Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns.

BACKGROUND: After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication. METHODS: From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes. RESULTS: The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3+ T cell infiltration, a phenotype associated with a short median RFS of 7.9 months. CONCLUSIONS: Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence.

Effect of intraoperative hypovolemic phlebotomy on transfusion and clinical outcomes in patients undergoing hepatectomy: a retrospective cohort study.

BACKGROUND: There is no consensus on how to best achieve a low central venous pressure during hepatectomy for the purpose of reducing blood loss and red blood cell (RBC) transfusions. We analyzed the associations between intraoperative hypovolemic phlebotomy (IOHP), transfusions, and postoperative outcomes in cancer patients undergoing hepatectomy. METHODS: Using surgical and transfusion databases of patients who underwent hepatectomy for cancer at one institution (11 January 2011 to 22 June 2017), we retrospectively analyzed associations between IOHP and RBC transfusion on the day of surgery (primary outcome), and with total perioperative transfusions, intraoperative blood loss, and postoperative complications (secondary outcomes). We fitted logistic regression models by inverse probability of treatment weighting to adjust for confounders and reported adjusted odds ratio (aOR). RESULTS: There were 522 instances of IOHP performed during 683 hepatectomies, with a mean (standard deviation) volume of 396 (119) mL. The IOHP patients had a 6.9% transfusion risk on the day of surgery compared with 12.4% in non-IOHP patients (aOR, 0.53; 95% confidence interval [CI], 0.29 to 0.98; P = 0.04). Total perioperative RBC transfusion tended to be lower in IOHP patients compared with non-IOHP patients (14.9% vs 22.4%, respectively; aOR, 0.72; 95% CI, 0.44 to 1.16; P = 0.18). In patients with a predicted risk of ≥ 47.5% perioperative RBC transfusion, 24.6% were transfused when IOHP was used compared with 56.5% without IOHP. The incidence of severe postoperative complications (Clavien-Dindo scores ≥ 3) was similar in patients whether or not IOHP was performed (15% vs 16% respectively; aOR, 0.97; 95% CI, 0.53 to 1.54; P = 0.71). CONCLUSIONS: The use of IOHP during hepatectomy was associated with less RBCs transfused on the same day of surgery. Trials comparing IOHP with other techniques to reduce blood loss and transfusion are needed in liver surgery.

RéSUMé: CONTEXTE: Il n'existe pas de consensus quant à la meilleure façon d'obtenir une pression veineuse centrale basse pendant une hépatectomie dans le but de réduire les pertes et les transfusions sanguines. Nous avons analysé les associations entre la phlébotomie hypovolémique peropératoire, les transfusions, et les résultats cliniques postopératoires chez les patients qui subissent une hépatectomie pour cancer. MéTHODE: À l'aide de bases de données chirurgicales et transfusionnelles de patients ayant subi une hépatectomie pour cancer dans un seul établissement (du 11 janvier 2011 au 22 juin 2017), nous avons rétrospectivement analysé les associations entre la phlébotomie hypovolémique peropératoire et les transfusions érythrocytaires le jour de la chirurgie (critère d'évaluation principal) et avec les transfusions périopératoires totales, les pertes sanguines peropératoires, et les complications postopératoires (critères d'évaluation secondaires). Nous avons utilisé des modèles de régression logistique avec pondération de probabilité inverse de traitement afin de tenir compte des facteurs de confusion et rapporté les rapports de cotes ajustés (RCa). RéSULTATS: Il y a eu 522 phlébotomies hypovolémiques peropératoires exécutées au cours de 683 hépatectomies, avec un volume moyen (écart type) de 396 (119) mL. Les patients ayant eu une phlébotomie hypovolémique peropératoire avaient un risque transfusionnel de 6,9 % le jour de la chirurgie, comparativement à 12,4 % pour les patients sans phlébotomie (RCa, 0,53; intervalle de confiance [IC] de 95 %, 0,29 à 0,98; P = 0,04). Les transfusions périopératoires totales d'érythrocytes tendaient à être moins fréquentes chez les patients ayant subi une phlébotomie hypovolémique peropératoire par rapport aux patients sans phlébotomie (14,9 % vs 22,4 %, respectivement; RCa, 0,72; IC 95 %, 0,44 à 1,16; P = 0,18). Pour les patients présentant un risque prédit de transfusion périopératoire d'érythrocytes ≥ à 47,5 %, 24,6 % de ceux qui ont eu une phlébotomie hypovolémique peropératoire ont été transfusés, comparativement à 56,5 % sans phlébotomie. L'incidence des complications postopératoires graves (scores de Clavien-Dindo ≥ 3) était semblable chez tous les patients, avec ou sans phlébotomie hypovolémique peropératoire (15 % vs 16 % respectivement; RCa, 0,97; IC 95 %, 0,53 à 1,54; P = 0,71). CONCLUSIONS: L'utilisation de la phlébotomie hypovolémique peropératoire pendant une hépatectomie était associée à un moins grand nombre de transfusions érythrocytaires le jour de la chirurgie. Des études qui compareront la phlébotomie hypovolémique peropératoire à d'autres techniques visant à réduire les pertes et les transfusions sanguines sont nécessaires en chirurgie hépatique.

