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Purpose Many questions concerning Turner syndrome (TS) remain unresolved, such as the long-term complications and, therefore, the optimal care setting for adults. The primary aim of this long-term cohort study was to estimate the incidence of comorbid conditions along the life course. Methods A total of 160 Italian patients with TS diagnosed from 1967 to 2010 were regularly and structurally monitored from the diagnosis to December 2019 at the University Hospital of Bologna using a structured multidisciplinary monitoring protocol. Results The study cohort was followed up for a median of 27 years (IQR 12–42). Autoimmune diseases were the comorbid condition with the highest incidence (61.2%), followed by osteoporosis and hypertension (23.8%), type 2 diabetes (16.2%) and tumours (15.1%). Median age of onset ranged from 22 years for autoimmune diseases to 39 years for type 2 diabetes. Malignant tumours were the most prominent type of neoplasm, with a cumulative incidence of 11.9%. Papillary thyroid carcinoma was the most common form of cancer, followed by skin cancer and cancer of the central nervous system. Only one major cardiovascular event (acute aortic dissection) was observed during follow-up. No cases of ischaemic heart disease, heart failure, stroke or death were recorded. Conclusions This cohort study confirms the need for continuous, structured and multidisciplinary lifelong monitoring of TS, thus ensuring the early diagnosis of important comorbid conditions, including cancer, and their appropriate and timely treatment. In addition, these data highlight the need for the increased surveillance of specific types of cancer in TS, including thyroid carcinoma.

Background. Irreversible bilateral sensorineural hearing loss is a common side effect of platinum compounds. Because of extended overall survival period of children, a prolonged hearing surveillance and management of hearing impairments are emerging concerns for pediatric oncology. Methods. In this retrospective observational study we enrolled 38 children out of 116 treated at our institution by chemotherapy (cisplatin and/or carboplatin) with or without irradiation between 2007–2014, and submitted to hearing monitoring before every cycle of chemotherapy and that completed a 5 years long-term follow-up. Chemotherapy regimens, demographic findings, cumulative doses and cranial irradiation were compared. Results. At the end of 5-years follow-up ototoxicity was significantly increased compared to that at observed the end of chemotherapy (52.5% vs 39.5%, p 0.05). 13.1% of children needed hearing aids at the end of follow-up. Conclusions. Our study confirms the effectiveness of long-term follow-up in identifying late onset/progressive hearing loss after platinum compound chemotherapy and allows us to avoid the harmful effects of hearing deprivation with hearing aid intervention.

El presente trabajo se propone revisar un conjunto de crónicas urbanas de dos escritores latinoamericanos que compartieron su estadía en París en el entresiglos xix-xx. Los textos que elegimos circularon en publicaciones periódicas de Latinoamérica y luego fueron reunidos en tres volúmenes, que aún hoy siguen siendo escasamente trabajados: Peregrinaciones del nicaragüense Rubén Darío y Crónicas del bulevar y Paisajes parisienses del argentino Manuel Ugarte. El énfasis de la lectura estará puesto en el contrapunto de las miradas de los dos escritores-intelectuales y en las diferentes imágenes relevadas en sus crónicas, con el fin de descubrir los tornasoles de la mirada periférica a la cosmópolis y al proyecto de progreso, que caracterizan la modernidad central en el fin-de-siècle, además de perfilar sus proyecciones hacia la otra orilla del Atlántico.

© 2020, The Author(s). Individuals with Angelman syndrome (AS) are characterized by severe cognitive impairments alongside an enhanced drive for social engagement. As knowledge on imitation skills in this population is limited, we conducted the first controlled study of imitation in AS. We examined how 23 individuals with AS and 21 typically developing young children with similar mental age imitated novel actions in response to socially or non-socially engaging models, and in response to video-recorded versus live demonstrations of novel actions. Individuals with AS imitated as frequently and as accurately as typical young children in response to live demonstrations; but they imitated less frequently and less accurately in response to video-recorded demonstrations. Further, imitation was modulated by whether the demonstrator was socially engaging or emotionally neutral in the AS group, while this modulation was not present in the comparison group. Individuals with higher mental age imitated more frequently and more accurately across groups. Imitation performance in AS appears to be more modulated by the social context compared to typical infants and young children with similar mental age, possibly reflecting an enhanced drive for social engagement. A socially engaging instructional style might facilitate imitative learning in this population.

Background:The pathogenesis of otitis media is related to Eustachian tube dysfunction. The tensor veli palatini muscle actively opens the Eustachian tube and promotes middle-ear ventilation. This study describes a technique for paratubal electromyography that uses a surface, non-invasive electrode able to record tensor veli palatini muscle activity during swallowing.Methods:Twenty otitis media patients and 10 healthy patients underwent tensor veli palatini electromyography. Activity of this muscle before and after Eustachian tube rehabilitation was also assessed.Results:In 78.5 per cent of patients, the electromyography duration phase and/or amplitude were reduced in the affected side. The muscle action potential was impaired in all patients who underwent Eustachian tube rehabilitation.Conclusion:This study confirmed that Eustachian tube muscle dysfunction has a role in otitis media pathogenesis and showed that muscle activity increases after Eustachian tube rehabilitation therapy.

