Clinical Characterization of Targetable Mutations (BRAF V600E and KRAS G12C) in Advanced Colorectal Cancer-A Nation-Wide Study.

BRAF V600E and KRAS mutations that occur in colorectal cancer (CRC) define a subpopulation of patients with an inferior prognosis. Recently, the first BRAF V600E-targeting therapy has been approved and novel agents targeting KRAS G12C are being evaluated in CRC. A better understanding of the clinical characteristics of the populations defined by those mutations is needed. We created a retrospective database that collects clinical characteristics of patients with metastatic CRC evaluated for RAS and BRAF mutations in a single laboratory. A total of 7604 patients tested between October 2017 and December 2019 were included in the analysis. The prevalence of BRAF V600E was 6.77%. Female sex, primary in the right colon, high-grade, mucinous, signet cell, partially neuroendocrine histology, perineural and vascular invasion, and surgical tissue sample were factors associated with increased mutation rates. The prevalence of KRAS G12C was 3.11%. Cancer of primary origin in the left colon and in samples from brain metastases were associated with increased mutation rates. The high prevalence of the BRAF V600E mutation in cancers with a neuroendocrine component identifies a potential candidate population for BRAF inhibition. The association of KRAS G12C with the left part of the intestine and brain metastases of CRC are new findings and require further investigation.

The Elemental Profile of Beer Available on Polish Market: Analysis of the Potential Impact of Type of Packaging Material and Risk Assessment of Consumption.

Twenty-five elements, including the most essential and toxic metals, were determined in fifty beer samples stored in cans and bottles by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES) and Cold Vapor Atomic Absorption Spectroscopy (CVAAS) techniques. The packaging material was analyzed using the Scanning Electron Microscopy with Energy Dispersive Spectroscopy (SEM-EDS) technique. The control of the level of individual metals is necessary, not only to maintain the organoleptic properties of the product, but also to fulfill the standards regarding the permissible maximum concentrations. Metals can originate from different sources, including the brewing water, malt grains, hops, adjuncts, fruits, and spices. They may also come from contamination from the brewery equipment, i.e., vessels and tanks, including beer packing, storing and transporting (kegs, casks, cans). Discriminant analysis revealed that the differentiation of three types of beer (Lager, Ale, Craft) was possible, based on elemental concentrations, for the reduced data set after their selection using the Kruskal-Wallis test. The analysis of the impact of the packaging material (can or bottle) proved that when this parameter was used as a differentiating criterion, the difference in the content of Na, Al, Cu and Mn can be indicated. The risk assessment analysis showed that the consumption of beer in a moderate quantity did not have any adverse effect in terms of the selected element concentrations, besides Al. However, in the case of Al, the risk related to consumption can be considered, but only for the beer stored in cans produced from aluminum.

Increasing integrated testing in community settings through interventions for change, including the Spring European Testing Week.

BACKGROUND: Maximising access to testing by targeting more than one infection is effective in identifying new infections in settings or populations. Within the EU funded Joint Action INTEGRATE, this paper examined the feasibility and impact of expanding integrated testing for HIV, hepatitis C (HCV), chlamydia, gonorrhoea and/or syphilis in four community-based pilots through targeted interventions in Croatia, Italy and Poland and the Spring European Testing Week since community settings are key in detecting new infections and reaching key populations. METHODS: Pilots led by local INTEGRATE partners prioritised testing for other infections or key populations. The Croatian pilot expanded testing for men who have sex with men to syphilis, chlamydia and gonorrhoea. Italian partners implemented a HIV and HCV testing/information event at a migrant centre. A second Italian pilot tested migrants for HIV and HCV through outreach and a low-threshold service for people who use drugs. Polish partners tested for HIV, HCV and syphilis among people who inject drugs in unstable housing via a mobile van. Pilots monitored the number of individuals tested for each infection and reactive results. The pilot Spring European Testing Week from 18 to 25 May 2018 was an INTEGRATE-driven initiative to create more testing awareness and opportunities throughout Europe. RESULTS: The Croatian pilot found a high prevalence for each syphilis, chlamydia and gonorrhoea respectively, 2.1%, 12.4% and 6.7%. The Italian migrant centre pilot found low proportions who were previously tested for HIV (24%) or HCV (11%) and the second Italian pilot found an HCV prevalence of 6.2%, with low proportions previously tested for HIV (33%) or HCV (31%). The Polish pilot found rates of being previously tested for HIV, HCV and syphilis at 39%, 37%, and 38%, respectively. Results from the Spring European Testing Week pilot showed it was acceptable with increased integrated testing, from 50% in 2018 to 71% in 2019 in participants. CONCLUSIONS: Results show that integrated testing is feasible and effective in community settings, in reaching key populations and minimising missed testing opportunities, and the pilots made feasible because of the European collaboration and funding. For sustainability and expansion of integrated community testing across Europe, local government investment in legislation, financial and structural support are crucial.