Trigeminal nerve stimulation triggers oral mast cell activation and vascular permeability.

BACKGROUND: The nervous system contributes to the pathophysiology of allergic and inflammatory diseases, including oral inflammation. Mast cells (MCs) are involved in their pathogenesis through proinflammatory mediator release. OBJECTIVE: To investigate the effect of trigeminal nerve (TN) stimulation compared with sham operation on MC activation and oral vascular permeability in the gingiva, palate, buccal mucosa, and tongue of the rat and to examine the possible role of substance P using rats treated with capsaicin as neonates to deplete substance P. METHODS: Six male Sprague-Dawley rats (250 g) were anesthetized and injected intravenously with Evans Blue (EB). Six other rats were injected neonatally with capsaicin (n = 3) or solvent (n = 3) and then injected with EB when they reached 250 g. The mandibular branch of the TN was stimulated for 1 minute (n = 3), and the remaining rats (n = 3) were subjected to sham operation. The ipsilateral and contralateral sides of the mouth were examined for EB extravasation, and tissue sections were removed for light and electron microscopy. RESULTS: TN stimulation resulted in EB extravasation in the ipsilateral side compared with the contralateral side or the ipsilateral side of sham-operated rats. Significant degranulation of MCs also was evident only on the ipsilateral side (P < .0001). There was no difference in MC degranulation between the vehicle- and capsaicin-treated rats, implying that neuropeptides other than substance P may be involved. CONCLUSION: This is the first time that TN stimulation has been shown to result in MC activation and oral vascular permeability, suggesting that MC inhibitors may be used for the treatment of oral inflammatory diseases.

Homogeneity in immune features between colorectal liver metastases better identifies patients with good prognosis compared to pathological response to preoperative chemotherapy.

In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3+ T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months, p = .0018) and disease-specific survival (DSS) (not reached vs. 48 months, p = .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.

Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study.

BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. FUNDING: Pfizer.

Is intra-operative ultrasound still useful for the detection of a hepatic tumour in the era of modern pre-operative imaging?

BACKGROUND: The current role of intra-operative ultrasound (IOUS) is questioned because of recent progress in medical imaging. The aim of the present study was to determine the accuracy of IOUS in the detection of a hepatic tumour (HT) compared with a pre-operative multi-detector computed tomography (MDCT) scan and magnetic resonance imaging (MRI). METHODS: This retrospective study included 418 patients evaluated using an 8-slice MDCT scan (SCAN8), 64-slice MDCT scan (SCAN64) and MRI alone or combined with a computed tomography (CT) scan. The pathological result was used as a gold standard. RESULTS: Correlation rates for the number of detected lesions compared with pathology results were 0.627 for SCAN8, 0.785 for SCAN64, 0.657 for MRI and 0.913 for IOUS. Compared with pathology, the rate of concordance was significantly higher with IOUS (0.871) than with SCAN8 (0.736; P=0.011), SCAN64 (0.792; P<0.001) and MRI (0.742; P<0.001). IOUS was responsible for a change in operative strategy in 16.5% of patients. Surgery was extended in 12.4%, limited in 1.7% and abandoned in 2.4%. CONCLUSIONS: Compared with cross-sectional pre-operative imaging, IOUS is still superior for the detection of HT and the planning of surgery. IOUS remains recommended as a routine procedure in patients having a hepatic resection in the era of modern pre-operative imaging.

