Extended total colonic aganglionosis and total intestinal aganglionosis: Challenging enemies.

AIM: Extended total colonic aganglionosis (ETCA) represents uncommon forms of Hirschsprung disease (HD), with aganglionosis extending into the proximal small bowel. ETCA management is challenging and associated with poor outcomes and high mortality. This study compares management and outcomes of ETCA to more common HD forms. METHODS: A retrospective cohort of HD patients (2012-2023) from two institutions. Three HD forms were compared: short-segment HD (SSHD, n = 19), long-segment HD or total colonic aganglionosis (LS/TCA, n = 9) and ETCA (n = 7). RESULTS: Normally innervated segments in ETCA patients ranged 0-70 cm. Median times to first surgery were; ETCA = 3 days versus TCA = 21 days (p = 0.017) and SSHD = 95 days (p < 0.001), respectively. Median number of surgeries were; ETCA = 4, versus TCA = 2 (p = 0.17) and SSHD = 1 (p = 0.002), respectively. All the patients underwent a definitive pull-through procedure, except four ETCA patients with a permanent jejunostomy and residual aganglionic segment of 57-130 cm. ETCA patients had 92% lower odds of enterocolitis (14%) compared to TCA patients (67%, p = 0.054), and comparable odds to SSHD patients (16%, p = 0.92). ETCA mortality was 14%. CONCLUSION: Extended total colonic aganglionosis patients require earlier and multiple interventions. Leaving an aganglionic segment may be advantageous, without increasing risk for enterocolitis. Tailored surgical treatment and rehabilitation programmes may prevent mortality and need for transplantation.

Suggested role for neutrophil extracellular trap formation in Ewing sarcoma immune microenvironment.

Ewing sarcoma (EWS) is a highly aggressive cancer with a survival rate of 70%-80% for patients with localized disease and under 30% for those with metastatic disease. Tumor-infiltrating neutrophils (TIN) can generate extracellular net-like DNA structures known as neutrophil extracellular traps (NETs). However, little is known about the presence and prognostic significance of tumor-infiltrating NETs in EWS. Herein, we investigated 46 patients diagnosed with EWS and treated in the Tel Aviv Medical Center between 2010 and 2021. TINs and NETs were identified in diagnostic biopsies of EWS by immunofluorescence. In addition, NETs were investigated in neutrophils isolated from peripheral blood samples of EWS patients at diagnosis and following neoadjuvant chemotherapy. The relationships between the presence of TINs and NETs, pathological and clinical features, and outcomes were analyzed. Our results demonstrate that TIN and NETs at diagnosis were higher in EWS patients with metastatic disease compared with those with local disease. High NET formation at diagnosis predicted poor response to neoadjuvant chemotherapy, relapse, and death from disease (p < 0.05). NET formation in peripheral blood samples at diagnosis was significantly elevated among patients with EWS compared with pediatric controls and decreased significantly following neoadjuvant chemotherapy. In conclusion, NET formation seems to have a role in the EWS immune microenvironment. Their presence can refine risk stratification, predict chemotherapy resistance and survival, and serve as a therapeutic target in patients with EWS.

The mechanism of intestinal stem cells differentiation after ischemia-reperfusion injury in a rat model.

PURPOSE: Notch and Wnt/ß-catenin signaling are responsible for regulation of intestinal stem cells (ISCs) proliferation and differentiation. The purpose of the study was to evaluate Wnt/ß-catenin and Notch signaling roles in regulation of ISC differentiation following ischemia-reperfusion (IR) injury in a rat. METHODS: Rats were assigned into two groups: Sham rats underwent laparotomy without vascular intervention and IR rats underwent occlusion of SMA and portal vein for 20 min followed by 48 h of reperfusion. Wnt/ß-catenin and Notch-related gene expression were determined using Real-Time PCR. Enterocyte proliferation, differentiation and Wnt-related proteins were determined by immunohistochemistry. RESULTS: IR rats demonstrated a significant decrease in ß-catenin gene expression, a decrease in cyclin D1 and ß-catenin positive cells in jejunum and ileum compared to Sham rats. IR rats demonstrated a significant increase in Notch-related gene expression in jejunum and ileum compared to Sham rats. The number of secretory cells was higher mainly in the jejunum and number of absorptive cells was significantly lower in jejunum and lower in ileum in IR rats compared to Sham rats. CONCLUSIONS: Intestinal stem-cell differentiation is toward secretory cells 48 h after IR injury; however, Wnt/ß-catenin pathway inhibition and Notch-related gene expression stimulation suggest crosstalk between pathways.

