A low-cost, DIY tourniquet simulator with built-in self-assessment for prehospital providers in Guatemala city.

BACKGROUND: Hemorrhage is the leading cause of preventable death after trauma. In high-income countries first responders are trained in hemorrhage control techniques but this is not the case for developing countries like Guatemala. We present a low-cost training model for tourniquet application using a combination of virtual and physical components. METHODS: The training program includes a mobile application with didactic materials, videos and a gamified virtual reality environment for learning. Additionally, a physical training model of a bleeding lower extremity is developed allowing learners to practice tourniquet application using inexpensive and accessible materials. Validation of the simulator occurred through content and construct validation. Content validation involved subjective assessments by novices and experts, construct validation compared pre-training novices with experts. Training validation compared pre and post training novices for improvement. RESULTS: Our findings indicate that users found the simulator useful, realistic, and satisfactory. We found significant differences in tourniquet application skills between pre-training novices and experts. When comparing pre- and post-training novices, we found a significantly lower bleeding control time between the groups. CONCLUSION: This study suggests that this training approach can enhance access to life-saving skills for prehospital personnel. The inclusion of self-assessment components enables self-regulated learning and reduces the need for continuous instructor presence. Future improvements involve refining the tourniquet model, validating it with first-responder end users, and expanding the training program to include other skills.

Changes in substance use among adolescents before and during the COVID-19 pandemic in Guatemala.

Objectives: Due to the COVID-19 pandemic, on March 16th, schools had to be closed in Guatemala and went to online teaching. We sought to analyze the change in substance use among high school students in Guatemala associated with the lockdown. Methods: Data from two surveys (2019, n=2096, and 2020, n=1606) of a student cohort in private high schools in Guatemala City was used. Logistic models for past 30-day cigarette, e-cigarette, marijuana, and alcohol (including binge drinking) were used, regressing these on survey wave, while adjusting for sex, scholastic performance, high school year of student, parental education, substance use, and household member tobacco use. Results: Prevalence declined for smoking (10% to 3%, p<0.001), e-cigarette (31% to 14%, p<0.001), marijuana (4.3% to 1.9%, p<0.001), and alcohol use (47% to 38.5%, p<0.001), and binge drinking (24% to 13%, p<0.001). Adjusted models showed wave 2 associated with lower odds of using cigarettes (AOR=0.44, 95%CI=0.32-0.62), e-cigarettes (AOR=0.41, 95% CI=0.35-0.49, p<0.001), and binge drinking (AOR=0.73, 95%CI=0.59-0.89; p=0.002). Conclusion: Among Guatemalan adolescents, COVID-19 restrictions were associated with a significant decrease in smoking, e-cigarette use, and binge drinking.

Factors Associated With the Changes in Smoking and Electronic cigarette use in Adolescents During the COVID-19 Pandemic: A Longitudinal Analysis.

PURPOSE: Explore the factors associated with the changes in smoking and electronic cigarette (e-cigarette) use and susceptibility among adolescents during the COVID-19 pandemic. METHODS: We surveyed a cohort of students (7th-12th grade) from private schools in Guatemala. Baseline (May-September 2019) was conducted in-person and follow-up (June-November 2020) online during the lockdown. Separate Generalized Estimating Equations logistic models regressed current smoking (n = 3,729), current e-cigarette use (n = 3,729), smoking susceptibility among never-smokers (n = 2,596), and susceptibility to e-cigarette use among never-users (n = 1,597) on online ad exposure, visiting stores, social network smoking/e-cigarette use, substance use (alcohol, marihuana, and cigarette or e-cigarette), perceived harm of using cigarettes/e-cigarettes, sociodemographic characteristics, and survey wave. Interactions were assessed between time and ad exposures, friends smoking and e-cigarette use. RESULTS: Frequency of store visits, exposure to online ads, and the use of cigarette and e-cigarette lowered at follow-up. Online e-cigarette ads, having family and friends who smoke, and current e-cigarette use increased the likelihood of being a current smoker. Frequent exposure to online e-cigarette ads, having family who use e-cigarettes, and being a current smoker were associated with higher likelihood of current e-cigarette use. Exposure to either online ads or having friends that smoke or use e-cigarettes, increased susceptibility to using either product. Interaction results showed that high exposure to online e-cigarette ads overtime increased the susceptibility to use e-cigarettes. DISCUSSION: Exposure to online ads and friends and family cigarette and e-cigarette use increased adolescent consumption and susceptibility during the pandemic.

