Latin American Consensus for the Evaluation and Treatment of Patients With Metastatic/Locally Advanced Urothelial Carcinoma.

PURPOSE: Urothelial cancer accounts for approximately 3% of new cancer cases worldwide, with a high burden of disease in countries with medium and low human development indexes where its incidence and mortality are increasing. The purpose of this consensus is to develop statements on the evaluation and treatment of locally advanced and metastatic urothelial carcinoma that would further guide the clinical practice in Latin America. METHODS: A systematic review of the literature was conducted by an independent team of methodologists. Then, a modified Delphi method was developed with clinical specialists from different Latin American countries. RESULTS: Forty-two consensus statements, based on evidence, were developed to address the staging, the evaluation (suitability for chemotherapy, risk assessment, and biomarkers), and systemic treatment (first-line and subsequent therapies) of locally advanced or metastatic urothelial carcinoma. The statements made in this consensus are suggested practice recommendations in the Latin American context; however, the importance of a complete and individualized patient evaluation as a guide for therapeutic selection is highlighted. The availability and affordability of support tools for the evaluation of the disease, as well as specific therapies, may limit the application of the best practices suggested. RECOMMENDATIONS: Therapeutic decisions need to be tailored to the context-specific clinical setting and availability of resources. Local research is promoted to improve outcomes for patients with this challenging cancer in Latin America.

Taxanes for the treatment of breast cancer during pregnancy: an international cohort study.

INTRODUCTION: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy. METHODS: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data. RESULTS: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%). CONCLUSION: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated.

Comparison among three predictive models for cancer-associated thromboembolism in a hispanic population.

In this study we aimed to evaluate and compare the overall performance of the Khorana, PROTECHT, and CONKO scores as predictive scores for the occurrence of venous thromboembolism (VTE) among ambulatory Hispanic patients with solid tumors. We included all outpatients with newly diagnosed solid tumors receiving systemic chemotherapy in Hospital San Juan Dios, San José, Costa Rica, from January to December 2021. For each patient the Khorana, PROTECHT, and CONKO scores were calculated at the beginning of treatment. The sixth-month cumulative incidence of VTE was estimated using the Fine & Gray competing risk model. The receiver operating characteristic (ROC) curve was used to assess the performance of each predictive tool through the analysis of the c-statistic, sensitivity, and specificity. A total of 708 patients were included in the research. After a median follow-up of 8.13 months, the cumulative VTE incidence at six months was 4.45% (95%CI: 3.25-6.91%) for the overall population. At the conventional positivity threshold of 3 points, these scores classified from 17.7 to 32.5% of all patients as high-risk for VTE. Patients belonging to the high-risk category of the Khorana, PROTECHT, and CONKO scores had significantly higher risk of VTE in comparison to low-risk patients (Khorana score: Hazard Ratio (HR): 2.66; 95%CI:1.20-5.89; p = 0.042; PROTECHT score: HR: 3.44; 95%CI:1.63-7.21; p = 0.001; CONKO score HR: 3.68; 95%CI:1.72-7.85; p = 0.001). The c-statistic of the ROC curve was: 0.62 (95%CI: 0.52-0.72), 0.62 (95%CI: 0.52-0.73), and 0.65 (95%CI: 0.56-0.76) for the Khorana, PROTECHT, and CONKO scores, respectively; with similar sensitivity (range: 67-70%) and specificity (range: 52-62%) among them. For Hispanic patients with solid tumors the Khorana, PROTECHT, and CONKO scores accurately categorize their risk of VTE. However, the overall discriminatory performance of these models remains poor (c-statistic from 0.62 to 0.65) for predicting all patients at risk for thromboembolic events.

A systematic review and meta-analysis on overall survival, failure-free survival and safety outcomes in patients with metastatic hormone-sensitive prostate cancer treated with new anti-androgens.

OBJECTIVE: Androgen-deprivation therapy (ADT) combined with new antiandrogens have shown to improve the outcomes of patients with hormone-sensitive metastatic prostate cancer. This systematic review and meta-analysis aim to compare the efficacy and toxicity of these agents in this specific scenario. METHODS: Randomized clinical trials (RCT) were identified after systematic searching of databases. A random-effect model was used to determine the pooled hazard ratio (HR) for overall survival (OS) and failure-free survival according to the inverse-variance method. The Mantel-Haenszel method was used to calculate the pooled odds ratio (OR) for treatment-related adverse events (AEs) grade 3 or higher. Heterogeneity was determined using the Tau 2 and I2 statistics. RESULTS: Seven trials were included in this meta-analysis ( n = 7544). The addition of ADT plus new-generation anti-androgens, specifically: abiraterone, apalutamide, darolutamide or enzalutamide was associated with improved OS (pooled HR, 0.66; 95% CI, 0.61-0.71; P < 0.00001) with no significant heterogeneity detected among trials. (Tau 2 = 0; I2 = 0%; P = 0.88). Failure-free survival was significantly longer in the combination-therapy group than in the control group (pooled HR, 0.43; 95% CI, 0.39-0.47; P < 0.00001) This effect was consistent among trials (Tau 2 = 0; I2 = 27%; P = 0.22). The overall OR of AEs grade 3 or higher was significantly increased with the use of the combination therapy (pooled OR, 1.40; 95% CI, 1.13-1.74; P = 0.002), with significant heterogeneity among trials (Tau 2 = 0.07; I2 = 82%; P < 0.0001). CONCLUSION: The addition of either abiraterone, apalutamide, darolutamide or enzalutamide to ADT improves OS and failure-free survival in hormone-sensitive metastatic prostate cancer, albeit an increase in AEs.

