Eastern Canadian Gastrointestinal Cancer Consensus Conference 2018.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference was held in Halifax, Nova Scotia, 20-22 September 2018. Experts in radiation oncology, medical oncology, surgical oncology, and pathology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of pancreatic cancer, pancreatic neuroendocrine tumours, hepatocellular cancer, and rectal and colon cancer, including ■ surgical management of pancreatic adenocarcinoma,■ adjuvant and metastatic systemic therapy options in pancreatic adenocarcinoma,■ the role of radiotherapy in the management of pancreatic adenocarcinoma,■ systemic therapy in pancreatic neuroendocrine tumours,■ updates in systemic therapy for patients with advanced hepatocellular carcinoma,■ optimum duration of adjuvant systemic therapy for colorectal cancer, and■ sequence of therapy in oligometastatic colorectal cancer.

A rare case of primary thyroid amyloidosis.

INTRODUCTION: Amyloid goiter is due to the deposition of amyloid in the thyroid, resulting with enlargement of the gland and compressive symptoms. CASE: We herein present a case of a 45-year-old male patient who complained of a big swelling in the neck. Ultrasound showed an enlarged thyroid gland with mediastinal involvement. The multinodular appearance was consistent with the diagnosis of multinodular goiter. He had a history of multiple myeloma but no sign of systemic amyloidosis. DISCUSSION: Thyroid gland was removed and the histopathological examination revealed a diffuse deposition of amyloid associated with metaplastic lipomatosis of the stroma. CONCLUSIONS: The treatment of choice in patients with amyloid goiter is total thyroidectomy to solve compression symptoms.

Factor XI deficiency is not associated with an increased risk of pneumonia and pneumonia-related mortality.

INTRODUCTION: Drugs targeting factor XI (FXI) shows promising results in reducing postoperative VTE. Recently, researchers have shown that FXI knockout mice had a worse outcome when infected with pathogens for pneumonia, raising concerns about the safety of these drugs. AIM: To investigate the effect of FXI deficiency on the incidence of pneumonia and outcomes of pneumonia in humans. METHODS: Using the computerized database of the largest healthcare provider in Israel, we identified adults who were tested for FXI activity between January of 2002 and December of 2014 (n = 10 193). Patients were followed up until December of 2016 for the occurrence of pneumonia and pneumonia requiring hospitalization as a proxy of severe pneumonia. RESULTS: A total of 8958 (87.9%) had normal FXI activity, 804 (7.9%) had partial deficiency and 431 (4.2%) had severe deficiency; 722 individuals had pneumonia during 70 881 person-years of follow-up (incidence rate: 10.2 per 1000 person-years). Compared to those with normal FXI activity, the adjusted HR for pneumonia was 0.87 (95% CI, 0.67-1.14), and 0.95 (0.69-1.30) for those with partial and severe FXI deficiency, respectively. Overall, 256 individuals were hospitalized for pneumonia during 72 209 person-years of follow-up (incidence rate: 3.5 per 1000 person-years). The corresponding HR for severe pneumonia was 1.0 (0.70-1.48) and 0.86 (0.53-1.40) in those with partial and severe FXI deficiency, respectively. FXI deficiency was not significantly associated with 30-day and 90-day mortality among patients with pneumonia. CONCLUSION: FXI deficiency was not associated with an increased risk of pneumonia, pneumonia severity or short-term mortality among patients with pneumonia.

Tyrosine kinase-targeting drugs-associated heart failure.

BACKGROUND: The impact of cancer therapies on cardiac disease in the general adult cancer survivor population is largely unknown. Our objective was to evaluate which tyrosine kinase-targeting drugs are associated with greater risk for new-onset heart failure (HF). METHODS: A nested case-control analysis was conducted within a cohort of 27 992 patients of Clalit Health Services, newly treated with a tyrosine kinase-targeting, and/or chemotherapeutic drug, for a malignant disease, between 1 January 2005 and 31 December 2012. Each new case of HF was matched to up to 30 controls from the cohort on calendar year of cohort entry, age, gender, and duration of follow-up. Main outcome measure was odds ratio (OR) with 95% confidence interval (CI) of new-onset HF. RESULTS: There were 936 incident cases of HF during 71 742 person-years of follow-up. Trastuzumab (OR 1.90, 95% CI 1.46-2.49), cetuximab (OR 1.72, 1.10-2.69), panitumumab (OR 3.01, 1.02-8.85), and sunitinib (OR 3.39, 1.78-6.47) were associated with increased HF risk. Comorbidity independently associated with higher risk in a multivariable conditional regression model was diabetes mellitus, hypertension, chronic renal failure, ischaemic heart disease, valvular heart disease, arrhythmia, and smoking. CONCLUSIONS: Trastuzumab, cetuximab, panitumumab, and sunitinib are associated with increased risk for new-onset HF.