Adjuvant Systemic Therapies for Resected Stages III and IV Melanoma: A Multi-Center Retrospective Clinical Study.

BACKGROUND: Adjuvant therapies have been approved for resected melanoma based on improved recurrence-free survival. We present early findings from a real-world study on adjuvant treatments for melanoma. METHODS: A comprehensive chart review was conducted for patients receiving adjuvant systemic therapy for resected high-risk stages III and IV melanoma. Statistical analysis was performed to assess recurrence-free survival and subgroup differences. RESULTS: A total of 149 patients (median age = 58.0 years, 61.1% men, 49.7% with BRAF V600E/K genotypes) were included, with 94.6% having resected stage III melanoma. Anti-PD-1 immunotherapy was received by 86.5% of patients, while 13.4% received BRAF-targeted therapy. At a median follow-up of 22.4 months, the recurrence rate was 31.5%, with 1-year and 2-year recurrence-free survival rates of 79% and 62%, respectively. Similar recurrence rates were observed between anti-PD-1 immunotherapy and BRAF-targeted therapy. Long-term toxicity affected 27.4% of patients, with endocrinopathies and late-emergent immune-related adverse events being common. CONCLUSIONS: Real-world adjuvant systemic therapy aligns with clinical trial practice. Recurrence rates remain high despite treatment, and long-term toxicities, including endocrinopathies and chronic inflammatory conditions, are not uncommon.

Chemicals in cigarette flavor capsules from Guatemala and Mexico.

BACKGROUND: The global market share for cigarettes with flavor capsules has grown exponentially over the last decade, particularly in Latin America. When smoking, consumers crush a liquid capsule in the filter that flavors the smoke. Little is known about the chemical constituents of the liquids in capsules or their potential health risks. METHODS: Based on consumer data and availability in Mexico and Guatemala, 31 flavor capsule brands were purchased (19 and 12, respectively) in 2020. Since some cigarettes included multiple capsules in a stick (up to 2) or pack (up to 4), the final analytic sample included 50 capsules. We conducted qualitative and quantitative analysis using gas chromatography with mass spectrometry (GC-MS, Agilent Technologies, Inc.). RESULTS: The qualitative analysis detected 296 compounds (range=9 to 67 per capsule), and all capsules contained menthol. Among the compounds detected in more than half the sample were limonene, menthone, benzaldehyde, eucalyptol and triacetin. Traces of nicotine were found in 22% of the capsules. In the quantitative analysis, menthol concentrations were 33 times greater than the next most common compound (limonene). Benzyl alcohol and vanillin were also found in high concentrations. Comparing same brand varieties across countries showed substantial variability in the concentration of menthol and other compounds. CONCLUSION: Menthol is an omnipresent constituent in capsule cigarettes, perhaps because of its anesthetizing and reinforcing addictive properties. Other compounds found are toxic, potentially carcinogenic, and may enhance addictiveness. Variance in the presence and concentrations of such compounds highlights the importance of product standards to regulate capsule content. IMPLICATIONS: This study evaluated the chemical content of capsule cigarettes from two Latin American countries that have two of the highest market shares for capsule cigarettes worldwide. Compared to other studies, our assessment included brand varieties from two countries to compare the differences in chemical content by country. Our results yield that menthol is found in all capsules, and that other chemicals found may prolong nicotine exposure and therefore reinforce the addictive properties of cigarettes.

NCI Rectal-Anal Task Force consensus recommendations for design of clinical trials in rectal cancer.

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.

Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab-Ipilimumab for Advanced Melanoma.

Importance: Treatment-free survival (TFS) represents an alternative time-to-event end point, accurately characterizing time spent free of systemic therapy, providing a more patient-centric view of immune checkpoint inhibitor (ICI) therapy regimens. There remains a lack of studies evaluating TFS outcomes among patients with advanced melanoma who are receiving immunotherapy, especially outside of the clinical trial setting. Objective: To evaluate TFS outcomes for patients with advanced melanoma receiving first-line ICI therapy outside of a clinical trial setting. Design, Setting, and Participants: This multicenter cohort study of patients with advanced melanoma receiving first-line ICI therapy between August 1, 2013, and May 31, 2020, was conducted in Alberta, Canada. Data analysis was performed in August 2022. Exposures: Patients received standard-of-care, first-line ICI therapy treatment regimens including single-agent nivolumab, single-agent pembrolizumab, or ipilimumab-nivolumab. Main Outcomes and Measures: Treatment-free survival was defined as the difference in the 36-month restricted mean survival time between 2 conventional survival end points: (1) time from treatment initiation to ICI cessation, death, or censoring at last follow-up and (2) time from treatment initiation to subsequent systemic anticancer therapy, death, or censoring at last follow-up. Results: A total of 316 patients with advanced melanoma receiving first-line nivolumab (n = 51; median age, 66 years [IQR, 56-78 years]; 31 men [60.8%]), pembrolizumab (n = 158; median age, 69 years [IQR, 60-78 years]; 112 men [70.9%]), or combination nivolumab-ipilimumab (n = 107; median age, 53 years [IQR, 42-60 years]; 72 men [67.3%]) were included. Treatment groups were similar with regard to sex, primary tumor location, and presence of metastasis, although patients receiving combination nivolumab-ipilimumab had a lower Eastern Cooperative Oncology Group status, were younger, and were more likely to be BRAF V600E positive than those receiving anti-programmed cell death protein 1 (anti-PD-1) monotherapy. The restricted mean TFS was longer for nivolumab-ipilimumab (12.4 months [95% CI, 8.8-16.0 months]) compared with nivolumab (8.9 months [95% CI, 4.4-13.5 months]) and pembrolizumab (11.1 months [95% CI, 8.5-13.8 months]). During the 36-month follow-up interval, patients treated with nivolumab-ipilimumab spent 34.4% of their time (12.4 of 36 months) not receiving systemic anticancer treatments compared with 30.8% (11.1 of 36 months) and 24.7% (8.9 of 36 months) of the time for the pembrolizumab and nivolumab treatment groups, respectively. Conclusions and Relevance: This cohort study of patients with advanced melanoma receiving first-line ICI therapy suggests that TFS represents a patient-centric, informative end point. Patients treated with combination nivolumab-ipilimumab spent more time alive and free from systemic anticancer therapy than those treated with anti-PD-1 monotherapy alone.

Development and Validation of a Prognostic Risk Model for Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Risk stratification tools for patients with advanced melanoma (AM) treated with immune checkpoint inhibitors (ICI) are lacking. We identified a new prognostic model associated with overall survival (OS). PATIENTS AND METHODS: A total of 318 treatment naïve patients with AM receiving ICI were collected from a multi-centre retrospective cohort study. LASSO Cox regression identified independent prognostic factors associated with OS. Model validation was carried out on 500 iterations of bootstrapped samples. Harrel's C-index was calculated and internally validated to outline the model's discriminatory performance. External validation was carried out in 142 advanced melanoma patients receiving ICI in later lines. RESULTS: High white blood cell count (WBC), high lactate dehydrogenase (LDH), low albumin, Eastern Cooperative Oncology Group (ECOG) performance status ≥1, and the presence of liver metastases were included in the model. Patients were parsed into 3 risk groups: favorable (0-1 factors) OS of 52.9 months, intermediate (2-3 factors) OS 13.0 months, and poor (≥4 factors) OS 2.7 months. The C-index of the model from the discovery cohort was 0.69. External validation in later-lines (N = 142) of therapy demonstrated a c-index of 0.65. CONCLUSIONS: Liver metastases, low albumin, high LDH, high WBC, and ECOG≥1 can be combined into a prognostic model for AM patients treated with ICI.

