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This study was done to compare the growth of pathogens in paired aerobic/anaerobic blood culture bottles versus the use of only aerobic bottles, and to analyze the time to growth in both atmospheres.We retrospectively evaluated the results of all blood cultures collected over a 2-y period for the diagnosis of central venous catheter-related bloodstream infections or other severe infections in oncology patients.Among the 487 isolates, 174 (35.7%), all aerobic, grew only in the aerobic bottle; 250 (51.3%), all aerobic, grew in both bottles; and 63 (12.9%) grew only in the anaerobic bottle, of which 24 were anaerobic and 39 were aerobic microorganisms (8% of positive blood cultures). Of these 39 aerobic microorganisms, 12 were Gram-negative, 17 staphylococci (4 were Staphylococcus aureus), 5 streptococci, 2 Gram-positive bacilli, and 3 mixed growth. Though the mean time to positivity of pathogens grown in both atmospheres was significantly lower in the aerobic bottle than in the anaerobic bottle, in 71 cases (28.4%) the pathogens developed earlier in the anaerobic bottle than in the aerobic bottle - in 36 of these cases at least 1 h earlier, which is significant for starting targeted therapy.The use of paired aerobic/anaerobic blood culture bottles allowed the diagnosis of a percentage of bacteraemia due to either anaerobic or aerobic pathogens that would have been missed, as they grew only in the anaerobic atmosphere. Moreover in 8% of bacteraemia we identified a significant decrease in the time to detection, resulting in the opportunity to better manage the infections without an increase in costs.

Diagnosis of Arrhythmogenic CardioMyopathy (ACM) is challenging and often late after disease onset. No circulating biomarkers are available to date. Given their involvement in several cardiovascular diseases, plasma microRNAs warranted investigation as potential non-invasive diagnostic tools in ACM. We sought to identify circulating microRNAs differentially expressed in ACM with respect to Healthy Controls (HC) and Idiopathic Ventricular Tachycardia patients (IVT), often in differential diagnosis. ACM and HC subjects were screened for plasmatic expression of 377 microRNAs and validation was performed in 36 ACM, 53 HC, 21 IVT. Variable importance in data partition was estimated through Random Forest analysis and accuracy by Receiver Operating Curves. Plasmatic miR-320a showed 0.53 ± 0.04 fold expression difference in ACM vs. HC (p

Background: Low-dose estrogen might induce apoptosis in breast cancer cells that develop resistance to antihormonal therapy. Letrozole withdrawal for 3-month might permit estrogenic stimulation in residual resistant disease susceptible to letrozole reintroduction. We investigated the impact of a 3-month letrozole free interval on serum Estradiol levels in patients with early stage breast cancer. Patients and methods: Postmenopausal women with ER and/or PgR ≥ 10% of the cells, node-negative early breast cancer were eligible. Patients (pts) received letrozole (2.5 mg daily) for five years with a 3-month treatment free interval after the 1st year of therapy. The primary endpoint was to evaluate the increase in serum estradiol absolute levels after 3-month treatment free interval. The secondary endpoints were the evaluation of others biological markers (e.g. FSH, LH, Cholesterol, HDL, triglycerides, osteocalcin). Estradiol levels were quantified by ECLIA assay that measured estradiol concentrations with a 5 pg/ml lower detection limit. FSH and LH levels (mU/ml) were measured by ECLIA assay, Osteocalcin (ng/ml) by RIA assay, Cholesterol, HDL, and Triglycerides (mg/ml) by colorimetric assay. Results: From November 2007 to February 2012, 130 evaluable pts were enrolled. The median age was 61 years. One-hundred ten pts (85%) had pT1 tumor, 88 pts (68%) presented grade 2 and 83 pts (64%) showed a Ki-67 LI Conclusions: Intermittent Letrozole significantly impact on estradiol levels. This study provides further evidence supporting the role of intermittent letrozole in the adjuvant treatment of postmenopausal patients with endocrine responsive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-12.

Aim: To shed light on the clinical role of HER2 status in serum as extracellular domain (ECD) and corresponding circulating tumor cells (CTCs) in metastatic breast cancer patients. Methods: 68 patients were analyzed. Serum HER2 was determined by ADVIA Centaur® Serum HER2 test. CellSearch System was performed for CTC quantification. Results: HER2 was overexpressed in 21 primary tumors. In total, 19 patients had ECD >15 ng/ml (the cut-off used), 48 patients had at least one CTC. ECD positivity was associated with CTC number (p = 0.01), HER2-positive CTC (p = 0.01) and the ratio HER2-positive CTC/total CTC (p = 0.02). ECD was not associated with survival. Conclusion: ECD in combination with HER2 CTC status would deserve further investigation in larger series for addressing its putative prognostic relevance.

This study describes a validation of the BD Onclarity HPV (Onclarity) assay using the international guidelines for HPV test requirements for cervical cancer screening of women 30 years old and older using Danish SurePath screening samples. The clinical specificity (0.90, 95% confidence interval [CI] = 0.88 to 0.91) and sensitivity (0.97, 95% CI = 0.87 to 1.0) of the Onclarity assay were shown to be not inferior to the reference assay (specificity, 0.90 [95% CI = 0.88 to 0.92]; sensitivity, 0.98 [95% CI = 0.91 to 1.0]). The intralaboratory reproducibility of Onclarity was 97%, with a lower confidence bound of 96% (kappa value, 0.93). The interlaboratory agreement was 97%, with a lower confidence bound of 95% (kappa value, 0.92). The BD Onclarity HPV assay fulfills all the international guidelines for a new HPV test to be used in primarily screening. This is the first clinical validation of a new HPV assay using SurePath screening samples, and thus the Onclarity HPV assay is the first HPV assay to hold an international validation for both SurePath and ThinPrep.

Pericardial effusion is characterized by progressive accumulation of fluid within the pericardial space, resulting in increased intra-pericardial pressure and compression of the heart. As B-type natriuretic peptide (BNP) is secreted by the ventricles in response to increased myocardial stretch, we hypothesized that pericardial effusion, as well as its resolution, might influence BNP plasma levels.We prospectively measured, in 146 consecutive patients with pericardial effusion, BNP plasma levels at baseline, soon after, and 24h after pericardiocentesis. A scoring system based on 7 clinical and echocardiographic parameters was developed, and patients were classified according to the number of variables as having low (0-2), intermediate (3-4), or high (5-7) severity score.Out of the 146 patients, 42 (29%) had normal values (100pg/ml), whereas 104 (71%) had high BNP values at baseline. In the whole population, baseline BNP levels significantly decreased as the severity score increased (r=-0.21; P=0.01). 24h after pericardiocentesis, a significant increase in BNP was observed in patients with intermediate (P=0.004) score and with high (P0.001) severity score; no increase occurred in low score patients (P=0.56). The higher was the severity score, the steeper was the increase in BNP through the three time-points considered (P=0.04).The results of the present study show that BNP plasma levels are suppressed in the presence of severe pericardial effusion, and that they rise after pericardiocentesis. Future studies should investigate the role of BNP in assisting clinicians in the decision-making process of pericardial fluid drainage.

