How we improve the transoral resection for oral and oropharyngeal cancer: the CO2 waveguide laser.

PURPOSE: The main aim of this study was to evaluate the CO2 waveguide laser (CO2 WGL) with flexible fiber (Lumenis, Santa Clara, CA) in the treatment of oral and oropharyngeal cancers specifically focusing on the lateral thermal damage (LTD) induced by this instrument and therefore on the reliability of the analysis of frozen sections collected during margin mapping. METHODS: A total of 48 patients with oral and oropharyngeal cancers from T1 to T4a were prospectively enrolled in the study. We collected data about LTD, pathologic tumor and node stage (pTNM), surgical intervention, kind of reconstruction (no flap, local vs free flap), need for tracheotomy and time of removal, postoperative complications (such as bleeding, mucosal dehiscence, and fistula), need for feeding tube and time of removal. RESULTS: Mean LTD was 164.7 ± 92.4 µm. Comparing frozen section histology before and after formalin embedding we found 5 true positives, 170 true negatives, 4 false positives and 4 false negatives, with a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 55.6%, 98%, 55.6%, 98%, and 96.1%, respectively. CONCLUSION: CO2 WGL is a very manageable tool, which allows a precise cut. However, its high costs, the inability to re-use the fibers and its low coagulation capability must be considered.

NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease.

Disarrangement in functions and quality control of mitochondria at synapses are early events in Alzheimer's disease (AD) pathobiology. We reported that a 20-22 kDa NH2-tau fragment mapping between 26 and 230 amino acids of the longest human tau isoform (aka NH2htau): (i) is detectable in cellular and animal AD models, as well in synaptic mitochondria and cerebrospinal fluids (CSF) from human AD subjects; (ii) is neurotoxic in primary hippocampal neurons; (iii) compromises the mitochondrial biology both directly, by inhibiting the ANT-1-dependent ADP/ATP exchange, and indirectly, by impairing their selective autophagic clearance (mitophagy). Here, we show that the extensive Parkin-dependent turnover of mitochondria occurring in NH2htau-expressing post-mitotic neurons plays a pro-death role and that UCHL-1, the cytosolic Ubiquitin-C-terminal hydrolase L1 which directs the physiological remodeling of synapses by controlling ubiquitin homeostasis, critically contributes to mitochondrial and synaptic failure in this in vitro AD model. Pharmacological or genetic suppression of improper mitophagy, either by inhibition of mitochondrial targeting to autophagosomes or by shRNA-mediated silencing of Parkin or UCHL-1 gene expression, restores synaptic and mitochondrial content providing partial but significant protection against the NH2htau-induced neuronal death. Moreover, in mitochondria from human AD synapses, the endogenous NH2htau is stably associated with Parkin and with UCHL-1. Taken together, our studies show a causative link between the excessive mitochondrial turnover and the NH2htau-induced in vitro neuronal death, suggesting that pathogenetic tau truncation may contribute to synaptic deterioration in AD by aberrant recruitment of Parkin and UCHL-1 to mitochondria making them more prone to detrimental autophagic clearance.

AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons.

Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20-22kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau -but not the physiological full-length protein- interacts with Aß at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clearance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin-mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autophagic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles.

Abdominal asymmetry in a 17 year old girl.

The pseudopapillary pancreatic solid tumor (TPSP) is a rare malignancy typical of young adult women (only 12 pediatric cases from 2000 to 2009), it can recur and metastasize. The prognosis is usually good after radical surgical removal. We emphasize the importance of TPSP in differential diagnosis of retrogastric, peripancreatic masses especially in puberal females. We describe the case of an adolescent girl with an abdominal mass revealed as a rare pancreatic neoplasia.

Extranodal extension in head and neck squamous cell cancer: is there a role for further stratification?

To investigate the prognostic significance of the stratification of extranodal extension (ENE) into ENE minor (ENEmi, up to 2mm) and ENE major (ENEma, over 2mm) in non-HPV-related squamous cell cancers of the head and neck, we retrospectively reviewed microscopic slides from neck dissection specimens of ENE-positive patients and subcategorised them into ENEmi and ENEma. We then compared the two groups in terms of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Forty-four patients with pathologically positive necks had ENE in the histological report. Twenty-six had ENEmi and 18 ENEma. The three-year OS was 46% in the ENEmi group and 38.9% in the ENEma group. DSS and DFS were 80.8% and 80.8%, respectively, in the ENEmi group and 61.1% and 77.8%, respectively, in the ENEma group. None of the comparisons revealed any statistically significant difference. The results of our survival analysis seem to show a trend towards better survival rates in the ENEmi group, particularly regarding OS. Nonetheless, extension of the tumour outside the lymph node capsule by more than 2mm was not found to be significantly associated with any of the explored survival outcomes.

