Colorectal cancer survival in the USA and Europe: a CONCORD high-resolution study.

OBJECTIVES: To assess the extent to which stage at diagnosis and adherence to treatment guidelines may explain the persistent differences in colorectal cancer survival between the USA and Europe. DESIGN: A high-resolution study using detailed clinical data on Dukes' stage, diagnostic procedures, treatment and follow-up, collected directly from medical records by trained abstractors under a single protocol, with standardised quality control and central statistical analysis. SETTING AND PARTICIPANTS: 21 population-based registries in seven US states and nine European countries provided data for random samples comprising 12 523 adults (15-99 years) diagnosed with colorectal cancer during 1996-1998. OUTCOME MEASURES: Logistic regression models were used to compare adherence to 'standard care' in the USA and Europe. Net survival and excess risk of death were estimated with flexible parametric models. RESULTS: The proportion of Dukes' A and B tumours was similar in the USA and Europe, while that of Dukes' C was more frequent in the USA (38% vs 21%) and of Dukes' D more frequent in Europe (22% vs 10%). Resection with curative intent was more frequent in the USA (85% vs 75%). Elderly patients (75-99 years) were 70-90% less likely to receive radiotherapy and chemotherapy. Age-standardised 5-year net survival was similar in the USA (58%) and Northern and Western Europe (54-56%) and lowest in Eastern Europe (42%). The mean excess hazard up to 5 years after diagnosis was highest in Eastern Europe, especially among elderly patients and those with Dukes' D tumours. CONCLUSIONS: The wide differences in colorectal cancer survival between Europe and the USA in the late 1990s are probably attributable to earlier stage and more extensive use of surgery and adjuvant treatment in the USA. Elderly patients with colorectal cancer received surgery, chemotherapy or radiotherapy less often than younger patients, despite evidence that they could also have benefited.

Meta-analysis of studies analyzing the role of human papillomavirus in the development of bladder carcinoma

PURPOSE We aimed to ascertain the degree of association between bladder cancer and human papillomavirus (HPV) infection. MATERIALS AND METHODS We performed a meta-analysis of observational studies with cases and controls with publication dates up to January 2011. The PubMed electronic database was searched by using the key words "bladder cancer and virus." Twenty-one articles were selected that met the required methodological criteria. We implemented an internal quality control system to verify the selected search method. We analyzed the pooled effect of all the studies and also analyzed the techniques used as follows: 1) studies with DNA-based techniques, among which we found studies with polymerase chain reaction (PCR)-based techniques and 2) studies with non-PCR-based techniques, and studies with non-DNA-based techniques. RESULTS Taking into account the 21 studies that were included in the meta-analysis, we obtained a heterogeneity chi-squared value of Q(exp)=26.45 (p=0.383). The pooled odds ratio (OR) was 2.13 (95% confidence interval [CI], 1.54 to 2.95), which points to a significant effect between HPV and bladder cancer. Twenty studies assessed the presence of DNA. The overall effect showed a significant relationship between virus presence and bladder cancer, with a pooled OR of 2.19 (95% CI, 1.40 to 3.43). Of the other six studies, four examined the virus's capsid antigen and two detected antibodies in serum by Western blot. The estimated pooled OR in this group was 2.11 (95% CI, 1.27 to 3.51), which confirmed the relationship between the presence of virus and cancer. CONCLUSIONS The pooled OR value showed a moderate relationship between viral infection and bladder tumors.

Fluorodeoxyglucose-positron emission tomography scan-positive recurrent papillary thyroid cancer and the prognosis and implications for surgical management.

