Publications by authors named "Jose Monzon"

42 Publications

La escala de afluencia familiar en la investigación sobre inequidades sociales en salud en adolescentes latinoamericanos.

Salud Publica Mex 2021 Jan 15;63(2, Mar-Abr):201-210. Epub 2021 Jan 15.

Centro de Estudios de Estado y Sociedad. Buenos Aires, Argentina..

Objetivo. Evaluar la escala de afluencia familiar (EAF), que consiste en el autorreporte sobre número de computadoras y automóviles del hogar, dormitorio propio y vacaciones, como indicador de nivel socioeconómico (NSE) familiar en adolescentes escolarizados de tres países latinoamericanos. Material y métodos. Fueron encuestados 14 717 estudiantes de secundaria de Argentina, México y Guatemala. Se evaluó la asociación de la EAF con otros indicadores de NSE a nivel familiar (nivel educativo parental, posesión de bienes y servicios tecnológicos) y de entorno escolar (índice de marginación, escuela pública o privada y matrícula escolar). Resultados. La EAF mostró menos datos faltantes que los otros indicadores familiares de NSE. Además, mostró asociaciones en la dirección esperada con los otros indicadores de NSE. Conclusiones. La EAF parece constituir un indicador válido tanto de la riqueza material familiar como del NSE a nivel de la escuela, útil para estudios sobre inequidades en salud en adolescentes latinoamericanos.
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http://dx.doi.org/10.21149/11793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189546PMC
January 2021

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

Eur J Cancer 2021 Jul 8;151:115-125. Epub 2021 May 8.

Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejca.2021.04.004DOI Listing
July 2021

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

Prev Med 2021 Jul 27;148:106590. Epub 2021 Apr 27.

Instituto de Investigación en Ciencias de la Salud (IECIS), Rafael Landívar University, Guatemala City, Guatemala; Unidad de Cirugía Cardiovascular de Guatemala (UNICAR), Guatemala City, Guatemala. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ypmed.2021.106590DOI Listing
July 2021

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.

J Cutan Med Surg 2021 Feb 2:1203475420988862. Epub 2021 Feb 2.

2129 Department of Oncology, Division of Surgical Oncology, University of Calgary, Calgary, AB, Canada.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Objectives: To provide long-term data on patients with a complete response to IL-2 therapy for ITM.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.
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http://dx.doi.org/10.1177/1203475420988862DOI Listing
February 2021

Cross-sectional study on the awareness, susceptibility and use of heated tobacco products among adolescents in Guatemala City, Guatemala.

BMJ Open 2020 12 13;10(12):e039792. Epub 2020 Dec 13.

Instituto de Investigación y Estudios Superiores en Ciencias de la Salud, Universidad Rafael Landivar, Guatemala, Guatemala.

Objectives: Heated tobacco products (HTPs) are increasingly marketed worldwide, yet limited research on HTPs has been conducted in low and middle-income countries (LMICs) or among adolescents. Guatemala is one of the few LMICs where HTPs are available. This study examined prevalence and correlates of HTP awareness, susceptibility and use among adolescents in Guatemala.

Design, Setting And Participants: A cross-sectional survey on HTP awareness, susceptibility and use was conducted among 2870 students between the ages of 13 and 17 in private schools in Guatemala City, Guatemala.

Primary And Secondary Outcome Measures: The primary outcome was susceptibility to future use of HTP among school-aged current and never smokers in Guatemala. We also explored awareness and use of HTPs. Multivariate binomial regression models were used to explore associations between these outcomes and both sociodemographic factors and established smoking correlates.

Results: Of all students (n=2870), about half were aware of HTPs (52.4%) and susceptible to future or continued use (52.4%). Whereas 8.4% of students had tried HTPs in the lifetime (but not in the last month), only 2.9% used HTPs in the past month. Independent correlates of HTP susceptibility and ever-use included: use of other tobacco products (current smoking: adjusted OR (AOR)=10.53 and 6.63, respectively; current e-cigarette use: AOR=21.87 and 10.40, respectively), moderate alcohol consumption (AOR=1.49 and 1.19, respectively), marijuana use in the past 30 days (AOR=3.49 and 2.29, respectively) and having friends who use HTPs (AOR=1.83 and 7.28, respectively).

Conclusions: Among this sample of adolescents in Guatemala City, where tobacco control is weak, the prevalence of HTP use was low but susceptibility to future use was high. Tobacco prevention and intervention strategies for cigarettes and e-cigarettes should now also include HTPs, which tend to be used by similar adolescent populations (ie, those who use other substances or are exposed to tobacco through family and friends).
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http://dx.doi.org/10.1136/bmjopen-2020-039792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737060PMC
December 2020

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

Melanoma Res 2021 02;31(1):67-75

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.
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http://dx.doi.org/10.1097/CMR.0000000000000708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757740PMC
February 2021

CKD Care and Research in Guatemala: Overview and Meeting Report.

