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Aim: To evaluate the long-term success rate of treatment with the Surgisis® (Biodesign®) anal fistula plug for complex anal fistulas, assess fistula plug failure over time and compare success rates for fistula plug between a group of patients with cryptoglandular fistula and another group with Crohn's fistula. Method: This is a single-centre study of consecutive patients treated with the Surgisis® (Biodesign®) anal fistula plug between May 2006 and October 2009. All patients had complex anal fistulas in need of surgical treatment. The patients were assessed preoperatively by physical examination and three-dimensional (3D) endoanal ultrasound, and treated with a loose seton. Postoperative assessment by clinical examination and 3D endoanal ultrasound was performed at 2 weeks, 3 months and 6–12 months. Long-term follow-up was carried out in 2017 using a questionnaire, and clinical examination combined with 3D endoanal ultrasound was performed if the questionnaire indicated any signs of fistula recurrence. Results: A total of 95 patients were included; 30 had quiescent Crohn's disease. Overall, 151 plug procedures were performed. Long-term follow-up was undertaken in 90 (95%) patients; the results showed that after a median period of 110 months, the overall healing rate after one to five plug procedures was 38%. No statistically significant difference in success rate was found between the cryptoglandular fistula group and the Crohn's fistula group (P = 0.37). No further healing was observed after the use of three plugs. Conclusion: Considering its low morbidity in a complex disease with high recurrence rates over time, the anal fistula plug may still be considered as one of the first-line treatments for patients with complex anal fistulas. (Less)

Background The aim of the present study was to evaluate percutaneous tibial nerve stimulation (PTNS) for treatment resistant chronic anal fissure. Methods Consecutive patients with chronic anal fissure were treated with neuromodulation via the posterior tibial nerve between October 2013 and January 2014. Patients had PTNS for 30 min on 10 consecutive days. All patients had failed conventional medical treatment. The visual analogue scale (VAS) score, St. Marks score, Wexner’s constipation score, Brief Pain Inventory (BPI-SF), bleeding and mucosal healing were evaluated before treatment, at termination, after 3 months, and then yearly for 3 years. Results Ten patients (4 males and 6 females; mean age 49.8 years) were identified but only 9 were evaluated as one patient’s fissure healed before PTNS was started. At 3-year follow-up, fissures had remained completely healed in 5 out of 9 patients. All patients stopped bleeding and were almost completely pain-free at 3 years (VAS p = 0.010) and pain relief improved from 50% at completion to 90% at 3 years. The patients’ Wexner constipation scores improved significantly (p = 0.007). Conclusions In this small series, PTNS enhanced healing of chronic anal fissure and reduced pain and bleeding with an associated improvement in bowel function.

Background Oral administration of health-promoting bacteria is increasingly used in clinical practise. These bacteria have anti-inflammatory characteristics and modulate the immune system without major reported side effects. The mechanisms of action are not yet fully defined. Our aim was to study systemic effects of probiotics by measurements of leukocytes as well as local effects on rectal mucosal biopsies after adding a standardized inflammatory stimulus in vitro. Methods Fourteen healthy subjects were randomized to receive 1010 colony forming units/day orally of the probiotic strain Lactiplantibacillus plantarum 299 (Lp299), n = 7, or Bifidobacterium infantis CURE21 (CURE21), n = 7, for six weeks. Rectal biopsies were taken before and after ingestion of either probiotic strain product, for stimulation in vitro with tumour necrosis factor alpha (TNF-α) at 10 and 100 ng/ml respectively up to 8 h. Blood tests were sampled before and after treatment. Lactate dehydrogenase (LDH) confirmed viable tissue. Results Composition of the intestinal microbiota was not changed. Systemic leukocytes decreased after administration of CURE21 (PP Conclusions Administration of these probiotic strains to healthy humans show both a systemic and local reduction of inflammatory response by lowering leukocyte counts, and for Lp299 IL-6 levels in rectal mucosa. Probiotics may play an important role in the reduction of inflammatory responses expected after trauma during surgery or after pelvic irradiation. Trial registration Clinical Trials, registration number NCT01534572, retrospectively registered (http://www.clinicaltrials.gov).

