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.

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.

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.

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.

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.

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.

Hepatopulmonary fusion in a newborn. An uncommon intraoperatory finding during right congenital diaphragmatic hernia surgery: case description and review of literature.

Hepatic pulmonary fusion is a rare malformation associated with right congenital diaphragmatic hernia (CDH), often only discovered during surgical repair of the defect. Fourteen previous cases have been reported in the literature. We describe a case of a full term male newborn with prenatal ultrasound diagnosis of right CDH who underwent a thoracoscopy converted to a thoracotomy, due to this rare aforementioned intraoperative incidental finding. We reviewed the previous reported literature, especially focusing on the chosen surgical approach, concluding that an early and appropriate preoperative imaging investigation may be crucial for the best management of these kinds of patients.

Damage to the vascular structures in inguinal hernia specimens.

BACKGROUND: Few scientific reports to date describe the histological modification of structures outlining a hernia opening. This article is focused on the identification of the pathological changes in vascular structures in tissues excised from cadavers with inguinal hernia. A deeper comprehension of this topic could lead to essential improvements in the detection of hernia genesis. MATERIALS AND METHODS: Different kinds of hernia, including indirect, direct and mixed, were identified in 30 autopsied subjects. Tissue samples were resected for histological study from abdominal wall structures close to the hernia opening. Histological examination focused on the detection of structural changes in arteries and veins. The results were compared with tissue specimens excised from equivalent sites of the inguinal area in a control group of 15 fresh cadavers without hernia. RESULTS: Significant modification of vascular structures were identified in the tissue specimens examined. The veins demonstrated parietal fibrosis, perivascular edema and vascular dilation due to congestion and stasis. The arterial structures detected showed thickening of the media due to medial hyperplasia, ranging from luminal sub-occlusion to a manifest artery occlusion. These findings are present independent of hernia type in cadavers with inguinal hernia. These pathological changes were lacking in the control group of cadavers without hernia. CONCLUSIONS: The notable changes in vascular structures described in the report could be the result of a steady compressive effect exerted by the abdominal viscera in the inguinal area. These pathological changes could represent one of the factors involved in the weakening of the inguinal region leading to hernia protrusion.

Muscle degeneration in inguinal hernia specimens.

BACKGROUND: There are few articles in the literature reporting the histological changes of groin structures affected by inguinal hernia. A deeper knowledge of this matter could represent an important step forward in the identification of the causes of hernia protrusion. This study aimed to recognise the pathological modifications of muscular structures in autopsy specimens excised from tissues surrounding the hernia orifice. METHODS: Inguinal hernia was identified in 30 autopsied cadavers, which presented different varieties of hernia, including indirect, direct and mixed. Tissue specimens were resected for histological study from structures of the inguinal area surrounding the hernia opening, following a standardised procedure. The histological examination was focussed on the detection of structural changes in the muscle tissues. The results were compared with biopsy specimens resected from corresponding sites of the inguinal region in a control group of 15 fresh cadavers without hernia. RESULTS: Significant modification of the muscular arrangement of the inguinal area was recognized. Pathological alterations such as atrophy, hyaline and fibrotic degeneration, as well as fatty dystrophy of the myocytes were detected. These findings were observed consistently in the context of multistructural damage also involving vessels and nerves. In cadavers with hernia these alterations were always present independent of hernia type. No comparable damage was found in control cadavers without hernia. CONCLUSIONS: The high degree of degenerative changes in the muscle fibres in the inguinal area involved in hernia protrusion described in this report seems to be consistent with chronic compressive damage. These alterations could embody one important factor among the multifactorial sources of hernia genesis. Conjectures concerning its impact on the physiology and biodynamics of the inguinal region are made. The relationship between the depicted degenerative injuries and the genesis of inguinal hernia is also a focus of discussion in this article.

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.

Nerve degeneration in inguinal hernia specimens.

