tbuckley/cabot-search huggingface dataset:
Validation of IHC4 algorithms for prediction of risk of recurrence in early breast cancer using both conventional and quantitative IHC approaches.
Authors: Jason Christiansen, John M. S. Bartlett, Mark Gustavson, David Rimm, Tammy Robson, Cornelis J. H. Van De Velde, Annette Hasenburg, Dirk Guenter Kieback, Hein Putter, Christos Markopoulos, Luc Yves Dirix, Caroline M. Seynaeve, Daniel Rea
Journal: Journal of Clinical Oncology (2012)

517 Background: Hormone receptors, HER2 and Ki67 are residual risk markers in early breast cancer. Combining these markers into a unified algorithm (IHC4) provides information on residual recurrence risk of patients treated with hormone therapies. This study aimed to independently investigate the validity of the IHC4 algorithm for residual risk prediction using both conventional (DAB)-IHC and quantitative immunofluorescence (QIF-AQUA). Methods: The TEAM pathology study recruited &gt;4500 samples from patients treated in the TEAM trial. TMAs were stained for ER, PgR, HER2 and Ki67 using QIF-AQUA technology or DAB-based immunohistochemistry (DAB-IHC). Central HER2 FISH was performed. Quantitative image analysis was used to generate expression scores that were normalized to produce “IHC4 algorithm” as well as novel algorithm scores. Algorithm scores were compared with disease recurrence in univariate and multivariate Cox Proportional Hazards models. Results: Both DAB-IHC and QIF-AQUA IHC4 continuous models were significant (P&lt;0.0001) for prediction of disease recurrence with a continuous Hazard Ratio (HR) of 1.011 (1.010 – 1.013) for QIF-AQUA IHC4 versus 1.008 (1.007 – 1.010) for the DAB-IHC IHC4 model using the published IHC4 algorithm (Cuzick et al 2011). Binning continuous model scores (4 bins) by Kaplan-Meier survival analysis was used to graphically illustrate these effects. De novo models for both DAB-IHC and QIF-AQUA were also significantly (P&lt;0.0001) predictive of residual risk in early breast cancer. Additionally, all 4 models were independent predictors of recurrence (P&lt;0.0001) with other recognized clinical prognostic factors in multivariate analysis. Although results from DAB and QIF-AQUA were modestly correlated, the QIF-AQUA model showed enhanced prediction of recurrence in both Cox Proportional Hazards Modeling and C-index calculations. Conclusions: Either conventional DAB or QIF-AQUA methods of IHC provided evidence supporting the clinical utility of IHC4 algorithms in the context of the TEAM study. With careful standardization, either of these IHC4 assays should be considered for prediction of residual risk in early breast cancer.
Adalimumab in Crohn's strictures––the CREOLE study
Authors: Ajinkya Ashok Sonambekar, Devendra C Desai, Anand Joshi, Pavan Dhoble
Journal: Gut (2017)

Adalimumab in Crohn's strictures--the CREOLE studyWe compliment the authors of the CREOLE study 1 evaluating the efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture.That about two-thirds of patients responded at 24 weeks and about a third of the symptomatic patients were able to avoid surgery at 4 years is impressive.The authors also need to be complimented for attempting to develop a predictive model.A typographical error seems to have unfortunately crept into their manuscript.Table 3 mentions the length of the strictures on MRI in millimetres, when they probably meant centimetres.Three of the ninety-seven patients in this study had L2 disease; the inclusion criteria were restricted to patients with small bowel strictures.Did these patients have colonic strictures as well?Would the symptoms then not be misleading?Crohn's disease obstructive score is a tool based on the experience of the authors and needs validation.It is subjective and difficult to use.Especially grade 3, which suggests different severity of obstructive pain.It needs modification to a simpler grading system such as mild, moderate (associated symptoms and dietary restriction) and severe.Only two small earlier studies have looked into the effect of biologics (infliximab) on strictures in Crohn's disease. 2 3 It would therefore be interesting to know the outcome of the 35 patients in this study who received infliximab.If the results from the CREOLE study are reproduced in more randomised controlled trials, it will have significant impact on decision-making in these patients.
A phase II trial of conventional radiation therapy (XRT) plus high dose tamoxifen (TAM) for the treatment of supratentorial glioblastoma multiforme (GBM): RTOG protocol BR-0021
Authors: H. I. Robins, M. Won, C. Schultz, A. Choucair, D. Brachman, W. Demas, M. Mehta
Journal: Journal of Clinical Oncology (2004)

