Preliminary clinical experience with a dedicated interventional robotic system for CT-guided biopsies of lung lesions: a comparison with the conventional manual technique.

OBJECTIVE: Evaluate the performance of a robotic system for CT-guided lung biopsy in comparison to the conventional manual technique. MATERIALS AND METHODS: One hundred patients referred for CT-guided lung biopsy were randomly assigned to group A (robot-assisted procedure) or group B (conventional procedure). Size, distance from entry point and position in lung of target lesions were evaluated to assess homogeneity differences between the two groups. Procedure duration, dose length product (DLP), precision of needle positioning, diagnostic performance of the biopsy and rate of complications were evaluated to assess the clinical performance of the robotic system as compared to the conventional technique. RESULTS: All biopsies were successfully performed. The size (p = 0.41), distance from entry point (p = 0.86) and position in lung (p = 0.32) of target lesions were similar in both groups (p = 0.05). Procedure duration and radiation dose were significantly reduced in group A as compared to group B (p = 0.001). Precision of needle positioning, diagnostic performance of the biopsy and rate of complications were similar in both groups (p = 0.05). CONCLUSION: Robot-assisted CT-guided lung biopsy can be performed safely and with high diagnostic accuracy, reducing procedure duration and radiation dose in comparison to the conventional manual technique. KEY POINTS: • CT-guided biopsy is the main procedure to obtain diagnosis in lung tumours. • The robotic device facilitates percutaneous needle placement under CT guidance. • Robot-assisted CT-guided lung biopsy reduces procedure duration and radiation dose.

Caveolin-1 overexpression is associated with simultaneous abnormal expression of the E-cadherin/α-ß catenins complex and multiple ErbB receptors and with lymph nodes metastasis in head and neck squamous cell carcinomas.

The presence of lymph node metastases is one of the most important prognostic indicators in head and neck squamous cell carcinomas (HNSCCs). An alteration of the E-cadherin-catenins complex and EGFR is essential for the invasiveness of cancer cells. Caveolin-1, the major structural protein of the caveolae, represents a scaffolding molecule for several signaling proteins including EGFR. Although caveolin-1 has been shown to play a role in inducing the invasive phenotype of cancer cells, its role appears to be cell-type specific and for some tumors it has not been defined yet. In this study we used 57 HNSCC specimens to investigate whether the abnormal expression of caveolin-1 was associated with the derangement of the E-cadherin-catenins complex and with the overexpression of ErbB receptors. We demonstrate that in HNSCCs caveolin-1 overexpression is associated with the simultaneous abnormal expression of at least one member of the E-cadherin/α-ß catenins complex and multiple ErbB receptors as well as with lymph node metastases. We also demonstrate that chronic stimulation of a human hypopharyngeal carcinoma cell line (FaDu) with EGF induced the internalization of ß-catenin and caveolin-1 and their co-localization with EGFR. Moreover, EGF treatment induced an increased physical interaction between EGFR/ß-catenin/caveolin-1 and between E-cadherin/ß-catenin/caveolin-1. These molecular events were associated with an increased directional motility of FaDu cells in vitro. These findings may provide new insight into the biology of HNSCC progression and help to identify subgroups of primary HNSCCs with a more aggressive behavior.

Dermatomyositis as first clinical appearance for a thymic epidermoid cell carcinoma.

Primary thymic carcinoma is a rare and heterogeneous group of tumours of the anterior mediastinum that includes different histological types. Frequently, it first comes to clinical attention through paraneoplastic syndromes such as dermatomyositis. We report the case of a 54-year-old woman with several episodes of fever and chest pain in the previous 5 months. The patient was admitted to the Rheumatology Department with a peri-ungual erythema and papular lesions on both sides of each hand and alteration at biochemistry tests. A left deltoid muscle biopsy specimen showed a histological pattern compatible with the diagnosis of dermatomyositis. A computed tomography of the chest, abdomen and pelvis, showed a solid mass in the upper anterior mediastinal area and a mediastinoscopy with mass-biopsy was performed. Only the immunohistochemical staining technique allowed a definitive histological diagnosis. We report the diagnostic challenge and the therapeutic approach of thymic neoplasia.

