Chronic radiation enteritis.

Radiation enteritis is an iatrogenic disease of the intestines caused by radiation therapy. Two entities, chronic and acute radiation enteritis, are described. The acute symptoms (abdominal pain, loss of appetite, diarrhea) develop within the first hours or days after radiation therapy and can be treated medically. Chronic radiation enteritis leads to a chronic sub-obstructive and/or malabsorption syndrome developing at least two months after the end of radiation therapy. Cases occurring 30 post-radiation are reported. Treatment is surgical with extended resection of all involved elements of the digestive tract and ileocolonic anastomosis in healthy zones. The diagnosis is confirmed by the anatomopathology report of fibrous intestinal lesions associated with obliterating arterial lesions.

Increasing polymorphism of the RAET1E/ULBP4 gene in humans.

Description of three novel RAET1E/ULBP4 allele and promoter polymorphisms identified by sequence-based typing.

Further diversity of the 5' promoter region of the MHC class I-related chain B gene.

We have now found a total of 15 individual MICB promoter sequences, varying by combination of 18 polymorphic positions within the MICB minimal promoter sequence. Sequence-based typing and cloning characterized the three new 5' promoter sequences as MICB-P13, MICB-P14 and MICB-P15.

Giant colon diverticulum.

Giant colonic diverticulum is defined by a diverticulum whose diameter is greater than 4 cm. This is a rare entity, arising mainly in the sigmoid colon. The diagnosis is based on abdominal computed tomography that shows a gas-filled structure communicating with the adjacent colon, with a smooth, thin diverticular wall that does not enhance after injection of contrast. Surgical treatment is recommended even in asymptomatic diverticula, due to the high prevalence and severity of complications. The gold standard treatment is segmental colectomy. Some authors propose a diverticulectomy when the giant diverticulum is unique.

Two novel 5' promoter sequences of the MHC class I-related chain A gene.

In this study, we have characterized two novel polymorphism of the 5' promoter sequence of MICA gene, MICA-P13 and MICA-P14, by sequence-based typing and cloning.

Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation.

Allo-SCT using unrelated donors is a curative treatment for patients with hematological disorders. The best donor is one matched for 10/10 HLA alleles, however studies have shown an additional survival benefit when considering other genetic factors. It has been shown that a six-nucleotide insertion/deletion polymorphism in the CASP8 gene promoter results in reduced susceptibility of T lymphocytes to undergo apoptosis. In 186 SCT recipients, we found a significantly better OS in those who received a transplant from a WT/WT donor compared with donors with a deletion (3 years: 52 vs 34%; P=0.03; multivariate analysis; RR 0.61; 95% CI 0.38-0.98, P=0.04). This was more marked when both the patient and the donor had a deletion (3 years OS: 62% compared with 36%, P=0.01). As the majority of these patients received Alemtuzumab during conditioning, we went on to analyze the in vitro effect of the polymorphism on Alemtuzumab-induced apoptosis. We showed statistically significantly higher percentages of apoptotic naïve CD4 (P<0.0005) and CD8 (P<0.0005) T cells in WT/WT donors in comparison with donors with a deletion. These data imply an unrecognized role for the CASP8 promoter polymorphism on survival following unrelated SCT particularly in the context of T-cell depletion with Alemtuzumab.

Diversity and characterization of polymorphic 5' promoter haplotypes of MICA and MICB genes.