Treatment of Unresectable Cutaneous Squamous Cell Carcinoma with Cemiplimab in a Patient on Dialysis.

Program death-1 inhibitors, a class of immune-checkpoint inhibitors, are now the standard of care in a variety of cancer settings, including cutaneous malignancies, such as melanomas, Merkel cell, and cutaneous squamous cell carcinomas (cSCCs). The clinical trials that led to the approval of the programmed death-1 inhibitor cemiplimab-rwlc (Libtayo®) for use in advanced cSCC excluded patients with autoimmune disease and those that required systemic immunosuppressive treatments, or had undergone solid-organ transplantation. Also, to be eligible, patients had to have adequate organ function. Here, we present the first report of a patient that has been successfully treated with cemiplimab for locally advanced cSCC while simultaneously on dialysis for treatment of renal failure following renal transplant.

First tobacco product tried and current use of cigarettes and electronic cigarettes among adolescents from Guatemala City.

OBJECTIVE: To assess how first experimenting with ciga-rettes or e-cigarettes is associated with current use in Gua-temala, a middle-income country with weak tobacco control and no e-cigarette regulations. MATERIALS AND METHODS: We surveyed students from private schools in Guatemala City, limiting analyses to ever users (n=1 026). Multinomial logistic models regressed current product use on first product used, adjusting for sociodemographics and friends and family use. RESULTS: The most common first product used was e-cigarettes (56%), followed by flavored cigarettes (24%) and regular cigarettes (20%). At the time of the survey, 4% were exclusive smokers, 37% were exclusive e-cigarette users, 18% dual users, and 40% had ever tried either but were not current users. Compared to those who first tried cigarettes, students who first tried e-cigarettes were less likely to be current smokers (RR=0.19 [CI: 0.11,0.31]) or dual users (RR=0.26 [CI: 0.14,0.49]) and students who first tried flavored cigarettes were more likely to be current smokers (RR=1.66 [CI=1.13,2.42]). CONCLUSIONS: In our sample, Guatemalan adolescents from private schools more frequently experiment and continue to use e-cigarettes than cigarettes. There is urgent need to implement e-cigarette restrictions in addition to tobacco control policy implementation.

Management of Uveal Melanoma: Updated Cancer Care Alberta Clinical Practice Guideline.

OBJECTIVE: The purpose of this guideline update is to reassess and update recommendations in the prior guideline from 2016 on the appropriate management of patients with uveal melanoma. METHODS: In 2021, a multidisciplinary working group from the Provincial Cutaneous Tumour Team, Cancer Care Alberta, Alberta Health Services was convened to update the guideline. A comprehensive review of new research evidence in PubMed as well as new clinical practice guidelines from prominent oncology groups informed the update. An enhancement in methodology included adding levels of evidence and strength of recommendations. The updated guideline was circulated to all members of the Provincial Cutaneous Tumour Team for review and endorsement. RESULTS: New and modified recommendations address provider training requirements, diagnostic imaging for the detection of metastases, neo-adjuvant pre-enucleation radiotherapy, intravitreal anti-vascular endothelial growth factor agents for radiation retinopathy, genetic prognostic testing, surveillance following definitive local therapy, and systemic therapy for patients with metastatic uveal melanoma. DISCUSSION: The recommendations represent evidence-based standards of care agreed to by a large multidisciplinary group of healthcare professionals.

Association of Immune-Related Adverse Events, Hospitalization, and Therapy Resumption With Survival Among Patients With Metastatic Melanoma Receiving Single-Agent or Combination Immunotherapy.

