A prospective Canadian gastroesophageal cancer database: What have we learned?

BACKGROUND: Minimal literature exists on outcomes for Canadian patients with gastroesophageal adenocarcinoma (GEA). The objective of our study was to establish a prospective clinical database to evaluate demographic characteristics, presentation and outcomes of patients with GEA. METHODS: Patients diagnosed with GEA were recruited from Jan. 30, 2017, to Aug. 30, 2020. Data collected included demographic characteristics, presentation, treatment and survival. A multivariable model for overall survival in patients treated with curative intent was created using sex, lymph node status, resection margin status, age and tumour location as variables. RESULTS: A total of 122 patients with adenocarcinoma of the stomach or gastroesophageal junction were included. Median age was 65 years (interquartile range [IQR] 59-74), 70% of patients were male and 26% were born outside of Canada. Median follow-up time was 14.5 (IQR 8.0-31.0) months. Following staging computed tomography scanning, 88% of patients were deemed to have potentially resectable disease. Eighty-one (76%) received staging laparoscopy and 74 (61%) were treated with curativeintent surgery. Forty-six (62%) patients had nodal metastases. The median number of nodes harvested was 22 (IQR 18-30). The R0 resection margin rate was 82%. The 3-year overall survival for patients who received curative-intent treatment was 63% and 38% for all patients. On multivariable analysis, female sex (hazard ratio [HR] 3.88, p = 0.01), positive nodal status (HR 3.58, p = 0.02), positive margins (HR 3.11, p = 0.03) and tumour location (HR 3.00, p = 0.03) were associated with decreased overall survival. CONCLUSION: Many of the patients with GEA in this study presented with advanced disease, and only 61% were offered curative-intent surgery. A prospective multicentre national GEA database is now being established.

Evidence-Based Strategies for the Treatment of Peritoneal Malignancies during Health Care Resource Restriction: The COVID-19 Pandemic.

Background: The COVID-19 pandemic has put enormous pressure on hospital resources, and has affected all aspects of patient care. As operative volumes decrease, cancer surgeries must be triaged and prioritized with careful thought and attention to ensure maximal benefit for the maximum number of patients. Peritoneal malignancies present a unique challenge, as surgical management can be resource intensive, but patients have limited non-surgical treatment options. This review summarizes current data on outcomes and resource utilization to help inform decision-making and case prioritization in times of constrained health care resources. Methods: A rapid literature review was performed, examining surgical and non-surgical outcomes data for peritoneal malignancies. Narrative data synthesis was cross-referenced with relevant societal guidelines. Peritoneal malignancy surgeons and medical oncologists reviewed recommendations to establish a national perspective on case triage and mitigating treatment strategies. Results and Conclusions: Triage of peritoneal malignancies during this time of restricted health care resource is nuanced and requires multidisciplinary discussion with consideration of individual patient factors. Prioritization should be given to patients where delay may compromise resectability of disease, and where alternative treatment options are lacking. Mitigating strategies such as systemic chemotherapy and/or surgical deferral may be utilized with close surveillance for disease stability or progression, which may affect surgical urgency. Unique hospital capacity, and ability to manage the complex post-operative course for these patients must also be considered to ensure patient and system needs are aligned.

Structured simulation improves learning of the Fundamental Use of Surgical Energy™ curriculum: a multicenter randomized controlled trial.

BACKGROUND: Energy devices can result in devastating complications to patients. Yet, they remain poorly understood by trainees and surgeons. A single-institution pilot study suggested that structured simulation improves knowledge of the safe use of electrosurgery (ES) among trainees (Madani et al. in Surg Endosc 28(10):2772-2782, 2014). The purpose of this study was to estimate the extent to which the addition of this structured bench-top simulation improves ES knowledge across multiple surgical training programs. METHODS: Trainees from 11 residency programs in Canada, the USA and UK participated in a 1-h didactic ES course, based on SAGES' Fundamental Use of Surgical Energy™ (FUSE) curriculum. They were then randomized to one of two groups: an unstructured hands-on session where trainees used ES devices (control group) or a goal-directed hands-on training session (Sim group). Pre- and post-curriculum (immediately and 3 months after) knowledge of the safe use of ES was assessed using separate examinations. Data are expressed as mean (SD) and N (%), *p < 0.05. RESULTS: A total of 289 (145 control; 144 Sim) trainees participated, with 186 (96 control; 90 Sim) completing the 3-month assessment. Baseline characteristics were similar between the two groups. Total score on the examination improved from 46% (10) to 84% (10)* for the entire cohort, with higher post-curriculum scores in the Sim group compared with controls [86% (9) vs. 83% (10)*]. All scores declined after 3 months, but remained higher in the Sim group [72% (18) vs. 64% (15)*]. Independent predictors of 3-month score included pre-curriculum score and participation in a goal-directed simulation. CONCLUSIONS: This multi-institutional study confirms that a 2-h curriculum based on the FUSE program improves surgical trainees' knowledge in the safe use of ES devices across training programs with various geographic locations and resident volumes. The addition of a structured interactive bench-top simulation component further improved learning.

