Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

BACKGROUND: Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. METHODS: This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. RESULTS: Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. CONCLUSIONS: Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Detection of somatic and germline pathogenic variants in adult cohort of drug-resistant focal epilepsies.

OBJECTIVE: This study investigates the prevalence of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway in surgical specimens of malformations of cortical development (MCDs) and cases with negative histology. The study also aims to evaluate the predictive value of genotype-histotype findings on the surgical outcome. METHODS: The study included patients with drug-resistant focal epilepsy who underwent epilepsy surgery. Cases were selected based on histopathological diagnosis, focusing on MCDs and negative findings. We included brain tissues both as formalin-fixed, paraffin-embedded (FFPE) or fresh frozen (FF) samples. Single-molecule molecular inversion probes (smMIPs) analysis was conducted, targeting the MTOR gene in FFPE samples and 10 genes within the mTOR pathway in FF samples. Correlations between genotype-histotype and surgical outcome were examined. RESULTS: We included 78 patients for whom we obtained 28 FFPE samples and 50 FF tissues. Seventeen pathogenic variants (22 %) were identified and validated, with 13 being somatic within the MTOR gene and 4 germlines (2 DEPDC5, 1 TSC1, 1 TSC2). Pathogenic variants in mTOR pathway genes were exclusively found in FCDII and TSC cases, with a significant association between FCD type IIb and MTOR genotype (P = 0.003). Patients carrying mutations had a slightly better surgical outcome than the overall cohort, however it results not significant. The FCDII diagnosed cases more frequently had normal neuropsychological test, a higher incidence of auras, fewer multiple seizure types, lower occurrence of seizures with awareness impairment, less ictal automatisms, fewer Stereo-EEG investigations, and a longer period long-life of seizure freedom before surgery. SIGNIFICANCE: This study confirms that somatic MTOR variants represent the primary genetic alteration detected in brain specimens from FCDII/TSC cases, while germline DEPDC5, TSC1/TSC2 variants are relatively rare. Systematic screening for these mutations in surgically treated patients' brain specimens can aid histopathological diagnoses and serve as a biomarker for positive surgical outcomes. Certain clinical features associated with pathogenic variants in mTOR pathway genes may suggest a genetic etiology in FCDII patients.

Contemporary outcomes of left thoraco-abdominal esophagectomy due to cancer in the esophagus or gastroesophageal junction, a multicenter cohort study.

Surgery for cancer of the esophagus or gastro-esophageal junction can be performed with a variety of minimally invasive and open approaches. The left thoracoabdominal esophagectomy (LTE) is an open technique that gives an opportunity to operate in the chest and abdomen with excellent exposure of the gastro-esophageal junction through a single incision, and there is currently no equivalent minimally invasive technique available. The aim of this multi-institutional review was to study a large contemporary international study cohort of patients treated with LTE. An international multicenter cohort study was performed including all patients treated with LTE at six high-volume centers for gastro-esophageal cancer surgery between 2012 and 2022. Patient data were prospectively collected in each participating centers' institutional database. Information about patient, tumor, and treatment details were collected. The study cohort included a total of 793 patients treated with LTE during the study period. The most frequently observed complications were pneumonia in 185/727 (25.5%) patients and atrial fibrillation in 91/727 (12.5%). Anastomotic leak occurred in 35/727 (4.8%) patients; no patient suffered from conduit necrosis. Thirty-day mortality occurred in 15/785 (1.9%) patients and 90-day mortality in 39/785 (5.0%) patients. Factors with statistically significant association with survival were American Society for Anesthesiologists-score, tumor location, tumor stage, and tumor free resection margins. Neoadjuvant therapy was not associated with increased survival compared to surgery alone but neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy showed statistically significant improved survival with hazard ratio 0.60 (95% confidence intervals:0.44-0.80, P = 0.001) in a multivariable adjusted model. This study demonstrates that LTE can be applied in selected patients with results that are comparable to other large studies of open and minimally invasive surgery for esophageal or gastro-esophageal cancer at high-volume centers.

Open left thoracoabdominal esophagectomy a viable option in the era of minimally invasive esophagectomy.