Recommendations for collection and integration of community-based testing and linkage to care data into national surveillance, monitoring and evaluation systems for HIV, viral hepatitis and sexually transmitted infections: results from the INTEGRATE Joint Action.

BACKGROUND: National testing strategy, including monitoring and evaluation, is critical in responding to HIV, sexually transmitted infections, and viral hepatitis. Community-based voluntary counselling and testing contributes to early HIV diagnoses among key populations. Countries providing community-based testing, should integrate some core data on testing and linkage to care in these services into national surveillance and monitoring and evaluation systems. This study aimed to support the integration of community-based voluntary counselling and testing data into respective national surveillance and M&E systems for those infections. METHODS: Preliminary consensus on indicators for the integration of community-based voluntary counselling and testing data into respective national surveillance and monitoring and evaluation systems was reached. Pilot studies were conducted in Estonia, Poland, Serbia, Slovakia, Slovenia and Spain. After pilot activities were implemented, the final consensus on indicators was reached. An analysis of the facilitators and barriers faced during pilot studies was conducted to inform the final recommendations for implementation. RESULTS: The minimum set of six indicators to be integrated into national surveillance and monitoring and evaluation systems were: number of tests, number of clients tested, reactivity rate for tests and clients, positivity (active infection) rates for tests and clients, linkage to care rates for clients with reactive and/or positive test result, proportion of all new diagnoses in a country with first reactive test result at community-based voluntary counselling and testing service. Seven additional indicators were identified. Each indicator should be disaggregated by key population, sex and age group. A list of 10 recommendations for the collection and integration of community-based voluntary counselling and testing data into national surveillance and monitoring and evaluation systems for HIV, sexually transmitted infections and viral hepatitis was identified. CONCLUSIONS: Integration of some community-based voluntary counselling and testing monitoring and evaluation data into national surveillance and monitoring and evaluation systems in all pilot countries was achieved. The recommendations will support such integration in other European countries. European Centre for Prevention and Control of Diseases included questions from the minimum list of indicators into their Dublin Declaration questionnaire 2020 to contribute to evidence based community testing policies in European countries.

Integration of community-based testing data into national HIV surveillance in Poland, Serbia and Slovakia within the framework of INTEGRATE project.

BACKGROUND: Community-based voluntary counselling and testing contributes to early HIV diagnoses among key populations. Testing data from such decentralized services is however often not standardized nor linked to national surveillance systems. This study aimed to support the integration of community testing data into respective national surveillance and monitoring and evaluation systems for those infections. We present results from three national pilots, focused on improved data collection and transfer. METHODS:  Within the Joint Action INTEGRATE different pilot activities were planned and implemented according to the local context. In Slovakia, standardised data collection tools were implemented in three community testing services. The data generated was used to calculate the proposed indicators. In Poland, positive test results from the community testing database were linked to the national case-based surveillance database using confirmatory test number, to improve the completeness of behavioural data in the national database. In Serbia, voluntary counselling and testing forms were improved enabling identification of community-based testing. A system to generate unique client identifiers was initiated in the National registry of HIV cases to monitor linkage to care. RESULTS: All three sites were able to estimate most of the agreed indicators. In Slovakia during the study period 675 people were tested for HIV, 410 for hepatitis C and 457 for syphilis, with reactivity rates of 0.4, 2.5 and 1.8%, respectively. For HIV, 66.7% of reactive cases were confirmed and linked to care. In Poland, 28.9% of the community testing sites' records were linked to the national surveillance database (and accounted for 14.3% of all new diagnoses registered here during 2017-2018). Reactivity rate ranged between 1.9% and 2.1%. In Serbia, 80 persons were tested at community sites, from which two had a reactive HIV test result. By linking unique client identifiers from voluntary counselling and testing and National Registry of HIV cases databases, linkage to care within a two-month period was observed for one of two people with reactive HIV test result. CONCLUSIONS:  Pilot activities in the three countries demonstrate that integration of community-based testing data into surveillance systems is feasible and can help improve national surveillance data by providing key information.

