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.

The Impact of Sidedness on the Efficacy of Anti-EGFR-Based First-Line Chemotherapy in Advanced Colorectal Cancer Patients in Real-Life Setting-A Nation-Wide Retrospective Analysis (RACER).

Anti-EGFR antibodies combined with chemotherapy doublets are a cornerstone of the upfront treatment of colorectal cancer. RAS and BRAF mutations are established negative predictive factors for such therapy. The primary tumour located in the proximal colon has recently emerged as another negative predictive factor. We have conducted a retrospective multicentre study to collect data on real-world population characteristics, practice patterns, and outcomes in patients with metastatic colorectal cancer treated in a first-line setting with either cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI chemotherapy. The presented analysis focuses on the impact of the primary tumour location. 126 of 842 patients analysed (15.0%) had proximal primary. It was associated with a lower BMI at diagnosis, mucinous histology, and peritoneal metastases. It was also associated with inferior treatment outcomes in terms of response ratio: 59.4% vs. 74.22% (odds ratio [OR] 0.51, 95% CI 0.33-0.78, p = 0.010), and median depth of response: -36.7% vs. -50.0% (p = 0.038). There was only a borderline non-significant trend for inferior PFS in patients with proximal tumours. OS data was incomplete. The presented analysis confirms the negative impact of tumour sidedness on the efficacy of an upfront anti-EGFR-chemotherapy combination and provides valuable data on real-world population characteristics.

Immunogenicity and safety of SARS-CoV-2 recombinant protein nanoparticle vaccine GBP510 adjuvanted with AS03: interim results of a randomised, active-controlled, observer-blinded, phase 3 trial.

Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18-64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68-14.32) also satisfied the non-inferiority criterion (95% CI lower limit > -5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

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.

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 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.

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.

Assessment of the Authenticity of Whisky Samples Based on the Multi-Elemental and Multivariate Analysis.

Two hundred and five samples of whisky, including 170 authentic and 35 fake products, were analyzed in terms of their elemental profiles in order to distinguish them according to the parameter of their authenticity. The study of 31 elements (Ag, Al, B, Ba, Be, Bi, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Sb, Sn, Sr, Te, Tl, U, V, Ca, Fe, K, Mg, P, S, Ti and Zn) was performed using the Inductively Coupled Plasma Mass Spectrometry (ICP-MS), Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) and Cold Vapor-Atomic Absorption (CVAAS) techniques. Additionally, the pH values of all samples were determined by pH-meter, and their isotopic ratios of 88Sr/86Sr, 84Sr/86Sr, 87Sr/86Sr and 63Cu/65Cu were assessed, based on the number of counts by ICP-MS. As a result of conducted research, elements, such as Mn, K, P and S, were identified as markers of whisky adulteration related to the age of alcohol. The concentrations of manganese, potassium and phosphorus were significantly lower in the fake samples (which were not aged, or the aging period was much shorter than legally required), compared to the original samples (in all cases subjected to the aging process). The observed differences were related to the migration of these elements from wooden barrels to the alcohol contained in them. On the other hand, the sulfur concentration in the processed samples was much higher in the counterfeit samples than in the authentic ones. The total sulfur content, such as that of alkyl sulfides, decreases in alcohol with aging in the barrels. Furthermore, counterfeit samples can be of variable origin and composition, so they cannot be characterized as one group with identical or comparable features. Repeatedly, the element of randomness dominates in the production of these kinds of alcohols. However, as indicated in this work, the extensive elemental analysis supported by statistical tools can be helpful, especially in the context of detecting age-related adulteration of whisky. The results presented in this paper are the final part of a comprehensive study on the influence of selected factors on the elemental composition of whisky.

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.

Metronomic Chemotherapy in Prostate Cancer.

