Sebastiano Bonventre

Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells

Although CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIP(L) (cFLIP(L)) and PED/PEA-15, two antiapoptotic proteins whose exogenous expression in normal thyrocytes inhibited the death-inducing signaling complex of CD95. Additionally, small interfering RNA FLIP and PED antisense sensitized thyroid cancer cells to CD95-mediated apoptosis. Exposure of normal thyrocytes to IL-4 and IL-10 potently up-regulated cFLIP and PED/PEA-15, suggesting that these cytokines are responsible for thyroid cancer cell resistance to CD95 stimulation. Moreover, treatment with neutralizing antibodies against IL-4 and IL-10 or exogenous expression of suppressor of cytokine signaling-1 of thyroid cancer cells resulted in cFLIP and PED/PEA-15 down-regulation and CD95 sensitization. More importantly, prolonged IL-4 and IL-10 neutralization induced cancer cell growth inhibition and apoptosis, which were prevented by blocking antibodies against CD95 ligand. Altogether, autocrine production of IL-4 and IL-10 neutralizes CD95-generated signals and allows survival and growth of thyroid cancer cells. Thus, IL-4 and IL-10 may represent key targets for the treatment of thyroid cancer.

KPC - 3 Klebsiella pneumoniae ST258 clone infection in postoperative abdominal surgery patients in an intensive care setting: analysis of a case series of 30 patients.

BackgroundAbdominal surgery carries significant morbidity and mortality, which is in turn associated with an enormous use of healthcare resources. We describe the clinical course of 30 Intensive Care Unit (ICU) patients who underwent abdominal surgery and showed severe infections caused by Klebsiella pneumoniae sequence type (ST) 258 producing K. pneumoniae carbapenemase (KPC-Kp). The aim was to evaluate risk factors for mortality and the impact of a combination therapy of colistin plus recommended regimen or higher dosage of tigecycline.MethodsA prospective assessment of severe monomicrobial KPC-Kp infections occurring after open abdominal surgery carried out from August 2011 to August 2012 in the same hospital by different surgical teams is presented. Clinical and surgical characteristics, microbiological and surveillance data, factors associated with mortality and treatment regimens were analyzed. A combination regimen of colistin with tigecycline was used. A high dose of tigecycline was administered according to intra-abdominal abscess severity and MICs for tigecycline.ResultsThe mean age of the patients was 56.6 ± 15 and their APACHE score on admission averaged 22.72. Twenty out of 30 patients came from the surgical emergency unit. Fifteen patients showed intra-abdominal abscess, eight anastomotic leakage, four surgical site infection (SSI) and three peritonitis. The overall crude ICU mortality rate was 40% (12 out of 30 patients). Twelve of the 30 patients were started on a combination treatment of high-dose tigecycline and intravenous colistin. A significantly lower mortality rate was observed among those patients compared to patients treated with approved dose of tigecycline plus colistin. No adverse events were reported with high doses of tigecycline.ConclusionsCritically-ill surgical patients are prone to severe post-surgical infectious complications caused by KPC-Kp. Timely microbiological diagnosis and optimizing antibiotic dosing regimens are essential to prevent worse outcomes. Further studies and well-controlled clinical trials are needed to define the optimal treatment of infections by KPC-Kp and, more generally, carbapenem-resistant bacteria.

Cytokines and growth factors in wound drainage fluid from patients undergoing incisional hernia repair

Knowing the dynamics of growth factor and cytokine secretion within the site of a surgical operation is important, as they play a crucial role in the pathophysiology of wound healing and are a target for modifying the repair response. The aim of this study was to evaluate the production of several cytokines and growth factors in the drainage wound fluid from patients undergoing incisional hernia repair: namely, interleukin (IL)‐6, IL‐10, IL‐1α, IL‐1 ra, interferon‐γ, vascular endothelial growth factors and basic fibroblast growth factor. Ten female patients with abdominal midline incisional hernia undergoing surgical repair were included in this study. In all cases, a closed‐suction drain was inserted in the wound below the fascia and removed on postoperative day 4. Wound fluid was collected on postoperative days 1–4 and the amount was recorded each time. Growth factors and cytokines production was evaluated as the whole amount produced over a 24‐hour period. In all patients, the amount of drain fluid from surgical wounds was more copious the first day after surgery, it decreased significantly afterward. The presence of all cytokines was highest on postoperative day 1, decreasing over the following days. More specifically, the production of IL‐1 ra, IL‐6, IL‐1α, and IL‐10 on postoperative day 1 fell sharply on postoperative days 3 and 4, whereas, after an initial reduction, interferon‐γ showed an increase from day 2 onward. Vascular endothelial‐derived growth factor production increased progressively after the operation reaching statistical significance only on day 4. As for basic fibroblast growth factor, it showed an opposite pattern: it was higher on postoperative day 1 decreasing thereafter. This analysis of cytokine and growth factor production in the drain fluid will lead us to a better evaluation of the events that follow a surgical wound and to a better understanding of the healing process.