Importance: Immune-related adverse events (irAEs) due to immune checkpoint blockade (ICB) have been shown to be positively associated with survival. Among patients with metastatic melanoma, evidence supporting this association has been conflicting, while ipilimumab-nivolumab combination ICB has been examined only in small clinical cohorts. Objective: To examine the association between irAEs and survival among patients with metastatic melanoma, in particular for those receiving combination ICB. Design, Setting, and Participants: A retrospective cohort of 492 consecutive patients with metastatic melanoma treated with ICB at 2 tertiary and 4 regional cancer centers in Alberta, Canada, from August 1, 2013, to May 31, 2020, was observed. Patients were aged 18 years or older with metastatic melanoma agnostic to primary site, who received 1 or more doses of an anti-programmed cell death protein 1 agent as single or combination ICB. Clinically significant irAEs requiring systemic corticosteroids and/or treatment delay were captured. To minimize immortal time bias, only patients surviving 12 weeks after ICB initiation were included in survival analyses. Statistical analysis was conducted on December 10, 2021. Exposures: Development of irAEs requiring systemic corticosteroids and/or treatment delay. Main Outcomes and Measures: The primary outcome was overall survival (OS), with the association of irAE development with OS assessed via Kaplan-Meier and Cox proportional hazards regression analyses. The association of hospitalization for irAEs and ICB resumption after irAE with OS was examined. Results: Among 492 patients, the median age of those with irAEs was 61.8 years (IQR, 52.9-72.1 years), and the median age of those without irAEs was 65.5 years (IQR, 56.5-76.9 years), while sex distribution was comparable (137 of 198 men [69.2%] with irAEs vs 183 of 294 men [62.2%] without irAEs). There was an association between irAEs and OS both in the overall cohort (with irAEs: median OS, 56.3 months [95% CI, 38.2 months to not evaluable] vs without irAEs: median OS, 18.5 months [95% CI, 14.4-23.2 months]; P < .001) and in the 124 patients (25.2%) receiving combination ICB (with irAEs: median OS, 56.2 months [95% CI, 52.2 months to not evaluable] vs without irAEs: median OS, 19.0 months [95% CI, 6.6 months to not evaluable]; P < .001). Hospitalization for irAE did not alter this positive association with OS compared with outpatient treatment (median OS, not evaluable [95% CI, 31.5 months to not evaluable] vs median OS, 52.2 months [95% CI, 35.2 months to not evaluable]; P = .53), while resumption of ICB was associated with longer OS than not resuming ICB (median, 56.3 months [95% CI, 40.8 months to not evaluable] vs 31.5 months [95% CI, 21.0 months to not evaluable]; P = .009). A favorable independent association of irAEs with OS was confirmed in multivariable analysis (hazard ratio for death, 0.382 [95% CI, 0.254-0.576]; P < .001). Conclusions and Relevance: This study suggests an association between irAEs and OS for patients with metastatic melanoma, including those treated with combination ICB and those with severe irAEs requiring hospitalization. The potential benefit associated with ICB resumption after irAEs warrants further investigation.

Complementary Medicine Use Amongst Patients with Metastatic Cancer Enrolled in Phase III Clinical Trials.

BACKGROUND: Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. METHODS: Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. RESULTS: Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. CONCLUSION: One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

The Impact of Chronic Kidney Disease in Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiation.