Probiotic administration in patients with ileal pouch-anal anastomosis for ulcerative colitis is associated with expansion of mucosal regulatory cells.

BACKGROUND: Probiotics have anti-inflammatory effects in patients with inflammatory bowel disease and appear to regulate mucosal immune response through reductions in proinflammatory cytokines. The probiotic VSL#3 prevents pouchitis if started within a week of ileostomy closure and maintains remission following antibacterial treatment in patients with refractory or recurrent pouchitis. However, the efficacy of probiotics and their effects on regulatory cells if started at a greater time after surgery in patients undergoing ileal pouch anal anastomosis (IPAA) for ulcerative colitis are unknown. METHODS: We conducted an open-label study in which 31 patients at different periods from surgery without signs and symptoms of pouchitis were randomized to 2 sachets of VSL#3 once daily or no treatment for 12 months. Pouchitis disease activity index (PDAI) was evaluated at baseline and after 3, 6, and 12 months. The percentage of CD4+ T lymphocytes expressing CD25 and the inactive form of transforming growth factor-beta [latency-associated peptide (LAP)] were evaluated at baseline and after 3 and 6 months in peripheral-blood mononuclear cells and mucosal biopsies. Variation in tissue interleukin-1beta and Foxp3 mRNA expression was also evaluated. RESULTS: During the study period, VSL#3-treated patients showed a significant reduction in PDAI score and a significant increase in the percentage of mucosal CD4+CD25(high) and CD4+ LAP-positive cells compared with baseline values. Tissue samples at different points showed a significant reduction in IL-1beta mRNA expression, and a significant increase in Foxp3 mRNA expression. CONCLUSIONS: We conclude that VSL#3 administration in patients with IPAA modulates the PDAI and expands the number of mucosal regulatory T cells.

Pancreatic intraductal papillary mucinous neoplasms: a paradigmatic case. A case report and review of the literature.

Pancreatic intraductal papillary mucinous neoplasms constitute an increasingly frequent clinical entity. The definition and clinical behaviour of these tumours are still a subject of debate. As a consequence, their clinical management is also presents controversial aspects ranging from follow-up to the advisability or otherwise of an aggressive surgical approach, even in the case of small non-malignant lesions. In 2002 we observed a patient affected by a large pancreatic mass with the endoscopic and radiological features of an intraductal papillary mucinous tumour. Over a 20-year clinical history the patient had been considered and treated as affected by chronic pancreatitis. In spite of the tumour size and possible vascular infiltration, surgical exploration was considered. Total pancreatectomy was performed and final histology revealed a non-invasive papillary mucinous carcinoma of the pancreas. Twenty-six months after surgical resection the patient is alive and free of disease. In the present paper we re-assess the clinical history of this patient and review the most recent literature on such tumours.

Gene-specific inhibition of breast carcinoma in BALB-neuT mice by active immunization with rat Neu or human ErbB receptors.

Employing the transgenic BALB-neuT mouse tumor model, we explored the in vivo biologic relevance of immunocompetent epitopes shared among the four ErbB receptors. The outcome of neu-mediated tumorigenesis was compared following vaccination with isogeneic normal rat ErbB2/Neu (LTR-Neu) or xenogeneic human ErbB receptors (LTR-EGFR, LTR-ErbB2, LTR-ErbB3 and LTR-ErbB4), each recombinantly expressed in an NIH3T3 murine cell background. Vaccination using rat LTR-Neu at the stage of atypical hyperplasia potently inhibited neu-mediated mammary tumorigenesis. Moreover, all human ErbB receptors specifically interfered with tumor development in BALB-neuT mice. Relative increase in tumor-free survival and reduction in tumor incidence corresponded to structural similarity shared with the etiologic neu oncogene, as rat orthologue LTR-Neu proved most effective followed by the human homologue LTR-ErbB2 and the other three human ErbB receptors. Vaccination resulted in high titer specific serum antibodies, whose tumor-inhibitory effect correlated with cross-reactivity to purified rat Neu extracellular domain in vitro. Furthermore, a T cell response specific for peptide epitopes of rat Neu was elicited in spleen cells of mice immunized with LTR-Neu and was remotely detectable for discrete peptides upon vaccination with LTR-ErbB2 and LTR-EGFR. The most pronounced tumor inhibition by LTR-Neu vaccination was associated with leukocyte infiltrate and tumor necrosis in vivo, while immune sera specifically induced cytotoxicity and apoptosis of BALB-neuT tumor cells in vitro. Our findings indicated that targeted inhibition of neu oncogene-mediated mammary carcinogenesis is conditional upon the immunization schedule and discrete immunogenic epitopes shared to a variable extent by different ErbB receptors.