Despite the significant expansion of the therapeutic armamentarium associated with the introduction of novel endocrine therapies, cytotoxic agents, radiopharmaceuticals, and PARP inhibitors, progression of metastatic castration-resistant prostate cancer (mCRPC) beyond treatment options remains the leading cause of death in advanced prostate cancer patients. Metronomic chemotherapy (MC) is an old concept of wise utilization of cytotoxic agents administered continuously and at low doses. The metronomic is unique due to its multidimensional mechanisms of action involving: (i) inhibition of cancer cell proliferation, (ii) inhibition of angiogenesis, (iii) mitigation of tumor-related immunosuppression, (iv) impairment of cancer stem cell functions, and (v) modulation of tumor and host microbiome. MC has been extensively studied in advanced prostate cancer before the advent of novel therapies, and its actual activity in contemporary, heavily pretreated mCRPC patients is unknown. We have conducted a prospective analysis of consecutive cases of mCRPC patients who failed all available standard therapies to find the optimal MC regimen for phase II studies. The metronomic combination of weekly paclitaxel 60 mg/m2 i.v. with capecitabine 1500 mg/d p.o. and cyclophosphamide 50 mg/d p.o. was selected as the preferred regimen for a planned phase II study in heavily pretreated mCRPC patients.

Reduction of Cancer-Induced Thrombocytosis as a Biomarker of Improved Outcomes in Advanced Gastric Cancer.

BACKGROUND: Interplay between non-specific inflammatory reaction and tumor microenvironment in gastric cancer (GC) can be measured indirectly by assessing fluctuations in concentration of platelets. Cytotoxic chemotherapy affects these morphotic elements directly by inducing myelosuppression. It was hypothesized that chemotherapy not only directly affects malignant cells, but also through immunomodulation related to myelosuppression. METHODS: Metastatic GC patients (N: 155) treated with chemotherapy +/- trastuzumab were enrolled in this retrospective study. Platelet pretreatment concentration (PLT-count) and the deepest level of platelet reduction, as well as other inflammatory and general confounders were collected in the first 12 weeks of treatment (PLT-red). Martingale residuals were used to visualize the relationship between PLT-count, PLT-red, and overall survival (OS). Multiple multivariate Cox regression models were built to assess the impact of platelet reduction on OS and progression-free survival (PFS). RESULTS: Reduction of PLT (PLT-red) to 60% of baseline concentration was associated with improved survival rates (HR = 0.60, p = 0.026 for OS and HR 0.56, p = 0.015 for PFS). Cross-classification into four groups based on PLT-count (high vs low) and PLT-red (high vs low) showed significantly worse survival rates in both high PLT-count (HR = 3.60, p = 0.007 for OS and HR = 2.97, p = 0.024 for PFS) and low PLT-count (HR = 1.75, p = 0.035 for OS and HR = 1.80, p = 0.028 for PFS) patients with insufficient platelets reduction. CONCLUSION: Thrombocytosis reduction represents a novel, clinically important, prognostic factor for OS and PFS in patients with stage IV GC.

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial.

Early clinical data indicate that some patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide. The IMbassador250 trial (no. NCT03016312) enrolled 759 men with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The addition of atezolizumab to enzalutamide in an open-label randomized trial did not meet the primary endpoint of improved overall survival in unselected patients (stratified hazard ratio 1.12, 95% confidence interval (0.91, 1.37), P = 0.28), despite an acceptable safety profile. In archival tumor samples, prostate tumors showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, phosphatase and tensin homolog status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers. In planned biomarker analysis, longer progression-free survival was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked progression-free survival in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including phosphatase and tensin homolog alterations. Together these data indicate that the expected biology associated with response to immune checkpoint inhibitors is present in prostate cancer, albeit in fewer patients. Careful patient selection may be required for immune checkpoint inhibitors to identify subgroups of patients who may benefit from this treatment approach.

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab.