Determinantes de supervivencia en una cohorte de pacientes costarricenses con cáncer colorrectal / Determinants of survival in a cohort of Costa Rican patients with colorectal cancer

Objetivo: Identificar las variables pronósticas de supervivencia global en una cohorte de pacientes costarricenses con adenocarcinoma colorrectal que fueron atendidos en el Hospital San Juan de Dios entre enero de 2010 y diciembre de 2015 y determinar sus tasas de supervivencia a los 5 años. Métodos: Se realizó un estudio retrospectivo en el cual se incluyó a todos los pacientes diagnosticados con adenocarcinoma de colon o recto durante el período de estudio. Se obtuvieron las variables clínicas del expediente médico y se identificaron los factores determinantes de supervivencia global mediante un método de regresión de Cox univariado y multivariante, con el cual se calculó el hazard ratio (HR) y su respectivo intervalo de confianza del 95% (IC 95%). Resultados: Se incluyó a un total de 667 pacientes con una mediana de seguimiento de 25.4 meses. La supervivencia a 5 años según estadio clínico fue de 91.7%, 60%, 44.9% y 18.9% para los estadios I, II, III y IV, respectivamente. En el análisis univariado, la edad mayor de 65 años, el bajo grado de diferenciación tumoral, un estadio clínico elevado, un pobre desempeño funcional, el origen proximal del tumor primario, un alto índice de ganglios positivos entre ganglios negativos y la ausencia de inestabilidad microsatelital fueron las variables asociadas estadísticamente a mayor riesgo de muerte. No obstante, después del ajuste multivariado, solo el estado funcional al inicio del tratamiento (HR: 4.24; IC 95%: 2.20-8.19; p<0.001 para la comparación de estado funcional 0 vs. 1 y 2) y la edad mayor de 65 años (HR: 1.90; IC 95%: 1.03-3.53; p=0.014) se asociaron independientemente a mortalidad. Conclusión: La edad avanzada (mayor de 65 años) y el estadio funcional fueron las variables independientes asociadas a supervivencia en la cohorte estudiada. Descriptores: neoplasias del colon, Costa Rica, mortalidad, pronóstico, supervivenciaObjetivo: Identificar las variables pronósticas de supervivencia global en una cohorte de pacientes costarricenses con adenocarcinoma colorrectal que fueron atendidos en el Hospital San Juan de Dios entre enero de 2010 y diciembre de 2015 y determinar sus tasas de supervivencia a los 5 años. Métodos: Se realizó un estudio retrospectivo en el cual se incluyó a todos los pacientes diagnosticados con adenocarcinoma de colon o recto durante el período de estudio. Se obtuvieron las variables clínicas del expediente médico y se identificaron los factores determinantes de supervivencia global mediante un método de regresión de Cox univariado y multivariante, con el cual se calculó el hazard ratio (HR) y su respectivo intervalo de confianza del 95% (IC 95%). Resultados: Se incluyó a un total de 667 pacientes con una mediana de seguimiento de 25.4 meses. La supervivencia a 5 años según estadio clínico fue de 91.7%, 60%, 44.9% y 18.9% para los estadios I, II, III y IV, respectivamente. En el análisis univariado, la edad mayor de 65 años, el bajo grado de diferenciación tumoral, un estadio clínico elevado, un pobre desempeño funcional, el origen proximal del tumor primario, un alto índice de ganglios positivos entre ganglios negativos y la ausencia de inestabilidad microsatelital fueron las variables asociadas estadísticamente a mayor riesgo de muerte. No obstante, después del ajuste multivariado, solo el estado funcional al inicio del tratamiento (HR: 4.24; IC 95%: 2.20-8.19; p<0.001 para la comparación de estado funcional 0 vs. 1 y 2) y la edad mayor de 65 años (HR: 1.90; IC 95%: 1.03-3.53; p=0.014) se asociaron independientemente a mortalidad. Conclusión: La edad avanzada (mayor de 65 años) y el estadio funcional fueron las variables independientes asociadas a supervivencia en la cohorte estudiada.

