Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond.

Malignant mesothelioma (MM) is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most commonly pleura and peritoneum. It is characterised by a poor prognosis and limited treatment options. A universally recognised risk factor for the development of MM is exposure to asbestos. However, evidence supporting a genetic susceptibility to the development of MM has been accumulating during the last decades. Intensive research for the identification of MM susceptibility genes has led to the discovery of BAP1 and to the definition of the so-called "BAP1-related tumour predisposition syndrome". Patients carrying germline BAP1 mutations have an increased risk for the early development of tumours, including MMs, uveal melanomas, cutaneous melanocytic lesions, clear cell renal cell carcinomas and basal cell carcinomas. Furthermore, pathogenic variants in tumour suppressor genes with a role in DNA repair have been recently described in families with clustered MM cases. These genetic alterations seem to confer exaggerate sensitivity to asbestos carcinogenic effect and, arguably, increased response to specific chemotherapeutic strategies. While the translational significance of BAP1 alterations is explored in the research field, the identification of families carrying germline BAP1 mutations is mandatory to start appropriate surveillance programs and guarantee the best clinical management to these patients.

In vivo assessment of tumour angiogenesis in colorectal cancer: the role of confocal laser endomicroscopy.

AIM: Tumour neoangiogenesis is a key factor in tumour progression and metastatic spread and the possibility to assess tumour angiogenesis might provide prognostic information. The aim of this study was to establish the role of probe-based confocal laser endomicroscopy (p-CLE) in the identification of vascular architecture and specific morphological patterns in normal colorectal mucosa and malignant lesions during routine endoscopy. METHOD: Fourteen consecutive patients with colorectal cancer were included. The following features were identified and then compared between normal and neoplastic mucosa on p-CLE images: vessel shape (straight vs irregular) vessel diameter the 'branching patterns' vessel permeability (fluorescein leakage) and blood flow (normal vs defective flux). Immunohistochemistry was used to confirm the presence and to study the morphology of vascular structures (CD-34 staining) and 'neo-vessels' (WT-1 staining) on tumour and normal mucosal sections. RESULTS: Tumour vessels appeared as irregular, ectatic and with a highly variable calibre and branching patterns on p-CLE images. The mean diameter of tumour vessels was significantly larger than those in normal mucosa (weighted mean difference 3.38, 95% CI 2.65-4.11, P = 0.01). Similarly, 'vessel branching' (OR 2.74, 95% CI 1.23-6.14, P = 0.01), fluorescent dye 'extravasation' (OR 3.46, 95% CI 1.39-8.57, P = 0.01) were significantly more frequent in colorectal cancer than in normal colorectal mucosa. Immunohistochemistry corroborated the p-CLE findings, showing higher vascularity in tumour sections due to neoformed vessels, presenting irregular patterns. CONCLUSION: Probe-based confocal laser endomicroscopy provides a noninvasive characterization of the microvascular architecture of colonic mucosa. Different morphological patterns have been described, discriminating normal and malignant microvascular networks in colorectal mucosa.

Hepatic epithelioid hemangioendothelioma: Pitfalls in the diagnosis on fine needle cytology and "small biopsy" and review of the literature.

Hepatic epithelioid hemangioendothelioma is a rare vascular neoplasm with an unpredictable malignant potential. Different therapeutic options are available, depending on the basis of disease extension and the patient's overall condition. A correct pathological diagnosis is necessary and is often based on scant material. Here, we report a case diagnosed on fine needle aspiration and on a small surgical biopsy. In addition, we will review the literature. The patient is a 54-year-old woman who presented with persistent pain in the right hypochondrium and suffered from weight loss. Ultrasound examination and CT scan showed several focal and confluent hepatic lesions. Thus, an ultrasound-guided fine-needle aspiration (US-FNA) was performed. A cytological diagnosis of vascular proliferation with epithelioid component was performed. Afterwards, a hepatic "small biopsy" (SB) was made. Histological and immunohistochemical data were consistent with a hepatic epithelioid hemangioendothelioma diagnosis. The patient, however, is in good general condition and is waiting for a hepatic transplantation; repeated total CT scan showed no signs of metastasis. The literature was reviewed in order to define the pathological features that were helpful in the cytological and histological diagnosis of hepatic epithelioid hemangioendothelioma, and to better understand if pathological data is prognostically useful.