Randomized clinical trial of botulinum toxin injection for pain relief in patients with thrombosed external haemorrhoids

Thrombosed external haemorrhoids are one of the most frequent anorectal emergencies. They are associated with swelling and intense pain. Internal sphincter hypertonicity plays a role in the aetiology of the pain. This study evaluated the efficacy and safety of an intrasphincteric injection of botulinum toxin for pain relief in patients with thrombosed external haemorrhoids.

Esophageal Motility Changes after Thyroidectomy; Possible Associations with Postoperative Voice and Swallowing Disorders Preliminary Results

Objective Swallowing and voice impairment are common after thyroidectomy. We evaluated short-term functional changes in esophageal motility in a series of patients who had undergone total thyroidectomy. Several studies have investigated these symptoms by means of interviews or questionnaires. Study Design Prospective study. Setting Academic research. Materials and Methods Thirty-six consenting patients were prospectively recruited. Eligibility criteria were thyroid volume ≤60 mL, benign disease, and age between 18 and 65 years. Exclusion criteria were previous neck surgery, severe thyroiditis, hyperthyroidism, and pre- or postoperative vocal cord palsy. Voice impairment score, swallowing impairment score, lower esophageal sphincter pressure, esophageal motility, upper esophageal pressure, and coordination were evaluated preoperatively and 30 to 45 days after surgery. Results Postoperative swallowing impairment (appearance or worsening of dysphagia) was found in 20% of patients and voice impairment in more than 30%. Both preoperative and postoperative esophageal motility were similar. All patients showed an average decrease of 25% in upper esophageal pressure, although the pressure was within normal range. Swallowing alterations were associated with upper esophageal incoordination (P < .03), and proximal acid reflux was significantly associated with voice impairment (P < .02). Conclusion After uncomplicated thyroidectomy, decreased upper esophageal pressure may explain both pharyngeal (dysphagia) and laryngeal (vocal impairment) exposure to acid. In the future, proton pump inhibitor therapy protocols should be evaluated.

Total Thyroidectomy Performed With the Starion Vessel Sealing System Versus the Conventional Technique: A Prospective Randomized Trial

Meticulous dissection and accurate hemostasis are required in thyroid surgery. The authors recently performed a number of thyroidectomies using a new device that combines heat and pressure for sealing and cutting tissue. A prospective randomized trial was conducted on 98 patients subjected to total thyroidectomy for benign disease: 49 patients (group A) with the Starion tissue welding system and 49 (group B) with the clamp-and-tie technique. The 2 groups were comparable in mean age, gender, thyroidal volume (20-60 mL), incision length (<35 mm), and pathology. The authors evaluated operative time, postoperative serum calcemia, dosage and length of postoperative calcium and vitamin D treatment, drainage volume, hospital stay, and complications. Student’s t test was used for quantitative variables; for categorical variables, the χ 2 test or Fisher’s exact test, as appropriate, was used. The mean operative time was 53.8 ± 6.1 minutes in group A and 63.2 ± 8 minutes in group B (P < .0001). The difference in terms of postoperative calcemia was significant (group A: 8.35 ± 0.39 mg/dL; group B: 8.08 ± 0.39 mg/dL; P < .001). The duration of postoperative treatment with calcium and vitamin D was significantly different (group A: 4 days; group B: 5 days; P < .039). No significant difference in terms of postoperative complications was found. The new system reduced operative time and the duration of postoperative hypocalcemia, and there was minimal tissue necrosis and thermal spread. The reduction in duration of postoperative calcium and vitamin D treatment is also an indication of improvement in quality of the treatment.

Oligo-Antigenic Diet in the Treatment of Chronic Anal Fissures. Evidence for a Relationship Between Food Hypersensitivity and Anal Fissures

OBJECTIVES:Patients with chronic constipation due to food hypersensitivity (FH) had an elevated anal sphincter resting pressure. No studies have investigated a possible role of FH in anal fissures (AFs). We aimed to evaluate (1) the effectiveness of diet in curing AFs and to evaluate (2) the clinical effects of a double-blind placebo-controlled (DBPC) challenge, using cows milk protein or wheat.METHODS:One hundred and sixty-one patients with AFs were randomized to receive a “true-elimination diet” or a “sham-elimination diet” for 8 weeks; both groups also received topical nifedipine and lidocaine. Sixty patients who were cured with the “true-elimination diet” underwent DBPC challenge in which cows milk and wheat were used.RESULTS:At the end of the study, 69% of the “true-diet group” and 45% of the “sham-diet group” showed complete healing of AFs (P<0.0002). Thirteen of the 60 patients had AF recurrence during the 2-week cows milk DBPC challenge and 7 patients had AF recurrence on wheat challenge. At the end of the challenge, anal sphincter resting pressure significantly increased in the patients who showed AF reappearance (P<0.0001), compared with the baseline values. The patients who reacted to the challenges had a significantly higher number of eosinophils in the lamina propria and intraepithelial lymphocytes than those who did not react to the challenges.CONCLUSIONS:An oligo-antigenic diet combined with medical treatment improved the rate of chronic AF healing. In more than 20% of the patients receiving medical and dietary treatment, AFs recurred on DBPC food challenge.