Aim: To identify prognostic variables of overall survival in a cohort of Costa Rican patients with colorectal adenocarcinoma who were treated at the San Juan de Dios Hospital between January 2010 and December 2015. Methods: A retrospective cohort study was conducted with all patients diagnosed with colorectal adenocarcinoma during the study period. Clinical variables were obtained from medical records. Determinants of overall survival were identified by a Cox univariate and multivariate regression analysis, with its respective hazard ratio (HR) and 95% confidence interval (IC 95%). Results: A total of 667 patients were included in this study. Median follow-up was 25.4 months. Five-year survival according to clinical stage was 91.7%, 60%, 44.9% and 18.9% for stages I, II, III, and IV, respectively. In the univariate analysis, age greater than 65 years, tumor grade, dvanced clinical stage, poor performance status, proximal location of the primary tumor, a high index of positive nodes and negative retrieved nodes, and the absence of microsatelital instability were statistically associated to death. However, after adjustment for potential confounders, only the performance status at the beginning of treatment (HR: 3.06; IC 95%: 1.65-5.69; p<0.001 for the comparison of ECOG 0 vs 1 and 2.) and age older than 65 years (HR: 1.64, IC 95%: 1.10-2.43; p=0.014) were independently associated with overall survival. Conclusion: Functional status at the time of diagnosis and clinical stage were the independent variables associated to survival in the studied cohort.

BRAF Testing in Melanoma and Colorectal Cancer in Latin America: Challenges and Opportunities.

The incidence of colorectal cancer in Argentina and Brazil has reached levels comparable to those in higher-income countries. Similarly, the incidence of melanoma in Latin America has increased during the past decades. BRAFmutation is seen frequently in melanomas and colorectal cancer. Discovering the expression of this specific biomarker in both cancers has unleashed the potential for targeted molecular therapies.In patients with BRAF-mutated melanoma, adopting a combined targeted treatment approach has shown a dramatic increase in overall survival. However, several barriers impede the development of early BRAF testing in Latin America, jeopardizing the potential for personalized therapies and care. To address this, the Americas Health Foundation convened a virtual meeting of Latin American oncologists to address the barriers to BRAF testing in melanoma and colorectal cancer. During a three-day conference, expert oncologists used literature reviews and personal experience to detail the barriers to early BRAF testing in their region. They proposed actionable steps to overcome the barriers identified, which included deficiencies in knowledge, treatment options, equitable distribution, timely results, and local data on BRAF mutations. Oncologists proposed several actions to overcome barriers, including raising public and healthcare awareness about the importance of BRAF testing, expanding treatment options in clinics across the region, developing centers in underserved areas, and increasing affordable treatment options for patients who test positive for BRAF mutations.

Using the Khorana risk score to predict venous thromboembolism and overall survival in a cohort of Hispanic patients with solid malignancies.

Background: The Khorana risk score (KRS) for prognosis of venous thromboembolism (VTE) has been rarely explored in Hispanic populations. Objective: To determine the value of the KRS for prediction of VTE and overall survival (OS) among Hispanic individuals with cancer. Methods: We retrospectively evaluated all outpatients with newly diagnosed solid tumours receiving systemic chemotherapy in Hospital San Juan Dios, San José, Costa Rica, from January to December 2021. The 6-month cumulative VTE incidence according to the KRS categories was estimated using the Fine & Gray competing risk model. A Kaplan-Meier analysis was used to compare OS among KRS categories. The Cox regression analysis was performed to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI). The receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff value to predict VTE during follow-up. Results: A total of 708 patients were included in the analysis. After a median follow-up of 8.13 months, the cumulative incidence of VTE at 6 months was 1.56% (95% CI: 0.83%-6.82%), 4.83% (95% CI: 2.81%-7.66%) and 8.84% (95% CI: 4.30%-15.42%) for low-, intermediate- and high-risk Khorana score categories, respectively (Gray's p value: 0.0178). The optimal cutoff for the KRS to predict VTE was 2 (area under the ROC curve: 0.65; 95% CI: 0.55-0.756). The KRS was independently associated with overall mortality (HR: 1.83; 95% CI: 1.46-2.29; p < 0.001, for the comparison of 'high-risk' and 'low-risk' KRS). Conclusions: The KRS is a valid tool to predict VTE and mortality in a cohort of Hispanic outpatients with newly diagnosed solid tumours.

Correction: BRAF Testing in Melanoma and Colorectal Cancer in Latin America: Challenges and Opportunities.

[This corrects the article DOI: 10.7759/cureus.31972.].