Treatment of gastric cancer with peritoneal carcinomatosis by cytoreductive surgery and HIPEC: a systematic review of survival, mortality, and morbidity.

Gastric cancer with peritoneal carcinomatosis has an extremely poor prognosis, which may be improved with cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). We systematically reviewed the literature regarding the efficacy of CRS + HIPEC in these patients. Electronic databases were searched from 2000 to 2010. Following CRS + HIPEC, overall median survival was 7.9 months and improved to 15 months for patients with completeness of cytoreduction scores of 0/1, however with a 30-day mortality rate of 4.8%.

Management of appendiceal pseudomyxoma peritonei diagnosed during pregnancy.

BACKGROUND: The incidence of cancer during pregnancy is approximately 1 in 1000. The most common types encountered during pregnancy are cervical, breast and ovarian. Epithelial tumors of the appendix on the other hand are rare and account for only approximately 1% of all colorectal neoplasms; the occurrence of this neoplasm during pregnancy is extremely rare. CASE PRESENTATION: The medical history of a 30 year old woman diagnosed at 17 weeks gestation with an appendiceal mucinous tumor with large volume pseudomyxoma peritonei was presented. Her pregnancy was preserved and she had an early vaginal delivery of a healthy baby at 35 weeks. At 2 1/2 weeks postpartum the patient underwent extensive cytoreductive surgery and intraperitoneal chemotherapy. She remains disease-free 5 years after her initial diagnosis. A literature review of this clinical situation and a discussion of treatment plans were presented. CONCLUSION: The management of an appendiceal tumor with pseudomyxoma peritonei diagnosed during pregnancy requires full knowledge of the natural history of this disease to achieve a balance of concern for maternal survival and fetal health.

Oxidative stress and matrix metalloproteinase-9 activity in the liver after hypoxia and reoxygenation with 21% or 100% oxygen in newborn piglets.

We designed a randomized controlled study to identify and compare the liver tissue responses in systemic hypoxia and resuscitation with 21% and 100% oxygen using an animal model of neonatal hypoxia and reoxygenation. Twenty-seven piglets (1-3 days old, weight 1.5-2.0 kg) were acutely instrumented and mechanically ventilated. The animals underwent 2 h of normocapnic alveolar hypoxia (10-15% oxygen) then reoxygenation with 21% or 100% oxygen for 1 h, then 1 h with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. After 2 h of reoxygenation liver tissue samples were immediately processed for histological and biochemical analyses of markers of oxidative stress and tissue injury. Two hours of hypoxia caused a significant reduction in mean arterial pressure with cardiogenic shock and metabolic acidemia, with similar recovery upon resuscitation with 21% and 100% oxygen. After 2 h of reoxygenation, the hepatic GSSG:total glutathione ratio and matrix metalloproteninase-9 activity, which correlated with the portal venous oxygenation at 15 min of reoxygenation, were greater in the 100% group and hepatic lactate level was higher in the 21% group than the controls (all P<0.05). Both hypoxic-reoxygenated groups had similarly elevated hepatic Bcl-2 levels. Apart from more non-distinct mitochondria identified in the 100% group, hepatic tissue adenylate energy charge and plasma transaminases levels did not differ among groups. We concluded that in this acute model of neonatal hypoxia and reoxygenation, resuscitation using 21% oxygen avoids the excess oxidative stress and elevated matrix metalloproteninase-9 activity in the liver when 100% oxygen was used. The study supports the conservative use of oxygen in optimizing post-hypoxic hepatic recovery.

Resuscitation with 21% or 100% oxygen is equally effective in restoring perfusion and oxygen metabolism in the liver of hypoxic newborn piglets.

