Role of Hyperthermic Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery as Consolidation Therapy for Advanced Epithelial Ovarian Cancer.

BACKGROUND: Patients with advanced epithelial ovarian cancer who undergo incomplete surgery followed by six cycles of chemotherapy could benefit from second-look or consolidation cytoreductive surgery (CCRS). The primary goal of this study was to evaluate the overall survival (OS) in patients undergoing complete CCRS and the factors affecting survival. The secondary goal was to study the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. METHODS: This was a retrospective analysis of 173 patients with CCRS with (n = 118) or without (n = 55) HIPEC treated at 12 French centers. Only patients having a completeness of cytoreduction (CC) 0/1 resection and a minimum of 5 years of follow-up were included. HIPEC was performed systematically for all patients except those treated at the four centers that did not perform HIPEC. RESULTS: The median Peritoneal Cancer Index was 6 (range 0-33). Closed HIPEC was performed in 59 (34.1%) patients and open HIPEC was performed in 56 (32.3%) patients. Grade 3-4 complications occurred in 64 (36.9%) patients. The median OS was 35.67 months (95% confidence interval [CI] 29.8-46.1) and was significantly longer for CCRS + HIPEC (31.4 months without HIPEC and 42.5 months with HIPEC; p = 0.022). On multivariate analysis, closed HIPEC (hazard ratio [HR] 0.46, 95% CI 0.29-0.73; p < 0.001) resulted in a longer OS, and age > 65 years (HR 2.17, 95% CI 1.14-4.11; p = 0.018) and bowel resection (HR 1.98, 95% CI 1.27-3.08; p = 0.020) led to a shorter OS. On multivariate logistic regression analysis, closed HIPEC (odds ratio 0.18; p = 0.001) was associated with a lower risk of dying at 5 years. CONCLUSIONS: CCRS was performed with an acceptable morbidity and resulted in good overall survival. The role of HIPEC in addition to CCRS should be evaluated in prospective, randomized studies and the closed technique prospectively compared with the open technique.

Genomic profile concordance between pancreatic cyst fluid and neoplastic tissue.

BACKGROUND: DNA mutational analysis of pancreatic cystic fluid (CF) is a useful adjunct to the evaluation of pancreatic cysts. KRAS/GNAS or RAF/PTPRD/CTNNB1/RNF43 mutations are highly specific to precancerous or advanced neoplasia. Several studies recently demonstrated the ability of next-generation sequencing (NGS) analysis to detect DNA mutations in pancreatic CF, but few studies have performed a systematic comparative analysis between pancreatic CF and neoplastic surgical tissue (NT). The value of CF-NGS analysis indicators for determining surgical resection necessitates evaluation. AIM: To confirm whether CF genomic profiles are a reliable malignancy predictor by comparing NGS mutational analyses of CF and NT. METHODS: Patients requiring surgery for high-risk pancreatic cysts were included in a multicenter prospective pilot study. DNA from CF (collected by endoscopic ultrasound-guided fine needle aspiration (known as EUS-FNA)) and NT (collected by surgery) were analyzed by NGS. The primary objective was to compare the mutation profiles of paired DNA samples. The secondary objective was to correlate the presence of specific mutations (KRAS/GNAS, RAF/ PTPRD/CTNNB1/RNF43/POLD1/TP53) with a final cancer diagnosis. Sensitivity and specificity were also evaluated. RESULTS: Between December 2016 and October 2017, 20 patients were included in this pilot study. Surgery was delayed for 3 patients. Concordant CF-NT genotypes were found in 15/17 paired DNA, with a higher proportion of mutated alleles in CF than in NT. NGS was possible for all pancreatic CF collected by EUS-FNA. In 2 cases, the presence of a KRAS/GNAS mutation was discordant between CF and NT. No mutations were found in 3 patients with NT or pancreatic cysts with high-grade dysplasia. The sensitivity and specificity of KRAS/GNAS mutations in CF to predict an appropriate indication for surgical resection were 0.78 and 0.62, respectively. The sensitivity and specificity of RAF/PTPRD/CTNNB1 /RNF43/POLD1/TP53 mutations in CF were 0.55 and 1.0, respectively. CONCLUSION: Mutational analyses of CF and NT were highly concordant, confirming the value of NGS analysis of CF in the preoperative malignancy assessment. However, these results need to be confirmed on a larger scale.

