Laryngopharyngeal reflux as a potential cause of persistent local neck symptoms after total thyroidectomy.

PURPOSE: Local neck symptoms (LNS) may be related to goiter, but are also reported by patients suffering from laryngeal-pharyngeal reflux (LPR). The aim of this study was to investigate whether LPR could play a role in the persistence of some LNS after total thyroidectomy (TT). METHODS: A consecutive case series of 160 patients with multinodular goiter (MNG) candidate for TT were included in this study. Each patient was closely studied for both the thyroid pathology and reflux disease before and 6 months after surgery to assess the persistence of LNS after surgery. RESULTS: Only throat discomfort showed a significant improvement (p = 0.031) after surgery. On the other hand, swallowing and voice disorders persisted after surgery in 82.3% and 77.3% of patients, respectively (p = 0.250 and p = 0.062), such as the correlated reflux laryngopharyngitis (p = 0.5). CONCLUSIONS: LPR can be considered a predisposing factor or an important concurrent causa to the persistence of LNS after TT, in particular for swallowing disorders and voice disorders. In patients with non-toxic MNG who complain of local neck symptoms, the investigation of a possible coexistence of a reflux disease is appropriate before surgery. Patients should be informed about the possibility that some symptoms can persist even after removal of the goiter.

Local neck symptoms before and after thyroidectomy: a possible correlation with reflux laryngopharyngitis.

Local symptoms in the neck such as swallowing and voice disorders, and throat discomfort might be related to a goiter if present, but are also reported by patients suffering from reflux laryngopharyngitis. The aim of our study was to investigate the presence of reflux laryngopharyngitis in patients with nodular goiter before and after uncomplicated total thyroidectomy (TT) using a prospective study in University Hospital setting. We considered 25 patients, affected by non-toxic nodular goiter and candidates for TT, who complained of local symptoms in the neck. All the patients were carefully interviewed, with emphasis on swallowing and voice disorders, throat discomfort and reflux-related symptoms and underwent a videolaryngoscopy (VLS) and a videofluoroscopic swallowing study (VFSS) before and 3 months after TT. Before thyroidectomy, reflux laryngopharyngitis-related alterations were present in 68 and 50% at VLS and VFSS, respectively. After thyroidectomy, the swallowing and voice disorders persisted in 79 and 75%, respectively, while throat discomfort persisted in 91%. The results show that patients with a non-toxic nodular goiter who complain of local neck symptoms, before surgery it is appropriate to see if a reflux laryngopharyngitis is present; VLS and VFSS could be indicated for this and if necessary an antireflux treatment should be administered.

A minor modification of Lichtenstein repair of primary inguinal hernia: postoperative discomfort evaluation.

The aim of this study was to evaluate the usefulness of a modification of the Lichtenstein hernioplasty procedure by evaluating its impact on postoperative discomfort. From December 1999 to May 2006, the Lichtenstein inguinal hernioplasty was performed in 406 patients with noncomplicated unilateral inguinal hernia. During reconstruction, the mesh was fixed to the inguinal canal floor without stitching its upper margin to the internal oblique muscle. Control of postoperative pain proved to be satisfactory; 72 hours after surgery, 26.1 per cent of patients no longer felt any pain, whereas 54.4 per cent had slight pain without the need for painkillers; on Day 7, 92.8 per cent felt no pain at all. After 10 days, 86.7 per cent of those with sedentary jobs were able to return to work, whereas 79.1 per cent of those with heavier jobs resumed work in 11 to 15 days. Our modification of the original Lichtenstein procedure permitted us to obtain satisfactory results with regard to the control of postoperative chronic pain and a rapid reprisal of normal working activity.

Keratin 7 expression as an early marker of reflux-related columnar mucosa without intestinal metaplasia in the esophagus.

BACKGROUND: The role of Barrett esophagus in carcinogenesis is widely accepted, but the significance of esophageal columnar mucosa without histological intestinal metaplasia, known as columnar-lined esophagus, is debated. MATERIAL/METHODS: We studied 128 patients free of Helicobacter pylori with reflux-related symptoms and columnar mucosa in the esophagus at endoscopy, 106 patients with Barrett esophagus (referred to as the Barrett group) and 22 patients without intestinal metaplasia (columnar group). Samples from 20 subjects free of H. pylori were used as controls. Immunostaining for keratin 7 (KRT7), keratin 20 (KRT20), caudal type homeobox 2 (CDX2), mucin 2, oligomeric mucus/gel-forming (MUC2), and tumor protein p53 (TP53) was assessed. RESULTS: Samples taken 1 cm above the gastroesophageal junction showed KRT7 staining in all cases in the Barrett and columnar groups and none in the control group. Immunostaining for TP53 was absent in the control group, and more frequent in the columnar group (7, 31.8%) compared with the Barrett group (14, 13.2%, P=0.033). In the columnar group, low grade dysplasia and TP53 expression was seen in 7 of 22 biopsy specimens (31.8%) at baseline and in 4 additional specimens after 2 years, for a total of 11 specimens (50.0%). CONCLUSIONS: The expression of KRT7 might help to explain the pathological, reflux-related nature of columnar-lined esophagus, as aberrant expression in a very early stage of the multistep Barrett esophagus progression. Expression of KRT7 may occur in basal glandular cells as a result of their multipotentiality and susceptibility to immunophenotype changes induced by reflux.