Neutrophils extracellular traps formation may serve as a biomarker for disease activity in oligoarticular juvenile idiopathic arthritis: a pilot study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, causing significant morbidity. Despite the dramatic improvement in treatment, many patients do not achieve complete remission, and biomarkers for subclinical disease, flares, and response to treatment are lacking. Neutrophils and neutrophil extracellular traps (NETs) play key roles in the pathogenesis of autoimmune and inflammatory conditions. In this study, we characterized neutrophil enzyme activity and NETs formation in oligoarticular and polyarticular JIA and explored their association with disease activity. METHODS: Neutrophils from 6 healthy controls and 7 patients with oligoarticular and polyarticular JIA were freshly isolated at time of diagnosis and after glucocorticoid intra-articular injection. Enzymatic activity of neutrophil granular enzymes was monitored by colorimetry and PMA-activated NETs formation was assessed using fluorescent microscopy. RESULTS: In this pilot and feasibility study, we revealed that NETs were significantly increased in oligoarticular JIA patients at time of diagnosis compared to healthy controls. Anti-inflammatory treatment using intra-articular steroid injection normalized NETs formation in these patients. Correlation between NETs formation and clinical Juvenile Activity Disease Activity Score-10 (cJADAS-10) was linear and significant (P = 0.007) in oligo but not in poly JIA patients. CONCLUSIONS: This is the first study exploring the link of NETs formation with oligo and poly JIA activity. We demonstrated a statistically significant linear correlation between cJADAS-10 and NETs formation in oligo but not in poly JIA patients. Hence, we suggest that NETs may reflect clinical disease activity in JIA, and may serve as a putative biomarker. Further work is needed to validate these initial results and determine the dynamics of NETs formation in JIA.

The role of gastrostomy feeding during intestinal rehabilitation for children with short bowel syndrome.

PURPOSE: Following extensive bowel resection, many children with short bowel syndrome (SBS) are routinely offered a placement of gastrostomy tube (G-tube) for feeding. This nutritional pathway is aimed to accommodate the gastric and small bowel motor disturbances related to SBS, and to promote weaning off parenteral nutrition (PN) to achieve enteral autonomy (EA). The aim of this study was to investigate the effect of gastrostomy feeding in outcomes of children with SBS. METHODS: A retrospective cohort of all SBS children managed at our multidisciplinary Intestinal Rehabilitation Center as part of an Intestinal Rehabilitation Program. SBS was defined as PN dependence for more than six weeks following extensive bowel resection. Patients treated with G-tube feeding were compared with patients without G-tube in terms of PN duration, reaching EA, physical development, and surgical parameters. RESULTS: A total of 36 SBS patients diagnosed between 2003 and 2022 were included. The most common etiologies included congenital intestinal atresia (31%) and necrotizing enterocolitis (25%). SBS-G-tube (group A) contained 20 children, and SBS (group B) contained 16 children. A total of 21 children reached EA (58%); ten from group A (50%), and 11 from group B (69%) (p > 0.05). Within EA patients, mean PN duration was 49 ± 44 months in group A, and 24 ± 33 months in group B (p > 0.05). Patients who reached EA had 22% longer residual small bowel when compared with PN-dependent patients (p = 0.003). However, the outcomes were adjusted for residual small and large bowel length and percentages, a residual ileocecal valve, and a colon in continuity with no differences between the groups. Two-thirds of children from group A reported G-tube related complications (mechanical, bleeding, or infections). We did not find differences in mean height and weight percentiles between the groups (p > 0.05). CONCLUSION: We did not find significant advantage of gastrostomy feeding in reaching EA. Because there are surgical and mechanical complications related to this procedure, further prospective studies are required to determine G-tube relevance for children with SBS.

Motility disorders in children with intestinal failure: a national tertiary referral center experience.