Strong coupling in the sub-wavelength limit using metamaterial nanocavities.

The interaction between cavity modes and optical transitions leads to new coupled light-matter states in which the energy is periodically exchanged between the matter states and the optical mode. Here we present experimental evidence of optical strong coupling between modes of individual sub-wavelength metamaterial nanocavities and engineered optical transitions in semiconductor heterostructures. We show that this behaviour is generic by extending the results from the mid-infrared (~10 µm) to the near-infrared (~1.5 µm). Using mid-infrared structures, we demonstrate that the light-matter coupling occurs at the single resonator level and with extremely small interaction volumes. We calculate a mode volume of 4.9 × 10(-4) (λ/n)(3) from which we infer that only ~2,400 electrons per resonator participate in this energy exchange process.

Monolithic metallic nanocavities for strong light-matter interaction to quantum-well intersubband excitations.

We present the design, realization and characterization of strong coupling between an intersubband transition and a monolithic metamaterial nanocavity in the mid-infrared spectral range. We use a ground plane in conjunction with a planar metamaterial resonator for full three-dimensional confinement of the optical mode. This reduces the mode volume by a factor of 1.9 compared to a conventional metamaterial resonator while maintaining the same Rabi frequency. The conductive ground plane is implemented using a highly doped n+ layer which allows us to integrate it monolithically into the device and simplify fabrication.

Herbal hepatotoxicity: a case of difficult interpretation.

Herbal medicines are widely used in the world and are generally considered effective and safe, although many studies have demonstrated their potential toxic effects, particularly for the liver. We present a case of a woman, who developed a mixed cholestatic/hepatocellular liver injury due to herbal products. Firstly, she was admitted to Division of Surgery for right upper abdominal pain and jaundice and, for the suspect of biliary obstruction, she underwent to cholecystectomy. For persistence of liver enzymes elevation, she was admitted to our Gastroenterology Unit. We excluded every etiologies of hepatitis and, after an intensive dialogue with the patient, we obtained a history of herbal medicines use. Then, we performed a liver biopsy which was compatible with hepatotoxic injury. Therapy with ursodeoxycholic acid (UDCA) was started. Liver function tests returned to normal in two months. We describe this clinical case to encourage the communication doctor/patient in phytotherapy area and physician knowledge about efficacy and side effects of herbal medicine to avoid delayed diagnosis.

The high expression of p53 in sporadic colorectal carcinoma is associated with metastasis and decreased survival.

INTRODUCTION: Alteration in the p53 tumour suppressor gene is an event that occurs frequently in human cancer, although its role as predictive and/or prognostic marker is still unclear. The aim of this study was to compare the expression profiles of p53 in colorectal carcinoma with clinicopathological features and survival rate at 5 years from diagnosis. METHODS: One hundred and twenty cases of primary sporadic colorectal cancers (CRCs) and 80 matched normal mucosas were analyzed by immunohistochemistry on paraffin-embedded specimens. The correlation between protein expression profiles, clinicopathological parameters and survival was investigated. RESULTS: In tumour tissues, the expression of p53 was high in 41 cases, low in 38 and negative in 41. A significant correlation was observed between increased p53 expression presence of lymph node (p = 0.002) or liver metastasis (p = 0.008). Moreover, higher levels of p53 were related with advanced tumour stage (III-IV; p = 0.007), poor survival and disease recurrence (p < 0.01). Interestingly, in multivariate analysis p53 expression and distant metastasis were independent prognostic markers. DISCUSSION: Our results suggest that nuclear p53 accumulation in sporadic CRC may have prognostic significance and contribute to identification of patients at high risk of mortality. The current findings may be relevant for management of patients with CRC.

Colorectal endometriosis: aggressive surgical management and practical considerations in a patient with advanced disease.

The aim of this study was to evaluate the results of bowel resection in a patient with obstructive colorectal endometriosis. The presentation will acquaint the physician with the signs and symptoms, evaluation, and surgical treatment of colorectal endometriosis. We emphasize that our findings strongly support an aggressive surgical approach with resection for all visible cases of colorectal endometriosis in women with advanced disease.

