Cancer via Alexandros G.Sfakianakis on Inoreader

Source:  Cancer via Alexandros G.Sfakianakis on Inoreader    Tag:  partial trisomy 9p
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Cancer via Alexandros G.Sfakianakis on Inoreader

The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer
1:28:31 AM
Publication date: Available online 13 August 2015
Source:European Journal of Cancer
Author(s): R.J. van Soest, A.J.M. Nieuweboer, E.S. de Morrée, D. Chitu, A.M. Bergman, S.H. Goey, M.M. Bos, N. van der Meer, P. Hamberg, R. de Wit, R.H.J. Mathijssen
IntroductionThe treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC.Patients and methodsData from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (?50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel.ResultsFrom the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P=0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0months, respectively, logrank P=0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase.ConclusionOur study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.



High subcutaneous adipose tissue predicts the prognosis in metastatic castration-resistant prostate cancer patients in post chemotherapy setting
1:28:31 AM
Publication date: Available online 13 August 2015
Source:European Journal of Cancer
Author(s): Sami Antoun, Amine Bayar, Ekatarina Ileana, Agnès Laplanche, Karim Fizazi, Mario di Palma, Bernard Escudier, Laurence Albiges, Christophe Massard, Yohann Loriot
BackgroundCancer studies have shown that body mass index (BMI), skeletal muscle mass (SMM) and adipose tissue indexes are linked to overall survival (OS) and progression-free survival (PFS). New treatments (abiraterone acetate, enzalutamide cabazitaxel, radium-223, sipuleucel-T) have improved patient outcomes in metastatic castration-resistant prostate cancer (mCRPC). Our objective was to analyse whether body composition parameters exert a prognostic role in mCRPC patients treated with next generation of androgen receptor (AR) axis inhibitors (abiraterone and enzalutamide).MethodsAll mCRPC patients from our institution who were enrolled in two prospective trials, assessing the efficacy of abiraterone acetate and the efficacy of enzalutamide, were selected. SMM, visceral and subcutaneous adipose tissue (SAT) indexes were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues.ResultsIn the 120 patients with available data, median OS and PFS were respectively: 16months (95% confidence interval [CI]=12-19) and 4months (95% [CI]=3-6). OS was associated with the SAT index: median survival was 15months (95% [CI] 9-18) for patients with a SAT index<median value and 18months (95% [CI] 13-30) for patients with a SAT index above (P=0.008). In multivariate analyses, only the occurrence of visceral metastasis (P=0.004), pain (P=0.015) and SAT index (P=0.036) were statistically significant predictors of OS. From baseline to 3months, the SMM index loss was 2.49±0.44cm2/m2 (P<0.001) corresponding to nearly 3.4kg of muscle loss.ConclusionsHigh volume of SAT is independently associated with overall survival in mCRPC patients treated with next generation AR axis inhibitors.



Non-invasive, serum DNA pregnancy testing leading to incidental discovery of cancer: A good thing?
1:28:31 AM
Publication date: Available online 13 August 2015
Source:European Journal of Cancer
Author(s): Vinay Prasad
Cell-free DNA for perinatal screening is a growing industry. Non-invasive prenatal testing (NIPT) is based on the premise that foetal DNA is able to cross the placental barrier and enter the mother's circulation, where it can be examined for chromosomal abnormalities, such as trisomy 13, 18 or 21. Such tests are expected to be widely used by pregnant women, with the annual market expected to surpass $1 billion.Recently, a number of case reports have emerged in the haematology-oncology literature. The routine use of NIPT has led to the discovery of maternal neoplasms. Most writers have concluded that this is yet another benefit of the test; however, a closer examination of the cases reveals that this incidental detection may not improve patient outcomes. In some cases, early detection provides lead time bias, but does not change the ultimate clinical outcome, and in other cases, detection constitutes earlier knowledge of a cancer whose natural history cannot be altered. Here, we explore in detail cases where cancer was incidentally discovered among women undergoing routine non-invasive pregnancy testing, and investigate whether or not these women were benefitted by the discovery.