The ribosomal P0 protein induces a spontaneous immune response in patients with head and neck advanced stage carcinoma that is not dependent on its overexpression in carcinomas.

A typical feature in systemic lupus erythemathosus patients is the presence of autoantibodies to the carboxyl-terminal homologous P proteins (P0, P1, P2) domain (C-22 P0 epitope). In this report we provide evidence for the in vivo immunogenicity of the P0 protein in head and neck cancer patients as well as overexpression by immunohistochemistry of the C-22 P0 epitope in invasive carcinomas (55/57). Overexpression of this epitope was also significantly associated with a number of pathological lesions arising in the head and neck stratified epithelium including acanthosis (8/8), benign tumors (11/11), dysplasia (23/25) and in situ carcinomas (9/9). Intermediate cell layer restricted epitope overexpression was observed in well differentiated carcinomas, while undifferentiated tumors showed overexpression throughout the cell layers. Employing recombinant P proteins, sera from 40 of the 57 carcinoma patients and 39 normal donors, were subjected to immunoblot analysis. Immunity to P0 protein (7/40) was associated with malignancy and with advanced disease stage, but it was not dependent on the C-22 P0 epitope overexpression, although it was the preferential autoantibody target in 4 patients. Increased expression of the C-22 P0 epitope on the surface of pharynx cancer cells following cellular stress in vitro, may imply P0 protein presentation as an in vivo autoantibody target in cancer patients. Evidence for immunity to the P0 protein, as well as overexpression in patients with head and neck carcinoma may be relevant for monitoring cancer progression, in planning immunotherapeutic strategies, and contribute to the understanding of immuno-biological behaviour of head and neck carcinomas.

Ambulatory blood pressure monitoring in secondary arterial hypertension due to adrenal diseases.

The aim of this study was to evaluate ambulatory blood pressure monitoring in patients with essential hypertension and hypertension caused by adrenal pathology. Sixty-six patients with primary aldosteronism, 37 with pheochromocytomas, and 45 with adrenal incidentalomas were included. These patients were compared with 152 essential hypertensive patients and 64 normotensive subjects. Ambulatory blood pressure monitoring evaluated daytime and nighttime systolic and diastolic blood pressure and heart rate. The authors found that the "nondipper" phenomenon was present in 51.5% of patients with primary aldosteronism, 43.2% with pheochromocytomas, 42.2% with incidentalomas, 34.2% with hypertension, and 15% of subjects who were normotensive. In 58% of primary aldosteronism patients with idiopathic adrenal hyperplasia, there was an absence of the physiologic blood pressure nocturnal fall (nondipper), which was statistically significant (P<.001) compared with nondipper primary aldosteronism patients with adrenocortical adenoma (38%). In conclusion, the prevalence of the nondipping pattern was higher in patients with adrenal hypertension compared with patients with essential hypertension, suggesting an independent cardiovascular risk factor.

Circulating miR-21-5p and miR-148a-3p as emerging non-invasive biomarkers in thymic epithelial tumors.

Thymic epithelial cells give rise to both thymoma and thymic carcinoma. A crucial advance in thymic epithelial tumors (TET) management may derive from the identification of novel molecular biomarkers able to improve diagnosis, prognosis and treatment planning.In a previous study, we identified microRNAs that were differentially expressed in tumor vs normal thymic tissues. Among the microRNAs resulted up-regulated in TET tissues, we evaluated miR-21-5p, miR-148a-3p, miR-141-3p, miR-34b-5p, miR-34c-5p, miR-455-5p as blood plasma circulating non-invasive biomarkers for TET management.We firstly report that the expression levels of specific onco-miRNAs, that we found upregulated in the blood plasma collected from TET patients at surgery, resulted significantly reduced in follow-up samples.This pilot study suggests that circulating miR-21-5p and miR-148a-3p could represent novel non-invasive biomarkers to evaluate the efficacy of therapy and the prognosis of TET.

