Transcriptomic Meta-Analysis Identifies Upregulated Clotting and Fibrinolysis Pathways in Colorectal Cancer Tumors Containing Hereditary PMS2 Mismatch Repair Deficiency.

Lynch Syndrome is characterized by deficient mismatch repair (dMMR) components. We performed a meta-analysis of multiple RNA-sequencing datasets from patients with different dMMR variants (PMS2, MLH1, and MSH2) to better characterize the unique transcriptional profiles. Our results reveal enriched signaling pathways from tumor samples with germline mutations in the PMS2 gene including upregulation in pathways related to intrinsic and extrinsic prothrombin activation, fibrinolysis, and uPA/uPAR-mediated signaling. These pathways have been associated with tumor growth, invasiveness, and metastasis. This work provides support for further exploration into the role of PMS2 in tumor development, and as a potential therapeutic mechanism.

CRIPTO promotes extracellular vesicle uptake and activation of cancer associated fibroblasts.

Expression of CRIPTO, a factor involved in embryonic stem cells, fetal development, and wound healing, is tied to poor prognosis in multiple cancers. Prior studies in triple negative breast cancer (TNBC) models showed CRIPTO blockade inhibits tumor growth and dissemination. Here, we uncover a previously unidentified role for CRIPTO in orchestrating tumor-derived extracellular vesicle (TEV) uptake and fibroblast activation through discrete mechanisms. We found a novel mechanism by which CRIPTO drives aggressive TNBC phenotypes, involving CRIPTO-laden TEVs that program stromal fibroblasts, toward cancer associated fibroblast cell states, which in turn prompt tumor cell invasion. CRIPTO-bearing TEVs exhibited markedly elevated uptake in target fibroblasts and activated SMAD2/3 through NODAL-independent and - dependent mechanisms, respectively. Engineered expression of CRIPTO on EVs enhanced the delivery of bioactive molecules. In vivo , CRIPTO levels dictated TEV uptake in mouse lungs, a site of EV-regulated premetastatic niches important for breast cancer dissemination. These discoveries reveal a novel role for CRIPTO in coordinating heterotypic cellular crosstalk which offers novel insights into breast cancer progression, delivery of therapeutic molecules, and new, potentially targetable mechanisms of heterotypic cellular communication between tumor cells and the TME.

Real-World Treatment Patterns in Patients With Metastatic Castration-Resistant Prostate Cancer in Greece: The PROSPECT Study.

INTRODUCTION: Real-world data on management of metastatic castration resistant prostate cancer (mCRPC) with novel therapies is sparse. The aim of this study was to capture real-world management strategies in patients with mCRPC who initiated first line (1L) systemic therapy with chemotherapy or novel hormonal agents (NHAs) in Greece and describe the therapeutic sequencing strategy among patients who advanced to 2L and 3L treatment. PATIENTS AND METHODS: In this noninterventional, multicentre, retrospective study (PROSPECT), a medical chart review of 149 patients with mCRPC who initiated 1L systemic therapy with chemotherapy or NHAs in 7 major anticancer hospital clinics, from public, academic, and private sectors in Greece was conducted. All endpoints were descriptively analysed. Kaplan-Meier was used for time-to-event outcomes. RESULTS: At 1L (N = 149), most (78.5%) patients received NHAs; enzalutamide (52.3%), and abiraterone (26.2%). At 2L (N = 68), most (72.1%) patients received chemotherapy, most frequently docetaxel (50.0% of all patients). At 3L (N = 32), 56.3% and 31.3% of patients received chemotherapy and NHAs, respectively. Regarding treatment sequencing from 1L→2L (N = 68), most patients (55.9%) advanced from NHA→chemotherapy. Regarding treatment sequencing from 1L→2L→3L (N = 32), 34.4% advanced from NHAs→chemotherapy→chemotherapy and 31.3% from NHAs→chemotherapy→NHA. Estimated median times spent on treatment at 1L, 2L, and 3L were 9.8, 4.4, and 3.7 months, respectively. CONCLUSION: Most patients were treated with 1L NHAs, in accordance to established guidelines (which suggest both NHA and chemo as preferred 1st line options). There appeared to be a longer time on treatment of NHAs at 1L than chemotherapy, suggesting an unmet need for treatment optimisation/recommendations for 2L and 3L treatment in mCRPC.