BACKGROUND To compare outcomes for patients with recurrent or persistent papillary thyroid cancer (PTC) who had metastatic tumors that were fluorodeoxyglucose-positron emission tomography (FDG-PET) positive or negative, and to determine whether the FDG-PET scan findings changed the outcome of medical and surgical management. METHODS From a prospective thyroid cancer database, we retrospectively identified patients with recurrent or persistent PTC and reviewed data on demographics, initial stage, location and extent of persistent or recurrent disease, clinical management, disease-free survival and outcome. We further identified subsets of patients who had an FDG-PET scan or an FDG-PET/CT scan and whole-body radioactive iodine scans and categorized them by whether they had one or more FDG-PET-avid (PET-positive) lesions or PET-negative lesions. The medical and surgical treatments and outcome of these patients were compared. RESULTS Between 1984 and 2008, 41 of 141 patients who had recurrent or persistent PTC underwent FDG-PET (n = 11) or FDG-PET/CT scans (n = 30); 22 patients (54%) had one or more PET-positive lesion(s), 17 (41%) had PET-negative lesions, and two had indeterminate lesions. Most PET-positive lesions were located in the neck (55%). Patients who had a PET-positive lesion had a significantly higher TNM stage (P = 0.01), higher age (P = 0.03), and higher thyroglobulin (P = 0.024). Only patients who had PET-positive lesions died (5/22 vs. 0/17 for PET-negative lesions; P = 0.04). In two of the seven patients who underwent surgical resection of their PET-positive lesions, loco-regional control was obtained without evidence of residual disease. CONCLUSION Patients with recurrent or persistent PTC and FDG-PET-positive lesions have a worse prognosis. In some patients loco-regional control can be obtained without evidence of residual disease by reoperation if the lesion is localized in the neck or mediastinum.

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours.

BACKGROUND Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. METHODS Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5-12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. RESULTS Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m2, which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in Cmax and AUC0-t were dose proportional for the 6-12 mg/m2 doses. CONCLUSION The MTD of weekly cabazitaxel was 12 mg/m2 and the recommended weekly dose was 10 mg/m2. The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. TRIAL REGISTRATION The study was registered with ClinicalTrials.gov as NCT01755390.

Surgical excision with left atrial reconstruction of a primary functioning retrocardiac paraganglioma.

About 2% of all paragangliomas are located in the chest, and a few have been described to be found in the heart. Primary cardiac paragangliomas are extremely uncommon tumors and surgical experience with this neoplasm is limited. Treatment strategies described in the literature have included simple excision, excision with reconstruction, autotransplantation after excision of the tumor and even orthotopic cardiac transplantation, depending on the extent of disease. A primary retrocardiac paraganglioma catecholamine-productive was identified in an asymptomatic 49-year old female associated to familial pheochromocytoma-paraganglioma syndrome caused by germline mutation of the gen which codifies for the subunit B of succinate dehydrogenase enzyme (SDHB). The neoplasm was surgically excised from the posterior surface of the left atrium via median sternotomy using cardiopulmonary bypass. Direct ligation of feeding vessels of the tumor along with left atrial reinforcement using a pericardial patch was performed. The post-operative course was uneventful, with normalization of catecholamine secretion and no recurrence at three-month follow-up. We review the current literature about this exceptional cardiac tumor, pathophysiological conditions and options for surgical management.

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis.

INTRODUCTION Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.

PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation.

PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells.

Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index.

INTRODUCTION Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes. METHODS Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14), luminal B (ER + and/or PR+, HER2-, Ki-67 ≥14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER-, PR-, HER2-, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2-, Ki-67 ≥14, any CK 5/6, any EGFR), HER2-enriched (ER-, PR-, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER-, PR-, HER2-, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER-, PR-, HER2-, any Ki-67, CK 5/6-, EGFR-). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki-67 ≥14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value. RESULTS Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 ≥14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 ≥14% show sharp peak at nearly 18 months. CONCLUSIONS Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients.

Perioperative anemia management in colorectal cancer patients: A pragmatic approach.

Anemia, usually due to iron deficiency, is highly prevalent among patients with colorectal cancer. Inflammatory cytokines lead to iron restricted erythropoiesis further decreasing iron availability and impairing iron utilization. Preoperative anemia predicts for decreased survival. Allogeneic blood transfusion is widely used to correct anemia and is associated with poorer surgical outcomes, increased post-operative nosocomial infections, longer hospital stays, increased rates of cancer recurrence and perioperative venous thromboembolism. Infections are more likely to occur in those with low preoperative serum ferritin level compared to those with normal levels. A multidisciplinary, multimodal, individualized strategy, collectively termed Patient Blood Management, minimizes or eliminates allogeneic blood transfusion. This includes restrictive transfusion policy, thromboprophylaxis and anemia management to improve outcomes. Normalization of preoperative hemoglobin levels is a World Health Organization recommendation. Iron repletion should be routinely ordered when indicated. Oral iron is poorly tolerated with low adherence based on published evidence. Intravenous iron is safe and effective but is frequently avoided due to misinformation and misinterpretation concerning the incidence and clinical nature of minor infusion reactions. Serious adverse events with intravenous iron are extremely rare. Newer formulations allow complete replacement dosing in 15-60 min markedly facilitating care. Erythropoiesis stimulating agents may improve response rates. A multidisciplinary, multimodal, individualized strategy, collectively termed Patient Blood Management used to minimize or eliminate allogeneic blood transfusion is indicated to improve outcomes.