Minimally invasive surgical technique has become standard at many institutions in esophageal cancer surgery. In some situations, however other surgical approaches are required. Left thoracoabdominal esophagectomy (LTE) facilitates complete resection of esophageal cancer particularly for bulky distal esophageal tumors, but there are concerns that this approach is associated with significant morbidity. Prospectively entered esophagectomy databases from three high-volume centers were reviewed for patients undergoing LTE or MIE 2009-2019. Patient demographics, tumor characteristics, operative outcomes, postoperative outcomes, and pathologic surrogates of oncologic efficacy (R0 resection rate, and number of resected lymph nodes) were compared. In total 915 patients were included in the study, LTE was applied in 684 (74.8%) patients, and MIE in 231 (25.2%) patients. LTE patients had more locally advanced tumor stage and received more neoadjuvant treatment. Patients treated with MIE had more comorbidities. The results showed no difference in overall postoperative complications (LTE = 61.7%, MIE = 65.7%, P = 0.289), severe complications (Clavien-Dindo ≥IIIa (LTE = 25.9%, MIE 26.8%, P = 0.806)), pneumonia (LTE = 29.0%, MIE = 24.7%, P = 0.211), anastomotic leak (LTE = 7.8%, MIE = 11.3%, P = 0.101), or in-hospital mortality (LTE = 2.6%, MIE = 3.5%, P = 0.511). Median number of resected lymph nodes was 24 for LTE and 25 for MIE (P = 0.491). LTE was used for more advanced tumors in patients that were more likely to have received neoadjuvant treatment compared with MIE, however postoperative morbidity, mortality, and oncologic outcomes were equivalent to that of MIE in this cohort. In conclusion open resection with left thoracoabdominal approach is a valid option in selected patients when performed at high-volume esophagectomy centers.

Neoadjuvant chemoradiotherapy or chemotherapy alone for oesophageal cancer: population-based cohort study.

BACKGROUND: Although both neoadjuvant chemoradiotherapy (nCRT) and chemotherapy (nCT) are used as neoadjuvant treatment for oesophageal cancer, it is unknown whether one provides a survival advantage over the other, particularly with respect to histological subtype. This study aimed to compare prognosis after nCRT and nCT in patients undergoing oesophagectomy for oesophageal adenocarcinoma (OAC) or squamous cell carcinoma (OSCC). METHODS: Data from the National Cancer Database (2006-2015) were used to identify patients with OAC and OSCC. Propensity score matching and Cox multivariable analyses were used to account for treatment selection biases. RESULTS: The study included 11 167 patients with OAC (nCRT 9972, 89.3 per cent; nCT 1195, 10.7 per cent) and 2367 with OSCC (nCRT 2155, 91.0 per cent; nCT 212, 9.0 per cent). In the matched OAC cohort, nCRT provided higher rates of complete pathological response (35.1 versus 21.0 per cent; P < 0.001) and margin-negative resections (90.1 versus 85.9 per cent; P < 0.001). However, patients who had nCRT had similar survival to those who received nCT (hazard ratio (HR) 1.04, 95 per cent c.i. 0.95 to 1.14). Five-year survival rates for patients who had nCRT and nCT were 36 and 37 per cent respectively (P = 0.123). For OSCC, nCRT had higher rates of complete pathological response (50.9 versus 30.4 per cent; P < 0.001) and margin-negative resections (92.8 versus 82.4 per cent; P < 0.001). A statistically significant overall survival benefit was evident for nCRT (HR 0.78, 0.62 to 0.97). Five-year survival rates for patients who had nCRT and nCT were 45.0 and 38.0 per cent respectively (P = 0.026). CONCLUSION: Despite pathological benefits, including primary tumour response to nCRT, there was no prognostic benefit of nCRT compared with nCT for OAC suggesting that these two modalities are equally acceptable. However, for OSCC, nCRT followed by surgery appears to remain the optimal treatment approach.

Fit-for-Discharge Criteria after Esophagectomy: An International Expert Delphi Consensus.