CARDIOCARE: An integrated platform for the management of elderly multimorbid patients with breast cancer therapy induced cardiac toxicity.

Breast cancer (BC) remains the most diagnosed cancer in women, accounting for 12% of new annual cancer cases in Europe and worldwide. Advances in surgery, radiotherapy and systemic treatment have resulted in improved clinical outcomes and increased survival rates in recent years. However, BC therapy-related cardiotoxicity, may severely impact short- and long-term quality of life and survival. This study presents the CARDIOCARE platform and its main components, which by integrating patient-specific data from different categories, data from patient-oriented eHealth applications and wearable devices, and by employing advanced data mining and machine learning approaches, provides the healthcare professionals with a valuable tool for effectively managing BC patients and preventing or alleviating treatment induced cardiotoxicity.Clinical Relevance- Through the adoption of CARDIOCARE platform healthcare professionals are able to stratify patients for their risk for cardiotoxicity and timely apply adequate interventions to prevent its onset.

Hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of primary advanced and recurrent ovarian cancer: a systematic review and meta-analysis of randomized trials.

INTRODUCTION: Ovarian cancer is the most lethal gynecologic malignancy. Although treatment with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results, its role remains elusive. The aim of this study was to assess the comprehensive randomized evidence for the use versus non-use of HIPEC in primary and recurrent ovarian cancer. MATERIALS AND METHODS: The Medline, Embase and Cochrane databases, as well as the European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) conference abstracts of the last 5 years, were scrutinized in January 2022 for randomized, controlled trials that studied the use of HIPEC in ovarian cancer. Overall survival (OS), disease-free survival (DFS) and progression-free survival, as well as post-operative morbidity were the outcomes of interest. This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. RESULTS: Six randomized, controlled trials that randomized 737 patients were included in our analysis; of these, four studies (519 patients) were in primary and two (218 patients) in recurrent settings. In primary ovarian cancer, the combination of HIPEC with interval cytoreductive surgery (CRS) and neoadjuvant chemotherapy significantly improved the 5-year OS [393 patients, risk ratio (RR) = 0.77; 95% confidence interval (CI) 0.67-0.90; P value = 0.001] and DFS (hazard ratio = 0.60; 95% CI 0.41-0.87; P value = 0.008) compared with standard treatment alone. In the absence of neoadjuvant chemotherapy, the use of HIPEC + CRS was not associated with any survival advantage (126 patients, 4-year OS, RR = 0.93; 95% CI 0.57-1.53; P value = 0.781), but the sample size was smaller in this subset. Use of HIPEC in recurrent ovarian cancer did not provide any survival advantage (5-year OS: 218 patients, RR = 0.85; 95% CI 0.45-1.62; P value = 0.626). The risk for grade ≥3 adverse events was similar between HIPEC and no HIPEC (RR = 1.08; 95% CI 0.98-1.18; P value = 0.109). CONCLUSIONS: In primary ovarian cancer the combination of HIPEC with interval CRS and neoadjuvant chemotherapy is a safe option that significantly improved 5-year OS and DFS. Its use in other settings should continue to be considered investigational.

The prognostic and predictive impact of low estrogen receptor expression in early breast cancer: a systematic review and meta-analysis.