PURPOSE: Intestinal dysmotility (ID) problems are common in patients with pediatric-onset intestinal failure (IF) and short bowel syndrome (SBS), leading to significant morbidity and delays in the advancement of enteral nutrition (EN). We aimed to investigate the clinical features and complications of ID in children with IF and SBS. METHODS: Retrospective chart review of all children with IF and/or SBS who required parenteral nutrition (PN) > 6 weeks or small-intestinal resection ≥ 50%. Patients were divided into SBS and non-SBS groups. SBS group was divided into two subgroups: with and without ID. Patients with ID were identified (clinically, radiologically and functionally) and analyzed with regard to demographics, intestinal anatomy, complications and outcomes (short and long term). RESULTS: A total of 42 children with IF were treated in our institution during 2003-2022. In non-SBS group (n = 10), ID was the most common cause of IF (80%). SBS-group included 32 children; 18 children (56%) developed ID. The clinical profile of SBS-ID patients (vs SBS) was: female gender (56%), remaining small bowel length ≤ 55 cm, estimated residual small bowel ≤ 28% (p = 0.045) and absence of ICV (56%). Common symptoms of the SBS-ID group were: food intolerance (61%), abdominal distension (50%), vomiting (44%), malabsorption and severe constipation. Complications included FTT (67%) (p = 0.003), bacterial overgrowth with subsequent bloodstream infection (33%) (p = 0.75), and lactic acidosis (11%). Lengthening procedure (STEP) was performed in 11 SBS-ID patients (61%) (p = 0.002). In all patients, STEP operation "rescued" their dysfunctional intestine. Eight of these patients (73%) were weaned from TPN. Survival rate was 100%; however, one SBS-ID patient is a candidate for combined intestinal and liver transplantation. CONCLUSIONS: ID is the most common complication of SBS and is the most common cause of IF in non-SBS patients. ID has a high morbidity rate and various clinical manifestations. Successful treatment of these infants may be achieved with the use of tapering enteroplasty.

The Mechanisms of the Anti-Inflammatory and Anti-Apoptotic Effects of Omega-3 Polyunsaturated Fatty Acids during Methotrexate-Induced Intestinal Damage in Cell Line and in a Rat Model.

Background: The aim of this study was to examine the anti-inflammatory and anti-apoptotic patterns of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during methotrexate (MTX) induced intestinal damage in cell culture and in a rat model. Methods: Non-treated and treated with MTX HT 29 and HCT116cells were exposed to increasing doses of n-3 PUFAs and cell viability was evaluated using PrestoBlue® assay. Male Sprague-Dawley rats were divided into 4 experimental groups: Control rats, CONTR+n-3 PUFA rats that were treated with oral n-3 PUFA, MTX rats were treated with MTX given IP, and MTX+n-3 PUFA rats were treated with oral n-3 PUFA before and following injection of MTX. Intestinal mucosal parameters and mucosal inflammation, enterocyte proliferation and apoptosis, TNF-α in mucosal tissue and plasma (ELISA), NF-κB, COX-2, TNF-α, Fas, FasL, Fadd, Bid, Bax and Bcl-2gene and protein levels were determined 72 h following MTX injection. Results: Exposure of HT 29 and HCT116cells to n-3 PUFA attenuated inhibiting effects of MTX on cell viability. MTX-n-3 PUFA rats demonstrated a lower intestinal injury score and enhanced intestinal repair. A significant decrease in enterocyte apoptosis in MTX+n-3 PUFA rats was accompanied by decreased TNF-α, FAS, FasL, FADD and BID mRNA levels. Decreased NF-κB, COX-2 and TNF-α levels in mucosa was accompanied by a decreased number of IELs and macrophages. Conclusions: n-3 PUFAs inhibit NF-κB/COX-2 induced production of pro-inflammatory cytokines and inhibit cell apoptosis mainly by extrinsic pathway in rats with MTX-induced intestinal damage.

Cell death induction (extrinsic versus intrinsic apoptotic pathway) by intestinal ischemia-reperfusion injury in rats is time-depended.

PURPOSE: We investigate the mechanism of intestinal cell apoptosis and its relation to the time of reperfusion in a rat model of intestinal ischemia-reperfusion (IR). METHODS: Rats were divided into 4 groups: Sham-24 and Sham-48 rats underwent laparotomy without an intentional ischemic intervention and were sacrificed 24 or 48 h hours later; IR-24 and IR-48 rats underwent occlusion of SMA and portal vein for 20 min followed by 24 or 48 h of reperfusion, respectively. Park's injury score, cell proliferation and apoptosis were determined at sacrifice. Proliferation and apoptosis-related gene and protein expression were determined using Real-Time PCR, Western Blot and Immunohistochemistry. RESULTS: IR-24 rats demonstrated a strong increase in cell apoptosis along with an elevated Bax and decreased Bcl-2 expression and a decrease in cell proliferation (vs Sham-24). IR-48 group showed an increase in cell proliferation and a decrease in cell apoptosis compared to IR-24 animals. IR-48 rats demonstrated an increase in apoptotic rate that was accompanied by greater TNF-α mRNA, Fas mRNA and FasL mRNA compared to Sham-48 animals. CONCLUSION: While cell apoptosis in IR-24 rats is regulated mainly by intrinsic apoptotic pathway, 48 h followed ischemia extrinsic apoptotic pathway is responsible for pro-apoptotic effects of IR injury.