There are no internationally recognized criteria available to determine preparedness for hospital discharge after esophagectomy. This study aims to achieve international consensus using Delphi methodology. The expert panel consisted of 40 esophageal surgeons spanning 16 countries and 4 continents. During a 3-round, web-based Delphi process, experts voted for discharge criteria using 5-point Likert scales. Data were analyzed using descriptive statistics. Consensus was reached if agreement was ≥75% in round 3. Consensus was achieved for the following basic criteria: nutritional requirements are met by oral intake of at least liquids with optional supplementary nutrition via jejunal feeding tube. The patient should have passed flatus and does not require oxygen during mobilization or at rest. Central venous catheters should be removed. Adequate analgesia at rest and during mobilization is achieved using both oral opioid and non-opioid analgesics. All vital signs should be normal unless abnormal preoperatively. Inflammatory parameters should be trending down and close to normal (leucocyte count ≤12G/l and C-reactive protein ≤80 mg/dl). This multinational Delphi survey represents the first expert-led process for consensus criteria to determine 'fit-for-discharge' status after esophagectomy. Results of this Delphi survey may be applied to clinical outcomes research as an objective measure of short-term recovery. Furthermore, standardized endpoints identified through this process may be used in clinical practice to guide decisions regarding patient discharge and may help to reduce the risk of premature discharge or prolonged admission.

Simple fistula-in-ano: is it all simple? A systematic review.

BACKGROUND: Simple anal fistula is one of the most common causes of proctological surgery and fistulotomy is considered the gold standard. This procedure, however, may cause complications. The aim of this systematic review was to assess the surgical treatment of simple anal fistula with traditional and sphincter-sparing techniques. METHODS: A literature research was performed using PubMed, Cochrane, and Google Scholar to identify studies on the surgical treatment of simple anal fistulas. Observational studies and randomized clinical trials were included. We assessed the risk of bias of included studies using the Jadad scale for randomized controlled trials, and the MINORS Scale for the remaining studies. RESULTS: The search returned 456 records, and 66 studies were found to be eligible. The quality of the studies was generally low. A total of 4883 patients with a simple anal fistula underwent a sphincter-cutting procedure, mainly fistulotomy, with a weighted average healing rate of 93.7%, while any postoperative continence impairment was reported in 12.7% of patients. Sphincter-sparing techniques were adopted to treat 602 patients affected by simple anal fistula, reaching a weighted average success rate of 77.7%, with no study reporting a significant postoperative incontinence rate. The postoperative onset of fecal incontinence and the recurrence of the disease reduced patients' quality of life and satisfaction. CONCLUSIONS: Surgical treatment of simple anal fistulas with sphincter-cutting procedures provides excellent cure rates, even if postoperative fecal incontinence is not a negligible risk. A sphincter-sparing procedure could be useful in selected patients.

Dynamic Alteration of Neutrophil-to-Lymphocyte Ratio over Treatment Trajectory is Associated with Survival in Esophageal Adenocarcinoma.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been identified as a biomarker for multiple malignancies. There is emerging evidence that implicates neutrophils in cancer progression. Alterations of neutrophil counts and NLR during treatment may reflect a change in oncologic outcome that is more important than baseline values. The aim of this study is to investigate the prognostic role of NLR changes during the treatment trajectory of patients with esophageal adenocarcinoma. PATIENTS AND METHODS: NLR values of patients with esophageal adenocarcinoma who underwent surgery between 2005 and 2016 were measured at baseline and in the late postoperative period. Primary outcomes were overall survival (OS) and disease-free survival (DFS). The secondary outcome was pathological response to neoadjuvant chemotherapy. RESULTS: 330 patients were included; mean age was 65.6 years, and 82% were male. Most patients had cT3 (74.8%), cN-positive (59.7%) disease. Two-thirds (65.2%) received neoadjuvant chemotherapy. The independent predictors of OS were pathological N-stage, size of primary tumor, and delta NLR (late - baseline NLR). Patients with persistently elevated NLR did worse than those with decreasing NLR trends between baseline and postoperative time points (3-year OS 43.4% versus 71.3%, p < 0.0001, 3-year DFS 29.7% versus 61.9%, p < 0.0001). High baseline and postoperative NLR were associated with significantly worse OS and DFS. Patients with complete pathological response had lower mean baseline NLR. CONCLUSION: Dynamic changes in NLR during treatment are associated with survival and may be more informative than static baseline values.

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process.

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription.