PURPOSE: It has been proposed that biological/chemical substances in the intestine might play a role in the occurrence and deterioration of perianal fistulas. Elimination of such unidentified factors from the lower gastrointestinal tract might offer a new strategy for the management of anal fistulas. The aim of this study was to evaluate the clinical effects on non-Crohn's disease perianal fistula healing, and the safety and tolerability of a new medical device that applies high-purity, high-activity granular activated carbon locally into the rectum twice daily of patients with perianal fistulas without any concomitant medication.METHODS: An open, single-arm, prospective study with active treatment for 8 weeks and an optional follow-up until week 24 ( ClinicalTrial.gov identifier NCT01462747) among patients with chronic, uncomplicated perianal fistulas scheduled for surgery was conducted.RESULTS: Of 28 patients included, 10 patients (35.7%) showed complete fistula healing (closed, no discharge on palpation) after 8 weeks; seven of these patients, corresponding to 25% of the enrolled patients, remained in remission for up to 31 weeks. At week 8, there was a statistically significant reduction in the discharge visual analog scale (p = 0.04), a significant improvement in the patient-perceived quality of life for the category of embarrassment (p = 0.002), and a trend toward improvement in the other assessment categories.CONCLUSIONS: The treatment was well tolerated, and patient acceptance was high. The results support the efficacy and safety of locally administered activated carbon for the treatment of patients with chronic uncomplicated perianal fistulas not receiving any other medication for fistula problems.

Secondary hyperparathyroidism in elderly fragile patients presents clinical difficulties due to severity of symptoms and related comorbidity. The optimal surgical approach for this group of patients is still debated. The aim of the study was to define the optimal technique of parathyroidectomy in elderly patients with secondary hyperparathyroidism. Retrospective analysis in a series of 253 patients including 35 elderly individuals at a single institution was carried out. Postoperative parathyroid hormone decrease, surgical complications and symptoms control were analyzed for all patients in relation to the types of parathyroidectomy performed. In elderly patients, total parathyroidectomy was the most used approach. Subtotal parathyroidectomy was mostly reserved for younger patients suitable for kidney transplantation. No elderly patients treated with total parathyroidectomy were autotransplanted. No significant difference in surgical complications was observed between younger and elderly patients and considering the different procedures. Adequate symptom control after surgery was achieved in almost 90% of patients. A limited rate of recurrence requiring repeat surgery was observed only after subtotal parathyroidectomy. Considering the features of all types of parathyroidectomy, very low recurrence rate, contained postoperative hypocalcemia and limited complications following total parathyroidectomy, might represent specific advantages for elderly patients. Total parathyroidectomy without parathyroid transplantation is safe for elderly patients with secondary hyperparathyroidism and a good alternative to the well-established total parathyroidectomy with autografting.

Background/Aim: Matrix metalloproteinase 7 (MMP7) expression is highly associated with colorectal cancer and modulates tumour growth and invasion. Radiation injury induces inflammation with increases in MMP7 and in transforming growth factor beta (TGFβ). The aim of this study was to investigate the effect on MMP7 and TGFβ. expression in patients with rectal cancer undergoing different regimens of neoadjuvant radiotherapy (RT). Patients and Methods: We studied 53 patients in three RT treatment groups receiving RT of 25 Gy, long-term RT 50 Gy and controls receiving no RT. Three biopsies were obtained from each patient during the treatments: before RT, after RT and after surgery. Tissue samples were formalin fixed, paraffin embedded and tissue microarrays were constructed and stained for MMP7 and TGFβ. Mann–Whitney U-tests and Wilcoxon Z-tests were used to determine differences between patients before and after RT, and after surgery, as well as between the RT groups. Results: In all three patient groups, increases of MMP7 and TGFβ expression were observed after surgery. MMP7 expression was significantly increased in patients receiving short-term RT but TGFβ expression was not affected by RT. Conclusion: 50 Gy Irradiation of rectal cancer gives less tumour activation of MMP7, whilst it is up-regulated by 25 Gy and surgery regardless of RT. (Less)

