Pavlos Msaouel

The role of the insulin-like growth factor-1 system in breast cancer.

IGF-1 is a potent mitogen of major importance in the mammary gland. IGF-1 binding to the cognate receptor, IGF-1R, triggers a signaling cascade leading to proliferative and anti-apoptotic events. Although many of the relevant molecular pathways and intracellular cascades remain to be elucidated, a growing body of evidence points to the important role of the IGF-1 system in breast cancer development, progression and metastasis. IGF-1 is a point of convergence for major signaling pathways implicated in breast cancer growth. In this review, we provide an overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies.

Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis

BackgroundThe diagnostic value and prognostic significance of circulating tumor cell (CTC) detection in patients with bladder cancer is controversial. We performed a meta-analysis to consolidate current evidence regarding the use of CTC detection assays to diagnose bladder and other urothelial cancers and the association of CTC positivity with advanced, remote disease.MethodsStudies that investigated the presence of CTCs in the peripheral blood of patients with bladder cancer and/or urothelial cancer were identified and reviewed. Sensitivities, specificities, and positive (LR+) and negative likelihood ratios (LR-) of CTC detection in individual studies were calculated and meta-analyzed by random effects model. Overall odds ratio of CTC positivity in patients with advanced disease versus those with organ-confined cancer was also calculated.ResultsOverall sensitivity of CTC detection assays was 35.1% (95%CI, 32.4-38%); specificity, LR+, and LR- was 89.4% (95%CI, 87.2-91.3%), 3.77 (95%CI, 1.95-7.30) and 0.72 (95%CI, 0.64-0.81). CTC-positive patients were significantly more likely to have advanced (stage III-IV) disease compared with CTC-negative patients (OR, 5.05; 95%CI, 2.49-10.26).ConclusionsCTC evaluation can confirm tumor diagnosis and identify patients with advanced bladder cancer. However, due to the low overall sensitivity, CTC detection assays should not be used as initial screening tests.

Oncolytic measles virus strains as novel anticancer agents

Introduction: Replication-competent oncolytic measles virus (MV) strains preferentially infect and destroy a wide variety of cancer tissues. Clinical translation of engineered attenuated MV vaccine derivatives is demonstrating the therapeutic potential and negligible pathogenicity of these strains in humans. Areas covered: The present review summarizes the mechanisms of MV tumor selectivity and cytopathic activity as well as the current data on the oncolytic efficacy and preclinical testing of MV strains. Investigational strategies to reprogram MV selectivity, escape antiviral immunity and modulate the immune system to enhance viral delivery and tumor oncolysis are also discussed. Expert opinion: Clinical viral kinetic data derived from noninvasive monitoring of reporter transgene expression will guide future protocols to enhance oncolytic MV efficacy. Anti-measles immunity is a major challenge of measles-based therapeutics and various strategies are being investigated to modulate immunity. These include the combination of MV therapy with immunosuppressive drugs, such as cyclophosphamide, the use of cell carriers and the introduction of immunomodulatory transgenes and wild-type virulence genes. Available MV retargeting technologies can address safety considerations that may arise as more potent oncolytic MV vectors are being developed.

The non-genomic crosstalk between PPAR-γ ligands and ERK1/2 in cancer cell lines

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily acting as transcription factors. PPAR-γ, one of the three PPAR subtypes, is expressed in many malignant and non-malignant cells and tissues. PPAR-γ ligands influence cancer biology via both genomic as well as non-genomic events. The non-genomic action of PPAR-γ ligands, including the activation of MAPK signaling pathways, is under intense investigation. In the presence of PPAR-γ ligands, a rapid phosphorylation of ERK1/2 is observed in many cancer cell lines. Activated ERK1/2 elicits rapid, non-genomic cellular effects and can directly repress PPAR-γ transcriptional activity by phosphorylation. This paper reviews the interrelation of PPAR-γ ligands and activated ERK1/2, in relation to their antineoplastic actions in cancer cell lines, which may offer the potential for improved anticancer therapies.

Diagnostic Accuracy of Transesophageal Echocardiogram for the Detection of Patent Foramen Ovale: A Meta‐Analysis

Patent foramen ovale (PFO) is a remnant of the fetal circulation present in 20% of the population. Right‐to‐left shunting (RLS) through a PFO has been linked to the pathophysiology of stroke, migraine with aura, and hypoxemia. While different imaging modalities including transcranial Doppler, intra‐cardiac echo, and transthoracic echo (TTE) have often been used to detect RLS, transesophageal echo (TEE) bubble study remains the gold standard for diagnosing PFO. The aim of this study was to determine the relative accuracy of TEE in the detection of PFO.

Accuracy of Conventional Transthoracic Echocardiography for the Diagnosis of Intracardiac Right‐to‐Left Shunt: A Meta‐Analysis of Prospective Studies

Paradoxical embolization through a right‐to‐left shunt (RLS), often from a patent foramen ovale (PFO), has been associated with cryptogenic stroke. While transesophageal echo (TEE) bubble study is the current standard reference for diagnosing PFO, transthoracic echo (TTE) remains the most commonly used screening test for RLS due to its noninvasiveness and easy availability. The aim of this meta‐analysis was to determine the accuracy of TTE compared to TEE as the reference.