Outcomes of Older Patients with Resectable Colorectal Liver Metastases Cancer (CRLM): Single Center Experience.

Surgery is the only potential curative option of CRLM if resectable. The curative approach in patients over 70 years old is challenging mainly because of comorbidities and other geriatric syndromes. Herein, we report outcomes of older patients with resectable CRLM in our center. We retrospectively analyzed characteristics and outcomes of older patients with CRLM operated at "Centre Hospitalier de l'Université de Montréal" (CHUM) between 2010 and 2019. We identified 210 patients aged ≥70 years with a median age of 76 (range: 70-85). CRLM were synchronous in 56% of patients. Median disease-free survival (DFS) was 41.3 months. Median overall survival (OS) was 62.2 months and estimated 5-year survival rate was 51.5% similar to those of younger counterparts. Patients with metachronous CRLM had a trend to a higher OS compared to those with synchronous disease (67.2 vs. 58.7 months; p = 0.42). Factors associated with lower survival in the multivariate analysis were right-sided tumors and increased Charlson Comorbidity index (CCI). Survival outcomes of patients aged ≥70 years were comparable to those of younger patients and those reported in the literature. Age should not be a limiting factor in the curative management of older patients with resectable CRLM.

Prognostic value of CD73 expression in resected colorectal cancer liver metastasis.

Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.

Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study.

BACKGROUND: Axitinib (AG-013736) is a potent and selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, which have an important role in pancreatic cancer. The aim of this study was to assess the safety and efficacy of gemcitabine plus axitinib versus gemcitabine alone. METHODS: Between January and August, 2006, 103 patients with unresectable, locally advanced, or metastatic pancreatic cancer were randomly assigned in a two to one ratio to receive gemcitabine (1000 mg/m(2)) plus axitinib 5 mg twice daily (n=69) or gemcitabine (1000 mg/m(2)) alone (n=34) by a centralised registration system. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00219557. FINDINGS: All randomised patients were included in the efficacy analyses. Median overall survival was longer with gemcitabine plus axitinib than with gemcitabine alone (6.9 [95% CI 5.3-10.1] months vs 5.6 [3.9-8.8] months). The hazard ratio for survival with gemcitabine plus axitinib versus with gemcitabine alone, adjusted for stratification factors, was 0.71 (95% CI 0.44-1.13). The most common grade 3 or worse adverse events were fatigue (15 [22%] patients in the gemcitabine plus axitinib group vs one [3%] in the gemcitabine alone group), abdominal pain (eight [12%] vs five [16%]), and asthenia (eight [12%] vs one [3%]). INTERPRETATION: Gemcitabine plus axitinib showed a similar safety profile to gemcitabine alone; the small, non-statistically significant gain in overall survival needs to be assessed in a randomised phase III trial.

When a Drain is the Culprit: An Unexpected Case of Small Bowel Obstruction with Biliary Peritonitis.

Although postoperative abdominal drains are useful in therapeutic settings, their prophylactic role is debatable. We herein describe the case of a 30-year-old male who underwent bile duct resection with hepaticojejunostomy for cholangiocarcinoma. On postoperative day four, the patient developed biliary peritonitis. Explorative laparotomy revealed an obstruction of the afferent limb caused by an intestinal loop around a Jackson-Pratt (JP) drain. Removal of the drain resolved the obstruction which led to a significant improvement of the patient's clinical state. To the best of our knowledge, this is the second report of a bowel obstruction from a surgical drain. When placing abdominal drains, surgeons must take into consideration their indication as well as possible related complications, including intestinal obstruction.

Portal vein embolization does not affect the long-term survival and risk of cancer recurrence among colorectal liver metastases patients: A prospective cohort study.

