The Length of the Transition Zone in Patients with Rectosigmoid Hirschsprung Disease.

Background: The transition zone (TZ) is defined by specific histological findings in patients with Hirschsprung Disease (HSCR). HSCR treatment includes surgical removal of the aganglionic zone (AZ). During the pull-through procedure, it is critical to resect the TZ. Given the TZ's wide histological heterogeneity, we wanted to know how extensive the histological transition zone is. Methods: A retrospective study of patients who had pull-through surgery for rectosigmoid HSCR between January 2010 and December 2020 was carried out. Demographics, length of TZ and AZ, age and symptoms upon presentation, and complications after surgery were also obtained. Results: The inclusion criteria were met by 50 patients. The mean age of all patients was 10 months (0.1-107.5 months), with a mean age at pull-through of 16.3 months (3-112 months). Thirty-one out of fifty patients (62%) received primary laparoscopic endorectal pull-through surgery (LEPT). The average TZ length of all patients was 2.6 cm (0-10 cm), and the AZ length was 9.6 cm (1-30 cm). The length of the AZ and TZ were shown to have no correlation (r² = 0.237). Conclusions: The current study found that the mean length of the TZ in individuals with rectosigmoid HSCR is less than 5 cm in most cases and has no correlation with the length of the AZ.

Impact of hepatopathy in pediatric patients after surgery for complex congenital heart disease.

Patients undergoing complex pediatric cardiac surgery in early infancy are at risk of postoperative secondary end-organ dysfunction. The aim of this study was to determine specific risk factors promoting the development of peri- and postoperative hepatopathy after surgery for congenital heart disease. In this retrospective study, we identified 20 consecutive patients operated between 2011 and 2019 from our institutional cohort who developed significant postsurgical hepatic dysfunction. These patients were compared to a control group of 30 patients with comparable initial cardiac conditions and STS-EACTS risk score. Patients who developed hepatopathy in the intensive care unit have chronic cholestasis and decreased liver synthesis. The impact of postoperative hepatopathy on morbidity was marked. In six patients (30%), liver transplantation was executed as ultima ratio, and two (10%) were listed for liver transplantation. The overall mortality related to postoperative hepatopathy is high: We found nine patients (45%) having severe hepatopathy and mostly multiple organ dysfunction who died in the postoperative course. According to risk analysis, postoperative right and left heart dysfunction in combination with a postoperative anatomical residuum needing a re-operation or re-intervention in the postoperative period is associated with a high risk for the development of cardiac hepatopathy. Furthermore, postoperative complications (pleural effusion, heart rhythm disorders, etc.), postoperative infections, and the need for parenteral nutrition also raise the risk for cardiac hepatopathy. Further investigations are needed to reduce hepatic complications and improve the general prognosis of such complex patients.

Combined liver-kidney transplantation for children with autosomal recessive polycystic kidney disease (ARPKD): indication and outcome.

In ARPKD, mutations in the PKHD1 gene lead to remodeling of the kidneys and liver. These may result in progressive liver fibrosis with portal hypertension requiring combined liver and kidney transplantation (CLKT). There is currently no consensus on the indication for CLKT and data on long-term outcomes are scarce. We analyzed in detail the pretransplant liver symptomatology, laboratory and ultrasound data, histological studies, and genotypes in eight patients undergoing CLKT. The median age was 10.1 years (range 1.7-16) and median follow-up was 4.6 years (range 1.1-8.9). All patients had clinical signs of portal hypertension and abnormal ultrasound findings. Congenital hepatic fibrosis was present in all pretransplant biopsies (6 out of 8 patients) and in all explanted livers. All patients survived; liver and kidney graft survival was 72% and 88%, respectively. Liver and kidney function were stable in all patients with a median eGFR of 70 ml/min/1.73 m² (range 45-108 ml/min/1.73 m²). Height-SDS improved significantly after 12, 24, and 36 months (P = 0.016, 0.022 and 0.018 respectively). The indication for CLKT remains challenging and controversial. A favorable outcome for patients with ARPKD can be achieved by using the degree of portal hypertension, longitudinal ultrasound examinations, and preoperative liver histology as parameters for CLKT.

Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations.

BACKGROUND: Autosomal recessive mutations in MPV17 (OMIM *137960) have been identified in the hepatocerebral form of mitochondrial DNA depletion syndrome (MDS). OBJECTIVE: To describe the clinical, morphologic, and genetic findings in 3 children with MPV17-related MDS from 2 unrelated families. DESIGN: Case report. SETTING: Academic research. MAIN OUTCOME MEASURES: We identified 3 novel pathogenic mutations in 3 children. RESULTS: Two children were homozygous for nonsense mutation p.W120X. A third child was compound heterozygous for missense mutation p.G24W and for a macrodeletion spanning MPV17 exon 8. All patients demonstrated lactic acidosis, hypoglycemia, hepatomegaly, and progressive liver failure. Neurologic symptoms manifested at a later stage of the disease. Death occurred within the first year of life in all 3 patients. CONCLUSIONS: These data confirm that MPV17 mutations are associated with a 2-stage syndrome. The first symptoms are metabolic and rapidly progress to hepatic failure. This stage is followed by neurologic involvement affecting the central and peripheral systems.