Optimal breast cancer pathology manifesto
1:28:31 AM
Publication date: Available online 14 August 2015
Source:European Journal of Cancer
Author(s): T. Tot, G. Viale, E. Rutgers, E. Bergsten-Nordström, A. Costa
This manifesto was prepared by a European Breast Cancer (EBC) Council working group and launched at the European Breast Cancer Conference in Glasgow on 20 March 2014.It sets out optimal technical and organisational requirements for a breast cancer pathology service, in the light of concerns about variability and lack of patient-centred focus.It is not a guideline about how pathology services should be performed. It is a call for all in the cancer community - pathologists, oncologists, patient advocates, health administrators and policymakers - to check that services are available that serve the needs of patients in a high quality, timely way.



A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer
1:28:31 AM
Publication date: Available online 14 August 2015
Source:European Journal of Cancer
Author(s): G. Giaccone, L.A. Bazhenova, J. Nemunaitis, M. Tan, E. Juhász, R. Ramlau, M.M. van den Heuvel, R. Lal, G.H Kloecker, K.D. Eaton, Q. Chu, D.J. Dunlop, M. Jain, E.B. Garon, C.S. Davis, E. Carrier, S.C. Moses, D.L. Shawler, H. Fakhrai
BackgroundTreatment options after first-line chemotherapy are limited in non-small cell lung cancer (NSCLC). Belagenpumatucel-L is a therapeutic vaccine comprised of 4 transforming growth factor (TGF)-?2-antisense gene-modified, irradiated, allogeneic NSCLC cell lines that may be useful for maintenance after initial treatment.MethodsStage III/IV NSCLC patients who did not progress after platinum-based chemotherapy were randomised 1:1 to receive maintenance belagenpumatucel-L or placebo. Patients were eligible for randomisation between one and four months from the end of induction chemotherapy. The primary endpoint was overall survival.ResultsThis phase III trial enrolled 270 patients in the belagenpumatucel-L arm and 262 in the control arm. Belagenpumatucel-L was well tolerated with no serious safety concerns. There was no difference in survival between the arms (median survival 20.3 versus 17.8months with belagenpumatucel-L versus placebo, respectively; hazard ratio (HR) 0.94, p=0.594). There were also no differences in progression-free survival (4.3months versus 4.0 for belagenpumatucel-L vs placebo, respectively; HR 0.99, p=0.947). A prespecified Cox regression analysis demonstrated that the time elapsed between randomisation and the end of induction chemotherapy had a significant impact on survival (p=0.002) and that prior radiation was a positive prognostic factor (median survival 28.4months with belagenpumatucel-L versus 16.0months with placebo; HR 0.61, p=0.032).ConclusionsAlthough the overall trial did not meet its survival endpoint, improved survival for belagenpumatucel-L is suggested in patients who were randomised within 12weeks of completion of chemotherapy and in those who had received prior radiation. Further studies of belagenpumatucel-L in NSCLC are warranted.



Imatinib in advanced chordoma: A retrospective case series analysis
1:28:31 AM
Publication date: Available online 14 August 2015
Source:European Journal of Cancer
Author(s): Nadia Hindi, Paolo G. Casali, Carlo Morosi, Antonella Messina, Elena Palassini, Silvana Pilotti, Elena Tamborini, Stefano Radaelli, Alessandro Gronchi, Silvia Stacchiotti
IntroductionImatinib showed activity in 50 chordoma patients treated within a Phase II study. In that study, 70% of patients remained with stable disease (SD), median progression free survival (PFS) was 9months and median overall survival (OS) was 34months. We now report on a retrospective series of PDGFB/PDGFRB positive advanced chordoma patients treated with imatinib as a single agent within a compassionate-use programme at Istituto Nazionale Tumori, Milan, Italy (INT) between August 2002 and November 2010, when the programme was closed.Methods48 patients were consecutively treated with imatinib 800mg/d. All patients had inoperable and progressive disease before starting imatinib. Demographics, treatment duration, toxicity and response rate by Response Evaluation Criteria in Solid Tumors (RECIST) were retrospectively recorded.ResultsThe median duration of therapy was 7months (1-46.5). No patient is on therapy at present. 46 patients were evaluable for response. No partial responses were detected. Best response was: stable disease 34 (74%), progressive disease 12 (26%). At a median follow-up of 24.5months (0.5-117), median PFS was 9.9months (95% confidence interval (CI) 6.7-13). Eight patients (16.5%) remained on therapy >18months and 10 patients (21%) remained progression-free >18months. Median OS was 30months (95% CI 20-40), with 24 (50%) patients dead at the time of the present analysis.ConclusionsWe confirm the activity of imatinib in locally advanced and metastatic chordoma, in terms of >70% tumour growth arrest in previously progressive patients. Median duration of response lasted almost 10months, with >20% of patients progression-free at 18+ months.