Aim To evaluate the role of pegylated liposomal doxorubicin with low-dose metronomic cyclophosphamide as primary systemic treatment in locally advanced breast cancer. Patients and Methods The activity and safety of intravenous pegylated liposomal doxorubicin 20 mg sqm−1 biweekly for eight courses in combination with metronomic cyclophosphamide 50 mg day−1 orally were evaluated in 29 patients with locally advanced breast cancer who were not suitable to receive a standard chemotherapy due to age or co-morbidities or who asked for a regimen with low incidence of toxic effects irrespective of age. Results The rate of breast-conserving surgery was 44.8%. Eighteen patients (62.1%) achieved a partial response (including one pathological complete response), 10 (34.5%) a stable disease and one patient experienced a progressive disease. Treatment was well tolerated, with no grade 4 toxicities, and with grade 3 skin toxicity in three patients and hand–foot syndrome in four patients. Conclusion The regimen was well tolerated but with limited activity in the preoperative setting. Other options (e.g., endocrine therapy in estrogen receptor -positive disease) should be considered in locally advanced breast cancer patients who are not suitable to receive a standard chemotherapy.

Purpose To explore the activity of pegylated liposomal doxorubicin (PLD) as neoadjuvant therapy of breast cancer. Methods The combination of PLD with cisplatin and infusional fluorouracil (CCF) for 8 courses was investigated in patients with primary or recurrent T2-T4a-d N0-3 M0 breast cancer. Patients with ER and/or PgR ≥10% tumors also received letrozole (±triptorelin). Results Forty patients entered the study. Four patients had recurrent tumors and 13 had cT4d tumors. Overall, clinical response rate was 77.5% whereas a pathological complete response (pCR) was obtained in 3 patients (7.7%), 4 when considering bilateral tumors. Noticeably 3 pCR were observed among the 10 patients with T4d ER positive tumors (33%). Eleven patients discontinued treatment before completion of the 8 planned courses. Conclusions Our results indicated that CCF yielded an appreciable rate of clinical responses in a series of very locally advanced tumors and an unusually high rate of pCR in T4d ER positive tumors, suggesting an enhanced cutaneous activity of PLD.

The objective of this study was to evaluate the clinical and biological activities of bevacizumab in combination with preoperative anthracyclines and taxane-based chemotherapy in locally advanced breast cancer selected for unfavorable prognostic features. Patients with cT2-4c, cN0-2, estrogen and progesterone receptors less than 10% of the cells or cT4d and any estrogen/progesterone receptors expression received four courses of ECF-chemotherapy (epirubicin, cisplatin, fluorouracil as continuous infusion) followed by three courses of weekly paclitaxel in combination with bevacizumab. Thirty patients were included in the study. An objective response, either complete or partial, was observed in 26 patients (87%; 95% confidence interval: 69-96%), stable disease was observed in two patients (7%), and two patients (7%) progressed. A pathological complete response was obtained in 10 patients (33%; 95% confidence interval: 17-53%). Side effects related to bevacizumab with grade >or=2 included headache and hypertension. A nonstatistical significant decrease in the median value of circulating endothelial cells was observed at surgery (3.0/microl vs. 5.7/microl, P=0.19). In conclusion, high rates of both clinical and pathological responses with anthracycline-containing chemotherapy followed by weekly paclitaxel plus bevacizumab were observed in locally advanced breast cancer with unfavorable prognostic features. A non-negligible rate of progressive disease was observed, suggesting careful monitoring of the patients. Further studies evaluating the potential benefit of bevacizumab in neoadjuvant treatment need to be tested.

The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.