National multi-stakeholder meetings: a tool to support development of integrated policies and practices for testing and prevention of HIV, viral hepatitis, TB and STIs.

BACKGROUND: Country level policies and practices of testing and care for HIV, viral hepatitis and sexually transmitted infections are lagging behind European recommendations on integration across diseases. Building on previous experiences and evidence, the INTEGRATE Joint Action arranged four national stakeholder meetings. The aim was to foster cross-disciplinary and cross-disease collaborations at national level as a vehicle for strengthened integration of testing and care services. This article presents the methodology and discusses main outcomes and recommendations of these meetings. METHODS: Local partners in Croatia, Italy, Lithuania and Poland oversaw the planning, agenda development and identification of key persons to invite to ensure that meetings addressed main challenges and issues of the respective countries. Invited national stakeholders represented policy and public health institutions, clinical settings, testing sites and community organisations. National experts and experts from other European countries were invited as speakers and facilitators. Main topic discussed was how to increase integration across HIV, viral hepatitis and sexually transmitted infections in testing and care policies and practice; tuberculosis was also addressed in Lithuania and Italy. RESULTS: The agendas reflected national contexts and the meetings provided a forum to engage stakeholders knowledgeable of the national prevention, testing and care systems in interaction with international experts who shared experiences of the steps needed to achieve integration in policies and practice. The evaluations showed that participants found meetings relevant, important and beneficial for furthering integration. Of the respondents 78% agreed or strongly agreed that there was a good representation of relevant national stakeholders, and 78% that decision/action points were made on how to move the agenda forward. The importance of securing participation from high level national policy makers was highlighted. Outcomes were nationally tailored recommendations on integrated policies and strategies, diversification of testing strategies, stigma and discrimination, key populations, cost effectiveness, surveillance and funding. CONCLUSIONS: Shifting from single to multi-disease approaches require collaboration among a broad range of actors and national multi-stakeholder meetings have proven excellent to kick-start this. Face-to-face meetings of key stakeholders represent a unique opportunity to share cross-sectoral perspectives and experiences, identify gaps in national policies and practices and agree on required next steps.

Primary bilateral angiosarcoma of the breast treated with neoadjuvant chemotherapy combined with propranolol.

A case report of bilateral primary angiosarcoma treated with neoadjuvant chemotherapy was presented. A routine diagnostic mammography and ultrasound examinations indicated abnormalities in both breasts of the patient, confirmed on MRI as large bilateral masses. Core needle biopsy revealed angiosarcoma G1. The treatment agreed during the interdisciplinary meeting involved chemotherapy combined with simultaneous blockade of beta-adrenergic receptors, followed by bilateral simple mastectomy. This case highlights the importance of a patient-focused care.

Elemental Characterization of Ciders and Other Low-Percentage Alcoholic Beverages Available on the Polish Market.

Seventy-three samples of alcoholic beverages and juices that were purchased on the Polish market and home-made were analyzed for their elemental profiles. The levels of 23 metals were determined by ICP-MS (Ag, Ba, Bi, Cd, Co, Cr, Li, Mn, Ni, Pb, Sr and Tl), ICP-OES (Al, B, Ca, Cu, Fe, K, Mg, Na, Ti and Zn) and CVAAS (Hg) techniques in twenty-five samples of ciders widely available on the Polish market; six samples of home-made ciders; two samples of juices used in the production of these ciders; and forty samples of low-percentage, flavored alcoholic beverages based on beer. The gathered analytical data confirmed that the final elemental fingerprint of a product is affected by the elemental fingerprint of the ingredients used (apple variety) as well as the technology and equipment used by the producer, and in the case of commercial ciders, also the impact of type of the packaging used was proven. These factors are specific to each producer and the influence of the mentioned above parameters was revealed as a result of the performed analysis. Additionally, the inclusion of the home-made ciders in the data set helped us to understand the potential origin of some elements, from the raw materials to the final products. The applied statistical tests revealed (Kruskal-Wallis and ANOVA) the existence of statistically significant differences in the concentration of the following metals: Ag, Al, B, Bi, Co, Cr, Cu, Fe, K, Li, Mg, Na, Ni, Ti and Zn in terms of the type of cider origin (commercial and home-made). In turn, for different packaging (can or bottle) within one brand of commercial cider, the existence of statistically significant differences for Cu, Mn and Na was proved. The concentrations of all determined elements in the commercial cider from the Polish market and home-made cider samples can be considered as nontoxic, because the measured levels of elements indicated in the regulations were lower than the allowable limits. Moreover, the obtained results can be treated as preliminary for the potential authentication of products in order to distinguish the home-made (fake) from the authentic products, especially for premium-class alcoholic beverages.