Long-term survival in patients with acute leukemia and chronic disseminated candidiasis despite minimal antileukemic therapy.

Infections may require discontinuation of antineoplastic chemotherapy, which, in turn, renders patients vulnerable to disease progression or relapse. We identified six patients with acute leukemia in whom antineoplastic treatment had to be discontinued because of chronic disseminated candidiasis (CDC). However, despite minimal antileukemic treatment, all patients remained in complete remission. Immunologic mechanisms associated with CDC might have had an antileukemic effect.

Microsatellite DNA alterations of gastrointestinal stromal tumors are predictive for outcome.

PURPOSE: In gastrointestinal stromal tumors (GIST), loss of heterozygosity (LOH) on chromosome 22 and its presumptive biological function has been described. The prognostic value of these and other DNA regions for patient survival remains unclear. EXPERIMENTAL DESIGN: Sixty patients who underwent surgery at our institution between 1992 and 2003 for GIST were histopathologically reclassified by immunohistochemistry and the GIST consensus group criteria 2001. Twenty-one microsatellite loci on chromosomes 3, 9, 13, 17, 18, and 22 were screened for alterations in tumor and healthy DNA. Survival was calculated by Kaplan-Meier plots. RESULTS: Eleven (18.3%) of 60 patients showed metastases at presentation. Thirteen (21.7%) of 60 were high-risk GISTs. LOH was found in all tumors. Twenty-eight (46.7%) of 60 showed more than two LOH in 21 microsatellite marker sites. The frequency of single marker LOH varied from 1.7% to 28.3% among tumors. Frequent LOH was found on chromosomes 22 and 17. The correlation of LOH positivity and the consensus scoring was significant (P=0.005, chi2 test). After a median observation time of 33.3 months (95% confidence interval, 23.9-42.6), overall survival was best for patients with tumors of very low, low, and intermediate risks with only 6 of 36 death events, whereas 14 of 24 high-risk and metastasized patients had died (P<0.001, log-rank test). Likewise, LOH significantly predicted survival (P=0.013) and the effect was particularly detrimental for LOH on chromosome 17 (P<0.001). CONCLUSIONS: LOH is a useful phenomenon for the prognosis of GIST. Rather than chromosome 22 markers, chromosome 17 markers independently predict survival.

L1 (CD171) is highly expressed in gastrointestinal stromal tumors.

The treatment strategy for mesenchymal tumors of the gastrointestinal tract is based upon typing of the tumor. Especially differential diagnosis of gastrointestinal stromal tumors (GISTs) to leiomyomas is crucial for determining radicality of surgery. L1 cell adhesion molecule (CD171) plays an essential role in tumor progression. The aim of this study was to determine expression of L1 in GISTs, smooth muscle tumors, desmoid-type fibromatosis and peripheral nerve sheath tumors (PNSTs). We retrospectively analyzed a total of 129 surgically resected primary tumors or metastases of 72 GISTs, 29 smooth muscle tumors, seven PNSTs and 21 desmoid-type fibromatosis by immunohistochemistry for c-kit, CD34, smooth muscle actin, desmin, vimentin, S-100 and L1 expression. L1 expression was detected in 53 (74%) of 72 GISTs but in none of 29 smooth muscle tumors or 21 desmoid-type fibromatosis (P<0.01 by Fisher's test). In all, four (57%) of seven peripheral nerve sheath tumors were L1-positive. Survival analysis of 55 surgically completely resected GISTs presenting without metastasis at initial diagnosis revealed no tumor-specific death among L1-negative patients (P=0.13 by log-rank test; median follow-up time 41 months) and one recurrence was observed (P=0.12). Interestingly high levels of L1 were seen in tumor vascular endothelial cells of smooth muscle tumors and PNSTs, but not in GISTs. Our data show that L1 is highly expressed in GISTs but not in smooth muscle tumors and desmoid-type fibromatosis being important differential diagnoses. The trend towards a reduced survival of L1-positive patients in this study has to be further evaluated in future trials with higher patient numbers.

Amplified Muc1-specific gene expression in colon cancer cells utilizing a binary system in adenoviral vectors.

Mucin-1 is expressed in a variety of colon carcinomas and Muc-1/DF3 promoters have been utilized to reduce systemic toxicity through specific gene expression. To overcome weak expression, which is much lower than the widely used cytomegalovirus-promoter (CMV), new adenoviral vectors containing a binary system of transgene amplification have been developed. The Muc-1/DF3 promoter was used to control the expression of a Gal4VP16 fusion protein. This vector also contained Gal4 binding sites enabling the fusion protein to act as a transactivator, inducing transgene expression within the same construct. Mucin-1 expression was analyzed in a variety of colon cancer cell lines. After infection with recombinant adenoviruses, transgene expression was quantified using the luciferase system. Integration of the Gal4VP16-binary resulted in an up to 250-fold increase of Muc-1/DF3-specific gene expression. In mucin-positive cell lines utilizing this amplified Muc-1/DF3 promoter, expression was up to 590-fold higher as compared to the CMV-promoter. Western blot detected the presence of Gal4VP16 in infected muc-1-positive but not-negative cell lines. These new adenoviral vectors combing highly efficient and specific transgene expression and will contribute to the safety and efficacy of experimental approaches in cancer gene therapy.