C677T and A1298C MTHFR gene polymorphisms and response to fluoropyrimidine-based chemotherapy in Mestizo patients with metastatic colorectal cancer.

OBJECTIVE: To assess the association between C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and response to first-line fluoropyrimidine-based chemotherapy for metastatic colorectal adenocarcinoma. METHODS: A total of 68 patients were prospectively followed up in San Juan de Dios Hospital (San José, Costa Rica) from January 2019 to November 2020. Patients received first-line therapy with capecitabine or 5-fluorouracil in combination with oxaliplatin or irinotecan. Germline and somatic DNA was extracted from blood samples and paraffin-embedded tissue, respectively. Overall response rate (partial response + complete response) was assessed according to RECIST 1.1 criteria. Cox regression models were performed to identify the effect of MTHFR C677T and A1298C SNPs on progression-free survival (PFS) and overall survival (OS) (NCT registration number: 03852290). RESULTS: Patients harboring one or both T alleles of the MTHFR C677T SNP had better overall response than homozygous wild-type individuals [odds ratio (OR): 3.21; 95% confidence interval (CI), 1.05-9.81; P = 0.03]. No association was found between the MTHFR A1298C genotypes and overall response (OR: 0.75; 95% CI, 0.26-2.20; P = 0.60). Patients with the MTHFR 677 TT and CT genotypes had longer PFS than CC individuals (hazard ratio: 0.53; 95% CI, 0.28-0.98; P = 0.045), even after adjustment for confounders (hazard ratio: 0.50; 95% CI, 0.25-0.98; P = 0.04). We found no association between the MTHFR A1298C SNP and PFS (hazard ratio: 1.35; 95% CI, 0.72-2.55; P = 0.34). None of the SNPs was associated with OS. CONCLUSION: Patients carrying at least one mutant allele of the MTHFR C677T SNP had a better overall response and longer PFS than wild-type homozygous patients.

Efectividad del tocilizumab intravenoso en la práctica clínica usual de una cohorte de pacientes costarricenses con artritis reumatoide / Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa Rican patients with rheumatoid arthritis

Objetivo: Determinar la efectividad y la incidencia de eventos adversos graves del tocilizumab (TCZ) en una cohorte de pacientes costarricenses con artritis reumatoide (AR). Pacientes y métodos: Se realizó un análisis retrospectivo de 45 pacientes con AR, refractarios al uso previo de fármacos modificadores de la enfermedad reumática (FAME), que utilizaron TCZ a una dosis inicial de 4mg/kg intravenoso (IV) cada 4 semanas en asociación con metotrexato o leflunomida. La medida de efectividad fue la incidencia de remisión clínica, determinada cada 3 meses y definida por un puntaje de actividad de la enfermedad en 28 articulaciones con velocidad de sedimentación globular (DAS28-VSG) menor de 2,6. La seguridad del fármaco se evaluó mediante la tasa de incidencia de eventos adversos severos. Se realizó un modelo de regresión logística uni- y multivariado para determinar las variables asociadas con la probabilidad de remisión a los 3 meses de iniciado el tratamiento. Resultados: A los 3 meses de tratamiento un total de 22 pacientes (48,9%; intervalo de Confianza [IC] del 95%: 34,3-63,5%) alcanzaron remisión, en tanto que a los 12 meses de terapia con TCZ el valor aumentó a 34 pacientes (75%; IC 95%: 62,3-87,6%). Un total de 18 pacientes (40%; IC 95%: 25,7-54,3%) requirieron aumento de dosis del TCZ de 4 a 8mg/kg ante la ausencia de remisión. La tasa de incidencia de eventos adversos severos fue de 0,98 por 100 pacientes/año, correspondiendo todos ellos a cuadros infecciosos que resolvieron sin ningún desenlace fatal. Solo el DAS28-VSG inicial se asoció de forma independiente con la probabilidad de remisión a los 3 meses. Conclusiones: El uso de TCZ IV a una dosis inicial de 4mg/kg en pacientes costarricenses con AR es efectivo y seguro en la práctica clínica.(AU)