Kidney Int Rep 2020 Sep 2;5(9):1567-1575. Epub 2020 Jul 2.

Centro para Investigaciones sobre la Salud Indígena, Wuqu' Kawoq | Maya Health Alliance, Tecpán, Guatemala.

On October 14-15, 2019, the 1st Symposium to Promote Chronic Kidney Disease (CKD) Research in Guatemala was held in Guatemala City, Guatemala. The Symposium hosted more than 50 attendees, including health care professionals, policy makers, researchers, and leaders of nongovernmental organizations. The meeting's objectives were to (1) share clinical and health delivery experiences, (2) disseminate local research, and (3) establish consensus priorities for future research. In this report, we review the state of CKD nephrology in Guatemala, summarize experiences shared during the meeting from representatives of the clinical settings in Guatemala where CKD care is provided, and describe consensus priorities for future research.
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http://dx.doi.org/10.1016/j.ekir.2020.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486195PMC
September 2020

Successful Treatment of Cytokine Release Syndrome with IL-6 Blockade in a Patient Transitioning from Immune-Checkpoint to MEK/BRAF Inhibition: A Case Report and Review of Literature.

Oncologist 2020 07 2;25(7):e1120-e1123. Epub 2020 Jun 2.

Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

There are now multiple targeted and immunotherapies available for the treatment of metastatic melanoma. Although these agents have dramatically improved the survival of patients, the appropriate sequencing and the safety during the transition between these drugs remains unknown. Recently two cases of cytokine release syndrome (CRS) following transition from immune-checkpoint inhibitors to BRAF and MEK inhibitors (BRAFi/MEKi) in patients with metastatic melanoma have been reported. CRS is a systemic cytokine-driven inflammatory reaction, previously well reported in chimeric antigen receptor T-cell therapies for hematologic malignancies. Here, we report a third case in which severe CRS resistant to glucocorticoid therapy following transition to a MEKi/BRAFi was treated successfully with tocilizumab, an interleukin-6 (IL-6) inhibitor. CRS should be on the differential diagnosis of immune-related adverse events of immunotherapies or targeted cancer therapies for metastatic melanoma, and clinicians in multiple disciplines should be aware of this rare complication and the potential benefits of IL-6 blockade.
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http://dx.doi.org/10.1634/theoncologist.2020-0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356700PMC
July 2020

Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma.

Oncologist 2020 05 12;25(5):438-446. Epub 2020 Feb 12.

Department of Oncology, University of Calgary, Calgary, Alberta, Canada.

Introduction: Objective response rates (ORR) appear to be higher in melanoma patients who develop immune-related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown.

Materials And Methods: Patients with advanced melanoma treated with single-agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti-programmed cell death protein 1 (PD-1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression-free survival (PFS) and ORR.

Results: Among 186 patients, any-grade and grade ≥3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12 weeks, the median follow-up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p = .006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p = .001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ≥3 irAEs and no grade ≥3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p = .001), whereas each additional cycle of treatment received (HR, 0.94; p < .001) and development of grade ≥3 irAEs (HR, 0.29, p = .024) were significantly associated with longer OS.

Conclusion: Anti-PD-1-associated grade ≥3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival.

Implications For Practice: Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population-based real-world study in advanced melanoma reports an association with anti-programmed cell death protein 1 (PD-1)-induced grade ≥3 immune-related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD-1-directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes.
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http://dx.doi.org/10.1634/theoncologist.2019-0674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216458PMC
May 2020

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation.

BMC Cancer 2019 Jul 5;19(1):664. Epub 2019 Jul 5.

The Ottawa Hospital Cancer Centre/University of Ottawa, Ottawa, Ontario, Canada.

Background: A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC.

Methods: We reviewed patients with LARC undergoing nCRT followed by surgery from 2005 to 2013 across 8 Canadian cancer centres. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for associations between baseline hematologic variables and outcomes.

Results: Of 1527 identified patients, 1237 (81%) were included in the DFS/OS analysis. Median age was 62 (range 23-88), 69% were male, and 80% had performance status (PS) 0-1. Twenty-six percent had elevated NLR (≥ 4), and 66% had elevated PLR (≥ 150). Ninety-seven percent of patients received FP-based nCRT, with 96% receiving ≥44 Gy. 81% completed neoadjuvant chemotherapy and 95% completed neoadjuvant radiotherapy, with a pCR rate of 18%. After a median follow-up time of 71 months, 8% developed local recurrence, 22% developed distant recurrence and 24% died. 5-year DFS and OS were 69% (95% CI 66-72%) and 79% (95% CI 77-82%), respectively. In multivariate analyses, elevated baseline NLR and PLR were neither prognostic for DFS and OS nor predictive of pCR.

Conclusions: NLR and PLR were not found to be independently prognostic for DFS or OS and did not predict for pCR in patients with LARC undergoing nCRT followed by surgery.
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http://dx.doi.org/10.1186/s12885-019-5892-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612202PMC
July 2019

Appendiceal Carcinoid Tumors: Is There a Survival Advantage to Colectomy over Appendectomy?

