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The molecular background of hepatocellular carcinoma (HCC) is highly heterogeneous, and biomarkers predicting response to treatments are an unmet clinical need. We investigated miR-30e-3p contribution to HCC phenotype and response to sorafenib, as well as the mutual modulation of TP53/MDM2 pathway, in HCC tissues and preclinical models. MiR-30e-3p was downregulated in human and rat HCCs, and its downregulation associated with TP53 mutations. TP53 contributed to miR-30e-3p biogenesis, and MDM2 was identified among its target genes, establishing an miR-30e-3p/TP53/MDM2 feedforward loop and accounting for miR-30e-3p dual role based on TP53 status. EpCAM, PTEN, and p27 were demonstrated as miR-30e-3p additional targets mediating its contribution to stemness and malignant features. In a preliminary cohort of patients with HCC treated with sorafenib, increased miR-30e-3p circulating levels predicted the development of resistance. In conclusion, molecular background dictates miR-30e-3p dual behavior in HCC. Mdm2 targeting plays a predominant tumor suppressor function in wild-type TP53 contexts, whereas other targets such as PTEN, p27, and EpCAM gain relevance and mediate miR-30e-3p oncogenic role in nonfunctional TP53 backgrounds. Increased circulating levels of miR-30e-3p predict the development of sorafenib resistance in a preliminary series of patients with HCC and deserve future investigations. Significance: The dual role of miR-30e-3p in HCC clarifies how the molecular context dictates the tumor suppressor or oncogenic function played by miRNAs.

Predicting response to definitive treatmentsis a fascinating challenge which develops throughthe evolution of a panel of convincing molecularbiomarkers capable of adding in clinical decissionsdespite interpatient and intratumoral heterogenicity.Muscle-invasive bladder cancer (MIBC) can be locallytreated either with radical cystectomy (RC) with or withoutneoadyuvant chemotherapy or bladder preservationapproaches such as trimodal therapy (TMT) includingmaximal transurethral resection of bladder tumor(TURBt) followed by external beam radiotherapy withconcurrent systemic radio-sensitizing chemotherapy.Conventional or novel/targeted systemic agents areessential parts of perioperative multidisciplinary managementconsidering both neoadjuvant and adjuvantsetting. Advances in molecular biology such as next generation sequencing and whole genome or transcriptomicanalysis, provided novel insights to achieve a fullunderstanding of the biology behind MIBC helping toidentify emerging predictive signatures. Although severalprogresses have been made, real-world applicationof molecular biomarkers in MIBC scenario is hinderedby lack of standardization, and low reproducibility. Inthis review we aim to present the emerging role of novelmolecular biomarkers in predicting response to localtreatments and systemic agents in MIBC.La predicción de respuesta a tratamientosdefinitivos en un tumor es un desafío fascinantemediada por un panel de biomarcadores quepuedieran aportar información para tomar decisionesterapéuticas, pese a la heterogenicidad entrepacientes e intratumoral. El tumor vesical infiltrante(TVI) puede tratarse con cistectomía radical (CR) cono sin neoadyuvancia (NAD) o estrategias de preservaciónvesical como la terapia trimodal (TMT), que incluyeresección transuretral (RTU) máxima seguidade radioterapia externa con una quimioterapia radiosensibilizadoraconcomitante. Las terapias convencionaleso dirigidas son esenciales dentro del manejomultidisciplinar necesario en sus facetas neo y adyuvantes.Los avances en biología molecular, como lasecuenciación moderna y el análisis transcriptómicodel genoma, han permitido empezar a entenderel comportamiento molecular del TVI ayudando aidentificar firmas predictivas. Aunque se han hechoprogresos, la aplicación asistencial de biomarcadores en TVI está frenada por la falta de estandarización yla baja reproducibilidad de distintos resultados esperanzadores.En esta revisión, pretendemos exponerel papel emergente de nuevos marcadores molecularesen la predicción de respuesta a tratamientos localesy sistémicos en el TVI.

Background and objectives: We studied a large series of ductal carcinoma in situ with microinvasion (MIDC) an infrequent disease whose diagnosis and management are not well defined. Methods: 17,431 cases of breast carcinoma were treated between 2011 and 2016 by ten Italian Breast Units. Our analysis included diagnostic and clinic-pathological characteristics, surgical management, and the use of adjuvant therapies. Results: 15,091 cases (86.6%) were infiltrating carcinomas (IC), 2107 (12.1%) ductal carcinoma in situ (DCIS), and 233 (1.3%) MIDC. Age at diagnosis did not differ between DCIS and MIDC. MIDC were usually larger and expressed more frequently biologically aggressive features (higher Ki67 values, hormone receptor negativity and HER2/neu over-expression) (p < 0.01). Axillary lymph nodes were involved in 25 MIDC cases (12%), but >3 lymph nodes were involved in two cases only (1%). At multivariable analysis, only lymphovascular invasion (LVI) was associated with lymph node status (p < 0.01). Hormone therapy was prescribed in 388/1462 DCIS cases (26.5%), in 84/200 MIDC cases (42%), and in 11,086/14,188 IC cases (84.7%) (p < 0.01). Chemotherapy was administered in 28/190 MIDC cases (14.7%), and in 4080/11,548 IC cases (35.3%) (p < 0.001). Conclusions: This is one of the largest studies of MIDC reported in the literature. Approximately 10% of DCIS harbor one or more foci of MIDC, and the latter often expresses aggressive biological features. LVI is a predictor of axillary node involvement, but this is infrequent and usually limited. Conservative surgery is performed less often than in DCIS, and adjuvant chemotherapy is less frequently utilized compared to IC.

Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior of in various PC-derived cells, at different degree of malignancy. The effect of the compounds was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected compounds were lastly identified using transcriptional and non-transcriptional reporter assays. TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a ‘druggable’ target in the androgen receptor-expressing prostate cancers.

The oncological benefit of achieving a negative pancreatic neck margin through re-resection after a positive frozen section (FS) is debated. Aim of this network meta-analysis is to evaluate the survival benefit of re-resection after intraoperative FS neck margin examination following pancreatectomy for ductal adenocarcinoma.A systematic search of studies comparing different strategies for the management of positive FS was performed. Patients were classified in three groups based on FS and permanent section (PS): Group A (FS-, PS-R0), Group B (FSthorn, PS-R0), Group C (FS +/-, PS-R1). A frequent random-effects network-meta-analysis was made reporting the surface under the cumulative ranking (SUCRA). Primary endpoint was overall survival (OS). Secondary endpoints were pathological outcomes.Seven retrospectives studies with 4205 patients were included and 99.1% of the pancreatic resections were pancreatoduodenectomies. Group A had the highest probability of better OS (SUCRA = 90%), compared to Group B (SUCRA = 48.7%) and Group C, which was the worst prognostic scenario (SUCRA = 11.3%). Group B had still a probability of longer OS compared to Group C (SUCRA 1/4 48.7% vs 11.3%). Pathological features were more favourable in Group A, with the highest SUCRA for T1-T2 tumors (92.6%), N0 status (89.4%), absence of perineural invasion (92.3%). Heterogeneity was low (tau-value

Tumours of the small intestine are rare and account for about 5% of gastrointestinal tract neoplasms. The angle of Treitz (AT) could be defined as the intestinal loop comprised between the third duodenal portion and the first 10 cm of jejunum. A gold standard surgical treatment for AT neoplasm has not yet been well defined. This paper is focused on a very rare disease and at the best of our knowledge this is the largest case series in the literature about the Laparoscopic Segmental Resection (LSR) of AT tumours. Using a prospectively collected database, all data of consecutive patients, from January 2007 to May 2019, who underwent LSR for AT tumours at two different institutions were analysed. Patients’ demographics, intra and post-operative data, 30-day mortality and overall survival were collected. A total of 16 patients were retrieved from our database. The mean operative time was 206,5 ± 79 min. Conversion to open surgery was needed in two cases due to tumor size and, respectively, invasion of the transverse colon which required a multivisceral resection. The mean distal and proximal resection margins were 7.4 ± 2.2 and 3.9 ± 1.2 cm. The median number of harvested nodes was 9 ± 3. Pathological diagnosis was GIST in 11 cases, adenocarcinoma in 4 and sarcoma in 1 case. In conclusion, in experienced hands, LSR appears to be a safe and effective treatment option for tumours of the AT. Prospective studies are needed to confirm these findings. Electronic supplementary material The online version of this article (10.1007/s13304-020-00910-7) contains supplementary material, which is available to authorized users.

To compare FDG-PET/unenhanced MRI and FDG-PET/diagnostic CT in detecting infiltration in patients with newly diagnosed Hodgkin lymphoma (HL). The endpoint was equivalence between PET/MRI and PET/CT in correctly defining the revised Ann Arbor staging system. Seventy consecutive patients with classical-HL were prospectively investigated for nodal and extra-nodal involvement during pretreatment staging with same-day PET/CT and PET/MRI. Findings indicative of malignancy with the imaging procedures were regarded as lymphoma infiltration; in case of discrepancy, positive-biopsy and/or response to treatment were evidenced as lymphoma. Sixty of the 70 (86%) patients were evaluable having completed the staging program. Disease staging based on either PET/MRI or PET/CT was correct for 54 of the 60 patients (90% vs. 90%), with difference between proportions of 0.0 (95% CI, −9 to 9%; P=0.034 for the equivalence test). As compared with reference standard, invasion of lymph nodes was identified with PET/MRI in 100% and with PET/CT in 100%, of the spleen with PET/MRI in 66% and PET/CT in 55%, of the lung with PET/MRI in 60% and PET/CT in 100%, of the liver with PET/MRI in 67% and PET/CT in 100%, and of the bone with PET/MRI in 100% and PET/CT in 50%. The only statistically significant difference between PET/MRI and PET/CT was observed in bony infiltration detection rates. For PET/CT, iodinate contrast medium infusions’ average was 86 mL, and exposure to ionizing radiation was estimated to be 4-fold higher than PET/MRI. PET/MRI is a promising safe new alternative in the care of patients with HL. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04537-5.