BACKGROUND: Patients with chronic kidney disease are commonly excluded from clinical trials. The impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer has not been previously studied. OBJECTIVE: This study aimed to investigate the impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer. DESIGN: This is a multi-institutional, retrospective cohort study. SETTINGS: This study was conducted at academic and community cancer centers participating in the Canadian Health Outcomes Research Database Consortium Rectal Cancer Database. PATIENTS: Consecutive patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation before curative-intent surgery from 2005 to 2013 were selected. MAIN OUTCOME MEASURES: Disease-free survival, overall survival, pathologic complete response, and neoadjuvant chemotherapy/radiotherapy completion rate were the primary outcomes measured. RESULTS: A total of 1254 patients were included. Median age was 62, and 29%/69% had clinical stage II and III disease. Median estimated creatinine clearance was 93 mL/min, with 11% <60 mL/min (n = 136). There was no significant difference in the completion rate of neoadjuvant chemotherapy (82% vs 85%, p = 0.36) or radiotherapy (93% vs 95%, p = 0.45) between patients with and without chronic kidney disease. Patients with chronic kidney disease were less likely to receive adjuvant chemotherapy (63% vs 77%, p < 0.01). On multivariate analysis, patients with chronic kidney disease had decreased disease-free survival (HR, 1.37; 95% CI, 1.03-1.82; p = 0.03) but not overall survival (HR, 1.23; 95% CI, 0.88-1.75; p = 0.23) or pathologic complete response (OR, 0.83; 95% CI, 0.50-1.39; p = 0.71). LIMITATIONS: This study was limited by its retrospective design and by limited events for overall survival analysis. CONCLUSIONS: In patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation, baseline chronic kidney disease was associated with less use of adjuvant chemotherapy and decreased disease-free survival. Chronic kidney disease was not independently associated with neoadjuvant chemotherapy/radiotherapy completion rate, pathologic complete response, or overall survival. These data suggest that patients with locally advanced rectal cancer with chronic kidney disease may have distinct outcomes and, accordingly, the results of landmark clinical trials may not be generalizable to this population. See Video Abstract at http://links.lww.com/DCR/B694. LA REPERCUSIN DE LA ENFERMEDAD RENAL CRNICA EN PACIENTES CON CNCER DE RECTO LOCALMENTE AVANZADO TRATADOS CON QUIMIORRADIOTERAPIA NEOADYUVANTE: ANTECEDENTES:Los pacientes con enfermedad renal crónica generalmente se excluyen de los ensayos clínicos. La repercusión de la enfermedad renal crónica en el desenlace en pacientes con cáncer de recto localmente avanzado no se ha estudiado previamente.OBJETIVO:Investigar la repercusión de la enfermedad renal crónica en los desenlaces en pacientes con cáncer de recto localmente avanzado.DISEÑO:Estudio de cohorte retrospectivo multiinstitucional.ESCENARIO:Centros oncológicos académicos y comunitarios que participan en la base de datos de cáncer rectal del consorcio CHORD.PACIENTES:Pacientes consecutivos con cáncer de recto localmente avanzado, tratados con quimiorradioterapia neoadyuvante, previa a la cirugía con intención curativa del 2005 al 2013.PRINCIPALES VARIABLES EVALUADAS:Sobrevida libre de enfermedad, sobrevida global, respuesta patológica completa, tasa de conclusión de quimioterapia / radioterapia neoadyuvante.RESULTADOS:Se incluyeron 1254 pacientes. El promedio de edad fue de 62, y el 29% / 69% tenían enfermedad en estadio clínico II y III, respectivamente. El promedio de la depuración de creatinina estimada fue de 93 mililitros / minuto, con un 11% <60 mililitros / minuto (n = 136). No hubo diferencias significativas en la tasa de conclusión de la quimioterapia neoadyuvante (82% vs 85%, p = 0,36) o radioterapia (93% vs 95%, p = 0,45) entre pacientes con y sin enfermedad renal crónica. Los pacientes con enfermedad renal crónica tenían menos probabilidades de recibir quimioterapia adyuvante (63% contra el 77%, p <0,01). En el análisis multivariado, los pacientes con enfermedad renal crónica tenían una sobrevida libre de enfermedad menor (HR 1,37, IC 95% 1,03-1,82, p = 0,03) pero no en la sobrevida global (HR 1,23, IC 95% 0,88-1,75, p = 0,23) o respuesta patológica completa (OR 0,83, IC 95% 0,50-1,39, p = 0,71).LIMITACIONES:Diseño retrospectivo y acontecimientos limitados para el análisis de sobrevida global.CONCLUSIONES:En pacientes con cáncer de recto localmente avanzado tratados con quimiorradioterapia neoadyuvante, la enfermedad renal crónica de base se asoció con un menor uso de quimioterapia adyuvante y una menor sobrevida libre de enfermedad. La enfermedad renal crónica no se asoció de forma independiente con la tasa de conclusión de la quimioterapia / radioterapia neoadyuvante, la respuesta patológica completa o la sobrevida global. Estos datos sugieren que los pacientes con cáncer de recto localmente avanzado con enfermedad renal crónica pueden tener resultados distintos y, en consecuencia, los resultados de los ensayos clínicos de referencia pueden no ser generalizables a esta población. Consulte Video Resumen en http://links.lww.com/DCR/B694.