Barth syndrome (BTHS) is an X-linked inborn error of metabolism which affects males. The main manifestations are cardiomyopathy, myopathy, hypotonia, growth delay, intermittent neutropenia and 3-methylglutaconic aciduria. Diagnosis is confirmed by mutational analysis of the TAZ gene and biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin (MLCL:L4-CL) ratio. We report a 6-year-old boy who presented with severe hypoglycemia, lactic acidosis and severe dilated cardiomyopathy soon after birth. The MLCL:L4-CL ratio confirmed BTHS (3.90 on patient's fibroblast, normal: 0-0.3). Subsequent sequencing of the TAZ gene revealed only the new synonymous variant NM_000116.3 (TAZ):c.348C>T p.(Gly116Gly), which did not appear to affect the protein sequence. In silico prediction analysis suggested the new c.348C>T nucleotide change could alter the TAZ mRNA splicing processing. We analyzed TAZ mRNAs in the patient's fibroblasts and found an abnormal skipping of 24 bases (NM_000116.3:c.346_371), with the consequent ablation of 8 amino acid residues in the tafazzin protein (NP_000107.1:p.Lys117_Gly124del). Molecular analysis of at risk female family members identified the patient's sister and mother as heterozygous carriers. Apparently harmless synonymous variants in the TAZ gene can damage gene expression. Such findings widen our knowledge of molecular heterogeneity in BTHS.

Treatment choices and outcomes of patients with manometrically diagnosed achalasia.

This prospective population-based study was designed to evaluate treatment choices in patients with new manometrically diagnosed achalasia and their outcomes. Patients referred to the esophageal function laboratory were enrolled after a new manometric diagnosis of achalasia. Patients completed an initial achalasia symptom score validated questionnaire on their symptom severity, duration, treatment pre-diagnosis and Medical Outcomes Study 36-item Short-Form (SF-36) survey. Treatment decisions were made by the referring physician and the patient. Follow-up questionnaires were completed every 3 months for 1 year. Patients who chose not to undergo treatment at 1-year follow-up completed another questionnaire after 5 years. Between January 2004 and January 2005, 83 of 124 eligible patients were enrolled. Heller myotomy was performed on 31 patients, three patients received botulinum toxin injections, and 25 patients received 29 pneumatic balloon dilatations. Twenty-four patients chose to receive no treatment. Following treatment, patients treated with surgery, dilatation and botulinum toxin had an average improvement in achalasia symptom score of 23 +/- 12.2, 17 +/- 10.9, and 9 +/- 14, respectively. Patients receiving no treatment had worsening symptoms with a symptom score change of -3.5 +/- 11.4. Surgery and dilatation resulted in significant improvement (P < 0.01) relative to no treatment. In univariate logistic regression, symptom severity score (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.00 to 1.08), sphincter tone (OR 1.04, 95% CI 1.00 to 1.09), difficulty swallowing liquids (OR 3.21, 95% 1.15 to 8.99), waking from sleep (OR 2.75, 95% 1.00 to 7.61), and weight loss (OR 5.99, 95% CI 1.93 to 18.58) were all significant in predicting that patients would select treatment. In the multivariate analysis, older age (OR 1.05, 95% CI 1.01 to 1.09) and weight loss (OR 3.91, 95% CI 1.02 to 15.2) were statistically significant for undergoing treatment. At 5 years, five (21%) of those who had initially declined treatment at 1 year ultimately chose a treatment. Patients who finally chose Heller myotomy had lower mental component dimension scores on the SF-36 at 1 year than those who did not. This study shows that almost one third of patients with manometrically diagnosed achalasia choose not to undergo treatment within 1 year of their diagnosis. Patients who are more symptomatic appear to be more likely to undergo treatment by univariate analysis. In multivariate analysis, increasing age and weight loss are predictive of those who will undergo treatment, with weight loss having the greatest influence. Patients who choose not to undergo treatment make lifestyle changes to maintain their quality of life, and only a minority of them ultimately undergo treatment.

Management of Dysphagia in Esophageal Adenocarcinoma Patients Undergoing Neoadjuvant Chemotherapy: Can Invasive Tube Feeding be Avoided?

