CRS-HIPEC Prolongs Survival but is Not Curative for Patients with Peritoneal Carcinomatosis of Gastric Cancer.

PURPOSE: Peritoneal carcinomatosis (PC) is a dismal feature of gastric cancer that most often is treated by systemic palliative chemotherapy. In this retrospective matched pairs-analysis, we sought to establish whether specific patient subgroups alternatively should be offered a multimodal therapy concept, including cytoreductive surgery (CRS) and intraoperative hyperthermic chemotherapy (HIPEC). METHODS: Clinical outcomes of 38 consecutive patients treated with gastrectomy, CRS and HIPEC for advanced gastric cancer with PC were compared to patients treated by palliative management (with and without gastrectomy) and to patients with advanced gastric cancer with no evidence of PC. Kaplan-Meier survival curves and multivariate Cox regression models were applied. RESULTS: Median survival time after gastrectomy was similar between patients receiving CRS-HIPEC and matched control patients operated for advanced gastric cancer without PC [18.1 months, confidence interval (CI) 10.1-26.0 vs. 21.8 months, CI 8.0-35.5 months], resulting in comparable 5-year survival (11.9 vs. 12.1 %). The median survival time after first diagnosis of PC for gastric cancer was 17.2 months (CI 10.1-24.2 months) in the CRS-HIPEC group compared with 11.0 months (CI 7.4-14.6 months) for those treated by gastrectomy and chemotherapy alone, resulting in a twofold increase of 2-year survival (35.8 vs. 16.9 %). CONCLUSIONS: We provide retrospective evidence that multimodal treatment with gastrectomy, CRS, and HIPEC is associated with improved survival for patients with PC of advanced gastric cancer compared with gastrectomy and palliative chemotherapy alone. We also show that patients treated with CRS-HIPEC have comparable survival to matched control patients without PC. However, regardless of treatment scheme, all patients subsequently recur and die of disease.

Prognosis according to histochemical analysis of liver metastases removed at liver resection.

BACKGROUND: Liver metastases occur in 40-50 per cent of patients with colorectal cancer and determine long-term survival. The aim of this study was to examine the immunological architecture of colorectal liver metastases and its impact on patient survival. METHODS: Specimens from patients with colorectal liver metastases were stained with haematoxylin and eosin and Masson trichrome, immunostained for α-smooth muscle actin, CD4, CD45RO and CD8, and analysed by flow cytometry. In addition to histomorphological evaluation, immunohistochemically stained sections were analysed for cell numbers in the tumour area, infiltrative margin and distant liver stroma separately. These findings were correlated with clinical data and patient outcome. RESULTS: Tumour containment by a fibrotic capsule around liver metastases was observed in 37·8 per cent of 201 patients and was prognostic for improved survival (median (s.e.) survival 64 (6) and 31 (4) months for patients with capsule and no capsule respectively; P < 0·001) and independently led to higher R0 resection rates (P = 0·040). In multivariable analysis, CD45RO(+) cell infiltration at the peritumoral margin with low CD45RO(+) cell infiltration in the distant liver stroma (P = 0·001) and fibrotic capsule formation (P = 0·008) both independently prolonged patient survival. Using these two factors, a cellular immune score was designed and shown to stratify patient survival in test and validation samples (both P < 0·001). CONCLUSION: Fibrotic capsule formation and localized cell infiltration of colorectal liver metastases by CD45RO(+) cells were related to prolonged patient survival. Based on these immunological criteria a cellular immune score was developed to stratify patients according to prognosis.

The role of dendritic cells in the gastrointestinal field effect.

INTRODUCTION: Intestinal manipulation leads to local bowel wall inflammation that subsequently spreads over the entire gastrointestinal tract. Previously, this gastrointestinal field effect had been demonstrated by us in a rodent model. We herein postulated an immunologic mechanism mediated by activated leukocytes. The aim of this study was to investigate the activation, maturation and migration of dendritic cells (DC) of the intestinal smooth muscle following surgical trauma and i.p. lipopolysaccharide challenge. METHODS: Mice underwent standardized intestinal manipulation or iP LPS administration and tissues (intestinal muscularis, Peyer's patches, mesenteric lymph nodes, and spleen) were obtained at various times after manipulation. DC were isolated by tissue digestion and separated by CD11c-iMAG. The harvested DC were analyzed by FACS. The activation pattern of DC was analyzed by polymerase chain reaction. RESULTS: We found a significant increase in DC within the intestinal muscularis, the Peyer's patches and the mesenteric lymph nodes at 6 and 12 hours following intestinal manipulation and injection of LPS. There was an upregulation of the costimulatory molecules major histocompatibility complex II, CD40, CD80, CD86, and CD205 in the DC after intestinal manipulation. CCR-2, CCR-5, CCR-7, CCL-19, and interleukin-12a were upregulated in a time- and tissue-dependent manner. CONCLUSION: Intestinal manipulation or LPS challenge induced a recruitment of DC into the muscularis externa and mesenteric lymph nodes combined with an upregulation of costimulatory immunocompetent molecules and migratory surface markers in DCs. These findings demonstrate a precondition for an immunologic response and a possible immunologically mediated gastrointestinal field effect.

Inhibition of alfentanil metabolism by erythromycin.