Purpose: This study investigated the prevalence of Chlamydia trachomatis infection, co-infection with Human Papillomavirus (HPV) and associated risk factors in a cohort of sexually active young women enrolled in an ongoing trial on HPV vaccination at the European Institute of Oncology (IEO, Milan, Italy). Methods: Cervical samples were collected from 591 girls (median age 18.8 years) at the beginning of their sexual activity. At the time of sample collection, 354 women had not yet been vaccinated, and 237 women had been vaccinated for at least 12 months. All samples were analyzed through a molecular assay for the detection of C. trachomatis infection. Demographic, behavioral risk factors and high-risk HPV (HR-HPV) status were investigated. Results: The prevalence of C. trachomatis infection was 4.9 % and HPV/C. trachomatis co-infection rate was 1.5 %. The exact analysis has not underlined statistical significance for the variables considered, except for the infection with HR-HPV (p

OBJECTIVE We performed a prospective, randomized clinical study to assess whether prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, reduces the incidence of postoperative atrial fibrillation. BACKGROUND Postoperative atrial fibrillation is a well recognized complication after lung cancer surgery, with an incidence as high as 30%. Perioperative increase of NT-proBNP has been demonstrated to be a strong independent predictor of postoperative atrial fibrillation in this setting. METHODS NT-proBNP concentration was measured 24 hours before surgery and soon after surgery in 1116 patients. Three hundred twenty (29%) patients showed a high NT-proBNP value and were enrolled: 108 were assigned to the metoprolol group, 102 to the losartan group, and 110 to the control group. RESULTS Overall, the incidence of postoperative atrial fibrillation was 20% (n = 64); it was significantly lower in the metoprolol and losartan groups compared with the control group [6%, 12%, and 40%, respectively; relative risk 0.19, 95% confidence intervals (CIs), 0.09-0.37; P < 0.001 in the metoprolol group; and 0.29, 95% CI, 0.16-0.52; P < 0.001 in the losartan group). No significant difference was found when the metoprolol and losartan groups were directly compared (P = 0.21). CONCLUSIONS A prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with high NT-proBNP levels, significantly reduced the occurrence of postoperative atrial fibrillation.

Breast cancer is a heterogeneous disease. Circulating tumor cell (CTC) enumeration might be useful to identify different risk categories within each molecular subtype.We retrospectively analyzed 203 consecutive patients with metastatic breast cancer with baseline CTC enumeration performed with CellSearch (Veridex Corp, Warren, NJ) between March 2005 and July 2011. Patients were categorized into 3 prognostic groups based on the number of CTCs (0, 1-4, and ≥ 5) and into 5 categories based on tumor biological characteristics: luminal-A (estrogen receptor [ER] and progesterone receptor [PR]1%, grade 1/2, human epidermal growth factor 2 [HER2]-negative [HER2(-)], Ki67 value14%); luminal-B (ER and/or PR1%, grade 3, HER2(-), Ki67 value14%); luminal-B HER2-positive [HER2(+)] (ER and/or PR1%, any grade, HER2(+), Ki-67 value any); HER2(+) (HER2 overexpressed/fluorescence in situ hybridization [FISH] amplified, ER and PR absent); triple negative (TN) (ER and PR 0%, HER2 not overexpressed/FISH not amplified).Median age was 57 years (range 31-78 years). Twenty-seven patients (13.3%) had luminal-A category, 105 (51.7%) patients had luminal-B, 29 (14.3%) patients had luminal-B HER2(+), 24 patients (11.8%) had HER2(+), and 18 patients (8.9%) had TN. CTCs were mostly found in patients with luminal-A/luminal-B HER2(-) subtype. At multivariable analysis, CTC count was a significant predictive factor for overall survival (OS) in all molecular subtypes (log-rank P.01). Patients with 0 CTCs/7.5 mL blood and all subtypes, except HER2(+), seem to perform better compared with other categories.These findings confirm CTCs as an important prognostic factor for metastatic breast cancer in all molecular subtypes. Larger studies could help identify metastatic breast cancer subgroups in which CTC analysis would be particularly useful.

Evaluation of: Powell AA, Talasaz AH, Zhang H et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS ONE 7(5), e33788 (2012). Circulating tumor cells (CTCs) may represent a possible useful tool to better define the prognosis of patients. The presence of CTCs can help to predict an increased risk for disease relapse, and they might be an early marker for treatment efficacy that could help in deciding treatment continuation. Cancer metastasis occurs when cells, shed from the primary tumor, enter the circulation and begin to grow in distant locations around the body. In metastatic stages, shed cells may differ from those of the primary tumor, as the tumor phenotype can change during the course of the disease. It is important to identify relevant targets expressed on these cells to provide clinical information on therapy choice, efficacy and drug resistance. Many efforts are now devoted to the characterization of the single cell. This article focuses on the possibility of profiling single CTCs in patients with breast cancer.

Background There is an urgent need for the identification of commonly assessable predictive factors in the treatment of patients with metastatic breast cancer. Methods During the course of a treatment including low dose metronomic oral cyclophosphamide and capecitabine plus i.v. bevacizumab (plus erlotinib in one third of the patients) for metastatic breast cancer, we observed that a relevant number of patients developed repeatedly elevated levels of mean corpuscular volume (MCV) of red blood cells without a significant fall in hemoglobin levels. We conducted a retrospective analysis on these 69 patients to evaluate if the increase in MCV could be associated to tumor response. Results During the course of treatment 42 out of 69 patients (61%) developed macrocytosis. Using Cox proportional hazards modeling that incorporated macrocytosis (MCV≥100 fl) as a time-dependent covariate, macrocytosis resulted in a halved risk of disease progression (HR 0.45; 95% CI, 0.22–0.92, p-value 0.028). In a landmark analysis limited to patients with no sign of progression after 24 weeks of treatment, median time to progression was 72 weeks (48 weeks after landmark) in patients who had developed macrocytosis, and 43 weeks (19 weeks after landmark) in patients who had not (p = 0.023). Conclusion Macrocytosis inversely related to risk of disease progression in patients treated with metronomic capecitabine plus cyclophosphamide and bevacizumab for metastatic breast cancer. This finding may be explained through thymidylate synthase inhibition by capecitabine. Whether bevacizumab has a role in determining macrocytosis, similarly to what happens with sunitinib, has to be further investigated. If other studies will confirm our findings, macrocytosis might be used as an early marker of response during metronomic treatment with capecitabine and cyclophosphamide with or without bevacizumab.

Human papillomavirus (HPV) testing is more sensitive and has higher negative predictive value (NPV) than the Pap test for the detection of cervical intraepithelial neoplasia (CIN) in patients with atypical squamous cells of undetermined significance (ASCUS) cytology, but has low specificity, leading to high referral rates to second-level triage. Our goal was to identify the prognostic significance of HPV viral load figures. We evaluated whether a correlation between viral load, expressed as relative light units/cutoff (RLU/CO), and the severity of cervical lesions existed in 614 ASCUS cases. Hybrid Capture 2 (HC2®) RLU/CO values, categorised into five classes, were correlated to clinical outcomes and statistically analysed. A significant correlation (p 0.0001) was observed between increasing RLU values and the prevalence of high-grade CIN (CIN2/CIN3). The mean RLU values for negative, low-grade and high-grade lesions were 68.1, 172.5 and 1,020.0 RLU/CO, respectively (p 0.0001). CIN2/CIN3 ranged from 4% for 0 RLU/CO values ≤ 1, to 5% for 1 RLU/CO values ≤ 10, to 9% for 10 RLU/CO values ≤ 100, to 23% for 100 RLU/CO values ≤ 1,000 and to 48% when RLU/CO values were 1,000 (p 0.05). The HPV viral load in ASCUS cases significantly correlates with the severity of cervical cancer precursors. These data may have prognostic value, as they significantly correlate with the probability of a CIN2+ .

Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer. Patients and Methods We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period. Results At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels. Conclusion Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.