This chapter briefly summarizes the epidemiology, pathophysiology, clinical management, and outcomes of patients with pancreatic neuroendocrine tumors (PNETs) and highlights recent advances in PNET research. PNETs are rare neoplasms, compared with carcinomas arising from pancreatic exocrine tissue. They, like other neuroendocrine tumor types, display variable malignant potential, hormone-related syndromes (functionality), localization, and genetic background. Although tumor origin and molecular pathogenesis remain poorly understood, recently established grading and staging systems facilitate patient risk stratification and thereby directly impact clinical decision-making. Although the optimal clinical management of PNETs involves a multidisciplinary approach, surgery remains the only curative treatment for early-stage disease. Surgery may also have a role in patients with advanced stage disease, including those with hepatic metastases. Alternative therapeutic approaches applied to PNETs, including chemotherapy, radiofrequency ablation, transarterial chemoembolization, biotherapy, polypeptide radionuclide receptor therapy, antiangiogenic therapy, and selective internal radiotherapy, have failed to demonstrate a long-term survival benefit. Surgery remains the primary therapeutic option for patients with PNETs. Research on PNETs is desperately needed to improve the therapeutic options for patients with this disease.

This study presents the results of surgery in the elderly for primary hyperparathyroidism (PHPT) from a single institution's experience. We retrospectively analyzed 898 cases of surgically treated PHPT, divided into two groups: 135 elderly patients (A) and 763 patients younger than 65 years (B). PHPT was symptomatic in 68.8 per cent patients in group A and in 81.6 per cent in group B. Unilateral temporary recurrent laryngeal nerve palsy was observed in 0.9 per cent in group A and 0.1 per cent in group B (P > 0.05). No cervical hematomas, mortality or major cardiovascular, neurological, respiratory or metabolic postoperative complications were registered. All the patients evaluated at one year had improvement in the quality of life, with increase of bone mineral density (BMD) in 85.6 per cent and 79.8 per cent of patients in groups A and B, with no significant differences between symptomatic and asymptomatic patients. Parathyroidectomy in elderly PHPT patients is safe, with rate of morbidity similar to what observed in younger individuals. Further investigations are recommended to confirm the role of surgery as an effective approach in elderly PHPT patients.

Laparoscopic liver resection (LLR) appears to be safe and effective as open liver resection (OLR) for hepatocellular carcinoma (HCC). However, studies comparing LLR with ORL in elderly patients are limited. The purpose of this study is to compare the clinical outcomes of LLR versus OLR for HCC in elderly patients. A retrospective analysis was made comparing laparoscopic (n = 11) and open (n = 18) liver resections in elderly patients performed at the University of Naples “Federico II” between January 2010 and December 2014. Demographic data, operative and postoperative outcomes were analyzed. Demographic and tumor characteristics of laparoscopic and OLRs were similar. There were also no significant differences in operating room time. Patients undergoing OLR had increased rate of minor complications (33 vs. 0%), longer lengths of stay (6 vs. 3 days) and higher blood loss (310 ± 84 vs. 198 ± 34 ml). There were no significant differences in major complication rates or 90-day mortality. LLR is safe and feasible as OLR for treatment of HCC in selected elderly patients.

Laparoscopic distal pancreatectomy (LDP) appears to be safe and effective as open distal pancreatectomy (ODP) for benign or borderline malignant lesion. However, studies comparing LDP with ODP in elderly patients are limited. The purpose of this study is to compare the clinical outcomes of these two several approaches in elderly patients. A retrospective analysis was carried out by comparing laparoscopic (n = 7) and open (n = 15) distal pancreatectomy in elderly patients performed at the University of Naples “Federico II” and University of Perugia between January 2012 and December 2015. Demographic data, operative and postoperative outcomes were analyzed. Demographic and tumor characteristics of laparoscopic and ODP were similar. There were also no significant differences in operating room time. Patients undergoing LDP had lower blood loss, first flatus time, diet start time and postoperative hospital stay. There were no significant differences in complication rates or 90-day mortality. LDP is safe and feasible as ODP in selected elderly patients.

