tbuckley/cabot-search huggingface dataset:
Precision prevention of <i>TMPRSS2:ERG</i> prostate cancer.
Authors: Lorelei A. Mucci, Thomas Ahearn, Kathryn Penney, Andreas Pettersson, Rebecca E Graff, Philip W. Kantoff, Stephen Finn, Massimo Loda
Journal: Journal of Clinical Oncology (2016)

78 Background: Increased integration of tumor biomarker data into prostate cancer epidemiology studies is needed to identify molecular subtypes that underlie its etiology and progression. We hypothesize that the TMPRSS2:ERG gene fusion is a unique prostate cancer subtype that is etiologically distinct from cancers lacking TMPRSS2:ERG. Methods: We leveraged the Physicians’ Health Study and Health Professionals Follow-up Study cohort data on pre- and post-diagnostic lifestyle factors, inherited genetic variants, circulating biomarkers, and clinical data and follow-up for 30 years. We have a tumor repository of men with prostate cancer and tumor tissue microarrays. Using immunohistochemistry, we characterized TMPRSS2:ERG status for 1,491 incident prostate cancer cases in these cohorts, and also have biomarker data on a range of additional markers from immunohistochemistry and mRNA expression profiling. Results: Fifty percent of prostate cancer cases were ERG-positive. ERG-positive cancers show much higher expression of insulin/IGF signaling, PTEN loss, higher VDR expression, as well as expression of mismatch repair genes. In contrast, ERG-negative prostate cancer is characterized by increased presence of chronic inflammation and atrophy. We found higher pre-diagnostic free testosterone levels, but not other sex hormones, were associated with increased risk of ERG-positive (OR = 1.4, 95% CI = 1.0-1.8) but not ERG-negative disease (OR = 0.9, 95% CI = 0.7-1.2). Of 39 known genetic risk loci, six were significantly associated (p &lt; 0.05) with ERG+ versus ERG- cancer (2 expected by chance). Prostate cancer risk factors such as taller height (an indicator of growth factors in puberty) are uniquely associated with ERG-positive prostate cancer. Moreover, we observe a complex interaction of components of insulin/IGF and ERG-status on prostate cancer mortality. Conclusions: TMPRSS2:ERG is a highly prevalent somatic event in prostate cancer that likely defines a unique molecular subtype of this common disease. Understanding the differences between these two prostate cancer subtypes may enhance opportunities for prevention.
Surgical treatment of colon cancer in patients older than age 80.
Authors: H. B. Neuman, E. S. O'Connor, J. Weiss, N. K. LoConte, D. Y. Greenblatt, M. Smith
Journal: Journal of Clinical Oncology (2011)

6071 Background: Individuals >80 years represent a growing proportion of colon cancer patients and create a decision-making challenge for surgeons due to frequent comorbidities. Our objective was to describe patterns of surgery in colon cancer patients >80 years and examine outcomes with and without colectomy. Methods: Medicare beneficiaries >80 years with colon cancer diagnosed from 1992-2005 were identified from the Surveillance, Epidemiology, and End Results-Medicare database; stage IV was excluded. χ2 and two-way ANOVA assessed differences in patient characteristics. Kaplan-Meier survival analysis determined one-year overall and disease-specific survival. Results: Of 35,080 patients, 80% underwent colectomy within 90 days of diagnosis. 46% were for urgent/emergent reasons. Post-operative complications occurred in 4%, and 9% died within 30 days. Patients not selected for colectomy had more comorbidities (higher HCC risk score), were more likely to have a wheelchair and use home oxygen (Table). 11% of these non-operative patients ultimately required a cancer-related intervention (delayed colectomy 9%, stoma 1.4%, stent 0.4%). One-year overall survival with and without colectomy was 77 vs. 58%. One-year disease-specific survival was 89 vs. 76%. Conclusions: Most older colon cancer patients undergo colectomy, although many for urgent/emergent reasons. Disease-specific survival after colectomy is greater than overall survival, confirming that many die due to competing causes. Further research should focus on improving mechanisms to identify those patients >80 years at increased risk for a poor outcome after elective colectomy. Colectomy(n=28,070) No colectomy(n=7,010) P value Age at diagnosis* 85.0 (4.2) 85.9 (4.6) <0.0001 Male gender 37% 39% <0.001 HCC risk score** 2.32 (1.5) 2.58 (1.8) <0.0001 Mobility No device 91.7% 87.6% <0.001 Crutch, cane, or walker 4.6% 5.9% Wheelchair 3.7% 6.6% Home oxygen use 2.3% 3.8% <0.001 No. of hospitalizations in year prior to diagnosis* 1.49 (0.90) 1.70 (1.16) 0.010 Surgical evaluation after diagnosis 61% 46% <0.001 SEER historic stage Local 46.6% 47.4% <0.001 Regional 52.1% 23.3% Unstaged 1.2% 29.3% Abbreviation: HCC, hierarchical condition categories (measure of comorbidity). * Mean, standard deviation.
Identifying BRAF mutations in colorectal cancer (CRC) by initial immunohistochemical (IHC) staining for mismatched protein expression as part of a Lynch syndrome screening program: A distinct clinicopathologic entity.
Authors: Thomas H. Grote, Scott E. Kilpatrick, Dena B. Webb, Amy Herndon Hughes, Sarah Hughes
Journal: Journal of Clinical Oncology (2014)