1529 Background: Preclinical studies support the concept that inhibition of protein kinase C (PKC) by TAM should provide both anti-neoplastic effects and radiosensitization. Methods: High dose TAM (80 mg/m2PO daily in divided doses) was given with and after conventional XRT to inhibit PKC mediated signaling, which is known to be enhanced in GBM. Patients (n=77) were accrued between 12/00–12/01; 75 patients were analyzable. Pretreatment characteristics included: 52%<60 years of age; 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms; 65% were RTOG -recursive partition analysis (RPA) class III & IV. Results: A sample of 46 patients was reviewed for TAM delivery; 78% achieved acceptable dosing. Notable toxicity included: Late radiation Grade (G) G3 =2; Thrombo-embolic disease G2=2, G3=8, G4=3, G5=1 for an incidence of 18.7%, (which is lower than expected, based on the literature for DVT in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months (M). This result was compared (using 3 different statistical methodologies) to the historical GBM control database of 1443 drug / XRT treated patients RPA class III, IV, & V. After controlling for RPA class IV, the MST was 11.3M, which compares to the historical RPA control of 11.2 M (p=0.38).Conclusions: 1) The results obtained do not exhibit a substantial advance over previous studies with various XRT/drug doublets including BCNU. As TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trails. 2) Historically the incidence of thrombo-embolic events in GBM patients is ∼30%. The lower than expected incidence seen here has also been observed in other high dose TAM GBM studies. We speculate that TAM inhibited the PKC mediated phosphorylation of coagulation factors. No significant financial relationships to disclose.
LOTUS: A randomized, phase II, multicenter, placebo-controlled study of ipatasertib (Ipat, GDC-0068), an inhibitor of Akt, in combination with paclitaxel (Pac) as front-line treatment for patients (pts) with metastatic triple-negative breast cancer (TNBC).
Authors: Sung-Bae Kim, Antoinette R. Tan, Seock-Ah Im, Rafael Villanueva, Vicente Valero, Cristina Saura, Mafalda Oliveira, Steven J. Isakoff, Stina Mui Singel, Rebecca Alexandra Dent
Journal: Journal of Clinical Oncology (2015)

TPS1111 Background: The PI3K/Akt pathway is often activated in TNBC through loss of PTEN expression, low INPP4B expression, and/or increased AKT3 amplification. Activation of Akt may then lead to chemoresistance; thus, inhibition of Akt signaling may result in improved efficacy of chemotherapy in TNBC. Ipatasertib (GDC-0068) is an oral, potent ATP-competitive small molecule inhibitor of all three isoforms of Akt. In preclinical breast cancer models, the combination of Ipat with taxanes enhanced efficacy. In a Phase Ib clinical study, the combination of Ipat with Pac was well-tolerated; the most commonly reported adverse events associated with Ipat were Grade 1-2 diarrhea, nausea, fatigue, vomiting, decreased appetite, and rash. RECIST responses were seen with the combination, including pts with tumors having PI3K/Akt activation. Methods: LOTUS is a randomized, double-blind, placebo-controlled, global Phase II study designed to estimated the efficacy and safety profile of Pac plus Ipat versus Pac plus placebo in pts with inoperable locally advanced or metastatic TNBC not amenable to resection with curative intent. Approximately 120 pts with measurable TNBC will be randomized (1:1) and stratified by prior adjuvant/neoadjuvant treatment, disease free interval from last dose of chemotherapy, and tumor PTEN status. Pts will receive Ipat or placebo 400 mg orally once daily on Days 1 to 21 of each 28-day cycle with Pac 80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle until disease progression, intolerable toxicity, withdrawal, or study completion. Pts will then be followed every 3 months for survival. The primary efficacy outcome is progression-free survival in all pts and in pts with PTEN-low tumors. Additional endpoints include overall survival, objective response rate, duration of response, safety, pharmacokinetics, patient-reported outcomes, and correlative biomarkers. The study is open for accrual.Clinical trial information: NCT02162719.
Low-grade inflammation and exercise training in women with breast cancer: A meta-analysis with meta-regression.
Authors: Jose F Meneses-Echavez, Robinson Ramirez-Velez, Jorge Enrique Correa Bautista
Journal: Journal of Clinical Oncology (2015)