J Gastrointest Surg 2020 05 3;24(5):1149-1157. Epub 2019 Jul 3.

Department of Surgery, Bassett Medical Center, Bassett Healthcare Network, One Atwell Road, Cooperstown, NY, 13326, USA.

Background: Guidelines recommend colectomy for appendiceal carcinoid tumors larger than 2 cm, but physicians debate whether colectomy would be beneficial in treating smaller tumors. We sought to determine when colectomy confers a survival advantage over appendectomy.

Methods: Appendiceal carcinoid patients in the US Surveillance, Epidemiology, and End Results (SEER) database (1988-2011) were stratified by age group, gender, TNM stage, tumor grade, and race. Kaplan-Meier and logistic regression analyses relating grade, stage, and receipt of colectomy to overall and cancer-specific survival were performed.

Results: Of 817 patients who underwent surgical extirpation of an appendiceal carcinoid, 338 (41%) had appendectomy alone and 479 (59%) had additional colectomy. Surprisingly, patients who underwent colectomy had worse cancer-specific survival (HR 1.98, 95% CI 1.32-2.98, p = 0.001) than those who underwent appendectomy, and colectomy did not confer a survival advantage over appendectomy in any subset analysis including low-grade or high-grade tumors, smaller or larger than 2 cm, or node-positive, non-metastatic tumors. Even when accounting for stage and grade, colectomy was not associated with significantly better survival rates. Furthermore, as colectomy frequency has increased over the last decade, the 5-year survival rate has trended down. The main predictors of cancer-specific mortality in carcinoid patients were high-grade (grades 3-4) and high-stage (node positive or metastatic) tumors.

Conclusions: Survival in patients with carcinoid tumor of the appendix is primarily determined by tumor grade and stage. Our study found no survival advantage to colectomy over appendectomy in a large cohort of patients with the disease. Further investigation is necessary prior to recommending change of practice for patients with appendiceal carcinoid tumors.
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http://dx.doi.org/10.1007/s11605-019-04306-wDOI Listing
May 2020

Outcome Definition Influences the Relationship Between Genetic Polymorphisms of , , and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients.

Genes (Basel) 2019 05 10;10(5). Epub 2019 May 10.

Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study ( rs316019; rs11615 and rs3212986; rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009-2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (OR = 0.24; 95% CI:0.08-0.70; 0.009) compared to genotype CC. In contrast, addition of allele A at rs316019 was associated with increased risk (OR = 4.41; 95% CI:1.96-9.88; < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (OR = 5.06; 95% CI:1.69-15.16; 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.
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http://dx.doi.org/10.3390/genes10050364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562793PMC
May 2019

Association of Indoor Tanning Exposure With Age at Melanoma Diagnosis and BRAF V600E Mutations.

J Natl Cancer Inst 2019 11;111(11):1228-1231

There is limited information on how indoor tanning promotes melanoma development. We investigated indoor tanning use in patients with melanomas in sun-exposed skin and studied the clinicopathological and molecular characteristics in relation to indoor tanning exposure. Patients from a multidisciplinary clinic for cutaneous cancers completed standardized questionnaires on risk factors for melanoma as a component of medical history at their initial consultations. For this study, we included patients from December 2013 to May 2015. The 114 patients who reported indoor tanning exposure were younger at diagnosis than the 222 patients who did not (51.5 vs 64.0 years, two-sided P < .001). BRAF V600E genotype was more prevalent in ever-users than in nonusers (42.9% vs 28.3%, two-sided P = .04) and higher in ever-users who initiated indoor tanning prior to age 25 years compared with age 25 years or older (62.2% vs 31.1%, two-sided P = .003). There were more melanomas in intermittently sun-exposed skin in ever-users than nonusers (65.7% vs 51.9%, respectively, two-sided P = .02). Our data suggest indoor tanning may promote melanomas that arise in skin with low-chronic sun-induced damage through BRAF V600E-mediated melanomagenesis.
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http://dx.doi.org/10.1093/jnci/djz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855935PMC
November 2019

CYP2D6 as a treatment decision aid for ER-positive non-metastatic breast cancer patients: a systematic review with accompanying clinical practice guidelines.

Breast Cancer Res Treat 2019 Feb 8;173(3):521-532. Epub 2018 Nov 8.

BC Children's Hospital Research Institute, Vancouver, BC, Canada.

Purpose: Tamoxifen is one of the principal treatments for estrogen receptor (ER)-positive breast cancer. Unfortunately, between 30 and 50% of patients receiving this hormonal therapy relapse. Since CYP2D6 genetic variants have been reported to play an important role in survival outcomes after treatment with tamoxifen, this study sought to summarize and critically appraise the available scientific evidence on this topic.

Methods: A systematic literature review was conducted to identify studies investigating associations between CYP2D6 genetic variation and survival outcomes after tamoxifen treatment. Critical appraisal of the retrieved scientific evidence was performed, and recommendations were developed for CYP2D6 genetic testing in the context of tamoxifen therapy.

