Colorectal metastases with intrabiliary growth: incidence, treatment, and outcomes.

Intrabiliary growth (IG) is an unusual modality for colorectal metastases to spread. Relatively little is known about this condition because large series are lacking. The aim of the study was to compare the surgical and oncological outcomes of patients with or without IG. From 01/2010 to 12/2020, 999 patients underwent hepatectomy for colorectal metastases. Clinicopathological variables were retrospectively analyzed from a prospective-collected database of patients with or without IG. A propensity score matched (PSM) analysis to compare OS and DFS was performed. At first hepatectomy, 29 patients (2.9%) had IG: 7 isolated IG and 22 mixed-type (mass-forming lesion with IG). 4 patients presented IG at repeat hepatectomy for recurrence, of whom 3 had no biliary invasion at initial surgery. IG resulted to be more common in older patients (median age 70 in IG vs 60 years of no-IG, p = 0.004). Mean time from colorectal tumor was longer in IG (20.4 months) than no-IG (12.9 months), p = 0.038. Major hepatectomies (55.2% IG vs 29.7% no-IG, p = 0.003) and anatomic resections (89.7% vs 58.2%, p = 0.001) were more frequently required to treat IG. In 5 (17%) of IG, a resection of main bile duct was performed. Overall postoperative mortality and complications were similar in the two groups, while bile leak was 17.2% IG vs 5.6% no-IG (p = 0.024). Median margin width was comparable in IG (1.4 mm) and no-IG (2 mm). Five-year overall survival (IG 45.9% vs no-IG 44.5%) and Disease-Free Survival (IG 35.9% vs no-IG 36.6%) were similar in the two groups. According to PSM, 145 patients with no-IG were compared to 29 of IG group. After PSM, OS and DFS did not show any statistically significant difference. IG has similar oncological outcomes of resected colorectal metastases without IG, although it affects surgical management.

Preoperative neck ultrasound combined with pathological data can significantly impact the outcome of medullary thyroid carcinoma.

The diagnosis of medullary thyroid carcinoma (MTC) is challenging since the accuracy of ultrasound (US) and fine-needle aspiration cytology are suboptimal. As a result, MTC has a generally poor prognosis. The aim of this study was to analyze whether perioperative data can modify the risk of relapse in these patients. The institutional database of Turin Mauriziano Hospital was searched to extract records of MTCs diagnosed between 2000 and 2021. Kaplan-Meier curves and Cox and logistic regression analyses were performed, and the hazard ratio (HR) was calculated. Seventy-three MTC patients (median age 58 yr) were found. Disease-free survival was significantly different according to staging (HR: 9.12; p = 0.037), capsular status (HR: 5.49; p = 0.02), and neck US (HR: 9.19; p = 0.04). In the logistic regression analysis, CEA level (ß: -0.01; p = 0.043), histological multifocality (OR: 7.4; p = 0.034), and metastatic lymph nodes at histology (ß: -0.13; p = 0.006) were significantly associated with structural recurrence. Two logistic multivariate models best explained the variance in recurrence: 1) neck US presentation plus histological multifocality (AIC: 27; r2: 0.37; x2: 12.4; p = 0.002) and 2) number of neck metastases plus capsular invasion (AIC: 26; r2: 0.40; x2: 13.7; p = 0.001). Pathological data are associated with MTC prognosis. Preoperative neck US can significantly help to predict MTC outcome.

Clinical and Pathological Features and Gene Expression Profiles of Clinically Aggressive Papillary Thyroid Carcinomas.

