Trial of complete weaning from immunosuppression for liver transplant recipients: factors predictive of tolerance.

Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty-four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4(+) , CD8(+) , and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range = 8.5-22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P = 0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P = 0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n = 7 for an interval > 10 years and an SI < 20), 100% reached tolerance; in the second group (n = 10 for an interval > 10 years and an SI > 20 or an interval < 10 years and an SI < 20), 60% reached tolerance; and in the third group (n = 7 for an interval < 10 years and an SI > 20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables-the time from transplantation and the SI-may help to identify these patients.

Surgical training on rectal cancer surgery: do supervised senior residents differ from consultants in outcomes?

INTRODUCTION: The present work is a comparative study to investigate the independent effect of tutored senior residents on rectal cancer surgery in an academic university hospital. The variable "surgeon" is held to be a major determinant of outcome following total mesorectal excision (TME) for rectal cancer. OBJECTIVE: We hypothesized that TME can be tutored to senior surgical residents without compromising surgical and oncological outcomes. METHODS: Demographics, preoperative characteristics, and surgical data from consecutive patients undergoing elective TME in an academic center over the last decade were retrospectively reviewed from a prospectively collected database. Outcomes were compared in the two cohorts by a principal surgeon (senior resident or staff) and supervised in all cases by a senior colorectal consultant. Association of outcome variables with the type of surgeon was determined by univariate and multivariate analyses and results were corrected by tumor's height. RESULTS: A total of 230 patients were treated over the study period; 136 (59 %) surgeries were performed by staff surgeons (group S) and 94 (41 %) by residents (group R). Both groups were comparable except for distance to anal verge; staff surgeons operated on lower tumors and performed a high percentage of coloanal anastomosis. There were no statistical differences between groups in terms of surgical and oncological outcomes when tumors were located over 7 cm from the anal verge. CONCLUSIONS: Rectal surgery can be performed by senior residents with equal results to staff surgeons when there is direct supervision by a senior consultant and when the tumor is located in the mid-upper rectum (>7 cm from the anal verge). For lower tumors, a careful selection must be made as the operation may require a higher level of training.

microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells.

PURPOSE: microRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors. This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer. EXPERIMENTAL DESIGN: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data. RESULTS: The results revealed that down-regulation of miR-451 was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues. Overexpression of miR-451 in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451. In fact, overexpression of miR-451 down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. Moreover, we found a significant inverse correlation between miR-451 and MIF expression in tumoral gastric biopsies. CONCLUSIONS: These findings support the role of miR-451 as a regulator of cancer proliferation and open new perspectives for the development of effective therapies for chemoradioresistant cancers.

The diffuse endocrine system: from embryogenesis to carcinogenesis.

In the present review we will summarise the current knowledge about the cells comprising the Diffuse Endocrine System (DES) in mammalian organs. We will describe the morphological, histochemical and functional traits of these cells in three major systems gastrointestinal, respiratory and prostatic. We will also focus on some aspects of their ontogeny and differentiation, as well as to their relevance in carcinogenesis, especially in neuroendocrine tumors. The first chapter describes the characteristics of DES cells and some of their specific biological and biochemical traits. The second chapter deals with DES in the gastrointestinal organs, with special reference to the new data on the differentiation mechanisms that leads to the appearance of endocrine cells from an undifferentiated stem cell. The third chapter is devoted to DES of the respiratory system and some aspects of its biological role, both, during development and adulthood. Neuroendocrine hyperplasia and neuroendocrine lung tumors are also addressed. Finally, the last chapter deals with the prostatic DES, discussing its probable functional role and its relevance in hormone-resistant prostatic carcinomas.

Fine-needle aspiration cytology and immunocytochemistry in the diagnosis of 24 gastrointestinal stromal tumors: a quick, reliable diagnostic method.

The diagnosis of gastrointestinal stromal tumors (GISTs) is generally established on histopathologic examination of surgical specimens. Fine-needle aspiration (FNA), performed under the guidance of ultrasound or computed tomography, is being used with increasing frequency in an attempt to diagnose primary and/or metastatic GISTs before surgery. The present study was undertaken to characterize the cytological appearance of these tumors and to assess the role of cytology, together with immunocytochemistry (ICC), in the diagnosis of GISTs. Twenty-four GISTs diagnosed by FNA cytology at our institution have been reviewed. Immunocytochemical studies with c-kit and CD34 were performed in all cases on current or archival Papanicolaou-stained smears. All cases stained with c-kit, and 19 reacted with CD34. Cytomorphology and immunocytochemical characteristics are discussed. Our results confirm the utility of FNA together with ICC in the diagnosis of primary and/or metastatic GISTs.