Nowadays oral appliance therapy is recognised as an effective therapy for many patients with primary snoring and mild to moderate obstructive sleep apnoea (OSA), as well as those with more severe OSA who cannot tolerate positive airway pressure (PAP) therapies. For this reason, it is important to focus on objective criteria to indicate which subjects may benefit from treatment with a mandibular advancement device (MAD). Various anthropometric and polysomnographic predictors have been described in the literature, whereas there are still controversies about the role of drug-induced sleep endoscopy (DISE) and advancement bimanual manoeuvre as predictor factors of treatment outcome by oral device. Herein, we report our experience in treatment of mild moderate OSA by oral appliance selected by DISE. We performed a single institution, longitudinal prospective evaluation of a consecutive group of mild moderate patients with obstructive sleep apnoea syndrome who underwent DISE. During sleep endoscopy, gentle manoeuvre of mandibular advancement less than 5 mm was performed. In 30 of 65 patients (46.2%) we obtained an unsuccessful improvement of airway patency whereas in 35 of 65 patients (53.8%) the improvement was successful and patients were considered suitable for oral device application. Because 7 of 35 patients were excluded due to conditions interfering with oral appliance therapy, we finally treated 28 patients. After 3 months of treatment, we observed a significant improvement in the Epworth medium index [(7.35 ± 2.8 versus 4.1 ± 2.2 (p0.05)], in mean AHI [(21.4 ± 6 events per hour versus 8.85 ± 6.9 (p0.05)] and in mean ODI [(18.6 ± 8 events per hour to 7 ± 5.8 (p0.05)]. We observed that the apnoea/hypopnoea index (AHI) improved by up to 50% from baseline in 71.4% of patients selected after DISE for MAD therapy. In the current study, mandibular advancement splint therapy was successfully prescribed on the basis not only of severity of disease, as determined by the subject's initial AHI, but also by DISE findings combined with results of gentle mandibular advancement manoeuvre allowing direct view of the effects of mandibular protrusion on breathing spaces in obstruction sites, and showing good optimisation of selection of patients for oral device treatment.Il trattamento con dispositivi di avanzamento mandibolare (MAD) rappresenta un'efficace alternativa terapeutica per i pazienti affetti da roncopatia semplice, OSAS di grado lieve/moderato e in casi selezionati di OSAS grave con scarsa tollerabilità alla terapia ventilatoria con C-PAP. Pertanto è importante identificare dei criteri oggettivi per selezionare i pazienti che possono beneficiare del trattamento con i sistemi di avanzamento mandibolare (MAD). In letteratura sono stati descritti vari fattori predittivi sia antropometrici che polisonnografici, mentre esistono ancora controversie circa il ruolo della Sleep Endoscopy e della manovra di avanzamento mandibolare bimanuale durante lo stesso esame come fattori predittivi del successo terapeutico con MAD. In questo studio descriviamo la nostra esperienza nel management di pazienti affetti da OSAS lieve/moderata trattati con MAD e selezionati mediante "sleep endoscopy". Abbiamo eseguito una valutazione prospettica longitudinale di una serie consecutiva di pazienti giunti alla nostra osservazione con diagnosi di OSAS lieve/moderata e sottoposti a sleependoscopy. Durante il sonno indotto farmacologicamente è stata eseguita una delicata manovra di avanzamento mandibolare con escursione inferiore ai 5 mm e abbiamo riscontrato che in 30 dei 65 pazienti (46,2%) lo spazio respiratorio non migliorava in modo significativo a livello dei siti di ostruzione osservati, mentre in 35 dei 65 pazienti (53,8%) si osservava un miglioramento significativo tale da poter indicare terapia con MAD. In 7 dei 35 pazienti venivano riscontrate condizioni che ostacolavano l'applicazione del MAD per cui 28 dei 35 pazienti sono stati sottoposti a terapia con MAD. Dopo 3 mesi di trattamento abbiamo documentato un miglioramento significativo dell'indice di Epworth medio [(7,35 ± 2,8 vs 4,1 ± 2,2 (p0.05)], dell'AHI medio [(21.4 ± 6 eventi per ora verso 8,85 ± 6,9 (p0.05) ] e dell'ODI medio [(18.6 ± 8 eventi per ora versus 7 ± 5.8 (p0.05)]. Abbiamo inoltre osservato che l'AHI migliorava di almeno il 50% rispetto al basale nel 71.4% dei pazienti selezionati mediante sleep endoscopy. In questo studio, la terapia con i dispositivi di avanzamento mandibolare è stata prescritta con successo sulla base non soltanto dell'indice di apnea/ipopnea, ma anche dei reperti della sleep endoscopy e della manovra di avanzamento mandibolare, ottenendo una visione diretta degli effetti della protrusione mandibolare sullo spazio respiratorio in corrispondenza dei siti di ostruzione, e ottenendo una buona ottimizzazione della selezione dei pazienti per il trattamento con MAD.