Results: Although conflicting literature exists, the majority of the current evidence points toward CYP2D6 genetic variation affecting survival outcomes after tamoxifen treatment. Of note, review of the CYP2D6 genotyping assays used in each of the studies revealed the importance of comprehensive genotyping strategies to accurately predict CYP2D6 metabolizer phenotypes.

Conclusions And Recommendations: Critical appraisal of the literature provided evidence for the value of comprehensive CYP2D6 genotyping panels in guiding treatment decisions for non-metastatic ER-positive breast cancer patients. Based on this information, it is recommended that alternatives to standard tamoxifen treatments may be considered in CYP2D6 poor or intermediate metabolizers.
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http://dx.doi.org/10.1007/s10549-018-5027-0DOI Listing
February 2019

Intensive Care to Facilitate Organ Donation: A Report on the Experience of 2 Spanish Centers With a Common Protocol.

Transplantation 2019 03;103(3):558-564

Organización Nacional de Trasplantes, Madrid, Spain.

Background: The aim of this study is to report the experience with a program of Intensive Care to facilitate Organ Donation (ICOD) in 2 Spanish centers based on a common protocol.

Methods: Retrospective review of clinical charts of patients with a devastating brain injury whose families were approached to discuss the possibility of ICOD once further treatment was deemed futile by the treating team. Study period is from January 1, 2011, to December 31, 2015.

Results: ICOD was discussed with families of 131 patients. Mean age of possible donors was 75 years (SD = 11 years). The main cause of brain injury was an intracranial hemorrhage (72%). Interviews with families were held after the decision had been made not to intubate/ventilate in 50% of cases, and after the decision not to continue with invasive ventilation in the remaining cases. Most interviews (66%) took place in the emergency department. The majority of families (95%) consented to ICOD. Of the 125 consented cases, 101 (81%) developed brain death (BD), most in 72 hours or less. Ninety-nine (98%) patients transitioned to actual donation after BD, with 1.2 organs transplanted per donor. Of patients who did not evolve to BD, 4 died after an unexpected cardiac arrest and 18 after the withdrawal of life-sustaining measures. ICOD contributed to 33% of actual donors registered at both centers.

Conclusions: ICOD is well accepted by families. Most patients evolve to BD within a short period of time. The practice substantially contributes to increasing organ donation and offers more patients the chance of donating their organs after death.
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http://dx.doi.org/10.1097/TP.0000000000002294DOI Listing
March 2019

A multicentre, open-label phase II study of Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Invest New Drugs 2018 08 4;36(4):674-682. Epub 2018 May 4.

Medical Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m & I-160 mg/m IV, Day 2-15 X-1900 mg/m/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m & I-120 mg/m IV, Day 2-15 X-1425 mg/m/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials.
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http://dx.doi.org/10.1007/s10637-018-0599-4DOI Listing
August 2018

Further Investigation of the Role of and Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients.

Clin Cancer Res 2018 04 22;24(8):1866-1871. Epub 2018 Jan 22.

Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Adverse drug reactions such as ototoxicity, which occurs in approximately one-fifth of adult patients who receive cisplatin treatment, can incur large socioeconomic burdens on patients with testicular cancer who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in and that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in patients with testicular cancer. Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, rs1872328 and rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult patients with testicular cancer. Pharmacogenomic analyses revealed that rs1872328 was significantly associated with cisplatin-induced ototoxicity [ = 2.83 × 10, OR (95% CI):14.7 (2.6-84.2)]. rs62283056 was not significantly associated with ototoxicity caused by cisplatin ( = 0.39); however, this variant was associated with hearing loss attributable to any cause [ = 5.67 × 10, OR (95% CI): 3.2 (1.4-7.7)]. This study has provided the first evidence for the role of rs1872328 in cisplatin-induced ototoxicity in patients with testicular cancer. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2810DOI Listing
April 2018

Survival trends in patients with tracheal carcinoma from 1973 to 2011.

Am J Otolaryngol 2017 Nov - Dec;38(6):673-677. Epub 2017 Aug 26.

Department of Surgery, Bassett Healthcare Network, Cooperstown, NY, USA. Electronic address:

Purpose: The prognosis for primary tracheal cancer is dismal. We investigated whether there has been improvement in survival in tracheal cancer patients and how treatment modality affected overall and cancer-specific survival.

Materials And Methods: Using the Surveillance, Epidemiology, and End Results database, 1144 patients with tracheal cancer were identified between 1973 and 2011. Patients were stratified by age group, gender, race, tumor histology, and treatment modality. Radical surgery and survival rates based upon these stratifications were determined. Longitudinal analyses of survival and the percentage of patients undergoing surgery and radiation were conducted.

