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.

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.

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.

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.

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.

The oncology phone: an innovative program for the management of the oncology population in an academic medical center.

The Oncology Nursing Leadership Team at the Hospital of the University of Pennsylvania designed and implemented a phone consultation and intervention service to address increasing needs for specialty oncology nursing consultation and care for patients located on nononcology units. This article describes the planning, implementation, and evaluation of this service, which the team named the oncology phone. The service is available 24 hours per day, seven days per week by members of the Oncology Nursing Leadership Team and designated senior members of the clinical nursing staff. Consultation is initiated by any clinical nurse throughout the hospital who determines the need for oncology nursing expertise. Those needs include support for chemotherapy administration, symptom management, and care coordination. Data are collected from each call as well as subsequent face-to-face consultations and interventions. Evaluation of the data reveals important areas for education. A similar program may be valuable to other inpatient settings in addressing the needs of patients and staff.

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.

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.

Temporal coherence of MgO based magnetic tunnel junction spin torque oscillators.

Single-shot, time-resolved measurements are presented to investigate the temporal coherence of the microwave emission for MgO based magnetic tunnel junction spin torque oscillators. The time-domain data reveal that the steady state regime obtained from frequency-domain analysis can be subdivided into two regimes as a function of spin polarized current amplitude. According to these two regimes, two mechanisms that limit the temporal coherence are identified. At low current, extinctions of the steady state oscillations lead to a very short coherence time on the order of a few nanoseconds, while at higher current, the extinctions vanish and the coherence time saturates around 40 ns. As an important result it is shown that the latter is limited by frequency fluctuations. Quenching these frequency fluctuations suggests an intrinsic linewidth that is by a factor of 20 below the one of the free running oscillator.

Tyrosine kinase inhibitors in treatment of fibrous histiocytoma.

AIM: To describe potential beneficial effects of tyrosine kinase inhibitor in the treatment of unresectable/metastatic fibrous histiocytoma. METHODS: We report a case of advanced stage fibrous histiocytoma with locally recurrent disease plus lung and bone metastatic deposits. Patient was treated with the tyrosine kinase inhibitor sunitinib. RESULTS: Treatment with Sunitinib resulted in disease stabilization in the regional lesion and in good partial response for metastatic foci (reduction in number and size). After 13 months of treatment the patient is doing well with no tumor progression. CONCLUSIONS: This case appears to be one of the first documentations of beneficial effect and potential long-term benefit of TKIs in the treatment of fibrous histiocytoma.

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.

Tumour marker prescriptions for cancer screening in the Hellenic primary care.

Tumour markers are neither sensitive nor specific enough for cancer screening. Despite established guidelines, tumour marker 'screening myth' may be alive among physicians, but no study has analysed the phenomenon. This study aims to investigate tumour marker recommendation for screening purposes in primary care setting. A total of 209 Hellenic physicians were surveyed for screening activities by a multiple-choice questionnaire. Data were abstracted for the following tumour marker recommendations: carcinoembryonic antigen (CEA); cancer antigens 19.9, 125 and 15.3; alpha-fetoprotein and beta-human chorionic gonadotropin (beta-HCG). A high rate of physicians advocate that tumour markers in cancer screening (range from 24% for beta-HCG to 46% for CEA). This phenomenon is not related to age, sex, type and level of physicians' specialization. In conclusion, many physicians recommend tumour markers for screening purposes. This may be harmful, since their prescriptions unnecessarily burden health economics, and further evaluation of false-positive findings might be associated with increased costs and risk from additional diagnostic/therapeutic interventions.

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.