Introduction: The combination of immunotherapy and targeted therapy is currently marking a new era in the treatment of renal cancer. The latest clinical guidelines recommend the use of drug combinations for the first-line treatment of advanced renal cancer. The aim of this review is to compare the efficacy of combined cabozantinib + nivolumab therapy with other immune checkpoint inhibitors combined with tyrosine kinase inhibitors or monoclonal antibodies blocking the CTLA-4 (cytotoxic T cell antigen 4) in the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC). Methodology: A systematic literature search was carried out in the PubMed and EMBASE databases. Randomized controlled trials (RCTs) on therapies recommended by the latest EAU and ESMO guidelines for treatment-naïve metastatic RCC (i.e., lenvatinib + pembrolizumab, axitinib + pembrolizumab and nivolumab + ipilimumab) were searched. A network meta-analysis (NMA) was performed for data synthesis. The methodology of included RCTs was assessed using the Cochrane RoB two tool. The data were analyzed in the overall population as well as in risk subgroups defined according to the International Metastatic Database Consortium (IMDC) i.e., patients with a favorable and intermediate or poor prognoses. The most recent cut-off dates from included studies were analyzed. Results: Four RCTs (CheckMate 9 ER, KEYNOTE-426, CLEAR and CheckMate 214) were included in the review. No studies directly comparing cabozantinib + nivolumab with any of the drug combinations included in this review were available. NMA showed that cabozantinib + nivolumab was superior compared to axitinib + pembrolizumab and nivolumab + ipilimumab in all analyzed comparisons (overall population and IMDC risk subgroups), both in terms of overall survival and progression-free survival (PFS). The advantage of cabozantinib + nivolumab was statistically significant only for PFS when compared to nivolumab + ipilimumab in the overall population. The results for the comparison of cabozantinib + nivolumab with lenvatinib + pembrolizumab showed numerical superiority of lenvatinib + pembrolizumab combination in terms of overall survival, but none of the results were statistically significant. The advantage of lenvatinib + pembrolizumab over cabozantinib + nivolumab in terms of PFS was statistically significant in the overall and favorable prognosis population. Conclusion: Inclusion of the most recent cut-off data from CheckMate 9 ER did not affect the role of the cabozantinib + nivolumab combination for treatment-naïve metastatic RCC. Cabozantinib + nivolumab is an effective therapeutic option for the first-line treatment of advanced renal cancer that is recommended both in the latest European and American guidelines for all IMDC risk groups.

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.

Combined Neutrophil-to-Lymphocyte and Platelet-Volume-to-Platelet Ratio (NLR and PVPR Score) Represents a Novel Prognostic Factor in Advanced Gastric Cancer Patients.

BACKGROUND: Chemotherapy is a cornerstone of treatment in advanced gastric cancer (GC) with a proven impact on overall survival, however, reliable predictive markers are missing. The role of various inflammatory markers has been tested in gastric cancer patients, but there is still no general consensus on their true clinical applicability. High neutrophil-to-lymphocyte (NLR) and low (medium)-platelets-volume-to-platelet ratio (PVPR) are known markers of unspecific immune system activation, correlating significantly with outcomes in advanced GC patients. METHODS: Metastatic GC patients (N:155) treated with chemotherapy +/- trastuzumab were enrolled in this retrospective study. Pre-treatment NLR and PVPR, as well as other inflammatory markers were measured in peripheral blood. Univariate Cox regression was conducted to find markers with a significant impact on overall survival (OS) and progression-free survival (PFS). Spearman correlation and Cohen's kappa was used to analyze multicollinearity. Multiple multivariable Cox regression models were built to study the combined impact of NLR and PVPR, as well as other known prognostic factors on OS. RESULTS: Elevated NLR was significantly associated with increased risk of death (HR = 1.95; 95% CI: 1.17-3.24), and lower PVPR was significantly associated with improved outcomes (HR = 0.53; 95% CI: 0.32-0.90). A novel inflammatory marker, based on a combination of NLR and PVPR, allows for the classification of GC patients into three prognostic groups, characterized by median OS of 8.4 months (95% CI 5.8-11.1), 10.5 months (95% CI 8.8-12.1), and 15.9 months (95% CI 13.5-18.3). CONCLUSION: The NLR and PVPR score (elevated NLR and decreased PVPR) is a marker of detrimental outcome of advanced GC patients treated with chemotherapy.