The special AT-rich sequence-binding protein 2 (SATB2), a nuclear matrix-associated transcription factor and epigenetic regulator, was identified as a tissue type-specific protein when screening protein expression patterns in human normal and cancer tissues using an antibody-based proteomics approach. In this respect, the SATB2 protein shows a selective pattern of expression and, within cells of epithelial lineages, SATB2 expression is restricted to glandular cells lining the lower gastrointestinal tract. The expression of SATB2 protein is primarily preserved in cancer cells of colorectal origin, indicating that SATB2 could function as a clinically useful diagnostic marker to distinguish colorectal cancer (CRC) from other types of cancer. The aim of this study was to further explore and validate the specific expression pattern of SATB2 as a clinical biomarker and to compare SATB2 with the well-known cytokeratin 20 (CK20). Immunohistochemistry was used to analyze the extent of SATB2 expression in tissue microarrays with tumors from 9 independent cohorts of patients with primary and metastatic CRCs (n=1882). Our results show that SATB2 is a sensitive and highly specific marker for CRC with distinct positivity in 85% of all CRCs, and that SATB2 and/or CK20 was positive in 97% of CRCs. In conclusion, the specific expression of SATB2 in a large majority of CRCs suggests that SATB2 can be used as an important complementary tool for the differential diagnosis of carcinoma of unknown primary origin.

Background. The systemic and local tissue repair responses of radiation in combination with surgery are still unclear. We have studied the effect of fractionated pre-operative radiotherapy with or without subsequent laparotomy on collagen accumulation using a rodent model. Materials and methods. Thirty-two male Sprague-Dawley rats were divided into four groups (eight rats per group): 1) sham radiation and sham laparotomy (control); 2) sham radiation and laparotomy; 3) radiation and sham laparotomy; and 4) radiation followed by laparotomy. Expanded polytetrafluoroethylene (ePTFE) tubes were implanted subcutaneously in the abdominal wall in the radiotherapy field and on the back outside the radiotherapy field day 0. The abdomen (3 cm x 4 cm) was irradiated day 3 (10 Gy) and again day 7 (10 Gy). On day 10, implants were extirpated, laparotomy undertaken in groups 2 and 4 and new ePTFE tubes implanted subcutaneously. The second implants were extirpated on day 20. Implants were analyzed for hydroxyproline, total protein and transforming growth factor-ss 1 (TGF-ss 1) levels. Results. On day 10, hydroxyproline (P < 0.05) and TGF-ss 1 (P < 0.001) were lower in ePTFE tubes in irra-diated compared with non-irradiated rats. On day 20, the abdominal ePTFE hydroxyproline remained low (P < 0.001) in animals subjected to laparotomy and pre-operative irradiation while hydroxyproline levels of rats subjected to irradiation only were similar to controls. The effects of radiation on hydroxyproline were confined to the irradiated abdominal area. There was a positive correlation between hydroxyproline and TGF-ss 1 levels in the abdominal wall implant day 20 (r = 0.53, P < 0.005). Conclusion. A clinically relevant fractionated radiation scheme reduced subcutaneous collagen accumulation pre-operatively and profoundly within the radiation field post-operatively after laparotomy, possibly because of lowered TGF ss 1 levels. (c) 2006 Elsevier Inc. All rights reserved.

Preoperative, high-dose radiotherapy for rectal cancer reduces local recurrence rates and improves overall survival. However, adverse effects in varying degrees include impaired wound healing and local infection. This study investigates the influence of preoperative, high-dose radiotherapy on subcutaneous accumulation of collagen in a primary rectal cancer group operated on with or without adjuvant radiotherapy.Forty-two eligible patients who underwent total mesorectal excision surgery with or without radiotherapy were included in the study. Polytetrafluoroethylene tubings were implanted in the arm ten days before surgery (three days before the start of radiotherapy). Implants were extracted the day before surgery. New implants were inserted before surgery and were extracted ten days after surgery. The hydroxyproline and proline contents of the implants were measured and the hydroxyproline/proline ratio was calculated as a measure for deposited collagen relative to protein. Blood loss, postoperative complications, and blood levels of hemoglobin, leukocytes, and albumin were recorded.The two groups were similar in relation to Dukes stage, age, and body mass index. Infectious complications developed in 39 percent of patients after radiotherapy compared with 16 percent in the nonirradiated group. In the irradiated patients with infective complications we found a significant decrease in the hydroxyproline/proline ratio compared with that of irradiated patients without infections (P = 0.037). There was a significant decrease in the leukocyte count preoperatively and postoperatively in the irradiated group compared with surgery alone.High-dose, short-term radiotherapy does not have a systemic effect on collagen accumulation, but a significant reduction is manifested in infected patients. Radiotherapy also impairs leukocyte production and increases the postoperative infective complication rate.