Intestinal dysmotility after bowel resection in rats is associated with decreased ghrelin and vimentin expression and loss of intestinal cells of Cajal.

This study provides novel insight into the mechanisms of intestinal dysmotility following massive small bowel resection. We show that 2 wk after bowel resection in rats, impaired intestinal motility was associated with loss of interstitial cells of Cajal (ICC; downregulation of transmembrane member 16A (TMEM16A) and c-kit expression) as well as with decreased vimentin, desmin, and ghrelin levels. Impaired intestinal motility led to a decrease in final body weight, suggesting less effective nutrient absorption. The purpose of this study was to evaluate the mechanisms of intestinal motility in a rat model of short bowel syndrome (SBS). Rats were divided into three groups: Sham rats underwent bowel transection; SBS-NSI rats underwent a 75% bowel resection and presented with normal intestinal size (NSI) at euthanasia and hypermotility patterns; SBS-DYS showed dysmotile (DYS) enlarged intestine and inhibited motility patterns. Animals were euthanized after 2 wk. Illumina's digital gene expression (DGE) analysis was used to determine the intestinal motility-related gene expression profiling in mucosal samples. Intestinal motility-related and ICC genes and protein expression in intestinal muscle layer were determined using real-time PCR, Western blotting, and immunohistochemistry. Gastrointestinal tract motility was studied by microcomputer tomography. From 10 Ca2+ signaling pathway-related genes, six genes in jejunum and seven genes in ileum were downregulated in SBS vs. Sham animals. Downregulation of TMEM16A mRNA and protein was confirmed by real-time PCR. Rapid intestinal transit time in SBS-NSI rats correlated with a mild decrease in TMEM16A, c-kit, and vimentin mRNA and protein expression (vs/. Sham animals). SBS-DYS rats demonstrated enlarged intestinal loops and delayed small intestinal emptying (on imaging studies) that were correlated with marked downregulation in TMEM16A, c-kit, vimentin, and ghrelin mRNA and protein levels compared with the other two groups. In conclusion, 2 wk following massive bowel resection in rats, impaired intestinal motility was associated with decreased vimentin and ghrelin gene and protein levels as well as loss of ICC (c-kit and TMEM16A).NEW & NOTEWORTHY This study provides novel insight into the mechanisms of intestinal dysmotility following massive small bowel resection. We show that 2 weeks after bowel resection in rats, impaired intestinal motility was associated with loss of interstitial cells of Cajal (downregulation of TMEM 16A, and c-kit expression) as well as with decreased vimentin, desmin, and ghrelin levels. Impaired intestinal motility led to decrease in final body weight, suggesting less effective nutrient absorption.

Predictive Value of Alvarado Score and Pediatric Appendicitis Score in the Success of Nonoperative Management for Simple Acute Appendicitis in Children.

INTRODUCTION: During the past decade, nonoperative management (NOM) for simple acute appendicitis (SAA) in children has been proven safe with noninferior complications rate. The aim of this study was to examine Alvarado score and pediatric appendicitis score (PAS) together with other factors in predicting failure of NOM in children presenting with SAA. MATERIALS AND METHODS: Patients aged 5 to 18 years admitted to our department between 2017 and 2019 diagnosed with SAA were given a choice between surgical management and NOM. We divided the NOM patients into two groups: successful treatment and failed NOM, comparing their files for Alvarado score and PAS and other clinical and demographic factors, with a mean follow-up of 7 months. Failure was determined as need for appendectomy following conservative treatment due to any reason. RESULTS: A total of 85 patients answered criteria and chose NOM. Overall failure rate was 32.9%. We found no difference in the mean Alvarado score and PAS as well as in each component of both scores between success and failed NOM groups. However, when using the risk classification of the scores, we found a significant correlation between high-risk Alvarado score and failed NOM. After adjusting for age, gender, duration of symptoms, diagnosis of tip appendicitis, and presence of appendicolith, the odds of failure were four times higher among high-risk Alvarado group. CONCLUSION: Alvarado score of 7 or higher, older age, and diagnosis of an appendicolith on imaging are possible predictors for failure of NOM for SAA in children.

