A retrospective analysis of the diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) at The Ottawa Hospital Cancer Centre (TOHCC) over the last decade including COVID-19 pandemic period.

INTRODUCTION: The incidence of NETs is rising. Our objective was to assess trends in GEP-NETs diagnosis (June 2010 to June 2021) at TOHCC and to explore whether early COVID-19 pandemic data impacted these trends. METHODS: This was a single center retrospective chart review of data collected from June 2010 to June 2021. We searched all databases, including OACIS/EPIC, PACS and OPIS and found 647 GEP-NET patients. Descriptive analyses were performed using frequencies and related percentages. RESULTS: Of 647 patients with GEP-NETs, the small bowel was the most common primary location (n=210, 32.4%), followed by the pancreas (n=118, 18.2%), and unknown primary location (n=99, 15.3%). Most of the cases were classified as metastatic or locally advanced at the initial presentation. There has been no significant variation in the frequency distribution of these cases over the last decade. Stages 1 and 2 were found in 158 cases (23.8%), and lower GI tumors were the most common disease among them (n=88, 55.7%). There were 5 lower GI cases in 2010-2011 and average number per registration year was 5.5 until 2016-2017, after which time the number of cases increased to 10, 15, 11 and 13 during the last 4 years. Regarding early stage pancreatic and upper GI NETs, the total number of cases was 52 (32.9%) and 18 (11.4%), respectively. The average number of cases per registration year for pancreatic tumors was 4.7, while that for upper GI tumors was 1.6 over the last decade. DISCUSSION: At our center, most GEP-NETs presented in an advanced setting. Small bowel is the most common location overall. The incidence of early stage disease has increased. Disease detection for all GEP-NETs was consistent throughout the last decade, except for the lower GI cases that have increased since mid-2017, perhaps reflecting the adoption of Ontario FIT testing. Despite endoscopy closures and disruption of some diagnostic services during the pandemic, cases of GEP-NETs for all stages did not decrease.

Comparing the Risk of Infusion-Related Reactions and Tolerability in Patients Given Cetirizine or Diphenhydramine Prior to Ocrelizumab Infusion (PRECEPT).

Background: Ocrelizumab is an effective medication for multiple sclerosis. However, infusion-related reactions (IRRs) are a concern for patients and may lead to discontinuation of ocrelizumab. To minimize IRRs, pre-medications are administered. However, from our experience, these medications, especially diphenhydramine, can cause marked drowsiness. The primary objective of this study was to evaluate whether cetirizine is non-inferior to diphenhydramine in limiting the proportion and severity of reactions from ocrelizumab infusions. Methods: Twenty participants were serially randomized in a 1:1 ratio to receive 10 mg of cetirizine or 25 mg of diphenhydramine orally prior to their first three ocrelizumab infusions. Results: The rate of IRRs in this study was similar across both treatment groups with no increase in the risk of severity, and no grade 3 IRRs. Further, patients receiving cetirizine experienced a reduction in fatigue. While there was not a significant difference in global satisfaction, this score increased over time in the cetirizine arm while it remained unchanged in the diphenhydramine arm. Conclusions: Overall, our results suggest that cetirizine does not increase the risk of infusion-related reactions compared to diphenhydramine.

Evaluating the efficacy and safety of transitioning patients with multiple sclerosis from natalizumab to ocrelizumab (OCTAVE).

INTRODUCTION: Natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients infected with John Cunningham virus (JCV). Ocrelizumab has demonstrated efficacy to treat MS; however, its safety in patients previously treated with natalizumab is unclear. OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab in patients with relapsing MS (RMS) previously treated with natalizumab. METHODS: Clinically and radiographically stable RMS patients, ages 18-65 treated with natalizumab for ⩾ 12 months, were enrolled in the study and initiated ocrelizumab 4-6 weeks after their final dose of natalizumab. Relapse assessment, expanded disability status scale, and brain magnetic resonance imaging (MRI) were performed prior to starting ocrelizumab and at months 3, 6, 9, and 12. RESULTS: Forty-three patients were enrolled, and 41 (95%) completed the study. Two patients had a relapse while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. Thirteen serious adverse events (SAEs) were recorded, four of which were considered possibly related to ocrelizumab. CONCLUSION: Overall, our study indicates clinical and MRI stability for most patients transitioning from natalizumab to ocrelizumab. CLINICALTRIALS.GOV IDENTIFIER: NCT03157830.