Papillary thyroid carcinoma (PTC) is considered an indolent neoplasm but it may demonstrate aggressive behavior. We aimed to identify clinical and pathological characteristics and molecular signatures associated with aggressive forms of PTCs. We selected 43 aggressive PTC cases based on the presence of metastases at the time of diagnosis, the development of distant metastasis during follow-up, and/or biochemical recurrence, and 43 PTC patients that were disease-free upon follow-up, matching them according to age, sex, pT, and pN parameters. Twenty-four pairs (a total of 48 cases) and 6 normal thyroid tissues were studied using targeted mRNA screening of cancer-associated genes employing NanoString nCounter® technology. In general, aggressive PTCs showed distinctive clinical and morphological features. Among adverse prognostic parameters, the presence of necrosis and an increased mitotic index were associated with shorter disease-free and overall survivals. Other parameters associated with shorter disease-free or overall survivals include a lack of tumor capsule, the presence of vascular invasion, tumor-infiltrating lymphocytes, fibrosclerotic changes, age > 55 years, and a high pTN stage. Various pathways were differentially regulated in non-aggressive as compared to aggressive PTC, including the DNA damage repair, the MAPK, and the RAS pathways. In particular, the hedgehog pathway was differentially de-regulated in aggressive PTC as compared to non-aggressive PTC cases, being WNT10A and GLI3 genes significantly up- and down-regulated in aggressive PTC and GSK3B up-regulated in non-aggressive PTC cases. In conclusion, our study revealed specific molecular signatures and morphological features in aggressive PTC that may be useful to predict more aggressive behavior in a subset of PTC patients. These findings may be useful when developing novel, tailored treatment options for these patients.

Proteomic analysis identifies deregulated metabolic and oxidative-associated proteins in Italian intrahepatic cholangiocarcinoma patients.

BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line. METHODS: Proteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues. RESULTS: We identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed. CONCLUSIONS: This study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression.

Adrenal Rests in the Uro-genital Tract of an Adult Population.

Ectopic adrenal rests are a rare condition which can be found in various sites, generally in the retroperitoneum or pelvis along the path of gonadal descent. Their real prevalence is unknown. Males are more commonly affected, at least in the pediatric age. Adrenal rests are usually clinically silent and incidentally found in surgical samples, mostly in the pediatric population, and rarely in adults. With the aim of increasing knowledge and estimating the prevalence of ectopic adrenocortical tissue in the adult population, 44 adrenal rests in the urogenital tract of 40 adults are described. These represent approximately 0.07% of the total number of urogenital and gynecological surgeries performed in the 22 considered years. Adrenal rests were identified in the spermatic cord (10 males) and in paraovarian, parasalpingeal, or infundibulopelvic ligament locations (30 females). All but one was incidental findings. One case regarded an adrenocortical carcinoma arisen in adrenal rests. A literature review of adrenal ectopia in the urogenital tract of adults identified 57 reported cases from 53 patients, with similar clinicopathological features as those of our series, with the exception of a lower incidence of parasalpingeal locations. Despite their limited clinical implications, awareness of ectopic adrenal rests is essential also in adults for at least two reasons: (a) to correctly identify sources of adrenocortical hormone production in case of adrenal insufficiency or hormonal imbalance and (b) to avoid misinterpretations in the diagnostic workup of renal cell carcinoma, adrenocortical tumors, and rare gonadal neoplasms, including Sertoli/Leydig cell tumors.

Natural history of widespread high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: should we rebiopsy them all?

OBJECTIVE: To evaluate the premalignant potential of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP). METHODS: Patients diagnosed with monofocal HGPIN (mHGPIN), widespread HGPIN (≥4 cores, wHGPIN) and/or ASAP who underwent at least one rebiopsy during their follow-up, were enrolled. All enrollment biopsies underwent central pathologic revision. Risks for PCa were estimated using Fine and Gray method for competing risk. RESULTS: Pathologic revision changed the original diagnosis in 32.3% of cases. Among 336 cases enrolled, PCa was diagnosed in 164 (48.8%), and more specifically in 20 (30.3%) mHGPIN, 10 (34.5%) wHGPIN, 101 (54.0%) ASAP, and 33 (61.1%) HGPIN + ASAP (mean follow-up 124 months). Most PCa were Gleason score 6(3 + 3) (51.0%) and 7(3 + 4) (34.3%). On multivariate analysis, HGPIN + ASAP (HR 2.76, p < 0.001) and ASAP alone (HR 2.41, p < 0.001) were the only lesions significantly associated with PCa development. Of all cancers detected, 64.3% were at first rebiopsy. A rebiopsy performed within 3 months after ASAP diagnosis had a 45% chance of finding PCa. At Kaplan-Meier survival curves, median PCa-free survival was 48.1 months for HGPIN + ASAP and 64.9 months for ASAP (p 0.0005 at Log-rank test). At 1 year, 70% of HGPIN + ASAP, 73% of ASAP, 89% of wHGPIN, and 84% of mHGPIN were PCa-free. CONCLUSION: The diagnosis of ASAP and HGPIN strongly relies on the expertise of dedicated uro-pathologists. Finding of ASAP is a strong risk factor for a subsequent PCa diagnosis, advising a rebiopsy, possibly within 3 months. m/wHGPIN should not be routinely rebiopsied.

