Lessons following implementation of a colorectal enhanced recovery after surgery (ERAS) protocol in a rural hospital setting.

INTRODUCTION: Enhanced recovery after surgery (ERAS) programs have become increasingly popular in the management of patients undergoing colorectal resection. However, the validity of ERAS in rural hospital settings without intensive care facilities has not been primarily evaluated. This study aimed to assess an ERAS protocol in a rural surgical department based in Invercargill New Zealand. METHODS: Ten years of prospectively collected data were analysed retrospectively from an ERAS database of all patients undergoing open, converted, or laparoscopic colorectal resections. Data were collected between two time periods: before the implementation of an ERAS protocol, from January 2011 to December 2013; as well as after the implementation of an ERAS protocol, from January 2014 to December 2020. The primary outcome measures were hospital length of stay (LOS) and LOS in the critical care unit (LOS-CCU). Secondary outcomes were compliance with ERAS protocol, mortality, readmission, and reoperation rates. RESULTS: A total of 118 and 558 colorectal resections were performed in the pre-ERAS and ERAS groups respectively. A statistically significant reduction in hospital LOS was achieved from a median of 8 to 7 days (P = 0.038) when comparing pre-ERAS to ERAS groups respectively. Furthermore, a significant reduction in re-operation rates was observed (7.6% vs. 3% in the ERAS group, P = 0.033) which was seen without a rise in readmission rates (13.6% vs. 13.6% in the ERAS group). CONCLUSION: The implementation of ERAS in a rural surgical setting is feasible, and these initial findings suggest ERAS adds value in optimizing the colorectal patient's surgical journey.

Diagnosis and treatment of a rare case of an incarcerated bilateral Spigelian hernia with the vermiform appendix and caecum.

Spigelian hernia is a rare form of abdominal wall defect. Bilateral Spigelian hernias are even less common. Surgical repair of Spigelian hernias is recommended due to their high risk of incarceration and strangulation of abdominal contents. A variety of surgical approaches to repair these hernias have been described in the literature including the traditional open approach, laparoscopic transabdominal preperitoneal approach, laparoscopic intraperitoneal repair and laparoscopic totally extraperitoneal repair. Here, we present the case of an elderly female patient with rare bilateral Spigelian hernias, the right side containing incarcerated appendix and caecal pole. The left hernia was unrecognised on preoperative CT imaging. To our knowledge, very few cases have been reported in the literature. The patient underwent bilateral laparoscopic intraperitoneal mesh repair. All technical aspects of the treatment are discussed here, in the context of the current literature, including the surgical technique and the limitations of the CT diagnosis. We aim to summarise the background of these uncommon hernias, the limitations of preoperative investigations and the differences between the available operative approaches.

Integrating palliative surgery and palliative care.

We report a challenging patient journey at a rural New Zealand hospital affiliated with a hospice programme. This case illustrates the complexities and rewards of achieving a valuable and sensible collaboration among various teams to ensure the best possible outcome for surgical patients receiving palliative care.

Mutational status of KIT and PDGFRA and expression of PDGFRA are not associated with prognosis after curative resection of primary gastrointestinal stromal tumors (GISTs).

BACKGROUND: The aim of this study was to investigate if immunohistochemical expression and mutational status of KIT and PDGFRA in GISTs are associated with the clinical course and disease-free survival after curative resection of the primary tumor without adjuvant systemic therapy. METHODS: Paraffin-embedded tumor sections of 95 GISTs were analyzed for KIT and PDGFRA expression by immunohistochemistry. PDGFRA expression was judged using a scoring system subdividing tumors in negative/weak and strong immunoreactivity groups. For mutation analysis, exons 9, 10, 11, 13, and 17 of KIT and exons 10, 12, 14, and 18 of PDGFRA were sequenced. RESULTS: Of 95 R0-resected GISTs, 69% showed strong PDGFRA immunoreactivity. Gastric GISTs revealed a significantly higher rate of strong PDGFRA immunoreactivity (P = 0.01) and longer DFS (P = 0.015) than GISTs of the small intestine. KIT mutations were detected in 43 of 63 (68.3%) completely sequenced cases while PDGFRA mutations were identified in 6 cases (10%). In multivariate analysis, neither KIT/PDGFRA expression nor mutational status of KIT or PDGFRA were independent prognostic factors. Only mitotic rate predicted recurrence independently. CONCLUSION: Our data do not support the notion that expression of PDGFRA or mutations in KIT or PDGFRA are independent prognostic factors after curative resection of primary GIST.