Consumption of soy isoflavone enriched bread in men with prostate cancer is associated with reduced pro-inflammatory cytokines and immunosuppressive cells.
12:45:48 AM Lesinski, G. B., Reville, P. K., Mace, T. A., Young, G. S., Ahn-Jarvis, J., Thomas-Ahner, J., Vodovotz, Y., Ameen, Z., Grainger, E. M., Riedl, K., Schwartz, S. J., Clinton, S. K.

We hypothesized that soy phytochemicals may have immunomodulatory properties that may impact prostate carcinogenesis and progression. A randomized, phase II trial was conducted in 32 prostate cancer patients with asymptomatic biochemical recurrence but no measurable disease on standard staging studies. Patients were randomized to 2 slices of soy bread (34 mg isoflavones/slice) or soy bread containing almond powder daily as a source of ?-glucosidase. Flow cytometry and bioplex assays were used to measure cytokines or immune cell phenotype in blood at baseline (day 0) and following intervention (day 56). Adequate blood samples were available at enrollment and day 56 and evaluated. Multiple plasma cytokines and chemokines were significantly decreased on Day 56 versus baseline. Subgroup analysis indicated reduced Th1 (p=0.028) and MDSC-associated cytokines (p=0.035). Th2 and Th17 cytokines were not significantly altered. Phenotypic analysis revealed no change in CD8+ or CD4+ T cells, but showed increased CD56+ NK cells (p=0.038). The percentage of cells with a T regulatory cell phenotype (CD4+CD25+FoxP3+) were significantly decreased after 56 days of soy bread (p=0.0136). Significantly decreased monocytic (CD33+HLADRnegCD14+) MDSC were observed in patients consuming soy bread (p=0.0056). These data suggest that soy bread modulates systemic soluble and cellular biomarkers relevant to immunomodulation consistent with limiting inflammation and suppression of MDSCs. Additional studies to elucidate impact on the carcinogenic process or as a complement to immune-based therapy are required.



Colon tumors with the simultaneous induction of APC, KRAS and PIK3CA mutations still progress through the adenoma-to-carcinoma sequence
12:45:48 AM Hadac, J. N., Leystra, A. A., Paul Olson, T. J., Maher, M. E., Payne, S. N., Yueh, A., Schwartz, A. R., Albrecht, D. M., Clipson, L., Pasch, C. A., Matkowskyj, K. A., Halberg, R. B., Deming, D. A.

Human colorectal cancers often possess multiple mutations, including 3-6 driver mutations per tumor. The timing of when these mutations occur during tumor development and progression continues to be debated. More advanced lesions carry a greater number of driver mutations, indicating that colon tumors might progress from adenomas to carcinomas through the stepwise accumulation of mutations following tumor initiation. However, mutations that have been implicated in tumor progression have been identified in normal-appearing epithelial cells of the colon, leaving the possibility that these mutations might be present prior to the initiation of tumorigenesis. We utilized mouse models of colon cancer to investigate whether tumorigenesis still occurs through the adenoma-to-carcinoma sequence when multiple mutations are present at the time of tumor initiation. To create a model in which tumors could concomitantly possess mutations in Apc, Kras, and Pik3ca, we developed a novel minimally invasive technique to administer an adenovirus expressing Cre recombinase to a focal region of the colon. Here we demonstrate that the presence of these additional driver mutations at the time of tumor initiation results in increased tumor multiplicity and an increased rate of progression to invasive adenocarcinomas. These cancers can even metastasize to retroperitoneal lymph nodes or the liver. However, despite having as many as three concomitant driver mutations at the time of initiation, these tumors still proceed through the adenoma-to-carcinoma sequence.



Double-blind randomized 12-month soy intervention had no effects on breast MRI fibroglandular tissue density or mammographic density
12:45:48 AM Wu, A. H., Spicer, D., Garcia, A., Tseng, C.-C., Hovanessian-Larsen, L., Sheth, P., Martin, S. E., Hawes, D., russell, c., MacDonald, H., Tripathy, D., Su, L. M.-y., Ursin, G., Pike, M. C.