Objective Recent data showed that HPV16 infections in young women can lead to CIN3 formation very quickly and questioned the common assumption that invasive cervical cancer develops through slowly progressing pre-cancer lesions, CIN1, CIN2 and CIN3. The aim of the study is to compare the age distribution of HPV 16/18 related and HPV16/18 not related CIN. Methods We used the data generated from the clinical use of HPV genotyping (LINEAR ARRAY, Roche Diagnostics). Patients were grouped on the basis of histology, CIN1 vs. CIN2+ and on HR-HPV genotype status. Results The probability to develop a CIN2+ seemed to decrease with age in patients infected with HR-HPV genotype 16/18 while the inverse effect was observed in CIN2+ patients who were HR-HPV positive but HPV16/18 negative (Chi-square test, p trend =0.01). Only in HR-HPV positive but HPV 16/18 negative patients, a relative reduction of CIN1 vs. CIN2+ was observed with increasing age (Cochran-Armitage test, p trend =0.01); finally, in HR-HPV non-16/18 infected patients only a statistically significant difference in mean age between CIN1 and CIN2+ patients below age 35 was observed. Conclusions Besides the limitations of the present cross-sectional analysis, these data suggest a genotype specific natural history of cervical cancer precursors development: one type, more frequent, HPV16/18 related, which develops quick and early in life; another one, non-16/18 HR-HPV related, which develops later, slowly, through low- to high-grade lesions. If confirmed, this hypothesis could influence screening policies, especially in the vaccinated population.

ABO blood type has been associated with various malignancies, including pancreatic cancer. Our aim was to study this association using data from a hospital-based tumour registry.From the tumour registry, we retrieved data from 15,359 cancer patients treated during 2000-2003 at the European Institute of Oncology (Milan, Italy), with defined ABO blood type. We performed a case-control analysis, comparing the distribution of ABO blood types of patients with each specific form of cancer against that of patients with other forms of cancer. We also reviewed the literature and performed a meta-analysis on the association between ABO blood group and pancreatic cancer.We observed a significantly lower frequency of blood type O in patients with exocrine pancreatic cancer compared to patients with other forms of cancer (29% versus 44%; P0.001; odds ratio (OR), 0.53; 95% confidence intervals (CI), 0.33-0.83). This association was confirmed by the meta-analysis of seven prior studies (summary relative risk, 0.79; 95% CI, 0.70-0.90). No association was found for endocrine pancreatic cancer or for cancer originating in other organs.Our data suggest that the association between ABO blood group and cancer is limited to exocrine pancreas malignancy.

Background HER2/ neu status of tumor cells at metastatic sites in patients with advanced disease may differ from that of the primary tumor. Assessing the presence of target antigens on circulating tumor cells (CTCs) might affect treatment choice. Patients and Methods From June 2007 to October 2008, we collected 23 mL of blood from each of the 76 consecutive patients before and during chemotherapy to determine CTC numbers and HER2 overexpression. CTCs were isolated with the CellSearch System® (Veridex, LLC; Raritan, NJ) and fluorescently stained with the Epithelial Cell Kit®. Tumor Phenotyping Reagent® was used to investigate HER2/ neu overexpression. Results Concordance of HER2 status between the primary tumor and CTCs was 86% (49 out of 57 patients) at baseline and 82% (50 out of 61 patients) in the treatment samples. HER2 overexpression in CTCs was acquired in 8 out of 45 patients (18%) and lost in 3 out of 16 patients (19%) during a treatment containing trastuzumab. The overall discordance rate between the primary tumor and CTCs was 18% (11 out of 61 patients). Patients with HER2 overexpression in CTCs had poorer progression-free survival compared with those without CTCs or with HER2− CTCs (log-rank P =.036). Conclusion Information on the presence or absence of HER2 overexpression can be obtained in CTCs. Larger trials are needed to evaluate the activity of HER2-targeted therapy in patients with acquired HER2 overexpression in CTCs.

Chemotherapy-induced cardiotoxicity remains an unresolved problem strongly impacting the quality of life and the overall survival of cancer patients. The main strategy for minimizing cardiotoxicity is early detection of high-risk patients and prompt prophylactic treatment. The current standard for monitoring cardiac function detects cardiotoxicity only when a functional impairment has already occurred, not allowing for any early preventive strategies. Measurement of cardiospecific biomarkers can be a valid diagnostic tool for early identification, assessment, and monitoring of cardiotoxicity. In particular, the role of troponin in identifying patients at risk of cardiotoxicity and of angiotensin-converting enzyme inhibitors in preventing cardiac dysfunction and cardiac events is clearly emerging as a new effective approach. Therefore, we propose troponin as a criterion standard marker for the assessment of cardiac risk of both old and new antineoplastic treatments, and its evaluation should be included among the criteria utilized to define cardiotoxicity.

Circulating Tumour Cells (CTCs) can be released from the primary tumour into the bloodstream and may colonize distant organs giving rise to metastasis. The presence of CTCs in the blood has been documented more than a century ago, and in the meanwhile various methods have been described for their detection. Most of them require an initial enrichment step, since CTCs are a very rare event. The different technologies and also the differences among the screened populations make the clinical significance of CTCs detection difficult to interprete. Here we will review the different assays up to now available for CTC detection and analysis. Moreover, we will focus on the relevance of the clinical data, generated so far and based on the CTCs analysis. Since the vast majority of data have been produced in breast cancer patients, the review will focus especially on this malignancy.

Background HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66 are considered carcinogenic for human beings. DNA-chip technology, Papillocheck ® HPV-screening (Greiner) and reverse dot blot, Linear Array (LA) (Roche) are tools to assess the distribution of HPV genotypes. Objectives The aim of the study was to compare the clinical performance of Papillocheck and LA assays using a clinical cut-off of CIN2+. The secondary aim was to comparatively assess the distribution of HPV types using these two assays. Study design The study population comprised 239 women referred for colposcopy and histology. Papillocheck, LA, and Hybrid Capture II (HCII) tests were done on all samples. Results All tests showed good sensitivity and NPV (greater than 90%). None of the comparisons of sensitivities, specificities, PPVs, and NPVs showed statistically relevant differences between tests. High-risk HPV positivity rate was similar for all tests (Papillocheck 75%, LA 77%, and HCII 73%). Agreement between tests was good. The concordance levels between HCII and Papillocheck and between HCII and LA were 93% ( k =0.82) and 92% ( k =0.80), respectively. Papillocheck and LA tests showed a high overall concordance rate of 96% ( k =0.90). HPV16 was the most detected type (45% with Papillocheck, and 47% with LA), and HPV31 was the second most detected type (13% with Papillocheck, and 14% with LA). Conclusions The Papillocheck HPV-screening test and LA test have a good clinical sensitivity to detect HPV types in CIN2+ patients. These assays allow, in the same experiment, to detect and determine the virus type. Our study showed that HPV types 16 and 31/33 are the most prevalent.

Human papillomavirus (HPV) are distributed widely and persistent infection with high-risk (HR) HPV is recognized as a necessary cause of cervical cancer. The aim of this study was to evaluate the distribution of different HR-HPV genotypes in 199 women with cervical pre-invasive lesions undergoing conservative treatment. A Linear Array HPV Genotyping Test was used to identify individual HPV genotypes in cervical samples. It was observed that the most prevalent HPV genotypes were HPV 16 (52.6%), HPV 51 (13.5%), and HPV 31 (10.9%); HPV 18 was found in 7.3% of the patients. Stratifying the different HPV genotypes according to the severity of the cervical lesion, a strong association between the increasing severity of the histological diagnosis and the detection of more carcinogenic HR-HPV type was found, and in all but one cervical intraepithelial neoplasia of grade 3 the presence of at least one HR-HPV could be detected, with more than 70% of cervical intraepithelial neoplasia of grade 3 patients bearing HPV 16. Multiple infections, comprising between 2 and 6 HPV types, were found in 43% of patients; however, the presence of more than 1 HR-HPV type was not associated with an increased risk of high grade lesions. In conclusion, this data show that HPV 16, 51, 31, 52, and 18 were the prevalent types found in patients with cervical lesion undergoing conservative treatment, with a high prevalence of HPV 16 in cervical intraepithelial neoplasia of grade 3 patients. No association between multiple infection and severity of the lesion could be found.