Objective: To determine the effectiveness and the incidence of severe adverse events in a cohort of Costa Rican patients with Rheumatoid Arthritis (RA) treated with intravenous (IV) tocilizumab (TCZ). Patients and methods: A retrospective analysis was carried out in 45 patients that were unresponsive to disease-modifying antirheumatic drugs (DMARDs). The study included patients who received IV TCZ every 4 weeks (4mg/kg) along with methotrexate or leflunomide. Effectiveness was measured through the incidence of clinical remission according to a disease activity score - erythrocyte sedimentation rate (DAS28-ESR) less than 2.6. Safety was assessed by the incidence rate of serious adverse events. An univariate and multivariate logistic regression analysis was performed to assess the association of potential variables with the probability of achieving remission during the first 3 months of TCZ therapy. Results: During the 3rd month of TCZ therapy, a total of 22 patients (48.9%; 95% Confidence Interval (CI) 34.3-63.5%) achieved remission. The cumulative incidence of patients with remission at month 12 was 75.0% (n=34) (95% CI: 62.3-87.6%). A total of 18 patients (40%; 95% CI: 25.7-54.3%) were switched to a 8mg/kg dose due to the absence of remission. The incidence rate of serious adverse events was .98 per 100 patients/year, all of them due to infectious diseases with no fatal events reported. Only basal DAS28-ESR was associated with the probability of achieving remission at month 3. Conclusions: IV TCZ (4mg/kg) is an effective and safe treatment for RA patients in a clinical setting in Costa Rica.(AU)

Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa Rican patients with rheumatoid arthritis. / Efectividad del tocilizumab intravenoso en la práctica clínica usual de una cohorte de pacientes costarricenses con artritis reumatoide.

OBJECTIVE: To determine the effectiveness and the incidence of severe adverse events in a cohort of Costa Rican patients with Rheumatoid Arthritis (RA) treated with intravenous (IV) tocilizumab (TCZ). PATIENTS AND METHODS: A retrospective analysis was carried out in 45 patients that were unresponsive to disease-modifying antirheumatic drugs (DMARDs). The study included patients who received IV TCZ every 4 weeks (4mg/kg) along with methotrexate or leflunomide. Effectiveness was measured through the incidence of clinical remission according to a disease activity score - erythrocyte sedimentation rate (DAS28-ESR) less than 2.6. Safety was assessed by the incidence rate of serious adverse events. An univariate and multivariate logistic regression analysis was performed to assess the association of potential variables with the probability of achieving remission during the first 3 months of TCZ therapy. RESULTS: During the 3rd month of TCZ therapy, a total of 22 patients (48.9%; 95% Confidence Interval (CI) 34.3-63.5%) achieved remission. The cumulative incidence of patients with remission at month 12 was 75.0% (n=34) (95% CI: 62.3-87.6%). A total of 18 patients (40%; 95% CI: 25.7-54.3%) were switched to a 8mg/kg dose due to the absence of remission. The incidence rate of serious adverse events was .98 per 100 patients/year, all of them due to infectious diseases with no fatal events reported. Only basal DAS28-ESR was associated with the probability of achieving remission at month 3. CONCLUSIONS: IV TCZ (4mg/kg) is an effective and safe treatment for RA patients in a clinical setting in Costa Rica.

Barriers to lung cancer referral, diagnosis, and treatment in Central America and the Caribbean: the health professionals' perspectives.

PURPOSE: To identify the perspectives from healthcare providers about the limitations in referral, diagnosis, and treatment of lung cancer (LC) patients. METHODS: A cross-sectional study through an Internet-based survey was addressed to physicians of multidisciplinary teams in charge of LC patients from Cuba, Curacao, Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Jamaica, Panama, and Trinidad and Tobago. The questions focused on physicians' perspectives concerning waiting times and the availability of diagnostic and staging procedures in their settings, as well as the access to systemic therapies and continuous medical education (CME). RESULTS: A total of 152 physicians responded to the online questionnaire (response rate 24.9%). Delays in biopsy results were the main barrier for LC diagnosis as identified by 48.2% of the respondents, followed by patients not being referred in time (31.3%), delays for staging procedures (11.4%), and time taken for biopsy (9%). Almost one-half of physicians perceived that patients are diagnosed in advanced stages. A total of 29 respondent physicians (19.1%) reported limited access to immunohistochemical or genetic analysis for common mutations. Although 73 physicians (48.0%) confirmed that their centers provided radiotherapy and systemic therapy for their patients, immunotherapy was not available in the institutions of 30 physicians (19.7%). A total of 42 practitioners (27.6%) reported that they did not have access to CME on LC topics due to working or budget restrictions. CONCLUSIONS: This study revealed among respondents the main barriers for an appropriate management of LC patients in the Central American and Caribbean Region. Further studies must validate these findings.

Association of C677T and A1298C MTHFR Polymorphisms and Fluoropyrimidine-induced Toxicity in Mestizo Patients With Metastatic Colorectal Cancer.