Soy supplementation by breast cancer patients remains controversial. No controlled intervention studies have investigated the effects of soy supplementation on mammographic density in breast cancer patients. We conducted a double-blind, randomized, placebo-controlled intervention study in previously treated breast cancer patients (n=66) and high-risk women (n=29). We obtained digital mammograms and breast magnetic resonance imaging (MRI) scans at baseline and after 12 months of daily soy (50 mg isoflavones per day) (n=46) or placebo (n=49) tablet supplementation. The total breast area (MA) and the area of mammographic density (MD) on the mammogram was measured using a validated computer-assisted method, and mammographic density percent (MD% = 100 x MD/MA) was determined. A well-tested computer algorithm was used to quantitatively measure the total breast volume (TBV) and fibroglandular tissue volume (FGV) on the breast MRI, and the FGV percent (FGV% = 100 x FGV/TBV) was calculated. On the basis of plasma soy isoflavone levels, compliance was excellent. Small decreases in MD% measured by the ratios of month 12 to baseline levels, were seen in the soy (0.95) and the placebo (0.87) groups; these changes did not differ between the treatments (P=0.38). Small decreases in FGV% were also found in both the soy (0.90) and the placebo (0.92) groups; these changes also did not differ between the treatments (P=0.48). Results were comparable in breast cancer patients and high-risk women. We found no evidence that soy supplementation would decrease mammographic density and that MRI might be more sensitive to changes in density than mammography.



Physical activity and prostate tumor vessel morphology: data from the Health Professionals Follow-up Study
12:45:48 AM Van Blarigan, E. L., Gerstenberger, J. P., Kenfield, S. A., Giovannucci, E. L., Stampfer, M., Jones, L. W., Clinton, S. K., Chan, J. M., Mucci, L. A.

Vigorous activity is associated with lower risk of prostate cancer progression, but biologic mechanisms are unknown. Exercise affects vascularization of tumors in animal models, and small, irregularly shaped vessels in prostate tumors are associated with fatal prostate cancer. We hypothesized that men who engaged in vigorous activity or brisk walking would have larger, more regularly shaped vessels in their prostate tumors. We prospectively examined whether physical activity was associated with prostate tumor microvessel morphology among 571 men in the Health Professionals Follow-up Study using ordinal logistic regression. Vessel size (µm2), vessel lumen regularity (perimeter2 / 4 · · area), and microvessel density (number per high powered field) were ascertained in tumor sections stained for endothelial cell marker CD34. Vigorous activity [metabolic equivalent task (MET) ? 6], non-vigorous activity (MET <6), and walking pace were assessed a median of 14 months prior to diagnosis. Prostate tumors from men who reported a brisk walking pace (3+ mph) had larger, more regularly shaped blood vessels compared to those of men who walked at a less than brisk pace [vessel regularity odds ratio (OR): 1.59; 95% confidence interval (CI): 1.11, 2.27; p-value: 0.01; vessel size OR: 1.48; 95% CI: 1.04, 2.12; p-value: 0.03]. Brisk walking was not associated with microvessel density; total vigorous and non-vigorous activities were not associated with vessel size, shape, or number. Brisk walking may be associated with larger, more regularly shaped vessels in prostate tumors. Additional research elucidating the effect of physical activity on prostate tumor biology is needed.



EFFECT OF METFORMIN ON BREAST DUCTAL CARCINOMA IN SITU PROLIFERATION IN A RANDOMIZED PRE-SURGICAL TRIAL
12:45:48 AM De Censi, A., Puntoni, M., Guerrieri-Gonzaga, A., Cazzaniga, M., Serrano, D., Lazzeroni, M., Vingiani, A., Gentilini, O., Petrera, M., Viale, G., Cuzick, J., Bonanni, B., Pruneri, G.