Results: In the final cohort, 327 tracheal cancer patients (34%) underwent radical surgery. Patients of younger age, female gender, and who presented with non-squamous cell tumors were statistically more likely to undergo surgery. Over time, utilization of radiation has declined while use of radical surgery has increased. Concomitantly, 5-year survival has increased from approximately 25% in 1973 to 30% by 2006. Those who did not have surgery were 2.50 times more likely to die of tracheal cancer (95% Confidence Interval 2.00-3.11, p<0.001) than those who did have surgery. Additionally, patients who underwent radical surgery alone (without adjuvant radiation therapy) were 50% or 19% less likely to die of tracheal cancer than those who underwent no treatment or combination therapy, respectively (both p<0.001).

Conclusions: Survival in patients with tracheal cancer is improving over time. The utilization of radical surgery is increasing and confers the highest survival advantage to patients who are candidates.
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http://dx.doi.org/10.1016/j.amjoto.2017.08.005DOI Listing
July 2018

Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

Cancer 2017 Dec 17;123(23):4672-4679. Epub 2017 Aug 17.

Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites.

Methods: Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites.

Results: A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer.

Conclusions: Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30919DOI Listing
December 2017

The Evolution of Metastatic Colorectal Cancer Clinical Trials: Application of the ASCO Framework for Assessing Value.

J Natl Compr Canc Netw 2017 08;15(8):1005-1013

Phase III trials in metastatic colorectal cancer (mCRC) have collectively led to progressive advancements in patient outcomes over the past decades. This study characterizes the evolution of mCRC phase III trials through assessing the value of cancer therapy, as measured by the ASCO Value Framework. Phase III trial results of systemic therapy for mCRC published between 1980 and 2015 were identified, and their outcome, statistical significance, journal impact factor, and citation by the 2016 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CRC were recorded. For each trial, the net health benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Framework: Advanced Disease. There were 114 mCRC phase III trials eligible for calculation of the NHB score. Using the revised framework, the median NHB score was 4.6 (range, -30 to 43.5); 12% of trials received bonus points. Trials with statistically significant results had higher NHB scores compared with nonsignificant trials (median NHB score, 21.6 vs 2.9; <.0001). Clinical trials cited in the NCCN Guidelines had higher NHB scores than those not cited (median score, 8.0 vs 0.3; =.02). In multivariate linear regression analysis, the only significant predictor of high NHB score was statistically significant studies. The median NHB score for mCRC phase III trials was 4.6. Higher NHB scores are associated with statistically significant studies and are cited in the NCCN Guidelines, a surrogate for practice-changing trials. The 2016 ASCO Value Framework may not fully capture the benefits on an individual patient level.
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http://dx.doi.org/10.6004/jnccn.2017.0137DOI Listing
August 2017

Socioeconomic and gender disparities in anal cancer diagnosis and treatment.

Surg Oncol 2017 Jun 6;26(2):212-217. Epub 2017 Apr 6.

Department of Surgery, Bassett Healthcare Network, Cooperstown, NY, United States.

Background And Objectives: We investigated whether receipt of radiation in patients with anal carcinoma is related to income level and other demographic factors.

Methods: The SEER database (1988-2011) was queried and linked to the Area Health Resources File (AHRF). We used logistic regression and Kaplan-Meier analyses to correlate receipt of radiation and overall and cancer-specific survival with tumor stage, age, gender, and income.

Results: Of 28,028 patients with anal cancer, 14,783 (53%) received radiation. Patients in the lowest quartile for median household income were significantly more likely to present at higher stages, were 1.87 times more likely to receive radiation (95% CI 1.74-2.00, p < 0.001), and 1.27 times more likely to die of anal cancer (95% CI 1.18-1.33, p < 0.001) than those in the highest income quartile. Within most stages, however, the wealthiest patients were more likely to receive radiation therapy than the poorest patients. Additionally, we found that women presented at higher stages (p < 0.001), were 2.67 times more likely to receive radiation (95% CI 2.55-2.81, p < 0.001), and were 1.25 times more likely to die of anal cancer than men (95% CI 1.17-1.32, p < 0.001).

Conclusions: Women and poorer patients present with more advanced stages of anal cancer, more commonly receive radiation, and are more likely to die of anal cancer than men and wealthier patients, respectively.
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http://dx.doi.org/10.1016/j.suronc.2017.03.008DOI Listing
June 2017

Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer.

JAMA Oncol 2017 Nov;3(11):1558-1562

Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Importance: Cisplatin-induced ototoxic effects are an important complication that affects testicular cancer survivors as a consequence of treatment. The identification of genetic variants associated with this adverse drug reaction will further our mechanistic understanding of its development and potentially lead to strategies to prevent ototoxic effects.

Objective: To identify the genetic variants associated with cisplatin-induced ototoxic effects in adult testicular cancer patients.

Design, Setting, And Participants: This retrospective study was performed by the Canadian Pharmacogenomics Network for Drug Safety using patients recruited from 5 adult oncology treatment centers across Canada. Male patients who were 17 years or older, diagnosed with germ cell testicular cancer, and previously treated with cisplatin-based chemotherapy were recruited from July 2009 to April 2013 using active surveillance methodology. Cisplatin-induced ototoxic effects were independently diagnosed by 2 audiologists. Patients were genotyped for 7907 variants using a custom pharmacogenomic array. Logistic regression was used to identify genetic variants that were significantly associated with ototoxic effects. The validity of these findings was confirmed through independent replication and cell-based functional assays.

