Multi-level and hybrid modelling approaches for systems biology.

During the last decades, high-throughput techniques allowed for the extraction of a huge amount of data from biological systems, unveiling more of their underling complexity. Biological systems encompass a wide range of space and time scales, functioning according to flexible hierarchies of mechanisms making an intertwined and dynamic interplay of regulations. This becomes particularly evident in processes such as ontogenesis, where regulative assets change according to process context and timing, making structural phenotype and architectural complexities emerge from a single cell, through local interactions. The information collected from biological systems are naturally organized according to the functional levels composing the system itself. In systems biology, biological information often comes from overlapping but different scientific domains, each one having its own way of representing phenomena under study. That is, the different parts of the system to be modelled may be described with different formalisms. For a model to have improved accuracy and capability for making a good knowledge base, it is good to comprise different system levels, suitably handling the relative formalisms. Models which are both multi-level and hybrid satisfy both these requirements, making a very useful tool in computational systems biology. This paper reviews some of the main contributions in this field.

A systematic review of segmental vs subtotal colectomy and subtotal colectomy vs total proctocolectomy for colonic Crohn's disease.

AIM: Surgical management of colonic Crohn's disease (CD) is still unclear because different procedures can be adopted. The choice of operation is dependent on the involvement of colonic disease but the advantages and disadvantages of the extent of resection are still debated. METHOD: The aim of the present study was to evaluate the differences in short-term and long-term outcomes of adult patients with colonic CD who underwent either subtotal colectomy and ileorectal anastomosis (STC) or segmental colectomy (SC) or total proctocolectomy and end ileostomy (TPC). Studies published between 1984 and 2012 including comparisons of STC vs SC and of STC vs TPC were selected. The study end-points were overall and surgical recurrence, postoperative morbidity and incidence of permanent stoma. Fixed effect models were used to evaluate the study outcomes. RESULTS: Eleven studies, consisting of a total of 1436 patients (510 STC, 500 SC and 426 TPC), were included. Analysis of the data showed no significant difference between STC and SC in terms of overall and surgical recurrence of CD. In contrast, STC showed a higher risk of overall and surgical recurrence of CD than TPC (OR 3.53, 95% CI 2.45-5.10, P < 0.0001; OR 3.52, 95% CI 2.27-5.44, P < 0.0001, respectively). SC had a higher risk of postoperative complications compared to STC, and STC had a lower risk of complications than TPC (OR 2.84, 95% CI 1.16-6.96, P < 0.02; OR 0.19, 95% CI 0.09-0.38, P < 0.0001, respectively). SC resulted in a lower risk of permanent stoma than STC (OR 0.52, 95% CI 0.35-0.77). CONCLUSION: All three procedures were equally effective as treatment options for colonic CD and the choice of operation remains intrinsically dependent on the extent of colonic disease. However, patients in the TPC group showed a lower recurrence risk than those in the STC group. Moreover, SC had a higher risk of postoperative complications but a lower risk of permanent stoma. These data should be taken into account when deciding surgical strategies and when informing patients about postoperative risks.

Esophagogastric junction morphology is associated with a positive impedance-pH monitoring in patients with GERD.

BACKGROUND: High-resolution manometry (HRM) provides information on esophagogastric junction (EGJ) morphology, distinguishing three different subtypes. Data on the correlation between EGJ subtypes and impedance-pH detected reflux patterns are lacking. We aimed to correlate the EGJ subtypes with impedance-pH findings in patients with reflux symptoms. METHODS: Consecutive patients with suspected gastroesophageal reflux disease (GERD) were enrolled. All patients underwent HRM and impedance-pH testing off-therapy. EGJ was classified as: Type I, no separation between the lower esophageal sphincter (LES) and crural diaphragm (CD); Type II, minimal separation (>1 and <2 cm); Type III, ≥ 2 cm separation. We measured esophageal acid exposure time (AET), number of total reflux episodes and symptom association analysis. KEY RESULTS: We enrolled 130 consecutive patients and identified 46.2% Type I EGJ, 38.5% Type II, and 15.4% Type III patients. Type III subjects had a higher number of reflux episodes (61 vs 45, p < 0.03, vs 25, p < 0.001), a greater mean AET (12.4 vs 4.2, p < 0.02, vs 1.5, p < 0.001) and a greater positive symptom association (75% vs 72%, p = 0.732 vs 43.3%, p < 0.02) compared with Type II and I patients, respectively. Furthermore, Type II subjects showed statistically significant (overall p < 0.01) increased reflux when compared with Type I patients. Type III and II EGJ morphologies had a more frequent probability to show a positive multichannel intraluminal impedance pH monitoring than Type I (95% vs 84% vs 50%, p < 0.001). CONCLUSIONS & INFERENCES: Increasing separation between LES and CD can cause a gradual and significant increase in reflux. EGJ morphology may be useful to estimate an abnormal impedance-pH testing in GERD patients.

Plexiform fibromyxoma of the gallbladder.