Oro-pharyngeal dysphagia is frequently present during the acute phase of stroke. The aim of the present study was to evaluate whether the recording of surface EMG using a nasopharyngeal (NP) electrode could be applied to evaluation of pharyngeal muscle activity in acute stroke patients and if this neurophysiological measure is related with clinical assessment of swallowing. Patients were examined and clinical severity was assessed with the National Institute of Health Stroke Scale (NIHSS) score; dysphagia was evaluated through bedside screening test using the Gugging Swallowing Scale (GUSS). Extension of the ischaemic lesion was measured by quantitative score, based on CT scan [Alberta Stroke Programme Early CT Score (ASPECTS)]. We analysed 70 patients; 50 were classified as dysphagic (Dys+), and 20 as non-dysphagic (Dys-). Each participant underwent a surface NP EMG recording performed with a NP electrode, made of a Teflon isolated steel catheter, with a length of 16 cm and a tip diameter of 1.5 mm. The electrode was inserted through the nasal cavity, rotated and positioned approximately 3 mm anteroinferior to the salpingo-palatine fold. At least four consecutive swallowing-induced EMG bursts were recorded and analysed for each participant. Swallowing always induced a repetitive, polyphasic burst of activation of the EMG, lasting around 0.25 to 1 sec, with an amplitude of around 100-600mV. Two parameters of the EMG potentials recorded with the NP electrode were analyzed: duration and amplitude. The duration of the EMG burst was increased in Dys+ patients with a statistically significant difference compared to Dys- patients (p0.001). The amplitude was slightly reduced in the Dys+ group, but statistically significant differences were not observed (p = 0,775). Nevertheless, the burst amplitude showed a significant inverse correlation with NIHSS [r(48) = -0.31; p0.05] and ASPECTS scores [r(48) = -0.27; p0.05], meaning that the burst amplitude progressively reduced with an increase of clinical severity (NIHSS) and topographic extension of brain lesions in CT (ASPECTS). These results suggest that NP recordings can give a semi-quantitative measure of swallowing difficulties originating from pharyngeal dysfunction, in fact, electromyographic findings suggest reduced pharyngeal motility.La disfagia orofaringea è spesso presente durante la fase acuta di un ictus. Lo scopo di questo lavoro è stato quello di valutare se la registrazione elettromiografica di superficie tramite un elettrodo nasofaringeo può essere impiegata per testare l’attività muscolare del faringe nei pazienti con ictus acuto e se queste misurazioni elettrofisiologiche possono essere correlate con la valutazione clinica della deglutizione. Dal punto di vista clinico la severità del quadro è stata valutata mediante l’utilizzo della scala del National Institute of Health Stroke (NIHSS); la disfagia è stata valutata mediante il test di screening Gugging Swallowing Scale (GUSS); l’estensione della lesione ischemica alla TAC è stata misurata attraverso l’Alberta Stroke Programme Early CT Score (ASPECTS). Abbiamo valutato 70 pazienti di cui 50 disfagici (Dys+), e 20 non disfagici (Dys–). Ciascun partecipante è stato sottoposto a un’elettromiografia di superficie registrata mediante un elettrodo NP costituito da un catetere di Teflon isolato in acciaio (lungo 16 cm e con un diametro in punta di 1,5 mm). L’elettrodo è stato inserito attraverso la cavità nasale, ruotato e posizionato approssimativamente 3 mm antero-inferiormente rispetto alla volta salpingo-palatina. Per ogni partecipante sono state registrate ed analizzate le risposte elettromiografiche di almeno quattro deglutizioni volontarie ripetute. La deglutizione induce sempre all’elettromiografia burst ripetitivi e polifasici di durata compresa fra 0,25 e 1 secondo, con un’ampiezza intorno ai 100-600mV. I disfagici hanno mostrano una maggiore durata del burst rilevato all’elettromiografia rispetto ai non disfagici, con una differenza statisticamente significativa (p0,001), ma non hanno mostrano differenze in termini di ampiezza del burst stesso (p = 0,775); quest’ultima invece era inversamente correlata con lo NIHSS score [r(48) = –0,31; p0,05)] e con lo ASPECTS score [r(48) = –0,27; p0,05]. Questi risultati suggeriscono che le registrazioni nasofaringee possono rappresentare un indice semi-quantitativo delle difficoltà deglutitorie secondarie a disfunzione faringea ed in particolare, i risultati dell’elettromiografia sarebbero indicativi di una ridotta motilità faringea durante la fase acuta di un ictus.

Histatin 1 (His-1) derivatives showing serial mass increases of 80.0 +/- 0.1 Da were detected in human saliva by HPLC-ESI-MS. The same derivatives were also found in granules of submandibular glands and secretions of submandibular/sublingual glands, but not in granules and secretions of parotid glands. Only one phosphate group was present in His-1 and its derivatives, since treatment with alkaline phosphatase provided an 80.0 Da mass decrease. His-1 derivatives were almost completely transformed into His-1 by treatment with 1 M HCl at 100 degrees C, suggesting the presence of O-sulfotyrosine, which is more labile than phospho-Tyr to acidic hydrolysis. CE-MS analysis of pronase extensive digestion of derivatives confirmed the presence of sulfotyrosine. Derivatives were digested by trypsin, proteinase K, and protease V-8 and analyzed by different MS strategies. The results allowed locating sulfation on the last four tyrosines (Tyr 27, 30, 34, and 36). This study is the first report of the gland-specific sulfation of a salivary phosphopeptide in vivo.

Turner syndrome (TS) is one of the most common chromosomal abnormalities, occurring in about 50 per 100,000 female live births characterized by the total or partial loss of one X-chromosome in all or some cells. Frequently observed manifestations of TS include short stature, lymphedema, cardiac abnormalities, gonadal dysgenesis, dysmorphic features, ear and hearing problems, and a variety of other problems. Conductive hearing loss (CHL) in patients (pts) with TS is due to recurrent otitis media with effusion, chronic middle ear infection, and cholesteatoma probably as the result of malfunction of the Eustachian tube associated with lymphedema and anatomic shortening of the skull base. The high prevalence of middle ear infections and CHL in TS are probably due to growth disturbances of the structures from the first and second branchial arches. Sensorineural hearing loss (SNHL) is also reported in TS and the hearing decline seems to consist of two patterns: a mid-frequency dip (0.5–3 kHz region) (MF-HL) and a high-frequency loss (>3 kHz region) (HF-HL). SNHL is associated with genotype and phenotype. It seems that SNHL in these pts can become clinically evident during childhood or adolescence, progressive with time, and is independent of middle ear diseases. The evaluation in follow-up of hearing impairment shows that the high-frequency HL remained stable in time. Instead, SNHL with typical dip had a progressive decline. The rate of hearing loss is high at all frequencies but most prominent in the mid-frequency region and the presence of a mid-frequency dip is an especially strong predictor for a progressive decline of hearing. Hearing loss (HL) could have an important impact on social functioning for pts with TS. Clinicians proposed a regular audiological follow-up in TS, especially during childhood, to prevent important middle ear anatomic sequelae and to identify HL at an early stage.