BACKGROUND/AIM: Enzymatic variants involved in fluoropyrimidine metabolism have been associated with adverse events (AEs). We assessed the association between C677T (rs1801133) and A1298 (rs1801131) methylenetetrahydrofolate reductase (MTHFR) polymorphisms and AEs in patients with first-line fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were prospectively followed-up during the first 4 cycles of fluoropyrimidine-based treatment to assess AEs. Germline DNA was analyzed to determine the C677T and A1298C MTHFR polymorphisms. The associations between MTHFR polymorphisms and toxicity were examined. RESULTS: Individuals carrying at least one mutant allele of the MTHFR C677T polymorphism had increased risk to experience anemia (OR=1.69, 95% CI=1.13-2.53, p=0.005), neutropenia (OR=2.27, 95% CI=1.47-3.42, p<0.001) thrombocytopenia (OR=1.91, 95% CI=1.30-2.70, p<0.001), neuropathy (OR=1.77, 95% CI=1.16-2.70, p=0.02), diarrhea (OR=1.69, 95% CI=1.13-2.53, p=0.005), and hand-foot syndrome (OR=1.56, 95% CI=1.08-2.27, p=0.013), compared to patients carrying the wild type alleles. The presence of the mutant allele C of the MTHFR A1298C polymorphism was associated with increased risk of anemia (OR=2.75, 95% CI=1.01-7.48, p=0.02) and thrombocytopenia (OR=3.14, 95% CI=1.01-9.78, p=0.03); however, the prevalence of this allele in the sample was quite low (20%). CONCLUSION: MTHFR C677T and A1298C polymorphisms predicted toxicity in a subset of Mestizo patients with colorectal adenocarcinoma.

Cyclin­dependent kinase 4/6 inhibitors in combination with fulvestrant for previously treated metastatic hormone receptor­positive breast cancer patients: A systematic review and meta­analysis of randomized clinical trials.

PURPOSE: To compare the efficacy and safety profile of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and fulvestrant versus fulvestrant alone in previously treated patients with advanced hormone-receptor positive breast cancer. METHODS: Phase III randomized clinical trials (RCTs) were retrieved from a systematic review of electronic databases. A random-effect model was employed to determine the pooled hazard ratio (HR) for Progression-Free Survival (PFS) and Overall Survival (OS) using the inverse-variance method. The Mantel Haenszel method was used to calculate the pooled odds ratio (OR) for treatment-related side effects. Heterogeneity was measured using the tau-squared and I2 statistics. RESULTS: Three phase III RCTs (n = 1916) were included in the systematic review. Use of abemaciclib, palbociclib, or ribociclib in combination with fulvestrant was significantly associated with longer PFS compared to use of fulvestrant alone (HR: 0.53; 95%CI: 0.47-0.60; p<0.00001), with no significant heterogeneity found among trials. Similarly, OS was significantly longer for patients who received combination therapy in comparison with those allocated to receive fulvestrant alone (HR: 0.77; 95%CI: 0.67-0.89; p<0.0004). The overall odds ratio of serious adverse events (AE) was not significantly increased with the use of the combination therapy (OR: 1.51; 95%CI: 0.74-3.08), with significant heterogeneity found among trials (tau2=0.34; I2=86%; p = 0.0006). CONCLUSION: The addition of CDK 4/6 inhibitors (either abemaciclib, palbociclib, or ribociclib) to fulvestrant significantly improved PFS and OS in comparison with fulvestrant alone in patients previously treated with endocrine therapy for advanced breast cancer. No significant heterogeneity was found among CDK 4/6 inhibitors.

Subcutaneous Tocilizumab in Monotherapy or in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Latin American Patients With Moderate to Severe Active Rheumatoid Arthritis: A Multicenter, Phase IIIb Study.

OBJECTIVE: To assess the efficacy and safety of subcutaneous tocilizumab (TCZ) in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Latin American patients with rheumatoid arthritis (RA) and inadequate response to previous csDMARDs. METHODS: ML28700 was a multicenter, open-label, single-arm trial. Previously treated RA patients who had not received treatment with TCZ or any biological agent (n = 284) and with a baseline Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or greater were assigned to receive subcutaneous TCZ (162 mg/wk) in association with csDMARD for 24 weeks. Patients who achieved remission (DAS28-ESR <2.6) at week 24 continued with TCZ as monotherapy until week 52; otherwise, they continued with their assigned treatment. The primary efficacy end point was remission rate (DAS28-ESR <2.6) at weeks 24 and 52. Secondary objectives included disease activity scores, safety, and quality of life. RESULTS: At week 24, a total of 169 patients (59.5%; 95% confidence interval, 53.5%-65.3%) achieved remission, 91 patients (32.0%) had low disease activity, and 46 patients (8.4%) were not responders. Sustained remission at week 52 was achieved by 80.8% (n = 126) of patients who continued with TCZ monotherapy versus 44.6% (n = 37) of those on combination therapy. A total of 241 patients (84.9%; 95% confidence interval, 80.2%-88.8%) had at least 1 adverse event during follow-up. Adverse events led to drug modification in 32 patients (11.3%) or discontinuation in 21 patients (7.4%). CONCLUSIONS: Subcutaneous TCZ is an efficacious therapy with long-lasting results and tolerable adverse events in Latin American patients with RA.Trial registration no.: NCT02011334 Tozura Study Program.