Maternal Group B Streptococcus Prophylaxis Improvement using an Electronic Medical Record Dynamic Order Set.

OBJECTIVE: To develop and implement a Group B Streptococcal (GBS) dynamic order set to improve adherence to the American College of Obstetricians and Gynecologists/Centers for Disease Control and Prevention (ACOG/CDC) guidelines. STUDY DESIGN: A team of information technology and clinical experts developed a dynamic order block. The content was patterned after the CDC "Prevent GBS" mobile app. It was then embedded in the labor and delivery/induction order set and piloted at a single high-volume obstetric unit. Following the pilot and incorporation of the 2019 ACOG update of the CDC guidelines, the order set was rolled out in five additional hospitals within a region of a large health system. Information on GBS prophylaxis performance before and after implementation was available for the pilot site and four of the additional hospitals. Information before implementation was obtained electronically from electronic medical record (EMR) laboratory and pharmacy data and supplemented by manual chart review. Postimplementation data were obtained from discrete order set EMR data elements. Adherence to the guidelines before and after were compared using chi-squared test. RESULTS: There were 7,114 deliveries before implementation and 4,502 after implementation. Preterm delivery occurred in 6.8 and 6.9%, respectively. There was an increase in appropriate treatment of preterm patients (positive and unknown GBS) delivering after implementation (88.7-99.1%, p < 0.001). More patients were reported to have a penicillin allergy before implementation than after implementation (14.7 vs. 11.1%, respectively, p = 0.01). Associated changes in therapy noted after implementation included a nonsignificant decrease in the proportion reporting a high-risk allergy (50.3 vs. 41.9%, p = 0.18), an increase in the appropriate use of clindamycin and vancomycin (64.4 vs. 92.3%, p < 0.001) and a decrease in clindamycin use in those without sensitivity testing. CONCLUSION: Routine universal use of a dynamic admission labor/induction order set was associated with high and improved adherence to GBS prophylaxis guidelines. KEY POINTS: · Lapses in GBS prophylaxis are associated with early-onset GBS disease.. · Preterm delivery and penicillin allergic patients are commonly associated with lapses in prophylaxis.. · Dynamic EMR order set use can improve adherence to clinical guidelines..

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.

Imaging Intensity and Survival Outcomes in High-Risk Resected Melanoma Treated by Systemic Therapy at Recurrence.

BACKGROUND: Intensive imaging in melanoma remains controversial because its survival impact is unknown. We investigated the impact of imaging intensity on the rates of asymptomatic surveillance-detected recurrence (ASDR) and subsequent treatment outcomes in patients with access to immune checkpoint inhibitors (ICIs) and targeted therapy (TT). METHODS: Patients with resected malignant melanoma undergoing imaging surveillance at a single center between 2006 and 2016 were identified. Surveillance and recurrence characteristics (imaging, symptom, treatment, and survival data) were retrospectively collected. Univariate (t test, Chi square test) and multivariate Cox regression analyses were conducted. RESULTS: Of 353 high-risk melanoma patients (stage IIB, 24%; IIC, 19%; IIIA, 27%; IIIB, 16%; IIIC, 14%), 71 (45%) had ASDR and 88 (55%) had symptomatic recurrence (SR). Shorter imaging intervals identified more ASDR (57%, 0-6 months; 34%, 6-12 months; 33%, > 12 months; p = 0.03). ASDR had better prognostic factors than SR [fewer than three metastatic sites (43 vs. 21%, p = 0.003), normal lactate dehydrogenase (LDH; 53 vs. 38%, p = 0.09), brain metastases (11 vs. 40%, p < 0.001)] and received more systemic treatment (72 vs. 49%, p = 0.003; ICIs 55 vs. 31%, p = 0.002; TT 8 vs. 13%, p = 0.41). ASDR had better survival outcomes on ICI treatment (2-year OS, 56 vs. 31%, p < 0.001). Median OS from surveillance start was 39.6 vs. 22.8 months (p < 0.001). ASDR was independently associated with survival (hazard ratio 0.47, 95% confidence interval 0.29-0.78, p = 0.003), adjusting for stage, sex, age, disease burden, LDH, era of recurrence, brain metastases, and ICI/TT treatment. CONCLUSIONS: These real-world data support further study on intensified imaging surveillance protocols for high-risk resected melanoma, as ASDR was associated with superior survival outcomes from ICI therapy.