Gastro-oesophageal reflux and "epileptic" attacks: casually associated or related? Efficiency of antireflux surgery: a case report.

Although a possible link between gastro-oesophageal reflux disease (GORD) and obstructive sleeping apnoea has already been reported in the literature, there has never been any suggestion of an association with epilepsy, and epileptic attacks have not so far been included among gastro-oesophageal reflux disease symptoms. We report the case of a patient with gastro-oesophageal reflux disease associated with a sliding hiatus hernia, a short oesophagus and oesophagitis, who for the last ten years had not only presented the typical symptoms of gastrooesophageal reflux, but also symptoms of obstructive sleep apnoea and epileptic-like attacks occurring occasionally and only during sleep. Partial posterior fundoplication was performed and considerably reduced the reflux symptoms, and in addition brought about a drastic decrease in the number of epileptic-like attacks. Our case suggests that epileptic-like episodes in patients with obstructive sleeping apnoea may well be linked to the simultaneous presence of GORD associated with hiatus hernia, and surgical treatment of GORD may bring about an improvement of the neurological problems.

The value of total thyroidectomy as the definitive treatment for Graves' disease: A single centre experience of 594 cases.

PURPOSE: Thyroidectomy is the preferred approach as the definitive treatment for Graves' disease. The outcomes for total thyroidectomy in a large series of 594 patients, who were observed in the last decade, will be presented in this study. METHODS: The study concerned a retrospective review of 594 patients, undergoing a total thyroidectomy for Graves' disease. The incidence of complications and outcomes on hyperthyroidism and correlated symptoms resolution were also evaluated. RESULTS: The mean age of the patients was of 44.7 ±â€¯12.7 years and 456 patients (76.7%) were females. The mean gland weight was 67.3 ±â€¯10.8 g (range: 20-350 g) and, in 397 patients (66.8%), the gland weighed >40 g. The mean operative time was 125 ±â€¯23.1 min (range: 65-212 min). Temporary and permanent hypocalcaemia developed in 241 (40.6%) and 3 patients (0.5%), respectively. Temporary and permanent recurrent laryngeal nerve palsy were recorded in 31 (5.2%) and 1 patients (0.16%) respectively. No patient developed a thyroid storm. On multivariate analysis, patient age ≤50 years (Odds ratio: 1; 95% Confidence Interval: 0.843-0.901) and thyroid weight >40 g (Odds ratio: 1; 95%, Confidence Interval: 0.852-0.974), were mainly associated with the occurrence of complications. CONCLUSION: This high-volume surgeon experience demonstrates that total thyroidectomy is a safe and effective treatment for Graves' disease. It is associated with a very low incidence rate of post-operative complications, most of which are transitory; therefore, it offers a rapid and definitive control of hyperthyroidism and its related symptoms.

Nintedanib in NSCLC: evidence to date and place in therapy.

The treatment of advanced non-small cell lung cancer (NSCLC) is currently driven by the detection of targetable oncogenic drivers, i.e. epidermal growth factor receptor, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, etc. Those patients who are wildtype for known and valuable oncogenes can receive standard chemotherapy as first-line treatment, with the possibility of adding bevacizumab. With regard to second-line treatment, nintedanib can improve the efficacy of docetaxel. Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors. The usefulness of nintedanib as an anticancer agent for NSCLC has been proved by both preclinical and clinical phase I and II trials; however, its approval for the use in clinical practice has been possible because of the positive results of the LUME-Lung 1 trial (nintedanib + docetaxel versus docetaxel alone) in terms of progression-free survival and overall survival, and a manageable tolerability profile. Therefore, the good results seen in the clinical trials with nintedanib in the second-line setting for NSCLC patients with adenocarcinoma subtype are encouraging enough to recommend it in clinical practice.

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma.

The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug. In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role. The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to translate into clinical practice. We propose a classification of these miRNAs, that we could name HepatomiRNoma as a whole. Anyway prospective studies have to be designed to clarify the real clinical impact of this new tool.