Exposures: Cisplatin-based chemotherapy.

Main Outcomes And Measures: Cisplatin-induced ototoxic effects.

Results: After exclusions, 188 patients (median [interquartile range] age, 31 [24-39] years) were enrolled in this study to form the discovery and replication cohorts. Association and fine-mapping analyses identified a protein-coding variant, rs4788863 in SLC16A5, that was associated with protection against cisplatin-induced ototoxic effects in 2 independent cohorts (combined cohort: odds ratio, 0.06; 95% CI, 0.02-0.22; P = 2.17 × 10-7). Functional validation of this transporter gene revealed that in vitro SLC16A5-silencing altered cellular responses to cisplatin treatment, supporting a role for SLC16A5 in the development of cisplatin-induced ototoxic effects. These results were further supported by the literature, which provided confirmatory evidence for the role that SLC16A5 plays in hearing.

Conclusions And Relevance: This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.
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http://dx.doi.org/10.1001/jamaoncol.2017.0502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824214PMC
November 2017

Trends in lymph node excision and impact of positive lymph node ratio in patients with colectomy for primary colon adenocarcinoma: Population based study 1988 to 2011.

Surg Oncol 2016 Sep 20;25(3):158-63. Epub 2016 May 20.

Department of Surgery, Bassett Healthcare, Cooperstown, NY, USA.

Background: Studies suggest increased lymph node excision in patients with colon cancer portends improved survival. Guidelines recommend excising 12 or more lymph nodes during colectomy. There is an inverse correlation between the positive lymph node ratio and survival in patients of these patients.

Objective: We sought to determine whether colon cancer patients have adequate lymph node excision and whether positive lymph node ratio can be used as a guiding factor for their treatment plan.

Design: Retrospective, Observational.

Settings: United States, 1988-2011.

Patients: Utilizing the Surveillance, Epidemiology, and End Results registry, we identified 318,323 patients who underwent colectomy for colonic adenocarcinoma. Patients were stratified by age, tumor stage, tumor grade, race, ratio of positive nodes, and year of diagnosis.

Main Outcome Measures: We determined the percentage of patients undergoing lymph node excision and mean number of nodes excised by year of diagnosis. In patients with adequate lymph node excision, positive lymph node ratio versus overall and cancer-specific survival was evaluated.

Results: 302,620 patients (95%) had at least 1 lymph node excised and 164,583 patients (52%) had 12 or more lymph nodes excised. This correlates to an increase from approximately 30% in 1988 to 80% by 2011. The mean number of nodes excised doubled from 9 to 18 in the entire cohort over the timeframe studied. On multivariate analysis, the 4 year cluster of diagnosis was the largest predictor of receipt of adequate lymph node excision with a 1.68 times higher odds per 4-year increase from 1988 (95% CI 1.67-1.69, p < 0.001). Higher positive lymph node ratio correlated with significantly worse overall and cancer-specific survival in those who had 12 or more lymph nodes excised. At a positive lymph node ratio of 0.16, there is a 15.7% increased rate of cancer specific mortality.

Conclusions: Despite improvement in the performance of lymph node excision in patients undergoing colectomy for colon adenocarcinoma since 1988, only 80% of patients had adequate lymph node excision in 2011. Increasing positive lymph node ratio predicts significantly worse cancer-specific survival and a ratio of 0.16 may be considered an indication for a more aggressive therapeutic plan.

Category: Colorectal/Anal Neoplasia.
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http://dx.doi.org/10.1016/j.suronc.2016.05.013DOI Listing
September 2016

Compliance to the smoke-free law in Guatemala 5-years after implementation.

BMC Public Health 2016 04 12;16:318. Epub 2016 Apr 12.

Department of Environmental Health Sciences and Institute for Global Tobacco Control, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD, 21205, USA.

Background: Smoke-free environments decrease smoking prevalence and consequently the incidence of heart disease and lung cancer. Due to issues related to poor enforcement, scant data is currently available from low/middle income countries on the long-term compliance to smoke-free laws. In 2006, high levels of secondhand smoke (SHS) were found in bars and restaurants in Guatemala City. Six months after a smoking ban was implemented in 2009, levels significantly decreased. However, in 2010, poor law compliance was observed. Therefore, we sought to assess long-term compliance to the ban using SHS measurements.

Methods: In 2014 we assessed SHS exposure using airborne nicotine monitors in bars (n = 9) and restaurants (n = 12) for 7 days using the same protocol as in 2006 and in 2009. Nicotine was measured using gas-chromatography (μg/m(3)) and compared to levels pre- (2006) and post-ban (2009). Employees responded to a survey about SHS exposure, perceived economic impact of the ban and customers' electronic cigarette use. In addition, we estimated the fines that could have been collected for each law infringement.