Correction to: Imaging Intensity and Survival Outcomes in High-Risk Resected Melanoma Treated by Systemic Therapy at Recurrence.

In the original article, the survival curves are missing in Fig. 1c, d.

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

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.

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.

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/m2 & I-160 mg/m2 IV, Day 2-15 X-1900 mg/m2/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2-15 X-1425 mg/m2/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.

Clinical and demographic correlates of medication and visit adherence in a large randomized controlled trial.

BACKGROUND: Patient characteristics are associated with adherence, which has implications for planning clinical research or designing payment systems that reward superior outcomes. It is unclear to what extent clinician efforts to improve adherence can attenuate these associations. METHODS: To identify factors predicting visit and medication adherence in settings designed to optimize adherence, we did a retrospective analysis of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants at 632 sites in North America, Puerto Rico, and the U.S. Virgin Islands for random assignment to antihypertensive treatment with amlodipine, chlorthalidone, or lisinopril. Site investigators reported clinic characteristics at the time they applied to participate in the study and research coordinators used standardized methods to measure patient characteristics. We defined adequate visit adherence as attending at least 80 % of scheduled visits; adequate medication adherence was defined as taking 80 % or more of the randomly assigned medication at all study visits. RESULTS: The 31,250 ALLHAT participants eligible for the visit adherence analysis attended 78.5 % of scheduled study visits; 68.9 % attended more than 80 % of scheduled visits. Clinic setting was predictive of both forms of adherence; adherence was worst at private clinics; clinics that enrolled more study participants had superior adherence. Adjusting for clinic characteristics and clinical factors, women, younger participants, Blacks and smokers were less likely to have adequate visit adherence. Among the 28,967 participants eligible for the medication adherence analysis, 21,261 (73.4 %) reported adequate medication adherence. In adjusted analyses, younger and less educated participants, Blacks, and smokers were less likely to report adequate adherence. CONCLUSIONS: Participant demographics were associated with adherence despite strenuous efforts to optimize adherence. Our results could inform decisions by researchers planning trials and policymakers designing payment systems. TRIAL REGISTRATION: NCT00000542 . Registered 27 October 1999.

Impact of oral melatonin supplementation on urine and serum melatonin concentrations and quality-of-life measures in persons with relapsing multiple sclerosis.

INTRODUCTION: Melatonin is an antioxidant and anti-inflammatory agent that modulates the immune system by scavenging free radicals, reducing the upregulation of pro-inflammatory cytokines, and reducing transendothelial cell migration. Therefore, melatonin may play a role in regulating multiple sclerosis (MS) disease activity. However, little is known about how melatonin supplementation effects individuals with MS. OBJECTIVE: Determine if there was a dose-dependent elevation in urine and serum melatonin concentrations. Determine if melatonin supplementation had an impact on patient reported outcomes. METHODS: This was a randomized, dose-blinded exploratory study. Adults (age 18-65) with relapsing forms of multiple sclerosis (RMS) treated with a stable dose of oral disease modifying therapy for at least 6 months were randomized into melatonin 3 mg or 5 mg daily. Urinary and serum melatonin levels and modified fatigue impact scale (MFIS), multiple sclerosis impact scale (MSIS-29), and Pittsburgh sleep quality index (PSQI), patient determined disease steps (PDDS) and performance scales (PS) were measured at baseline, 3, 6, and 12 months. Urinary and serum melatonin analyses was performed to estimate mean concentrations and their differences between treatment arms over time by a repeated measures linear mixed model. The model included treatment, assessment time, and treatment × time interaction. RESULTS: Thirty patients, randomized 1:1, were analyzed in an intent to treat population. Twenty-three completed the study. The repeated measures linear mixed model analysis of all timepoints revealed higher melatonin concentrations in patients on 5 mg compared to 3 mg melatonin for both urinary 6-SMT (p = 0.03) and serum melatonin (p = 0.04). MFIS, MSIS-29, PSQI, and PDSS-PS scores did not significantly change from baseline to month 12. No significant differences in these measures were seen between the two doses. Five patients stopped melatonin (three on 5 mg and two on 3 mg) due to adverse events, including one patient who developed focal spongiotic dermatitis. One patient experienced three consecutive serious adverse events that were unrelated to melatonin supplementation. CONCLUSIONS: The 5 mg melatonin supplementation group had higher concentrations of urinary 6-SMT and serum melatonin compared to the 3 mg group over 12 months of treatment. There was a correlation between 6-SMT and serum melatonin concentrations. This suggests that measuring serum melatonin is a reliable alternative to measuring urinary 6-SMT. However, no differences in clinical benefit between the two dosage groups were demonstrated in the patient reported outcomes. TRIAL REGISTRATION NUMBER: NCT03498131.