Incidencia y mortalidad del cáncer de vejiga en Costa Rica y Panamá, 2007-2013 / Incidence and mortality of bladder cancer in Costa Rica and Panama, 2007-2013

Resumen Objetivo: Se desconoce el comportamiento epidemiológico del cáncer de vejiga en Panamá y Costa Rica; globalmente, se reporta un aumento de la incidencia de dicha patología. Este estudio tiene como propósito reportar la incidencia, mortalidad y severidad del cáncer de vejiga, durante el período comprendido entre 2007 y 2013, en ambos países. Métodos: Se realiza un análisis epidemiológico transversal en el periodo comprendido entre 2007 y 2013, contemplando los casos incidentes y fallecidos por cáncer de vejiga en Costa Rica y Panamá. La tasa de incidencia y mortalidad anual para cada uno de los países y según sexo fue estimada de acuerdo con las proyecciones anuales de población. La severidad del comportamiento de la esta neoplasia se evaluó mediante la razón de incidencia / mortalidad. Resultados: Se identifica un total de 2048 casos de cáncer de vejiga. Se evidencia un aumento de las tasas de incidencia y mortalidad en los últimos 3 años del periodo de estudio, con un compromiso mayor en el sexo masculino. La tasa de incidencia aumentó de 2007 a 2013 en un 42,3 % en Costa Rica y un 71,4 % en Panamá. En dicho periodo, la mortalidad aumentó un 25,9 % para Costa Rica y un 44,7 % para Panamá. La razón de incidencia / mortalidad se mantuvo estable para ambos países durante el periodo de estudio. Conclusión: Existe una tendencia creciente en las tasas de incidencia y mortalidad por cáncer de vejiga, en Costa Rica y Panamá.

Abstract Aim: The incidence and mortality of bladder cancer has increased in some regions of the world. However, the epidemiological profile of this neoplasia is largely unknown in Panama and Costa Rica. Therefore, the aim of this study was to report the incidence, mortality, and severity of this disease during years 2007 to 2013. Methods: An epidemiological cross-sectional study was conducted between 2007 and 2013 with all incident and mortality cases of bladder cancer in Costa Rica and Panama. The annual incidence and mortality rates for each country, and according by sex were estimated based on the annual population estimates. The incidence/mortality ratio was estimated as a measure to evaluate the severity of the pathology. Results: A total of 2048 cases of bladder cancer were included. During the last 3 years of the study period we detected an increased in incidence and mortality rates, predominately in males. The incidence rate increased from year 2007 to year 2013 in 42.3% and 71.4% in Costa Rica and Panama, respectively. During the same period the mortality rate also increased 25.9% in Costa Rica and 44.7% in Panama. The incidence/ mortality rate had a steady behavior during the study period. Conclusion: These findings confirm a growing trend in the incidence and mortality rates of bladder cancer in Costa Rica and Panama.

Evaluation of pharmacological therapies used in Costa Rica in patients with metastatic gastric cancer: a retrospective study.

BACKGROUND: Gastric cancer is one of the leading causes of cancer death worldwide. Surgery is regarded as the best curative treatment option for gastric cancer; however, a high proportion of cases are diagnosed at advanced stages, when tumors are unresectable. In the present study, we evaluated the impact of pharmacological therapies in the survival of 168 patients diagnosed with metastatic gastric cancer from Costa Rica, a country with very high incidence and mortality rates for this malignancy. METHODS: We retrospectively reviewed 168 clinical records of patients diagnosed with metastatic gastric cancer from January 2009 to January 2012 at four major hospitals in Costa Rica. The Chi-square test or Fisher's exact test was used for comparison of frequencies, while the ANOVA test was used for comparison of quantitative variables. OS and PFS analyses were performed using the Kaplan-Meier method. The Log-rank test was used to compare survival curves. Univariate and multivariate COX regression analyses were used to calculate the crude and adjusted hazard ratios (HR) with their 95% confidence interval (95% CI). RESULTS: After a median follow-up of 46.5 months, the median survival difference between the two groups (pharmacological therapy vs. supportive care) was 5.6 months for PFS and 8.3 months for OS. Patients receiving triple therapy had 69% higher chance of progression than those receiving double therapy (HR =1.69, 95% CI: 1.04-2.73). The probability of dying is 88% higher for the patients receiving triple therapy than for those using double therapy (HR =1.88, 95% CI: 1.15-3.11). CONCLUSIONS: This study demonstrates that pharmacological therapies significantly increase the PFS and OS of those patients with metastatic gastric cancer in Costa Rica. The greatest benefit in terms of survival is observed with the use of duplets in comparison with the triplets in these patients.

