Supplementary Data 2 from Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Supplementary Data 4 from Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Supplementary Data 1 from Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Supplementary Data 7 from Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Supplementary Data 6 from Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Sarcoidosis is a multisystemic granulomatous disease characterized by the presence of noncaseating granulomas, the exact etiology of which is yet to be determined. Most of patients show granulomas located in the lungs or in the related lymph nodes. However, lesions can affect any organ. Noncaseating granulomas are not a pathognomonic sign of sarcoidosis, being observed also in other diseases, therefore the diagnosis is often of exclusion. We report a case of sarcoidosis with parotid gland involvement in the context of a Heerfordt syndrome, discussing about its clinical presentation, pathogenesis, pathology and differential diagnosis with other granulomatous diseases.

Inverted papilloma (IP) is a locally destructive, benign neoplasm of the nose and paranasal sinuses with a high tendency for recurrence, a significant potential for malignancy, and an etiology that today is still uncertain. The expression of hormonal receptors in neoplastic tissues has been the focus of intensive research for its potential diagnostic, prognostic, and therapeutic significance. The aim of this study was to assess the potential estroprogestinic receptor expression in patients undergoing sinus surgery for IP. A retrospective study was carried out, on surgical specimens of 73 patients who underwent endoscopic sinus surgery for first manifestation of sinonasal IP (primitive IP group) and in 21 subjects who had developed a recurrence (relapsed IP group). The results of the immunohistochemical analysis of the first group showed the absence of receptor expression for PGR in all cases analyzed and the presence of a low positivity for ER in 11 cases (P > 0.082). Similarly, in the second group the results showed a low presence of ER receptors in 3 of the 21 cases (P > 0.068), while there was no evidence of PGR receptors in the examined samples. In addition, in 11 of the cases only 3 were considered positive (27.2%) showing a recurrence during follow-up (P > 0.068).Our results suggest that the sinonasal IP is a benign tumor independent of estrogen and progesterone, and the receptors for these hormones are therefore unsuitable as predictors of relapse or possible prognostic indicators and therapeutic targets.

Mucocele-Like Tumor of the Breast: A Pathological Continuum of Mucinous Breast Lesions. Report of a Case Giuseppe Broggi1, Matteo Angelo Cannizzaro2, Salvatore Lo Bianco2, Salvatore Lanzafame1 and Rosario Caltabiano1* 1Department G.F. Ingrassia, Section of Anatomic Pathology, University of Catania, Italy 2Department G. F. Ingrassia”, Endocrine surgery Unit, University of Catania, “Policlinico-Vittorio Emanuele” Hospital, Italy Case Report Open Access Journal of Clinical Trails in Oncology

The INI1/SMARCB1 gene protein product has been implicated in the direct pathogenesis of schwannomas from patients with one form of schwannomatosis [SWNTS1; MIM # 162091] showing a mosaic pattern of loss of protein expression by immunohistochemistry [93% in familial vs. 55% in sporadic cases].

The authors describe the sixth pediatric case to date of primary vulvar melanoma associated with lichen sclerosus and propose a practical management for such a rare cancer.

MiR-671-5p is encoded by a gene localized at 7q36.1, a region amplified in human glioblastoma multiforme (GBM), the most malignant brain cancer.To investigate whether expression of miR-671-5p were altered in GBM, we analyzed biopsies from a cohort of forty-five GBM patients and from five GBM cell lines.Our data show significant overexpression of miR-671-5p in both biopsies and cell lines.By exploiting specific miRNA mimics and inhibitors, we demonstrated that miR-671-5p overexpression significantly increases migration and to a less extent proliferation rates of GBM cells.Through a combined in silico and in vitro approach, we identified CDR1-AS, CDR1, VSNL1 as downstream miR-671-5p targets in GBM.Expression of these genes significantly decreased both in GBM biopsies and cell lines and negatively correlated with that of miR-671-5p.Based on our data, we propose that the axis miR-671-5p / CDR1-AS / CDR1 / VSNL1 is functionally altered in GBM cells and is involved in the modification of their biopathological profile.