BACKGROUND: Previous studies comparing the survival outcomes of liver resections with and without preoperative portal vein embolization (PVE) for colorectal liver metastases (CLM) have linked PVE to higher rate of tumor progression, lower overall survival (OS) and lower disease-free survival (DFS). The lack of adjusted models to compare these outcomes is a limitation of these studies since patients requiring PVE may differ significantly from the ones receiving upfront surgery. MATERIALS AND METHODS: Prospective cohort study of 128 patients undergoing CLM resection. The OS analysis followed an intent-to-treat (ITT) approach. The adjusted impact of PVE on OS and DFS was evaluated using multivariate Cox regression models. RESULTS: Seventy-one patients underwent PVE before attempting a liver resection while 57 received upfront surgery (NoPVE). All NoPVE patients were resected while 14 PVE participants (19.7%) were not operated (tumor progression = 9/14). PVE patients had a significantly higher preoperative lesions count (3 [1.75-4] vs 1 [1-2.5]; p < 0.001), a higher prevalence of bilateral metastases (23.5% vs 8.8, p = 0.028) and a higher count of neo-adjuvant chemotherapy cycles compared to NoPVE patients. The OS of PVE patients was similar to NoPVE participants (44.7 months [26.9-69.5] vs 49.0 [24.9-64.8], p = 0.761). The DFS of resected PVE patients was higher than NoPVE patients (33.2 months [10.7-54.6] vs 23.4 months [14.1-58.1], p = 0.991). In the adjusted models, preoperative lesions count was the only significant predictor of overall mortality (HR+IC95 = 1.06 (1.02-1.11) p = 0.005) and cancer recurrence (HR+IC95 = 1.14 (1.03-1.27) p = 0.012). CONCLUSION: In the context of CLM, patients requiring PVE differ significantly from patients receiving upfront surgery. This confirms the need for adjusted models when comparing the clinical outcomes of both groups. Our adjusted analysis suggests that PVE is not a significant predictor of a lower OS or DFS. PVE allowed the resection of 80% of participants with initially unresectable CLM. INSTITUTIONAL PROTOCOL NUMBER: 12.106 STUDY REGISTRATION NUMBER: NCT03168230.

Transjugular intrahepatic portosystemic shunt before abdominal surgery in cirrhotic patients: a retrospective, comparative study.

Surgery in cirrhotic patients is associated with high morbidity and mortality related to portal hypertension and liver insufficiency. Therefore, preoperative portal decompression is a logical approach to facilitate abdominal surgery and hopefully to improve postoperative survival. The present study evaluated the clinical outcomes of 18 patients (mean age 58 years) with cirrhosis (seven alcoholics and 11 nonalcoholics) who underwent transjugular intrahepatic portosystemic shunt (TIPS) placement before antrectomy (n=5), colectomy (n=10), small-bowel resection (n=1), pancreatectomy (n=1) and nephrectomy (n=1). TIPS was performed a mean (+/-SD) of 72+/-21 days before surgery and induced a marked mean decrease in portohepatic gradient from 21.4+/-3.9 mmHg to 8.4+/-3.4 mmHg. Cirrhotic patients (n=17) who underwent elective abdominal surgery without preoperative TIPS placement were used as the control group. Both groups were matched for age, etiology of cirrhosis, indications for surgery, type of surgery and coagulation parameters. The mean Pugh score was significantly higher in the TIPS group (7.7 versus 6.2). No significant differences were observed for operative blood loss, postoperative complications, duration of hospitalization and one-month (83% versus 88%) or one-year (54% versus 63%) cumulative survival rate. Analysis using the Cox proportional hazards model showed that neither TIPS placement nor preoperative Pugh score were independent predictors for survival. The present study suggests that preoperative TIPS placement does not improve postoperative evolution after abdominal surgery in cirrhotic patients with good or moderately impaired liver function.

nab-Paclitaxel Plus Gemcitabine Versus Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma: Canadian Subgroup Analysis of the Phase 3 MPACT Trial.