Analysis of tissue and circulating microRNA expression during metaplastic transformation of the esophagus.

Genetic changes involved in the metaplastic progression from squamous esophageal mucosa toward Barrett's metaplasia and adenocarcinoma are almost unknown. Several evidences suggest that some miRNAs are differentially expressed in Barrett's esophagus (BE) and esophageal adenocarcinoma. Among these, miR-143, miR-145, miR-194, miR-203, miR-205, miR-215 appear to have a key role in metaplasia and neoplastic progression. The aim of this study was to analyze deregulated miRNAs in serum and esophageal mucosal tissue biopsies to identify new biomarkers that could be associated with different stages of esophageal disease. Esophageal mucosal tissue biopsies and blood samples were collected and analyzed for BE diagnosis. Quantitative Real-time PCR was used to compare miRNA expression levels in serum and 60 disease/normal-paired tissues from 30 patients diagnosed with esophagitis, columnar-lined esophagus (CLO) or BE. MiRNA expression analysis showed that miR-143, miR-145, miR-194 and miR-215 levels were significantly higher, while miR-203 and miR-205 were lower in BE tissues compared with their corresponding normal tissues. Esophageal mucosa analysis of patients with CLO and esophagitis showed that these miRNAs were similarly deregulated but to a lesser extent keeping the same trend and CLO appeared as intermediate step between esophagitis and BE. Analysis on circulating miRNA levels confirmed that miR-194 and miR-215 were significantly upregulated in both BE and CLO compared to esophagitis, while miR-143 was significantly upregulated only in the Barrett group. These findings suggest that miRNAs may be involved in neoplastic/metaplastic progression and miRNA analysis might be useful for progression risk prediction as well as for monitoring of BE/CLO patients.

[Digital videofluorography and esophageal achalasia: from diagnosis to follow-up]. / Videofluorografia digitale e acalasia esofagea: dalla diagnosi al follow-up postoperatorio.

The aim of this retrospective study was to evaluate the use of digital videofluorography in the preoperative and postoperative management of esophageal achalasia surgical treatment. From 1990 to 2004, 25 patients with achalasia, diagnosed by digital videofluorography and confirmed by motility studies and endoscopy, underwent surgery. All patients underwent digital videofluorography at 1, 6 and 12 months in order to evaluate the completeness of the myotomy and the efficacy of the antireflux procedures. At postoperative videofluorography esophageal transit time was decreased in all patients (100%); esophageal motor activity was unchanged in 23 (92%), and modified in two patients (8%) with onset of peristaltic-like motor activity; 8 patients (35%) presented decreased preoperative dilatation; all patients had a WST negative for post-myotomy reflux. On the basis of our experience and the advantages of the procedure we suggest videofluorography as a first-approach diagnostic examination useful for surgical indications and postoperative follow-up in achalasic patients.

[Laparoscopic Nissen fundoplication and esophageal intestinal metaplasia: preliminary observations]. / Fundoplicatio secondo Nissen videolaparoscopica e metaplasia intestinale in esofago: osservazioni preliminari.

The aim of this preliminary study conducted in a few cases was the retrospective evaluation of the effects of laparoscopic Nissen fundoplication on oesophageal intestinal metaplasia. Seventy-seven patients with hiatal hernia underwent digital videofluorography, endoscopy with biopsies, motility studies and 24-h oesophageal pH-monitoring. On the basis of the results of the diagnostic procedures and considering the patients' ages and response to proton-pump inhibitor treatment, 8 patients underwent laparoscopic Nissen fundoplication; in 5 cases intestinal metaplasia was present at histopathological examination. Two of these had Barrett's oesophagus at endoscopy and intestinal metaplasia was associated with low-grade dysplasia in both at histology; the other 3 did not present a columnar mucosa at endoscopy and 1 had low-grade dysplasia. In all 5 patients, at 1 year postoperative histopathological control, disappearance or decrease of metaplastic epithelium and regression of dysplasia were noted, with excellent results in terms of reflux symptoms at clinical control. On the basis of these preliminary data, it is our opinion that antireflux surgery is not only a suitable treatment in the management of Barrett's oesophagus but also has a favourable effect on intestinal metaplasia regression when a normal oesophageal mucosa is present.

Farletuzumab for NSCLC: exploiting a well-known metabolic pathway for a new therapeutic strategy.