A functional study of the esophagus in patients with non-cardiac chest pain and dysphagia.

BACKGROUND/AIMS Nutcracker esophagus and non-specific motility disorders are the main causes of non-cardiac chest pain (NCCP), with gastroesophageal reflux in 60% of cases. Achalasia and diffuse esophageal spasm are the most frequent anomalies described in patients with dysphagia. The goal of this study was to evaluate the occurrence of esophageal body and lower esophageal sphincter motor abnormalities in patients with dysphagia, NCCP, or both. MATERIALS AND METHODS This study is a retrospective analysis of 716 patients with NCCP and/or dysphagia tested between January 1994 and December 2010. 1023 functional studies were performed, 707 of which were esophageal manometries, 225 esophageal pH-meters, and 44 bilimetries. We divided the patients into three groups: group 1 was composed of patients affected with dysphagia, group 2 with NCCP and group 3 with NCCP and dysphagia. RESULTS Manometric anomalies were detected in 84.4% of cases (p<0.001). The most frequent esophageal motility alteration was achalasia (36%). The lower esophageal sphincter was normal in 45.9% of patients (p<0.001). In all 3 groups, 80.9%, 98.8%, and 93.8, respectively, of patients showed normal upper esophageal sphincter (p=0.005). CONCLUSION Our data differs from those of other studies because they were collected from and analyzed by a single tertiary level referral center by a single examiner. This could have eliminated the variability found in different hands and different experiences. The high percentage of symptomatic patients with non-pathologic esophageal motility pattern suggests an unclear origin of the disease, with possible neuromuscular involvement. As a result, these patients may need more-detailed diagnostic studies.

Effects of transcranial direct current stimulation on esophageal motility in patients with gastroesophageal reflux disease.

OBJECTIVE To evaluate the effects of transcranial direct current stimulation (tDCS) on esophageal peristalsis in patients with gastroesophageal reflux disease (GERD). METHODS Patients with GERD preliminary diagnosis were included in a randomized double-blind sham-controlled study. Esophageal manometry was performed before and during transcranial direct current stimulation (tDCS) of the right precentral cortex. Half of patients were randomly assigned to anodal, half to sham stimulation. Distal waves amplitude and pathological waves percentage were measured, after swallowing water boli, for ten subsequent times. Last, a 24h pH-bilimetry was done to diagnose non-erosive reflux disease (NERD) or functional heartburn (FH). The values obtained before and during anodal or sham tDCS were compared. RESULTS Sixty-eight patients were enrolled in the study. Distal waves mean amplitude increased significantly only during anodal tDCS in NERD (p=0.00002) and FH subgroups (p=0.008) while percentage of pathological waves strongly decreased only in NERDs (p=0.002). CONCLUSIONS Transcranial stimulation can influence cortical control of esophageal motility and improve pathological motor pattern in NERD and FH but not in erosive reflux disease (ERD) patients. SIGNIFICANCE Pathophysiological processes in GERD are not only due to peripheral damage but to central neural control involvement as well. In ERD patients dysfunctions of the cortico-esophageal circuit seem to be more severe and may affect central nervous system physiology.

Swallowing disorders after thyroidectomy: What we know and where we are. A systematic review

INTRODUCTION Dysphagia and hoarseness are possible complications that can be observed in patients undergoing thyroidectomy or other neck surgery procedures. These complaints are usually related to superior and inferior laryngeal nerves dysfunction, but these can appear even after uncomplicated surgical procedure. METHODS We reviewed the current literature available on MEDLINE database, concerning the swallowing disorders appearing after the thyroidectomy. The articles included in the review reported pathophysiology and diagnostic concerns. RESULTS Twenty articles were selected for inclusion in the review. Depends on the possible causes of the difficulty swallowing (related to nerve damage or appearing after uncomplicated thyroidectomy), different types of diagnostic procedures could be used to study patient discomfort, as well as intraoperative nerve monitoring, fiber optic laryngoscopy, endoscopy, pH monitoring, esophageal manometry and videofluorography. Among all these procedures, videofluorography is considered the gold standard to evaluate the entire swallowing process, since that allows a real-time study of all the three phases of swallowing: oral phase, pharyngeal phase and esophageal phase. CONCLUSION The diagnostic procedures described can help to identify the mechanisms involved in swallowing disorders, with the aim to choose the best therapeutic option. More studies are needed for understanding the causes of the dysphagia appearing after thyroidectomy.