Laparoscopic spleen-preserving dome resection for a giant primary epithelial splenic cyst.

Non-parasitic splenic cysts are rare and are seldom diagnosed outside the paediatric surgical practice. Giant true primary epithelial cysts greater than 14 cm in diameter are even rarer. Laparoscopic surgery is preferable; however, bleeding, splenectomy and recurrence are recognised risks. Here, we report a young female patient with a 21 cm symptomatic primary splenic cyst. The patient underwent a spleen-preserving laparoscopy and was followed up for 2 years when she had an MRI of the abdomen. Surgical, technical and perioperative treatment aspects are discussed here, in the context of the current literature.

Biallelic variants in EFEMP1 in a man with a pronounced connective tissue phenotype.

Connective tissue disorders are a spectrum of diseases that affect the integrity of tissues including skin, vasculature, and joints. They are often caused by variants that disrupt genes encoding components of extracellular matrix (ECM). The fibulin glycoproteins are ECM proteins important for integrity of tissues including dermis, retina, fascia, and vasculature. The fibulin family consists of seven members (fibulins-1 to -7) and is defined by a fibulin-type domain at the C-terminus. The family is associated with human diseases, for instance a variant in FBLN1, encoding fibulin-1, is associated with synpolydactyly, while one in EFEMP1, encoding fibulin-3, causes Doyne honeycomb degeneration of the retina. Loss-of-function of fibulins-4 and -5 causes cutis laxa, while variants in fibulins-5 and -6 are associated with age-related macular degeneration. Of note, EFEMP1 is not currently associated with any connective tissue disorder. Here we show biallelic loss-of-function variants in EFEMP1 in an individual with multiple and recurrent abdominal and thoracic herniae, myopia, hypermobile joints, scoliosis, and thin translucent skin. Fibroblasts from this individual express significantly lower EFEMP1 transcript than age-matched control cells. A skin biopsy, visualised using light microscopy, showed normal structure and abundance of elastic fibres. The phenotype of this individual is remarkably similar to the Efemp1 knockout mouse model that displays multiple herniae with premature aging and scoliosis. We conclude that loss of EFEMP1 function in this individual is the cause of a connective tissue disorder with a novel combination of phenotypic features, and can perhaps explain similar, previously reported cases in the literature.

Long-term follow-up in 54 surgically treated patients with gastrointestinal stromal tumours.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the alimentary tract. Since these tumours are rather resistant to radiation and conventional chemotherapy, prognosis may be poor. Imatinib, a KIT tyrosine kinase inhibitor, has been shown to have dramatic antitumour effects on GISTs; however, surgical en bloc resection of the tumour with free resection margins remains still the first option for cure. MATERIALS AND METHODS: Here, we present a retrospective study with 54 consecutive GIST patients who were treated surgically at our University Hospital between 1993 and 2005 and were followed up at 5 and 10 years. RESULTS: The disease-specific survival rate was 94% at 1 year, 91% at 3 years, 76% at 5 years, and 72% at 10 years. In univariate analysis, tumour size, mitotic rate, morphology, and necrosis predicted survival in patients with negative margins. Age, sex, and symptoms did not influence outcome. CONCLUSION: GISTs have a high incidence of associated secondary malignancies which may have a significant influence on prognosis and outcome. Patients with R0 resections had a significantly better survival rate of 86% at 5 years and of 81% at 10 years than those with R1 and R2 resections (21% and 0%).