OBJECT The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. METHODS A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m(2) starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30-72 years (mean 56.1 years), received 150 mg/m(2) for 5 days every 28 days for more than 6 cycles (range 7-101 cycles). The 18 patients in Group B, aged 46-82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. RESULTS All patients but 1 in Group A survived at least 18 months (range 18-101 months), and patients in Group B survived no more than 17 months (range 2-17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. CONCLUSIONS This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract, while osseous metaplasia of this tumour is an unexpected event. To date, no cases have been reported in the literature. Herein, we report a case of a 60-year-old man affected by a GIST with benign osseous metaplasia and mature bone formation. We also discuss the pathogenesis of intratumoural ossification and review the relevant literature. The prognostic significance of ossification in GIST remains unclear because of the limited cases reported.

Background: The assessment of human epidermal growth factor receptor 2 (HER2) gene amplification is essential in order to identify those patients affected by advanced gastric cancer who may benefit from Trastuzumab targeted therapy. Materials and Methods: With the aim to investigate the concordance rate in HER2 status between primary gastric carcinoma (GC) and synchronous lymphnode metastases, we investigated HER2 status in a cohort of 108 surgical formalin-fixed paraffin-embedded specimens of GC and matched synchronous metastatic lymph nodes collected from three different units of Anatomic Pathology in southern of Italy. Fleiss-Cohen weighted k statistics were used to assess the concordance rate of HER2 status. Results: HER2 amplification was observed in 17% of primary GCs and the overall concordance rate with corresponding nodal metastases was 90.74%. Changes in HER2 status between primary GC and matched synchronous metastases were evidenced in 10 (9.26%) cases. Of these, 6 cases were HER2 amplified in the primary GC and not amplified in the metastases, while 4 were HER2 not amplified in the primary tumour and amplified in the lymph node metastases. Conclusions: Although at present the simultaneous determination of HER2 in advanced gastric cancer and corresponding metastatic lymph nodes is not mandatory, the possibility that the synchronous metastases of GC have a different HER2 status from that of the primary tumour is of remarkable significance; Indeed this may have influence on the therapeutic management and prognosis of the patients.

BACKGROUND:Human epidermal growth factor receptor 2 (HER2) is considered to be a therapeutic and prognostic marker in the management of breast carcinoma (BC), although discordance rates between primary and metastatic or locally recurrent lesions have been reported.METHODS:One hundred and forty-eight paraffin-embedded BC tissues from patients of mean age 59.27 (33-96) years and corresponding synchronous lymph node metastases were collected and retrospectively studied using immunohistochemistry and fluorescence in situ hybridization to evaluate HER2 status. Fleiss-Cohen weighted k statistics were used to assess the concordance rate between HER2 status of the primary BC and the synchronous metastatic lesions.RESULTS:The overall concordance rate for HER2 was 95.28%. Eighty-nine cases were concordantly HER2-negative in primary BC and nodal metastases, and 52 cases were HER2-positive in both primary and metastatic tumors. Changes in HER2 status between primary BC and corresponding synchronous metastases were observed in seven (4.72%) cases. Three of the discordant cases were HER2-negative in the primary tumor and HER2-positive in the metastases, while four cases were HER2-positive in the primary BC and HER2-negative in the metastases. No significant correlations were identified between HER2 status and expression of hormone receptors, growth fraction (Ki-67), or other histopathological parameters (pT, pN, grade).CONCLUSION:Simultaneous determination of HER2 in BC and corresponding metastatic lymph nodes is not mandatory, but may strongly influence the therapeutic management. It was demonstrated that loss of HER2 amplification results in worse post-relapse survival and overall survival in BC patients and, on the other hand, a gain in HER2 expression in metastatic lymph nodes of BC may allow the possibility of a targeted treatment. Thus, our opinion is that significant prognostic information may be obtained by simultaneous assessment of HER2 status in both primary and synchronous metastatic BC.