e12581 Background: Strong evidence has demonstrated that exercise training reduces breast cancer risk by 10-25%, and several biological mechanisms have been proposed to explain the positive modulation of inflammatory mediators associated with the tumor microenvironment. This study aims to determine the effects of exercise training on markers of low-grade inflammation in breast cancer survivors. Methods: A systematic literature review of randomized controlled trials (RCTs) evaluating the changes in inflammatory mediators in breast cancer survivors after exercise training was performed. The PubMed, Embase, Scopus and CENTRAL databases and other gray literature resources were searched without language restrictions from January 1990 to March 2014. Two investigators screened and identified the studies that met the inclusion criteria. An inverse of variance model of meta-analysis was performed using a random effects model in the presence of statistical heterogeneity (I2< 50%). Publication bias was evaluated using Egger’s test (p < 0.05). Results: Nine high-quality RCTs (n = 349) were ultimately included. Exercise training improved the serum concentrations of IL-6 (mean difference (MD) = -0.37, 95%CI -0.61 to -0.12), IL-2 (MD = 1.03, 95%CI 0.39 to 1.66), IL-8 (MD = -0.49, 95%CI -0.89 to-0.08) and TNF-α (MD = -0.48, 95%CI -0.96 to -0.003, p = 0.04). Conversely, no significant differences were found in the serum concentrations of C-reactive protein (CRP) or IL-10. There was no evidence of publication bias (p= 0.06). Conclusions: Exercise training positively modulates low-grade inflammation in women with breast cancer, impacting carcinogenic mechanisms and the tumor microenvironment. Additional RCTs are required to further elucidate the anti-inflammatory effects of exercise on breast cancer survivors.
Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy
Authors: Fei Yue, Wenjiao Li, Jing Zou, Xianhan Jiang, Guibin Xu, Hai Huang, Leyuan Liu
Journal: Cancer Research (2017)

Abstract Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost, and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy, which trigger oxidative stress–induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S, which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration, which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan. Cancer Res; 77(11); 2938–51. ©2017 AACR.
A possible association of human papilloma virus with a subset of colorectal adenocarcinomas
Authors: P. M. Weinberger, Z. Yu, M. Zerkowski, G. Chung, R. L. Camp, D. L. Rimm, A. Psyrri
Journal: Journal of Clinical Oncology (2004)