Long-term follow-up study of gastroduodenal lesions after radioembolization of hepatic tumors.

AIM: To evaluate the long-term natural history of the gastroduodenal lesions secondary to extrahepatic embolization with Ytrium 90 (9°Y) spheres. METHODS: From September 2003 to January 2012, 379 procedures of liver radioembolization (RE) using resin microspheres loaded with 9°Y were performed in our center. We have retrospectively compiled the data from 379 RE procedures performed in our center. We report a comprehensive clinical, analytical, endoscopic and histologic long-term follow-up of a series of patients who developed gastroduodenal lesions after the treatment. RESULTS: Six patients (1.5%) developed gastrointestinal symptoms and had gastrointestinal lesions as shown by upper endoscopy in the next 12 wk after RE. The mean time between RE and the appearance of symptoms was 5 wk. Only one patient required endoscopic and surgical treatment. The incidence of gastrointestinal ulcerations was 3.75% (3/80) when only planar images were used for the pre-treatment evaluation. It was reduced to 1% (3/299) when single-photon emission computed tomography (SPECT) images were also performed. The symptoms that lasted for a longer time were nausea and vomiting, until 25 mo after the treatment. CONCLUSION: All patients were free from severe symptoms at the end of follow-up. The routine use of SPECT has decreased the incidence of gastrointestinal lesions due to unintended deployment of 9°Y particles.

Patterns of response after preoperative treatment in gastric cancer.

PURPOSE: To analyze the rate of pathologic response in patients with locally advanced gastric cancer treated with preoperative chemotherapy with and without chemoradiation at our institution. METHODS AND MATERIALS: From 2000 to 2007 patients were retrospectively identified who received preoperative treatment for gastric cancer (cT3-4/ N+) with induction chemotherapy (Ch) or with Ch followed by concurrent chemoradiotherapy (45 Gy in 5 weeks) (ChRT). Surgery was planned 4-6 weeks after the completion of neoadjuvant treatment. Pathologic assessment was used to investigate the patterns of pathologic response after neoadjuvant treatment. RESULTS: Sixty-one patients were analyzed. Of 61 patients, 58 (95%) underwent surgery. The R0 resection rate was 87%. Pathologic complete response was achieved in 12% of the patients. A major pathologic response (<10% of residual tumor) was observed in 53% of patients, and T downstaging was observed in 75%. Median follow-up was 38.7 months. Median disease-free survival (DFS) was 36.5 months. The only patient-, tumor-, and treatment-related factor associated with pathologic response was the use of preoperative ChRT. Patients achieving major pathologic response had a 3-year actuarial DFS rate of 63%. CONCLUSIONS: The patterns of pathologic response after preoperative ChRT suggest encouraging intervals of DFS. Such a strategy may be of interest to be explored in gastric cancer.

Fibrosing cholestatic hepatitis following cytotoxic chemotherapy for small-cell lung cancer.

Fibrosing cholestatic hepatitis (FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver, renal or bone transplantation recipients and in leukemia and lymphoma patients after conventional cytotoxic chemotherapy. FCH constitutes a well-described form of fulminant hepatitis having extensive fibrosis and severe cholestasis as its most characteristic pathological findings. Here, we report a case of a 49-year-old patient diagnosed with small-cell lung cancer who developed this condition following conventional chemotherapy-induced immunosuppression. This is the first reported case in the literature of FCH after conventional chemotherapy for a solid tumor. In addition to a detailed report of the case, a physiopathological examination of this potentially life-threatening condition and its treatment options are discussed.

Large cell carcinoma of the lung: an endangered species?