The role of CHADS2 and CHA2 DS2 -VASc scores in the prediction of stroke in individuals without atrial fibrillation: a population-based study.

UNLABELLED: Essentials CHADS2 and CHA2 DS2 -VASc scores are used to predict stroke in atrial fibrillation (AF). These scores were calculated for a large cohort from the largest healthcare provider in Israel. The risk of stroke gradually increased with an increase in the scores in individuals without AF. Both scores have a relatively high performance for stroke prediction in individuals without AF. Click to hear Prof. Lowe's perspective on Arterial Thrombosis, Pathogenesis and Epidemiology SUMMARY: Background CHADS2 and CHA2 DS2 -VASc are validated scores used to predict stroke in patients with atrial fibrillation (AF). We aimed to examine the performance of these scores in predicting stroke in individuals without AF. Methods Using the computerized database of the largest HMO in Israel, we identified all not-anticoagulated adults, aged 50 years or older on 1 January 2012. The cohort was followed for the occurrence of stroke or transient ischemic attack (TIA) until 31 December 2014. Results Of 1 053 871 individuals without AF at baseline, 34 215 developed stroke/TIA during a follow-up of 3 014 002 person-years (stroke/TIA incidence rate, 1.14 per 100 person-years). The incidence rate of stroke/TIA increased in a graded manner with increasing CHADS2 score: 0.36, 0.89, 1.89, 2.96, 4.31, 5.37 and 6.62 per 100 person-years for CHADS2 scores of 0 to 6 points, respectively (P < 0.001). Results were similar for the CHA2 DS2 -VASc score. A similar graded increasing trend in the stroke/TIA incidence rate was observed in a cohort of 46 657 patients with AF at baseline; however, stroke/TIA rates were higher in each score stratum compared with the rates of individuals without AF. The area under the receiver operating characteristic curve was 0.718 (95% CI, 0.715-0.721) and 0.714 (0.711-0.717) for CHADS2 and CHA2 DS2 -VASc scores, respectively, in individuals without AF, and 0.606 (0.598-0.614) and 0.610 (0.602-0.618), respectively, in individuals with AF. Conclusions CHADS2 and CHA2 DS2 -VASc scores have a relatively high performance for prediction of stroke/TIA in individuals without AF, which is comparable to their performance in patients with AF.

Neutrophil to lymphocyte ratio and risk of a first episode of stroke in patients with atrial fibrillation: a cohort study.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is associated with increased risk of cardiovascular morbidity and mortality. We aimed to assess the association between NLR and first episode of stroke in patients with atrial fibrillation. METHODS: Using the computerized database of the largest HMO in Israel, we identified a cohort of adults, aged 20 years or older, with atrial fibrillation diagnosed before 1 January 2012. Eligible subjects had no prior stroke or TIA, were not on anticoagulants at baseline, and had at least one blood cell count performed in 2011. The cohort (32,912 subjects) was followed for the first event of stroke or TIA until 31 December 2012. RESULTS: Overall 981 subjects developed stroke during a follow-up of 30,961 person-years (stroke rate, 3.17 per 100 person-years). The incidence rate of stroke increased across NLR quartiles: 2.27, 2.72, 3.26 and 4.54 per 100 person-years, respectively. Cox proportional hazard regression analysis adjusting for the individual CHA2 DS2 -VASc score risk factors showed that, compared with the lowest NLR quartile, the HR for stroke was 1.11 (95% CI, 0.91-1.35), 1.25 (1.03-1.51) and 1.56 (1.29-1.88) for the second, third and highest quartile, respectively. On stratified analysis, NLR refined the risk of stroke across all CHA2 DS2 -VASc score strata. Adding NLR to the CHA2 DS2 -VASc score increased the AUC from 0.627 (95% CI, 0.612-0.643) to 0.635 (0.619-0.651) (P = 0.037). CONCLUSIONS: The neutrophil to lymphocyte ratio is directly associated with the risk of stroke in patients with atrial fibrillation. Future studies are needed to replicate these findings.

Glycated hemoglobin and risk of first episode stroke in diabetic patients with atrial fibrillation: A cohort study.

