenic sublines harbouring critical secondary mutations (T670I, D816E, D820A, A829P). Each subline was transduced with specific marker proteins allowing detection of resistant subclones by FACS or IHC. Proliferation and cell viability for individual cell lines and mixed cell populations (+/- IM) were evaluated in vitro and in vivo. Results: IM-resistant cell-lines grew faster in the presence of IM compared to no treatment. Resistant sublines were xenogenic in nude mice but were overgrown by parental GIST-T1 in mixed populations in the absence of IM. Tumors derived from mixed GIST populations contained high levels of resistant clones in IM-treated mice. To estimate the proportion of resistant cells within a population necessary to display resistance, we mixed resistant sublines with sensitive cells at known percentages. Sensitivity to IM was lost when the fraction of resistant cells was >50% compared to parental cells (3- and 6 day time point). Conclusions: GIST with acquired resistance likely harbor mixed populations of drug-sensitive and resistant cells which exhibit differential growth rates. Our studies show that tumor populations with low levels of resistant clones may still respond to treatment. Secondary KIT mutations confer a growth disadvantage in the absence of IM. Selective pressure by IM results in partial KIT inhibition which may reduce the oncogenic stress of kinase hyperactivation in GIST harbouring secondary mutations. Altering the selective pressure could therefore delay the emergence of resistant clones and our models could be applied toward optimization of drug selection and dosing strategies.
Impact of variant histology on disease-specific mortality and survival in patients with non-muscle invasive bladder cancer (NMIBC): A population-based analysis.
Authors: Abhishek Tripathi, Mark A Preston, Michelle S. Hirsch, Quoc-Dien Trinh, James A. Stewart, Joaquim Bellmunt, Toni K. Choueiri, Adam S. Kibel, Lauren Christine Harshman
Journal: Journal of Clinical Oncology (2017)

332 Background: Prior studies have reported that variant histology is associated with poor outcomes in NMIBC. We utilized the Surveillance, Epidemiology and End Results (SEER) database to compare disease specific survival (DSS) and mortality (DSM) among the different variant histologies and urothelial carcinoma (UC). Methods: Patients diagnosed with NMIBC (Ta, Tis, T1) between 2004 and 2012 were eligible for analysis. Patients were separated into cohorts based on histology: UC and variant histology which included micro-papillary variant (MPV), neuroendocrine (NEC), squamous (SCC), adenocarcinoma (AC) and other variants (e.g., lymphoepithelial, giant cell, undifferentiated/anaplastic, sarcomatoid). Univariate and multivariable Cox proportional hazard analysis was used to evaluate the impact of variant histology on DSM after adjusting for other covariates. DSS was estimated amongst the different histologic and treatment groups using the Kaplan-Meier method and compared using Log-rank test. Results: We identified 111,756 patients, who were predominantly Caucasian (90%) and older than 70 years (57.5%; n=64,314). Variant histology accounted for 1.2% (n=1354) of cases. AC and SCC were the most common variant subtypes (26.4%; n=357 and 25.6%; n=347 respectively) followed by NEC (11.2%; n=151) and MPV (7.1%; n=96). On multivariable analysis adjusting for age, sex, race, T-stage, histologic grade and number of primary tumors, all variant subgroups except MPV were associated with increased DSM compared to UC (p&lt;0.001). SCC had the worst 5-year DSS (53.8%; P&lt;0.001) followed by NEC (65.1%) and AC (77.8%). Compared to treatment with TURBT or intravesical BCG, cystectomy was associated with improved DSS for variant histology patients with T1 tumors (75.8% vs. 66.3%; P&lt;0.001). Conclusions: Variant histology, specifically SCC and NEC, was associated with significantly worse 5-year DSS in NMIBC. MPV, which is generally thought to be aggressive, had outcomes comparable to UC. Cystectomy was associated with improved DSS in patients with T1 disease and should be considered for NMIBC with variant histology.
Safety and tolerability of regorafenib (REG) in Italian patients: Subgroup analysis of the phase III CORRECT study in metastatic colorectal cancer (mCRC).
Authors: Alberto F. Sobrero, Alfredo Falcone, Carlo Barone, Alberto Zaniboni, Fortunato Ciardiello, Gabriele Luppi, Giacomo Carteni, Daniela Carpani, Daniela Curzio, Corrado Boni, Salvatore Siena
Journal: Journal of Clinical Oncology (2014)