Purpose: In this study, we investigated the prognostic impact of human RBM3 expression in colorectal cancer using tissue microarray-based immunohistochemical analysis. Experimental design: One polyclonal antibody and four monoclonal anti-RBM3 antibodies were generated and epitope mapped using two different methods. Bacterial display revealed five distinct epitopes for the polydonal antibody, while the four mouse monoclonal antibodies were found to bind to three of the five epitopes. A peptide suspension bead array assay confirmed the five epitopes of the polydonal antibody, while only one of the monoclonal antibodies could be mapped using this approach. Antibody specificity was confirmed by Western blotting and immunohistochemistry, including siRNA-mediated knock-down. Two of the antibodies (polydonal and monoclonal) were subsequently used to analyze RBM3 expression in tumor samples from two independent colorectal cancer cohorts, one consecutive cohort (n = 270) and one prospectively collected cohort of patients with cancer of the sigmoid colon (n = 305). RBM3-expression was detected, with high correlation between both antibodies (R = 0.81, p < 0.001). Results: In both cohorts, tumors with high nuclear RBM3 staining had significantly prolonged the overall survival. This was also confirmed in multivariate analysis, adjusted for established prognostic factors. Conclusion and clinical relevance: These data demonstrate that high tumor-specific nuclear expression of RBM3 is an independent predictor of good prognosis in colorectal cancer.

Background Matrilysin (MMP-7) elevation after radiotherapy is shown in humans. Matrilysin regulates certain cytokines and the production of bactericidal proteins when the mucosa is exposed to bacterial antigens. We investigate the effect of irradiation on matrilysin and microflora in murine bowel, after modulation with antibiotics. Methods Animals were divided into two different groups a radiation group (72 animals) and sham radiation group (36 animals). Animals were divided into smaller groups of six according to radiation dose (19 or 38 Gy or sham). Seven days before radiotherapy ampicillin 500 mg/kg/d was administered intramuscularly, in the antibiotic groups. An exteriorized segment of ileum was subjected to single high dose radiation (19 or 38 Gy). Samples were collected 2, 24, and 48 h and analyzed for microflora, MIP-2, TGF-β, and MMP-7. Results The combination of antibiotics and irradiation leads to an early significant reduction of bacteria, down-regulates MIP-2, up-regulates TGF-β and elevation of MMP-7 to levels achieved by antibiotics or irradiation alone. Lactobacilli were reduced to non-existent levels after antibiotics. Conclusions Pretreatment with Ampicillin before irradiation and laparotomy in a murine model leads to Matrilysin over-expression as achieved by radiotherapy alone. Microfloral regulation does not affect MMP-7 stimulation after surgical or radiological trauma. Radiotherapy overrides the effect of antibiotics leading to an up-regulation of MMP-7, TGF-β and MIP-2 expression between 24 h and 48 h.

Background We have previously demonstrated that elevated concentrations of tumour-associated trypsin inhibitor (TATI) in both tumour tissue (t-TATI) and in serum (s-TATI) are associated with a poor prognosis in colorectal cancer patients. It was also found that s-TATI concentrations were lower in patients with rectal cancer compared to patients with colon cancer. In this study, we investigated the effects of neoadjuvant radiotherapy (RT) on concentrations of t-TATI and s-TATI in patients with rectal cancer. Methods TATI was analysed in serum, normal mucosa and tumour tissue collected at various time points in 53 rectal cancer patients enrolled in a case-control study where 12 patients received surgery alone, 20 patients 5 × 5 Gy (short-term) preoperative RT and 21 patients 25 × 2 Gy (long-term) preoperative RT. T-TATI was analysed by immunohistochemistry and s-TATI was determined by an immunofluorometric assay. Mann-Whitney U test and Wilcoxon Z (Z) test were used to assess t-TATI and s-TATI concentrations in relation to RT. Spearman's correlation (R) test was used to explore the associations between t-TATI, s-TATI and clinicopathological parameters. Overall survival (OS) according to high and low t-TATI and s-TATI concentrations was estimated by classification and regression tree analysis, Kaplan-Meier analysis and the log rank test. Results RT did not affect concentrations of t-TATI or s-TATI. In patients receiving short-term but not long-term RT, s-TATI concentrations were significantly higher 4 weeks post surgery than in serum drawn prior to surgery (Z = -3.366, P < 0.001). T-TATI expression correlated with male gender (R = 0.406, P = 0.008). High t-TATI expression in surgical specimens was associated with a significantly shorter OS (P = 0.045). S-TATI concentrations in serum drawn at all time points were associated with an impaired OS (P = 0.035 before RT, P = 0.001 prior to surgery, P = 0.043 post surgery). At all time points, s-TATI correlated with higher age (P < 0.001-0.021) and with increased s-creatinine concentrations assessed prior to surgery (P = 0.041). Conclusions The results presented here further validate the utility of t-TATI and s-TATI as prognostic biomarkers in patients with rectal cancer, independent of neoadjuvant RT.