Survival and prognostic factors after adjuvant 131iodine-labeled lipiodol for hepatocellular carcinoma: a retrospective analysis of 106 patients over 20 years.

OBJECTIVE: Hepatocellular carcinoma (HCC) has high recurrence rate after curative treatment. The aim of the present study was to report our experience with adjuvant use of 131I-lipiodol after curative treatment of HCC in terms of recurrence and survival in a large cohort of patients with a long follow-up. METHODS: All patients treated with 131I-lipiodol after curative treatment of HCC in two French centers from 1991 to 2009 were included in a retrospective cohort study. RESULTS: One hundred and six patients were included. The median (range) follow-up was 6 years (0.3-22). Forty-three patients (41%) had cirrhosis. Recurrence-free survival rates at 1, 2, 5, 10, and 20 years were 73, 57, 40, 30, and 14%, respectively. Cirrhosis was an independent predictive factor of recurrence [RR = 1.18, 95% CI (1.11-3.02), p = 0.019]. Overall, survival rates at 1, 2, 5, 10, and 20 years were 90, 83, 59, 37, and 23%, respectively. Prognostic factors were recurrence [RR = 2.73, 95% CI (1.35-5.54); p = 0.005], age over 60 years (RR = 1.91, 95% CI [1.02-3.61]; p = 0.044), and tumor number over 3 [RR = 3.31, 95% CI (1.25-8.77); p = 0.016]. CONCLUSION: Our results suggest that the effect of 131I-lipiodol after curative treatment of HCC could be related to a beneficial impact on risk factors of early tumor recurrence. This could be evaluated in further studies using modern radioembolization methods.

Complete pathological response of unresectable liver metastases from colorectal cancer after trans-arterial chemoembolization with drug-eluting beads loaded with irinotecan (DEBIRI) and concomitant systemic FOLFOX: A case report from the FFCD 1201 trial.

INTRODUCTION: Most liver metastases from colorectal cancer (CRC) are unresectable at diagnosis. Systemic chemotherapy allows secondary surgical resection in 10 to 20% of patients. Hepatic intra-arterial treatments could enhance response and resection rate. We therefore designed a prospective phase II trial testing the transarterial chemoembolization (TACE) using drug-eluting beads loaded with irinotecan (DEBIRI) with concomitant systemic FOLFOX regimen, the FFCD 1201 trial, in patients with liver limited metastatic CRC. CASE REPORT: A 48-year old patient was operated from an occlusive sigmoid adenocarcinoma. Magnetic resonance imaging showed 6 bilobar liver metastasis. The patient was considered as non-eligible for surgery initially. Patient was included in the FFCD 1201 trial and received 5 cycles of FOLFOX and 2 sessions of DEBIRI, with a quite good tolerability. Post-treatment evaluation showed a partial response and sufficient tumor shrinkage to make liver metastasis resectable. Right hepatectomy associated with wedge resection in the left liver was performed and pathological findings showed a complete pathological response (CPR). CONCLUSION: Combination of DEBIRI with FOLFOX could increase tumor shrinkage leading to secondary resection of liver metastases from CRC. This combination may also, as shown here for the first time in a patient with unresectable LM, induce CPR of all LM, known to be associated with better outcome. Our case also emphasizes the difficulty to morphologically assess pathological response and the need for new tool to better select patients who should be resected. Further results of the FFCD 1201 trial will bring more information on this new combination therapy.

Territorial inequalities in management and conformity to clinical guidelines for sarcoma patients: an exhaustive population-based cohort analysis in the Rhône-Alpes region.