Spontaneous recanalization of occluded internal carotid artery after minor stroke. The role of surgical treatment.

Late spontaneous recanalization of internal carotid artery is a very rare event. We describe three cases which came to our observation in which the occlusion was demonstrated both by angiography and Doppler ultrasound. Two of them had surgical treatment and the histological exam of the plaque showed multiple recanalization foci. Our experience confirmed the possibility of a successful surgical treatment that offers a good patency in the short and medium term.

Prognosis of oral cancer: a comparison of the staging systems given in the 7th and 8th editions of the American Joint Committee on Cancer Staging Manual.

The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual introduces "depth of invasion" and "extranodal extension" into the head and neck section, and our aim was to find out if these changes have an impact on prognosis. We evaluated 174 patients who had had oral squamous cell carcinomas (SCC) resected between 2003 and 2012. The clinical records were reviewed, the patients' tumours restaged according to the 8th edition of the AJCC, and we analysed five-year survival to verify whether different correlations were made between the T and N stages and disease-specific survival using the 7th and 8th editions. We excluded seven cases because information was incomplete, and the final sample was 167 patients. The five-year overall survival was 68% and the five-year disease-specific survival was 78%. The variable pT was upstaged in 51 patients (31%), and no tumour was downstaged. When we used the 7th edition, the pT category did not correlate with survival (p=0.055), but when we used the 8th edition, there was a significant association between increased pT categories and disease-specific survival (p=0.01). In the pN category 23 cases were upstaged (14%) and this affected disease-specific survival using both the 7th and the 8th editions (p=0.001). When patients were restaged, there was an improvement in discrimination between T categories in relation to disease-specific survival, and confirmation of the prognostic impact of the variable pN. T stage and depth of invasion are complementary predictors of disease-specific survival, and their combination results in the new AJCC staging system giving a better prognosis.

AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy.

The NH2tau 26-44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20-22-kDa NH2-truncated form of human tau-a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)-which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies.

Cardiac metastases.

Tumours metastatic to the heart (cardiac metastases) are among the least known and highly debated issues in oncology, and few systematic studies are devoted to this topic. Although primary cardiac tumours are extremely uncommon (various postmortem studies report rates between 0.001% and 0.28%), secondary tumours are not, and at least in theory, the heart can be metastasised by any malignant neoplasm able to spread to distant sites. In general, cardiac metastases are considered to be rare; however, when sought for, the incidence seems to be not as low as expected, ranging from 2.3% and 18.3%. Although no malignant tumours are known that diffuse preferentially to the heart, some do involve the heart more often than others--for example, melanoma and mediastinal primary tumours. This paper attempts to review the pathophysiology of cardiac metastatic disease, epidemiology and clinical presentation of cardiac metastases, and pathological characterisation of the lesions.

Intraocular lens decentration and posterior capsule opacification: anatomo-pathologic findings after implantation of AMOSI40 IOLS.

PURPOSE: To evaluate the incidence of intraocular lens (IOL) decentration and posterior capsule opacification (PCO) after implantation of a three-piece posterior chamber silicone IOL in a series of eyes examined postmortem. METHODS: Twenty-three pseudophakic enucleated human cadaver eyes, implanted with AMO SI40NB IOLs after phacoemulsification, were analyzed. Eyes obtained postmortem were sectioned at the equatorial plane and the anterior segment photographed from a posterior view. Location of IOL optic and haptics, type of fixation, and centration of IOL was evaluated. PCO was graded and the presence of Nd:YAG laser posterior capsulotomy was noted. RESULTS: Mean age at the time of surgery was 77.83 years, mean time since implantation was 18.26 months. In all the eyes examined, IOL haptics were positioned in the capsular bag. Mean decentration was 0.20+/-0.16 mm. No correlation was found between IOL decentration and time since implantation. The degree of peripheral PCO ranged from none (13.0%) to mild (39.1%) to moderate (26.1%) to severe (21.7%). The degree of central PCO ranged from none (52.2%) to mild (30.4%) to moderate (4.3%). Three patients (13.0%) underwent Nd:YAG laser posterior capsulotomy. CONCLUSIONS: A very good centration can be obtained when silicone AMOSI40NB IOLs are correctly implanted with the haptics inside the capsular bag. About half of the implants showed no central PCO while Nd:YAG laser posterior capsulotomy rates documented a relatively low PCO 18 months after surgery. A careful in the bag haptics placement is needed in order to reduce the IOL decentration and to prevent central PCO.

VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans.