BACKGROUND: Diabetes is associated with an increased risk of stroke in patients with atrial fibrillation. Whether glycemic control, evaluated by glycated hemoglobin, affects the risk of stroke in diabetic patients with atrial fibrillation remains unknown. OBJECTIVE: To examine the association between glycated hemoglobin and risk of first episode stroke in diabetic patients with atrial fibrillation. METHODS: By using the computerized database of the largest health maintenance organization in Israel, we identified a cohort of adults (age ≥20 years) in whom atrial fibrillation was diagnosed before January 1, 2012. Eligible subjects had no previous stroke or transient ischemic attack and were not on anticoagulants at baseline. The cohort (37,358 subjects) was followed for the first episode stroke or transient ischemic attack up to December 31, 2012. RESULTS: A total of 1052 subjects had stroke during 35,278 person-years of follow-up (stroke rate 2.98 per 100 person-years). Cox proportional hazards regression analysis adjusting for CHA2DS2-VASc score risk factors revealed that compared with subjects without diabetes, the hazard ratio for stroke was 1.04 (95% confidence interval [CI] 0.83-1.30) for the lowest glycated hemoglobin quartile (<6.35%), 1.14 (95% CI 0.92-1.42) for the second quartile (6.35%-6.90%), 1.46 (95% CI 1.19-1.79) for the third quartile (>6.90%-7.70%), and 1.63 (95% CI 1.33-2.00) for the highest quartile(>7.70%) (for trend, P < .001). In diabetic patients (n = 11,176), the hazard ratio for stroke was 1.17 (95% CI 1.09-1.26) for every 1% increment in glycated hemoglobin level. The area under the receiver operating characteristic curve was 0.585 for the CHA2DS2-VASc score, which increased to 0.604 when glycated hemoglobin was included in the model (P = .038). CONCLUSION: Glycated hemoglobin is directly associated with stroke risk, and it improves the predictive accuracy for stroke in diabetic patients with atrial fibrillation.

Statins use and risk of mortality in patient with Clostridium difficile infection.

Current evidence suggests that statins may improve outcome in infectious diseases. This study aims to assess whether statins use is associated with reduced risk of 30-day mortality in Clostridium difficile infection (CDI). Using the computerized database of Clalit, the largest healthcare provider in Israel, we identified a cohort of adult subjects (age ≥40 years) who tested positive on a C. difficile toxin assay performed between January 2011 and December 2012. Subjects were defined as current statins users if they filled at least one prescription during the 90 days before the laboratory assay date. Current users were classified into long-term users if at least one additional prescription was filled during the previous 91-180 days; otherwise they were defined as short-term users. A total 1888 patients with CDI were included. Of them, 340 (18.0%) died during the first 30 days after diagnosis. The 30-day mortality rate was lower among current statins users 89/669 (13.3%) compared with 251/1219 (20.6%) in non-users (p <0.001). A significant reduced risk of 30-day mortality existed after adjustment for potential confounders; adjusted OR = 0.57 (95% CI 0.42-0.79) and was unique to long-term users; 0.53 (0.38-0.73) but not short-term users; 1.15 (0.56-2.34). The risk of 30-day mortality decreased with increasing number of filled statins prescriptions; adjusted OR = 0.77 (95% CI 0.67-0.89) for each additional prescription. Current aspirin use was also independently associated with reduced mortality; adjusted OR = 0.64 (95% CI 0.43-0.88). In conclusion, current statins use, particularly long-term use, has a dose-response protective effect on mortality in patients with CDI.

The relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation.

UNLABELLED: This study examines the relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation among adults with baseline serum 25(OH)D levels<50 nmol/L. This study revealed that the increase in serum 25(OH)D in response to vitamin D supplementation was higher in lean subjects as compared to obese subjects. INTRODUCTION: Serum 25(OH)D is lower among obese than non-obese. This study examines the relationship between obesity and the increase in serum 25(OH)D in response to vitamin D supplementation in a large sample of adults with baseline serum 25(OH)D<50 nmol/L, relatively long average treatment duration and large average daily cholecalciferol. METHODS: The computerized database of the Clalit Health Services, which the largest nonprofit health maintenance organization in Israel, was retrospectively searched for all subjects aged≥20 years who performed serum 25(OH)D test in 2011. Subjects with more than one test at different occasions in 2011 were identified and were included if the result of the first test was <50 nmol/L, and were treated with cholecalciferol between the first and the last test in 2011 (n=16,540 subjects). RESULTS: The mean increase in serum 25(OH)D level after treatment was 28.7 (95% confidence interval (CI), 28.0-29.4) nmol/L, 23.6 (23.0-24.2) nmol/L, and 20.1 (19.6-20.6) nmol/L in subject with BMI of <25, 25-29.9, and ≥30 kg/m2, respectively (P<0.001). The results were similar after adjustment for the potential confounders. Similarly, the proportion of subjects who achieved serum 25(OH)D≥50 nmol/L after treatment was inversely associated with BMI; 65.1, 58.3, and 49.1% for BMI of <25, 25-29.9, and ≥30 kg/m2, respectively. Compared to BMI of ≥30 kg/m2, the adjusted odds ratio for achieving levels of ≥50 nmol/L were 2.12 (95 % CI, 1.94-2.31) and 1.42 (1.31-1.54) for BMI of <25 kg/m2, and BMI of 25-29.9 kg/m2, respectively. CONCLUSIONS: BMI is inversely associated with the increase in serum 25(OH)D levels in response to vitamin D supplementation.