BACKGROUND: Sarcomas are rare cancers with great variability in clinical and histopathological presentation. The main objective of clinical practice guidelines (CPGs) is to standardize diagnosis and treatment. METHODS: From March 2005 to February 2007, all patients diagnosed with localized sarcoma in the Rhône-Alpes region were included in a cohort-based study, to evaluate the compliance of sarcoma management with French guidelines in routine practice and to identify predictive factors for compliance with CGPs. RESULTS: 634 (71 %) patients with localized sarcoma satisfying the inclusion criteria were included out of 891 newly diagnosed sarcomas. Taking into account initial diagnosis until follow-up, overall conformity to CPGs was only 40 % [95 % confidence interval (CI) = 36-44], ranging from 54 % for gastrointestinal stromal tumor to 36 % for soft tissue sarcoma and 42 % for bone sarcoma. In multivariate analysis, primary tumor type [relative risk (RR) = 4.42, 95 % CI = 2.79-6.99, p < 0.001], dedicated multidisciplinary staff before surgery (RR = 4.19, 95 % CI = 2.39-7.35, p < 0.001) and management in specialized hospitals (RR = 3.71, 95 % CI = 2.43-5.66, p < 0.001) were identified as unique independent risk factors for conformity to CPGs for overall treatment sequence. CONCLUSIONS: With only 40 % of total conformity to CPGs, the conclusions support the improvement of initial sarcoma management and its performance in specialized centres or within specialized dedicated networks.

Leukocyte-endothelial cell interaction is necessary for photodynamic therapy induced vascular permeabilization.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) affects vascular barrier function and thus increases vessel permeability. This phenomenon may be exploited to facilitate targeted drug delivery and may lead to a new clinical application of photodynamic therapy. Here, we investigate the role of leukocyte recruitment for PDT-induced vascular permeabilization. STUDY DESIGN/MATERIAL AND METHODS: Fluorescein isothiocyanate dextran (FITC-D, 2,000 kDa) was injected intravenously 120 minutes after focal PDT on striated muscle in nude mice bearing dorsal skinfold chambers (Visudyne® 800 µg/kg, fluence rate 300 mW/cm2 , light dose of 200 J/cm2). Leukocyte interaction with endothelial cells was inhibited by antibodies functionally blocking adhesion molecules ("MABS-PDT" group, n = 5); control animals had PDT but no antibody injection (group "PDT", n = 7). By intravital microscopy, we monitored leukocyte rolling and sticking in real-time before, 90 and 180 minutes after PDT. The extravasation of FITC-D from striated muscle vessels into the interstitial space was determined in vivo during 45 minutes to assess treatment-induced alterations of vascular permeability. RESULTS: PDT significantly increased the recruitment of leukocytes and enhanced the leakage of FITC-D. Neutralization of adhesion molecules before PDT suppressed the rolling of leukocytes along the venular endothelium and significantly reduced the extravasation of FITC-D as compared to control animals (156 ± 27 vs. 11 ± 2 (mean ± SEM, number of WBC/30 seconds mm vessel circumference; P < 0.05) at 90 minutes after PDT and 194 ± 21 vs. 14 ± 4 at 180 minutes after PDT). In contrast, leukocyte sticking was not downregulated by the antibody treatment. CONCLUSION: Leukocyte recruitment plays an essential role in the permeability-enhancing effect of PDT.

Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer.

In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4(+)CD123(+)BDCA2(+) pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1ß, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-ß. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4(+) T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance.

Automatic temperature control for MR-guided interstitial ultrasound ablation in liver using a percutaneous applicator: ex vivo and in vivo initial studies.