To investigate a possible connection between erythromycin administration and reduced elimination of alfentanil, a controlled crossover study of alfentanil pharmacokinetics was undertaken. Six subjects were monitored for alfentanil plasma levels for 8 hours after alfentanil was administered. These measurements were obtained after a 0-, 1-, and 7-day course of erythromycin. Elimination half-life increased significantly (p less than 0.01) after 7 days from the control value of 84.0 +/- 8.2 minutes to 131.4 +/- 43.5 minutes. Clearance was decreased significantly (p less than 0.05) from 3.9 +/- 0.8 ml/kg/min to 2.9 +/- 1.2 ml/kg/min after 7 days. Values after 1 day were intermediate. Distribution volume did not change significantly. Subjects differed sharply in their sensitivity to erythromycin. Because of the interaction between erythromycin and alfentanil, we recommend that patients who are receiving erythromycin should be given alfentanil in reduced amounts or should avoid the drug completely.

Use of plastome and nuclear mutants of higher plants to study the genetic control of plastid formation and function.

We conducted comparative biochemical and electron-microscopic studies of several types of plastome and nuclear mutants of Antirrhinum majus and Pelargonium zonale. It was shown that specific blocking of the photosynthetic reaction occurs in plastome mutants of A. majus; Photosystem II was found to be damaged in the en:alba-1 mutant and photo-system I was affected in the en:viridis-1 mutant. The plastid mutations in these mutants caused loss of certain soluble lamellar proteins and pigment--protein complexes or a reduction in their content, which led to disappearance of photosynthetic activity. When the content of high-molecular ribosomal RNA in the leaves of normal and mutant P. zonale plants was compared, the normal plants were found to have four types of RNA: two types of cytoplasmic-ribosome RNA and two types of plastid-ribosome RNA. No plastid-ribosome RNA was detected in the mutant. These results were confirmed by electron-microscopic examination: no ribosomes were detected in the mutant plastids. Thus, use of plastome mutants made it possible to establish that the genetic information concentrated in the plastid DNA controls formation of ribosomes and lamellae in the chloroplasts and thus affects chloroplast photosynthetic function.

Time-course of respiratory depression after an alfentanil infusion-based anesthetic.

Postoperative respiratory depression after alfentanil administration has been described in several case reports. The effects of a prolonged alfentanil infusion on the CO2 response curve or cognitive function have not been studied. Twenty-one ASA physical status I or II patients were studied after a prolonged alfentanil infusion (> 90 min) to determine the incidence of postoperative respiratory depression, arterial O2 desaturation, and impairment of cognitive function. Each patient's recovery was observed at 30-min intervals for evidence of respiratory depression (utilizing the Read CO2 rebreathing method), desaturation by pulse oximetry (severe desaturation defined as arterial O2 saturation < 90%), and cognitive function (utilizing Trieger dot and digit substitution tests). Plasma samples were also examined for secondary elevations in alfentanil plasma concentrations. Significant depression of the CO2 response curve and cognitive function was found up to 1 h postoperatively. Arterial O2 desaturation was seen in 11 of 21 patients (52%). No correlation was found between arterial O2 desaturation and cognitive function scores or CO2 rebreathing results. Increased depression of the CO2 response curve was not necessarily associated with severe desaturation episodes. A secondary increase in plasma alfentanil concentration was detected in 5 of the 21 patients (24%), but these patients did not experience further depression of the CO2 response curve. We conclude that prolonged alfentanil administration may result in severe arterial O2 desaturation with significant depression of the hypercapnic respiratory drive during the first hour in the postanesthesia care unit, even though the majority of our patients were easily aroused in response to verbal stimuli.

Treatment of postoperative nausea and vomiting with single intravenous doses of dolasetron mesylate: a multicenter trial. Dolasetron Mesylate PONV Treatment Study Group.

UNLABELLED: This study was conducted to determine the efficacy and safety of four intravenous (I.V.) doses of dolasetron, an investigational 5-HT3 receptor antagonist, for the treatment of postoperative nausea and/or vomiting (PONV) after outpatient surgery under general anesthesia. This multicenter, randomized, double-blind trial compared the antiemetic efficacy of 12.5, 25, 50, or 100 mg I.V. dolasetron with placebo over 24 h using complete response (no emetic episodes and no rescue medication), time to first emetic episode or rescue medication, and patient nausea and satisfaction with antiemetic therapy as rated by visual analog scale (VAS). Of 1557 patients enrolled, 620 patients were eligible for treatment. Complete response rates for all dolasetron doses--12.5 mg (35%), 25 mg (28%), 50 mg (29%), and 100 mg (29%)--were significantly more effective than placebo (11%, P < 0.05). There was a significant gender interaction for complete response (P < 0.01). Of the patients in the 25-mg and 100-mg dose groups, 12% and 13%, respectively, experienced no nausea (VAS score < 5 mm) versus 5% in the placebo group (P < 0.05). There were no clinically relevant changes in vital signs or laboratory values and no trends with dose for adverse events. Dolasetron is effective for treating PONV and has an adverse event profile similar to that of placebo. The 12.5-mg dose was as effective as larger doses for complete response. IMPLICATIONS: Nausea and vomiting are common problems for postsurgical patients. In this study of 620 patients undergoing surgery, a 12.5-mg dose of intravenous dolasetron, a new serotonin-receptor blocker, was significantly more effective than placebo in treating established postoperative nausea and vomiting. Dolasetron 12.5 mg was as safe as placebo.