Development of a prediction model and risk score for procedure-related complications in patients undergoing percutaneous computed tomography-guided lung biopsy.

OBJECTIVES: To propose a risk score predicting the potential occurrence of procedure-related complications in patients undergoing computed tomography (CT)-guided lung biopsy. METHODS: Institution review board approval was obtained. A total of 342 CT-guided lung biopsies were retrospectively evaluated taking into account procedure-related complications and associated risk factors, including patient gender and age, previous radiation therapy (RT) and/or chemotherapy (CHT), lesion size, depth and location, incomplete pulmonary fissures, associated diffuse lung diseases, previous pneumothorax (PNX), lung volumes, punctured fissures, thoracic access, needle size and operator experience. Complications were assessed on chest X-ray and/or CT scans. Stepwise logistic regression was used to identify risk factors, to evaluate their correlation with procedure-related complications and to calculate models of risk (MoRs). RESULTS: PNX requiring chest tube placement occurred in 39 patients (11.4%), high-grade pulmonary parenchymal haemorrhage occurred in 62 patients (18.1%) and haemothorax occurred in 12 patients (3.5%). Risk factors increasing the incidence of complications were lesion size (P = 0.01), lesion depth (P = 0.01) and incomplete pulmonary fissures (P = 0.01); previous chemo-radiation therapy was correlated to a lower incidence of complications (P = 0.01). MoR for PNX was as follows: risk base line = 60%; age = +0.15%/year; punctured fissures = +20%; incomplete fissures = +9%; previous CHT/RT = -10%. MoR for parenchymal haemorrhage was as follows: risk base line = 20%, lesion depth = +0.8%/mm; age = +0.25%/year; incomplete fissures = +15%. MoR for haemothorax was as follows: risk base line = 1%; previous PNX = +20%; incomplete fissures = 7%; both previous PNX and incomplete fissures = +67%. CONCLUSION: This study provides MoRs to predict the risk of complications in patients undergoing CT-guided percutaneous lung biopsies.

Unusual symptomatic inclusion cysts in a newborn: a case report.

INTRODUCTION: Dental lamina cysts are cysts that occur as white or pink small nodules, often multiple, approximately 1 to 3mm in diameter. They are typically located on the midpalatine raphe and less frequently on the maxillary and mandibular alveolar mucosa; in the latter case these can be appear to be neonatal teeth.On microscopic examination, these lesions show a stratified squamous epithelium (two to three cell layers); it is possible to find protein, keratin and/or exfoliated epithelial cells in the lumen of the lesions.Neonatal cysts usually show no particular symptoms. They are associated with an excellent prognosis because they regress spontaneously within a few weeks and are not associated to any complications. However, if pain, bleeding or other symptoms occur, a surgical excision is required. CASE PRESENTATION: In this paper, we present an anomalous case of symptomatic dental lamina cyst which affected a 60-day-old male Caucasian newborn. The surgical treatment was elective in this case and 6-month follow-ups were mandatory. CONCLUSIONS: We can underline the successful predictability of the surgical approach; however, we consider that the treatment choice should take place in the light of medical history and clinical considerations, and always be evaluated on a case-by-case basis. Further studies and reviews in this field should be performed in order to suggest guidelines for clinicians, although these cases are rare.

MicroRNA expression profiling of thymic epithelial tumors.

BACKGROUND: Thymic epithelial tumors (TET) are the most frequent human primary mediastinal tumors in adults. A deep biological characterization of the processes at the basis of the transformed phenotype could strongly improve our understanding of the morphological and clinical heterogeneity of these diseases. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and their altered expression accounts for the pathogenesis of several tumors. OBJECTIVES: The aim of this study was to identify the miRNAs that are differentially expressed in tumor vs normal thymic tissues or among the different tumor histotypes and that could impact on the biology of TET. MATERIALS AND METHODS: microRNAs expression profiling was performed by microarray analysis of formalin-fixed paraffin embedded (FFPE) tissue from 54 thymic tumor samples and 12 normal counterparts, derived from two patient cohorts. RESULTS AND CONCLUSION: We identified groups of miRNAs differentially expressed between: (i) TET and normal thymic tissues, (ii) thymomas and thymic carcinomas, (iii) histotype groups. Moreover, we identified putative molecular pathways targeted by these differentially expressed miRNAs that could be involved in thymic carcinogenesis and in the maintenance and spreading of this tumor.