There is a wide spectrum of skin anomalies in TS related to fetal lymphoedema, GH therapy or elevated FSH level. AN is characterized by hyperkeratosis, pigmentation and small papillomatous elevation of the skin. Aim of the study: to evaluate the association between TS, AN and glucose-tolerance. Methods: 129 TS pts (45,X=43%; X-SA=41%; X-mosaicism=13%; Ymosaicism=3%) were studied for glucose tolerance and skin anomalies. All pts had GH-therapy (range3-12 yrs) alone or with EE-P. Beta-cell function and insulin sensitivity (IS) were studied with indices from fasting or OGTT (0,30,60,120’); beta-cell function: HOMA, insulinogenic (II) 30’, II-120’ indices; IS: fasting glucose to insulin ratio, HOMA IR, HOMA IS indices. Results: 13 pts (10%) showed AN (karyotype: 7 pts=45,X; 5 pts=X-SA and 1 pt=X-mosaicism). Age of GH-onset and duration were the same in pts with and without AN.GH therapy, according to its duration, determines a lowering of betacell function (HOMA p=0.048; II-120’ p=0.0002) and an increase of fasting glucose to insulin ratio. Age influences negatively HOMA IS (p=0.0001). Age(p=0.006) and BMI(p=0.04) correlated positively with II-120. There were no differences in glucose values (fasting and after OGTT) in pts with and without AN. AN pts had higher values of acute and complete serum insulin levels (II-30’ p=0.001; II-120’ p=0.019) and higher HOMA IR (p=0.02). Karyotype (45,X presence) influences the appearance of AN (p=0.008). Discussion: AN pts showed mean insulin level (fasting and after OGTT) significantly higher than pts without AN. The insulin AUC is greater in AN pts, but there were no differences in glucose AUC in pts with and without AN. Probably AN pts may need a higher production of insulin to keep glucose values within the normal range. This is the expression of insulin resistance, in fact HOMA IR is significantly higher in AN pts. GH therapy, according to its duration, does not influence betacell function in AN pts.

Aortic dilation (AoDil) occurs in Turner syndrome (TS) pts, although in absence of CHD as risk factor. There is limited information on its prevalence and natural history. Aim of our study: to evaluate AoDil prevalence (at echocardiography and MRI) in patients without CHD aged over 15 years, followed for at least 5 years. Methods: In our center 190 TS unselected pts were followed (2-25.5 yrs) with periodic cardiologic evaluations. Between 2000 and 2003, 52 consecutive patients without CHD and age over 15 yrs (15-35.2 yrs) had a cardiologic re-evaluation with echo (2D and color Doppler) and transthoracic MRI. Two had HBP. For Ao diameters the same criteria as for echo were used for MRI, taking as normal the values within the 95% normal confidence limits indexed to body surface area (Roman et al., 1989). Results: 30.7% of pts had Ao dimensions within upper normal limits, the same at echo and MRI (16/52 pts). In particular the prevalence of DilAo was the same (echo and MRI) at anulus and the sinuses of Valsalva (19.2% and 21% respectively). At proximal ascending Ao echography showed a higher prevalence of 28.8% (15/52) than MRI (19.2% -10 of 52). 13.5% (7/52) of pts were above upper normal limits at echo and 7.7% (4/52) at MRI. In our series the follow-up did not show any progressive and rapid evolution of AoDil. Conclusions: This data confirms the higher prevalence of AoDil in TS pts than in the GP also for severe dilation. An accurate echo follow-up of the different segments of Ao is highly recommendable in these pts even in absence of CHD. Echo pproach may cause some distortion in the image of the thoracic Ao in TS pts and this may explain the higher AoDil prevalence found at echo than at MRI in the proximal ascending Ao. The importance of AoMRI in these pts should be emphasize in particular when an ascending AoDil is detected at echo and in any case before seeking to become pregnant.