Multiplicative interaction between mean corpuscular volume and red cell distribution width in predicting mortality of elderly patients with and without anemia

Recent studies have shown that an elevated red cell distribution width (RDW) is an important predictor of adverse outcomes. However, the strength of this biomarker has not been tested in a large outpatient elderly population. Also since increased RDW can be due to a variety of etiologies, additional biomarkers are needed to refine the prognostic value of this variable. We assembled a cohort of 36,226 elderly (≥65yo) patients seen at an outpatient facility within the Einstein/Montefiore system from January 1st 1997 to May 1st 2008 who also had a complete blood count performed within 3 months of the initial visit. With a maximum follow‐up of 10 years, we found that an elevated RDW (>16.6) was associated with increased risk of mortality in both non‐anemic (HR = 3.66, p < 0.05) and anemic patients (HR = 1.87, p < 0.05). The effect of RDW on mortality is significantly increased in non‐anemic patients with macrocytosis (HR = 5.22, p < 0.05) compared to those with normocytosis (HR = 3.86, p < 0.05) and microcytosis (HR = 2.46, p < 0.05). When comparing non‐anemic patients with both an elevated RDW and macrocytosis to those with neither, we observed an elevated HR of 7.76 (higher than expected in an additive model). This multiplicative interaction was not observed in anemic patients (HR = 2.23). Lastly, we constructed Kaplan‐Meier curves for each RDW/MCV subgroup and found worsened survival for those with macrocytosis and an elevated RDW in both anemia and non‐anemic patients. Based on our results, the addition of MCV appears to improve the prognostic value of RDW as a predictor of overall survival in elderly patients. Am. J. Heamtol. 88:E245–E249, 2013.

Combined androgen blockade therapy can convert RT-PCR detection of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts from positive to negative in the peripheral blood of patients with clinically localized prostate cancer and increase biochemical failure-free survival after curative therapy.

BACKGROUND The clinical relevance of positive molecular staging as defined by reverse transcriptase-polymerase chain reaction (RT-PCR) detections of both prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts in the peripheral blood (PB) of patients with prostate cancer is still debatable. METHODS We analyzed the biochemical failure-free survival (bFFS) of prostate cancer patients with positive molecular staging who underwent immediate curative therapy (Group I, n=39) compared to prostate cancer patients who did convert their positive molecular staging by the administration of combined androgen blockade (CAB) for 12 months prior to curative treatment (Group II, n=15). RESULTS The median bFFS for Group I was 9 months (95% CI 5-13 months) and was significantly lower compared to Group II (>36 months, p<0.001). In Group I, the median time for PSA values of >2.0 ng/mL was 18 months (95% CI 12-21 months, range 12-36 months). Notably, only one patient from Group II reached PSA values>2.0 ng/mL at 36 months post-curative treatment. CONCLUSIONS In patients with clinically localized prostate cancer and positive RT-PCR detection of PSA and PSMA transcripts in PB, CAB can convert positive molecular staging status to negative and by doing so it modifies the post-curative therapy bFFS of patients with clinically localized prostate cancer.

Abnormal platelet count is an independent predictor of mortality in the elderly and is influenced by ethnicity

Even though alterations in platelet counts are presumed to be detrimental, their impact on the survival of patients has not been studied in large cohorts. The prevalence of thrombocytopenia and thrombocytosis was examined in a large inner city outpatient population of 36,262 individuals aged ≥65 years old. A significant association with shorter overall survival was found for both thrombocytopenia (HR=1.45; 95% CI: 1.36–1.56) and thrombocytosis (HR=1.75; 95% CI: 1.56–1.97) when compared to the survival of patients with normal platelet counts. This effect persisted across all ethnic groups. However, African-Americans (non-Hispanic Blacks) with either thrombocytopenia or thrombocytosis were at significantly lower risk compared to non-Hispanic Caucasians (HR=0.82; 95% CI: 0.69–0.96 and HR=0.70; 95% CI: 0.53–0.94, respectively). Furthermore, Hispanics with thrombocytosis were found to have a lower mortality risk compared to non-Hispanic Caucasians with thrombocytosis (HR=0.60; 95% CI: 0.44–0.81). A value of <125,000 platelets per microliter was a better prognostic marker for non-Hispanic Blacks and these subjects with this platelet count had similar overall survival to that of Caucasians with a value of <150,000 per microliter. In conclusion, thrombocytosis and thrombocytopenia are independently associated with shorter overall survival in elderly subjects and this effect is modified by ethnicity. Using different thresholds to define the association of thrombocytopenia and thrombocytosis with overall mortality risk among non-Hispanic Blacks may, therefore, be warranted.

The effort-reward imbalance questionnaire in Greek: translation, validation and psychometric properties in health professionals.

The Effort‐reward Imbalance Questionnaire in Greek: Translation, Validation and Psychometric Properties in Health Professionals: Pavlos MSAOUEL, et al. Greek Junior Doctors and Health Scientists Society, Greece—