A rare case of ovarian adenomyoma mimicking primary invasive ovarian cancer with a contralateral serous borderline ovarian tumor: A case report and review of the literature.

Extrauterine adenomyoma is a rare type of benign tumor, characterized by nodular aggregate of smooth muscle, endometrial glands and endometrial stroma, arising outside the uterus. In this study we describe a case of primary ovarian adenomyoma associated with endometriotic cysts with contralateral serous borderline tumor in a 40-year-old woman and we highlight how preoperative exams could lead to the suspicious of invasive cancer. We provide a review of the literature, analyzing all cases of extrauterine adenomyoma published so far, classifying them on the basis of pathogenetic theories proposed, localization of the lesion, imaging modalities and treatment adopted.

Neuroendocrine breast carcinoma: a rare but challenging entity.

Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2-5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.

Metastatic Bilateral Strumal Carcinoid: A Case Report and Review of the Literature.

Primary ovarian carcinoids are very rare tumors that belong to the germ cell family of ovarian malignancies. They account for less than 1% of all carcinoid tumors and for less than 0.1% of all ovarian neoplasms. Recurrences are even rarer, with only few cases reported in the literature. Strumal carcinoid has recently been recognized as an extremely rare distinct entity. We report on a patient with bilateral mature cystic teratoma with millimetric foci of ovarian strumal carcinoid who developed lymph node para aortic metastasis after 30 years from primary diagnosis. Our case is thus far the second report of a metastatic strumal carcinoid and the first one in which strumal carcinoid occurred bilaterally and was also metastatic.

[Infero-postero-lateral acute myocardial infarction caused by left ventricular myxoma embolism]. / Infarto miocardico infero-postero-laterale secondario ad embolizzazione di mixoma ventricolare sinistro.

The majority of myxomas are located in the left atrium (75%) followed by the right atrium (20%). In rare cases, myxomas can be found in the ventricles, with 2.5% reported for myxomas in the left ventricle. Systemic emboli, mostly cerebral, occur in two thirds of such patients, while coronary emboli are rare. Here we report a case of left ventricular myxoma causing infero-postero-lateral myocardial infarction, successfully treated by intracoronary thromboaspiration of myxoma embolus.

Ultrasound-guided fine needle aspiration cytology in the diagnosis of hepatic and pancreatic perivascular epithelioid cell tumors: A case series.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that can affect any part of the body. They can be sporadic or arise in the setting of tuberous sclerosis (TSC). In this article, we report a series of three hepatic and two pancreatic PEComas diagnosed preoperatively with ultrasound-guided fine needle aspiration (FNA). All patients were female (age range 28-70), had no personal history of TSC and presented with a single, localized painless mass. Rapid on-site evaluation (ROSE) of cytologic samples was performed for all cases to evaluate for cellular content and adequacy of specimens. Direct smears and cell block preparations revealed a proliferation of medium to large polygonal epithelioid cells, with abundant eosinophilic and vacuolated cytoplasm, arranged in sheets and nests. On immunohistochemistry (IHC), neoplastic cells showed co-expression of melanocytic and smooth muscle markers and a diagnosis of PEComa was rendered. PEComas of the pancreas and liver are rare neoplasms, but should always be considered when examining "clear cell" neoplasms, especially in young female patients. If good quality cytologic samples are obtained by FNA, a correct diagnosis can be achieved with the help of IHC. This is of particular importance in order to plan adequate surgical strategy and to avoid overtreatment.