The major histocompatibility complex (MHC) class I-related chain A (MICA) and B (MICB) are ligands for the natural killer group 2, member D (NKG2D) activating receptor expressed on natural killer (NK) cells, natural killer T (NKT) cells, CD8+ T cells and γδ T cells. Natural killer group 2, member D (NKG2D) ligand expression is stress-related and upregulated by infected or oncogenic cells leading to cytolysis. MICA and MICB genes display considerable polymorphism among individuals and studies have investigated allelic association with disease and relevance of MICA in transplantation, with variable success. It is now known that promoters of MICA and MICB are polymorphic with some polymorphisms associating with reduced expression. We sequenced International Histocompatibility Workshop (IHW) cell line DNA to determine promoter types and alleles encoded by exons 2-6. We found 8 of 12 known MICA promoter polymorphisms and although promoter P7 dominated, other promoters associated with the same allele. For example, MICA*002:01 had promoters P3, P4 or P7 and the common MICA*008:01/04 type had P1, P6 or P7. Similarly, we sequenced 8 of 12 known MICB promoter haplotypes. Some coding region defined MICB alleles had a single promoter, for example, MICB*002:01 and promoter P9, whereas the promiscuous MICB*005 allele had promoters P1, P2, P5, P6, P10 or P12. The results indicate potential for variation in expression of MICA and MICB ligands between individuals with the same allelic types. If differential expression by polymorphic MICA and MICB promoters is confirmed by functional studies, involvement of these genes in disease susceptibility or adverse transplantation outcomes may require knowledge of both promoter and allelic types to make meaningful conclusions.

Further polymorphism of the RAET1E/ULBP4 gene in humans.

Description of a novel RAET1E/ULBP4 allele characterized by sequence-based typing and cloning: RAET1E*011.

Three novel allelic variants of the RAET1E/ULBP4 gene in humans.

Discovery of three novel alleles of RAET1E/ULBP4 by sequence-based typing: RAET1E*008, RAET1E*009 and RAET1E*010.

p110delta is required for innate immunity to transplantable lymphomas.

NK cell (natural killer cells) are lymphocytes of innate immunity that kill tumour cells and respond to infections, without prior stimulation. A balance of activating and inhibitory signals regulates NK cell cytotoxicity, but the molecular mechanisms are not fully understood. General inhibitors of PI3K (phosphoinositide 3-kinase) suppress cytotoxicity in human and mouse NK cells. However, which isoforms and how they regulate NK cell activation is unknown, and no data have been published on mice carrying PI3K mutations. p110delta expression is restricted to leucocytes, where it plays central roles in lymphocyte development and signalling. We have used mice carrying a catalytically inactive mutant form of p110delta in order to determine its role in NK cell biology. We show here that p110delta is not required to kill tumour cells, but unexpectedly p110delta mutant mice failed to fully reject transplanted lymphomas. Our results show for the first time a critical role for p110delta in NK cell biology in vivo.

[Severe blunt liver injury: reappraisal of criteria for nonoperative management decision. Experience with 88 cases]. / Traumatismes graves fermés du foie: à la recherche de critères décisionnels pour le choix du traitement non-opératoire. A propos d'une série de 88 cas.

AIM OF THE STUDY: To analyze the predictive value of computed tomography (CT) and initial physiologic and laboratory data findings in the immediate operative (OP) or non-operative (NOP) management of blunt liver injury (BL). METHODS: Eighty-eight BL, grade III (51), grade IV (28) and nine grade V (9), aged 26.2 years (16-75) were identified. Hemoperitoneum on CT, hemodynamic status, physiologic and laboratory data <24 hours or preoperative (transfusion, vascular filling) and follow-up >48 hours were analyzed. RESULTS: Data of 71/88 (80%) NOP and 17/88 (20%) OP patients were reviewed. A secondary laparotomy or laparoscopy was necessary in 11/71 TNO. Six OP (35%) and 1 NOP patients died. Blood units transfused were 1.33 (0-10) vs 5.9 (0-22) and vascular filling 1.45 (0.5-5.5) vs 3.6L (2-12) (P<10(-6), P<4.10(-3) respectively). NOP patients had less severe hemoperitoneum (31 vs 94%, P<10(-5)) and hemodynamic instability (8.5 vs 94%, P<10(-4)). But, there was an overlap of values of blood units transfused, amount of vascular filling and initial haemoglobin levels between NOP and OP patients and among CT grades of liver injury. No cut-off values could be determined: 33% NOP received >4 blood units and >3 L vascular filling; 30% had severe hemoperitoneum. In OP group 23.5% patients had lower values and no severe hemoperitoneum. CONCLUSION: In the management of BL, vascular filling and blood transfusion increased with the grade of CT liver injury and were globally more elevated in the operative group but did not individually correlate with hemodynamic stability and did not authorize, by themselves, to decide between operative versus non-operative management.

Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells.

Chemotherapeutic drugs kill cancer cells mainly by direct cytotoxicity, but they might also induce a stronger host immune response by causing the tumor to produce costimulatory cell surface molecules like CD80. We previously reported that in myeloid leukemic cells, gamma-irradiation induced CD80 expression. In this study, we show that cytosine arabinoside (Ara-C), even at low doses, induced CD80 expression in vitro in mouse DA1-3b leukemic cells, by a mechanism that involved reactive oxygen species. In vivo experiments in the mouse DA1-3b/C3H whole-animal acute myeloid leukemia (AML) model showed that injection of Ara-C induced expression of CD80 and CD86, and decreased expression of B7-H1, indicating that chemotherapy can modify costimulatory molecule expression in vivo, in a way not necessarily observed in vitro. Mouse leukemic cells exposed in vivo to Ara-C were more susceptible to specific cytotoxic lymphocyte (CTL)-mediated killing. Ara-C also induced CD80 or CD86 expression in 14 of 21 primary cultured human AML samples. In humans being treated for AML, induction chemotherapy increased CD86 expression in the leukemic cells. These findings indicate possible synergistic strategies between CTL-based immunotherapy and chemotherapy for treatment. They also suggest an additional mechanism by which chemotherapy can eradicate AML blasts.

[Management of duodenal adenomatosis in patients with familial adenomatous polyposis]. / Prise en charge et traitement de l'adénomatose duodénale de la polypose adénomateuse familiale.

AIM OF THE STUDY: To review our global management of duodenal adenomas in patients with familial adenomatous polyposis and report the results of different therapeutic approaches. To present the outcome and possible sequels of pancreaticoduodenectomy. PATIENTS AND METHODS: We identified five cases of duodenal adenomas in patients with familial adenomatous polyposis over a period of 10 years (1992-2001), we followed the progression of their Spigelman score. Results of conservative and surgical treatment were collected. RESULTS: Duodenal adenomas were discovered 5-33 years after the first operation for colonic polyposis. The score of Spigelman was as follows: 2, stage 2; 3, stage 3; 1, stage 4. Endoscopic laser therapy followed by Sulindac prescription was proposed in three cases, with only one success. Duodenopancreatectomy was performed in four patients: once the diagnosis of adenoma was made in one patient, due to Spigelman stage 4 with severe dysplasia, because development of intramucosal carcinoma under surveillance in one patient, and after failure or complication of conservative treatment in two others. Worsening of Spigelman score was observed in two out of four patients submitted to conservative therapy. Correlation between Spigelman score and final examination of the specimen was correct in two cases. There was neither significant morbidity nor long-term nutritional sequel after pancreaticoduodenectomy. CONCLUSION: Duodenal adenomas may recur or progress into malignant degeneration under conservative treatment. The pancreaticoduodenectomy is an acceptable solution for stage 4 of Spigelman, especially when severe dysplasia is present.

Gamma-irradiation enhances transgene expression in leukemic cells.

The majority of immunotherapy-based gene therapy protocols consist of ex vivo gene transfer in tumor cells. To prevent further in vivo growth, modified cells must be irradiated before reinjection into patients. The present study examines the effects of gamma-irradiation on transgene expression in transduced leukemic cells. Human and murine leukemic cells were transfected with retroviral vectors or plasmids carrying beta-galactosidase, GM-CSF or CD80 genes. Fresh leukemic cells from patients with acute myeloid leukemia (AML) were transfected with AdZ.F(pK7) adenoviral vector. gamma-irradiation at various lethal doses enhanced transgene expression in leukemic cell lines and fresh AML cells when the gene of interest was under CMV promoter but not when SV40 promoter was used. Oxidative stress also enhanced transgene expression and both irradiation and oxidative stress effects were inhibited by addition of N-acetyl-L-cysteine, a thiol anti-oxidant, indicating the involvement of reactive oxygen species. Transgene expression was also enhanced in vivo 48 and 120 h after subcutaneous injection of irradiated leukemic cells in syngeneic mice. These results show that a cell vaccine protocol using ex vivo gene transfer of transduced cells might be feasible in acute leukemia even if leukemic cells must be irradiated at lethal doses prior to reinjection to patients.