Endoscopic surveillance after surgical or endoscopic resection for colorectal cancer: European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Digestive Oncology (ESDO) Guideline.

1:  We recommend post-surgery endoscopic surveillance for CRC patients after intent-to-cure surgery and appropriate oncological treatment for both local and distant disease.Strong recommendation, low quality evidence. 2:  We recommend a high quality perioperative colonoscopy before surgery for CRC or within 6 months following surgery.Strong recommendation, low quality evidence. 3:  We recommend performing surveillance colonoscopy 1 year after CRC surgery.Strong recommendation, moderate quality evidence. 4:  We do not recommend an intensive endoscopic surveillance strategy, e. g. annual colonoscopy, because of a lack of proven benefit.Strong recommendation, moderate quality evidence. 5:  After the first surveillance colonoscopy following CRC surgery, we suggest the second colonoscopy should be performed 3 years later, and the third 5 years after the second. If additional high risk neoplastic lesions are detected, subsequent surveillance examinations at shorter intervals may be considered.Weak recommendation, low quality evidence. 6:  After the initial surveillance colonoscopy, we suggest halting post-surgery endoscopic surveillance at the age of 80 years, or earlier if life-expectancy is thought to be limited by comorbidities.Weak recommendation, low quality evidence. 7:  In patients with a low risk pT1 CRC treated by endoscopy with an R0 resection, we suggest the same endoscopic surveillance schedule as for any CRC.Weak recommendation, low quality evidence.

Hepatitis C services at harm reduction centres in the European Union: a 28-country survey.

BACKGROUND: In the context of the WHO's 2016 Viral Hepatitis Strategy and the introduction of treatment that can cure more than 95% of cases with hepatitis C virus (HCV) infection, the European Joint Action on HIV and Co-infection Prevention and Harm Reduction (HA-REACT) undertook a study in the member states of the European Union (EU). It aimed to determine service providers' understanding of the current services in their respective countries and the barriers experienced by PWID in accessing HCV testing, care and treatment services in their country. METHODS: In 2017, 38 purposively selected harm reduction service providers completed a 26-item English-language online survey addressing the availability, accessibility and funding of HCV services at harm reduction centres. HCV-related data and reported findings were extracted by country or by responding organization. RESULTS: Responses were received from all EU member states. Respondents from 23 countries reported that HCV tests are offered by harm reduction services in their countries, and eight countries reported that addiction specialists in their countries are able to prescribe HCV therapy. Almost half of the respondents (45%) said that their respective organizations had established referral systems with centres providing HCV treatment. CONCLUSIONS: Not all EU member states have harm reduction services that provide HCV tests, and many do not have established referral systems with treatment providers. Moreover, the inability of addiction specialists to prescribe HCV treatment points to missed opportunities to make treatment more accessible. Further, discrepancies were noted between the available HCV services and stakeholders' knowledge about their availability.

Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129-2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.

Comparative mutational landscape analysis of patient-derived tumour xenografts.

BACKGROUND: Screening of patients for cancer-driving mutations is now used for cancer prognosis, remission scoring and treatment selection. Although recently emerged targeted next-generation sequencing-based approaches offer promising diagnostic capabilities, there are still limitations. There is a pressing clinical need for a well-validated, rapid, cost-effective mutation profiling system in patient specimens. Given their speed and cost-effectiveness, quantitative PCR mutation detection techniques are well suited for the clinical environment. The qBiomarker mutation PCR array has high sensitivity and shorter turnaround times compared with other methods. However, a direct comparison with existing viable alternatives are required to assess its true potential and limitations. METHODS: In this study, we evaluated a panel of 117 patient-derived tumour xenografts by the qBiomarker array and compared with other methods for mutation detection, including Ion AmpliSeq sequencing, whole-exome sequencing and droplet digital PCR. RESULTS: Our broad analysis demonstrates that the qBiomarker's performance is on par with that of other labour-intensive and expensive methods of cancer mutation detection of frequently altered cancer-associated genes, and provides a foundation for supporting its consideration as an option for molecular diagnostics. CONCLUSIONS: This large-scale direct comparison and validation of currently available mutation detection approaches is extremely relevant for the current scenario of precision medicine and will lead to informed choice of screening methodologies, especially in lower budget conditions or time frame limitations.