e14613 Background: In CORRECT, REG significantly improved overall survival vsplacebo (PBO) in 760 patients (pts) with treatment-refractory mCRC (hazard ratio 0.77; p=0.0052). The most frequent REG-related grade ≥3 adverse events (AEs) were hand–foot skin reaction (HFSR, 17%), fatigue (10%), diarrhea (7%), hypertension (7%) and rash/desquamation (6%). We analyzed the safety and tolerability of REG in pts enrolled in CORRECT at 9 Italian centers. Methods: Pts with mCRC that had progressed after all available standard therapy were randomized 2:1 to REG 160 mg or PBO orally once daily for weeks 1–3 of each 4-week cycle. Prespecified dose modifications were allowed to manage AEs. All patients who received ≥1 dose of study drug were included in the safety population. AEs were graded according to NCI CTCAE v 3.0. Results: Of 143 pts randomized in Italy, 142 were in the safety population (REG n=90; PBO n=52). Overall, 67% and 33% of pts had an ECOG performance status (PS) of 0 and 1, respectively, 56% were KRAS mutation positive, and 63% had received ≤3 previous lines of therapy for metastatic disease. A greater proportion of Italian than overall pts had PS 0. Other baseline characteristics were generally similar between treatment groups and representative of the overall study population. Median treatment duration (range) was 7.1 weeks (0.9–47.0) vs 7.0 weeks (1.1–35.9), 67% vs 37% of pts required dose modifications, and mean dose intensity was 83% vs 92% in the REG and PBO groups, respectively. Mean daily doses were 152 mg and 160 mg, respectively. Drug-related AEs of any grade were reported in 90% of REG and 50% of PBO pts; grade ≥3 drug-related AEs were reported in 42% and 10%, respectively (Table). Conclusions: This exploratory analysis suggests that the safety and tolerability of REG in Italian pts is similar to that in the overall CORRECT population. The rate of grade ≥3 HFSR was lower in Italian pts than in the overall study population. Clinical trial information: NCT01103323. PBO (n=52) REG (n=90) Drug-related AEs, % Any Grade 3/4* Any Grade 3/4* Any 50 10 90 42 Fatigue 27 2 49 10 Diarrhea 4 2 36 6 Rash/desquamation 4 0 33 11 HFSR 6 2 27 7 Hypertension 4 0 18 6 Leading to dose modification 8 47 Leading to permanent discontinuation 0 8 * No grade 5 AEs.
Implications of prostate cancer with diabetes mellitus on patient outcomes and care: A matched case-control study.
Authors: Nina J. Karlin, Heidi Kosiorek, Patricia M. Verona, Shailja Amin, Curtiss B. Cook
Journal: Journal of Clinical Oncology (2017)

101 Background: Diabetes mellitus (DM) has been associated with an increased risk of mortality among patients with many types of cancers. The aim of this case-control study was to determine the impact of DM on short-term overall survival in prostate cancer patients, and to examine the impact of prostate cancer on glycemic control in DM. Methods: 276 patients with newly diagnosed prostate cancer from 2007-2014 with DM were identified from the Institutional Cancer Registry and matched to 276 prostate cancer patients without DM according to age and year of prostate cancer diagnosis. The file was linked to the electronic medical record to obtain information on DM and cancer therapies, and laboratory results. Results: The mean age of the entire prostate cancer cohort was 72 years, most (93%) were white, the most common Gleason score (in 52%) was 7, and the majority (56%) were tumor stage 2. No differences in age, race/ethnicity, Gleason score, or tumor stage were detected between patients with and without DM, although DM patients had higher body mass index (P = .031). Among those with DM the mean hemoglobin A1c (HbA1c) was 6.7%. In Kaplan-Meier survival analysis (median follow-up time of 43.7 months), 5-year overall survival was estimated at 88% for DM patients versus 93% in non-DM patients. Hazard ratio (for matched pairs) was 1.64 (95% CI: 0.77-3.46, P = .20). Moreover, mean HbA1c and glucose values among DM cases did not significantly change over 1 year (P ≥ .13). Mean glucose among DM patients was significantly (p &lt; 0.01) higher compared to non-DM patients. Conclusions: DM did not adversely impact survival in prostate cancer patients. In addition, prostate cancer or its treatment does not appear to affect glycemic control. Both patients and their providers can be reassured that the two concurrent diagnoses do not adversely interact to worsen short term outcomes.
Impact of insulin resistance (IR) on the prognosis of metastatic breast cancer (MBC) patients treated with first-line chemotherapy (CT).
Authors: Alessandra Gennari, Matteo Puntoni, Oriana Nanni, Andrea De Censi, Paolo Bruzzi, Laura Paleari, Andrea Freschi, Laura Amaducci, Alessandra Bologna, Lorenzo Gianni, Dino Amadori
Journal: Journal of Clinical Oncology (2014)