We have read with great interest the article in press of Aurilio et al., A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases (http://dx.doi.org/10.1016/j.ejca.2003.10.004), which will appear in Eur J Cancer. In the paper, the Authors have performed a meta-analysis of the studies published in the literature concerning the discordance rate in oestrogen receptor (ER), progesterone receptor (PgR) and HER2 status between primary tumour and corresponding relapse. It is well known that a considerable controversy concerns the issue of hormone receptors (HRs) expression as well as HER2 status between primary breast carcinomas (BC) and metastatic sites from the same patient, as elsewhere reported in literature [ 1 Aitken S.J. Thomas J.S. Langdon S.P. et al. Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol. 2010; 21: 1254-1261 Crossref PubMed Scopus (141) Google Scholar , 2 Chen X. Yuan Y. Gu Z. et al. Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis. Breast Cancer Res Treat. 2012; 134: 957-967 Crossref PubMed Scopus (81) Google Scholar , 3 Hoefnagel L.D. Moelans C.B. Meijer S.L. et al. Prognostic value of estrogen receptor α and progesterone receptor conversion in distant breast cancer metastases. Cancer. 2012; 118: 4929-4935 Crossref PubMed Scopus (75) Google Scholar , 4 Curtit E. Nerich V. Mansi L. et al. Discordances in estrogen receptor status, progesterone receptor status, and HER2 status between primary breast cancer and metastasis. Oncologist. 2013; 18: 667-674 Crossref PubMed Scopus (72) Google Scholar , 5 Penault-Llorca F. Coudry R.A. Hanna W.M. et al. Experts' opinion: recommendations for retesting breast cancer metastases for HER2 and hormone receptor status. Breast. 2013; 22: 200-202 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar ]. In particular, the discordance between primary BC and metastases from negative to positive and vice versa potentially affects the treatment regimen [ [5] Penault-Llorca F. Coudry R.A. Hanna W.M. et al. Experts' opinion: recommendations for retesting breast cancer metastases for HER2 and hormone receptor status. Breast. 2013; 22: 200-202 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar ]; therefore, it has been suggested that neoplastic tissue of metastatic lesions should be systematically re-biopsied to optimally re-assess HR as well as HER2 [ 1 Aitken S.J. Thomas J.S. Langdon S.P. et al. Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol. 2010; 21: 1254-1261 Crossref PubMed Scopus (141) Google Scholar , 2 Chen X. Yuan Y. Gu Z. et al. Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis. Breast Cancer Res Treat. 2012; 134: 957-967 Crossref PubMed Scopus (81) Google Scholar , 4 Curtit E. Nerich V. Mansi L. et al. Discordances in estrogen receptor status, progesterone receptor status, and HER2 status between primary breast cancer and metastasis. Oncologist. 2013; 18: 667-674 Crossref PubMed Scopus (72) Google Scholar , 5 Penault-Llorca F. Coudry R.A. Hanna W.M. et al. Experts' opinion: recommendations for retesting breast cancer metastases for HER2 and hormone receptor status. Breast. 2013; 22: 200-202 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar , 6 Idirisinghe P.K. Thike A.A. Cheok P.Y. et al. Hormone receptor and c-ERBB2 status in distant metastatic and locally recurrent breast cancer. Pathologic correlations and clinical significance. Am J Clin Pathol. 2010; 133: 416-429 Crossref PubMed Scopus (93) Google Scholar , 7 Aurilio G. Disalvatore D. Pruneri G. et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014; 50: 277-289 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar , 8 Pérez-Fidalgo J.A. Eroles P. Ferrer J. et al. An evaluation of the impact of technical bias on the concordance rate between primary and recurrent tumors in breast cancer. Breast. 2013; 22: 974-979 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar ].