Outcome of surgically resected thymic carcinoma: a multicenter experience.

OBJECTIVE: Thymic carcinoma (TC) is a rare and invasive mediastinal tumor, with poor prognosis. Most of the previous published papers are single-institution based, reporting small series of patient, sometimes including palliative resection. This study collected patients with TC treated in 5 high-volume Italian Thoracic Surgery Institutions. METHODS: A multicenter retrospective study of patients operated for TC between 2000 and 2011 was conducted. Exclusion criteria were: Neuroendocrine thymic neoplasms, debulking/palliative resection and tumor biopsy. Cause specific survival (CSS) was the primary endpoint. RESULTS: Four hundred and seventy-eight patients underwent surgery for thymic malignancies: 40 of them (8.4%) had TC. Eleven (27.5%) received induction chemotherapy because of their radiological invasiveness. A complete resection (R0) was achieved in 36 (90%; 9/11 submitted to induction chemotherapy). Adjuvant radio/chemotherapy was offered to 37 patients, according to the type of surgical resection and tumor invasiveness. Three, 5 and 10-year survival rates were 79%, 75% and 58%. Recurrences developed in 10 patients. R0 resection (p<0.0003) and absence of tumor recurrences (p=0.03) resulted significant prognostic factors at univariate analysis. Independent CSS predictor was the achievement of a complete resection (p<0.05). CONCLUSIONS: TC is a rare and invasive mediastinal tumor. A multimodal approach is indicated especially in TC invasive forms. The achievement of a complete surgical resection is fundamental to improve survival.

von Hippel Lindau disease with colon adenocarcinoma, renal cell carcinoma and adrenal pheochromocytoma.

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome characterized by the presence of heterogeneous tumors derived from different organs. VHL is caused by germline mutations in the VHL tumor suppressor gene located on chromosome 3p25-26. The loss of functional VHL protein contributes to tumorigenesis. VHL tumors are most frequently derived from the kidneys, adrenal gland, central nervous system, eyes, inner ear, epididymis and pancreas. We herein describe the case of a 64-year-old man carrying the VHL gene mutation affected by simultaneous colon adenocarcinoma, renal clear cell carcinoma and adrenal pheochromocytoma.

Usefulness of the organ culture system when villous height/crypt depth ratio, intraepithelial lymphocyte count, or serum antibody tests are not diagnostic for celiac disease.

The existence of mild forms of celiac disease (CD) can make the histology-based diagnosis difficult to reach. Since anti-endomysium (EMA) and anti-tissue transglutaminase (anti-tTG) are detectable in culture supernatants of duodenal biopsies from CD patients, our aim was to assess if this system can support the histology in the diagnostic work-up. A total of 559 suspected CD patients underwent serum EMA/anti-tTG detection, upper endoscopy with duodenal biopsy sampling, histologic analysis, and organ culture to detect EMA/anti-tTG in supernatants. A subgroup of 30 patients with organ culture positive results were put on a gluten-free diet (GFD). Their gluten-dependency was evaluated by the psychological general well-being and beck depression inventory indexes. Statistical analysis was performed by Cohen k inter-test, Friedman test, and Dunn multiple comparison. Two hundred forty-one out of 559 (43.1%) patients showed intestinal villous atrophy, whereas serum and organ culture EMA/anti-tTG were positive in 293/559 (52.4%) and 334/559 (59.7%) patients, respectively. The strength of agreement resulted good for serology vs histology (k = 0.730), good for organ culture vs histology (k = 0.662), and very good for serology vs organ culture (k = 0.852). After 12 months of GFD, psychological general well-being index significantly increased, and beck depression inventory index significantly decreased (P < 0.001 for each one). Data highlight the organ culture system as a useful tool to assist the histology in diagnosing CD, mainly in cases without villous atrophy or in seronegative patients. The marked improvement in quality of life after a GFD further supports the reliability of this system in diagnosing CD.