Gene transfer of CD154 and IL12 cDNA induces an anti-leukemic immunity in a murine model of acute leukemia.

IL12 is an essential cytokine for the generation of T helper 1 response, natural killer (NK) cells and cytotoxic T lymphocyte (CTL) stimulation. CD154 triggers CD40 on antigen-presenting cells, thus inducing antigen presentation to the immune system and production of IL12. As IL12 and CD154 share several pathways mediating immune response, we investigated in an aggressive murine model of acute leukemia the relative antileukemic efficiency of IL12, CD154 and IL12 + CD154 gene transfer. Live leukemic cells transduced by IL12, CD154, and IL12 + CD154 showed reduced leukemogenicity but CD154 protective effect was reduced when 10(6) leukemic cells were injected. Vaccines with lethally irradiated IL12-transduced cells were able to cure mice previously injected with 10(4) leukemic cells and adoptive transfer of IL12-induced antileukemic immunity protected recipient mice. NK cytotoxicity was enhanced in mice vaccinated with leukemic cells transduced by IL12, CD154, and CD154 + IL12. IL12 transduced cells induced IFN-gamma mRNA in CD4(+) and CD8(+) T cells isolated from the spleen of vaccinated animals, however, in vivo depletion experiments showed that IL12 vaccine effect was CD4(+) but not CD8(+) T cell dependent. We conclude that IL12 gene is a more potent candidate than CD154 for gene therapy of acute leukemia.

Perforation of Barrett's ulcer: a challenge in esophageal surgery.

BACKGROUND: Barrett's ulcer, which develops within Barrett's esophagus, is frequently responsible for bleeding. Perforation is a rare complication constituting a great challenge for diagnosis and management. METHODS: Three personal cases and 31 published reports of perforated Barrett's ulcer were reviewed retrospectively. The site of perforation, clinical presentation, management, and outcome were assessed. RESULTS: The clinical presentation proved to be heterogeneous and was determined by the site of perforation: this was the pleural cavity (20% of cases), mediastinum (20%), left atrium (16.6%), tracheobronchial tract (13.3%), aorta (13.3%), pericardium (10%), or pulmonary vein (6.6%). Early esophagectomy and esophageal diversion-exclusion were the most frequent procedures, and overall mortality was 45%. CONCLUSIONS: The poor prognosis of perforated Barrett's ulcer should be improved by earlier diagnosis and adequate emergent operation. Although early esophagectomy constitutes the recommended procedure, esophageal diversion-exclusion, which allows control of both sepsis and bleeding, is also of interest.

[Celioscopic treatment of small intestine obstructions]. / Traitement coelioscopique des occlusions du grêle.

We evaluated the reliability and immediate results of celioscopic management of acute small bowel obstruction. From January 1995 to April 1998, 39 patients underwent a primary celioscopic procedure for small bowel obstruction. The most common etiology was post operative adhesions (34 patients). The whole operation could be carried out exclusively by celioscopy in 22 patients (56%). A laparotomy had to be performed in 17 patients due to: impossibility to identify or treat the cause of obstruction, bowel necrosis or intraoperative complication (3 bowel wounds). Post operative complications were: 1 death (not directly related to the surgical procedure), 2 early recurrences of obstruction after exclusive celioscopy, 1 evisceration after laparotomy and 1 small bowel fistula after conversion to laparotomy. Mean hospital stay was 5 days after exclusive celioscopy and 9.5 days after conversion to laparotomy. Celioscopic management of small bowel obstruction is feasible, but it is often difficult and may be hazardous; a careful selection of patients must be made, based on the importance of obstruction and the type of previous abdominal surgery.