Anti-TNF-α Therapy Exerts Intestinal Anti-inflammatory and Anti-apoptotic Effects After Massive Bowel Resection in a Rat.

OBJECTIVES: The aim of this study was to examine the effect of massive small bowel resection on proinflammatory cytokine intestinal expression and the effect of anti-TNF-α antibodies (ATA) on intestinal inflammation, epithelial cell turnover, and intestinal adaptation after bowel resection in rats. METHODS: Male Sprague-Dawley rats were divided into 4 experimental groups: Sham-rats underwent bowel transection; Sham-ATA rats underwent bowel transection and were treated with ATA; SBS-animals underwent 75% bowel resection; and SBS-ATA rats underwent bowel resection and were treated with ATA similarly to Group B. Parameters of intestinal adaptation, enterocyte proliferation, and apoptosis were determined at sacrifice. TNF-α and apoptosis-related gene and protein levels were determined by Illumina's Digital Gene Expression (DGE) analysis, Real Time PCR, Western blotting, and immunohistochemistry. RESULTS: From 25 genes related to TNF-α signalling that were investigated, 8 genes in the jejunum and 10 genes in the ileum were found to be up-regulated in resected versus sham animals. SBS rats demonstrated a significant increase in tissue and plasma TNF-α, IL-6 levels, intestinal mucosal TNF-α related gene expression, and microscopic parameters of inflammation. Treatment of resected animals with ATA resulted in a significant decrease in TNF-α levels, intestinal mucosal TNF-α-related gene expression, decreased number of intraepithelial lymphocytes and macrophages, and lower apoptotic index compared with SBS animals. CONCLUSIONS: In a rat model of SBS, ATA decreased plasma and tissue TNF-α levels, diminished mucosal inflammation, and inhibited cell apoptosis. Anti-apoptotic effects of ATA appear to be associated with an inhibited extrinsic apoptotic pathway.

Accelerated Intestinal Epithelial Cell Turnover Correlates with Stimulated BMP Signaling Cascade following Intestinal Ischemia-Reperfusion in a Rat.

INTRODUCTION: Bone morphogenetic proteins (BMPs) are a family of proteins that regulate proliferation and differentiation of intestinal epithelial cells. The purpose of this study was to evaluate the role of BMP signaling following intestinal ischemia-reperfusion (IR) in a rat model. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into four experimental groups: Sham-24 and Sham-48 rats underwent laparotomy and were sacrificed 24 or 48 hours later, respectively; IR-24 and IR-48 rats underwent occlusion of superior mesenteric artery and portal vein for 30 minutes followed by 24 or 48 hours of reperfusion, respectively. Enterocyte proliferation and apoptosis were determined at sacrifice. BMP-related genes and protein expression were determined using real-time polymerase chain reaction, Western blot, and immunohistochemistry for 48 hours followed by IR. RESULTS: IR rats demonstrated a significant increase in BMP2 (twofold increase, p < 0.05), BMP4 (sevenfold increase), STAT3 (70% increase), BMPR1 (70% increase) messenger ribonucleic acid levels in jejunum and was accompanied by a significant increase in BMP2 and BMP4 protein levels in jejunum (sixfold increase) (Western blot) and upward increase in the number of BMP-positive cells (by immunohistochemistry) in jejunal (48% increase) and ileal (56% increase) villi compared with Sham-48 animals. Elevation in BMP2 and BMP4 levels was associated with increased rates of cell proliferation and increased cell apoptosis. CONCLUSION: Forty-eight hours following intestinal IR in rats, BMP signaling pathway was stimulated. The increase in BMP signaling pathway activity correlates with accelerated cell turnover.

Effect of N-Acetylserotonin on TLR-4 and MyD88 Expression during Intestinal Ischemia-Reperfusion in a Rat Model.