3544 Background: There have been some reports of an association between human papilloma virus (HPV) and colonic neoplasms, but large scale investigations of this subject are particularly lacking. In this study we examined a cohort of colorectal adenocarcinomas for the presence of HPV 16 and 18 E6 viral protein expression. Methods: A tissue microarray including specimens from 447 patients with primary colorectal adenocarcinoma was employed. Using a novel quantitative protein analysis system (AQUA), expression levels of HPV 16/18 E6 oncoprotein were determined. This system uses an anti-cytokeratin antibody conjugated to Cy3 to define pixels as tumor within the tissue spot. The intensity of HPV 16/18 E6 expression is then measured using Cy5 conjugated antibody with signal amplification. Scores were divided into quartiles and correlated with clinical and pathological variables. Results: The primary sites were rectum/sigmoid (237), descending/transverse (84), ascending colon/cecum (61) and colon, not specified (65). Tumors were stage I (97), II (121), III (162), IV (46) and not specified (21). A significant relationship was found between high-risk HPV E6 protein expression and distal tumor location (p=0.007). High HPV E6 expression was also associated with lower stage (p<0.001). Analysis of a colon adenocarcinoma tumor with Real-Time PCR confirmed HPV16 presence. Conclusion: To our knowledge this is the largest cohort of colorectal adenocarcinomas examined specifically for HPV oncoprotein expression. Our findings indicate a possible association of HPV 16/18 types with colorectal adenocarcinoma. Specimens expressing higher levels of E6 protein were associated with lower stage and distal location. HPV-associated tumors of the head and neck area are also associated with a lower stage. The association of HPV with distal colonic location may be explained by retrograde viral transmission from the perineum to the lower gastrointestinal tract. No significant financial relationships to disclose.
Associations of HER2-specific immunity with survival during treatment with trastuzumab and chemotherapy in breast cancer.
Authors: Keith L. Knutson, Raphael A. Clynes, Patrick Yeramian, Kathleen P. Kemp, Barath Shreeder, Karla V. Ballman, Kathleen S. Tenner, Courtney L. Erskine, Nadine Norton, Donald W. Northfelt, Winston Tan, Mark D. Pegram, Carmen Julia Calfa, Elizabeth Ann Mittendorf, Edith A. Perez
Journal: Journal of Clinical Oncology (2015)

587 Background: The addition of trastuzumab to chemotherapy improves response to therapy and extends survival among patients with HER2-positive (HER2+) breast cancer. Prior work showed that trastuzumab and chemotherapy also induces HER2 extracellular domain (ECD)-specific antibodies which correlate with tumor shrinkage. The present study investigates whether combination therapy induced immune responses to other tumor antigens and whether immune responses are associated with survival. Methods: Pretreatment and posttreatment sera were obtained from 54 women with metastatic HER2+ breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies N0337 and N983252. IgG to HER2, p53, IGFBP2, CEA and tetanus toxoid were examined using ELISAs. Sera from an age-matched group (25 patients) of controls and 26 HER2+ adjuvant patients were also examined. Results: Prior to therapy, some patients with metastatic disease had elevated IgG levels to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and adjuvant patients. Elevated preexisting immunity to HER2 was associated with significantly worse outcome (p < 0.003). Following therapy, increases in levels of IgG to IGFBP2, HER2-ICD, HER2-ECD, and p53 were observed in metastatic patients who did not have elevated preexisting immunity. Increased immunity to HER2 was associated with improved progression-free (p < 0.003) and overall survival (p < 0.04). Conclusions: Combination treatment results in induction of adaptive immunity to multiple antigens that contribute to disease outcome. If these results are validated, this could provide the basis for the development of biomarkers predictive of therapeutic benefit and the development of new therapeutic approaches with monoclonal antibodies.
Differential serum protein expression in PSA-Stable and PSA-Rising hormone-sensitive advanced prostate cancer using SELDI-TOF mass spectrometry: A preliminary analysis
Authors: R. V. Shah, S. Bhattacharyya, E. Siegel, L. Suva, M. Kohli
Journal: Journal of Clinical Oncology (2004)