INTRODUCTION: The phase III MPACT trial in patients with metastatic pancreatic cancer (MPC) demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) compared with Gem monotherapy, including the primary endpoint of overall survival (OS; median 8.7 vs. 6.6 months; hazard ratio [HR] 0.72; P < 0.001). A significant treatment difference favoring nab-P + Gem over Gem was observed for OS in patients treated in North America. The majority of patients were from the US (88%) with only 12% from Canada. Healthcare systems and treatment patterns are different between the 2 countries, and there is limited published information on outcomes of Canadian patients treated with first-line nab-P + Gem. This analysis evaluated efficacy and safety outcomes in Canadian patients in the MPACT trial. METHODS: Treatment-naive patients with MPC (N = 861) received either nab-P 125 mg/m(2) + Gem 1000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle ≥2). RESULTS: The MPACT trial enrolled 63 patients in Canada. Baseline characteristics were well balanced and comparable with those of the intent-to-treat population. Both OS (median 11.9 vs. 7.1 months; HR 0.76; P = 0.373) and progression-free survival (median 7.2 vs. 5.2 months; HR 0.65; P = 0.224) were numerically longer and overall response rate (27% vs. 17%; P = 0.312) was numerically higher with nab-P + Gem vs. Gem. The most common grade ≥3 adverse events with nab-P + Gem vs. Gem were neutropenia (22% vs. 10%), fatigue (34% vs. 33%), and neuropathy (25% vs. 0%). CONCLUSION: This subanalysis confirmed that nab-P + Gem is an efficacious treatment option and has a manageable safety profile in patients with MPC treated in Canada. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00844649. FUNDING: Celgene Corporation, Summit, NJ, USA.

Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in Apolipoprotein E knockout mice.

OBJECTIVES: Cardiac mast cells have recently been found to be activated in atherosclerotic coronary arteries, but no mediator has so far been documented to be released from them, nor have they been investigated in Apolipoprotein (Apo) E knockout (k/o) mice that develop atherosclerosis. Psychological stress triggers acute coronary syndrome, while acute restraint stress stimulates rat cardiac mast cells, the main mediator of which histamine is a coronary constrictor. Here, we investigated the effect of acute stress on the activation of cardiac mast cells morphologically, as well as the levels of cardiac and serum histamine in normal and genetically deficient mice. METHODS: Male, 8-14 week-old ApoE k/o mice and their corresponding control C57BL/6J mice were used. Significant reduction of cardiac histamine from 396.7+/-45.6 to 214.6+/-41.5 ng/g was observed over 120 min restraint stress with a corresponding increase in serum histamine from 126.9+/-4.0 to 188.4+/-17.3 ng/ml in C57BL mice. Cardiac mast cell activation was observed by light and electron microscopy. Both basal cardiac and serum histamine in ApoE k/o mice was significantly higher than that in C57BL mice. Although the extent of mast cell activation in ApoE k/o mice was similar to that of C57BL mice, the number of cardiac mast cells in ApoE k/o mice was 37% higher. Histamine levels were hardly detectable with or without stress in W/W(v) mast cell deficient mice. CONCLUSIONS: Acute restraint stress triggered cardiac histamine release in mice that was clearly derived from mast cells, as it was absent in W/W(v) mice. The high basal cardiac and serum histamine in ApoE k/o mice, along with the high number of cardiac mast cells, suggest possible ongoing cardiac mast cell activation that may participate in atherosclerosis. These results may possibly help better understand stress-related cardiovascular pathology.

IL-10, an inflammatory/inhibitory cytokine, but not always.

IL-10 has been previously called cytokine synthesis inhibiting factor, produced mostly by Th2 cells, macrophages and CD8+ cell clones. IL-10 is capable of inhibiting the synthesis of several cytokines from different cells, antigen or mitogen activated. IL-10 exerts its inhibition at the mRNA transcriptional and translational level. In addition, IL-10 is a co-stimulatory cytokine on activated T cells. For example, IL-10 inhibits NK cell activity, the production of Th1 cytokines, cytokines generated by peripheral blood mononuclear cells, and macrophage activity. On the other hand, IL-10 exerts immunostimulatory effects on B cells, cytotoxic T cell development and thymocytes. In mast cells derived from CD4+/CD133+ cells, IL-10 inhibits IL-6 and TNFalpha, and prostaglandin E(1) and E(2) induced by IL-6. Here, we report for the first time that IL-10 fails to inhibit tryptase and IL-6 from human mast cell-1 (HMC-1) and human umbilical cord blood-derived mast cells.