Associations between feeding and development in preterm infants in the NICU and throughout the first year of life.

BACKGROUND: There is little published evidence regarding associations between feeding and development in preterm infants which could help identify infants most needing follow-up services. AIMS: To determine if preterm infant feeding and development were predictable throughout the first year of life and identify associations with maternal factors, neonatal factors, and socioeconomic measures. STUDY DESIGN: Prospective single-site study of the feeding and development of extremely and very preterm infants at three time points throughout the first year of life. SUBJECTS: Infants <32 weeks gestational age were followed from neonatal intensive care unit (NICU) discharge (DC) until 12 months corrected gestational age (CGA). OUTCOME MEASURES: Feeding and development were evaluated at NICU DC, 3 months and 12 months CGA. Maternal health, infant health, and socioeconomic measures were also recorded. RESULTS: Significant differences were found between assessments for feeding and development at each of the three time points: NICU DC (p = 0.026), 3 months CGA (p = 0.001), and 12 months CGA (p = 0.000); however, no associations were found between feeding and development at NICU DC and 12 months CGA (p = 0.137). Of the maternal factors determined to be significant, none were consistent enough as to be considered relevant. CONCLUSIONS: This study demonstrated that preterm infants with typical feeding and development at DC may go on to develop concerns in these areas, and those who scored abnormally at DC may perform typically during the first year of life. This study affirms the importance of NICU follow-up services to support feeding and development for all infants born <32 weeks gestation.

Real world use of lanreotide in neuroendocrine tumors.

Background: Treatment for metastatic neuroendocrine tumors (NETs) is often with somatostatin analogues (SSA) such as lanreotide in the first-line setting. Real world use of lanreotide in Canada is not well studied. Methods: We performed a retrospective chart review of 69 patients to study real world use of lanreotide at our centre. Results: Lanreotide was the first-line of systemic treatment in 60 patients. Watch-and-wait was a common strategy and was seen in 31 patients. SSA switch strategy was seldom applied. Majority of patients on lanreotide had low-grade NETs. Standard starting dose of lanreotide 120 mg every 28 days was used in 66 patients. Dose escalation to 120 mg every 21 days occurred in 7 patients. The primary intention for treatment was tumor control in 32 patients, and both tumor and symptom control in 34 patients. Median time on treatment was 21.6 months. Conclusions: Overall, our findings were in keeping with current guidelines. It will be interesting to assess how clinical practice evolves in the future and to determine the role of dose escalation for disease control.

Tumor differentiation impacts response to neoadjuvant therapy and survival in patients with esophageal adenocarcinoma.

OBJECTIVE: The current staging system for esophageal adenocarcinoma only considers tumor grade in early tumors. The aim of this study was to evaluate the impact of tumor differentiation on response to neoadjuvant chemoradiotherapy and survival in patients with locally advanced esophageal adenocarcinoma. METHODS: This was a multi-institution retrospective review of all patients with esophageal cancer who underwent neoadjuvant chemoradiotherapy followed by esophagectomy from January 2010 to December 2017. Response to neoadjuvant therapy and survival was compared between patients with well- or moderately differentiated (G1/2) tumors versus poorly differentiated (G3) tumors. RESULTS: There were 550 patients, 485 men (88.2%) and 65 women. The median age was 61 years, and the tumor was G1/2 in 288 (52.4%) and G3 in 262 patients. Overall clinical stage before neoadjuvant therapy was similar between groups. Pathologic complete response (pCR) was found in 87 patients (15.8%). The frequency of pCR was similar between groups, but residual disease in the esophagus and lymph nodes was significantly more likely with G3 tumors. Median follow-up was 63 months and absolute survival, overall survival, and disease-free survival were all significantly worse in patients with G3 tumors. Further, even with pCR, patients with G3 tumors had significantly worse survival. CONCLUSIONS: This study showed that response to neoadjuvant therapy was not affected by tumor differentiation. However, poor differentiation was associated with worse survival compared with patients with G1/2 tumors, even among those with pCR. These results suggest that poor differentiation should be considered as an added risk factor for clinical staging in patients with locally advanced esophageal adenocarcinoma.