Introduction: The therapeutic options for NSCLC are limited barring targeted drugs, such as EGFR tyrosine-kinase inhibitors and anaplastic lymphoma kinase inhibitors, for patients bearing oncogenic mutations. Platinum-based chemotherapy remains the best strategy for most patients. New targeted drugs, including mAbs and small molecules, are currently under clinical investigation for treating NSCLC patients. Areas covered: The authors of this article focus on farletuzumab , a mAb targeting folate receptor, which has been studied in ovarian cancer and various other malignancies. In this review, the authors review its potential as therapy for NSCLC, because of the biological rationale provided by the expression of folate receptor α in most of lung adenocarcinoma. The authors provide details of farletuzumab's mechanism of action and discuss the results from completed Phase I and Phase II clinical trials. They also highlight ongoing trials. Expert opinion: There are an increasing number of treatment options for NSCLC and it is hoped that farletuzumab could be added to them. That being said, further evidence for its use with NSCLC patients is still needed. It could have a synergic effect with pemetrexed, because these two drugs have a similar target, namely the folate pathway. This combined action could provide an improved efficacy, although there are some concerns about increased toxicity. However, the authors do note that the combination of farletuzumab with other cytotoxic drugs has not been shown to increase toxicity alone.

What can platinum offer yet in the treatment of PS2 NSCLC patients? A systematic review and meta-analysis.

BACKGROUND: Randomized phase III trials showed interesting, but conflicting results, regarding the treatment of NSCLC, PS2 population. This meta-analysis aims to review all randomized trials comparing platinum-based doublets and single-agents in NSCLC PS2 patients. MATERIALS AND METHODS: Data from all published randomized trials, comparing efficacy and safety of platinum-based doublets to single agents in untreated NSCLC, PS2 patients, were collected. Pooled ORs were calculated for the 1-year Survival-Rate (1y-SR), Overall Response Rate (ORR), and grade 3-4 (G3-4) hematologic toxicities. RESULTS: Six eligible trials (741 patients) were selected. Pooled analysis showed a significant improvement in ORR (OR: 3.243; 95% CI: 1.883-5.583) and 1y-SR (OR: 1.743; 95% CI: 1.203-2.525) in favor of platinum-based doublets. G3-4 hematological toxicities were also more frequent in this group. CONCLUSION: This meta-analysis suggests that platinum-combination regimens are superior to singleagent both in terms of ORR and survival-rate with increase of severe hematological toxicities.

[Supra-esophageal manifestations of gastroesophageal reflux, a different diagnostic approach and an indication for laparoscopic Nissen fundoplication: our experience]. / Manifestazioni sopraesofagee della GERD, un diverso approccio diagnostico ed un'indicazione alla Nissen laparoscopica: nostra esperienza.

24-hour oesophageal pH monitoring with a dual pH probe is considered to be the most sensitive test for diagnosing GORD-related otolaryngological manifestations. In this study we evaluate an initial diagnostic approach with digital videofluorography associated to the water siphon test and primary "ex juvantibus" therapy with proton pump inhibitors for patients with supra-oesophageal symptoms of GORD. The results of Nissen fundoplication surgical treatment are also assessed in some of these patients. Two hundred and thirty patients with suspected GORD-related supra-oesophageal symptoms were referred for videofluorography and the water siphon test. When hiatal hernia and/or reflux were found, patients were referred for medical therapy with proton pump inhibitors. Five patients, who had had a good or excellent response to the medical therapy, but had a recurrence underwent laparoscopic Nissen fundoplication and videofluorography 6 months after surgery. Within 6 months, more than 80% of patients had an excellent or good response to medical therapy. In patients undergoing laparoscopic Nissen fundoplication, hoarseness and chronic cough disappeared within 3 months and videofluorography showed good morphofunctional results of the surgery. In patients with GORD-related supra-oesophageal manifestations, videofluorography plus the water siphon test is useful initial investigation, and laparoscopic Nissen fundoplication can be a valid alternative therapeutic option.

[Hiatal hernia, gastro-oesophageal reflux and oesophagitis: videofluorographic, endoscopic and histopathological correlation]. / Ernia iatale, reflusso gastroesofageo ed esofagite: correlazione videofluorografica, endoscopica ed istopatologica.

The aim of the study was to evaluate the correlation between hiatal hernia and gastro-oesophageal reflux and related histological abnormalities in patients without endoscopic oesophagitis. A consecutive series of 78 patients with a history of gastro-oesophageal reflux symptoms and hiatal hernia, as defined by videofluorography combined with a water siphon test, underwent oesophagogastroduodenoscopy and multiple biopsies. Hiatal hernia was confirmed endoscopically in 99% of cases. The water siphon test was positive for reflux in 72% of cases. At endoscopy 42% of patients had oesophagitis and/or Barrett's oesophagus and 58% had no lesions. In the group without endoscopic lesions, at histology oesophagitis-related alterations were found in 98% and intestinal metaplasia in 27%. In conclusion, this study shows that symptomatic gastro-oesophageal reflux patients with radiologically defined hiatal hernia should undergo endoscopy with multiple biopsies above the squamocolumnar junction, even when endoscopy is normal. This is in order to detect histological gastro-oesophageal-reflux-related alterations, above all, when a positive water siphon test is also present, owing to its known correlation with intestinal metaplasia.