Image-guided thermal ablation offers minimally invasive options for treating hepatocellular carcinoma and colorectal metastases in liver. Here, the feasibility and the potential benefit of active temperature control for MR-guided percutaneous ultrasound ablation was investigated in pig liver. An MR-compatible interstitial ultrasound applicator (flat transducer), a positioning system with rotation-translation guiding frame, and an orbital ring holder were developed. Step-by-step rotated elementary lesions were produced, each being formed by directive heating of a flame-shaped volume of tissue. In vivo feasibility of automatic temperature control was investigated on two pigs. Proton Resonance Frequency Shift (PRFS)-based MR thermometry was performed on a 1.5-T clinical scanner, using SENSE acceleration and respiratory gating. MR follow-up of animals and macroscopic analysis were performed at 3 and, respectively, 4 days postprocedure. No sonication-related radiofrequency artifacts were detected on MR images. The temperature controller converged to the target elevation within +/-2 degrees C unless the requested power level exceeded the authorized limit. Large variability of the controller's applied powers from one sonication to another was found both ex vivo and in vivo, indicating highly anisotropic acoustic coupling and/or tissue response to identical beam pattern along different radial directions. The automatic control of the temperature enabled reproducible shape of lesions (15 +/- 2 mm radial depth).

Drug uptake in a rodent sarcoma model after intravenous injection or isolated lung perfusion of free/liposomal doxorubicin.

The distribution of free and liposomal doxorubicin (Liporubicin) administered by intravenous injection (IV) or isolated lung perfusion (ILP) was compared in normal and tumor tissues of sarcoma bearing rodent lungs. A single sarcomatous tumor was generated in the left lung of 35 Fischer rats, followed 10 days later by left-sided ILP (n=20) or IV drug administration (n=12), using 100 microg and 400 microg free or liposomal doxorubicin, respectively. The tumor and lung tissue drug concentration was measured by HPLC. Free doxorubicin administered by ILP resulted in a three-fold (100 microg) and 10-fold (400 microg) increase of the drug concentration in the tumor and normal lung tissue compared to IV administration. In contrast, ILP with Liporubicin resulted in a similar drug uptake in the tumor and lung tissue compared to IV injection. For both drug formulations and dosages, ILP resulted in a higher tumor to lung tissue drug ratio but also in a higher spatial heterogeneity of drug distribution within the lung compared to IV administration. ILP resulted in a higher tumor to lung tissue drug ratio and in a more heterogeneous drug distribution within the lung compared to IV drug administration.

Feasibility of using ultrasound contrast agents to increase the size of thermal lesions induced by non-focused transducers: in vitro demonstration in tissue mimicking phantom.

Miniature flat ultrasound transducers have shown to be effective for a large variety of thermal therapies, but the associated superficial heating implicates developing original strategies in order to extend therapeutic depth. The goal of the present paper is to use ultrasound contrast agents (UCA) to increase remote attenuation and heating. Theoretical simulations demonstrated that increasing attenuation from 0.27 to 0.8 Np/cm at 10 MHz beyond a distance of 18 mm from the transducer should result in longer thermal damages due to protein coagulation in a tissue mimicking phantom. Contrast agents (BR14, Bracco, Plan-les-Ouates, Switzerland) were embedded in thermo-sensitive gel and attenuations ranging from 0.27 to 1.33 Np/cm were measured at 10 MHz for concentrations of BR14 between 0 and 4.8%. Thermal damages were then induced in several gels, which had different layering configurations. Thermal damages, 12.8mm in length, were obtained in homogeneous gels. When mixing contrast agents at a concentration of 3.2% beyond a first 18 mm-thick layer of homogeneous gel, the thermal damages reached 21.5mm in length. This work demonstrated that contrast agents can be used for increasing attenuation remotely and extending therapeutic depth induced by a non-focused transducer. Additional work must be done in vivo in order to verify the remote-only distribution of bubbles and associated increase in attenuation.

Percutaneous sonographically guided interstitial US ablation: experimentation in an in vivo pig liver model.