Mitochondrial DNA "common deletion" in post-fine needle aspiration infarcted oncocytic thyroid tumors.

Thyroid fine needle aspiration (FNA) can rarely induce morphological changes potentially hindering the histopathological diagnosis, especially in Hurthle cell tumors (HCTs), which may easily undergo post-FNA infarction or necrosis. HCTs contain mitochondrion (mt)-rich cells that may bear mtDNA mutations, the most frequent being the so-called common deletion (CD). The aim of this study was to determine the presence and extent of the mtDNA CD in a series of thyroid HCTs that underwent extensive infarction following FNA procedure in comparison with a control series of HCTs lacking post-FNA ischemic/hemorrhagic alterations. Of 257 HCTs with available matched FNA and surgical specimens, 8 cases showed extensive (≥80%) infarction or necrosis in the resected nodule (4 adenomas, 1 carcinoma, 3 HCTs undefined for malignancy). Noninfarcted tumors in the control series included 9 adenomas, 1 carcinoma, and 1 follicular tumor of uncertain malignant potential. These lesions were significantly (P = .03) larger than infarcted nodules. The mtDNA CD was identified using semiquantitative real-time polymerase chain reaction in 2 of 8 (25%) infarcted tumors. In HCTs lacking infarction/necrosis of the control series, the CD was significantly (P = .05) more common (8/11 cases, 72.7%). In 7 of the 10 deleted cases, the CD was present also in the adjacent nonneoplastic parenchyma. In conclusion, the rare oncocytic tumors undergoing extensive infarction are smaller than those lacking ischemic changes and bear the mtDNA CD in a significantly lower proportion compared with control noninfarcted HCTs. This may suggest that mtDNA deletion confers a survival advantage to oncocytic cells in stress conditions, including FNA procedures.

Cell-cycle Progression-score Might Improve the Current Risk Assessment in Newly Diagnosed Prostate Cancer Patients.

OBJECTIVE: To assess whether cell-cycle progression (CCP)-score (Prolaris) can improve the current risk assessment in newly diagnosed prostate cancer (PCa) patients. CCP-score is a well-validated prognostic assay predictive of PCa death, biochemical recurrence, and progression. METHODS: We evaluated CCP-score at biopsy in 52 patients newly diagnosed with PCa who underwent radical prostatectomy. CCP-score was calculated as average RNA expression of 31 CCP genes, normalized to 15 housekeeping genes. The predictive ability of CCP-score was assessed in univariate and multivariate analyses, and compared to that of Ki-67 levels and traditional clinical variables including prostate-specific antigen, Gleason score, stage, and percentage of positive cores at biopsy. RESULTS: In spite of an overall good accuracy in attributing the correct risk class, 7 high-risk and 13 intermediate-risk patients were misclassified by the Prolaris test. On analysis of variance, mean CCP-score significantly differed across different risk classes based on pathologic results (-1.2 in low risk, -0.444 in intermediate risk, 0.208 in high risk). CCP-score was a significant predictor of high-risk PCa both on univariate and multivariate analyses, after adjusting for clinical variables. Combining CCP-score and the European Association of Urology clinical risk assessment improved the accuracy of risk attribution by around 10%, up to 87.8%. CCP-score was a significant predictor of biochemical recurrence, but only on univariate analysis. CONCLUSION: The CCP-score might provide important new information to risk assessment of newly diagnosed PCa in addition to traditional clinical variables. A correct risk attribution is essential to tailor the best treatment for each patient.

Global Hypomethylation (LINE-1) and Gene-Specific Hypermethylation (GSTP1) on Initial Negative Prostate Biopsy as Markers of Prostate Cancer on a Rebiopsy.