This study aims to evaluate large cell carcinomas (LCC) of the lung with a panel of immunohistochemical markers in an attempt to identify tumors belonging to other categories. We analyzed a tissue microarray platform of 101 LCC with a panel of 31 monoclonal antibodies. The tumors were 82 (81.3%) classic LCC, 7 (6.9%) neuroendocrine LCC, 6 (5.9%) lymphoepithelioma-like LCC, 3 (2.9%) basaloid LCC, 2 (2%) clear cell LCC, and 1 (1%) LCC with rhabdoid phenotype. Characteristic classic LCC immunophenotype was loss of staining with CK5/6, CK14 positive in most squamous cell carcinoma (SCC), lack of MOC 31 positive in most adenocarcinomas, and positive immunoreactivity to EGFR, PDGFR-alpha and c-kit. 27 of 82 classic LCC (32.9%) were re-classified as adenocarcinomas, because they coexpressed TTF-1, CK7, and CK19, and were negative for p63. 31 (37.8%) of 82 classic LCC were reclassified as poorly differentiated SCC, based on their immunoreactivity with 34betaE12, p63, thrombomodulin, and CD44v6. 16 (19.5%) of 82 classic LCC correspond to undifferentiated adenosquamous carcinomas, since they displayed conflicting immunostaining for markers of both SCC and adenocarcinomas. The use of 7 immunohistochemical markers, consisting of TTF-1, CK7, CK19, p63, 34betaE12, thrombomodulin, and CD44v6, markedly reduces dramatically to less than 10%, the number of classic LCC by readily identifying cases of poorly differentiated SCCs, adenosquamous carcinoma and adenocarcinomas.

Primary mixed squamous carcinoma and osteosarcoma (carcinosarcomas) of the lung have a CGH mapping similar to primitive squamous carcinomas and osteosarcomas.

Carcinosarcomas are malignant tumors with a mixture of carcinomatous and differentiated sarcomatous elements. We investigate the morphology, immunohistochemistry, and comparative genomic hybridization analysis of 3 mixed squamous carcinoma and osteosarcoma of the lung. All patients were male and their ages were 72, 43, and 58 years. The sizes of the neoplasms were 7, 5, and 5 cm in maximum diameter, respectively. Two patients died of the disease 9 and 14 months after surgery; and one is alive 6 months later. By light microscopy, all cases had both squamous and osteosarcomatous structures. Immunohistochemistry was positive for AE3AE1, p63, 34 E12, CAM 5.2 (2/3 cases), CK-7 (2/3 cases), epithelial membrane antigen, E-cadherin, p53, and carcinogenic embryonic antigen in carcinomatous areas, and for vimentin and CD-68 in sarcomatous component. Areas of transition positive for both cytokeratins and vimentin were seen in all cases. A total of 55 copy number changes were detected with a median of 18 abnormalities per case: 48 gains, 6 losses, and 1 high-level amplification. Chromosome alterations in osteosarcomatous areas were similar to those found in lung metastatic osteosarcoma, comparable to those found in carcinomatous areas and to lung squamous carcinomas. Coincidences between carcinomatous areas and osteosarcomatous zones were found as gains in chromosomes 1q, 3q, 5p, 8q, and 12p. These findings provide arguments that favor a common origin for both types of cells, supported by the mixture of cells, the existence of undifferentiated cells positive to both cytokeratin and vimentin markers, and the CGH overlaps of chromosomal gains between carcinomatous and sarcomatous areas.

Percutaneous extrahepatic portacaval shunt with covered prostheses: feasibility study.

PURPOSE: To assess the anatomic feasibility of creating a percutaneous extrahepatic portosystemic shunt (PEPS) between the main portal vein (MPV) and the inferior vena cava (IVC) in patients with cirrhosis and to evaluate the feasibility of this approach in an animal model. MATERIALS AND METHODS: In human studies, computed tomographic (CT) scans from 34 patients with cirrhosis were reviewed to assess the distance and anatomic structures found between the MPV and IVC. The MPV was divided into upper, middle, and lower thirds for analysis. In the experimental model, PEPS were created in 10 beagle dogs by placing between the MPV and IVC a tubular polyurethane-covered prosthesis with flared ends designed for this study. Different approaches, devices, and prostheses were assayed. RESULTS: In human studies, the shortest mean distance between the IVC and the MPV was found in the lower third of the MPV (1.18 cm +/- 0.6). The lower third, the nearest to the confluence of splenic and superior mesenteric veins, also presented fewer intervening structures, and the spatial relationship between the veins at this level was predictable. In the experimental model, direct portography was performed, with a small mesenteric vein catheterized through a minilaparotomy and a transjugular access to the IVC. A needle was advanced from the MPV to the IVC, and a polyurethane cone-shaped covered prosthesis was placed to bridge the path between the veins. Six of 10 animals died from bleeding that occurred either because several punctures were made during the procedure or because the prosthesis became dislodged when the mesentery was moved before suturing the minilaparotomy. The remaining four were kept alive for 1, 5, 60, and 90 days after the procedure. CONCLUSIONS: PEPS creation in patients with cirrhosis is anatomically possible. The lower third of the MPV should be the most suitable level at which to create the shunt. Preliminary studies carried out in beagle dogs support the feasibility of this approach. However, further work is needed to improve the efficacy of this technique.