PURPOSE: To test the feasibility and efficacy of a percutaneous sonographically guided high-intensity interstitial ultrasound (US) ablation applicator to create "macrolesions" of confluent coagulation in an in vivo pig liver model. MATERIALS AND METHODS: Eight pigs and an interstitial US ablation applicator were used for this study. Elementary lesions and macrolesions created by the confluence of several elementary lesions were successively analyzed. The first phase of the study was performed by varying the acoustic intensity (AI) to create elementary lesions. The second phase of the study aimed at creating macrolesions in three target zones previously defined in the liver. Mean (+/- SD) maximum and minimum diameters of the macrolesions were calculated. RESULTS: The elementary lesions created with AIs of 30, 40, and 55 W/cm(2) measured 14.9 mm +/- 3, 19.8 mm +/- 5, and 13.2 mm +/- 3, respectively. The AI retained for the second experimental phase was 40 W/cm(2). Because of the flamelike aspect of the elementary lesions, the macrolesion appeared as a cylinder with crenelated contours. On macroscopic examination, mean maximum diameters of the macrolesions were 28.7 mm +/- 3, 34.1 mm +/- 2, and 27.8 mm +/- 5 and mean minimum diameters of the macrolesions were 14 mm +/- 3, 18.7 mm +/- 2, and 14 mm +/- 3 for the three target zones, respectively. A single major complication, puncture of the gallbladder, occurred in one animal. CONCLUSIONS: A percutaneous sonographically guided interstitial ablation applicator is able to create macrolesions of coagulation in pig liver.

Mortality, complications and loss of pulmonary function after pneumonectomy vs. sleeve lobectomy in patients younger and older than 70 years.

Retrospective single institution analysis of all patients undergoing sleeve lobectomy or pneumonectomy between 2000 and 2005. Seventy-eight patients underwent pneumonectomy (65 patients <70 years, 13 patients >70 years) and 69 sleeve lobectomy (50 patients <70 years, 19 patients >70 years). Pre-existing co-morbidity, surgical indication and induction therapy was similarly distributed between treatment by age-groups. In patients <70 years, pneumonectomy and sleeve lobectomy resulted in a 30-day mortality of 3% vs. 0 and an overall complication rate of 26% vs. 44%, respectively. In patients >70 years, pneumonectomy and sleeve lobectomy resulted in a 30-day mortality of 15% vs. 0 and an overall complication rate of 23% vs. 32%. In both age groups, pneumonectomy was associated with more airway complications (NS) and a significantly higher postoperative loss of FEV(1) than sleeve lobectomy (P<0.0001, P<0.03). Age per se did not influence the loss of FEV(1) and DLCO for a given type of resection. Sleeve lobectomy may have a therapeutic advantage over pneumonectomy in the postoperative course of elderly patients.

Developing an interstitial ultrasound applicator for thermal ablation in liver: results of animal experiments.

BACKGROUND: In this project, an interstitial ultrasound applicator was developed for the treatment of primary and secondary cancers of the liver. Experiments on animals were used to check the destructive capabilities of this probe within the hepatic parenchyma of the pig in vivo, with a study of the physical parameters of the ultrasound treatment. In parallel, the possibility of visualizing the lesions induced by means of ultrasound imaging was also studied. MATERIALS AND METHODS: Thirteen pigs were used in this project, which had received the prior approval of the ethics committee of Lyon Veterinary School. Ultrasound lesions were performed by varying the physical parameters of the treatment (acoustic intensity and shot time) with the aim of obtaining larger and larger areas of destruction. An operative device was developed to ensure precision in treatments. Two types of lesions were performed: elementary lesions corresponding to single shots at 40 degrees to 50 degrees rotation intervals, and cylindrical lesions obtained by a continuous rotary deployment of the probe. The effect of hepatic pedicle clamping on the size of ultrasound lesions was studied. The aspect and dimension of the lesions were analyzed by means of operative ultrasound imaging and macroscopic examination. Histological analysis showed the impact of the treatment on the hepatic parenchyma. RESULTS: This work made it possible to study the elementary ultrasound lesions produced by our probe. Seventy elementary ultrasound lesions were analyzed. Treatments could be performed on all pigs without any difficulty. There were no operative incidents. The ultrasound-induced elementary lesions showed complete necrosis, with lesion length of up to 37 mm obtained without resort to pedicle clamping; this must be considered as a radius of the final lesion obtained over a complete rotary deployment (360 degrees ), then a diameter of 7 cm of thermal ablation can theoretically be obtained. The effect of pedicle clamping was studied and showed improvement of the lesion length. Results of continuous rotary deployment of the probe were encouraging. Operative ultrasound imaging proved to be a simple tool for directing and positioning the applicator in the target zone on the one hand and which, on the other hand, enabled accurate, real-time visualization of the ultrasound lesions. On histological analysis, the ultrasound-induced necrosis was complete and well defined. CONCLUSION: This work shows that it is feasible to treat cancers of the liver using interstitial ultrasound probe. Thermal damage obtained on the hepatic parenchyma of pigs in vivo is complete and can be monitored using simple diagnostic ultrasound. The ultrasound parameters can be adapted to obtain destruction of variable size.