514 Background: Higher insulin levels have been associated with a worse prognosis in early BC patients. However, the effect of higher insulin levels on MBC prognosis has not been explored so far. The aim of this study was to evaluate the influence of IR on the prognosis of HER2 negative, non-diabetic, MBC patients receiving first line CT. Methods: The relationship between IR, identified by HOMA index > 2.5 (fasting glucose [mmol/L] × insulin [mU/L]/22.5), and progression free (PFS) or overall survival (OS) was assessed in 87 MBC patients enrolled in a clinical trial of first line CT with non-pegylated liposomal doxorubicin 60 mg/sqm plus cyclophosphamide 600 mg/sqm Q21 days. PFS and OS were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed adjusting for age, PS, endocrine status, metastatic site and BMI. Results: Information on patient’s IR status at baseline was available on 79 women. Median follow up was 15 months (IQR 9-21). Overall,48.4% patients wereclassified as insulin resistant (HOMA > 2.5), 41.0% were overweight (BMI 25-30) and 19.2% were obese (BMI > 30). Median age was 61 years (range 36-77); PS was 0 in 76.6% of the patients. Endocrine status was positive in 87.5% and visceral disease was present in 63.6%. Overall, median PFS was 9 months (IQR 5-18): median PFS was 14 months (IQR 8-18) in patients with HOMA index ≤2.5 and 8 months (IQR 2-17), in patients with HOMA index >2.5; HR=1.79 (95%CI: 1.01–3.18, p 0.04). By multivariate analysis, after adjustment for age, PS, endocrine status, visceral disease and BMI, a statistically significant higher risk of disease progression was detected in patients with HOMA Index > 2.5 (HR 2.28; 95%CI: 1.06 – 4.89, p = 0.035). Conclusions: In this study IR, indicated by an HOMA Index >2.5, was associated with a significantly worse prognosis; after adjusting for other acknowledged prognostic factors, the IR status was the only one to maintain its adverse prognostic effect. These data suggest that host metabolic status might influence the prognosis of MBC treated with CT and therefore additional alternative strategies, targeting host metabolism, should be considered in this unfavorable subset of patients.
Association of MARCKS phosphorylation with breast cancer malignancy and paclitaxel unresponsiveness.
Authors: Ching-Hsien Chen, Chun-Ting Cheng, Yuan Yuan, Jing Zhai, Reen Wu, David Ann
Journal: Journal of Clinical Oncology (2015)

e22007 Background: Accumulating evidence has suggested that myristoylated alanine-rich C-kinase substrate (MARCKS) is critical for regulating multiple pathophysiological processes. However, the molecular mechanism underlying increased phosphorylation of MARCKS at Ser159/163 (phospho-MARCKS) and its functional consequence in neoplastic disease remain to be established. Herein, we investigated how phospho-MARCKS is regulated in breast carcinoma, and its role in the context of chemotherapy. Methods: The clinical relevance of phospho-MARCKS in breast cancer was first confirmed. Next, we used genetic approaches to verify the functionality and molecular mechanism of phospho-MARCKS. Finally, breast cancer cells were pharmacologically inhibited for MARCKS activity and subjected to functional bio-assays. Results: In a screen of patients with breast tumors, we find that the abundance of phospho-MARCKS, not MARCKS protein per se, increased in breast cancers and positively correlated with tumor grade and metastatic status. Among chemotherapeutic agents, mitotic inhibitors, including paclitaxel, vincristine or eribulin, notably promoted phospho-MARCKS accumulation in multiple breast cancer cells. We further show that phospho-MARCKS acted upstream of Src activation upon paclitaxel exposure. Reduction of phospho-MARCKS by knockdown of MARCKS or pharmacological agents increased paclitaxel sensitivity. Particularly, a known phospho-MARCKS inhibitor, MANS peptide, was demonstrated to increase paclitaxel efficacy and attenuate angiogenesis/metastasis of xenografted breast cancer cells by decreasing abundance of phospho-MARCKS and messages of inflammatory mediators. Conclusions: Our data suggest that unresponsiveness of breast cancer to paclitaxel treatment is, at least in part, mediated by phospho-MARCKS and also provide an alternative therapeutic strategy against breast cancer by improving taxanes sensitivity.