CFC syndrome is characterized by ectodermal abnormalities, coarse face, macrocephaly,postnatal short stature and MR and is in the spectrum of MCA/MR syndromes. Case report: 10 yr old boy with short stature and coarse face. Family history unremarkable. 2nd born to nonconsanguineous parents, 32 wks gestation. Pregnancy complicated by threat of miscarriage. At birth (length 49cm; weight 2400g and OFC 32cm) hospitalized for prematurity and respiratory problems. Motor delay of lower limbs. Karyotype: 46,XY. Haematological, biochemical, metabolic, hormonal tests, fundus oculi, skeletal X-ray: normal. At 2 yrs autoimmune hemolitic anemia; at 3 yrs autoimmune thrombocytopenia; at 9 yrs autoimmune neutropenia. Surgery for tight achilles tendons. At 10 yrs: H 3rd centile, W 75th centile for Height Age, OFC 90th centile for HA; PH 1; bilateral cryptorchidism. Severe GHdeficit was diagnosed and he was submitted to GH-therapy; cryptorchidism required surgery. Echocardiography excluded CHD. Clinical examination: macrodolicocephaly, bitemporal constriction; shallow orbital ridges, sparse eyebrows and eyelashes; facial hyperkeratosis and dermatitis; telecantus; epicanthal folds, ptosis, strabismus, nystagmus; large, depressed nasal bridge; large mouth; higharched palate; low-set and posteriorly rotated ears; broad and short neck; thin upper and lower limbs, incomplete extension of cubitus; genu valgum; flat foot; nail dysplasia; multiple lentigo; pigmented naevi; glabra, dry and hyperkeratosic skin; curly, woolly, frizzy hair; hypertonia; normal intelligence. Our pt had clinical manifestations of CFC syndrome without MR. Possible differential diagnoses were Noonan syndrome (PTPN11 mutation 50%) and Leopard syndrome (PTPN11 mutation 90%). In our pt no mutation in PTPN11 gene was found. GHdeficit is not reported in CFC syndrome and there is only one pt without MR (Manoukian et al,1996). Our case could be the second case without MR and with associated GH-deficit.

In past years, external dacryocystorhinostomy has been considered the gold standard in terms of functional outcome for treatment for nasolacrimal duct obstruction. In comparison, interest in the use of the recently developed endonasal dacyocystorhinostomy procedure has been rekindled because of advances in instrumentation. For the past 10 years, differences in the outcomes between the two techniques have been reduced; thus, currently, the choice of the type of surgery is associated with the experience of the surgeon, resources available in the healthcare system and patient preferences.In passato la dacriocistorinostomia per via esterna (EXT-DCR) è stata considerata il gold standard in termini di risultato funzionale nel trattamento delle ostruzioni del dotto naso lacrimale. L'innovazione della strumentazione ha recentemente incrementato l'interesse per la dacriocistorinostomia endoscopica per via endonasale (EES-DCR). Negli ultini 10 anni le differenze in termini di risultati tra le due tecniche chirurgiche sono andate riducendosi; la scelta del tipo di tecnica chirurgica è attualmente legata all'esperienza del chirurgo, alle risorse economiche del sistema sanitario e alle preferenze del paziente.

Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumours. We explored patterns of recurrence in 1691 women with pT1mic/T1a/T1b, pN0 and M0 breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67 < 14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67 ≥ 14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) Triple Negative. At multivariate analysis, women with the Triple Negative breast cancer subtype had an increased risk of loco-regional relapse (LRR) (Hazards Ratio (HR) 3.58; 95%CI: 1.40-9.13) and breast cancer related events (HR 2.18; 95%CI: 1.04-4.57). Overall, Luminal B subtype was not associated with a statistically significant increased risk of recurrence compared with Luminal A, while patients with Luminal B subtype tumours overexpressing HER2 had a 2 fold risk of reduced breast cancer related survival (BCS), but not an increased risk of LRR and distant metastases. Women with HER2 breast cancer subtype had a statistically significant increased risk of LRR (HR 4.53; 95%CI: 1.56-13.1), distant metastases and reduced BCS (HR 3.22; 95%CI: 1.44-7.18) and overall survival (HR 2.87; 95%CI: 1.05-7.89) when compared with the Luminal A subtype, at multivariate analysis. In conclusion, women with small size, node-negative, breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or Triple Negative disease.

Patients with large ER positive tumors candidate to preoperative chemotherapy may also benefit from a concurrent endocrine intervention, but this issue has been scarcely investigated due to concerns arising from unfavorable results emerged from an adjuvant trial of concurrent tamoxifen and chemotherapy. We retrospectively investigated the activity of letrozole plus GnRH analogue (GnRH-a) administered concurrently with preoperative chemotherapy and as adjuvant treatment in premenopausal women with locally advanced ER positive breast cancer consecutively admitted at the European Institute of Oncology. Results were compared with those of a non-randomized unmatched control group of premenopausal women with locally advanced ER positive breast cancer receiving preoperative chemotherapy, followed by tamoxifen and GnRH-a after surgery. Primary endpoints were pathological complete response (pCR) rate, decrease of Ki67 and disease free survival (DFS). One-hundred and nineteen women constituted the study group, while 95 patients served as controls. The pCR rate was 5.0 vs 1.1% in the study and control group, respectively. A statistically significant greater suppression of Ki67 was observed in patients receiving chemoendocrine therapy as compared with controls (P = 0.003). At a median follow up of 59 months, 26 events occurred in the chemoendocrine group and 48 in the control group. Five-year DFS was 78 vs 41% in the study and in the control group, respectively [adjusted HR 0.46, 95% CI 0.27-0.79, P = 0.0047]. The concurrent administration of letrozole and GnRH-a with preoperative chemotherapy was highly effective in premenopausal women with large ER positive breast cancer in terms of decreased proliferation and of improved DFS. Randomized studies are warranted to establish the role of the addition of endocrine therapy to chemotherapy as standard preoperative approach for ER positive locally advanced breast cancer as well as of letrozole in combination with GnRH-a for the treatment of premenopauasal women with early breast cancer. © 2011 Springer Science+Business Media, LLC.