4730 Background: We undertook a study in two groups of hormone sensitive prostate cancer patients treated with androgen deprivation therapy (ADT) to identify proteins expressed during disease progression using surface enhanced laser desorption/ionization time-of-flight mass spectroscopy (SELDI-TOF). Methods: Group I (n=18), constituted of patients with a stable-PSA response and Group II (n=16) with a rising PSA during ADT. Group II patients had serially rising PSA measurements. All patient samples were collected prospectively in previous trials and stored. Serum samples were fractionated via ion-exchange batch elution into 6 different fractions based on isoelectric point (pI). 1.4 μL aliquots from the most basic fraction (pI≥9) were applied in duplicate to IMAC 30 ProteinChip arrays, and adsorbed material was subjected to laser desorption/ionization. The resulting spectra were compiled via the ProteinChip Reader (Ciphergen PBS IIC), normalized to total ion current, and mass peaks with mass-to-charge ratios (m/z) ≤20,000 were detected using ProteinChip Reader Software (Ciphergen Biosystems). Masses were identified as peaks if they had a signal-to-noise ratio >2 and were present in at least 10% of the spectra. For each patient, the average intensity per peak was calculated and tested for univariately significant differences between the two groups via the Kruskal-Wallis test. Results: Of 119 peaks having m/z between 2000 and 20,000, seven were statistically significant (P<0.05), with Group II median intensities higher for three peaks and lower for four. An additional eight peaks were marginally significant (0.05≤P<0.10), with Group II median intensities higher for five peaks and lower for three. Conclusions: Rising PSA is an initial indicator of disease progression during ADT. At this stage we evaluated and found significant differential serum protein expression in these sequential stages. Further studies will identify these proteins. This information can be potentially used for targeting expressed proteins during relapse, which may contribute to enhancement of response. No significant financial relationships to disclose.
Indocyanine green fluorescence imaging system as an alternative to the conventional sentinel lymph node mapping using a radiotracer in breast cancer.
Authors: Tomoharu Sugie, Takayuki Kinoshita, Norikazu Masuda, Terumasa Sawada, Akira Yamauchi, Katsumasa Kuroi, Tetsuya Taguchi, Hiroko Bando, Hiroyasu Yamashiro, Tecchuu Lee, Nobuhiko Shinkura, Hironori Kato, Takafumi Ikeda, Kenichi Yoshimura, Hanae Ueyama, Masakazu Toi
Journal: Journal of Clinical Oncology (2014)

1091 Background: Near-infrared fluorescence signal of indocyanien green (ICG) can visualize subcutaneous lymphatic flows and draining (sentinel) lymph nodes (SLNs). In fluorescence ICG Breast Study Group 01 study (fICG BR01), this ICG fluorescence mapping was superior to the dye method in early stage breast cancer (Sugie T, et al. Ann Surg Oncol 2013). The following fICG BR02 study evaluates clinical usefulness of this ICG fluorescence method in comparison to the conventional radioisotope (RI) method. Methods: On the day before or on the day of SLN biopsy, 99mTc-labelled colloid was injected into the subareolar region of each patient. Before the start of operation, ICG was injected into the subareolar region and lymphatic flows bound for the axilla were traced with PDE camera (Hamamatsu Photonics Co, Japan). A real-time navigation surgery by ICG florescence imaging enabled to identify SLNs to be excised. A gamma probe was used to verify no residual radioactivity in the axilla after SLN removal. Results: A total of 847 women with T1-2 breast cancer were enrolled and 821 pts. were included in the per-protocol final analysis. The median pts. age was 55 (range, 22-80) years and the median BMI was 22.1 (range, 14.9-38.8) kg/m2. There was no significant difference in the detection rate between the ICG and RI method (97.2% vs 97.0%). However, a combination of ICG and RI achieved a significant higher detection rate than RI alone (99.8% vs 97%, p<0.001). The involvement of SLNs was found in 180 pts. and a detection rate of positive SLN using ICG fluorescence and RI was 93.3% and 90%, respectively. The detection rate of SLNs with a combination of ICG and RI was improved significantly compared with RI alone (97% vs 90%, p<0.001). There is no serious adverse event due to hypersensitivity to ICG. Conclusions: The ICG fluorescence method has a high detection rate of SLN comparable with that of the RI method. A combination of these two methods yield a significant improvement of SLN detection compared with RI alone. The results of this study confirm that ICG fluorescence imaging system is an alternative and/or additive to the conventional SLN mapping using a radioactive tracer in breast cancer. Clinical trial information: UMIN000005167.