Background Preoperative radiotherapy of the pelvic abdomen presents with complications mostly affecting the small bowel. The aim of this study was to define the features of early radiation-induced injury on small bowel. Methods 54 mice were divided into two groups (36 irradiated and 18 sham irradiated). Animals were placed on a special frame and (in the radiated group) the exteriorized segment of ileum was subjected to a single absorbed dose of 19 or 38 Gy radiation using 6 MV high energy photons. Specimens were collected for histology, immunohistochemistry (IHC) and ELISA analysis after 2, 24 and 48 hours. Venous blood was collected for systemic leucocyte count in a Burker chamber. Results Histology demonstrated progressive infiltration of inflammatory cells with cryptitis and increased apoptosis. MIP-2 (macrophage inflammatory protein) concentration was significantly increased in irradiated animals up to 48 hours. No significant differences were observed in IL-10 (interleukin) and TNF-α (tumour necrosis factor) levels. IHC with CD45 showed a significant increase at 2 hours of infiltrating leucocytes and lymphocytes after irradiation followed by progressive decrease with time. Caspase-3 expression increased significantly in a dose dependent trend in both irradiated groups up to 48 hours. Conclusion Acute small bowel injury caused by local irradiation is characterised by increased apoptosis of crypt epithelial cells and by lymphocyte infiltration of the underlying tissue. The severity of histological changes tends to be dose dependent and may affect the course of tissue damage.

Background Leucocyte recruitment and inflammation are key features of high dose radiation-induced tissue injury. The inflammatory response in the gut may be more pronounced following radiotherapy due to its high bacterial load in comparison to the response in other organs. We designed a model to enable us to study the effects of radiation on leucocyte-endothelium interactions and on intestinal microflora in the murine ileum. This model enables us to study specifically the local effects of radiation therapy. Method A midline laparotomy was performed in male C57/Bl6 mice and a five-centimetre segment of ileum is irradiated using the chamber. Leucocyte responses (rolling and adhesion) were then analysed in ileal venules 2 – 48 hours after high dose irradiation, made possible by an inverted approach using intravital fluorescence microscopy. Furthermore, intestinal microflora, myeloperoxidase (MPO) and cell histology were analysed. Results The highest and most reproducible increase in leucocyte rolling was exhibited 2 hours after high dose irradiation whereas leucocyte adhesion was greatest after 16 hours. Radiation reduced the intestinal microflora count compared to sham animals with a significant decrease in the aerobic count after 2 hours of radiation. Further, the total aerobic counts, Enterobacteriaceae and Lactobacillus decreased significantly after 16 hours. In the radiation groups, the bacterial count showed a progressive increase from 2 to 24 hours after radiation. Conclusion This study presents a refinement of a previous method of examining mechanisms of radiation enteropathy, and a new approach at investigating radiation induced leucocyte responses in the ileal microcirculation. Radiation induced maximum leucocyte rolling at 2 hours and adhesion peaked at 16 hours. It also reduces the microflora count, which then starts to increase steadily afterwards. This model may be instrumental in developing strategies against pathological recruitment of leucocytes and changes in intestinal microflora in the small bowel after radiotherapy.