We report the unusual case of a plexiform fibromyxoma, occasionally assessed in a lithiasic gallbladder. The full thickness assessment of the gallbladder wall revealed an intra-mural, well demarked multi-nodular tumor (1 cm), consisting of a plexiform growth of spindle cells, included within a fibromyxoid stroma with a rich micro-vascular network. The tumor cells featured no nuclear atypia, nor mitotic activity. At the immunohistochemical profiling, the spindle shaped cells unequivocally featured vimentin, SMA, HHF35, collagen IV, and CD34; no cells expressed CD117, PDGFRA, CD10, desmin, GFAP, EMA, and S-100. Faint STAT6 nuclear expression was observed in isolated tumor cells. The molecular profiling did not revealed any CKIT and PDGFRA genes mutations. The uncommon site of the tumor presentation and its aberrant CD34 expression both confer to the reported case a unique place among the myxoid tumors of the gastrointestinal tract.

Shorter myotomy on the gastric site (≤2.5 cm) provides adequate relief of dysphagia in achalasia patients.

The right length of the myotomy on the gastric side for esophageal achalasia is still a debated issue. We aimed to investigate the final outcome after classic myotomy (CM) as compared with a longer myotomy on the gastric side (LM) in two cohorts of achalasia patients. Forty-four achalasia patients who underwent laparoscopic Heller-Dor were considered; patients with a sigmoid-shaped esophagus were excluded. Symptoms were scored using a detailed questionnaire for dysphagia, regurgitation, and chest pain. Barium swallow, endoscopy, and esophageal manometry were performed before and 6 months after the surgical treatment; 24-hour pH-monitoring was also performed 6 months after the procedure. CM was defined as a gastric myotomy length in the range of 1.5-2.0 cm, while LM was 2.5-3 cm in length. The surgical treatment (CM or LM) was adopted in two consecutive cohorts. Treatment failure was defined as a postoperative symptom score >10th percentile of the preoperative score (i.e. >8). Of the 44 patients representing the study population, 20 had CM and 24 had LM. The patients' demographic and clinical parameters (age, sex, symptom score, duration of symptoms, esophageal diameter, and manometric pattern) were similar in the two groups. The median follow up was 24 months (interquartile range 12-39). One patient in each group was classified as a treatment failure. After the treatment, there was a significant decrease in both groups' symptom score, and resting and residual pressure (P < 0.01), with no statistically significant differences between the two groups in terms of postoperative symptom score, resting and residual pressure, or total and abdominal lower esophageal sphincter length and esophageal diameter. Extending the length of the myotomy on the gastric side does not seem to change the final outcome of the laparoscopic Heller-Dor procedure.

A 13 kg intra-abdominal mass: a case of mesenteric fibromatosis.

Mesenteric fibromatosis is a benign fibrous tumor, characterized by proliferations of fibroblasts and myofibroblasts, locally aggressive but non-metastasizing. It can occur rarely in association with familial adenomatous polyposis or sporadically (related with previous trauma, abdominal surgery or prolonged estrogens intake). Small bowel mesentery is the most common site of origin of mesenteric fibromatosis. The authors report a case of a 47-years-old male with a large mass involving the mesentery of the first jejunal loops. The patient was symptomatic for nausea and referred an increasing abdominal circumference; a CT scan showed a huge mass (34 × 29 × 15 cm) very close to the superior mesenteric vessel roots. The surgical treatment consisted in the en bloc removal of the mass weighting 13 kg.

Food groups and risk of squamous cell esophageal cancer in northern Italy.

To better understand the nutritional etiology of squamous cell esophageal cancer, we conducted a case-control study in 3 areas of northern Italy. A total of 304 incident, histologically confirmed cases of squamous cell carcinoma of the esophagus (275 men, 29 women) and 743 hospital controls (593 men, 150 women) with acute, non-neoplastic conditions, not related to smoking, alcohol consumption or long-term diet modification, were interviewed during 1992 to 1997. The validated food-frequency questionnaire included 78 questions on food items or recipes, which were then categorized into 19 main food groups, and 10 questions on fat intake pattern. After allowance for age, sex, education, area of residence, tobacco smoking, alcohol drinking and non-alcohol energy, a significant increased risk emerged for high consumption of soups (OR=2.1 for the highest vs. lowest quintile), whereas inverse associations with esophageal cancer risk were observed for pasta and rice (OR=0.7), poultry (OR=0.4), raw vegetables (OR=0.3), citrus fruit (OR=0.4) and other fruit (OR=0.5). The associations with dietary habits were consistent in different strata of tobacco smoking and alcohol drinking. Among added lipids, olive oil intake showed a significant reduction of esophageal cancer risk, even after allowance for total vegetable consumption (OR=0.4), while butter consumption was directly associated with this risk (OR=2.2). Our results thus provide further support to the evidence that raw vegetables and citrus fruit are inversely related to the risk of squamous cell esophageal cancer and suggest that olive oil may also reduce this risk.