BACKGROUND: Accumulating evidence indicates that changes in intestinal toll-like receptors (TLRs) precede histological injury in a rodent model of necrotizing enterocolitis. N-acetylserotonin (NAS) is a naturally occurring chemical intermediate in the biosynthesis of melatonin. A recent study has shown that treatment with NAS prevents gut mucosal damage and inhibits programmed cell death following intestinal ischemia-reperfusion (IR). The objective of this study was to determine the effects of NAS on TLR-4, myeloid differentiation factor 88 (Myd88), and TNF-α receptor-associated factor 6 (TRAF6) expression in intestinal mucosa following intestinal IR in a rat. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly assigned to one of the four experimental groups: 1) Sham rats underwent laparotomy; 2) Sham-NAS rats underwent laparotomy and were treated with intraperitoneal (IP) NAS (20 mg/kg); 3) IR rats underwent occlusion of both superior mesenteric artery and portal vein for 20 minutes followed by 48 hours of reperfusion; and 4) IR-NAS rats underwent IR and were treated with IP NAS immediately before abdominal closure. Intestinal structural changes, mucosal TLR-4, MyD88, and TRAF6 mucosal gene, and protein expression were examined using real-time PCR, Western blot, and immunohistochemistry. RESULTS: Significant mucosal damage in IR rats was accompanied by a significant upregulation of TLR-4, MyD88, and TRAF6 gene and protein expression in intestinal mucosa compared with control animals. The administration of NAS decreased the intestinal injury score, inhibited cell apoptosis, and significantly reduced the expression of TLR-4, MyD88, and TRAF6. CONCLUSION: Treatment with NAS is associated with downregulation of TLR-4, MyD88, and TRAF6 expression along with a concomitant decrease in intestinal mucosal injury caused by intestinal IR in a rat.

Sonic hedgehog signaling controls gut epithelium homeostasis following intestinal ischemia-reperfusion in a rat.

PURPOSE: One of the major regulators of gastrointestinal tract development is the hedgehog signaling pathway. The purpose of this study was to evaluate the role of sonic hedgehog (SHh) signaling 24 and 48 h following intestinal ischemia-reperfusion (IR) in a rat. MATERIALS AND METHODS: Male rats were divided into four experimental groups: (1) Sham-24 h rats underwent laparotomy and were sacrificed after 24 h, (2) Sham-48h rats underwent laparotomy and were sacrificed after 48 h, (3) IR-24h rats underwent occlusion of both superior mesenteric artery and portal vein for 20 min followed by 24 h of reperfusion, and (4) IR-48 h rats underwent ischemia for 20 min followed by 48 h of reperfusion. Intestinal structural changes, enterocyte proliferation and enterocyte apoptosis were determined by immunohistochemistry 24 and 48 h following IR. SHh-related genes and protein expression were determined using real-time PCR, Western blot and immunohistochemistry. RESULTS: IR-24 rats demonstrated a significant decrease in Shh, Ihh, GIL and Ptch2 mRNA in jejunum and ileum compared to Sham-24 animals that was accompanied by a significant decrease in the number of SHH-positive cells (Immunohistochemistry) in jejunum (2.5-fold decrease) and ileum (37%). After 48 h, IR rats demonstrated a significant increase in Dhh, Ihh, Gil and PTCH2 mRNA in jejunum as well as in Dhh, Ihh, SMO, GIL, PTCH2 mRNA in ileum compared to IR-24 animals that was coincided with increased number of SHH-positive cells in jejunum (2.6-fold increase) and ileum (1.4-fold increase). CONCLUSIONS: 24 h following intestinal IR, inhibited cell turnover was associated with inhibited SHh signaling pathway. Signs of intestinal recovery appeared 48 h after IR and were correlated with increase in SHh signaling pathway activity.

Effect of N-Acetylserotonin on Intestinal Recovery Following Intestinal Ischemia-Reperfusion Injury in a Rat.