The differential effects of the use of high or low oxygen levels during resuscitation on the neonatal liver are unknown. We compared the hepatic hemodynamics and oxygen metabolism in hypoxic newborn piglets resuscitated with 21% or 100% oxygen. Twenty-seven piglets (age, 1-3 days; weight, 1.5-2.0 kg) were acutely instrumented to measure cardiac output, hepatic artery, and portal venous blood flows (hepatic artery flow index [HAFI] and portal venous flow index [PVFI], respectively). The animals underwent 2 h of hypoxia (fraction of inspired oxygen, 0.10-0.15), then reoxygenation with 21% (n = 9) or 100% (n = 9) oxygen for 1 h, then 1 h with 21% oxygen. The controls (n = 9) were sham-operated without hypoxia-reoxygenation. Oxygen transport and plasma lactate concentrations were studied. Hypoxic animals had hypotension and decreased cardiac index with metabolic acidosis (mean pH, 7.00-7.02; P < 0.05 vs. controls). The PVFI and the total hepatic blood flow (THFI = PVFI + HAFI), despite the absence of significant change in HAFI, decreased to 16 +/- 2 mL/min/kg and 19 +/- 3 mL/min/kg, respectively (versus 24 +/- 2 mL/min/kg and 28 +/- 2 mL/min/kg of controls; P < 0.05). Fifteen minutes after reoxygenation, the cardiac index improved, PVFI recovered, HAFI was maintained, and THFI was not different between the groups. The hepatic oxygen consumption decreased (59%; P < 0.05) and the extraction increased (89%; P < 0.001) during hypoxia. Similarly, on reoxygenation, the hepatic oxygen consumption improved; however, extraction decreased versus controls on 100% but not on 21% oxygen (P < 0.05). The plasma lactate concentrations increased in both groups with hypoxia and were not different during reoxygenation between the group administered with 21% oxygen and the group administered with 100% oxygen. The hypoxic neonatal liver has reduced hepatic blood flow but has relatively preserved HAFI, and oxygen consumption recovered similarly on reoxygenation with 21% and 100% oxygen. The increased oxygen extraction during hypoxia normalized in 21% but reduced in 100% reoxygenation, with no differences in plasma lactate concentrations.

Tissue-specific changes in glutathione content of hypoxic newborn pigs reoxygenated with 21% or 100% oxygen.

We compared the responses towards oxidative stress in the liver, lung, brain, heart, kidney and small intestine of hypoxic newborn animals resuscitated with 21% or 100% oxygen. After stabilization, piglets (1-3 days, 1.6-2.0 kg, n=8/group) were randomized to receive 2 h of alveolar hypoxia (FiO(2)=0.10-0.14) followed by reoxygenation with 21% or 100% oxygen for 1 h and then another hour with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. At the end of the experiment, tissues from liver, lung, brain, heart, kidney and small intestine were collected and tested for GSH, GSSG and lipid peroxidation levels and histological examination. In normoxic controls, liver had the highest GSH level, followed by brain, heart, lung, small intestine and kidney which had the highest level of oxidative stress markers (GSSG level and GSSG:GSH ratio). Hypoxic-reoxygenated piglets had the highest GSSG levels and GSSG:GSH ratio in the kidney. Hypoxic piglets resuscitated with 100% oxygen had higher GSSG:GSH ratios in the lung and liver, but not in the kidney, brain, heart and small intestine, than controls, which were not different from the 21% group. No significant differences in peroxidation and histological tissue damage were found between groups in the liver and lung. We concluded that although hypoxic piglets resuscitated with 100% oxygen have higher oxidative stress in the liver and lung than with 21% oxygen, there are no significant differences in peroxidation and histological tissue damage acutely.

Dose response of intravenous sildenafil on systemic and regional hemodynamics in hypoxic neonatal piglets.