INTRODUCTION: Traditionally, estrogen receptor (ER)-positive breast cancer has been defined as tumors with ≥1% positive for ER. The updated American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines recommend that tumors with ER expression of 1%-10% should be classified as ER-low-positive, recognizing the limited clinical evidence on the prognostic and predictive role of low ER expression. We aimed to investigate the predictive role of ER-low expression to neoadjuvant chemotherapy (NeoCT) and the prognostic significance of ER-low expressing breast tumors compared with ER-positive or ER-negative breast tumors. METHODS: A meta-analysis was conducted using the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines and eligible articles were identified on PubMed and ISI Web of Science databases. The primary outcome was pathologic complete response and secondary outcomes were disease-free survival (DFS) and overall survival (OS). Twelve retrospective cohort studies were included in the meta-analysis. NeoCT resulted in higher pathologic complete response among patients with ER-low expression compared with ER-positive and comparable to ER-negative. Patients with ER-low breast cancer had a statistically significant worse DFS and OS compared with patients with ER-positive breast cancer, whereas no difference in DFS or OS was observed between ER-low and ER-negative subgroups. DISCUSSION: The current evidence suggests that ER-low breast cancer has a more similar outcome to ER-negative than to ER-positive breast cancer in terms of DFS and OS. ER-low expression seems also to have a predictive role regarding NeoCT. Considering the certainty of current evidence categorized as low to moderate, our results urge the need for well-designed prospective studies investigating the molecular background and the most appropriate treatment strategy for ER-low expressing breast cancer.

Plasma ctDNA RAS status selects patients for anti-EGFR treatment rechallenge in metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Recently one randomized trial and several phase II studies underscored that patients with metastatic colorectal cancer who progressed after an initial clinical benefit from anti-epidermal growth factor receptor (EGFR) treatment may further benefit from rechallenge with anti-EGFR therapy. Testing circulating tumor DNA (ctDNA) RAS status prior to anti-EGFR rechallenge seems a promising non-invasive method to predict and monitor response to anti-EGFR readministration. AIM: To assess the capability of liquid biopsy ctDNA in exploring RAS status and in predicting outcome of metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibody rechallenge. MATERIALS AND METHODS: Systematic review of literature and meta-analysis of the available evidence. RESULTS: Data from four studies involving 117 patients were available. All patients harbored RAS wild type tumors and derived benefit from first line anti-EGFR therapy. Of these, 65 underwent plasma ctDNA before anti-EGFR treatment rechallenge and were eligible for analyses: 35 patients had RAS wild type ctDNA, and 30 RAS mutated, indicating that 46% of patients underwent RAS status conversion after primary anti-EGFR therapy. Anti-EGFR rechallenge among patients with plasma ctDNA RAS wild type status was associated with a consistent benefit in progression free survival (hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.22-0.70; p = 0.001; I2 = 0) and overall survival (HR 0.37, 95% CI 0.16-0.85; p = 0.02; I2 = 74%) when compared to its use among patients with plasma ctDNA RAS mutation. Patients with plasma ctDNA RAS wild type profile also performed statistically better in term of disease control rate, risk for disease progression at 3 and 6 months, and risk for death at 6 and 12 months. CONCLUSION: RAS status assessment continues to be useful in predicting benefit for anti-EGFR treatment.

Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials.

Numerous studies have demonstrated that angiogenesis and in particular VEGF over-expression play an essential role in the progression and metastatic potential of breast cancer. Bevacizumab is a humanized recombinant monoclonal antibody that specifically blocks the binding of VEGF to high-affinity receptors and it has been recently used for the treatment of metastatic breast cancer. We conducted a meta-analysis to synthesize available evidence for use of bevacizumab in metastatic breast cancer patients. Systematic review and meta-analysis of available trials. Primary outcomes were overall survival, progression free survival (PFS) and objective response rate (ORR). Five trials were identified with 3,163 eligible patients. Combination of bevacizumab and chemotherapy resulted in a statistically significant improvement in PFS (HR = 0.70, 95% CI 0.60-0.82, P = 9.3 x 10(-6)) and ORR (RR = 1.26, 95% CI 1.17-1.37, P = 9.96 x 10(-9)) compared with chemotherapy alone. Differences in objective response rates were substantial independently by the type of chemotherapy used, while PFS advantages were observed only for taxanes. The pooled HR for overall survival did not show significant advantage for the use of bevacizumab compared to placebo arm (HR = 0.90, 95% CI 0.80-1.03, P = 0.119). This meta-analysis shows that the addition of bevacizumab to chemotherapy offers meaningful improvement in PFS and ORR in patients with metastatic breast cancer. Bevacizumab treatment might be suggested for treatment of 1st line metastatic breast cancer, but more data are needed until statistical overall survival differences will be documented and firm guideline recommendation could be given.