Background: Prostate adenocarcinoma is generally characterized by slow progression although some phenotypes have a more aggressive behavior with tendency to local invasion and distant metastases, mainly to bones. Better specific care could be provided to the aggressive phenotype-group of patients if pre-surgical identification were available. Material and Methods: Correlations between pre-surgical levels of 6 blood molecules and pathological tumour staging, post-surgical Gleason score and disease-free survival have been observed. Plasma and sera from 162 men affected by prostate adenocarcinoma were analysed with ELISA to assess levels of neovascularization-related molecule (VEGF), endothelial cell adhesion molecule (VCAM), extracellular matrix destruction- related molecules (MMP-2, MMP-9), and tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2). Results: The median values of serum determinations were for VEGF 279 pg/ml, VCAM 633 ng/ml, MMP-2 206 ng/ml and MMP-9 614 ng/ml. Plasma medians (ng/ml) were 94 for TIMP-1 and 90 for TIMP-2. Patients with VCAM values > 633 ng/ml had a worse disease-free survival than patients with values < 633 ng/ml with an adjusted Hazard Ratio of 2.1, significant (95% confidence interval 0.8-5.6). Patients with levels of MMP-2 < 206 ng/ml showed an increased risk of progression (adjusted HR 1.7; 95% C.I. 0.6-4.8). Conclusions: Levels of VCAM and MMP-2 should be checked in patients with prostate adenocarcinoma, because distant spread is more likely to occur in patients with high levels of VCAM and low levels of MMP-2. The scientific community should further investigate impact on prognosis of VCAM and MMP-2.

BACKGROUND The identification of circulating microRNAs (miRNAs) in the blood has been recently exploited for the development of minimally invasive tests for the early detection of cancer. Nevertheless, the clinical transferability of such tests is uncertain due to still-insufficient standardization and optimization of methods to detect circulating miRNAs in the clinical setting. METHODS We performed a series of tests to optimize the quantification of serum miRNAs that compose the miR-Test, a signature for lung cancer early detection, and systematically analyzed variables that could affect the performance of the test. We took advantage of a large-scale (>1000 samples) validation study of the miR-Test that we recently published, to evaluate, in clinical samples, the effects of analytical and preanalytical variables on the quantification of circulating miRNAs and the clinical output of the signature (risk score). RESULTS We developed a streamlined and standardized pipeline for the processing of clinical serum samples that allows the isolation and analysis of circulating miRNAs by quantitative reverse-transcription PCR, with a throughput compatible with screening trials. The major source of analytical variation came from RNA isolation from serum, which could be corrected by use of external (spike-in) or endogenous miRNAs as a reference for normalization. We also introduced standard operating procedures and QC steps to check for unspecific fluctuations that arise from the lack of standardized criteria in the collection or handling of the samples (preanalytical factors). CONCLUSIONS We propose our methodology as a reference for the development of clinical-grade blood tests on the basis of miRNA detection.

Persistent positivity of HPV-DNA testing is considered a prognostic index of recurrent disease in patients treated for CIN2+. HPV detection, and particularly genotyping, has an adequate high rate of sensitivity and specificity (along with an optimal reproducibility), for accurately predicting treatment failure, allowing for an intensified monitoring activity. Conversely, women with a negative HPV-test 6 months after therapy have a very low risk for residual/recurrent disease, which leads to a more individualized follow-up schedule, allowing for a gradual return to the normal screening scheme. HPV testing should be routinely included (with or without cytology) in post-treatment follow-up of CIN2+ patients for early detection of recurrence and cancer progression. HPV genotyping methods, as a biological indicator of persistent disease, could be more suitable for a predictive role and risk stratification (particularly in the case of HPV 16/18 persistence) than pooled HPV-based testing. However, it is necessary to be aware of the performance of the system, adhering to strict standardization of the process and quality assurance criteria.

Background Over the last two decades it has become clear that distinct types of human papillomavirus (HPV), the so-called high-risk types (hrHPV), are the major cause of cervical cancer. The hrHPV-DNA testing has shown excellent performance in several clinical applications from screening to the follow-up of conservatively treated patients. Methods We conducted a systematic review of the recent literature on the performance of HPV DNA testing in follow-up after treatment of high-grade cervical lesions, adenocarcinoma in situ, and microinvasive carcinoma compared to Pap smear cytology. Results Observational studies have demonstrated that the high risk hrHPV-DNA test is significantly more sensitive (95%) compared to follow-up cytology(70%) in detecting post-treatment squamous intraepithelial high-grade lesions. Moreover, in patients treated conservatively for cervical adenocarcinoma in situ, the hrHPV-DNA test is the most significant independent predictor of recurrent disease or progression to invasive cancer, and the combination of viral DNA testing and cytology reaches 90% sensitivity in detecting persistent lesions at the first follow-up visit and 100% at the second follow-up visit. The cause of microinvasive squamous cervical carcinoma is increasingly treated with conservative therapies in order to preserve fertility, and an effective strategy allowing early detection of residual or progressive disease has become more and more important in post-treatment follow-up. Primary results seem to indicate that the median time for viral clearance is relatively longer compared with patients treated for CIN and suggest a prolonged surveillance for these patients. However, the potential clinical value of HPV-DNA testing in this clinical setting needs to be confirmed by further observations. Conclusions The excellent sensitivity, negative predictive value, and optimal reproducibility of the hrHPV DNA testing, currently is considered a powerful tool in the clinicians' hands to better manage post-treatment follow-up either in cervical squamous lesion or in situ adenocarcinoma.

Since the introduction of biomolecular testing for the identification of high-risk human papillomavirus DNA (hrHPV-DNA) in cervical cancer preventive strategies, many interesting aspects have emerged in this field; firstly, HPV-DNA testing has been demonstrated to have better sensitivity than conventional cytology in several settings: screening, triage of ASC-US and in follow-up after treatment. Despite this, some limitations of these new technologies have also been underlined: the major issue is the low specificity of the tests, which cannot discriminate between regressive and progressive infections. Thus, recent research has moved the attention towards novel markers of progression that could more precisely detect cases at real risk of cancer development. In view of the fact that progression to cancer is dependable of the E6/E7 proteins integration and transforming action, the overexpression of E6/E7 transcripts has been seen as a valuable marker of this risk. This review aims to summarise the literature data on this topic and to provide a clear view of the emerging perspectives.

The use of tamoxifen as a breast cancer preventive agent may be contraindicated by an increased risk of endometrial cancer and venous thromboembolic events, particularly in postmenopausal women. Since these estrogenic effects may be dose-related, a dose reduction may reduce toxicity. We have recently shown a comparable activity of lower doses of tamoxifen on putative surrogate biomarkers of cardiovascular disease and breast cancer. To provide further insight into the effect of tamoxifen at low doses on the cardiovascular system, we compared the effect of three different doses on circulating levels of C-reactive protein (CRP), an independent risk marker for cardiovascular disease (CVD), which was lowered by tamoxifen at the standard dose of 20 mg day-1 in previous studies. We compared the changes in CRP after 2 months of either placebo (n = 24), or tamoxifen 10 mg alternate daily (n = 26), or 10 mg day-1 (n = 22), or 20 mg day-1 (n = 19) in healthy women aged 35-70 years. The median percent change was -2.2% (95% CI, -23.3 to 42.8) with placebo, -39.1 (95% CI, -59.9 to -28.7) with 10 mg alternate daily, -56.9% (95% CI, -68.6 to -38.4) with 10 mg day-1 and -42.9% (95% CI, -62.6 to 1.6) with 20 mg day-1 (P = 0.291 for the linear dose-response trend). Similar results were obtained when the data were classified according to blood tamoxifen concentrations, with a median reduction of 47% (95% CI, 65.5-36.3) for women with low tamoxifen concentrations (< 30 ng mL-1). We conclude that tamoxifen at low doses is able to lower ultrasensitive CRP and that this might be associated with a beneficial effect on CVD.