Real World Outcomes in Patients with Advanced Melanoma Treated in Alberta, Canada: A Time-Era Based Analysis.

Immune checkpoint and MAP kinase pathway inhibitors can significantly improve long-term survival for patients with melanoma. There is limited real-world data of these regimens' effectiveness. We retrospectively analyzed 402 patients with unresectable and metastatic melanoma between August 2013 and July 2020 treated with immune checkpoint inhibitors and MAP kinase pathway targeted therapy in Alberta, Canada. Overall survival (OS) was compared using Kaplan-Meier and Cox regression analyses. Subgroup survival outcomes were analyzed by first-line treatment regime and BRAF mutation status. Three treatment eras were defined based on drug access: prior to August 2013, August 2013 to November 2016, and November 2016 to July 2020. Across each era, there were improvements in median OS: 11.7 months, 15.9 months, and 33.6 months, respectively. Patients with BRAF mutant melanoma had improved median OS when they were treated with immunotherapy in the first line as opposed to targeted therapy (median OS not reached for immunotherapy versus 17.4 months with targeted treatment). Patients with BRAF wild-type melanomas had improved survival with ipilimumab and nivolumab versus those treated with a single-agent PD-1 inhibitor (median OS not reached and 21.2 months). Our real-world analysis confirms significant survival improvements with each subsequent introduction of novel therapies for advanced melanoma.

Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials.

BACKGROUND: Immuno-oncology (IO)-based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy. PATIENTS AND METHODS: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non-small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition-based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT). RESULTS: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status <70%/Eastern Cooperative Oncology Group performance status >1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate <40 mL/min (15%, 61 of 395). Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22-2.77), 2.21 (95% CI 1.58-3.11) and 1.82 (95% CI 1.21-2.74), respectively.. CONCLUSIONS: Thirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit.

Effects of tobacco product type and characteristics on appeal and perceived harm: Results from a discrete choice experiment among Guatemalan adolescents.

Guatemala is one of the few countries where both heated tobacco products (HTPs) and electronic cigarettes (e-cigarettes) remain unregulated. We used a discrete choice experiment (DCE) administered to 2038 high school students to assess how tobacco product attributes influence their appeal among Guatemalan adolescents. Participants were randomly assigned to evaluate 4 of 32 contrasting sets, each containing 3 packs (1 of each product type). Experimental manipulations included: product type, brand, nicotine content and flavor. Participants then indicated which product they were most and least interested in trying and would be most and least harmful to their health. Conditional logistic regression models were used to assess the impact of product characteristics on choice. Product type accounted for almost 90% of variation in choices. Respondents were less interested in trying HTPs (B = -0.93; p < 0.001) and viewed them as more harmful (B = 2.77; p < 0.001) compared to cigarettes. They were more interested in trying e-cigarettes (B = 1.22; p < 0.001), which were also perceived as less harmful (B = -1.47; p < 0.001) compared to cigarettes. Products without nicotine were of more interest for trying (B = 0.14; p < 0.001) and perceived as more harmful (B = 0.20; p < 0.001) than those with. Students were more interested in trying a flavor compared to regular tobacco and among the flavors, berry was the highest rated one (B = 0.28; p < 0.001). Finally, in this country with weak tobacco control, e-cigarettes appear to be more appealing and perceived as less harmful than HTPs and cigarettes. Packaging and flavoring regulations are urgently needed on these products as they are a marketing strategy targeting adolescents.

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis.

Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.