PURPOSE: Men at risk of missed prostate cancer on a negative biopsy often undergo a rebiopsy. We evaluated whether global hypomethylation, measured through LINE-1 methylation, and GSTP1 hypermethylation on a negative biopsy are associated with subsequent prostate cancer diagnosis. EXPERIMENTAL DESIGN: We performed a case-control study nested in an unselected series of 737 men who received at least two prostate biopsies at least three months apart at the Molinette Hospital (Turin, Italy). Two pathology wards were included for replication purposes. The study included 67 cases and 62 controls in Ward 1 and 62 cases and 66 controls in Ward 2. We used pyrosequencing to analyze LINE-1 and GSTP1 methylation in the negative biopsies. Odds ratios (OR) of prostate cancer diagnosis were estimated using conditional logistic regression. RESULTS: After mutual adjustment, GSTP1 hypermethylation was associated with an OR of prostate cancer diagnosis of 5.1 (95% confidence interval: 1.7-14.9) in Ward 1 and 2.0 (0.8-5.3) in Ward 2, whereas an association was suggested only for low LINE-1 methylation levels (<70% vs. 70%-74%) with an OR of 2.1 (0.5-9.1) in Ward 1 and 1.6 (0.4-6.1) in Ward 2. When the two wards were combined the association was stronger for tumors with Gleason score ≥ 4+3 [GSTP1 hypermethylation: 9.2 (2.0-43.1); LINE-1 (<70% vs. 70%-74%): 9.2 (1.4-59.3)]. GSTP-1 alone improved the predictive capability of the model (P = 0.007). CONCLUSIONS: GSTP1 hypermethylation on a negative biopsy is associated with the risk of prostate cancer on a rebiopsy, especially of high-grade prostate cancer. Consistent results were found only for extremely low LINE-1 methylation levels.

A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"?

BACKGROUND: Antioxidants effectiveness in prostate cancer (PCa) chemoprevention has been severely questioned, especially after the recent results of the Selenium and Vitamin E Cancer Prevention Trial. We present the results of a double-blind randomized controlled trial (dbRCT) on the pharmacokinetic, clinical, and molecular activity of dietary supplements containing lycopene, selenium, and green tea catechins (GTCs) in men with multifocal high grade prostatic intraepithelial neoplasia (mHGPIN) and/or atypical small acinar proliferation (ASAP). METHODS: From 2009 to 2014, we conducted a dbRCT including 60 patients with primary mHGPIN and/or ASAP receiving daily lycopene 35 mg, selenium 55 µg, and GTCs 600 mg, or placebo for 6 months. Pharmacokinetic analysis were performed with UV-Visible spectrophotometric assay under standard (SC) and accelerated (AC) conditions. Upon plasma lycopene concentrations falling within the expected range (1.2-90 mcg/l) and no side-effects of grade >1, study proceeded to phase II (n = 50). After unblinding of results, eight men (4 per arm, 2 without and 2 with PCa, respectively) were randomly selected and totRNA extracted from "non-pathological" tissues. MicroRNA profiling was performed with the Agilent platform. Raw data processing used R-statistical language and linear models for microarray analysis. RESULTS: Samples were stable except for lycopene, showing significant degradation (SC = 56%, AC = 59%) and consequently stabilized under vacuum in a dark packaging. Mean plasmatic lycopene concentration was 1,45 ± 0,4 µM. At 6 months, 53 men underwent re-biopsy and 13 (24.5%) were diagnosed with PCa (supplementation n = 10, placebo n = 3 [P = 0.053]). At a mean 37 months follow-up, 3 additional PCa were found in the placebo group. No significant variations in PSA, IPSS, and PR25 questionnaires were observed. Stronger modulation of miRNAs was present on re-biopsy in the supplementation group compared to the placebo, including: (i) overexpression of miRNAs present in PCa versus non-cancer tissue; (ii) underexpression of miRNAs suppressing PCa proliferation; (iii) detection of 35 miRNAs in PCa patients versus disease-free men, including androgen-regulated miR-125b-5p and PTEN-targeting miR-92a-3p (both upregulated). CONCLUSION: Administration of high doses of lycopene, GTCs, and selenium in men harboring HGPIN and/or ASAP was associated with a higher incidence of PCa at re-biopsy and expression of microRNAs implicated in PCa progression at molecular analysis. The use of these supplements should be avoided.