Corticotropin-releasing factor (CRF) can directly affect brain microvessel endothelial cells.

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis through release of corticotropin releasing factor (CRF), leading to production of glucocorticoids that down regulate immune responses. However, acute stress via CRF also has pro-inflammatory effects. We previously showed that acute stress increases rat blood-brain barrier (BBB) permeability, an effect involving brain mast cells and CRF, as it was absent in W/W(v) mast cell-deficient mice and was blocked by the CRF-receptor antagonist, Antalarmin. We investigated if CRF could also have a direct action on brain microvessel endothelial cells (BMEC) isolated from rat and bovine brain. BMEC were cultured and identified by electron microscopy. Western blot analysis of cultured BMEC identified CRF receptor protein; stimulation with CRF, or it structural analogue urocortin (Ucn) showed that the receptor is functionally coupled to adenylate cyclase as it increased cyclic AMP (cAMP) levels by 2-fold. These findings suggest that CRF could affect BMEC structure or function, as reported for increased cAMP levels by other studies. It is, therefore, possible that CRF may directly regulate BBB permeability, in addition to any effect mediated via brain mast cells.

Hypertrophy of the non-embolized liver after chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NC(+)) and portal vein embolization (PVE) enables curative resection in more patients with colorectal-liver metastases (CRLM). However, after NC(+), structural alterations have been reported with the risk of post-operative hepatic failure. We undertook to determine if NC(+) toxicity limits future remnant liver (FRL) hypertrophy after PVE. METHODS: PVE was performed in 20 patients, 13 (65%) of whom previously received a mean FOLFIRI (5-fluorouracil + leucovorin + irinotecan) regimen (NC(+)) of 6.6 cycles. The seven remaining patients served as the control group without NC (NC(-)). RESULTS: CRLM were bilateral in 69% (NC(+)) and 57% (NC(-)), and synchronous in 84% (NC(+)) and 14% (NC(-)). The FRL hypertrophy rate was 54.1% (NC(+)) and 43.7% (NC(-)) (P= 0.3). CRLM were unresectable in four of our 20 patients, i.e. group NC(+): one insufficient FRL hypertrophy and one severe steatosis; and group NC(-): two tumoral progressions. In both groups, the operative parameters were comparable except for pedicular clamping: 8 (NC(+)) and 36 min (NC(-)), respectively (P < 0.05). Also, the surgical outcome rate and hospital stay were comparable. No significant pathological difference was observed between the two groups. No mortality occurred in either group. CONCLUSION: In view of our limited experience, we conclude that hypertrophy of the non-embolized liver (FRL) is not altered after FOLFIRI-based NC.

Reuse of liver graft from a brain dead recipient.

BACKGROUND: Brain death in fulminant hepatic failure (FHF) is a rare occurrence after successful orthotopic liver transplantation (OLT). Reuse of the liver graft may be considered. We report a successful OLT using such an organ in a 62-yr-old man with hematochromatosis-related cirrhosis and hepatocellular carcinoma. METHODS: Liver donor was 56-yr-old man with normal liver function tests. First recipient was a 26-yr-old woman with an acetaminophen-induced FHF. Before OLT, she developed progressive coma without obvious cerebral edema on the cerebral CT-scan. The transplantation proceeded as planned and was uneventful. However, patient exhibited bilateral non-reactive mydriasis during postoperative hours and was declared brain dead. Transplanted liver was functioning adequately. Its reuse was discussed with her family and the second recipient. After informed consent, the transplanted liver and heart were harvested. First and second liver cold ischemia times were 10 h and 75 min, respectively. RESULTS: Second recipient recovered uneventful and discharged 23 d after OLT. Liver function is still normal 30 months after OLT without rejection or hepatocellular carcinoma recurrence. CONCLUSION: Even after OLT, brain death remains possible in FHF. In absence of contraindications, reuse of transplanted liver allows for a rational use of already rare liver grafts.