Tumor angiogenesis depends on the vascular endothelial growth factor (VEGF), which exists in multiple splicing isoforms, including the most abundant VEGF165 and VEGF121. We have previously shown that the differential capacity of these two VEGF isoforms to bind Neuropilin-1 accounts for their diverse ability to recruit Nrp1-expressing monocytes (NEMs), resulting in a different arteriogenic potential. Here we measure the expression of VEGF165 and VEGF121 in human cancer and their influence on tumor growth and vascularization. We measured the expression levels of VEGF165 and VEGF121 in human colorectal cancer and found that VEGF121 was more expressed than VEGF165, particularly in patients with extensive lymph node infiltration. Overexpressing either VEGF165 or VEGF121 in a cancer mouse model, we observed that the former decreased, whereas the latter increased tumor growth. In both clinical and experimental tumors, VEGF165 expression resulted in the recruitment of NEMs, paralleled by maturation of the tumor vascular network. Finally, hypoxia induced a shift toward the VEGF165 isoform in the central core of human cancers, as well as in various types of cultured cells. These results demonstrate that the two VEGF splicing isoforms are differentially expressed in colorectal cancers, exerting opposite effects on tumor growth and vessel maturation.

Intractable fever and cortical neuronal glycogen storage in glycogenosis type 2.

Glycogenosis type 2 is an autosomal recessive glycogen storage disorder caused by deficiency of lysosomal acid alpha-glucosidase. Different phenotypes are recognized. The authors describe two children affected by the late infantile form; both presented terminal hyperthermia not caused by infections. Autopsy performed in one case showed diffuse glycogen storage in the CNS neurons. In light of current interest in enzyme replacement therapy, this finding casts some doubt on how effective enzyme replacement therapy will be unless it can be targeted directly into the CNS.

Clinical and pathologic study of familial dilated cardiomyopathy.

To evaluate the occurrence of familial cases of dilated cardiomyopathy (DC), 165 consecutive patients were studied. Diagnosis of myocardial disease was based on clinical, hemodynamic, bioptic, postmortem or a combination of these criteria. Twelve patients (7% of cases) showed evidence of myocardial disease in greater than or equal to 1 relative; 27 patients with myocardial disease were detected in the 12 families, but a suspected history of myocardial involvement was present in a further 16 cases. In 6 families proband and relatives were affected by DC (total 14 cases); in 1 of these families the disease began with an atrioventricular block. In 4 families the relatives showed the presence of myocarditis at the endomyocardial biopsy. In 2 families the relatives presented a right ventricular cardiomyopathy. The mode of inheritance was autosomal dominant in 7 families, recessive in 4; X-linked pattern may be hypothesized in 1. Nine patients died under the age of 45 years: 2 of sudden death, 6 of chronic heart failure and 1 of cerebral embolism. Familial transmission is not rare. Different modes of genetic transmission (autosomal dominant, recessive and X-linked) and different forms of myocardial disease suggest that familial DC may be a multifactorial disease.

Magnetic resonance imaging in right ventricular dysplasia.

Fifteen patients with right ventricular dysplasia were investigated by T1-weighted spin- and gradient-echo pulse sequences, using a protocol that enabled both a subjective analysis of myocardial signal intensity and a quantitative/qualitative analysis of right and left ventricular function. In 8 patients, 3 investigators independently recognized abnormally hyperintense areas in the anatomic sites usually affected by the disease. In 7 of these patients, these areas showed an overlap with a-dyskinetic areas imaged by both magnetic resonance imaging (MRI) and echocardiography. In 1 patient who underwent a cardiac transplant, MRI of the explanted heart showed an excellent correlation between the distribution of the lesions and the in vivo/in vitro features. The data were compared with those from an equivalent sample of patients affected by dilated cardiomyopathy. In the latter patients, no focal hyperintensities were attributed to any anatomic sites in the right ventricule, and no focal a-dyskinetic foci were observed. Furthermore, the 2 groups of patients were significantly different in regard to dimensional and functional quantitative parameters. The results suggest that MRI is useful in integrating echocardiographic data and can be helpful in diagnosing this disease in late stages.

Nonpredictive value of fibrosis in dilated cardiomyopathy treated with metoprolol.