We analyzed the role of endocrine responsiveness and HER2/neu overexpression in inflammatory breast cancer treated with multimodality preoperative therapy. Thirty-eight patients (estrogen receptor [ER] and/or progesterone receptor [PgR] >or=10% of the cells 21, premenopausal 14, Ki-67 expression >or=20% of the cells 30, HER2/neu overexpressed 11) were treated with six courses of epirubicin, cisplatin and fluorouracil (FU) as continuous infusion, perioperative FU as continuous infusion, mastectomy and loco-regional radiotherapy. In endocrine-responsive patients, endocrine treatment (letrozole, either alone or if premenopausal with triptorelin) was given preoperatively and as adjuvant treatment. There were 32 objective responders (84.2%; 95% CI 70.0-94.6%), three of whom had pathologic complete remission. At the multivariate analysis disease-free survival was significantly worse in patients with ER and PgR absent tumors compared with the positive expression cohort (hazards ratio [HR]: 5.91; 95% CI 1.69-20.7; p = 0.005), in particular if HER2/neu overexpression was detected (HR: 16.5; 95% CI 4.24-64.5; p < 0.0001). New multimodality and targeted strategies should be explored in endocrine nonresponsive breast cancer.

Myxopapillary ependymomas represent the most frequent type of ependymomas found at the conus medullaris-cauda equina-terminal filum level. In this article the authors describe the clinical presentation, radiographic findings, operative details, and pathological features of a patient with a concomitant presentations of a thoracic spinal cord myxopapillary ependymoma and a filum terminale myxopapillary ependymoma. A 16-year-old man presented to the Neurosurgery Department of the S. Maria delle Grazie Hospital (Naples, Italy) with an increased weakness of both the legs with great difficulties with walking and with bowel and bladder dysfunction. In a few minutes he becomes paraplegic. Magnetic resonance (MR) imaging revealed two ependymomas: the first one was localized in the middle thoracic part of the spinal cord and, the second one was localized in the cauda at sacral level. Two operations were performed for gross total resection of the masses. The first operation was performed at thoracic level and the second one was performed at the sacral level after two months. The examination demonstrated in both cases a myxopapillary ependymoma. The patient experienced complete resolution of her preoperative symptoms. This article reports an unusual case of a concomitant presentations of a thoracic spinal cord myxopapillary ependymoma and a filum terminale myxopapillary ependymoma myxopapillary. To the best of the authors' knowledge, this association has not yet been reported. This raises the interesting question of a possible associative or causative relationship between these pathologies. The authors considered dissemination to be the spread of tumor along the neuraxis to a location separate from the primary site. They do not believe that the lesion at the cauda level was a drop metastase. As the entire spinal cord and the brain were imaged, and as the tumor in the thoracic spinal cord area was we well capsulated, a disseminated ependymoma was confidently excluded.

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6-87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33-4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61-4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42-3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC.

Purpose Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies. Patients and Methods Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). Results In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD ≥ 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD ≥ 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). Conclusion Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.

Cancer vaccine-based immunotherapy should potentiate immunosurveillance function, preventing and protecting against growing tumors. Tumor cells usually activate the immune system, including T lymphocytes and natural killer cells, which are able to eliminate the transformed cells. Immunosubversion mechanisms related to tumor cells antigenic immunoediting induces mechanisms of tolerance and immunoescape. This condition impairs not only host-generated immunosurveillance, but also attempts to harness the immune response for therapeutic purposes. Most trials evaluating breast cancer vaccines have been carried out in patients in the metastatic and adjuvant setting. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. We summarize the differential approaches, protein-based and cell-based vaccines, focusing on vaccines targeting HER2/neu protein. Another focus of the review is to provide the reader with future challenges in the field, taking into account both the immunological and clinical aspects to better target the goal.

The purpose of this study was to assess the effectiveness and safety of Ballon Kyphoplasty as a new method of treatment for traumatic fracture of the thoracolumbar junction.We treated twelve patients 8 patients male and 4 female. The average age was 47,3 years (22-75 years). The interested vertebrae and therefore the procedures have been 13 since in a patient two vertebrae have been treated. In 9 cases the interested vertebra was L1, in 2 cases L2 and one case D11 and D12. Following the classification of Magerl 9 fractures were of A1.2 fractures and one fracture respectively of type A1.3, A2.2, A2.3, A3.1. We have never placed indication to Balloon Kyphoplasty in the fractures of the type B and C, neither in the complete burst fractures (A3.2 and A3.3), neither in the fractures of the A1.1 type. Balloon Kyphoplasty has been carried out using the Kyphon system (Kyphon Inc. Sunnyvale, CA, USA). In the patients older than 50 years (7 cases) we have used polymethylmethacrylate (PMMA), as filling material, while in the patients younger than 50 years (5 in total), we have used Calcibon (Biomet, Inc.Warsaw, Indiana) in 4 cases and in one case a new material called KyphOs (Kyphon Inc. Sunnyvale, CA, USA). These last two types of material are made up of tricalcium phosphate that, although less manageable of the PMMA and less resistant initially, in the time it will be reabsorbed and osteointegrated.The method demonstrated swift pain relief associated with an evident augmentation in the resistance and restoration of the vertebral body's physiological shape. No patient has worn a postoperative orthesis. In all the cases we obtained an optimal stabilization in the follow-up minimal to 4 months. In no case we observed a structural yielding of the vertebra.Kyphoplasty is an effective, alternative, simple and safe treatment of traumatic fracture of the thoracolumbar junction.