A microRNA Signature Associated with Early Recurrence in Breast Cancer.

Recurrent breast cancer occurring after the initial treatment is associated with poor outcome. A bimodal relapse pattern after surgery for primary tumor has been described with peaks of early and late recurrence occurring at about 2 and 5 years, respectively. Although several clinical and pathological features have been used to discriminate between low- and high-risk patients, the identification of molecular biomarkers with prognostic value remains an unmet need in the current management of breast cancer. Using microarray-based technology, we have performed a microRNA expression analysis in 71 primary breast tumors from patients that either remained disease-free at 5 years post-surgery (group A) or developed early (group B) or late (group C) recurrence. Unsupervised hierarchical clustering of microRNA expression data segregated tumors in two groups, mainly corresponding to patients with early recurrence and those with no recurrence. Microarray data analysis and RT-qPCR validation led to the identification of a set of 5 microRNAs (the 5-miRNA signature) differentially expressed between these two groups: miR-149, miR-10a, miR-20b, miR-30a-3p and miR-342-5p. All five microRNAs were down-regulated in tumors from patients with early recurrence. We show here that the 5-miRNA signature defines a high-risk group of patients with shorter relapse-free survival and has predictive value to discriminate non-relapsing versus early-relapsing patients (AUC = 0.993, p-value<0.05). Network analysis based on miRNA-target interactions curated by public databases suggests that down-regulation of the 5-miRNA signature in the subset of early-relapsing tumors would result in an overall increased proliferative and angiogenic capacity. In summary, we have identified a set of recurrence-related microRNAs with potential prognostic value to identify patients who will likely develop metastasis early after primary breast surgery.

Preoperative chemoradiotherapy in rectal cancer induces changes in the expression of nuclear β-catenin: prognostic significance.

BACKGROUND Preoperative chemoradiotherapy (CRT) is the cornerstone of treatment for locally advanced rectal cancer (LARC). Although high local control is achieved, overall rates of distant control remain suboptimal. Colorectal carcinogenesis is associated with critical alterations of the Wnt/β-catenin pathway involved in proliferation and survival. The aim of this study was to assess whether CRT induces changes in the expression of β-catenin/E-cadherin, and to determine whether these changes are associated with survival. METHODS The Immunohistochemical expression of nuclear β-catenin and membranous E-cadherin was prospectively analysed in tumour blocks from 98 stage II/III rectal cancer patients treated with preoperative CRT. Tumour samples were collected before and after CRT treatment. All patients were treated with pelvic RT (46-50 Gy in 2 Gy fractions) and 5-fluorouracil (5FU) intravenous infusion (225 mg/m2) or capecitabine (825 mg/m2) during RT treatment, followed by total mesorectal excision (TME). Disease-free survival (DFS) was analysed using the Kaplan-Meier method and a multivariate Cox regression model was employed for the Multivariate analysis. RESULTS CRT induced significant changes in the expression of nuclear β-catenin (49% of patients presented an increased expression after CRT, 17% a decreased expression and 34% no changes; p = 0.001). After a median follow-up of 25 months, patients that overexpressed nuclear β-catenin after CRT showed poor survival compared with patients that experienced a decrease in nuclear β-catenin expression (3-year DFS 92% vs. 43%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.02). In the multivariate analysis for DFS, increased nuclear β-catenin expression after CRT almost reached the cut-off for significance (p = 0.06). CONCLUSIONS In our study, preoperative CRT for LARC induced significant changes in nuclear β-catenin expression, which had a major impact on survival. Finding a way to decrease CRT resistance would significantly improve LARC patient survival.

Bladder cancer index: cross-cultural adaptation into Spanish and psychometric evaluation.