Ileal carcinoid with liver metastasis presenting after ten years with abdominal mass and right heart failure: report of a case.

A case of ileal carcinoid metastatic to the liver is reported. The diagnosis was made and treatment given ten years after the detection of a left hypervascular liver mass, which was first confounded with a hemangioma. The onset of right heart failure led to surgical replacement of the tricuspid and pulmonary valves. After cardiac surgery the patient underwent an ileal resection and left hepatectomy for a cystic left liver metastasis. Isolated right heart failure and cystic degeneration of a liver metastasis are uncommon features of metastatic carcinoid tumors; only a few cases have been described in the literature. Cardiac surgery is recommended before liver surgery to reduce venous pressure and consequent bleeding during hepatectomy. Surgical treatment of liver metastases may relieve endocrine symptoms and result in an overall five-year survival rate of 47%.

Transpleurodiaphragmatic cryosurgical ablation for recurrent unresectable colorectal liver metastases.

BACKGROUND AND OBJECTIVES: Cryosurgical ablation (CSA) allows the focal destruction of unresectable liver metastases after previous liver resection. The abdominal approach may be difficult for recurrent colorectal cancer metastases located in the upper part of the remaining liver, close to the inferior vena cava (IVC), the hepatic veins, and the diaphragm. A transpleurodiaphragmatic access was assessed for safety and efficacy. METHODS: Between September 1999 and July 2004, 13 patients with recurrent unresectable colorectal liver metastases underwent transpleurodiaphragmatic CSA via limited right thoracotomy. Seventeen lesions were treated; median diameter was 31 mm (range 13-40 mm). One to three cryoprobes were used, depending on the size and location of metastases. RESULTS: There was no operative death; three patients developed minor complications (23%). Median hospital stay was 10 days (8-14 days). After a median follow-up of 26 months (range 8-69 months), 9 patients were alive, and 5 were disease-free. Six patients had liver recurrences outside the cryolesion. Median disease free survival was 12 months with 60% 3-year survival after CSA and 58% 5-year survival after first liver surgery. CONCLUSIONS: Transpleurodiaphragmatic CSA is safe and effective in selected patients with unresectable recurrent liver metastases from colorectal cancer.

Enteral immunotherapy in the treatment of chronic enterocolitis in interleukin-10-deficient mice.

BACKGROUND/AIMS: Transgenic IL-10-deficient mice (IL-10 ko mice) spontaneously develop a chronic inflammatory bowel disease that is reminiscent of Crohn's disease. In a randomized, prospective, comparative study, we evaluated the effect of local, endoluminal immunotherapy by duodenal injection of mouse recombinant IL-10 (rm IL-10), in IL-10 ko mice with chronic enterocolitis; the first of its kind. METHODOLOGY: Sixteen IL-10 ko mice received a monoinjection of rm IL-10 into the duodenum while a control group of 16 IL-10 ko mice received an injection of physiological saline. Histology of the entire bowel and plasma concentrations of IL-4, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma were analyzed on the 3rd or 7th postoperative day. RESULTS: The histological features of the specimens from IL-10 ko mice were, non-specific, segmentary and located mainly in the ileum. Lesions were of more significance in mice injected with physiological saline than in those receiving IL-10 in the proximal ileum, near to the site of injection. Plasma concentrations of IL-6 were higher in IL-10 ko mice than in the control group. CONCLUSIONS: This study confirms that there is hyperproduction of Th1 cytokines in IL-10 ko mice and also suggests that endoluminal administration of IL-10 may be envisaged for the treatment or prevention of enterocolitis.