Evaluating the strength of potential misplaced priorities in opportunistic cancer screening practice in Greece.

PURPOSE: Screening is a significant method for cancer control, nevertheless the implementation of non cost-effective screening tests at national level may constitute a major burden to health economics. The purpose of this study was to determine the cancer screening activities of a large sample of the Hellenic population, in a country with opportunistic screening practice. METHODS: A large survey on cancer screening in Greece was organized and conducted by the Panhellenic Association for Continual Medical Research (PACMeR). Screening performance of evidence-based (EB), non-evidence-based (non EB) and of undefined benefit tests was analysed. RESULTS: 7001 individuals were analysed. Eighty-eight percent of males and 93% of females stated that they were interested in cancer screening practices. Gynecological cancer screening was performed in the range of 23-38%. Colorectal cancer screening was rarely performed in both genders (1- 2%), while non-evidence-based tests were regularly performed (urinalysis 50% and chest radiography 15-18%). Full blood count and PSA measurement were widely accepted (over 45% in both genders and 19.5% in males, respectively). Sociodemographic characteristics did not influence the performance of EB tests in males while females' activities were highly influenced by such parameters. CONCLUSION: Opportunistic cancer screening in a primary health care system where national guidelines are missing may cause ambiguous results. Reconsideration of health policy in such cases is mandatory.

Moving ahead in diabetics' cancer screening; food for thought from the Hellenic experience.

Although data from literature suggest that diabetic women are frequently under screened for gynaecological cancers little is known about screening implementation for other cancers for both genders. This study investigates comprehensive cancer screening practices of diabetics as compared with non-diabetics; analyses screening patterns both by gender and level of evidence and reveals target subgroups that should be paid more attention for screening implementation. 675 diabetics vs. 5772 non-diabetic Greek individuals entered the PACMeR 02 cancer screening study. Diabetic women reported significantly lower performance for the sex-specific evidence-based cancer screening tests and digital rectal examination (DRE) as compared with non-diabetics (P < 0.05). Diabetic women older than 60 years old, of elementary education, housewives and farmers showed the lowest performance rates (P < 0.01). Prostate cancer screening was higher among diabetic men with ultrasound and DRE reaching statistical significance (P < 0.05). Subgroups analysis did not reveal a hidden relationship. Both genders of diabetics reported never performing skin examination at higher rates (P < 0.001), although screening intent is extremely low in both diabetics and non-diabetics (<1%). Evidence-based screening coverage was inconsistent in both genders independently by the diabetic status. Primary care efforts should be provided to implement presymptomatic cancer control.

Injection locking at 2f of spin torque oscillators under influence of thermal noise.

Integration of Spin Torque Nano-Oscillators STNO's in conventional microwave circuits means that the devices have to meet certain specifications. One of the most important criteria is the phase noise, being the key parameter to evaluate the performance and define possible applications. Phase locking several oscillators together has been suggested as a possible means to decrease phase noise and consequently, the linewidth. In this work we present experiments, numerical simulations and an analytic model to describe the effects of thermal noise in the injection locking of a tunnel junction based STNO. The analytics show the relation of the intrinsic parameters of the STNO with the phase noise level, opening the path to tailor the spectral characteristics by the magnetic configuration. Experiments and simulations demonstrate that in the in-plane magnetized structure, while the frequency is locked, much higher reference currents are needed to reduce the noise by phase locking. Moreover, our analysis shows that it is possible to control the phase noise by the reference microwave current (IRF) and that it can be further reduced by increasing the bias current (IDC) of the oscillator, keeping the reference current in feasible limits for applications.