Results: Most (71 %) venues still have a smoking section, violating the law. The percentage of samples with detectable nicotine concentrations was 100, 85 and 43 % in 2006, 2009 and 2014, respectively. In bars, median (25(th) and 75(th) percentiles) nicotine concentrations were 4.58 μg/m(3) (1.71, 6.45) in 2006, 0.28 (0.17, 0.66) in 2009, and 0.59 (0.01, 1.45) in 2014. In restaurants, the corresponding medians were 0.58 μg/m(3) (0.44, 0.71), 0.04 (0.01, 0.11), and 0.01 (0.01, 0.09). Support for the law continues to be high (88 %) among bar and restaurant employees. Most employees report no economic impact of the law and that a high proportion of customers (78 %) use e-cigarettes. A total of US$50,012 could have been collected in fines.

Conclusions: Long-term compliance to the smoking ban in Guatemala is decreasing. Additional research that evaluates the determinants of non-compliance is needed and could also contribute to improve enforcement and implementation of the smoke-free law in Guatemala.
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http://dx.doi.org/10.1186/s12889-016-2960-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852414PMC
April 2016

Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers.

Ther Drug Monit 2016 08;38(4):423-31

*Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; †Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada; ‡Child and Family Research Institute, Vancouver, British Columbia, Canada; §Department of Pediatrics, Division of Pediatric Hematology/Oncology/Bone Marrow Transplant, British Columbia Children's Hospital, Vancouver, British Columbia, Canada; ¶Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, Alberta, Canada; ‖Department of Medical Oncology, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada; **Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; ††Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; and ‡‡Institute of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland.

Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy.
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http://dx.doi.org/10.1097/FTD.0000000000000298DOI Listing
August 2016

Acute liver failure and seizures as a consequence of regorafenib exposure in advanced rectal cancer.

BMC Res Notes 2015 Oct 5;8:538. Epub 2015 Oct 5.

Tom Baker Cancer Centre, 1331, 29th Street, NW, Calgary, AB, T2N 4N2, Canada.

Background: Regorafenib is a multi-targeted tyrosine kinase inhibitor approved for use in refractory colorectal cancer. We report the first case of seizures secondary to acute liver failure, shortly after initiation of regorafenib in a patient with advanced rectal carcinoma.

Case Presentation: A 64 year-old Caucasian female presented with confusion and generalized tonic-clonic seizures, 5 days after initiation of regorafenib for advanced rectal cancer. Investigations revealed significant elevations in bilirubin and alanine aminotransferase. No other cause for seizures and liver dysfunction were found. After interruption of regorafenib, no further seizures occurred, the symptoms of confusion resolved and liver function returned to normal.

Conclusions: We report the first case of regorafenib-induced acute liver failure resulting in seizures. We suggest early monitoring for side effects, both clinically and biochemically after initiation of regorafenib.
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http://dx.doi.org/10.1186/s13104-015-1502-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593199PMC
October 2015

Predictors of Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer: A Multicenter Study.

Clin Colorectal Cancer 2015 Dec 18;14(4):291-5. Epub 2015 Jun 18.

The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.

Background: Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) for rectal cancer is associated with better long-term outcomes, and is used as an early indicator of response to novel agents. To assess the rate and predictors of pCR, we performed a retrospective multicenter study involving 5 Canadian cancer centers.

Patients And Methods: Cancer registries identified consecutive patients with locally advanced rectal adenocarcinoma from the Tom Baker Cancer Centre, Cross Cancer Institute, British Columbia Cancer Agency, Ottawa Hospital Cancer Centre, and the Dr H. Bliss Murphy Cancer Centre who received fluoropyrimidine-based CRT and had curative intent surgery from 2005 to 2012. Patient, tumor, and therapy characteristics were correlated with response.

Results: Of the 891 patients included, 885 patients had pCR data available. Of the included patients, 161 (18.2%) had a pCR to CRT, and 724 (81.8%) did not. Patients with a pCR had a lower pretreatment carcinoembryonic antigen (CEA) level, and higher hemoglobin level in univariate analysis. In multivariable analysis, statin use at baseline (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.02-2.92; P = .04), lower pretreatment CEA level (OR, 1.03; 95% CI, 1.01-1.06; P = .03), and distance closer to anal verge (OR, 1.07; 95% CI, 1.01-1.15; P = .04) were significant predictors of pCR. The 3-year disease-free survival was 86% in those with a pCR versus 62.5% in those without a pCR (P < .0001) and pCR was associated with improved overall survival (hazard ratio, 0.29; 95% CI, 0.17-0.51; P < .0001).

Conclusion: Lower pretreatment CEA level, proximity to anal verge, and statin use are predictors of pCR in our large retrospective cohort. Clinical trials to investigate statins combined with neoadjuvant CRT might be warranted.
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http://dx.doi.org/10.1016/j.clcc.2015.06.001DOI Listing
December 2015

Correlation of single arm versus randomised phase 2 oncology trial characteristics with phase 3 outcome.