Metformin is associated with lower breast cancer (BCa) risk in epidemiological studies and showed decreased proliferation in HER2-positive BCa in a pre-surgical trial. To provide insight into its preventive potential, we measured proliferation by Ki-67 labeling index (LI) of intraepithelial lesions surrounding breast cancer. We randomly assigned 200 non-diabetic patients diagnosed with invasive BCa in core biopsies to metformin, 1700 mg or placebo once daily for 28 days prior to surgery. Upon surgery, 5-7 specimens of cancer adjacent (=1 cm) and distant (>1 cm) tissue were screened for LCIS, DCIS and ductal hyperplasia (DH). The prevalence of LCIS, DCIS and DH was 4.5% (9/200), 67% (133/200) and 35% (69/200), respectively. Overall, metformin did not affect Ki-67 LI in pre-malignant disorders. The median post-treatment Ki-67 LI [IQR] in the metformin and placebo arm was, respectively, 15% [5-15] versus 5% [4-6] in LCIS (p= 0.1), 12% [8-20] vs. 10% [7-24] in DCIS (p=0.9) and 3% [1-4] vs. 3% [1-4] in DH (p= 0.5). However, post-treatment Ki-67 in HER2-positive DCIS lesions was significantly lower in women randomized to metformin especially when ER was co-expressed: 22% [11-32] versus 35% [30-40] in HER2-positive DCIS (n=22, p=.06); 12% [7-18] versus 32% [27-42] in ER-positive/HER2-positive DCIS (n=15, p=.004). Eight of 22 (36%) HER2-positive DCIS were adjacent to HER2-negative invasive BCa. In tissue samples obtained following 4 weeks of study drug, proliferation was lower in HER2-positive DCIS for women randomized to metformin vs. placebo. An adjuvant trial incorporating metformin in HER2-positive DCIS is warranted.



ER{beta} Expression and Breast Cancer Risk Prediction for Women with Atypias
12:45:48 AM Hieken, T. J., Carter, J. M., Hawse, J. R., Hoskin, T. L., Bois, M. C., Frost, M. H., Hartmann, L. C., Radisky, D. C., Visscher, D. W., Degnim, A. C.

Estrogen receptor beta (ER?) is highly expressed in normal breast epithelium and a putative tumor suppressor. Atypical hyperplasia substantially increases breast cancer risk, but identification of biomarkers to further improve risk stratification is needed. We evaluated ER? expression in breast tissues from women with atypical hyperplasia and association with subsequent breast cancer risk. ER? expression was examined by immunohistochemistry in a well-characterized 171 women cohort with atypical hyperplasia diagnosed 1967-1991. Nuclear ER? percent and intensity was scored in the atypia and adjacent normal lobules. An ER? sum score (percent + intensity) was calculated and grouped as low, moderate or high. Competing risks regression was used to assess associations of ER? expression with breast cancer risk. After 15 years median follow-up, 36 women developed breast cancer. ER? expression was lower in atypia lobules than normal lobules, by percent staining and intensity (both p<0.001). Higher ER? expression in the atypia or normal lobules, evaluated by percent staining, intensity or sum score, decreased the risk of subsequent breast cancer by 2 (p=0.04) and 2.5-fold (p=0.006). High normal lobule ER? expression conferred the strongest protective effect in pre-menopausal women: the 20-year cumulative incidence of breast cancer was 0% for women <age 45 with high versus 31% for low-moderate ER? expression (p=0.0008). High ER? expression was associated with a significantly decreased risk of breast cancer in women with atypical hyperplasia. These data suggest ER? may be a useful biomarker for risk stratification and a novel therapeutic target for breast cancer risk reduction.



Non-invasive molecular screening for oral precancer in Fanconi anemia patients
12:45:48 AM Smetsers, S. E., Velleuer, E., Dietrich, R., Wu, T., Brink, A., Buijze, M., Deeg, D. J. H., Soulier, J., Leemans, C. R., Braakhuis, B. J. M., Brakenhoff, R. H.