Therapy with ß-adrenergic blocking agents has been advocated as a potential useful approach in heart failure. Recent studies suggest that histologic parameters may be helpful in assessing the effectiveness of ß-blocker treatment in dilated cardiomyopathy (DCM). In order to predict the response to ß-blockers in DCM, fibrous tissue was evaluated at endomyocardial biopsy (EMB) in 45 patients (pts) with a mean left ventricular ejection fraction of 0.28 ± 0.07, who were successively long-term treated with metoprolol (M) (mean dosage 138 ±26 mg/die). EMB was performed from left (n = 32) or right (n = 13) ventricle by means of a King's bioptome or the Cordis adaptation of this instrument. Quantification of fibrous tissue was performed at 9 × magnification and with a computerized morphometric system. Qualitative evaluation at light microscopy distinguished four types of fibrosis: pericellular, perivascular, focal, and endocardial. Volume fraction of fibrous tissue ranged from 1.3 to 35.5% (mean 12.1 ± 9.3%) and was not significantly correlated with any clinical variable considered. After 24 ± 12 months of treatment, 25 pts were considered improved (group A), whereas the remaining 20 pts were considered not improved (group B), according to criteria based on ejection fraction, left ventricular end-diastolic diameter, filling pattern at Doppler-Echocardiography, cardiothoracic ratio, NYHA functional class, and exercise duration at ergometric test. Volume fraction of fibrous tissue did not differ significantly between the two groups (group A = 12.1 ± 9.1%; group B = 11.3 ± 9.6%;p = NS). Dominant pericellular type of fibrosis was equally distributed between the two groups (group A = 9 25 pts, 36%; group B = 10 20 pts, 50%), whereas a perivascular and/or focal replacement fibrosis was more frequent in group A (group A = 10 20 pts, 50%; group B = 2 20 pts, 10%; p = .05, OR 5.55 at univariate analysis). At multivariate analysis mean aortic blood pressure was the only variable discriminating the two groups; the type of fibrosis, although not statistically significant, maintained a high value of odds-ratio (5.23). In conclusion, extent of total fibrosis assessed by EMB may range widely in patients with DCM, is not correlated with the most important clinical variables, and is not predictive of long-term response to ß-blocker treatment. Otherwise, prevalent perivascular and/or focal replacement fibrosis could be associated with a higher probability of improvement after long-term ß-blocker treatment.

Right ventricular dilatation after left ventricular acute myocardial infarction is predictive of extremely high peri-infarctual apoptosis at postmortem examination in humans.

BACKGROUND: Cardiac remodelling after acute myocardial infarction (AMI) is characterised by molecular and cellular mechanisms involving both left and right ventricles, and biventricular failure identifies patients with an extremely unfavourable prognosis. AIMS: To assess whether a link exists between increased myocardial apoptotic rates (AR) at sites of recent infarction and patterns of unfavourable cardiac remodelling, such as biventricular enlargement after left ventricular (LV) infarction. METHODS: Twelve patients with recent AMI involving the LV and not the right ventricle (RV) and with permanent infarct related artery occlusion were selected at necropsy. Gross pathological characteristics, such as LV and RV dilatation, and AR at site of infarction were assessed. Potential false positive results (DNA synthesis and RNA splicing) were excluded from the cell count. RESULTS: RV enlargement, defined as a tricuspidal ring greater than 120 mm, was found in five cases and was associated with LV dilatation. These patients showed significantly higher AR than the others. When the subjects were divided into three groups according to progressive cardiac remodelling (absence of cardiac dilatation, isolated LV dilatation, and biventricular enlargement), the last group had significantly higher ARs than the other two groups, showing that myocardiocyte apoptosis is increased in more unfavourable forms of cardiac remodelling. CONCLUSION: Patients with severely unfavourable cardiac remodelling, such as biventricular enlargement, have extremely high myocardiocyte apoptosis at necropsy, even late after LV myocardial infarction, supporting the role of myocardiocyte loss in determining post-infarction adverse remodelling.

Surviving acute myocardial infarction: survivin expression in viable cardiomyocytes after infarction.

BACKGROUND: Apoptosis is a key feature in postinfarction remodelling leading to progressive myocyte loss. Both proapoptotic and antiapoptotic factors contribute to the delicate balance between death and survival. The survivin pathway has emerged as essential in the control of apoptosis, although its role in heart disease is unknown. AIM: To evaluate survivin expression after acute myocardial infarction (AMI). METHODS: Survivin expression was assessed immunohistochemically in the peri-infarct and remote viable myocardium in 17 consecutive patients who died 1-30 weeks after AMI and in four control hearts. RESULTS: Survivin was expressed by myocytes in the peri-infarct area in eight patients and in the remote region in 13 patients. The rate of survivin expression after AMI was significantly higher in the remote versus peri-infarct regions and compared with control hearts. Its expression was inversely associated with the presence of dilated cardiopathy and of apoptosis, independently from the gross pathology infarct size. CONCLUSIONS: Survivin myocardial expression after AMI may be associated with the survival of at risk myocardium and may be indicative of more favourable remodelling after AMI. These findings identify a potential new target for the treatment of postinfarction remodelling.

An uncommon cause of lower limb weakness.

We describe a case of a severely mentally disabled patient diagnosed as suffering from Guillain-Barré syndrome and treated with repeated plasma exchange. However, the abrupt onset of a cardiovascular collapse prompted a more in-depth diagnostic workup which demonstrated that the neurologic symptoms were likely to be ascribed to poisoning with heavy metals from a large number of ingested coins and other metallic items.