High-dose chemotherapy (HDC) has been widely utilized in high-risk breast cancer, but it may induce cardiac toxicity. Cardiac dysfunction may become evident weeks or months after HDC and, to date, no early markers of myocardial injury that are able to predict late ventricular impairment are available. We investigated the role of plasma troponin I (TnI) in this setting.We measured TnI plasma concentration after HDC in 211 high-risk breast cancer women (46 +/- 11 years, mean +/- SD). According to TnI value (0.5 oror = 0.5 ng/ml), patients were allocated into a troponin positive (TnI+; n = 70) and a troponin negative (TnI-; n = 141) group. All patients underwent left ventricular ejection fraction (LVEF, Echo) examination during the following 12 months.LVEF progressively decreased in the TnI+ group but not in the TnI- group. In TnI+ patients a close relationship between the TnI increase, as well as the number of positive TnI assays, and the maximal LVEF decrement, was found (r = -0.92, P0.0001 and r = -0.93, P0.0001, respectively).In our population, the elevation of TnI soon after HDC accurately predicts the development of future LVEF depression. In this setting, TnI can be considered a sensitive and reliable marker of myocardial damage with relevant clinical and prognostic implications.

BACKGROUND: Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents, including cyclophosphamide (CTX), methotrexate (MTX), anthracyclines and taxanes, postulating an antiangiogenic activity. PATIENTS AND METHODS: We evaluated the clinical efficacy and impact on serum vascular endothelial growth factor (VEGF) levels of low-dose oral MTX and CTX in patients with metastatic breast cancer. MTX was administered 2.5 mg bd on days 1 and 2 each week and CTX 50 mg/day administered continuously. RESULTS: Sixty-four patients were enrolled, 63 were evaluable: Eastern Cooperative Oncology Group (ECOG) performance status 0-1, > or =2 sites of metastatic disease (n = 50 patients), progressive disease at study entry (n = 51), 1 regimen for metastatic disease (n = 32) and > or =2 regimens (n = 20). Among the 63 evaluable patients, there were two complete remissions (CR), 10 partial remissions (PR) for an overall response rate of 19.0% (95% CI 10.2% to 30.9%) and an overall clinical benefit (CR+ PR+ stable disease >24 weeks) of 31.7% (95% CI 20.6% to 44.7%). Grade > or =2 leucopenia was registered in only 13 patients. The median serum VEGF level for the subgroup of patients on treatment for at least 2 months decreased with treatment from 315 pg/ml (95% CI 245 to 435) at baseline to 248 pg/ml (95% CI 205 to 311) at 2 months (P

Legionella pneumophila is known as an important cause of nosocomial pneumonia. This chapter discusses three cases in an oncological hospital. A 47-year-old woman with malignant non-Hodgkin lymphoma, was hospitalized for more than 10 days, treated with high-dose chemotherapy. During treatment she developed a pneumonia, with a positive urinary Legionella antigen test (Biotest enzyme immunoassay urinary Legionella antigen). Despite therapy with macrolides and fluoroquinolones, the patient died from respiratory failure 1 week after the diagnosis. Immediately after the detection of the first case of Legionella pneumonia, the water distribution system was sampled in several sites, including the shower in the patient’s room, the intake from the municipal water supply, the water storage tank, and some distant outlets. A therapy with macrolides and fluoroquinolones was effective in curing another patient with high-risk breast carcinoma being treated with high-dose chemotherapy. It is remarkable that the diagnosis has always been performed by the detection of the urinary Legionella antigen, although the colonizing subtype was of the serogroup 2-14. A 54-year old man had received appropriate chemotherapy and general condition was improving, but at the end of the month, the patient developed Legionella pneumonia, as documented by a positive urinary Legionella antigen. Despite macrolide and fluoroquinolone treatment, the patient died 5 days later. The flush and heat decontamination method is not effective in eradicating L. pneumophila from the hot water distribution system, and it is therefore mandatory to keep surveillance measures for early diagnosis and prompt treatment of possible new cases.

Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch(R) system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

We aimed to assess the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with metastatic breast cancer by undertaking a pooled analysis of individual patient data.We contacted 51 European centres and asked them to provide reported and unreported anonymised data for individual patients with metastatic breast cancer who participated in studies between January, 2003, and July, 2012. Eligible studies had participants starting a new line of therapy, data for progression-free survival or overall survival, or both, and CTC quantification by the CellSearch method at baseline (before start of new treatment). We used Cox regression models, stratified by study, to establish the association between CTC count and progression-free survival and overall survival. We used the landmark method to assess the prognostic value of CTC and serum marker changes during treatment. We assessed the added value of CTCs or serum markers to prognostic clinicopathological models in a resampling procedure using likelihood ratio (LR) χ(2) statistics.17 centres provided data for 1944 eligible patients from 20 studies. 911 patients (46·9%) had a CTC count of 5 per 7·5 mL or higher at baseline, which was associated with decreased progression-free survival (hazard ratio [HR] 1·92, 95% CI 1·73-2·14, p0·0001) and overall survival (HR 2·78, 95% CI 2·42-3·19, p0·0001) compared with patients with a CTC count of less than 5 per 7·5 mL at baseline. Increased CTC counts 3-5 weeks after start of treatment, adjusted for CTC count at baseline, were associated with shortened progression-free survival (HR 1·85, 95% CI 1·48-2·32, p0·0001) and overall survival (HR 2·26, 95% CI 1·68-3·03) as were increased CTC counts after 6-8 weeks (progression-free survival HR 2·20, 95% CI 1·66-2·90, p0·0001; overall survival HR 2·91, 95% CI 2·01-4·23, p0·0001). Survival prediction was significantly improved by addition of baseline CTC count to the clinicopathological models (progression-free survival LR 38·4, 95% CI 21·9-60·3, p0·0001; overall survival LR 64·9, 95% CI 41·3-93·4, p0·0001). This model was further improved by addition of CTC change at 3-5 weeks (progression-free survival LR 8·2, 95% CI 0·78-20·4, p=0·004; overall survival LR 11·5, 95% CI 2·6-25·1, p=0·0007) and at 6-8 weeks (progression-free survival LR 15·3, 95% CI 5·2-28·3; overall survival LR 14·6, 95% CI 4·0-30·6; both p0·0001). Carcinoembryonic antigen and cancer antigen 15-3 concentrations at baseline and during therapy did not add significant information to the best baseline model.These data confirm the independent prognostic effect of CTC count on progression-free survival and overall survival. CTC count also improves the prognostication of metastatic breast cancer when added to full clinicopathological predictive models, whereas serum tumour markers do not.Janssen Diagnostics, the Nuovo-Soldati foundation for cancer research.