405 Background: Multiple genetic mutations resulting in different clinical phenotypes have been found in colorectal adenocarcinoma. Mutation in the BRAF oncogene is a key step in malignant transformation within the methylator pathway leading to colorectal cancer. There is little data regarding the identification of the subset of CRCs exhibiting mutations in the BRAF oncogene with initial IHC staining, as well as a paucity of information describing this unique subset of colorectal cancers Methods: Between 1/1/11 to 12/31/12, all newly diagnosed CRCs underwent IHC testing for MLH1, MSH2, MHS6, and PMS2 protein expression if sufficient pathologic material existed. If MLH1 protein expression was absent, BRAF V600E mutation analysis was preformed. Patient demographics, pathology and outcomes were examined through chart review. Statistical associations were determined by the TTest, Fisher’s exact probability test and Cox regression analysis of Kaplan-Meier curves. Results: 314 newly diagnosed CRC patients were identified and 278 (89%) underwent IHC staining (study population). 48 had absent MLH1 protein expression (15%) and underwent BRAF mutational analysis. 35/48 had the V600E mutation. Comparing the BRAF mutated group to the study population without BRAF mutation showed statistically significant differences. These differences included median age at diagnosis (78 vs. 65 years, p &lt; 0.0001), female sex (77% vs. 51%, p = 0.0037), right colon location (77% vs. 42%, p = 0.0001) and significant mucinous component denoted pathologically (31% vs. 7%, p = 0.0001). There was no difference in stage of CRC at diagnosis between the groups. Survival rates at one year based on Kaplan Meier curves were 65% vs. 82% and results will be updated. Conclusions: BRAF mutations in CRC are associated with unique clinicopathologic characteristics and overall worse prognosis. This subgroup of CRC can be identified as part of a Lynch Screening program via ICH staining of the mismatch repair proteins MLH1, MSH2, MSH6, and PMS2.
Effects of a structured exercise program on physical activity and health-related fitness in colon cancer survivors: One year feasibility results from the NCIC CTG CO.21 (CHALLENGE) trial.
Authors: Christopher J. O'Callaghan, Kerry S. Courneya, Janette L. Vardy, Christine Friedenreich, Kristin L. Campbell, Harry Prapavessis, Jennifer J Crawford, Patti O'Brien, Haryana M. Dhillon, Derek J. Jonker, Neil Sun Chua, Sasha M. Lupichuk, Michael Susmoy Sanatani, Sharlene Gill, Ralph M. Meyer, Stephen Begbie, Antonino Bonaventura, Matthew E. Burge, Dongsheng Tu, Christopher M. Booth
Journal: Journal of Clinical Oncology (2016)

648 Background: There is strong interest in testing lifestyle interventions to improve cancer outcomes, however, the optimal methods for achieving behaviour change in large scale pragmatic trials are unknown. We report the 1 year feasibility results for behaviour change in NCIC CTG CO.21 Colon Health and Life-Long Exercise Change (CHALLENGE) Trial. Methods: Between 2009 and 2014, 273 high risk stage II and III colon cancer survivors who had recently completed chemotherapy at 50 centers in Canada and Australia were randomized to a structured exercise program (SEP n = 136) or health education materials (HEM n = 137). The primary feasibility outcome in an a priordefined interim analysis was a difference between groups of ≥ 5 metabolic equivalent task (MET) hours/week in self-reported physical activity (PA) after at least 250 participants had reached 1 year. Secondary feasibility outcomes included cardiorespiratory fitness, body weight and circumferences, and objective physical functioning. Results: The SEP group reported a mean increase from baseline to 1 year PA of 15.6 MET hours/week vs a mean increase of 5.1 in the HEM group (+10.5 hrs/wk [95% CI = +3.1 to +17.9]; p = 0.002). SEP also improved relative to HEM in mean differences for predicted VO 2max (+2.2ml/kg/min; p = 0.068), 6 minute walk (+29m; p &lt; 0.001), 30 second chair stand (+1.6reps; p &lt; 0.001), 8 foot up and go (-0.4s; p = 0.004), and the sit and reach (+2.1cm; p = 0.08). Conclusions: The behaviour change intervention in the CO.21 Trial produced an increase in self-reported PA that exceeded the feasibility criterion for trial continuation, resulted in objective fitness improvements, and is consistent with the amount of PA associated with improved colorectal cancer outcomes in observational studies. Recruitment to CO.21 remains ongoing. Clinical trial information: NCT00819208.
Effect of chemoradiotherapy, with adjuvant surgery for local control, on survival in AC and SCC of the esophagus.
Authors: Gary Alan Bass, Heidi Furlong, Katie E. O'Sullivan, Thomas P.J. Hennessy, Thomas Noel Walsh
Journal: Journal of Clinical Oncology (2014)