Loss of heterozygosity at chromosome arms 3p, 9p, 11q and 17p are well-established oncogenetic aberrations in oral precancerous lesions and promising biomarkers to monitor the development of oral cancer. Non-invasive LOH screening of brushed oral cells is a preferable method for precancer detection in patients at increased risk for head and neck squamous cell carcinoma (HNSCC) such as Fanconi anemia (FA) patients. We determined the prevalence of LOH in brushed samples of the oral epithelium of 141 FA patients and 144 aged subjects, and studied the association between LOH and HNSCC. LOH was present in 14 (9.9%) non-transplanted FA patients, whereas no LOH was detected in a low risk group (n=50, >58 years, non-smoking/non-alcohol history) and a group with somewhat increased HNSCC risk (n=94, >58 years, heavy smoking/excessive alcohol use); Fisher's exact test p=0.023 and p=0.001, respectively. Most frequent genetic alteration was LOH at 9p. Age was a significant predictor of LOH (OR 1.13, p=0.001). Five FA patients developed HNSCC during the study at a median age of 39.6 years (range 24.8-53.7). LOH was significantly associated with HNSCC (Fisher's exact test p=0.000). Unexpectedly, the LOH assay could not be used for transplanted FA patients since donor DNA in brushed oral epithelium, most likely from donor leukocytes present in the oral cavity, disturbed analysis. Non-invasive screening using a LOH assay on brushed samples of the oral epithelium has a promising outlook in FA patients. However, assays need to be adapted in case of stem cell transplantation, because of contaminating donor DNA.



Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model
12:45:48 AM Mazzilli, S. A., Hershberger, P. A., Reid, M. E., Bogner, P. N., Atwood, K., Trump, D. L., Johnson, C. S.

The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C) (80 ?g/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 µmol NTCU (N). After treatment with 15 ?mol NTCU, the % of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D-deficient +NTCU (DN), 22.7 % (p<0.05 compared to vitamin D-sufficient +NTCU (SN)); DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared to SN mice, DN mice exhibited a 3-fold increase (p <0.005) in circulating white blood cells (WBC), a 20% (p <0.05) increase in IL-6 levels, and a 4 -fold (p <0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted.



Low SFRP1 expression correlates with poor prognosis and promotes cell invasion by activating the Wnt/{beta}-catenin signaling pathway in NPC
12:45:48 AM Ren, X. Y., Zhou, G.-Q., Jiang, W., Sun, Y., Xu, Y. F., Li, Y. Q., Tang, X. R., Wen, X., He, Q.-M., Yang, X. J., Liu, N., Ma, J.

Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in NPC patients. SFRP1 function was evaluated using MTT, colony formation, wound healing, transwell assays and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/?-catenin signaling pathway genes was studied using western blotting. Compared to patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival (hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.36-3.94; P = 0.002), disease-free survival (HR, 1.98; 95% CI, 1.23-3.18; P = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19-3.59; P =0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. ?-Catenin, c-Myc, and Cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/?-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment.



Isoflavone pharmacokinetics and metabolism after consumption of a standardized soy and soy-almond bread in men with asymptomatic prostate cancer
12:45:48 AM Ahn-Jarvis, J., Clinton, S. K., Grainger, E. M., Riedl, K., Schwartz, S. J., Lee, M.-L. T., Raul, C.-C., Young, G. S., Lesinski, G. B., Vodovotz, Y.

Epidemiological associations suggest populations consuming substantial amounts of dietary soy exhibit a lower risk of prostate cancer. A 20-week randomized, phase II, cross-over trial was conducted in 32 men with asymptomatic prostate cancer. The crossover involved 8 weeks each of soy-bread and soy-almond bread. The primary objective was to investigate isoflavone bioavailability and metabolite profile. Secondary objectives include safety, compliance and assessment of biomarkers linked to prostate carcinogenesis. Two distinct soy breads were formulated to deliver ~60 mg aglycone equivalents of isoflavones/day. The isoflavones were present as aglycones (~78% as aglycones,) in the soy-almond bread (SAB) while in the standard soy bread (SB) predominantly as glucosides (18% total isoflavones as aglycones). Compliance to SB (97%±4%) and SAB (92%±18%) was excellent, toxicity was rare and limited to grade I gastrointestinal complaints. Pharmacokinetic studies between SB and SAB showed modest differences. Peak serum concentration time (Tmax) was significantly faster with SAB meal compared with SB in some isoflavonoids and AUC0 to 24 hr of dihydrodaidzein and O-desmethylangolensin was significantly greater after a SB meal. An exploratory cluster analysis was used to identify four isoflavone metabolizing phenotypes. Insulin-like growth factor binding protein increased significantly by 41% (p=0.024) with soy intervention. Findings from this study provide the necessary framework to study isoflavone metabolizing phenotypes as a strategy for identification of individuals that might benefit or show resistance to cancer preventive strategies using dietary soy. A standardized soy bread used for future large-scale randomized clinical trials to impact human prostate carcinogenesis is feasible.