OBJECTIVE: N-acetylserotonin (NAS) is a naturally occurring chemical intermediate in the biosynthesis of melatonin. Extensive studies in various experimental models have established that treatment with NAS significantly protects heart and kidney injury from ischemia-reperfusion (IR). The purpose of the present study was to examine the effect of NAS on intestinal recovery and enterocyte turnover after intestinal IR injury in rats. METHODS: Male Sprague-Dawley rats were divided into four experimental groups: (1) Sham rats underwent laparotomy, (2) sham-NAS rats underwent laparotomy and were treated with intraperitoneal (IP) NAS (20 mg/kg); (3) IR rats underwent occlusion of both superior mesenteric artery and portal vein for 30 minutes, followed by 48 hours of reperfusion, and (4) IR-NAS rats underwent IR and were treated with IP NAS (20 mg/kg) immediately before abdominal closure. Intestinal structural changes, Park injury score, enterocyte proliferation, and enterocyte apoptosis were determined 24 hours following IR. The expression of Bax, Bcl-2, p-ERK, and caspase-3 in the intestinal mucosa was determined using real-time polymerase chain reaction, Western blot, and immunohistochemistry. A nonparametric Kruskal-Wallis analysis of variance test was used for statistical analysis with p less than 0.05 considered statistically significant. RESULTS: Treatment with NAS resulted in a significant increase in mucosal weight in jejunum and ileum, villus height in the ileum, and crypt depth in jejunum and ileum compared with IR animals. IR-NAS rats also had a significantly proliferation rates as well as a lower apoptotic index in jejunum and ileum which was accompanied by higher Bcl-2 levels compared with IR animals. CONCLUSIONS: Treatment with NAS prevents gut mucosal damage and inhibits programmed cell death following intestinal IR in a rat.

[OUTCOMES OF HEPATIC, PANCREATIC AND GASTRIC SURGERY IN THE ELDERLY POPULATION: MORBIDITY, MORTALITY AND RESPONSE TO ONCOLOGIC TREATMENT].

INTRODUCTION: There is a continuous rise in the proportion of elderly people in the general population. Previously, old age was a contraindication for numerous medical procedures. AIM: To assess the postoperative outcome of elderly patients who underwent major surgery of the liver, pancreas and stomach. MATERIALS AND METHODS: A retrospective analysis of patients aged 75 and older who underwent elective operations for malignant tumors of the stomach, pancreas and liver between January 2005 and December 2009 in the Department of Surgery A, at Carmel Medical Center. RESULTS: Of 258 operations, 80 (31%) were performed on patients older than 75 years; 46 (57.5%) were for males and 34 (42.5%) for females, with a mean age of 79 years. One patient was operated on twice. In 68 Patients (85%) the disease was primary and in 12 (15%) it was metastatic; 28 (35.4%) tumors were in the distal stomach, 13 (16.5%) in the proximal stomach; in the pancreas 13 tumors (16.5%) were in the head and 8 (10.1%) in the body/tail; 17 patients had liver metastases (21.5%1; 68 operations (85%) were performed in an open approach and 12 (15%) laparoscopically. Median hospital stay was 12 (±7.48) days and median ICU stay was 2 (±3.53) days. Median followup was 23 (±23) months. Complete records of 76 patients showed that 33 (43.4%) are alive with no evidence of disease; 12 (15.8%) were alive with stable disease; 25 (32.89%) died of cancer and 6 (7.8%) of other causes. DISCUSSION: These favorable results allow us to offer elderly patients the entire spectrum of surgical and medical procedures without considering advanced age as an absolute contraindication. CONCLUSIONS: Chronological age as a single parameter should not be a contraindication for radical medical treatment.

[Intraoperative radiotherapy (IORT) in early breast cancer].

BACKGROUND: Breast-conservation therapy is widely accepted as an effective treatment option for patients with early stage carcinoma of the breast. The proportion of patients with recurrence after receiving partial breast irradiation is the same as that seen in patients treated with whole breast irradiation. Therefore, the necessity of whole breast irradiation has been questioned, and partial breast irradiation has emerged as a reasonable alternative. METHODS: Since 2006, 468 women with early breast cancer (age > 60 years, T1, infiltrative duct carcinoma and with no clinical or sonographic suspicion of involved axillary lymph nodes) were treated in the Carmel Medical Center with intraoperative radiotherapy, using the INTRABEAM System giving 20 Gy at the tumor bed. We report the cohort of the first 100 patients who have had a follow up period of more than 3 years. RESULTS: The median age was 70 years (range 56-87 years). Twenty four patients had mild to moderate local complications, while nine patients experienced major local complications. Eighteen patients had metastatic involvement of the axillary lymph nodes, and in 16 of them, only one node was involved. Five patients had additional local therapy (one patient underwent mastectomy and four patients received whole breast irradiation). During the follow up period, four ipsilateral breast failures were observed: two new primary tumors (by location and histology) and two local recurrences. CONCLUSIONS: Intraoperative radiotherapy using the INTRABEAM system is feasible and may offer an alternative to whole breast radiotherapy, in low risk early breast cancer patients with a low rate of local recurrence and morbidity. Longer follow up is required in order to evaluate long term results and late toxicity.