81 Background: Esophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. Aims:Long-term results of 2 simultaneous RCTs comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of AC (AC) and SCC (SCC) to identical regimens compared. Methods: Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately randomised to identical protocols of MMT or surgical monotherapy. Results: 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0·004), SCC (P=0·01). There was a 54% relative risk-reduction in lymph-node metastasis following MMT, compared with surgery(64% vs 29%, P&lt;0·001). MMT produced a pCR in 25% and 31% of AC and SCC respectively. Survival advantage accrued to MMT, pCR and node-negative patients: AC pCR vs surgical monotherapy(P=0·001); residual disease following MMT vs surgical monotherapy(P=0·008);SCC pCR vs surgical monotherapy (P=0·033). Conclusions: A survival advantage for MMT persisted long-term in AC and was replicated in SCC. MMT produced loco-regional tumor down-staging to extinction in 25-31% of patients, potentially permitting personalized treatment in this cohort that avoids the morbidity and mortality associated with resection. Node-negative patients with residual localized disease following MMT had a survival advantage over node-negative patients following surgery alone, supporting a systemic effect on micro-metastatic disease.
Perioperative chemotherapy using FOLFOX with panitumumab for locally advanced rectal cancer: Phase II trial.
Authors: Mitsuyoshi Ota, Jun Watanabe, Atsushi Ishibe, Hirokazu Suwa, Masashi Momiyama, Yasushi Ichikawa, Chikara Kunisaki, Itaru Endo
Journal: Journal of Clinical Oncology (2016)

502 Background: Neoadjuvant chemotherapy for locally advanced rectal cancer is required to achieve tumor reduction when skipping routine use of preoperative radiation therapy. It is known that EGFR inhibitor has impact on early tumor shrinkage in metastatic colorectal cancer. We evaluated the effect of preoperative infusional fluorouracil, leucovolin, and oxaliplatin (FOLFOX) with panitumumab. Methods: Forty-three patients with clinical stage III rectal cancer without invasion to other organs were enrolled in this multicenter phase II trial. All patients had KRAS wild tumors confirmed by biopsy. Patients received six cycles of FOLFOX with panitumumab. Reduction rate of primary tumor was measured by T2 weighted sagittal image of magnetic resonance imaging. Excluding patients whose disease progressed after the six cycles, total mesorectal excision was performed two weeks after neoadjuvant chemotherapy. After surgery, adjuvant chemotherapy with six cycles of FOLFOX without panitumumab was planned before diverting stoma closure. The primary outcome was the response rate of the primary lesion. Results: Between January 2012 and December 2014, 42 out of 43 patients completed preoperative chemotherapy; one patient did not complete the regimen due to grade III neutropenia. There was no progressive disease in the 42 patients and response rate was 69.8% in this series. Average reduction rate of the primary lesion was 47.6%. All of the 43 participants had R0 resections without mortality or severe complications. Pathological complete response rate to chemotherapy was 7.0% (3 of 43). Thirty-eight out of 43 patients started adjuvant chemotherapy and 32 patients completed the regimen. Grade 3 or worse peripheral neuropathy was not seen during neoadjuvant chemotherapy and seen in 2.6% (1 of 38) during adjuvant chemotherapy. Conclusions: Periopative chemotherapy using FOLFOX with panitumumab seemed to have two advantages; one is tumor reduction which enables skipping neoadjuvant radiation therapy, the other is safely administering a larger dose of chemotherapy than adjuvant only in locally advanced rectal cancer. Additional impact of EGFR inhibitor should be followed in long term results. Clinical trial information: UMIN000006039.
Kaiser Permanente HealthConnect Oncology Beacon module.
Authors: Mary Mitsuko Ichiuji, Joanne E. Schottinger, David Campen, Dean Fredriks
Journal: Journal of Clinical Oncology (2013)