In neonates with acute pulmonary hypertension (PHT), the dose-response effect of sildenafil citrate, a selective phosphodiesterase-5 inhibitor that can alleviate PHT, has not been detailedly examined. We tested the hypothesis that the treatment of hypoxia-induced acute PHT with sildenafil would dose-dependently reduce the elevated pulmonary and systemic arterial pressures (PAP and SAP, respectively) with no effect on the oxygenation in newborn animals. We also examined the regional hemodynamic responses. Using a randomized controlled design, piglets (age range, 1-3 days; weight range, 1.5-2.1 kg) were anesthetized and acutely instrumented to measure cardiac index, left common carotid, superior mesenteric and left renal arterial flow indexes, SAP, and PAP. After stabilization, hypoxia was induced with fractional inspired oxygen concentration at 0.15 and, subsequently, piglets were randomized to receive i.v. sildenafil at 0.06, 0.2, or 2.0 mg/kg per hour or normal saline (controls) for 90 min (n = 6 each). Within 30 min of hypoxia (PaO2, 31 +/- 5 mmHg), the piglets developed PHT (PAP, 33 +/- 5 vs. 26 +/- 4 mmHg at baseline; P < 0.05. Sildenafil dose-dependently reduced the hypoxia-induced PHT (PAP at 90 min: 33 +/- 6, 29 +/- 6, and 26 +/- 6 mmHg of 0.06, 0.2, and 2.0 mg/kg per hour, respectively, vs. 44 +/- 8 mmHg of controls; P < 0.05. Sildenafil at 2.0 mg/kg per hour had the greatest decrease in SAP (P < 0.05) with no significant change at 0.06 and 0.2 mg/kg per hour. Pulmonary selectivity (PAP:SAP ratio) was best in the group treated with 0.2 mg/kg per hour dosage of sildenafil (P < 0.05). There were no differences in cardiac index and regional flow indexes between groups. Although hypoxia decreased oxygen delivery and increased oxygen extraction with no significant effect on oxygen consumption, the administration of sildenafil did not affect the oxygen metabolism (vs. controls). In neonatal piglets, i.v. sildenafil dose-dependently alleviates the hypoxia-induced acute PHT, with the best pulmonary selectivity at 0.2 mg/kg per hour, and shows no significant effect on regional circulation and oxygen metabolism.

Platelet dysfunction in asphyxiated newborn piglets resuscitated with 21% and 100% oxygen.

Hemostatic disturbances are common in asphyxiated newborns after resuscitation. We compared platelet function in hypoxic newborn piglets reoxygenated with 21% or 100% oxygen. Piglets (1-3 d, 1.5-2.1 kg) were anesthetized and acutely instrumented for hemodynamic monitoring. After stabilization, normocapnic hypoxia was induced with an inspired oxygen concentration of 10-15% for 2 h. Piglets were then resuscitated for 1 h with 21% or 100% oxygen, followed by 3 h with 21% oxygen. Platelet counts and collagen (2, 5, and 10 microg/mL)-stimulated whole blood aggregation were studied before hypoxia and at 4 h of post-hypoxia/reoxygenation. Platelet function was studied using transmission electron microscopy and by measuring plasma thromboxane B2 (TxB2) and matrix metalloproteinase (MMP)-2 and -9 levels. Control piglets were sham-operated without hypoxia/reoxygenation. The hypoxemic (PaO2 33 mm Hg) piglets developed hypotension with metabolic acidosis (pH 7.02-7.05). Upon reoxygenation, piglets recovered and blood gases gradually normalized. At 4 h reoxygenation, platelet aggregation ex vivo was impaired as evidenced by a rightward-downward shifting of the concentration-response curves. Electron microscopy showed features of platelet activation. Plasma MMP-9 but not MMP-2 activity significantly increased. Resuscitation with 100% but not 21% oxygen increased plasma TxB2 levels. Platelet counts decreased after hypoxia/reoxygenation but were not different between groups during the experiment. Resuscitation of hypoxic newborn piglets caused platelet activation with significant deterioration of platelet aggregation ex vivo and increased plasma MMP-9 levels. High oxygen concentrations may aggravate the activation of prostaglandin-thromboxane mechanistic pathway.

A dose-response study of graded reoxygenation on the carotid haemodynamics, matrix metalloproteinase-2 activities and amino acid concentrations in the brain of asphyxiated newborn piglets.

PURPOSE: It is controversial to choose an appropriate oxygen concentration to resuscitate asphyxiated newborns regarding the clinical and biochemical oxidative effects. We examined the vasomotor response to reoxygenation with graded reoxygenation and the effects on matrix metalloproteinases and amino acids of the immature brain. METHODS: Thirty-two piglets (1-3 days, 1.5-2.1 kg) were instrumented for continuous monitoring of left common carotid and pulmonary arterial flows (Transonic). Piglets were randomized to a sham-operated control group (without hypoxia/reoxygenation) or 2 h hypoxia induced by decreasing the inspired oxygen concentration to 10-15%, followed by reoxygenation with 21, 50 or 100% oxygen for 1 h and then 21% oxygen for 3 h (n=8 each). The brains were then flash frozen and analyzed for matrix metalloproteinases and amino acid levels by zymography and HPLC, respectively. RESULTS: After 2 h oxygen deprivation, the absolute carotid flow remained similar but accounted for 38% of cardiac output (increased from 17% at baseline, p=0.001). During early reoxygenation, the flow rose in the piglets resuscitated with air (p<0.05), but not in those with supplemental oxygen. Carotid vascular resistance correlated significantly with the arterial partial pressure of oxygen (r=0.7). There was an oxygen-dependent increase in global cerebral activity of matrix metalloproteinase-2 with specific increases in the basal ganglia of all hypoxic-reoxygenated brains. There were no significant differences in glutamate and other amino acids in any brain regions. CONCLUSIONS: Although using high oxygen concentration to resuscitate asphyxiated newborn piglets increased carotid vascular resistance and cerebral matrix metalloproteinase-2 activity, there is no detrimental effect observed in this acute model of hypoxia-reoxygenation.

Cardiac function, myocardial glutathione, and matrix metalloproteinase-2 levels in hypoxic newborn pigs reoxygenated by 21%, 50%, or 100% oxygen.

After asphyxia, it is standard to resuscitate the newborn with 100% oxygen, which may create a hypoxia-reoxygenation process that may contribute to subsequent myocardial dysfunction. We examined the effects of graded reoxygenation on cardiac function, myocardial glutathione levels, and matrix metalloproteinase (MMP)-2 activity during recovery. Thirty-two piglets (1-3 days old, weighing 1.5-2.1 kg) were anesthetized and instrumented for continuous monitoring of cardiac index, and systemic and pulmonary arterial pressures. After 2 h of hypoxia, piglets were randomized to receive reoxygenation for 1 h with 21%, 50%, or 100% oxygen (n = 8 each), followed by 3 h at 21% oxygen. At 2 h of hypoxemia (PaO2 32-34 mmHg), the animals had hypotension, decreased cardiac index, and elevated pulmonary arterial pressure (P < 0.001 vs. controls). Upon reoxygenation, cardiac function recovered in all groups with higher cardiac index and lower systemic vascular resistance in the 21% group at 30 min of reoxygenation (P < 0.05 vs. controls). Pulmonary artery pressure normalized in an oxygen-dependent fashion (100% = 50% > 21%), despite an immediate recovery of pulmonary vascular resistance in all groups. The hypoxia-reoxygenated (21%-100%) hearts had similarly increased MMP-2 activity and decreased glutathione levels (P < 0.05, 100% vs. controls), which correlated significantly with cardiac index and stroke volume during reoxygenation, and similar features of early myocardial necrosis. In neonatal resuscitation, if used with caution because of a slower resolution of pulmonary hypertension, 21% reoxygenation results in similar cardiac function and early myocardial injury as 50% or 100%. The significance of higher oxidative stress with high oxygen concentration is unknown, at least in the acute recovery period.

Resuscitation with 100% oxygen causes intestinal glutathione oxidation and reoxygenation injury in asphyxiated newborn piglets.

OBJECTIVE: To compare mesenteric blood flow, oxidative stress, and mucosal injury in piglet small intestine during hypoxemia and reoxygenation with 21%, 50%, or 100% oxygen. SUMMARY BACKGROUND DATA: Necrotizing enterocolitis is a disease whose pathogenesis likely involves hypoxia-reoxygenation and the generation of oxygen-free radicals, which are known to cause intestinal injury. Resuscitation of asphyxiated newborns with 100% oxygen has been shown to increase oxidative stress, as measured by the glutathione redox ratio, and thus may predispose to free radical-mediated tissue injury. METHODS: Newborn piglets subjected to severe hypoxemia for 2 hours were resuscitated with 21%, 50%, or 100% oxygen while superior mesenteric artery (SMA) flow and hemodynamic parameters were continuously measured. Small intestinal tissue samples were analyzed for histologic injury and levels of oxidized and reduced glutathione. RESULTS: SMA blood flow decreased to 34% and mesenteric oxygen delivery decreased to 9% in hypoxemic piglets compared with sham-operated controls. With reoxygenation, SMA blood flow increased to 177%, 157%, and 145% of baseline values in piglets resuscitated with 21%, 50%, and 100% oxygen, respectively. Mesenteric oxygen delivery increased to more than 150% of baseline values in piglets resuscitated with 50% or 100% oxygen, and this correlated significantly with the degree of oxidative stress, as measured by the oxidized-to-reduced glutathione ratio. Two of eight piglets resuscitated with 100% oxygen developed gross and microscopic evidence of pneumatosis intestinalis and severe mucosal injury, while all other piglets were grossly normal. CONCLUSIONS: Resuscitation of hypoxemic newborn piglets with 100% oxygen is associated with an increase in oxygen delivery and oxidative stress, and may be associated with the development of small intestinal hypoxia-reoxygenation injury. Resuscitation of asphyxiated newborns with lower oxygen concentrations may help to decrease the risk of necrotizing enterocolitis.