Risk communication as a core public health competence in infectious disease management: Development of the ECDC training curriculum and programme.

Risk communication has been identified as a core competence for guiding public health responses to infectious disease threats. The International Health Regulations (2005) call for all countries to build capacity and a comprehensive understanding of health risks before a public health emergency to allow systematic and coherent communication, response and management. Research studies indicate that while outbreak and crisis communication concepts and tools have long been on the agenda of public health officials, there is still a need to clarify and integrate risk communication concepts into more standardised practices and improve risk communication and health, particularly among disadvantaged populations. To address these challenges, the European Centre for Disease Prevention and Control (ECDC) convened a group of risk communication experts to review and integrate existing approaches and emerging concepts in the development of a training curriculum. This curriculum articulates a new approach in risk communication moving beyond information conveyance to knowledge- and relationship-building. In a pilot training this approach was reflected both in the topics addressed and in the methods applied. This article introduces the new conceptual approach to risk communication capacity building that emerged from this process, presents the pilot training approach developed, and shares the results of the course evaluation.

The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial.

AIM OF THE STUDY: The BRAF inhibitor vemurafenib has improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. Here we present the results of an open-label safety study with vemurafenib in patients with metastatic melanoma enrolled in Polish oncological centres. MATERIAL AND METHODS: Patients with untreated or previously treated Stage IIIC/IV BRAFV600 mutation-positive melanoma were treated with oral vemurafenib in an initial dose of 960 mg twice daily. Assessments for safety and efficacy were made every 28 days. For the survival analysis the Kaplan-Meier estimator was used with the log-rank tests for bivariate comparisons. RESULTS: In total, 75 Polish patients were enrolled in the safety study across four centres. At data cut-off, 28 patients died (37%), mainly (26) due to disease progression; 33 (44%) patients continued vemurafenib after disease progression. The objective response rate was 46%, including two patients with a complete response and 29 with a partial response. Median progression-free survival was 7.4 months. The one-year overall survival rate was 61.9% (median overall survival was not reached). Seventy-three (97.3%) patients reported adverse events (AEs), and grade 3-5 toxicity was reported in 49.4% (37) patients. The most common AEs were: skin lesions (including rash and photosensitivity), arthralgia, and fatigue. CONCLUSIONS: The overall safety profile and response rate of vemurafenib were comparable to those reported in previous studies of this drug. Our study confirmed the value of well-established prognostic features for overall survival, such as initial LDH (lactate dehydrogenase) level and AJCC staging.

Pembrolizumab-combination therapy for NSCLC- effectiveness and predictive factors in real-world practice.

Introduction: Pembrolizumab combined with chemotherapy has become the standard of care for patients with non-small-cell lung cancer (NSCLC) and the expression of programmed death ligand 1 (PD-L1) in <50% of tumour cells (TC). Methods: We evaluated the efficacy of the treatment in real-world practice, paying attention to the predictive factors, with a special focus on low level of PD-L1 expression. This study is a multicenter retrospective analysis of patients with stage IV NSCLC. Results: A group of 339 consecutive patients was analysed, among them 51% patients with low PD-L1 expression. In the overall population, the ORR was 40.6%, median PFS and OS were 13 months (95% CI 11.4-15) and 16.8 months (95% CI 13.3-20.3), respectively. In multivariate analysis for the entire study population, performance status - ECOG 1 vs. 0 (HR 2.2, 95%CI 1.1-4.6; p=0.02), neutrophil to lymphocyte ratio (NLR)>3 (HR 2.3, 95%CI 1.3-4.2; p=0.04), presence of liver (HR 2.0, 95%CI 1-3.7; p=0. 03) and bone metastases (HR 1.3, 95%CI 1-3; p=0.04), weight loss (HR 1.8, 95%CI 1.1-2.8; p=0.01) and sum of measurable lesions diameters >110 mm (HR 1.7, 95%CI 1-2.9, p=0.049) had a negative impact on OS. Conclusions: In the real world, patients can clinically benefit from immunochemotherapy, regardless of the expression of PD-L1 and the histological type. Other clinicopathological factors such as performance status, extent, and location of secondary lesions have prognostic significance.

lncRNA DIRC3 regulates invasiveness and insulin-like growth factor signaling in thyroid cancer cells.