238 Background: Ordering and administration of chemotherapy was performed on paper in Kaiser Permanente until 2008. Chemotherapy is complex because treatments can be given over more than one day and over multiple cycles. Side effects may occur which require additional medications. Within the KP system, oncologists used more than 1,400 chemotherapy protocols. Each patient's regimen was physician dictated and standardization was rare. Reliable chemotherapy adminstration data did not exist for clinical quality, utilization and outcomes evaluation. The KP HealthConnect Oncology Beacon Module was created to standardize chemotherapy, enhance safety, and simplify ordering and administration of complex medications. This project required collaboration among oncologists, nurses, pharmacists and information technologists throughout the organization. This process assures that the right patient gets the right drug at the right dose at the right time. Methods: In 2005, a collaborative group of oncologists, nurses, pharmacists and IT from across KP began to develop chemotherapy protocols which included orders for medications, fluids, rates and routes of administration and nursing instructions. They worked with deployment teams to communicate change, assess workflows, develop and deliver training.The guiding principles for protocol development were: Evidence Based Effectiveness, Safety, Efficiency and Cost. Results: Decreased number of Chemotherapy Protocols through evidence review and consensus from 1,400 to 433 standardized templates. 84% or higher adherence to evidence-based templates. Reduced adverse events per 1,000 chemotherapy related medications by 9% at the San Jose Medical Center (pilot site). Increases capability to manage pharmacy and biotechnology resources and respond quickly to new knowledge about treatments or drug efficacy ( incorporated use of Gcsf to Docetaxol-Cyclophosphamide when excessive febrile neutropenia was found). Provides database for treatment outcomes research that is likely to generate important findings. Conclusions: The KP Health Connect Oncology Beacon Module exemplifies what KP is uniquely able to deliver: integration, standardization and use of technology to offer the highest quality care for our members.
Douglas B Brewer
Authors: Alexander J Howie
Journal: BMJ (2017)

Douglas Bertram Brewer was an eminent renal pathologist. He was important in the development both of the understanding of kidney diseases and of the specialty of renal biopsy pathology—for example, through his book, Renal Biopsy (1964 and 1973). He was nationally and internationally respected in this area and was a coauthor of the famous paper that established the value of steroids in the treatment of minimal change nephropathy.1

Douglas Brewer was born on 5 August 1919 in south Wales. His father was a general practitioner. Douglas studied medicine in Cardiff but took the University of London examinations and qualified MB BS in 1943, and later MD in 1947. After service in the Royal Army Medical Corps in Europe and East Africa from 1944 to 1946, he joined the department of pathology and bacteriology in the Welsh National School of Medicine. In November 1948, he moved to the University of Birmingham, where he spent …
Analysis of patterns of failure and prognostic factors in resected extrahepatic bile duct cancer: Implications for postoperative adjuvant radiotherapy.
Authors: Jae-Sung Kim, Tae Ryool Koo
Journal: Journal of Clinical Oncology (2013)

266 Background: This study is aimed to analyze the patterns of failure and evaluate the prognostic factors in the patients with extrahepatic bile duct cancer (EBDC) for the potential role of postoperative adjuvant radiotherapy (PORT). Methods: We retrospectively reviewed the medical records of 106 patients with EBDC who received curative intent surgical resection. The definitions of tumor location were as follows: proximal EBDC (n = 29) from the confluent portion of the bilateral hepatic bile ducts to the junction of cystic duct, and distal EBDC (n = 77) from the junction of cystic duct to intrapancreatic portion. Nine patients underwent adjuvant chemoradiotherapy or chemotherapy. Results: The median follow-up time was 24 months for the surviving patients. Forty patients experienced locoregional failure (LRF) initially; 13 (45%) with proximal EBDC and 27 (35%) with distal EBDC. The hepatoduodenal ligament (HL) and tumor bed were the most common LRF sites. Distant metastasis (DM) occurred in 10 patients (34%) with proximal EBDC and 15 patients (19%) with distal EBDC. The liver was the most common organ of DM. In the multivariate analysis, perineural invasion (PNI) and postoperative high carbohydrate antigen (CA) 19-9 were associated with poor LRPFS. Conclusions: Both proximal and distal EBDC showed remarkable proportion of LRF. Because the HL and tumor bed are where routinely covered by PORT, it can be speculated that the addition of PORT can improve LRPFS in these patients. Especially PORT needs to be considered in patients with PNI and postoperative high CA 19-9 to improve locoregional control.
Nimotuzumab different administration time due to human lung adenocarcinoma A549, CALU6 cell radio-sensitization study.
Authors: Z. Yuan, X. Liu
Journal: Journal of Clinical Oncology (2011)