Phosphorylated transducer and activator of transcription-3 (pSTAT3) immunohistochemical expression in paired primary and metastatic colorectal cancer.

BACKGROUND: Signal Transducer and Activator of Transcription-3 (STAT3) mediates cellular functions. We assessed the IHC expression of phosphorylated STAT3 (pSTAT3) in paired primary tumors and liver metastases in patients with advanced stage colorectal cancer (CRC). METHODS: We included patients with tissue blocks available from both the primary CRC and a surgically resected liver metastasis. The IHC pSTAT3 expression agreement was measured using Cohen's kappa statistic. RESULTS: The study included 103 patients, 55% male, median age was 64. 43% tumors originated in rectum, and 63% of the primary tumors were synchronous. Expression of pSTAT3 was 76% in liver metastases and 71% in primary tumors. A difference in pSTAT3 staining between the primary tumor and liver metastases was noted in 64%. There was lost expression of pSTAT3 in the liver metastases in 28% and gained expression in 36% of cases compared to the primary. The kappa statistic comparing agreement between staining patterns of the primary tumors and liver metastases was a "less-than-chance", at -0.02. Median survival was 4.9 years, with no difference in survival outcomes by pSTAT3 expression in the primary tumor or liver metastases. DISCUSSION: STAT3 is not a prognostic marker in the selective setting of metastatic CRC to liver, but it may remain a potential therapeutic target given most liver metastases expressed pSTAT3. Discordant pSTAT3 expression in between primary tumors and paired liver metastases suggests that use of this class of drug to treat liver predominant metastatic colorectal cancer in a biomarker-driven approach may require confirmatory liver tumor biopsy.

The impact of driving time, distance, and socioeconomic factors on outcomes of patients with locally advanced rectal cancer.

Objectives: Cancer patients experience disparities due to socioeconomic status (SES) factors. We assessed the impact of SES factors on outcomes in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiation (nCRT) and surgery (Sx) in 3 Canadian provinces. Study design: This study was a multi-institutional retrospective chart review. Methods: Associations among community characteristics (2016 Canadian Census data), distance and time to the cancer center (mapping software), and outcomes were evaluated using the CHORD multi-institutional database. Results: 1,064 patients were included. Median age 62, 68% male, 15% lived in a rural community, 19% with median community household income >$50,000 CAD, median community proportion with post-secondary education 66%, 12% lived >100km away, and 18% lived >1 â€‹h away.Factors predictive of worse disease-free survival (DFS) and overall survival (OS) in univariate analysis included driving time >1 â€‹h, median community income ≤$50,000 CAD, driving distance >100km, and lower median community proportion with post-secondary education. Driving time >1 â€‹h remained significant in multivariate analysis for worse DFS (HR 1.47; 95% CI 1.14-1.90; p â€‹= â€‹0.003) and OS (HR 1.60, 95% CI 1.19-2.16; p â€‹= â€‹0.002). Conclusion: Outcomes of patients with LARC undergoing nCRT are negatively associated with increased driving time to the cancer centre.

A Phase I Study of Irinotecan, Capecitabine (Xeloda), and Oxaliplatin in Patients With Advanced Colorectal Cancer.

BACKGROUND: The objective of the present phase I study was to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of irinotecan, capecitabine, and oxaliplatin given in combination (IXO regimen) to patients with previously untreated, unresectable advanced or metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients received oxaliplatin followed by irinotecan as intravenous infusions on day 1, with oral capecitabine taken twice daily (BID) on days 2 to 15 of a 3-week cycle. The dose ranges were explored as follows: oxaliplatin, 75 to 120 mg/m2; irinotecan, 160 to 230 mg/m2; capecitabine, 750 to 1000 mg/m2 BID. Dose escalation was performed individually for each drug at each dose level according to the type and severity of toxicity encountered in the previous cohort. RESULTS: A total of 39 patients were enrolled at 7 dose levels and the MTD. The recommended doses for phase II evaluation were oxaliplatin 100 mg/m2, irinotecan 160 mg/m2, and capecitabine 950 mg/m2 BID. Diarrhea and febrile neutropenia were DLTs. Of the 39 enrolled patients, 26 (67%) had confirmed objective responses. The median progression-free survival was 11 months, and the median overall survival was 25 months. The survival rate at 5 years was 23%. CONCLUSION: The IXO regimen has a manageable toxicity profile with promising antitumor activity as first-line treatment of advanced and metastatic CRC.