Differentiated thyroid cancers (DTCs) are malignancies that demonstrate strong but largely uncharacterized heritability. Germline variants that influence the risk of DTCs localize in disrupted in renal carcinoma 3 (DIRC3), a poorly described long non-coding RNA gene. Here, we investigated the function of DIRC3 in DTCs. Using patient-matched thyroid tissue pairs and The Cancer Genome Atlas data, we established that DIRC3 is downregulated in DTCs, whereas high expression of DIRC3 in tumors may reduce the risk of cancer recurrence. DIRC3 transcripts were enriched in cell nuclei, where they upregulated insulin-like growth factor binding protein 5 (IGFBP5), a gene that modulates the cellular response to insulin-like growth factor 1 (IGF1). Silencing DIRC3 in thyroid cancer cell lines (MDA-T32 and MDA-T120) had a dichotomous phenotypic influence: augmented cell migration and invasiveness, reduced apoptosis, but abrogated the MTT reduction rate. Transcriptomic profiling and gene rescue experiments indicated the functional redundancy in the activities of DIRC3 and IGFBP5. Moreover, the reduced level of DIRC3 enhanced the susceptibility of thyroid cancer cells to IGF1 stimulation and promoted Akt signaling via downregulation of the IGFBP5 protein. In conclusion, DIRC3 expression alters the phenotype of thyroid cancer cells and regulates the activity of the IGFBP5/IGF1/Akt axis. Our findings suggest that an interplay between DIRC3 and IGF signaling may play a role in promoting thyroid carcinogenesis.

Metronomic Chemo-Endocrine Therapy (FulVEC) as a Salvage Treatment for Patients with Advanced, Treatment-Refractory ER+/HER2-Breast Cancer-A Retrospective Analysis of Consecutive Patients Data.

BACKGROUND: Breast cancer, with 2.3 million new cases and 0.7 million deaths every year, represents a great medical challenge worldwide. These numbers confirm that approx. 30% of BC patients will develop an incurable disease requiring life-long, palliative systemic treatment. Endocrine treatment and chemotherapy administered in a sequential fashion are the basic treatment options in advanced ER+/HER2- BC, which is the most common BC type. The palliative, long-term treatment of advanced BC should not only be highly active but also minimally toxic to allow long-term survival with the optimal quality of life. A combination of metronomic chemotherapy (MC) with endocrine treatment (ET) in patients who failed earlier lines of ET represents an interesting and promising option. METHODS: The methodology includes retrospective data analyses of pretreated, metastatic ER+/HER2- BC (mBC) patients who were treated with the FulVEC regimen combining fulvestrant and MC (cyclophosphamide, vinorelbine, and capecitabine). RESULTS: Thirty-nine previously treated (median 2 lines 1-9) mBC patients received FulVEC. The median PFS and OS were 8.4 and 21.5 months, respectively. Biochemical responses (CA-15.3 serum marker decline ≥50%) were observed in 48.7%, and any increase in CA-15.3 was observed in 23.1% of patients. The activity of FulVEC was independent of previous treatments with fulvestrant of cytotoxic components of the FulVEC regimen. The treatment was safe and well tolerated. CONCLUSIONS: Metronomic chemo-endocrine therapy with FulVEC regimen represents an interesting option and compares favorably with other approaches in patients' refractory to endocrine treatments. A phase II randomized trial is warranted.

Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer.

Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the availability of active therapies and their applicability to often fragile, exhausted patients with poor performance status. Metronomic chemotherapy (MC) is a concept of a continuous administration of cytotoxic drugs, which is characterized by multidirectional activity (anti-proliferative, anti-angiogenic, and anti-immunosuppressive) and low toxicity. We have performed a retrospective analysis of consecutive, advanced, chemo-refractory OC patients treated with MC based on single-agent topotecan (1 mg p.o. q2d) or on a topotecan (1 mg q2d) and cyclophosphamide (50 mg p.o. qd) combination (CyTo). Metronomic chemotherapy demonstrated promising activity, with 72% and 86% of patients achieving biochemical or objective disease control and 18% and 27% of patients achieving a biochemical or objective response, respectively. The median PFS in the whole population was 3.65 months, but the median PFS in patients with a biochemical response to MC (18.2% of patients) reached 10.7 months. The study also suggested that overweight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m2. This article is the first report in the literature on metronomic chemotherapy based on a topotecan + cyclophosphamide combination (CyTo). The CyTo regimen demonstrated safety, clinical activity, and potential broad clinical applicability in advanced OC patients and will be evaluated in a forthcoming clinical trial.