BACKGROUND The Bladder Cancer Index (BCI) is so far the only instrument applicable across all bladder cancer patients, independent of tumor infiltration or treatment applied. We developed a Spanish version of the BCI, and assessed its acceptability and metric properties. METHODS For the adaptation into Spanish we used the forward and back-translation method, expert panels, and cognitive debriefing patient interviews. For the assessment of metric properties we used data from 197 bladder cancer patients from a multi-center prospective study. The Spanish BCI and the SF-36 Health Survey were self-administered before and 12 months after treatment. Reliability was estimated by Cronbach's alpha. Construct validity was assessed through the multi-trait multi-method matrix. The magnitude of change was quantified by effect sizes to assess responsiveness. RESULTS Reliability coefficients ranged 0.75-0.97. The validity analysis confirmed moderate associations between the BCI function and bother subscales for urinary (r = 0.61) and bowel (r = 0.53) domains; conceptual independence among all BCI domains (r ≤ 0.3); and low correlation coefficients with the SF-36 scores, ranging 0.14-0.48. Among patients reporting global improvement at follow-up, pre-post treatment changes were statistically significant for the urinary domain and urinary bother subscale, with effect sizes of 0.38 and 0.53. CONCLUSIONS The Spanish BCI is well accepted, reliable, valid, responsive, and similar in performance compared to the original instrument. These findings support its use, both in Spanish and international studies, as a valuable and comprehensive tool for assessing quality of life across a wide range of bladder cancer patients.

ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients.

BACKGROUND Tumor expression of estrogen receptor (ER) is an important marker of prognosis, and is predictive of response to endocrine therapy in breast cancer. Several studies have observed that epigenetic events, such methylation of cytosines and deacetylation of histones, are involved in the complex mechanisms that regulate promoter transcription. However, the exact interplay of these factors in transcription activity is not well understood. In this study, we explored the relationship between ER expression status in tumor tissue samples and the methylation of the 5' CpG promoter region of the estrogen receptor gene (ESR1) isolated from free circulating DNA (fcDNA) in plasma samples from breast cancer patients. METHODS Patients (n = 110) with non-metastatic breast cancer had analyses performed of ER expression (luminal phenotype in tumor tissue, by immunohistochemistry method), and the ESR1-DNA methylation status (fcDNA in plasma, by quantitative methylation specific PCR technique). RESULTS Our results showed a significant association between presence of methylated ESR1 in patients with breast cancer and ER negative status in the tumor tissue (p = 0.0179). There was a trend towards a higher probability of ESR1-methylation in those phenotypes with poor prognosis i.e. 80% of triple negative patients, 60% of HER2 patients, compared to 28% and 5.9% of patients with better prognosis such as luminal A and luminal B, respectively. CONCLUSION Silencing, by methylation, of the promoter region of the ESR1 affects the expression of the estrogen receptor protein in tumors of breast cancer patients; high methylation of ESR1-DNA is associated with estrogen receptor negative status which, in turn, may be implicated in the patient's resistance to hormonal treatment in breast cancer. As such, epigenetic markers in plasma may be of interest as new targets for anticancer therapy, especially with respect to endocrine treatment.

Antiretroviral therapy as a factor protective against anal dysplasia in HIV-infected males who have sex with males.

OBJECTIVES Chronic infection with oncogenic HPV genotype is associated with the development of anal dysplasia. Antiretroviral therapy (ART) has been shown to decrease the incidence of cervical carcinoma in women with HIV. We sought to: 1) describe the prevalence and grade of anal dysplasia and HPV infection in our study subjects; 2) analyze the grade of correlation between anal cytology, PCR of high-risk HPV, and histology; 3) identify the factors associated with the appearance of ≥ AIN2 lesions. DESIGN Cross-sectional, prospective study. METHODS A cohort of HIV-positive males (n = 140, mean age  = 37 years) who have sex with males (MSM) had epidemiological, clinical and analytical data collected. Anal mucosa samples were taken for cytology, HPV PCR genotyping, and anoscopy for histological analysis. RESULTS Within the cohort, 77.1% were being treated with ART, 8.5% anoscopy findings were AIN2, and 11.4% carcinoma in situ; 74.2% had high-risk (HR), 59.7% low-risk (LR) HPV genotypes and 46.8% had both. The combination of cytology with PCR identifying HR-HPV better predicts the histology findings than either of these factors alone. Logistic regression highlighted ART as a protective factor against ≥ AIN2 lesions (OR: 0.214; 95%CI: 0.054-0.84). Anal/genital condylomas (OR: 4.26; 95%CI: 1.27-14.3), and HPV68 genotype (OR: 10.6; 95%CI: 1.23-91.47) were identified as risk factors. CONCLUSIONS In our cohort, ART has a protective effect against dysplastic anal lesions. Anal/genital warts and HPV68 genotype are predictors of ≥ AIN2 lesions. Introducing PCR HPV genotype evaluation improves screening success over that of cytology alone.