Modulation of Breast Cancer Risk Biomarkers by High Dose Omega-3 Fatty Acids: Phase II Pilot Study in Post-menopausal Women
12:45:48 AM Fabian, C. J., Kimler, B. F., Phillips, T. A., Nydegger, J. L., Kreutzjans, A. L., Carlson, S. E., Hidaka, B. H., Metheny, T., Zalles, C. M., Mills, G. B., Powers, K. R., Sullivan, D. K., Petroff, B. K., Hensing, W. L., Fridley, B. L., Hursting, S. D.

Associational studies suggest higher intakes/blood levels of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) are associated with reduced breast cancer risk. We performed a pilot study of high dose EPA + DHA in post-menopausal women to assess feasibility prior to initiating a phase IIB prevention trial. Postmenopausal women with cytologic evidence of hyperplasia in their baseline random periareolar fine needle aspiration (RPFNA) took 1820 mg EPA +1530 mg DHA ethyl esters daily for 6 months. Blood and breast tissue was sampled at baseline and study conclusion for exploratory biomarker assessment, with p values uncorrected for multiple comparisons. Feasibility was pre-defined as 50% uptake, 80% completion and 70% compliance. Trial uptake by 35 study entrants from 54 eligible women was 65%, with 97% completion and 97% compliance. Favorable modulation was suggested for serum adiponectin (p=0.0027), TNF-alpha (p=0.016), HOMA 2B measure of pancreatic beta cell function (p=0.0048) and bioavailable estradiol (p=0.039). Benign breast tissue Ki-67 (p=0.036), macrophage chemoattractant protein-1 (p=0.033), cytomorphology index score (p=0.014), and percent mammographic density (p=0.036) were decreased with favorable effects in a proteomics array for several proteins associated with mitogen signaling and cell cycle arrest; but no obvious overall effect on proteins downstream of mTOR. Although favorable risk biomarker modulation will need to be confirmed in a placebo-controlled trial, we have demonstrated feasibility for development of high dose EPA and DHA ethyl esters for primary prevention of breast cancer.



Imatinib in advanced chordoma: A retrospective case series analysis
12:30:27 AM Nadia Hindi, Paolo G. Casali, Carlo Morosi, Antonella Messina, Elena Palassini, Silvana Pilotti, Elena Tamborini, Stefano Radaelli, Alessandro Gronchi, Silvia Stacchiotti
Imatinib showed activity in 50 chordoma patients treated within a Phase II study. In that study, 70% of patients remained with stable disease (SD), median progression free survival (PFS) was 9months and median overall survival (OS) was 34months. We now report on a retrospective series of PDGFB/PDGFRB positive advanced chordoma patients treated with imatinib as a single agent within a compassionate-use programme at Istituto Nazionale Tumori, Milan, Italy (INT) between August 2002 and November 2010, when the programme was closed.


A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer
12:30:27 AM G. Giaccone, L.A. Bazhenova, J. Nemunaitis, M. Tan, E. Juhász, R. Ramlau, M.M. van den Heuvel, R. Lal, G.H Kloecker, K.D. Eaton, Q. Chu, D.J. Dunlop, M. Jain, E.B. Garon, C.S. Davis, E. Carrier, S.C. Moses, D.L. Shawler, H. Fakhrai
Treatment options after first-line chemotherapy are limited in non-small cell lung cancer (NSCLC). Belagenpumatucel-L is a therapeutic vaccine comprised of 4 transforming growth factor (TGF)-?2-antisense gene-modified, irradiated, allogeneic NSCLC cell lines that may be useful for maintenance after initial treatment.


Optimal breast cancer pathology manifesto
12:30:27 AM T. Tot, G. Viale, E. Rutgers, E. Bergsten-Nordström, A. Costa
Pathology is a medical speciality that underpins decision-making in many crucial steps of cancer care. Pathologists in many countries are medical doctors who are responsible for a wide - and rapidly growing - range of diagnostic reports on tissue that supports detection and characterisation of disease, and informs the treatment and care carried out by surgeons, oncologists, radiotherapists and other health professionals in the cancer team.


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