Physiological concentrations of butyrate favorably modulate genes of oxidative and metabolic stress in primary human colon cells.

Butyrate, a metabolite of gut flora-mediated fermentation of dietary fibre, was analysed for effects on expression of genes related to oxidative stress in primary human colon cells. An induction of detoxifying, antioxidative genes is expected to contribute to dietary chemoprevention. Cells were treated with butyrate (3.125-50 mM; 0.5-8 h), and kinetics of uptake and survival were measured. Gene expression was determined with a pathway-specific cDNA array after treating colon epithelium stripes with nontoxic doses of butyrate (10 mM, 12 h). Changes of hCOX-2, hSOD2 and hCAT expression were confirmed with real-time polymerase chain reaction (PCR) and by measuring catalase-enzyme activity. Primary colon cells consumed 1.5 and 0.5 mM butyrate after 4- and 12-h treatment, respectively. Cell viability was not changed by butyrate during 0.5-2-h treatment, whereas cell yields decreased after 1 h. Metabolic activity of remaining cells was either increased (4 h, 50 mM) or retained at 97% (8 h, 50 mM). Expression of hCAT was enhanced, whereas hCOX-2 and hSOD2 were lowered according to both array and real-time PCR analysis. An enhanced catalase-enzyme activity was detected after 2 h butyrate treatment. Healthy nontransformed colon cells well tolerated butyrate (50 mM, 2 h), and lower concentrations (10 mM, 12 h) modulated cyclooxygenase 2 (COX-2) and catalase genes. This points to a dual role of chemoprotection, since less COX-2 could reduce inflammatory processes, whereas more catalase improves detoxification of hydrogen peroxide (H(2)O(2)), a compound of oxidative stress. Changes of this type could reduce damaging effects by oxidants and protect cells from initiation.

Risk Factors for Adverse Outcome for Elderly Patients undergoing Curative Oncological Resection for Gastrointestinal Malignancies.

BACKGROUND: The incidence of gastrointestinal cancer increases with age, with approximately 20% of these cases in people over 80 years of age. Due to pre-existing comorbidities, this onco-geriatric population often presents diagnostic and therapeutic challenges. METHODS: A systematic review of articles on PubMed was performed to determine the predictive ability of screening tools and their components regarding the occurrence of adverse outcomes in elderly onco-surgical patients with gastrointestinal malignancies. RESULTS: Surgical procedures in this patient cohort, particularly complex resections, may result in increased morbidity and mortality. The decision to treat an elderly patient with curative intent requires sound clinical judgment based on knowledge, consideration of objective parameters, and experience. These patients could potentially be optimized for surgery with the improvement of nutritional and overall performance status as well as with stabilizing comorbidities. CONCLUSION: Various geriatric assessment and screening tools have been developed to identify risk factors to assist the surgeon and the interdisciplinary team in treatment planning, including the Frailty Assessment Score, Timed Up and Go test, nutritional status, and Activities of Daily Living test. It is important to emphasize that transparent and open communication between the treating surgeon and the patient is crucial in that the patient fully understands the implications of the treatment plan.

Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: a preclinical study in a novel rat model.

PURPOSE: Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator. METHODS AND MATERIALS: Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the "scrotal hernia" was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation. RESULTS: Orazipone significantly ameliorated histologic injury and transforming growth factor-beta immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation. CONCLUSIONS: This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens.

Uranyl nitrilotriacetate, a stabilized salt of uranium, is genotoxic in nontransformed human colon cells and in the human colon adenoma cell line LT97.