External Quality Assessment (EQA) program for the preanalytical and analytical immunohistochemical determination of HER2 in breast cancer: an experience on a regional scale.

BACKGROUND: An External Quality Assessment (EQA) program was developed to investigate the state of the art of HER2 immunohistochemical determination in breast cancer (BC) in 16 Pathology Departments in the Lazio Region (Italy). This program was implemented through two specific steps to evaluate HER2 staining (step 1) and interpretation (step 2) reproducibility among participants. METHODS: The management activities of this EQA program were assigned to the Coordinating Center (CC), the Revising Centers (RCs) and the Participating Centers (PCs). In step 1, 4 BC sections, selected by RCs, were stained by each PC using their own procedures. In step 2, each PC interpreted HER2 score in 10 BC sections stained by the CC. The concordance pattern was evaluated by using the kappa category-specific statistic and/or the weighted kappa statistic with the corresponding 95% Jackknife confidence interval. RESULTS: In step 1, a substantial/almost perfect agreement was reached between the PCs for scores 0 and 3+ whereas a moderate and fair agreement was observed for scores 1+ and 2+, respectively.In step 2, a fully satisfactory agreement was observed for 6 out of the 16 PCs and a quite satisfactory agreement was obtained for the remaining 10 PCs. CONCLUSIONS: Our findings highlight that in the whole HER2 evaluation process the two intermediate categories, scores 1+ and 2+, are less reproducible than scores 0 and 3+. These findings are relevant in clinical practice where the choice of treatment is based on HER2 positivity, suggesting the need to share evaluation procedures within laboratories and implement educational programs.

Thymoma and thymic carcinoma.

Thymic tumors comprise a heterogeneous group of neoplasms with a wide spectrum of clinical presentations. The evolution of the disease is often unpredictable, ranging from an indolent attitude to the possibility of intra- and extrathoracic spread. From the histological point of view, thymoma and thymic carcinoma are the most frequent subtypes and arise only from thymic epithelial cells. Other histological types are even more rare and are usually considered separately. A number of prognostic factors have been validated as predictors of outcome: staging, World Health Organization histological classification, diameter of the tumor, associated paraneoplastic syndromes, completeness of resection, and early onset of recurrence. Complete surgical resection is the key factor for cure and should be considered the gold standard at any stage. Especially for more aggressive lesions, surgery should be considered with a multimodality approach, involving induction and adjuvant therapy according to the stage. Multimodality therapy protocols have been designed based on the integration of clinical staging and histology. Neoadjuvant therapy is now administered before surgical resection in patients with tumors considered inoperable as it improves resectability and survival and reduces the risk of recurrence. Adjuvant treatment has been extensively reported after both complete or partial resection. New targeted therapies are in the developmental stage, and in the future they will be part of the standard protocols. Integrated treatment modalities require strict cooperation between medical and radiation oncologists, thoracic surgeons, and pathologists.

Efficacy and tolerability of long-acting octreotide in the treatment of thymic tumors: results of a pilot trial.

OBJECTIVES: Octreotide is a somatostatin analog, long-acting formulations of which have been used experimentally for the treatment of patients with invasive tumors and/or residual disease after conventional therapies. The objective of this retrospective study was to evaluate the efficacy of long-acting octreotide (Sandostatin LAR) for the treatment of thymic tumors, with a primary efficacy end point of progression-free survival. METHODS: Between 1994 and 2010, 44 patients with thymic malignancies were evaluated. Twenty-seven patients underwent an OctreoScan, and 12 OctreoScan-positive patients were treated with long-acting octreotide at a dose of 20 mg, given as an intramuscular injection, every 2 weeks. RESULTS: Treatment with long-acting octreotide gave the following results: 3 cases of partial response (25%), 5 cases of stable disease (42%), and 4 cases of progressive disease (33%), with an average progression-free survival of 8 months (range, 3 to 21). Treatment compliance and tolerability were good for all evaluated patients. CONCLUSIONS: The results of this study confirm the somatostatin receptor as a valid target for the treatment of thymic malignancies. Overall, therapy with long-acting somatostatin analogs seems to be safe and effective.