e21044 Background: EGFR inhibitors can increase radiation sensitivity. We use in vitro cultured A549, Calu-6 cell lines as the objects to evaluate nimotuzumab’s radio sensitization. Methods: Cultured A549, Calu-6 cells, select cells in the logarithmic phase divided into six groups: control (O), nimotuzumab (N), radiation (R), radiation plus drug 24 hours before (N→R), applied radiation and drug at the same time (NR) and 24 hours posterior irradiation dosing (R→N). Thiazolyl blue (MTT) assay were detected nimotuzumab inhibitory effects, and calculated values of the IC50 and IC20, respectively. IC20 values were selected as future experimental concentration. Colony formation assay was administered for nimotuzumab in A549, Calu-6 cells and the mapping of Radio-sensitization of cell survival curves. Flow cytometry detection of the cell cycle and apoptosis index changes. Western blot in all experimental groups were detected EGFR, phospho-DNA-PK, Bcl-2, Bax, P21, Akt, pAkt and other proteins. Results: All cells express EGFR. A549 percentage of cells in each group the proportion of the cell cycle: with the O and N group were led to the highest proportion of G1/G0 phase cells, R group of the G2/M phase cells increased; with the R, N→R, NR, R→N groups were the G2/M phase cells increased, in which N→R group of G2/M phase cells are the highest. Calu-6 the percentage of cells in each group the proportion of the cell cycle: N group of cells in G1/G0 arrest was not obvious, N→R group of G2/M phase cells are the highest. Nimotuzumab in two cell lines can increase the radiation-induced apoptosis, but the N→R group the highest rate of apoptosis. Conclusions: Nimotuzumab dosing time does not affect A549 cells radio sensitization effect, but affect prior the radio-sensitizing of the most obvious. Calu-6 cells before irradiation add nimotuzumab produced a more radio sensitization effect.
Preoperative radiotherapy combined with simultaneous chemotherapy with capecitabine plus oxaliplatin versus surgery alone: A single-centered, phase II study in patients with mid/low rectal cancer.
Authors: Fulong Wang, Zhen-Hai Lu, Zhizhong PAN, Yuan-Hong Gao, Gong Chen, Xiaojun Wu, Pei-Rong Ding, Zhi-Fan Zeng, Desen Wan
Journal: Journal of Clinical Oncology (2014)

609 Background: Though total mesorectal excision (TME) has proved to effectively decrease local recurrence rate of mid/low rectal cancer, the efficacy of preoperative radiotherapy in Asian patients remains unclear. The present study aimed to compare the efficacy of TME alone versus TME after preoperative radiotherapy and simultaneous chemotherapy with capecitabine plus oxaliplatin in Chinese patients with stage II and III mid/low rectal adenocarcinoma. Methods: Patients (n=192) aged between 18 and 70 years enrolled from March 23, 2008 to August 2, 2012 were randomly divided into two groups. Group A (n=97) received preoperative radiotherapy and simultaneous chemotherapy [46-50 GY/23-25 with oxaliplatin 100 mg/m 2 (D1) and capecitabine 1,000 mg/m 2 (bid, D1-15), repeated since D22], which was followed by TME; while patients in group B (n=95) underwent TME alone. While disease free survival (DFS) was the primary endpoint; the following were evaluated as secondary endpoints: pathological response rate, pathologic complete response (PCR) rate, anal preservation rate, local recurrence rate, distant metastasis rate, acute toxic effects, and late toxic effects. Results: Excluding the drop outs, 90 and 94 patients were analyzed in group A and B, respectively. The median follow-up time was 29 (range: 0 to 59) months. PCR was achieved for 32 patients (35.6%). The median survival time and overall survival (OS) rate in group A were 24 months and 92.5% (95% CI: 88.3-96.7), respectively; while the same were 34 months and 88.7% (95% CI: 84.8-92.6) in group B. The median DFS time was 22 and 31 months in group A and B, respectively; and the overall DFS was 86.1% (95% CI: 81.6-90.6%) and 80.6% (95% CI: 74.8-85.4%) in both groups. No significant differences were observed between groups in OS rate (p=0.323), overall DFS, (p=0.612), and anal preservation rate (p=0.849). Conclusions: Preoperative radiotherapy combined with chemotherapy of capecitabine plus oxaliplatin could result in higher PCR rate. However, studies with long follow up and large sample are recommended to demonstrate the efficacy of this treatment strategy over TME alone. Clinical trial information: ChiCTR-TRC-00000122.