BACKGROUND: Neoadjuvant chemotherapy is an accepted standard for locally advanced esophagogastric junction adenocarcinoma. However, the dysphagia frequently associated with this condition may interfere with patient tolerance of this treatment. In many centers, invasive tube feeding, placed either endoscopically, radiographically, or surgically, is used to address this issue, but it can cause significant morbidity. We sought to determine if an approach of goal-directed dietary counseling and appropriately timed neoadjuvant chemotherapy could obviate the need for invasive tube feeding. METHODS: Patients with locally advanced (cT3 or N+) esophageal and esophagogastric junction adenocarcinoma undergoing neoadjuvant TCF [Taxotere, cisplatin 5-fluorouracil (5-FU)], ECF (epirubicin, cisplatin, 5-FU), or FLOT (docetaxel, oxaliplatin, leucovorin, and 5-FU) at the McGill University Health Center from March 2007 to September 2012 were identified from a prospective database. All received individualized goal-directed dietary counseling, were monitored for signs/symptoms of malnutrition with serial (baseline/presurgery) body mass index, albumin, and completed serial symptom scores (dysphagia), and quality-of-life questionnaires (Functional Assessment in Cancer Therapy with the esophageal subset, FACT-E). We assessed the response of dysphagia and nutritional status to neoadjuvant chemotherapy and the need for invasive tube feeding. RESULTS: Of 130 patients undergoing neoadjuvant chemotherapy, 78 had severe dysphagia (defined as dysphagia score ≥2 on a 5-point Likert scale), most of whom received TCF (91 %). Overall dysphagia scores improved in 75 (96 %) of 78 patients from a dysphagia score of 3-0, most of which improved after the first cycle of therapy. This was associated with an increase in quality of life (FACT-E scores 117 ± 23 to 140 ± 20). With maintenance of weight (70 ± 22 to 69 ± 24 kg), body mass index (24.5 ± 8 to 23.9 ± 7 kg/m(2)), and serum albumin (40 ± 5 to 37 ± 4 g/L). Only one patient required a stent, and none required jejunostomy or gastrostomy. CONCLUSIONS: Appropriately timed neoadjuvant chemotherapy with a highly effective regimen rapidly restores normal swallowing, maintains nutritional status, and obviates the need for invasive tube feeding in patients with significant dysphagia from esophageal adenocarcinoma.

Headache in epilepsy: prevalence and clinical features.

BACKGROUND: Headache and epilepsy are two relatively common neurological disorders and their relationship is still a matter of debate. Our aim was to estimate the prevalence and clinical features of inter-ictal (inter-IH) and peri-ictal headache (peri-IH) in patients with epilepsy. METHODS: All patients aged ≥ 17 years referring to our tertiary Epilepsy Centre were consecutively recruited from March to May 2011 and from March to July 2012. They underwent a semi-structured interview including the International Classification Headache Disorders (ICHD-II) criteria to diagnose the lifetime occurrence of headache.χ(2)-test, t-test and Mann-Whitney test were used to compare clinical variables in patients with and without inter-IH and peri-IH. RESULTS: Out of 388 enrolled patients 48.5 % had inter-IH: migraine in 26.3 %, tension-type headache (TTH) in 19.1 %, other primary headaches in 3.1 %. Peri-IH was observed in 23.7 %: pre-ictally in 6.7 %, ictally in 0.8 % and post-ictally in 19.1 %. Comparing patients with inter-ictal migraine (102), inter-ictal TTH (74) and without inter-IH (200), we found that pre-ictal headache (pre-IH) was significantly represented only in migraineurs (OR 3.54, 95 % CI 1.88-6.66, P < 0.001). Post-ictal headache (post-IH) was significantly associated with both migraineurs (OR 2.60, 95 % CI 1.85-3.64, P < 0.001) and TTH patients (OR 2.05, 95 % CI 1.41-2.98, P < 0.001). Moreover, post-IH was significantly associated with antiepileptic polytherapy (P < 0.001), high seizure frequency (P = 0.002) and tonic-clonic seizures (P = 0.043). CONCLUSIONS: Migraine was the most represented type of headache in patients with epilepsy. Migraineurs are more prone to develop pre-IH, while patients with any inter-IH (migraine or TTH) are predisposed to manifest a post-IH after seizures.

Aminoacylase I deficiency due to ACY1 mRNA exon skipping.

Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism of which less than 20 observations have been described. Patients exhibit urinary excretion of specific N-acetyl amino acids and manifest a heterogeneous clinical spectrum including intellectual disability, motor delay, seizures, moderate to severe mental retardation, absent speech, growth delay, muscular hypotonia and autistic features. Here, we report the case of ACY1 enzyme deficiency in a 6-year-old girl presenting severe intellectual disability, motor retardation, absence of spontaneous locomotor activity and severe speech delay. Urinary excretion of N-acetylated amino acids was present. Mutational analysis of ACY1 gene identified the new homozygous c.1001_1001+5del6 mutation, which alters the mRNA transcription leading to exon 13 skipping and inclusion of a premature stop codon (p.Lys308Glufs*7). A quantitative fluorescent multiplex-polymerase chain reaction (QFM-PCR) assay has been set up and confirmed homozygosity of the mutation in the patient's DNA. Biochemical analysis showed absence of ACY1 enzyme activity in the patient's fibroblasts. The structure of the mutated protein has been defined by homology modeling (HM). Our data endorse the hypothesis of a link between this inborn error of metabolism and the neurological manifestations observed in patients with ACY1 deficiency.

Recurrent miscarriages in women not fulfilling classification criteria for antiphospholipid antibody syndrome.

Obstetric antiphospholipid antibody syndrome (APS), is well defined by classification criteria. It is well known that women with APS should receive prophylactic anticoagulation therapy with subcutaneous low weight heparin all throughout pregnancy and in the first 6 weeks postpartum. However, the optimal treatment for pregnant women having positive anti-phospholipid antibodies, but not fulfilling classification criteria for APS is still unclear. In this retrospective study we report pregnancy outcomes of 10 patients affected by recurrent miscarriages and positive anti-cardiolipin or aß2GP1 antibodies with titers ranging from 10 to 20 GPL/MPL demonstrated at least twice before pregnancy.

Granuloma annularis revealing Wegener's granulomatosis.

Skin manifestations are often associated with systemic autoimmune diseases (SAD). Some SAD, such as systemic lupus erythematosus, psoriatic arthritis and scleroderma display pathognomonic dermatological features, whereas other systemic diseases such as sarcoidosis, vasculitis and rheumatoid arthritis can present with non-specific skin manifestations that range from erythema nodosum to necrotic lesions. Here we report the case of a 25-year-old man with uveitis, polyarthrirtis, pulmonary involvement, nephrotic syndrome, cutaneous granuloma and pneumonia by E. coli.

Economic impact of an enhanced recovery pathway for oesophagectomy.

BACKGROUND: Data are lacking to support the cost-effectiveness of enhanced recovery pathways (ERP) for oesophagectomy. The aim of this study was to investigate the impact of an ERP on medical costs for oesophagectomy. METHODS: This study investigated all patients undergoing elective oesophagectomy between June 2009 and December 2011 at a single high-volume university hospital. From June 2010, all patients were enrolled in an ERP. Clinical outcomes were recorded for up to 30 days. Deviation-based cost modelling was used to compare costs between the traditional care and ERP groups. RESULTS: A total of 106 patients were included (47 traditional care, 59 ERP). There were no differences in patient, pathological and operative characteristics between the groups. Median length of hospital stay (LOS) was lower in the ERP group (8 (interquartile range 7-18) days versus 10 (9-18) days with traditional care; P = 0·019). There was no difference in 30-day complication rates (59 per cent with ERP versus 62 per cent with traditional care; P = 0·803), and the 30-day or in-hospital mortality rate was low (3·8 per cent, 4 of 106). Costs in the on-course and minor-deviation groups were significantly lower after implementation of the ERP. The pathway-dependent cost saving per patient was €1055 and the overall cost saving per patient was €2013. One-way sensitivity analysis demonstrated that the ERP was cost-neutral or more costly only at extreme values of ward, operating and intensive care costs. CONCLUSION: A multidisciplinary ERP for oesophagectomy was associated with cost savings, with no increase in morbidity or mortality.

Pattern of esophageal eosinophilic infiltration in patients with achalasia and response to Heller myotomy and Dor fundoplication.