[Digital cineradiology in the diagnosis and surgical treatment of pharyngo-oesophageal junction motor disorders]. / La cineradiografia digitale nella diagnosi e nel trattamento chirurgico dei disordini motori della giunzione faringo-esofagea.

The aim of the study was to report our experience with the use of radiology in functional disorders of the cricopharyngeal muscle and their surgical therapy using digital cineradiology. Five-hundred and seventy dysphagic patients underwent dynamic study of the oral and pharyngeal phases of swallowing (Videofluoroscopic Swallowing Study, VFSS). A motor disorder of the cricopharyngeal muscle was diagnosed by videofluorography in 19 patients: the disorder was mild in 8, moderate in 7 and severe in 4. Two of these underwent cricopharyngeal myotomy, with an improvement in their dysphagia and swallowing mechanisms. VFSS provides a morphological and functional view of the aero-digestive tracts: this is essential in the diagnosis of cricopharyngeal dysfunction and is capable of revealing the related laryngeal penetration and tracheal aspiration. VFSS must always include an oesophageal phase study because of the known clinical and physico-pathological correlations between the gastro-oesophageal junction and the upper oesophageal sphincter. On the basis of our experience we believe that VFSS could be used as a primary investigation, followed by motility studies, and that it may be a useful complementary procedure both in the diagnosis of pharyngo-oesophageal junction motor disorders and with a view to surgical indications.

The role of targeted therapy for gastrointestinal tumors.

Many targeted drugs have been studied to target the molecular pathways involved in the development of gastrointestinal cancers. Anti-VEGF, anti-EGFR agents, and recently also multi-kinase inhibitor regorafenib, have already been available for the treatment of metastatic colorectal cancer patients. To date, Her-2 positive, gastric cancer patients, are also treated with trastuzumab, while the multi-targeted inhibitor, sorafenib, represents the standard treatment for hepatocellular carcinoma patients. Finally, sunitinib and everolimus, have been approved for the treatment of the neuroendocrine gastroenteropancreatic tumors. Actually a great number of further drugs are under preclinical and clinical development. The aim of this review is to provide a comprehensive overview of the state of art, focusing on the new emerging strategies in the personalized treatment of gastrointestinal tumors.

Are erlotinib and gefitinib interchangeable, opposite or complementary for non-small cell lung cancer treatment? Biological, pharmacological and clinical aspects.

Gefitinib and erlotinib are the two anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) approved for treatment of advanced NSCLC patients. These drugs target one of the most important pathways in lung carcinogenesis and are able to exploit the phenomenon of 'oncogene addiction', with different efficacy according to EGFR gene mutational status in tumor samples. Gefitinib has been approved only for EGFR mutation bearing patients regardless the line of treatment, while erlotinib is also indicated in patients without EGFR mutation who undergo second- or third-line treatment. Some studies evaluated the main differences between these drugs both for direct comparison and to improve their sequential use. In particular, toxicity profile resulted partially different, and these observations may be explained by several molecular and pharmacokinetic features. Therefore, this review integrates preclinical data with clinical evidences of TKIs to guide the optimization of currently available treatments in advanced NSCLC patients.

Immunotherapy for recurrent ovarian cancer: a further piece of the puzzle or a striking strategy?

INTRODUCTION: Treatment of ovarian cancer has been long standardized with the inclusion of surgery and chemotherapy based on platinum and taxanes, this strategy reaching high remission rates. However, when this treatment fails, further options are available with little benefit. Since ovarian cancer has specific immunologic features, actually immunotherapy is under evaluation to overcome treatment failure in patients experiencing recurrence. AREAS COVERED: Immunogenicity of ovarian cancer and its relationship with clinical outcomes is briefly reviewed. The kinds of immunotherapeutic strategies are summarized. The clinical trials investigating immunotherapy in recurrent ovarian cancer patients are reported. EXPERT OPINION: The results of these clinical trials about immunotherapy are interesting, but little clinical benefit has been achieved until now. For this reason, we could conclude that immunotherapy is quite different from other treatment options and it could change the global approach for recurrent ovarian cancer treatment. However, to date only fragmentary findings are available to define the real role of immunotherapy in this setting.