Previous uranium mining in the "Wismut" region in Germany enhanced environmental distribution of heavy metals and radionuclides. Carryover effects may now lead to contamination of locally produced foods. Compounds of "Wismut" origin are probably genotoxic via their irradiating components (radon) or by interacting directly with cellular macromolecules. To assess possible hazards, we investigated the genotoxic effects of uranyl nitrilotriacetate (U-NTA) in human colon tumor cells (HT29 clone 19A), adenoma cells (LT97), and nontransformed primary colon cells. These are target cells of oral exposure to environmentally contaminated foods and represent different cellular stages during colorectal carcinogenesis. Colon cells were incubated with U-NTA. Cell survival, cytotoxicity, cellular glutathione (GSH) levels, genotoxicity, and DNA repair capacity (comet assay), as well as gene- and chromosome-specific damage combination of comet assay and fluorescence in situ hybridization [FISH], 24-color FISH) were determined. U-NTA inhibited growth of HT29 clone 19A cells (75-2000 microM, 72 h) and increased GSH (125-2000 microM, 24 h). U-NTA was genotoxic (1000 microM, 30 min) but did not inhibit the repair of DNA damage caused by hydrogen peroxide (H(2)O(2)), 4-hydroxynonenal, and 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]-pyridine. U-NTA was also genotoxic in LT97 cells and primary colon cells, where it additionally increased migration of TP53 into the comet tail. In LT97 cells, 0.5-2mM U-NTA increased chromosomal aberrations in chromosomes 5, 12, and 17, which harbor the tumor-related genes APC, KRAS, and TP53. It may be concluded that uranium compounds could increase alimentary genotoxic exposure in humans if they reach the food chain in sufficient amounts.

Hemoglobin and hemin induce DNA damage in human colon tumor cells HT29 clone 19A and in primary human colonocytes.

Epidemiological findings have indicated that red meat increases the likelihood of colorectal cancer. Aim of this study was to investigate whether hemoglobin, or its prosthetic group heme, in red meat, is a genotoxic risk factor for cancer. Human colon tumor cells (HT29 clone 19A) and primary colonocytes were incubated with hemoglobin/hemin and DNA damage was investigated using the comet assay. Cell number, membrane damage, and metabolic activity were measured as parameters of cytotoxicity in both cell types. Effects on cell growth were determined using HT29 clone 19A cells. HT29 clone 19A cells were also used to explore possible pro-oxidative effects of hydrogen peroxide (H2O2) and antigenotoxic effects of the radical scavenger dimethyl sulfoxide (DMSO). Additionally we determined in HT29 clone 19A cells intracellular iron levels after incubation with hemoglobin/hemin. We found that hemoglobin increased DNA damage in primary cells (> or =10 microM) and in HT29 clone 19A cells (> or =250 microM). Hemin was genotoxic in both cell types (500-1000 microM) with concomitant cytotoxicity, detected as membrane damage. In both cell types, hemoglobin and hemin (> or =100 microM) impaired metabolic activity. The growth of HT29 clone 19A cells was reduced by 50 microM hemoglobin and 10 microM hemin, indicating cytotoxicity at genotoxic concentrations. Hemoglobin or hemin did not enhance the genotoxic activity of H2O2 in HT29 clone 19A cells. On the contrary, DMSO reduced the genotoxicity of hemoglobin, which indicated that free radicals were scavenged by DMSO. Intracellular iron increased in hemoglobin/hemin treated HT29 clone 19A cells, reflecting a 40-50% iron uptake for each compound. In conclusion, our studies show that hemoglobin is genotoxic in human colon cells, and that this is associated with free radical mechanisms and with cytotoxicity, especially for hemin. Thus, hemoglobin/hemin, whether available from red meat or from bowel bleeding, may pose genotoxic and cytotoxic risks to human colon cells, both of which contribute to initiation and progression of colorectal carcinogenesis.

Challenging differential diagnosis of a wild-type gastrointestinal stromal tumour (GIST) or rare reticular perineurioma of the stomach? The role for mutational analysis.