[Quadricuspid aortic valve insufficiency. Report of a case diagnosed with echocardiography and review of the literature]. / La valvola aortica quadricuspide insufficiente. Presentazione di un caso diagnosticato con ecocardiografia e revisione della letteratura.

The Authors describe the case of a woman with aortic regurgitation who was referred to the echo-lab for noninvasive evaluation of a diastolic murmur. Unexpectedly, a quadricuspid aortic valve was detected by echocardiography. A brief review of the literature is reported, focusing on the pathogenesis of valvular incompetence of the quadricuspid aortic valve and the importance of the echocardiographic technique during follow-up.

[Validity of the proximal isovelocity surface area color Doppler method for calculating the valve area in patients with mitral stenosis; comparison with the two-dimensional echocardiographic method]. / Validità del metodo dell' area della superficie di isovelocità prossimale (PISA) al color Doppler per il calcolo dell'area valvolare nei pazienti con stenosi mitralica; confronto con il metodo planimetrico ecocardiografico bidimensionale.

BACKGROUND: The proximal isovelocity surface area (PISA) method, assessed by color Doppler echocardiography, has gained acceptance as a means of calculating flow rate through regurgitant orifice. The method can also be used to derive mitral valve area (MVA), by continuity equation, in patients with mitral stenosis (MS). The aim of this study was to compare the PISA method with the two-dimensional echocardiographic planimetry (2D) method and pressure half-time method (PHT) in MVA calculations in a group of 37 patients with MS. METHODS AND RESULTS: All of these patients had satisfactory MVA by 2D method. There were 22 female and 15 male; age 56 +/- 11 years (range 32-71); 19 were in sinus rhythm (SR) and 18 in atrial fibrillation (AF); 17 patients had pure MS, while the remaining 20 had associated mitral regurgitation (MR); in 23 patients the orifice morphology was circular or elliptic, and was defined as regular; while in 14 patients the morphology was irregular for the presence of two or more nodular calcifications on the commissures or leaflet's edges. MVA by PISA method was calculated assuming a uniform radial flow convergence region along a hemispherical surface, according to the formula: MVA = 2 pi r2 Vn(1-cos theta)/Vmax; where r was the PISA radius measured in 2D from the first alias to the mitral leaflet's edge; Vn was the flow velocity at radial distance from the mitral orifice; Vmax was the peak transmitral velocity by CW Doppler; 1-cos theta was a factor that accounted for the inflow angle formed by the mitral leaflets. The Nyquist limit was lowered to 29 cm/sec. Alpha angle formed by the mitral leaflets ranged between 86 degrees and 134 degrees; average 110 degrees +/- 10 degrees. 2D MVA was 1.33 +/- 0.37 cm2; range 0.69-2.2 cm2; PHT MVA was 1.29 +/- 0.34 cm2; range 0.70-2.1 cm2; PISA MVA was 1.18 +/- 0.36 cm2; range 0.47-1.95 cm2. The PISA method underestimates MVA by 0.15 +/- 0.21 cm2, in comparison with the 2D method; and by 0.11 +/- 0.18 cm2 in comparison with PHT method (p ns). The correlation between 2D and PISA MVA was: r = 0.84; p < 0.001; y = 0.83x + 0.06; 95% confidence intervals +/- 0.40 cm2; and between PHT and PISA MVA was: r = 0.79; y = 0.84x + 0.09; p < 0.001; 95% confidence intervals +/- 0.46 cm2. The correlation coefficient was similarly good in patients with SR or AF, and did not significantly change in patients with pure MS or MS+MR; neither did it vary with respect to the orifice morphology (p < 0.001 for all the variables considered), except for the correlation PHT-PISA in the group of patients with irregular orifice morphology (r = 0.70; p = 0.005). The interobserver and intraobserver variability were, respectively: 2.2% and 4.4% for 2D MVA; 3.4% and 3.8% for PHT MVA; 5.2% and 3.5% for the PISA radius; 6.1% and 4.4% for the alpha angle; 10.2% and 7.2% for PISA MVA (F ratio of variances ns). CONCLUSIONS: In conclusion, the PISA method allows accurate assessment of MVA in patients with MS, regardless of cardiac rhythm or additional MR. Moreover, our study suggests that orifice morphology does not affect the accuracy of this method.