Non-small cell lung cancer in the young: a retrospective analysis of diagnosis, management and outcome data.

BACKGROUND: Non-small cell lung cancer (NSCLC) in young patients is uncommon and is thought to constitute a distinct oncological entity with characteristic clinicopathological patterns. Since the reported data are scant and discordant, the presentation, management and outcome data of NSCLC patients aged under 45 years of age were analyzed and compared with those of patients over 45 years old. Prognostic factors for risk classification were also evaluated. MATERIALS AND METHODS: The data were abstracted from the Hellenic Cooperative Oncology Group (HeCOG) cancer registry database. The presentation, management and outcome data of patients with histologically confirmed NSCLC, managed from 1989 until 2004 in HeCOG participating centers, were retrospectively analyzed. The clinicopathological characteristics of patients aged < and > than 45 years old were compared and evaluated for prognostic significance regarding outcome. RESULTS: The data for NSCLC patients (1906), of whom 115 were aged <45, were retrieved. In comparative analysis, the young patients were more frequently asymptomatic at diagnosis, while older patients presented significantly higher rates of thoracic pain, cough and fatigue (p<0.01). The young patients were more commonly diagnosed with adenocarcinoma and less frequently with squamous cancer than patients aged over 45. Although the stage distribution was distinct, with older patients presenting higher rates of stage IV disease (21.9% vs. 12.2%), the rates of early lung cancer (stages I-IIIa) were similar. The overall survival (OS) was not significantly different (median OS 12 vs. 11.5 months, p=0.277). Among patients who underwent first-line palliative chemotherapy, young individuals had a significantly shorter time to progression: 4.3 vs. 5.8 months (p=0.0049). Univariate and multivariate regression analyses established the prognostic usefulness of the performance status, disease stage and disease-free interval for the risk of death, both in the total number of patients (1906) and in young patients (115). CONCLUSION: This large retrospective series failed to present strong evidence that NSCLC among young individuals constitutes a distinct clinicopathological entity with differing biological behavior, since the same clinicopathological prognostic factors were valid in both age groups. Molecular phenotypic studies are needed to shed light on this controversial subject.

Is primidone the drug of choice for epileptic patients with QT-prolongation? A comprehensive analysis of literature.

Sudden unexplained/unexpected death (SUDEP) in epilepsy is a major cause of death accounting for 7-17% of the mortality among epileptic patients. Prolongation of QT-interval has been issued as a major mechanism in SUDEP since it is associated with fatal cardiac arrhythmias. This condition may be further precipitated by anti-epileptic treatment. Despite thorough literature research, we did not find any reports suggesting that primidone is responsible for QT-prolongation. On the contrary, all the retrieved reports addressed that the drug shortened QT-interval and corrected signs and symptoms of the underlying disease.

Chlamydia trachomatis: time for screening?

Genital Chlamydia trachomatis infection is the leading cause of bacterial sexually transmitted disease in industrialised countries, particularly among young people. The consequences of chlamydial infection may involve urethritis, cervicitis, pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, epididymitis and prostatitis. In addition, chlamydial infection increases the risk of acquisition of human immunodeficiency virus and has been associated with cervical cancer. Although screening programmes exist in a number of countries, the continuously increasing prevalence of chlamydial infections demonstrates the necessity for health authorities to establish effective screening policies, and the importance of defining a comprehensive European screening policy is emerging.

Successful treatment of chronic leg ulcers with epidermal equivalents generated from cultured autologous outer root sheath cells.