[Palliative treatment of esophageal and cardial carcinoma]. / La palliazione del carcinoma esofageo e cardiale.

Recent series reported increasing incidence of esophageal and cardial cancers with prognosis still severe in spite of surgical progress. The late diagnosis reduces the chance of radical surgery; on the other hand about 80-90% of patients develop local or distant recurrence. Therefore the treatment of esophageal and cardial cancer is often palliative: surgical resection is reserved only to selected cases. Endoscopic palliation was the treatment of choice in a total of 265 patients 174 of which received laser therapy and 91 prosthesis intubation. The results it good in about 80% of cases.

Disconnection of the ampulla of Vater: a new technique for reconstruction.

We report the case of a 42 year-old patient who had undergone gastric resection and Billroth I reconstruction for a duodenal ulcer 15 years earlier. The patient was admitted to our Department for a high output biliopancreatic fistula which developed after another gastric resection with Billroth II reconstruction which was performed for a peptic stricture of the gastroduodenal anastomosis. At laparotomy, a complete disconnection of the ampulla of Vater was found, with the duodenal stump oversewn 5 cm distally to the papillary area. After plasty of the biliary and pancreatic ducts, a direct anastomosis between the new ampulla and a Roux-en-Y jejunal loop was performed. The post-operative course was uneventful. The details of the surgical technique are reported.

Thoracoscopic resection of benign tumours of the esophagus.

Thoracoscopic excision of an esophageal leiomyoma was successfully performed in 5 patients. The tumours were enucleated easily without intraoperative complications. A patient in whom the muscular layer was not sutured after removal of the myoma, one year after the operation presented an esophageal pseudodiverticulum requiring a thoracotomy for resection. This new procedure which reduces the operative trauma and postoperative pain and allows quick recovery is described.

Aberrant right subclavian artery. An original median cervical approach.

The case of a 28-year-old woman with dysphagia secondary to oesophageal compression by an anomalous right subclavian artery is reported. A new single surgical approach, not previously described, for the treatment of dysphagia lusoria in the adults is presented. The aberrant vessel is dissected, divided close to its origin and implanted into the ipsilateral common carotid artery, all through a single median cervical incision.

Therapeutic options for cancer of the hypopharynx and cervical oesophagus.

Between 1980 and 1990, 291 patients with a cancer in the cervical area of the oesophagus were admitted to our Department: in 187 the cancer was located mainly in the cervical region, 76 in the hypopharynx and 28 had a tumour that had spread to the cervical oesophageal region following laryngectomy. Most tumours of the hypopharynx involved the cervical oesophagus when it was often difficult to define the site of origin. 153 patients (53%) underwent surgical resection which included a modified neck dissection followed by different kinds of reconstruction. 96 patients underwent pharyngogastric anastomosis. Twenty anastomotic leaks (23%) were recorded including both those clinically evident and asymptomatic ones detected radiologically. Moreover, segmental proximal necrosis was seen in ten patients. Hospital mortality rate after pharyngogastric anastomosis was 14.7% (14/95). Colon interposition was used in 11 patients. Two anastomotic leaks and two partial necroses were observed. Hospital mortality was 18% (2/11). Eighteen patients underwent laryngopharyngectomy and cervical oesophagectomy with reconstruction performed by means of revascularized jejunal loop. One anastomotic leak was observed and hospital mortality was nil in these cases. Twenty-four patients underwent total oesophagectomy with larynx preservation when the cancer was located at least 2 cm below the upper oesophageal sphincter. Five anastomotic leaks and two partial necroses occurred and hospital mortality was 8.3% (2/24) in these patients. The remaining five patients operated on underwent miscellaneous surgical procedures with one postoperative death. Overall survival for resections considered curative was 21%:37% for hypopharyngeal and 18% for cervical cancers respectively, while it was nil at three years after palliative resection and total oesophagectomy with larynx preservation.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-layered cervical esophageal anastomoses: a prospective study of two suturing techniques.

We carried out a prospective, randomized study over a 1-year period to compare the efficacy of a single layer of continuous absorbable monofilament (Maxon) with that of a single layer of interrupted Polyglactin sutures (Vicryl) in the performance of cervical esophagogastric anastomoses. Forty-two consecutive patients with carcinoma of the esophagus or cardia, in whom the stomach was transposed through the mediastinal route after esophagectomy, were enrolled in the study. There were 21 patients in each group. There was no hospital mortality. One asymptomatic anastomotic leak and two early anastomotic strictures requiring dilation occurred in patients in whom an interrupted technique was employed. The continuous technique required significantly less operative time (p < 0.0001), and the cost of the suture material was reduced markedly. We conclude that either a continuous or an interrupted monolayer esophagogastric anastomosis can give satisfactory results after esophagectomy for cancer, provided that the vascular supply to the gastric fundus is maintained adequately. The continuous technique has the advantages of being time-saving, cheaper, and easier to perform and to teach.