Hypofractionation Is an Acceptable Alternative to Conventional Fractionation in the Treatment of Postlumpectomy Ductal Carcinoma In Situ With Radiotherapy.

PURPOSE: The standard dose of postlumpectomy radiotherapy (RT) for ductal carcinoma in situ (DCIS) is 50 Gy in 25 fractions using conventional fractionation (CF). However, in invasive carcinoma, hypofractionation (HF) with 40 to 42.6 Gy in 15 to 16 fractions has largely become a standard of care. The purpose of this study was to review the management of postlumpectomy DCIS in terms of RT dose-fractionation and its impact on local recurrence (LR), in one of the largest Canadian academic centers. METHODS AND MATERIALS: Between 2003 and 2008, a total of 348 women with DCIS were treated with postlumpectomy RT. Patient characteristics, histopathology, dose-fractionation, use of endocrine therapy, local, regional, contralateral breast recurrences, and cause of death were collected. Local recurrence-free survival was determined. Univariate and multivariate analyses were performed to identify risk factors for LR. RESULTS: The median age of the cohort was 59 years. Two hundred two (58%) patients received CF and 146 (42%) HF. Initially, the yearly proportion of HF was 34%, but increased up to 68% since 2007. Estrogen receptor was positive in 195 patients, and 43% of those received endocrine therapy. With a median follow-up of 64.8 months, 36 LRs were detected. The 5-year local recurrence-free survival rate was 94% for the HF group versus 91% for the CF group (P = .80). On multivariate analysis, only the use of endocrine therapy showed a trend towards decreasing LR (hazard ratio, 0.44; 95% confidence interval, 0.18-1.08; P = .07). CONCLUSIONS: The utilization of HF for DCIS postlumpectomy has increased over time and is a valid option as it results in similar rates of local control.

Age-not Charlson Co-morbidity Index-predicts for mortality after stereotactic ablative radiotherapy for medically inoperable stage I non-small cell lung cancer.

PURPOSE: In this single institution retrospective study of patients with stage I medically inoperable non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR) we attempt to model overall survival (OS) using initial prognostic variables with specific attention on the Charlson co-morbidity index (CCI). METHODS: Between 2008 and 2013, 335 patients with medically inoperable stage I NSCLC were treated with SABR or hypofractionated radiotherapy (50-60 Gy in at least 5 Gy or 4 Gy fractions respectively) at our institution. Medical comorbidities and Charlson scores were determined by individual chart review. Patients were stratified into 3 groups based on the CCI score (0-1, 2-3, 4-9) and again based on the age-adjusted Charlson Comorbidity score (aCCI). Cumulative survival for each stratum was determined using the Kaplan-Meier method. Non-significant and confounding variables were identified and discounted from survival modeling. 3 sex stratified Cox regression models were tested: (1) aCCI with age and comorbidity combined; (2) age and CCI; (3) age alone, comorbidity removed. RESULTS: The median survival was 4.4 years and the median follow up 4.7 years. The median CCI and aCCI scores were 2 and 5 respectively. Patients with aCCI 7-12 had an increased hazard of death on univariate analysis HR 2.45 (1.15-5.22 95%CI, p = 0.02) and -excluding age as a competing variable- on multivariate analysis HR 2.25 (1.04-4.84 95%CI, p = 0.04). Patients with CCI 4-9 had an increased hazard of death on univariate analysis HR 1.57(1.30-2.90) but not on multivariate analysis. On formalized testing - with either continuous or categorical variables- all three survival models yielded similar coefficients of effect. CONCLUSION: We identify male gender, weight loss greater than 10% and age as independent prognostic factors for patients treated with medically inoperable NSCLC treated with SABR or hypofractionated radiotherapy. Based on our survival models, age alone can be used interchangeably with aCCI or CCI plus age with the same prognostic value. Age is more reliably recorded, less prone to error and therefore a more useful metric than Charlson score in this group of patients.

The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas.

OBJECTIVES: Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). MATERIALS AND METHODS: Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c-MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan-Meyer, and Cox regression were used for statistical analyses. RESULTS: Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). CONCLUSIONS: This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis.