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.

Carcinoma of the gallbladder: patterns of presentation, prognostic factors and survival rate. An 11-year single centre experience.

BACKGROUND: This report examines the patterns of presentation, prognostic factors and survival rate of all patients with gallbladder cancer (GBC) evaluated at our tertiary academic hospital over an 11-year period. METHODS: A retrospective review of a prospectively collected database of all patients with GBC presenting between January 1998 and December 2008 was performed. RESULTS: 102 GBC-patients were included: 69 women and 33 men (median age: 65,5 years). Forty-five patients presented with incidental gallbladder cancer (IGC) and 57 with nonincidental cancer (NIGC). Curative surgery rate was 84.4% for IGC and 29.8% for NIGC (p < 0.001). Five-year actuarial survival rate was 63.2% for patients with curative intent surgery and 0% for patients with palliative approach. Patients with IGC had a longer survival rate compared to patients with NIGC (median: 25.8 vs. 4.4 months, p < 0.0001). For patients with radical resection (42 patients), there was no difference between IGC and NIGC. The incidence of liver involvement was respectively 0%, 20.8%, 58.3%, 100% for pT1, pT2, pT3 and pT4 tumors. Univariate analysis showed that survival rate was significantly affected by perineural invasion, T, N and M-stage, R0 resection, liver involvement, CA-19.9. In multivariate analysis, liver involvement was the only independent factor. CONCLUSIONS: Majority of patients with a potentially curable disease had IGC. Almost 80% of patients with NIGC presented with unresectable disease. For patients who underwent resection with curative intent, actuarial 5-year survival was 63.2%. Liver involvement was the only independent prognostic factor. All patients with IGC and a pT2 or more advanced T stage should undergo a second radical resection.

Eastern Canadian Colorectal Cancer Consensus Conference: setting the limits of resectable disease.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Montreal, Quebec, October 22-24, 2009. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management colorectal cancer, such as the management of hepatic and pulmonary metastases, the role of monoclonal antibodies to the epidermal growth factor receptor, and the benefits and safety of chemotherapy in elderly patients. The management of gastrointestinal neuroendocrine tumours and gastric cancer are also discussed.

[Outpatient laparoscopic cholecystectomy: a one year experience on unselected patients]. / Cholécystectomie coelioscopique ambulatoire: expérience d'un an sur des patients non sélectionnés.

UNLABELLED: This study reviews our experience with outpatient laparoscopic cholecystectomy (CCA) to evaluate the benefits of this approach to routine clinical practice. PATIENTS AND METHODS: Of 217 consecutive patients undergoing laparoscopic cholecystectomy over a one-year period (2002-2003) at our university medical center, 151 were selected for same day surgery and discharge according to the following selection criteria: non-urgent surgery, no major co-morbidities, domicile within one hour of the hospital. Patients were typically discharged the afternoon of their surgery if their clinical condition was stable. RESULTS: Of 151 planned outpatient CCA's, 122 (81%) were discharged on the day of surgery. Of these, 16 had a post-operative complication and three required readmission; no patient required reoperation. Univariate analysis revealed three factors predictive of failure of the outpatient strategy: age >65 (p=0.015), operative duration (p<0.0001), and surgical start time after 11 am (p<0.0001). CONCLUSIONS: Outpatient laparoscopic cholecystectomy can be routinely accomplished in unselected patients in an academic center. The low rate of in-patient admission is acceptable. The out-patient strategy for laparascopic cholecystectomy allows for a reduction in waiting time at our institution.

Treatment of post liver transplantation bile duct stricture with self-expandable metallic stent.

OBJECTIVE: The aim of this study is to report our experience using self-expandable covered metallic stents (Wallstent) to treat different types of biliary strictures after orthotopic liver transplantation (OLT). PATIENTS AND METHODS: Between January 1999 and July 2004, 222 OLTs were performed with choledocho-choledochostomy (CC) bile duct reconstruction. An anastomotic biliary stricture was diagnosed and treated by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous procedures in 100 patients (45%). The group of 21 patients (mean age 57.0+/-5.6 years) that were eventually treated with a biliary Wallstent was studied retrospectively. RESULTS: Significant persistent proximal or anastomotic strictures were diagnosed in 4 and 17 patients, respectively. A Wallstent was inserted by ERCP or through a percutaneous route in 18 and 3 patients, respectively. The mean interval between diagnosis and Wallstent insertion was 179.7+/-292.8 (0-1113) days. The mean total number of procedures required per patient was 7.4+/-5.5. The mean stent primary patency duration was 10.8+/-7.8 (0.9-25.1) months with a 24-month primary patency rate of 26% at a mean follow-up time of 37.8+/-17.2 months. A hepatico-jejunostomy was performed in five patients (24%). Two patients (10%) underwent retransplantation for diffuse ischemic cholangitis or chronic rejection. The overall complication rate was 4%. CONCLUSION: Treatment of post-transplant biliary stenosis using a Wallstent is a valuable option for delaying or avoiding surgery in up to 70% of patients. Proximal stenosis can be treated in the same manner in selected patients with major comorbidities.

Phase II study of troxacitabine in chemotherapy-naive patients with advanced cancer of the pancreas: gastrointestinal tumors.

BACKGROUND: Troxacitabine (Troxatyl) is a novel L-enantiomer nucleoside analog with activity in pancreatic cancer xenograft models. PATIENTS AND METHODS: Troxacitabine 1.5 mg/m(2) was administered by 30-min infusions daily x5 every 4 weeks to 54 patients with advanced pancreatic cancer. Patients were evaluated for objective tumor response, time to tumor progression (TTP), changes in tumor marker CA 19-9, survival, safety, pain, analgesic consumption, Karnofsky performance status and weight change. RESULTS: Median TTP was 3.5 months (95% CI 2.0-3.8), median survival 5.6 months (95% CI 4.9-7.4), and the 1 year survival rate 19%. Best responses were stable disease in 24 patients with eight patients having stable disease for at least 6 months (15%). A 50% or greater decrease in CA 19-9 was seen in seven of 44 assessed patients (16%). Grade 3 and 4 neutropenia were observed in 37% and 30% of patients with one episode of febrile neutropenia. The most common drug-related non-hematological toxic effects reported were cutaneous, with 22% and 6% of patients reporting grade 2 and 3 skin rash, respectively and 4% grade 2 hand-foot syndrome. CONCLUSION: Troxacitabine administered by a bolus daily x5 monthly regimen has modest activity in advanced pancreatic adenocarcinoma.

Ultrastructural evidence of brain mast cell activation without degranulation in monkey experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). Increased permeability of the blood-brain barrier (BBB) precedes the development of clinical or pathologic findings in MS and may be induced by perivascular brain mast cells secreting vasoactive and proinflammatory molecules. Brain mast cells were investigated ultrastructurally in acute EAE of the non-human primate common marmoset Callithrix jacchus, which develops a mild neurologic relapsing-remitting course. Control diencephalic samples contained perivascular mast cells with mostly intact electron dense granules. In contrast, EAE samples had marked demyelination and mast cells with numerous altered secretory granules; their electron dense content varied in amount and texture with a "honeycomb" or "target" appearance, but without degranulation. These changes were evident even before the development of any clinical symptoms and suggest that brain mast cells may be involved in EAE, and possibly MS, through a unique process that may involve selective secretion of molecules able to disrupt the BBB.

IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26.

It has been reported that the CD4+ T cell is a very important source of interleukin 10 (IL-10), while CD8+ cells produce low amounts. IL-10 exerts several immune stimulating, as well as inhibitory effects. There are at least five novel human IL-10 family-related molecules: IL-19, IL-20, IL-22, IL-24, and IL-26. Activated T cells produce IL-19, IL-22 and IL-26, while IL-24 is produced by activated monocytes and T-cells. IL-20 induces cheratin proliferation and Stat-3 signal transduction pathway, while IL-22 induces acute-phase production by hepatocytes and neonatal lethality with skin abnormalities reminiscent of psoriasic lesions in humans. In addition, IL-22 mediates inflammation and binds class II cytokine receptor heterodimers IL-22 RA1/CRF2-4. This cytokine is also involved in immuno-regulatory responses. IL-26 (AK155) is a novel cytokine generated by memory cells and is involved in the transformed phenotype of human T cells after infection by herpes virus. All these new IL-10 subfamily member cytokines are strongly involved in immune regulation and inflammatory responses.

Inhibitory effect of retinoic acid on proliferation, maturation and tryptase level in human leukemic mast cells (HMC-1).

Mast cells play important role in allergic inflammation by releasing histamine, tryptase and several inflammatory cytokines. Human leukemic mast cells (HMC-1) have been used to study mast cell mediator and their role in inflammatory mechanisms. HMC-1 contain and release several inflammatory mediators, of which the proteolytic enzyme tryptase is most characteristic. Retinoids, including retinoic acid, are naturally occurring and synthetic derivatives of vitamin A. All-trans-retinoic (ATRA) acid had been previously reported to inhibit cell proliferation, differentiation and apoptosis. In the present study, we investigated the effect of ATRA on the proliferation and secretion of tryptase in HMC-1. HMC-1 were treated with ATRA at 10(-4M), 10(-5M) or 10(-6M) for 3, 4 or 5 days in culture. Control HMC-1 were treated with equal amount of culture medium only. ATRA decreased the number of HMC-1 as compared to the control group. The same treatment for 3, 4 or 5 days also decreased intracellular tryptase levels. These results indicate that ATRA significantly inhibits both proliferation and growth as shown by the decreased intracellular tryptase levels in HMC-1. ATRA may be a useful agent in the treatment of mast cell proliferative disorders.

Intravesical sodium hyaluronate inhibits the rat urinary mast cell mediator increase triggered by acute immobilization stress.

PURPOSE: Mast cell activation and stress have been suggested as factors in the pathogenesis of interstitial cystitis, a painful disorder of the bladder that is diagnosed more frequently in women and characterized by increased urgency and frequency with absent infection. Intravesical sodium hyaluronate has been used to treat interstitial cystitis due to its possible replenishment of bladder glycosaminoglycans. We investigated the effect of sodium hyaluronate on the activation of bladder mast cell and release of proinflammatory mediators in the urine induced by acute immobilization stress in rats. MATERIALS AND METHODS: Using anesthesia a catheter was inserted in the bladder of 170 gm. female Sprague-Dawley rats. After emptying post-void residual urine a solution of normal saline, 0.08% or 0.4% sodium hyaluronate was introduced for 30 minutes. Each rat was allowed to recover from anesthesia and stressed for 30 minutes by confining it in a clear acrylic plastic immobilizer, while urine was continuously collected. Urinary histamine, rat mast cell protease-I and interleukin (IL)-6 were then determined. At the end of the experiments each rat was sacrificed by CO2 asphyxiation, and the bladder was removed and fixed with 4% paraformaldehyde. Frozen sections were stained with acidified toluidine blue, and the mast cell number and degree of activation were determined by granule extrusion and reduced cellular staining. RESULTS: Mean bladder mast cell activation plus or minus standard deviation in 6 control rats was 30.4% +/- 3.7% but it increased to 76.2% +/- 6.1% in 6 stressed animals (p = 0.0001). Intravesical administration of 0.4% sodium hyaluronate for 30 minutes in 6 rats before stress reduced mean bladder mast cell activation by 69.7% to 23.1% +/- 6.1% compared with stressed controls (p = 0.0003). However, compared to itself before stress there was no significant difference, indicating complete inhibition in 6 rats. Intravesical 0.08% sodium hyaluronate had a weaker inhibitory effect in 6 rats, decreasing mean degranulation by 22.5% to 59.1% +/- 7.6% (p = 0.02). In 6 rats stress increased the total mean amount of urinary rat mast cell protease-I by 271% from 0.14 +/- 0.09 to 0.52 +/- 0.17 ng. (p = 0.008). Pretreatment with 0.4% sodium hyaluronate reduced mean rat mast cell protease-I 80.8% compared with stressed controls (p = 0.008) and prevented any increase in response to stress in the same group of 8 rats with a mean pre-stress and post-stress level of 0.09 +/- 0.04 and 0.1 +/- 0.04 ng., respectively (p = 0.8). Acute stress increased mean urinary histamine in 6 rats 40.2% from 137.3 +/- 29.7 before to 193.7 +/- 7.6 ng./ml. after stress (p = 0.004). Pretreatment with 0.4% sodium hyaluronate reduced mean histamine 7.1% compared with stressed controls but completely prevented any increase in the same group of 8 rats, in which it was 174.5 +/- 23.1 before and remained 179.4 +/- 9.9 ng./ml. after stress (p = 0.75). Acute stress in 7 rats also increased the mean amount of IL-6 released in the urine by 31.5% from 775.9 +/- 69.2 to 1,021.1 +/- 93.3 pg./ml. (p = 0.007). Pretreatment with 0.4% sodium hyaluronate in 9 rats reduced mean IL-6 17% compared with stressed controls but again prevented any increase from baseline, since the value was 898.6 +/- 299.3 before and 824.4 +/- 196.4 pg./ml. after stress (p = 0.03). CONCLUSIONS: Immobilization stress induces bladder mast cell activation and the secretion of proinflammatory mediators, which are inhibited by sodium hyaluronate. Intravesical sodium hyaluronate may be a useful therapeutic option for interstitial cystitis, especially in patients with bladder mastocytosis who have symptom exacerbation with stress.

Delayed inflammation in rat meninges: implications for migraine pathophysiology.

Nitric oxide (NO) has been implicated in migraine pathogenesis based on the delayed development of typical migraine headache 4-6 h after infusing the NO donor nitroglycerin [glyceryl trinitrate (GTN)] to migraineurs. Furthermore, inhibiting the synthesis of NO by treatment with a NO synthase (NOS) inhibitor attenuates spontaneous migraine headaches in 67% of subjects. Because NO has been linked to inflammation and cytokine expression, we investigated the delayed consequences of brief GTN infusion (30 min) on the development of meningeal inflammation in a rat model using doses relevant to the human model. We found dose-dependent Type II NOS [inducible NOS (iNOS)] mRNA upregulation in dura mater beginning at 2 h and an increase in the corresponding protein expression at 4, 6 and 10 h after infusion. Type II NOS immunoreactivity was expressed chiefly within resident meningeal macrophages. Consistent with development of a delayed inflammatory response, we detected induction of interleukin 1beta in dura mater at 2 and 6 h and increased interleukin 6 in dural macrophages and in rat cerebrospinal fluid at 6 h after GTN infusion. Myeloperoxidase-positive cells were rarely found. Leakage of plasma proteins from dural blood vessels was first detected 4 h after GTN infusion, and this was suppressed by administering a specific Type II NOS inhibitor [L-N(6)-(1-iminoethyl)-lysine (L-NIL)]. In addition to cytokine induction, macrophage iNOS upregulation and oedema formation after GTN infusion, dural mast cells exhibited granular changes consistent with secretion at 4 and 6 h. Because iNOS was expressed in dural macrophages following topical GTN, and in the spleen after intravenous injection, the data suggest that the inflammatory response is mediated by direct actions on the dura and does not develop secondary to events within the brain. Our findings point to the importance of new gene expression and cytokine expression as fundamental to the delayed response following GTN infusion, and support the hypothesis that a similar response develops in human meninges after GTN challenge.

Chondroitin sulphate inhibits connective tissue mast cells.

1. Mast cells derive from the bone marrow and are responsible for the development of allergic and possibly inflammatory reactions. Mast cells are stimulated by immunoglobulin E (IgE) and specific antigen, but also by a number of neuropeptides such as neurotensin (NT), somatostatin or substance P (SP), to secrete numerous pro-inflammatory molecules that include histamine, cytokines and proteolytic enzymes. 2. Chondroitin sulphate, a major constituent of connective tissues and of mast cell secretory granules, had a dose-dependent inhibitory effect on rat peritoneal mast cell release of histamine induced by the mast cell secretagogue compound 48/80 (48/80). This inhibition was stronger than that of the clinically available mast cell 'stabilizer' disodium cromoglycate (cromolyn). Inhibition by chondroitin sulphate increased with the length of preincubation and persisted after the drug was washed off, while the effect of cromolyn was limited by rapid tachyphylaxis. 3. Immunologic stimulation of histamine secretion from rat connective tissue mast cells (CTMC) was also inhibited, but this effect was weaker in umbilical cord-derived human mast cells and was absent in rat basophilic leukemia (RBL) cells which are considered homologous to mucosal mast cells (MMC). Oligo- and monosaccharides were not as effective as the polysaccharides. 4. Inhibition, documented by light and electron microscopy, involved a decrease of intracellular calcium ion levels shown by confocal microscopy and image analysis. Autoradiography at the ultrastructural level showed that chondroitin sulphate was mostly associated with plasma and perigranular membranes. 5. Chondroitin sulphate appears to be a potent mast cell inhibitor of allergic and nonimmune stimulation with potential clinical implications.

Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis.

PURPOSE: Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory molecules in response to immunoglobulin E (IgE) and specific antigen. Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses. An example is interstitial cystitis, which is a sterile painful bladder disorder that has been associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells. Pentosanpolysulfate is a synthetic, sulfated polysaccharide that has been approved for the treatment of interstitial cystitis on the premise that it may replenish the defective glycosaminoglycan layer. We hypothesize that pentosanpolysulfate may also have an additional or alternate action on bladder mast cells. We report that pentosanpolysulfate has a powerful dose dependent inhibitory effect on mast cell release of histamine induced by the mast cell secretagogue compound 48/80. MATERIALS AND METHODS: Inhibition of mast cell secretion was documented by light and electron microscopy and extended to stimulation by substance P or IgE and antigen. RESULTS: The inhibition was more potent than that seen with the clinically available mast cell stabilizer disodium cromoglycate (cromolyn). Maximal inhibition by pentosanpolysulfate was apparent within 1 minute, was unaffected by the length of pre-incubation and persisted after the drug was washed off. In contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In addition, while cromolyn has no effect on mucosal or rat basophilic leukemia cells, pentosanpolysulfate inhibited histamine secretion from both. Confocal microscopy using a calcium indicator dye showed that pentosanpolysulfate decreased intracellular calcium ion levels. CONCLUSIONS: Pentosanpolysulfate appears to be a potent inhibitor of allergic and nonimmune mast cell stimulation, which is an alternative explanation of its benefit in interstitial cystitis.

Cloning and cellular localization of the rat mast cell 78-kDa protein phosphorylated in response to the mast cell "stabilizer" cromolyn.

Disodium cromoglycate (cromolyn) inhibits mast cell secretion, but its mechanism has not been elucidated. One possibility is the phosphorylation of a 78-kDa mast cell protein, two fragments of which are homologous to moesin, a member of the ezrin, radixin, moesin family. These proteins appear to be involved in signal transduction by regulating functional associations between the cell surface and the cytoskeleton. Moesin cDNA was cloned from rat basophil leukemia cells, which are similar to mucosal mast cells, and polyclonal antiserum was prepared against recombinant moesin expressed in Escherichia coli. Moesin phosphorylated in mast cells treated with cromolyn shifted from the soluble to the precipitable fraction and associated with Sepharose-linked beta-actin. Recombinant moesin also associated with Sepharose-linked beta-actin, and so did purified RBL moesin, but only if the latter was first denatured. Moesin thus appears to have actin binding sites that are not exposed under normal conditions but may become available by in vivo phosphorylation or by denaturation. Immunocytochemistry using confocal microscopy showed moesin to be primarily localized on the inner aspect of the plasma membrane and around secretory granules. Double immunocytochemistry for moesin and actin colocalized them in most areas. Ultracryoimmunoelectron microscopy to preserve the antigenicity of moesin identified the protein close to the plasma and secretory granule membranes. Cromolyn appeared to induce clustering of moesin around secretory granules. It is hypothesized that conformational changes of moesin, regulated by phosphorylation/dephosphorylation, may lead to positional rearrangements with respect to the membrane/cytoskeleton that could possibly regulate mast cell secretion.

Pathologic and clinical features influencing outcome of thin cutaneous melanoma: correlation with newly proposed staging system.

The incidence of malignant melanoma is increasing. Because of increased awareness, early recognition of malignant melanoma has become more common. In 1997, a new staging system for cutaneous melanoma was proposed, with reclassification of thin melanoma < 1 mm, with and without ulceration. This report evaluates the pathologic and clinical features of thin melanomas influencing recurrence and survival from a tertiary cancer center in an attempt to correlate findings with the proposed staging system. A review of the Roswell Park Cancer Institute tumor registry identified 352 patients with thin cutaneous melanomas (< 1.0 mm) seen during an 18-year period ending August 30, 1998. Overall survival was 93 and 87 per cent at 5 and 10 years, respectively. Disease-free survival was 94 and 93 per cent at 5 and 10 years, respectively. Local recurrence occurred in 3 per cent of patients, regional recurrence in 3 per cent, and metastatic disease in 3 per cent, for an overall recurrence of 7 per cent, with a median follow-up of 118 months. Only the presence of ulceration was a significant prognostic factor for recurrence by both univariate and multivariate analysis. Failure rates (any recurrence) by Clark levels I, II, and III/IV were 3, 5, and 10 per cent, respectively (P = 0.14). Failure rates by tumor thickness (mm), for 0.0-0.24, 0.25-0.49, 0.50-0.74, and 0.75-0.99 were 3, 4, 7, and 10 per cent, respectively (P = 0.49). Ten-year disease-free survival for ulceration versus no ulceration was 40 and 94 per cent, respectively (P < 0.0001). We conclude that thin cutaneous melanoma carries an excellent prognosis with appropriate treatment. Our findings support inclusion of ulceration in a new staging system. Lesions 0.76 to 0.99 mm and Clark level III and IV may warrant close observation as a separate subgroup.