Clinical features and course of brain metastases in colorectal cancer: an experience from a single institution.

OBJECTIVES: Brain metastases from colorectal cancer (crc) are quite rare. Here, we review the characteristics, presentation, and clinical course of such patients at our institution. METHODS: We reviewed the medical records of patients with brain metastases from crc treated during 2000-2009. Associations between patient, tumour characteristics, treatment modality, and survival were assessed using the Kaplan-Meier method. RESULTS: We identified 48 patients (25 men, 23 women) who developed brain metastases from crc. The median age at diagnosis of the brain metastases was 63 years (range: 37-84 years). In 23 of the patients (48%), the primary tumour occurred in the rectum. At diagnosis of brain metastases, 43 patients (90%) also had other systemic metastases (mainly pulmonary and hepatic). The median interval between diagnosis of the primary tumour and of the brain metastases was 24 months. Median survival after a diagnosis of brain metastasis from crc was 4 months (range: 1-13 months). We observed substantially better survival (13 months, p < 0.001) in patients treated with surgery followed by whole-brain radiotherapy (wbrt) than in those treated with radiotherapy or surgery alone. Sex, age, location and number of brain metastases, and timing of diagnosis did not affect survival. CONCLUSIONS: Brain metastases from crc develop late in the course of the disease, given that most patients already have other secondary lesions. Prognosis in these patients is poor, with those receiving treatment with surgery and wbrt having the best overall survival. Early detection and treatment of brain metastases with new systemic therapies may improve outcomes.

Single measurement of serum 25(OH)D: is classification into month-specific cutpoints useful in accounting for seasonal variation?

Classification into month-specific cutpoints is used to minimize misclassification associated with single measurement of serum 25(OH)D. This study aims to evaluate this strategy, and to compare it with the widely used classification into overall cutpoints. For this purpose, we studied 69,553 subjects in whom serum 25(OH)D was tested on two different occasions. The level of agreement between the quartiles of the first and second tests was 43.8% between the month-specific quartiles and 43.1% between the overall quartiles. The level of agreement between the quartiles of the two approaches was 80.0% and 94.3% in the first and second test, respectively. The extent of seasonal variation (summer-autumn as compared with winter-spring) of serum 25(OH)D was higher in males and in Jews, inversely associated with baseline levels, body mass index and age, and directly associated with socioeconomic class. The month-specific cutpoint strategy does not seem to offer advantage over the overall cutpoints strategy.

Serum 25(OH)D concentrations in sunny Israel.

SUMMARY: This study assesses vitamin D status in Israel. Serum 25(OH)D levels <25 and <50 nmol/L are common in Israel with noted differences between Arabs and Jews, Arab females were particularly at high risk. These findings may require public health intervention at the population level. INTRODUCTION: Small studies from Israel have suggested a high prevalence of hypovitaminosis D. The objective of this study was to evaluate the extent of hypovitaminosis D among demographic subgroups in Israel. METHODS: The data of this study are from the Clalit Health Services (CHS) which is a non-for-profit health maintenance organization (HMO) covering more than half of the Israeli population. We included all CHS members for whom a 25(OH)D test result in 2009 was available and who were not taking vitamin D supplements in 2008-2009 before that 25(OH)D result. Complete data were available for 198,834 members. RESULTS: The mean level of 25(OH)D was 51.9 ± 24.5 nmol/L and was higher in summer compared to winter (P < 0.0001). Level <25, <37.5, and <50 nmol/L were detected in 14.4%, 30.7%, and 49.9% of tests; 16.4% had levels >75 nmol/L. Females had higher prevalence of 25(OH)D levels < 50 nmol/L which were found in 51.8% of females versus 45.0% in males (P < 0.0001); 76.7% of the Arabs had levels <50 nmol/L versus 46.5% in Jews (P < 0.0001). Arabs females were particularly at high risk for 25(OH)D <50 nmol/L; 84.8% of them had levels <50 nmol/L versus 48.1% of Jewish females (P < 0.0001). The relation of 25(OH)D levels with age had a sinusoidal shape among Jews, a U-shape in Arab females, and inverse linear pattern in Arab males. CONCLUSIONS: 25(OH)D levels <25 and <50 nmol/L are common in Israel. Public health measures are needed for values lesser than about 30 nmol/L and further monitoring of concentrations between about 30 and 50 nmol/L to determine if there are adverse health effects.

Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer.

Receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer is a specific entity with an aggressive behavior. Trastuzumab, a monoclonal antibody targeting erbB-2 (HER2) deeply transformed the outcome in patients. Nevertheless, resistance to trastuzumab is still a major concern. Lapatinib ditosylate is an orally available, small molecule targeting the tyrosine activity of the HER2 receptor. Lapatinib as a single agent and in combination therapy showed interesting activity in trastuzumab-resistant advanced tumors. In addition, lapatinib use seemed suitable in recurrent locally advanced inflammatory breast cancer and brain metastases. More recently, the Neo-ALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial showed that lapatinib in combination with trastuzumab and paclitaxel significantly improved the pathological complete response in a neoadjuvant setting. Several clinical trials are still ongoing and data that may change current clinical practice are awaited with much interest.

Fetal calf serum enhances in vitro production of Bos taurus indicus embryos.

The objective of this study was to determine the effect of fetal calf serum (FCS) on the quality of in vitro produced bovine embryos. Cumulus oocyte-complexes (COCs, n = 2 449) recovered by ovum pick-up from Bos taurus indicus donors were randomly assigned to experimental groups. Sperm selected by Percoll gradient was used for in vitro fertilization (insemination = Day 0). In Experiment 1 (n = 1 745 COCs), zygotes were cultured in vitro in Synthetic Oviduct Fluid + 4 mg/mL of bovine serum albumin (BSA), or BSA + 2% FCS (BSA+FCS). In Experiment 2 (n = 704 COCs), the COCs were cultured in SOF + BSA, BSA + 2% FCS, or BSA + 2% FCS on D4 (BSA + FCSD4). In Experiment 1, blastocyst yield (51%) and Quality I blastocysts (41%) at Day 7 were higher (P < 0.05) in the BSA + FCS treatment than in BSA (42 and 30%, respectively). In Experiment 2, blastocyst yield was higher (P < 0.05) in the BSA+FCS (47%) treatment. Quality I blastocyst yield was higher (P < 0.05) for BSA + FCS (34%) and BSA+FCSD4 (32%) compared to the BSA treatment (20%). A total of 820 embryos were transferred, with no significant differences among groups in pregnancy rates. In conclusion, in vitro culture in SOFaaci + BSA + FCS enhanced blastocyst yield and Quality I blastocysts; adding FCS to the culture medium increased the efficiency of IVP of bovine embryos.

Heart failure secondary to selenium deficiency, reversible after supplementation.

Selenium deficiency induced heart failure is a well known disease. The first reported cases were back in 1937 during an epidemic in some rural areas of China (Keshan Disease). It is a potentially fatal disease if untreated. Early diagnosis and treatment is essential since supplementation may reverse the outcome. Patients with non ischemic heart failure deserve a serum selenium level measurement as a part of their work up. We report a case of selenium deficiency induced heart failure reversed after treatment with selenium.

Systemic lupus erythematosus and inflammatory bowel disease.

We hereby summarize a case reported by the authors, as well as all of the previously reported cases, of patients suffering from both systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD) that have been published in the English literature. In most cases, SLE was diagnosed prior to IBD, and the latter was of the ulcerative colitis subtype. Interestingly, the first disease diagnosed was almost never active at the time the second disease manifested itself. Patients with both diseases tended to have less photosensitivity, less arthritis, and less serositis than patients with SLE alone. There were no cases with neurological disorders or overt nephritis. All of these patients had anti-dsDNA and there was a tendency towards more anemia and thrombocytopenia. These patients had a relatively benign course with no flare-ups of lupus during follow-up and a favorable course of their bowel disease as well.

Sweet's syndrome and sarcoidosis.

In this review we summarize a number of cases of Sweet's syndrome (SS) associated with sarcoidosis that have been reported in the English literature. In all of the cases, the two disorders were diagnosed simultaneously. Patients with both disorders were younger and had a higher rate of fever than patients with SS alone. In this group of patients, we found a trend toward less skin involvement of the face and trunk, more involvement of the upper limbs, and more atypical skin lesions, particularly papules. The association of the two disorders seems to be more related to a subset of acute sarcoidosis (Lofgren's syndrome). All of the patients in this group had a benign course and self-limiting disease. Thus, SS in association with sarcoidosis could be considered a favorable prognostic factor. Although SS has a high rate of recurrence, no recurrence occurred in this group of patients during follow-up.