Modern cancer therapies are highly effective in the treatment of malignancy; however, they are associated with the possible development of side effects, in particular involving heart function. This particular form of cardiotoxicity is related to many factors: age, cumulative dose of the drug administered, drug combination, smoking, prior radiotherapy, and prior cardiovascular disease. Different types of events may manifest: the more important and difficult to manage is a progressive LV dysfunction, which may lead to the development of cardiac failure. Other side effects are represented by acute coronary syndromes, hypertension, thromboembolic events, and arrhythmias. Anthracyclines are one of the anticancer drugs more studied, and they are known to cause CTX through different molecular mechanisms; the damage induced by AC is dose dependent and usually irreversible. Also newer therapies like targeted therapy (i.e., trastuzumab) or angiogenesis inhibitors are all associated with some form of cardiac toxicity: while targeted drugs may induce a reversible damage, angiogenesis inhibitors have a prothrombotic activity, which leads to a high incidence of thromboembolic events. Patients were followed up with serial cardiological visits and evaluation of the LVEF, which however detects the damage already installed. In the last 20 years, a new appealing approach has been proposed: it is based on the evaluation of circulating troponin and/or natriuretic peptides. Especially for troponin, many studies underlined the predictive value of this marker, which can detect minimal cardiac damage, well before the onset of cardiac dysfunction, allowing for a personalized follow-up and cardiological preventive treatment. In this light, many studies have recently evaluated the protective effect of different drugs, such as dexrazoxane, beta blockers, and ACE inhibitors, with in some cases very promising results. List of Abbreviations AC Anthracycline ACEIs Angiotensin-Converting Enzyme Inhibitors ANP Atrial Natriuretic Peptide ASCO American Society of Clinical Oncology BB b-blockers BNP Brain Natriuretic Peptide CHF Congestive Heart Failure CNP C-Type Natriuretic Peptide cTn Cardiac Troponin CT Chemotherapy CTX Cardiotoxicity *Email: maria.sandri@ieo.it Biomarkers in Cancer DOI 10.1007/978-94-007-7744-6_20-1 # Springer Science+Business Media Dordrecht 2014

10.2217/FON.15.126 © 2015 Future Medicine Ltd It is a great pleasure to introduce this special focus issue on cardio-oncology. The potential cardiotoxic effects of anthracyclines and radiation have of course been known for decades, with considerable research undertaken to elucidate the underlying mechanisms. Cardiovascular toxicities have been documented with most agents, including the newer, so-called ‘targeted therapies,’ which were initially considered to be have minimal cardiovascular adverse effects. In this context the speciality of cardio-oncology has emerged, with the scope of monitoring and treating cancer survivors for cardiotoxicity and also identifying potential cardiac side effects in novel cancer therapies. The monitoring of cancer survivors for cardiotoxicity continues to develop but clearly refinement and more research is needed. The subspeciality of cardio-oncology encompasses experts from both fields and also other disciplines and it is hoped that with this collaboration the quality of life of cancer survivors will improve. Dr Yang reviews the possible vascular effect of the newer chemotherapeutic agents [1] while Dr Tartarone discusses the cardiotoxicity concerns related to treatment with Crizotinib [2]. The cardiotoxic effects of radiation therapy are also a major theme in this issue, as Dr Yusuf discusses in his review. [3] Carotid artery inflammation associated with gemcitabine-based therapy is explored by Dr Chan et al. [4], while Dr Steingart discusses the effects of radiation on coronary artery inflammation [5]. Consequently over this time our understanding of cardiotoxicity has improved. Crucially over the last few years the importance of cardio-oncology as a separate discipline, in its own right, has become clear, both in terms of clinical care but also ongoing research. This is particularly important with improving survival rates for many cancers. This growing importance is reflected in a number of articles in this issue, including the interview with Dr Lenihan [6] and the commentary and review by Dr Elie Mouhayer, Dr Francis et al. and Dr Petek et al., respectively [7–9]. Dr Francis in particular touches on the importance of optimizing cardiooncology programs for cancer patients [8]. A key point that deserves attention is the importance of the early FORE ORD Special Focus Issue: Cardio-oncology

Background: Results of a clinical trial recently completed in the United States indicate that administration of tamoxifen (20 mg/day) to women at risk can reduce breast cancer incidence by approximately 50% but is associated with an increased risk of developing endometrial cancer and venous thromboembolic events. Since these adverse effects may be dose related, we investigated the effect of tamoxifen on several biomarkers when the drug was given at doses lower than those currently in use. Methods: In two sequential experiments, 127 healthy hysterectomized women aged 35-70 years were randomly assigned to one of the following four treatment arms: placebo (n = 31) or tamoxifen at 20 mg/day (n = 30) (first experiment); or tamoxifen at 10 mg/day (n = 34) or tamoxifen at 10 mg/ alternate days (n = 32) (second experiment). Baseline and 2-month measurements of the following parameters were compared: 1) total cholesterol (primary end point) and other surrogate markers of cardiovascular disease, e.g., low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a); 2) blood cell count; 3) fibrinogen; 4) antithrombin III; 5) osteocalcin; and, 6) in a subgroup of 103 women, insulin-like growth factor-I (IGF-I), a possible surrogate marker for breast cancer. Results : After adjustment for the baseline values, there were reductions in circulating levels of total cholesterol and IGF-I of the same magnitude in all three tamoxifen treatment arms. A similar pattern was observed for most of the other parameters. In the placebo arm, fibrinogen level, which showed a decrease, was the only parameter exhibiting change. Conclusions: Up to a 75% reduction in the conventional dose of tamoxifen (i.e., 20 mg/day) does not affect the activity of the drug on a large number of biomarkers, most of which are surrogate markers of cardiovascular disease. This study was hypothesis generating, and larger studies are warranted to assess the efficacy of tamoxifen at low doses.

Background Cervical cancer is caused by high-risk types of human papillomavirus (HPV). DNA testing of such high-risk types of HPV could improve cervical screening.The aim of the study was to compare the sensitivities and positive predictive values of two commercially available typing assays (Qiagen LQ and Roche LA) and to comparatively assess the distribution of HPV types with these two assays. Methods The study population comprised 311 ASCUS + women with abnormal pap tests who were HCII positive and who were admitted to three European referral gynecology clinics between 2007 and 2010 (Madrid, Marseille and Milan). All patients underwent LQ and LA tests. Results The sensitivity of the two assays for HPV typing was 94% for LQ and 99% for LA (compared with HCII). The overall concordance between LQ and LA was 93%. The three prevalent genotypes, HPV16, HPV18, and HPV31, were identified with a high concordance using the two assays: kappa 0.93, 0.83, and 0.91, respectively. Mixed genotypes were more frequently detected by LA than by LQ: 52% vs. 18%, respectively (p < .0001). Conclusions These assays have a good clinical sensitivity for detecting HPV types in CIN2+ patients and allow the virus type to be detected in the same experiment. Our study revealed no significant difference between LQ and LA for CIN2+ or CIN3+ diagnosis, indicating similar distributions of HPV types and a mixed genotype detection that is higher for LA than for LQ.

Tamoxifen and fenretinide have been extensively studied and exhibit breast cancer-preventing activity. We aimed to assess their effect on sex hormones, sex hormone binding globulin (SHBG) and retinol, and their association with mammographic density (MD) and breast cancer events. In a double-blind, placebo-controlled trial, premenopausal women at risk for breast cancer were randomized to tamoxifen 5 mg/day, fenretinide, both agents, or placebo for 2 years. We measured MD and circulating concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, testosterone, androstenedione, dehydro-epiandrosteronesulfate, prolactin, SHBG, and retinol at baseline and on yearly intervals. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models. Low-dose tamoxifen markedly and enduringly increased SHBG, whereas the increases in testosterone, estradiol, and prolactin and reduction in LH weakened after 1 year. Fenretinide increased testosterone and androstenedione and decreased retinol. MD correlated directly with SHBG and inversely with retinol. After a median follow-up of 12 years, the 10-year cumulative incidence of breast cancer events was 37 % in women with SHBG ≤ 59.3 nmol/L, 22 % in women with SHBG between 59.3 and 101 nmol/L, and 19 % in women with SHBG > 101 nmol/L (P = 0.018). The difference among SHBG tertiles remained statistically significant at multivariable analysis: HR = 2.26 (95 % CI 1.04, 4.89) for the lowest versus the highest tertile. We conclude that low-dose tamoxifen or fenretinide exhibits favorable hormonal profiles as single agents, further supporting their administration for prevention of breast cancer in premenopause. Notably, SHBG levels were inversely associated with breast neoplastic events.

Objective The rare occurrence of histology-proven cervical intraepithelial neoplasia grade 3 (CIN 3) or invasive cancer with a negative HC2 result is known. Tissue blocks of 37 cases of histology-diagnosed CIN 3+ with a concomitant negative HC2 test were genotyped to investigate the human papillomavirus (HPV) status within the lesion. Methods We considered 1,976 cervical excision specimens performed with concomitant HC2 test. Of these, 37 histology-confirmed CIN 3+ resulted HC2 negative. Thirty-three paraffin blocks, derived by the cervical excision, could be genotyped for high- (HR) and low-risk (LR) HPV genotypes. Results Detailed histology showed 30 CIN 3, 2 squamous cell invasive carcinomas, and 5 invasive adenocarcinomas. One specimen resulted not amplifiable at the genotyping. Twenty-two cases (68.7%) were positive for HR-HPV types, either in single (n = 17) or multiple HR-HPV infection (n = 5). Most of the HR-HPVs found were 16 or 18. Ten cases (31.3%) were negative for HR-HPV types; 5 of these were positive for probable HR-HPV types, not detectable with HC2 HR-probes, 1 was positive to LR-HPV types, while 1 had HPV-69/71. Three cases were negative for HPV DNA, either high or low risk. Conclusions Of the rare cases of CIN 3+ lesions with concomitant negative HC2 test, 69% are true failures in HR-HPV detection. One third of HC2-negative CIN 3+ is related to the presence of other HPV genotypes not covered by the HC2 panel or to undetectable HPV in the lesion; both these rare occurrences were already described in large cancer series and partially explain the occurrence of HPV-negative CIN 3+.

Since squamous cell carcinoma antigen (SCC-Ag) testing became commercially available on the Architect platform, the previously established method on the Abbott IMx platform has been progressively replaced. Aim of this work was to compare SCC-Ag values obtained with the 2 methods. Clinical and laboratory data of 188 patients for whom SCC-Ag determination was requested, were reviewed. IMx was used to determine the levels of SCC-Ag from June 2007 to May 2009, while the Architect system was used from June 2009 to April 2011. Only patients consistently diagnosed with no evidence of disease, for whom at least 2 determinations with each analyzer were available were used. Comparison of the results obtained with the 2 systems was then performed. Mean values for SCC-Ag were 0.56 ng/mL (Standard Error (SE): 0.08) with the IMx method, and 1.08 ng/mL (SE 0.10) with Architect (p

The quality of first surgery is one of the most important prognostic factors in ovarian cancer patients. Pre-surgical distinction of benign and malignant pelvic mass plays a critical role in ovarian cancer management and survival. The aim of this study was to evaluate the clinical performance of ROMA algorithm and of CA125 and HE4 in the triage of patients with a pelvic mass undergoing surgery, in order to discriminate benign from malignant disease.Three hundred and forty-nine pre- and post-menopausal women, aged 18 years or older undergoing surgery because of a pelvic mass were enrolled: serum concentrations of CA125 and HE4 were determined and ROMA was calculated for each sample.Median serum CA125 and HE4 levels were higher in patients with EOC compared to subjects with benign disease (p0.0001). The resultant accuracy (using Receiver Operating Characteristics, ROC Area) values for HE4, CA125 and ROMA showed a good performance ranging from 89.8% for CA125 in pre-menopausal patients to 93.3% for ROMA in post-menopausal patients: AUC for ROMA resulted significantly higher in comparison to CA125 alone (93.3% vs 90.3%, p=0.0018) in post menopausal patients. A sub-analysis considering the 40 patients with endometrioid disease showed the highest accuracy of HE4 in these patients.Data presented confirm the accuracy of HE4 and of the ROMA algorithm in the distinction of ovarian carcinoma from benign disease, with a trend towards better performance for ROMA than for CA125 alone, statistically significant in postmenopausal patients.

Background The increasing importance of high-risk human papillomavirus (hrHPV) testing in cervical cancer screening warrants evaluation of HPV DNA tests with an equivocal zone requiring retesting of samples in the low positive range. Objectives To compare the results of the digene hc2 High Risk HPV DNA Test (hc2), which has a manufacturer's recommended retesting zone with the cobas HPV Test, a real-time polymerase chain reaction amplification test without an equivocal range. Study design A retrospective subanalysis of the ATHENA study comparing results for hc2 High Risk HPV DNA Test and the cobas HPV Test using the LINEAR ARRAY HPV Genotyping Test (LA) and Sanger sequencing as comparators was performed. The ability of each test to detect high-grade cervical disease in the equivocal range was also evaluated. Results 5.2% of samples fell within the equivocal zone (RLU/CO 1.0–2.5) and required retesting with the hc2 High Risk HPV DNA Test. In this low-positive range the cobas HPV Test showed better positive percent agreement (PPA) than hc2 High Risk HPV DNA Test for LA and sequencing (84.2% vs.70.9% and 92.1% vs.82.5%, respectively). hc2 High Risk HPV DNA Test and the cobas HPV Test demonstrated comparable sensitivity for detection of high-grade disease in the equivocal range. In the low cobas HPV Test range (cycle threshold [ C t ] 40–35), the cobas HPV test again demonstrated a better PPA than hc2 High Risk HPV DNA Test with LA and sequencing as comparators and more high-grade disease was detected by the cobas HPV Test than hc2 High Risk HPV DNA Test. Conclusion The cobas HPV Test demonstrates reliable performance in the hc2 High Risk HPV DNA Test equivocal zone, thus supporting it as an option for HPV testing that avoids the need for retesting.

In addition to the myocardial necrosis extent, functional changes occurring in myocardial infarction (MI) may contribute to acute ventricular dysfunction. During MI, ischemia-reperfusion injury induces mitochondrial damage, resulting in cardiomyocytes homeostasis and contraction impairment, and

In patients with breast cancer, there is evidence correlating the presence of circulating tumor cells (CTCs) with disease-free survival, progression-free survival and overall survival. The detection of CTCs may be useful in gaining a better understanding of the mechanisms of tumor growth and in the improvement of patient management. This review analyzes the prognostic and predictive relevance of CTCs through the principal published studies, cytometric techniques and nucleic acid-based approaches to detect CTCs, phenotypic expression of specific receptors, molecular pathways and genetic signatures for potential tailored therapies.

Objective The present study assessed the clinical outcome of patients conservatively treated for cervical adenocarcinoma in situ (AIS) and their predictive factors using univariate and multivariate population averaged (PA) generalized estimating equation (GEE) model in a longitudinal setting. Methods A series of 166 consecutive women (mean age 39.8 yrs; range 23–63 yrs) underwent conservative treatment of AIS as the primary treatment and were followed-up (mean 40.9 mo) using colposcopy, PAP-smear, biopsy and HPV-testing with Hybrid Capture 2. Results Hysterectomy was performed as part of the primary management in 47 patients, who were excluded from the follow-up (FU) analysis. Out of 119 women closely followed-up, additional therapeutic procedures were performed in 69. At study conclusion, 7 patients (5.9%) showed persistent disease, while 8 (6.7%) had progressed to invasive adenocarcinoma (AC). Positive HR-HPV test was the only independent predictor of disease recurrence (adjusted OR = 2.72; 95%CI 1.08–6.87), and together with free cone margins (OR = 0.20; 95%CI 0.04–0.92), HR-HPV positivity was also the single most powerful predictor of disease progression to AC, with OR = 3.74; 95%CI 1.84–7.61 (p = 0.0001) in multivariate PA-GEE. Conclusions These results suggest that testing HR-HPV positive at any time point during FU is the most significant independent predictor of progressive disease, while showing free margins in cone has a significant protective effect against progression to AC. Furthermore, because 4.3% women with persistent, recurrent or progressive disease experienced a late (5th and 6th FU) diagnosis of HG-CGIN or microinvasive AC, a close surveillance should be scheduled for at least three years in conservatively treated AIS patients.

To assess the prognostic value of presurgical CA15.3 in a large cohort of patients with early breast cancer. A total of 7.942 consecutive patients with breast cancer operated at the European Institute of Oncology between 1998 and 2005 and with presurgical values of CA 15.3 available were included. We explored patterns of recurrence by baseline CA 15.3 values. Mean CA15.3 was 17.0 U/ml. CA15.3 was associated with age, tumor size, nodal involvement, Ki-67 labeling index, grade, HER2 expression, molecular subtype, and perivascular invasion. CA15.3 was independently associated with distant metastases [HR > 20 U/ml vs. ≤ 20 U/ml: 1.34 (95% CI 1.15-1.56)] and death [HR > 20 U/ml vs. ≤ 20 U/ml: 1.30 (95% CI 1.11-1.53)]. When considering CA15.3 as continuous variable, we observed a constant risk of metastasis and death from the lowest values to about 15-20 U/ml, and then a significantly increasing risk with increasing values of CA15.3. Finally, CA15.3 provided significant additional information to the common prognostic factors to predict the occurrence of metastases (C-index P value 0.04). In patients with operable breast cancer, presurgical CA15.3 value is an independent prognostic factor for metastases and deaths. CA15.3 provides additional information to the common prognostic factors and should be considered in the adjuvant therapeutic algorithm. © 2011 Springer Science+Business Media, LLC.

We propose a composite and reproducible neuroendocrine differentiation (NED)– assessing panel—including plasma chromogranin A (p-CgA), tissular CgA (t-CgA), somatostatin receptor 2 (SSTR2), and Ki-67— of needle biopsy specimens to be applied to patients with castration-resistant prostate cancer (CRPC). In our series, a high prevalence (85.1%) of NED was found. Neuroendocrine markers were associated with high prostatespecific antigen (PSA) levels, aggressive (high initial Gleason Score) and rapidly progressive disease, and consequent decreased overall survival (OS). Background: Assessing the neuroendocrine (NE) pattern in castration-resistant prostate cancer (CRPC) may prove useful in selecting potential responders to target therapies such as somatostatin analogues. The aim of this study was to define a panel of markers or examinations appropriate to characterize NE differentiation (NED). Methods: Forty-seven patients with CRPC underwent a systematic diagnostic attempt to characterize the NE phenotype using a plasma blood test for chromogranin A (CgA) and immunohistochemical staining of needle biopsy‐obtained specimens (CgA, somatostatin receptor 2 [SSTR2], Ki-67, and androgen receptors). In a subgroup of 26 patients, somatostatin receptor scintigraphy using 111 In-DTPA-d-Phe octreotide (octreotide scintigraphy; Octreoscan, Covidien, Hazelwood, MO) was also performed. Results: NED was found in 85.1% of patients (if serum CgA, tissular CgA, and tissular SSTR2 were considered separately: 54%, 67%, and 58%, respectively). Only 15% of the 26-patient subgroup had an abnormal octreotide scintigraphy result. Although p-CgA and t-CgA were associated with more aggressive disease with a worse prognosis, patients with positive tissular SSTR2 staining had longer overall survival (OS). Conclusion: This systematic approach to explore the NED in a quite homogeneous group of patients with CRPC seems reproducible and appropriate. Further investigations are required to validate this panel and better characterize potential responders to targeted therapy.

Human papillomavirus (HPV) is a causal agent of cervical cancer, and persistent HPV16 or HPV18 infection carries a particularly high risk. The cobas HPV Test (cobas) provides individual HPV16/HPV18 genotyping with a simultaneous result for 12 other high-risk HPV (hrHPV) genotypes. Its analytical performance for hrHPV genotype detection was retrospectively evaluated against the digene Hybrid Capture 2 HPV DNA test (HC2), in three European centers, in 1360 cervical samples. Both HPV tests performed similarly, with no significant difference in the number of positive and negative samples identified by each test and good agreement between the tests was observed. Discordant samples were analyzed with the Linear Array HPV genotyping test. More low-risk HPV (lrHPV) genotypes were detected in HC2-positive/cobas-negative samples compared with HC2-negative/cobas-positive samples. Conversely, more hrHPV genotypes were detected in HC2-negative/cobas-positive samples compared with HC2-positive/cobas-negative samples. Eight HC2-negative/cobas-positive samples were positive for HPV16 compared with five HC2-positive/cobas-negative samples; HPV18 was detected in one HC2-negative/cobas-positive sample and one HC2-positive/cobas-negative sample. The cobas HPV Test demonstrates comparable analytical performance to the HC2 test, but with a lower rate of cross-reactivity with lrHPV genotypes, and has the advantage of simultaneously providing HPV16/HPV18 identification.

Human papillomavirus (HPV) testing can be used as a primary test for cervical cancer screening. HPV self-sampling has the potential to replace physician/nurse sampling. Our objective was to compare the acceptability of two self-sampling methods among 205 women undergoing an excisional procedure for cervical intraepithelial neoplasia (CIN) at the European Institute of Oncology (IEO).One hundred eleven patients were given a Hybrid Capture (HC) Cervical Sampler™ (Qiagen, Hilden, Germany), and 94 received a self-lavaging device, the Delphi® Screener (Delphi Bioscience, Scherpenzeel, The Netherlands), both with written instructions. Self-sampling was performed just before the clinician-collected cervical sample. Women responded to questions using 5-point ordinal scales on the general acceptability of self-sampling and the physical comfort, embarrassment, pain, and difficulty experienced. Participants were also asked whether they prefer self-sampling or clinician sampling.Both self-sampling methods were generally accepted with a significantly high score (p = 0.005) and significantly lower embarrassment (p = 0.042) in favor of the Delphi Screener. Both self-sampling methods were physically well accepted, not painful, and easy to perform. Most women (n = 117, 68%) preferred the self-sampled compared to the clinician-sampled test, with a significantly higher proportion in the Delphi Screener group (n = 59, 77.6%) compared to those using the HC Sampler (n = 58, 60.4%) (p = 0.021).The present study shows that self-sampling for HPV testing is favorably received by women. A sampling device specifically developed for self-sampling, such as the Delphi Screener, shows the highest degree of satisfaction. A well-accepted HPV sampling method could be especially useful for women who do not take part in cervical screening or in settings where organized screening is not fully implemented.

The detection of circulating tumor cells (CTCs) has considerable utility in the clinical management of patients with solid cancers. However, the phenotypic heterogeneity of CTCs and their low numbers in the bloodstream of patients means that no standardized detection method currently exists for these cells. This, together with differences in pre-analytical sample processing, has led to the collection and accumulation of inconsistent data among independent studies. Here, we compare the ability of three methods to detect CTCs in the blood of colorectal cancer patients. Specifically, different aliquots of the same blood sample were screened for the presence of CTCs by a multimarker RT-PCR assay, the standardized CellSearch assay and dHPLC-based gene mutation analysis. In the population tested, none of the blood samples analysed appeared to be positive by all three methods. Of the samples, 75% were positive for the presence of CTCs by the RT-PCR method. Only 20% were positive by the CellSearch assay, while 14.3% of samples displayed gene mutations consistent with the presence of CTCs when the dHPLC method was applied. The samples which were positive for CTCs by the CellSearch assay did not overlap with those that were positive by dHPLC. Interestingly, however, all of these samples were positive when assessed by RT-PCR. Conversely, of the samples that resulted negative by RT-PCR analysis, none appeared to be positive by either of the other methods. These data, therefore, indicate that of the three methods tested, the multimarker RT-PCR assay provides maximal probability of CTC detection. Here, we present the preliminary results of an ongoing clinical study. Future follow-up involving detection of CTCs in the blood of colorectal cancer patients using these three distinct methods will allow us to verify whether either a single method, or a combination of different assays, is necessary to uncover further prognostic significance of circulating tumor cells.