BACKGROUND: The histological study of the herniated inguinal area is rare in the literature. This report is focused on the detection of structural changes of the nerves within tissues bordering the inguinal hernia of cadavers. Their physiopathological consequences are hypothesized. MATERIALS AND METHODS: Primary inguinal hernia was diagnosed in 30 fresh cadavers. Tissue specimens from the inguinal region close to and around the hernia opening were excised for histological examination. A control of the data was achieved through tissue samples excised from equivalent sites of the inguinal region in 15 cadavers without hernia. RESULTS: The detected nerves in the inguinal area demonstrated pathological changes such as fibrotic degeneration, atrophy, and fatty dystrophy of the axons. The thickening of the perineural sheath was constantly seen. These findings were consistently present, independent of the hernia type. CONCLUSIONS: The detected nerve alterations lead us to imagine a worsening, or even the cessation, of the nervous impulse to the muscles, leading to atrophy and weakening of the abdominal wall. This could represent one of the multifactorial causes of hernia genesis.

Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction.

BACKGROUND: Inherited mtDNA depletion syndromes (MDS) are a group of severe mitochondrial disorders resulting from defects in nucleus-encoded factors and often associated with severe or fatal liver failure. PATIENT: In this article, we describe the case of an 18-month-old patient with recurrent hypoketotic hypoglycaemia and fatal hepatic dysfunction with liver mtDNA depletion. METHODS: The assessment of mtDNA copy number was performed on leucocytes, liver and muscle biopsy by Quantitative Real Time PCR and total RNA from liver biopsy was used as a template to amplify the cDNA of the POLG1 gene. RESULTS: Sequence analysis identified two previously undescribed mutations (1868T>G and 2263A>G) located in the gene coding the catalytic subunit of mitochondrial DNA polymerase gamma (POLG), predicting an L623W and K755E amino acid change, respectively. Both mutations were located in the highly conserved linker region of the protein and were absent in more than 200 healthy unrelated control subjects. The identification of these two mutations allowed us to perform genetic counselling and prenatal diagnosis. CONCLUSION: Our data further expand the spectrum of POLG1 gene mutations and the unique phenotype reported (late onset isolated liver disease without lactic acidosis) increase the variability of clinical presentations associated with mutations in this gene.

Radiological-pathological correlation in intratumoural tissue components of solid lung tumours.

The aim of this paper is to describe the intratumoural tissue components of solid lung tumours evidenced by macroscopic and/or microscopic examination of the autopsy or surgical specimen and visible on computed tomography (CT) without and with contrast material administration. Seven intratumoural tissue components can be identified both at CT and at pathology: (1) solid component, (2) haemorrhagic component, (3) coagulation necrosis, (4) liquefaction necrosis, (5) parenchymal consolidation, (6) diffuse peripheral component and (7) fibrotic component. Necrotic and haemorrhagic components are typically observed in malignant lesions, whereas solid and fibrotic components may be seen both in solid lung malignancies and in benign lesions.

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.

Sudden coronary death, fatal acute myocardial infarction and widespread coronary and myocardial inflammation.

BACKGROUND: T-lymphocyte activation within atherosclerotic plaque, and widespread to the myocardium, has been shown in patients with acute coronary syndromes. OBJECTIVE: To investigate the presence of T-lymphocyte infiltrate at different stages of acute coronary syndromes by studying patients with sudden coronary death, acute myocardial infarction (AMI) and healed infarction, in comparison with patients with myocarditis and patients with non-ischaemic heart failure. METHODS: 72 cases were studied at autopsy: 12 dying of sudden coronary death (group 1), 12 dying <4 weeks (group 2) and 12 dying >4 months after AMI (group 3), 12 with active lymphocytic myocarditis (group 4), 12 with hypertensive heart disease (group 5), and 12 control subjects (group 6). Light microscopy was performed to measure the number of activated T-lymphocytes (CD3+/DR+) in the myocardium and coronary artery wall, and intercellular adhesion molecule-1 (ICAM-1) expression in the myocardium. RESULTS: Activated T-lymphocyte infiltrates and ICAM-1 myocardial expression in both remote and peri-infarction regions and activated T-lymphocytes within the epicardial coronary artery wall of both the infarct- and non-infarct-related arteries were found in groups 1, 2 and 3, whereas myocardial, but not coronary, infiltrates were found in groups 4 (p<0.001 vs groups 1, 2 and 3 for coronary infiltrates). Groups 5 and 6 had no evidence of myocardial or coronary inflammation (p<0.001 vs groups 1, 2 and 3). CONCLUSIONS: The study shows the presence of a lymphocytic infiltrate in both coronary arteries and myocardium and a proinflammatory phenotype shift in the myocardium associated with acute coronary thrombosis in patients dying suddenly, shortly, or even late after coronary thrombosis.

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.