Despite ongoing clinical trials, the efficacy of anti-angiogenic drugs for the treatment of brain metastases (BM) is still questionable. The lower response rate to anti-angiogenic therapy in the presence of BM than in metastatic disease involving other sites suggests that BM may be insensitive to these drugs, although the biological reasons underlining this phenomenon are still to be clarified. With the aim of assessing whether the targets of anti-angiogenic therapies are actually present in BM, in the present study, we analyzed the microvessel density (MVD), a measure of neo-angiogenesis, and the vascular phenotype (mature vs. immature) in the tumor tissue of a series of BM derived from different primary tumors. By using immunohistochemistry against endoglin, a specific marker for newly formed vessels, we found that neo-angiogenesis widely varies in BM depending on the site of the primary tumor, as well as on its histotype. According to our results, BM from lung cancer displayed the highest MVD counts, while those from renal carcinoma had the lowest. Then, among BM from lung cancer, those from large cell and adenocarcinoma histotypes had significantly higher MVD counts than those originating from squamous cell carcinoma (p = 0.0043; p = 0.0063). Of note, MVD counts were inversely correlated with the maturation index of the endoglin-stained vessels, reflected by the coverage of smooth muscle actin (SMA) positive pericytes (r = −0.693; p < 0.0001). Accordingly, all the endoglin-positive vessels in BM from pulmonary squamous cell carcinoma and renal carcinoma, displayed a mature phenotype, while vessels with an immature phenotype were found in highly vascularized BM from pulmonary large cell and adenocarcinoma. The low MVD and mature phenotype observed in BM from some primary tumors may account for their low sensitivity to anti-angiogenic therapies. Although our findings need to be validated in correlative studies with a clinical response, this should be taken into account in therapeutic protocols in order to avoid the adverse effects of useless therapies.

Background Familial spinal neurofibromatosis is a form of neurofibromatosis 1 (NF1), consisting of extensive, symmetrical, histologically proven, multiple neurofibromas of the spinal roots at every level and of all major peripheral nerves sometimes associated with typical NF1 stigmata; most cases underlie NF1 gene mutations. Objectives The objectives of this study are (1) to report the findings in a set of 16-year-old monozygotic twin girls and a 14-year-old boy and (2) to review the existing literature. Methods and Results In this article, we report the cases of three children who (1) had manifested mildly different symptomatic neuropathy (twins, aged 4 years; and a boy, aged 9 years) associated with massive, symmetrical neurofibromas; (2) had few cafe-au-lait spots with irregular margins and pale brown pigmentation; (3) were presented with, at brain magnetic resonance imaging (MRI), bilateral, NF1-like high-signal abnormalities in the basal ganglia; (4) yielded missense NF1 gene mutations in exon 39; and (5) had unaffected parents with negative NF1 genetic testing as well as discuss 12 families and 20 sporadic and 5 additional cases that presented spinal neurofibromatosis within classical NF1 families (53 cases) that were reported in the literature. Conclusions This article presents the first report on (1) spinal neurofibromatosis in a set of affected monozygotic twins; (2) the earliest onset of the disease; and (3) the occurrence of high signal lesions in the brain at MRI.

According to the ToGA trial, HER2 has been shown to be predictive for the success of treatment with trastuzumab in advanced gastric cancer (AGC). A number of studies have analyzed HER-2/neu overexpression in gastric carcinoma and identified the rate of HER2 positivity to be markedly varied. To date, the prevalence of HER2 overexpression in Sicilian people with AGC is unknown. Therefore, in the present study, a retrospective immunohistochemical analysis of HER2 was performed in a cohort of 304 AGC samples that were obtained from the archives of 10 Sicilian anatomopathological diagnostic units in order to verify the positive rate of HER2-positive cases. Furthermore, the characteristics of histotype, grade, stage and Ki-67 expression were also analyzed. HER2 overexpression was encountered in 17.43% of all the gastric adenocarcinomas, which was consistent with the results that have been reported elsewhere in the literature. A progressive increase in HER2 overexpression was observed, from the poorly cohesive histotype to the tubular adenocarcinomas and gastric hepatoid adenocarcinomas. HER2 overexpression was significantly associated with a high grade, advanced stage and high Ki-67 labeling index. Further investigations performed jointly by pathologists and oncologists within the geographical area of the present study should confirm that the association of trastuzumab with chemotherapy results in an improvement of survival in patients with AGC.