Eur J Cancer 2015 Nov 31;51(17):2501-7. Epub 2015 Aug 31.

NCIC Clinical Trials Group, Queen's University, Kingston, Canada.

Background And Aim: The primary aim of this study was to determine whether randomised phase 2 (RP2) trials predict phase 3 trial outcome better than single arm phase 2 (SAP2) studies. Although theoretical superiority of RP2 trials has been postulated, no empiric studies have been conducted.

Methods: Published phase 3 trials testing systemic cancer therapy were identified through a Medline search. Those of superiority design, which cited phase 2 trials supporting the experimental arm, were included. Trial design and outcome details were extracted. Statistical analysis was performed using the Generalized Estimating Equation method correlating phase 2 features with phase 3 outcome, accounting for any phase 3 duplication.

Results: Of 189 eligible phase 3 trials, 18.5% were in haematological malignancies and 81.5% in solid tumors. The primary outcome was positive in 79 (41.8%). These were supported by 336 phase 2 trials (range 1-9 per phase 3 trial) including 66 RP2 trials. Positive phase 2 outcome, randomised or not, correlated with positive phase 3 outcome (p=0.03). RP2 studies were not superior to SAP2 studies at predicting phase 3 study success. Phase 2 trial features not predictive of phase 3 outcome included primary endpoint, sponsorship, sample size, similarity in patient population and therapy.

Conclusions: RP2 studies were not superior to SAP2 trials at predicting phase 3 study success. Further research into phase 2 trial design is required given the added resources required to conduct RP2 studies and the lack of empiric evidence supporting superiority over single arm studies.
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http://dx.doi.org/10.1016/j.ejca.2015.08.004DOI Listing
November 2015

A phase 2 study of tremelimumab in patients with advanced uveal melanoma.

Melanoma Res 2015 Aug;25(4):342-7

aDepartment of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario bDepartment of Medical Oncology, Tom Baker Cancer Centre, Calgary cDepartment of Medical Oncology, Cross Cancer Institute, Edmonton, Alberta dDepartment of Medical Oncology, Royal Victoria Hospital, Montreal, Quebec, Canada.

Similar to cutaneous melanoma, several strategies of immune escape have been documented in uveal melanomas (UMs). We hypothesized that these cancers could respond to cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibition with tremelimumab by potentiating T-cell activation. This was an open-label, multicentre phase 2 study in patients with advanced UM who had not received prior immunotherapy. Patient received tremelimumab at 15 mg/kg administered every 90 days for up to four cycles. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were safety, durable response rate, objective response rate, duration of objective response, duration of complete response, and median overall survival (OS). Eleven patients, all with M1c disease, were enrolled with no responses observed. The median follow-up was 11 months (range 2-36 months). The median PFS was 2.9 months (95% confidence interval 2.8-3.0) and the 6-month PFS rate was 9.1%. The median OS was 12.8 months (95% confidence interval 3.8-19.7). Toxicities were consistent with CTLA-4 blockade and were manageable. Although the median OS of 12.8 months and the manageable toxicity profile of tremelimumab observed in this study seem promising, the modest 6-month PFS and the lack of responses observed resulted in the study being stopped due to futility at the first interim stage. To date, no systemic treatment has demonstrated a survival benefit in patients with advanced UM. The standard treatment for patients with advanced UM should be a clinical trial.
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http://dx.doi.org/10.1097/CMR.0000000000000175DOI Listing
August 2015

Management of metastatic kidney cancer in the era of personalized medicine.

Crit Rev Clin Lab Sci 2014 Apr 22;51(2):85-97. Epub 2014 Jan 22.

Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary , Calgary, AB , Canada.

Patients with localized renal cell cancer (RCC) are often cured following surgical resection. However, a significant proportion of patients will experience recurrence or present with metastatic disease at distant sites and may be deemed incurable. The worldwide incidence of RCC is rising, affecting more than 271,000 people and resulting in 116,000 deaths each year. Unfortunately, advanced RCC is typically resistant to classical chemotherapy and radiotherapy. Previously, non-specific immunotherapies such as interleukin-2 and interferon were used in hopes of improving cancer immunity, leading to rare but durable responses. However, enthusiasm for these immunotherapies has waned due to limited patient responses, their excessive toxicities, and the emergence of alternative targeted therapies that have resulted in improved clinical endpoints for patients with metastatic RCC (mRCC). Strides in targeted treatment can be attributed to an improved understanding of the molecular underpinnings that cause and drive the progression of renal cell cancers. More recently, interest in immunotherapies has resurfaced, as agents inhibiting specific checkpoints involved in cancer immune evasion have demonstrated promising activity in patients with mRCC. Here we review the novel targeted agents, biomarkers and immunotherapies that promise to change the clinical outcomes for patients with advanced RCC.
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http://dx.doi.org/10.3109/10408363.2013.869544DOI Listing
April 2014