The personal experience with the surgical treatment of reduction and fixation of comminuted fractures of the anterior wall of the frontal sinus is reported. Cosmetic results were examined with regard to patients' degree of satisfaction on a 0 to 2 scale and nasal function assessed via rhinoscopy and nasal endoscopy during clinical follow-up, in the course of which the integrity and functionality of the supraorbitary and facial nerves were evaluated. All patients were satisfied, on the whole, with the aesthetic result, with 0-degree satisfaction (no deformity compared with their condition prior to the injury). The operations were performed between the 2nd and 7th post-injury day. The importance of the preoperative clinico-radiological work-up is stressed, with particular regard to the detection of simultaneous involvement of the inferior and/or posterior wall, and to the choice of surgical approach. The evolution of the surgical techniques in the treatment of frontal sinus fractures is discussed. With reference to the new means of fixation, in cases of comminuted fractures of the anterior wall, titanium mesh is preferred. In the Authors' opinion it combines excellent fixation with easy adaptability (cosmetic results are good) without requiring in the majority of cases, autologous bone grafts.

Free radicals are involved in gentamicin ototoxicity and vestibular dysfunction and it has been demonstrated that free radical scavengers, such as alpha-tocopherol, are able to inactive free radicals, attenuating tissue damage This study was designed to investigate the possible protective effects of alpha-tocopherol against gentamicin-induced oto-vestibulo toxicity.Adult albino guinea pigs were divided into four groups and were treated for 2 weeks as follows: Group A, controls; Group B, gentamicin plus corn oil; Group C, gentamicin only; and Group D, gentamicin plus alpha-tocopherol. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VORs), respectively. Electrocochleographic recordings were performed using an implanted round window electrode. The compound action potentials (CAPs) at 2, 4, 8 and 16 kHz were measured every 5 days Morphological changes were analysed by means of scanning electron microscopy.Gentamicin induced a consistent reduction in VOR responses and a progressive high-frequency hearing loss of 50-60 dB sound pressure level. Alpha-Tocopherol co-therapy slowed the progression of hearing loss and significantly attenuated the final threshold shifts The impairment of vestibular function was reduced, as evidenced by an increased VOR gain. The massive loss of outer hair cells in the cochlear basal turn and of cristae ampullaris stereocilia in gentamicin-treated animals was not observed in the cochlea of animals protected with alpha-tocopherol.This study supports the hypothesis that alpha-tocopherol interferes with gentamicin-induced free radical formation, and suggests that this drug may be useful in preventing aminoglycoside oto-vestibulo toxicity.

The Authors report on their experience of 18 patients with isolated fractures of the zygomatic arch who were treated via intraoral approach. The procedures were performed between the 2nd and 8th post-trauma day and the results obtained were evaluated via post-operative CT scan and periodic follow-up visits for six months. In describing the surgical technique, the Authors recommend that the fracture be reduced with the patient's mouth open, in order to overcome the anatomical obstacle constituted by the coronoid process of the mandible and avoid, as far as possible, external approaches and osteosynthesis with screws or miniplates, which often give rise to unaesthetic results and localized pain. In conclusion, this approach is seen to be the method of choice in the treatment of isolated zygomatic arch fractures in that it is simple, effective and substantially free from complications.

OBJECTIVE: To quantitatively analyze modifications of the paratubal muscles in developing Wistar rats following nasal obstruction. MATERIAL AND METHODS: Twenty-four Wistar rats were used. Twelve were examined at 6, 8 and 12 weeks after birth and were considered normal controls. The nostrils of the remaining 12 rats were bilaterally obstructed by means of a synthetic resin 28 days after birth. The animals were sacrificed at either 2, 4 or 8 weeks after nostril occlusion. Serial sections were made in the dorsoventral plane and stained with hematoxylin-eosin. Four 5 x 5 microm2 areas, selected within the paratubal muscles, were histologically analyzed and the number of muscular fibers was counted manually. RESULTS: The number of tensor veli palatini muscle fibers progressively decreased in the obstructed rats compared with age-matched normal controls and in those that had been obstructed for 4 and 8 weeks these reductions were statistically significant. CONCLUSION: The correct development of the paratubal muscles seems to be linked to physiological nasal breathing and is negatively affected by oral breathing.