Eosinophilic esophagitis (EoE) is now recognized as a common cause of dysphagia. Eosinophilic infiltration of the esophagus has also been associated with other conditions, such as gastroesophageal reflux disease (GERD); however, the incidence, pattern, and clinical significance of eosinophilic infiltration in achalasia are poorly documented. We sought to characterize this histological finding in patients undergoing Heller myotomy (HM) for achalasia. Ninety-six patients undergoing laparoscopic HM for primary achalasia between 1999 and 2008 were identified from a prospective database. Serial mid and distal per-endoscopic esophageal biopsies taken from patients before and after surgery were assessed for the presence of elevated intraepithelial eosinophils (EIEs). Slides from patients with reports suggestive of EIE were reviewed independently by two pathologists, and the highest eosinophil count/high-power field (eos/hpf) was recorded. Dysphagia scores (0 = none to 5 = severe dysphagia), GERD health-related quality of life scores (0 = best to 45 = worst), and 24-hour pH results were compared before and 3 months after surgery. We related the highest eos to the symptoms and response to HM. Data are presented as median (range). Paired t-test and Wilcoxon signed-rank test determined significance, *P < 0.05. Of 96 patients with achalasia, 50 had undergone pre-HM biopsies revealing EIE in 17/50 (34%), with a median of 3 eos/hpf (1-21). Two patients were found to have superimposed esophageal candidiasis. One patient met the pathologic criteria for EoE. Twenty-five of 50 (50%) postoperative biopsies demonstrated a median of 5 eos/hpf (1-62) for a total of 28/50 patients (56%) with EIE in either the preoperative or postoperative period. Four patients (8%) met the pathologic criteria for EoE, and two demonstrated persistent esophageal candidiasis. A decrease in eosinophils was found in 6/28 patients (21%) from 3/hpf (1-21) to 0.5/hpf (0-4). Increase in eosinophils was found in 22/28 patients (79%) from 0.5/hpf (0-8) to 5/hpf (1-62). Preoperative and postoperative dysphagia scores were available in 23 patients. Dysphagia scores improved in 22/23 patients. (3 [0-5] to 0 [0-2])*. Preoperative and postoperative GERD scores were available in 21 patients. GERD scores improved in 20/21 patients (10 [3-38] to 2 [2-14])*. Four of 13 patients (30.7%) demonstrated significant reflux in the postoperative period. No difference in clinical response to HM was detected between patients with preoperative EIE compared with patients with no EIE. No correlation between postoperative esophageal pH and eos was observed. A significant number of patients with achalasia demonstrate esophageal eosinophilic infiltration even at numbers demonstrable in patients with EoE (8% 4/50). While the interaction between achalasia and esophageal eosinophilic infiltration needs further investigation, this does not represent a distinct clinical entity. Thus, the presence of esophageal eosinophils in patients presenting with dysphagia should not preclude further work-up for other etiologies, including achalasia.

Perioperative docetaxel, cisplatin, and 5-fluorouracil (DCF) for locally advanced esophageal and gastric adenocarcinoma: a multicenter phase II trial.

BACKGROUND: Although perioperative chemotherapy for esophagogastric adenocarcinoma (ADC) improves survival, the overall poor prognosis suggests that further refinement of treatment is required. Docetaxel, cisplatin, and 5-fluorouracil (5-FU) (DCF) is effective for metastatic ADC of the upper gastrointestinal (GI) tract; we thus sought to investigate the efficacy of this regimen in patients with resectable disease. PATIENTS AND METHODS: Patients with resectable ADC of the upper GI tract received DCF [docetaxel (Taxotere) 75 mg/m(2) I.V. day 1, cisplatin 75 mg/m(2) I.V. day 1, 5-FU 750 mg/m(2) continuous infusion for 120 h, every 3 weeks] for three cycles before and after resection. Primary end point was complete resection; secondary end points were response, toxicity, surgical morbidity, and overall survival. RESULTS: Forty-three patients with ADC of the esophagus (11), gastroesophageal junction (25), or stomach (7) started treatment and 86% completed all preoperative cycles with grade 3-4 toxicity arising in 47%. Metabolic response to chemotherapy (reduction in maximal standard uptake value >35%) was achieved in 25/33 (76%) patients. Surgery was carried out in 41/43 and complete resection was achieved in all 41 patients with pathologic complete response in 4/41. Postoperative chemotherapy was started in 29 patients and completed in 24. Three-year overall survival was 60%. CONCLUSION: Perioperative DCF is a tolerable and highly effective regimen for the treatment of esophagogastric ADC.