The differential diagnosis of submucosal stomach lesions includes gastrointestinal stromal tumour (GIST), leiomyoma, synovial sarcomas, perineurioma, myxoid chondrosarcoma, myoepithelial tumour and other rare mesenchymal tumours. GISTs are well-defined lesions with distinctive morphologic and histogenetic characteristics that show 95% positive staining for CD117. Differential diagnosis of wild-type GISTs can be challenging. Here, we present two stomach tumours that were operated on in our surgical department. Both presented with positive immunoreactivity for CD117. In one tumour, c-Kit mutation analysis demonstrated positivity of exon 11_c.1674_1676delGGT, thus confirming the diagnosis of a GIST. Mutational analysis of the second stomach lesion demonstrated negativity for all known c-KIT and PDGFRA exons. In situ hybridisation ruled out a synovial sarcoma. An additional immunohistochemical staining for epithelial membrane antigen eventually confirmed the diagnosis of an extremely rare reticular perineurioma in the stomach, so far reported for the second time worldwide. Both patients have not shown any signs of recurrence 2 years after surgery. The presented cases emphasise the benefits of performing a mutational analysis in difficult GISTs, including wt-GISTs, and demonstrates the importance and challenges in differentiating GISTs from other mesenchymal tumours.

Laparoscopic adrenalectomy for a rare 14-cm adrenal schwannoma.

Laparoscopic surgery for adrenal tumors is the gold standard for benign tumors; however, its role for adrenal cancer, metastases, and large suspicious lesions remains controversial. This aspect becomes clinically more important as larger incidentaloma are being detected with increasing frequency. Here, we discuss a rare case of a giant 14-cm adrenal schwannoma, which presented as an incidentaloma and was excised laparoscopically. Epidemiology, histology, and surgical treatment options were reviewed. An abdominal computerized tomography scan of a 30-year-old female weighing 130 kg revealed a large left adrenal mass. Preoperative biochemical and endocrine workup confirmed that it was nonfunctioning. The patient had a laparoscopic adrenalectomy without complication. The nodular tumor measured 145 × 100 × 80 cm in size and weighed 312 g. Histopathology showed myxoid areas and spindle cells arranged in a palisading manner. Mitoses were not observed. Tumor cells were immunohistochemically strongly positive for S-100, but negative for CD117, desmin, and muscle-specific actin. There was no evidence of malignancy. The diagnosis was of a benign schwannoma. Adrenal schwannoma is an extremely rare entity and can grow considerably in size. So far, this is the largest adrenal schwannoma reported in literature. In agreement with a growing number of publications, laparoscopic adrenalectomy can also be used for potentially malignant tumors larger than 10 cm in diameter provided the tumor does not infiltrate into other organs, conversion to open surgery is carefully considered, and resection occurs within the anatomic planes, thus ensuring the intactness of the tumor capsule.

Down-regulation of MTUS1 in human colon tumors.

Loss of proliferative control and failure to undergo cellular differentiation are key events during carcinogenesis. We recently identified a new potential tumor suppressor gene named MTUS1 (mitochondrial tumor suppressor 1), down-regulated in undifferentiated tumor cell lines, inhibiting tumor cell proliferation after recombinant over-expression. The aim of this study was to investigate whether MTUS1 is also down-regulated in human tumor tissues, and whether reduced expression of MTUS1 enhances cellular proliferation. Expression of MTUS1 in human colon cancer tissues was compared with corresponding normal colon tissues using Western blot analysis and RT-PCR. Investigation of the DNA sequence and methylation pattern was performed using bisulfite reaction and DNA sequencing. Promotor activity was measured by promoter assays. Silencing of MTUS1 was carried out by siRNA transfection. Proliferation was measured by cell count. MTUS1 expression is significantly down-regulated in colon cancer tissues, compared to the corresponding normal tissues, on protein and mRNA level. No mutations of MTUS1 were detected in the coding sequence or the predicted promoter region in cancer tissues. No difference of CpG methylation, but an altered CpNpG methylation was found in the predicted promoter region. Functional significance of the predicted promoter region was demonstrated by promoter assays. Down-regulation of the MTUS1 expression by siRNA transfection significantly increased cellular proliferation. This study demonstrates a significant down-regulation of the MTUS1 expression in human colon cancer tissues. Since reduced expression of MTUS1 results in increased cellular proliferation, these data suggest that MTUS1 could be involved in the loss of proliferative control in human colon cancer.