Expression analysis of genes involved in DNA repair or synthesis in mixed neuroendocrine/nonneuroendocrine carcinomas.

BACKGROUND: Mixed neuroendocrine/nonneuroendocrine carcinomas are heterogeneous tumors with poorly defined diagnostic and clinical features and without pathological or molecular markers of prognosis or markers predicting their response to therapy. We aimed at analyzing the pathological features and the expression of genes involved in DNA repair or synthesis in a cohort of patients with mixed carcinomas from different sites as compared to the patients' outcome. METHODS: Relative cDNA quantification of ribonucleotide reductase, large subunit 1, excision repair cross-complementation group 1, thymidylate synthase and topoisomerase IIa genes was tested using real-time PCR on microdissected neuroendocrine and nonneuroendocrine tumor components of 42 mixed cases (from the lung as well as the gastrointestinal and genitourinary tracts) and on 45 control cases of pure neuroendocrine and nonneuroendocrine carcinomas. RESULTS: The expression levels of all genes were stable comparing nonneuroendocrine and neuroendocrine components of mixed cases (except for topoisomerase IIa in lung samples) but significantly different as compared to control nonneuroendocrine and neuroendocrine tumors. In the multivariate analysis including all clinical and pathological parameters and gene expression levels available, a predominant nonneuroendocrine component, the administration of additional therapy other than surgery and a high thymidylate synthase expression in nonneuroendocrine tumor tissue were significantly associated with a lower risk of a patient's death. CONCLUSIONS: Our data show that mixed neuroendocrine/nonneuroendocrine carcinomas are different at the molecular level from their pure neuroendocrine and nonneuroendocrine counterparts, and detailed analyses of their clinical, pathological and molecular features may improve the clinical strategies for the treatment of these rare and underestimated tumors.

Proteomic identification of Reticulocalbin 1 as potential tumor marker in renal cell carcinoma.

Renal cell carcinoma (RCC) biomarkers are necessary for diagnosis and prognosis. They serve to monitor therapy response and follow-up, as drug targets, and therapy predictors in personalized treatments. Proteomics is a suitable method for biomarker discovery. Here we investigate differential protein expression in RCC, and we evaluate Reticulocalbin 1 (RCN1) use as a new potential marker. Neoplastic and healthy tissue samples were collected from 24 RCC patients during radical nephrectomy. Seven specimens were firstly processed by proteomic analysis (2-DE and MALDI-TOF) and 18 differentially expressed proteins from neoplastic and healthy renal tissues were identified. Among them, RCN1 was over-expressed in all cancer specimens analyzed by proteomics. Consequently RCN1 use as a potential marker was further evaluated in all 24 donors. RCN1 expression was verified by Western blotting (WB) and immunohistochemistry (IHC). WB analysis confirmed RCN1 over-expression in 21 out of 24 tumor specimens, whereas IHC displayed focal or diffuse expression of RCN1 in all 24 RCC tissues. Thus RCN1 appears as a potential marker for clinical approaches. A larger histopathological trial will clarify the prognostic value of RCN1 in RCC. BIOLOGICAL SIGNIFICANCE: The present work aimed at finding new biomarkers for RCC - a life-threatening disease characterized by high incidence in Western countries - by performing differential proteomic analysis of neoplastic and normal renal tissues obtained from a small cohort of RCC patients. Some of the identified proteins have been previously associated to renal cancer however data confirming the possible use of these proteins in clinical practice are not available to date. By IHC we demonstrated that RCN1 could be easily employed in clinical practice, confirming RCN1 over-expression in RCC tissues of all examined patients, and weak protein expression in healthy renal tissues only in correspondence to the renal tubule section. These data indicate a promising role of RCN1 as a possible marker in RCC and indicate the proximal convoluted renal tubule as a putative origin point for RCC. Since IHC staining displayed different grades of intensity in tested tissues, we hypothesized that RCN1 could also be employed as a prognostic marker or as a response predictor for RCC-targeted therapy. To test such a hypothesis, a larger retrospective trial on paraffin-embedded tissues obtained from radical or partial nephrectomy of RCC patients is planned to be performed by our group.