Time spent on erythropoietin stimulating agents administration in hemodialysis centers in Panama: a time and motion study.

Objectives: There is a lack of data in Panama on the potential differences in total healthcare professional (HCP) time between routine administrations of short-acting erythropoietin simulating agents (ESAs) (i.e. epoetin alfa) and continuous erythropoietin receptor activator (CERA) (i.e. methoxy polyethylene glycol-epoetin beta). This study aimed to quantify the HCP time associated with a single administration of epoetin alfa and CERA for the treatment of anemic patients with chronic kidney disease (CKD) on hemodialysis. Methods: This was a multi-center, cross-sectional study, using a time-and-motion methodology. Costs related to HCP time and consumables usage associated with administration of epoetin alfa and CERA were estimated. Results: Based on 60 administrations of either CERA or epoetin alfa, the estimated savings in mean total active HCP time were 2.34 (95% confidence interval = 1.87-2.81) min (-30%) per administration. When extrapolating to a full year's treatment with intravenous ESA, it would require a total of 20.3 (95% CI = 19.90-20.71) h of HCP time for epoetin alfa vs 1.1 (95% CI = 1.01-1.19) h for CERA per patient per year. Estimated savings in active HCP time per patient per year were 19.20 (95% CI = 19.20-19.21) h (-95%). This, in turn, translates into staff cost efficiency that favors Mircera with an estimated annual saving of $78.24 (95% CI = 78.24-78.28) (-95%) per patient. Conclusions: Data from a real-world setting showed that the adoption of CERA could potentially lead to a reduction in active HCP time. Highlights Few comparative data have explored the costs and potential savings of using long-acting erythropoietin-stimulating agents (ESA) instead of short-acting ESAs to treat anemia in CKD patients on hemodialysis. This time-and-motion study shows that use of CERA reduces total healthcare professional time and could represent a save for an institution in a real-world setting in Panama.

Limitaciones para la publicación científica biomédica en los países de Costa Rica, Guatemala y Panamá. Una visión de es pecialistas y residentes / Limitations for biomedical scientific publication in Cos ta Rica, Guatemala, and Panama. A vision from specialists and resident

Objetivo: Los países de Costa Rica, Guatemala y Panamá muestran una escasa producción biomé­dic a. El objetivo de este estudio es identificar las barreras para la publicación y establecer propues­tas para incentivar la investigación biomédica. Métodos: Se realizó una encuesta en línea con la participación de 76 médicos sobre 4 ejes relacio­nados con las limitantes para la investigación y publicación científica. Se realizó un modelo de re­gresión logística para identificar las variables asociadas con la probabilidad de publicación. Resultados: Un total de 63 encuestados (67.1%; IC 95%: 56.5 ­ 77.7) reportaron haber publicado al menos un estudio científico, en su mayoría reportes de casos (47.4%) y revisiones (40.8%). Los años de ejercicio profesional, el grado académico, o el tipo de institución del encuestado no se rela­cionaron con la probabilidad de realizar publicaciones científicas. El principal origen de los fondos fueron recursos propios (67.1%). Las principales limitaciones fueron la falta de tiempo y recurso hu­mano para investigación (88.2%). Los encuestados desearían tener más tiempo para la investiga­ción (92.1%) y mayor apoyo institucional (78.9%), a la vez que propusieron que los entes externos deben promover su participación en ensayos clínicos (65.8%) y en actividades académicas (61.8%). Conclusión: La mayoría de encuestados señaló que la falta de recursos, tiempo y personal como li­mitantes importantes para la publicación biomédica.

Aim: Costa Rica, Guatemala, and Panama are known by the scarce amount of biomedical produc­ tion. Our aim was to identify barriers to scientific publication and to establish proposals for increa­ sing biomedical investigation in these countries. Methods: An on­line questionnaire was completed by 76 physicians about 4 frameworks. A logistic regression model was done to identify variables associated with the probability of publication. Results: 63 physicians (67.1%; IC 95%: 56.5 ­ 77.7) have published at least one scientific paper. Most of these publications were cas e reports (47.4%) and reviews (40.8%). Physicians laboring in priv ate practices (p<0.001) and those specialists in medical oncology or hematology (p=0.02) were more likely to be involved in clinical trials (26.3%). Professional experience, academic al degree, and type of medical practice were not related to the number of scientific publications. The majority of phy sicians finance their projects by their own resources (67.1%). The main limitations were lack of time and human resources (88.2%). The respondents would like to have more time to spend in re­ search (92.1%), and more institutional support (78.9%). They also proposed that external entities should promote their participation in clinical (65.8%) and support academic activities (61.8%). Conclusion: Most of the physicians pointed that lack of human, time, and monetary resources are important barriers to scientific publication