The outer root sheath cells of hair follicles can substitute for interfollicular epidermal keratinocytes, as during healing of skin wounds when these cells migrate onto the denuded area and contribute to epidermal regeneration. Using improved culture techniques, we generated epidermal equivalents from cultured outer root sheath cells of patients suffering from recalcitrant chronic leg ulcers, primarily of vascular origin. In such epidermal equivalents, tissue organization as well as immunolocalization of epidermal differentiation products (keratin 10, involucrin, filaggrin) and integrins were indistinguishable from normal epidermis. As determined by the number of bromodeoxyuridine-incorporating cells, the basal layer contained a large compartment of proliferative cells irrespective of donor age. FACS analysis of the outer root sheath cells, used to prepare the epidermal equivalents, disclosed a fraction of small cells with enhanced expression of beta1-integrin, a potential stem cell marker. in contrast to acute wounds, a major definitive take of grafted cultured autologous keratinocytes has not been convincingly demonstrated in chronic wounds. In a pilot study, grafting of epidermal equivalents generated in vitro from autologous outer root sheath cells on 11 ulcers in five patients resulted in a definitive take rate of about 80%, with subsequent complete healing within 2 to 3 wk of five out of seven ulcers grafted with densely arranged cultures. This improvement in the treatment of chronic leg ulcers with cultured autologous keratinocytes probably depends on the large compartment of proliferative cells as well as on a well-developed horny layer which prevents disintegration of the grafts. Practical advantages of the new technique are its noninvasiveness, the lack of need for surgical facilities or anesthesia, and a short immobilization period after grafting.

Involvement of CD80 in the generation of CD4+ cytotoxic T cells.

CD4+ T cells can exert different effector functions, which are partly distinguishable by the secretion of different cytokines, namely by either IFN-gamma, IL-2 and lymphotoxins for Th1-like or IL-4, IL-5, IL-10 and IL-13 for Th2-like T cells. Th1-like T cells can exert cytotoxic functions, too. The cytokinetic phenotype of an activated T cell clone (TCC) is mainly influenced by the cytokinetic pattern of the microenvironment where it was activated. However, the interaction between certain adhesion molecules (i.e. CD28-CD80 and CD28-CD86) may also have an influence on the functionality of the reactive T cell. On the contrary, the requirements for the induction of CD4+ cytotoxic T cells (CD4+ CTLs) are not well understood. We have focused this review on studies investigating the development of CD4+ T cells with cytotoxic effector functions. In particular, we discuss here whether the type of antigen-presenting cells (APCs) and the distinct expression of important adhesion molecules like CD80 and CD86 may influence the generation of CD4+ CTLs. Among a large panel of APCs only dendritic cells and TCCs are able to induce cytotoxicity. The level of CD80, but not of CD86, present on the APCs appears to be crucial for the induction of CD4+ CTLs.

SESy-Europe: a multi-language database dedicated to cancer screening monitoring.

Cancer is the second cause of death in developed countries. Many efforts to educate the public to more tumor free life-style and screening practice have been therefore adopted. Considering the high costs of diagnostic procedures and educational programs a cancer prevention/screening practice monitoring system is required to reduce costs, to assist health making policy decisions, and to tailor more targeted interventions whenever indicated. We, therefore, realized a computerized data-base able to assist medical personnel in health intervention monitoring and making policy at community level with a focus on the European region. An international medical board provided the translation of medical-related contents in English, French, German, Greek, Italian, Rumanian, Spanish and Turkish. The electronic system recognizes and finds relationships between screening events or secondary prevention tests and various causes of medical examinations (symptoms, diseases, professions, presence and type of health insurance, sex, age, medical history, family history, educational level, knowledge about cancer screening and prevention, patient location, type of community, region of provenance, etc). Due to its multi-language standardized characteristics its application may bridge European countries in cancer screening monitoring policy.

Hyperpyrexia secondary to acute hypocalcemic status. Is there a role for calcitonin therapy in bone metabolism derangements due to anticonvulsant drugs?

Hypocalcemia, hyperparathyroidism, hypovitaminosis D, hypocalcitoninemia and decreased bone mass are side effects of several anticonvulsant drugs. Since calcitonin inhibits the mineral mobilization of bone and augments minerals bone content, combined therapy with calcitonin, calcium, vitamin-C and vitamin-D was administrated to a patient with severe anticonvulsant disturbances of bone metabolism. Calcitonin hypersensitivity was evident. The symptomatology, characterized by the rare hypocalcemic hyperpyrexia, regressed after calcium infusion.