Background Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. Methods EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m2 (arm A) or 125 mg/m2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9–8.9; p = 0.188) in arm A vs 8.3 months (90% CI, 6.2–9.7, p = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2–3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2–3 arm A vs B, 19% and 38%, respectively). Conclusion Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. Trial registration EudraCT, 2012-002707-18. Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222. Retrospectively registered on May 26, 2016.

Objectives Rete testis invasion by germ cell tumors is frequently concomitant with lymphovascular or spermatic cord invasion (LVI/SCI); independent implications for staging are uncertain. Methods In total, 171 seminomas and 178 nonseminomatous germ cell tumors (NSGCTs; 46 had 1%-60% seminoma component) came from five institutions. Metastatic status at presentation, as a proxy for severity, was available for all; relapse data were unavailable for 152. Rete direct invasion (ReteD) and rete pagetoid spread (ReteP) were assessed. Results ReteP and ReteD were more frequent in seminoma than NSGCT. In seminoma, tumor size bifurcated at 3 cm or more or less than 3 cm predicted metastatic status. Tumors with ReteP or ReteD did not differ in size from those without invasions but were less than with LVI/SCI; metastatic status or relapse did not show differences. In NSGCT, ReteP/ReteD did not correlate with size, metastatic status, or relapse. Conclusions Findings support retaining American Joint Committee for Cancer pathologic T1 stage designation for rete testis invasion and pT1a/pT1b substaging of seminoma.

Background We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Moreover, ENO1 silencing in PDA cells induces oxidative stress, senescence and profoundly modifies PDA cell metabolism. Although anti-ENO1 antibody inhibits PDA cell migration and invasion, little is known about the role of ENO1 in regulating cell-cell and cell-matrix contacts. We therefore investigated the effect of ENO1 silencing on the modulation of cell morphology, adhesion to matrix substrates, cell invasiveness, and metastatic ability. Methods The membrane and cytoskeleton modifications that occurred in ENO1-silenced (shENO1) PDA cells were investigated by a combination of confocal microscopy and atomic force microscopy (AFM). The effect of ENO1 silencing was then evaluated by phenotypic and functional experiments to identify the role of ENO1 in adhesion, migration, and invasion, as well as in senescence and apoptosis. The experimental results were then validated in a mouse model. Results We observed a significant increase in the roughness of the cell membrane due to ENO1 silencing, a feature associated with an impaired ability to migrate and invade, along with a significant downregulation of proteins involved in cell-cell and cell-matrix adhesion, including alpha v/beta 3 integrin in shENO1 PDA cells. These changes impaired the ability of shENO1 cells to adhere to Collagen I and IV and Fibronectin and caused an increase in RGD-independent adhesion to vitronectin (VN) via urokinase plasminogen activator receptor (uPAR). Binding of uPAR to VN triggers integrin-mediated signals, which result in ERK1-2 and RAC activation, accumulation of ROS, and senescence. In shENO1 cancer cells, the use of an anti-uPAR antibody caused significant reduction of ROS production and senescence. Overall, a decrease of in vitro and in vivo cell migration and invasion of shENO1 PDA cells was observed. Conclusion These data demonstrate that ENO1 promotes PDA survival, migration, and metastasis through cooperation with integrins and uPAR. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0385-8) contains supplementary material, which is available to authorized users.

Background Metformin, a biguanide, is one of the most commonly prescribed treatments for type 2 diabetes and has recently been recommended as a potential drug candidate for advanced cancer therapy. Although Metformin has antiproliferative and proapoptotic effects on breast cancer, the heterogenous nature of this disease affects the response to metformin leading to the activation of pro-invasive signalling pathways that are mediated by the focal adhesion kinase PYK2 in pure HER2 phenotype breast cancer. Methods The effect of metformin on different breast cancer cell lines, representing the molecular heterogenicity of the disease was investigated using in vitro proliferation and apoptosis assays. The activation of PYK2 by metformin in pure HER2 phenotype (HER2+/ER−/PR-) cell lines was investigated by microarrays, quantitative real time PCR and immunoblotting. Cell migration and invasion PYK2-mediated and in response to metformin were determined by wound healing and invasion assays using HER2+/ER−/PR- PYK2 knockdown cell lines. Proteomic analyses were used to determine the role of PYK2 in HER2+/ER−/PR- proliferative, migratory and invasive cellular pathways and in response to metformin. The association between PYK2 expression and HER2+/ER−/PR- patients’ cancer-specific survival was investigated using bioinformatic analysis of PYK2 expression from patient gene expression profiles generated by the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) study. The effect of PYK2 and metformin on tumour initiation and invasion of HER2+/ER−/PR- breast cancer stem-like cells was performed using the in vitro stem cell proliferation and invasion assays. Results Our study showed for the first time that pure HER2 breast cancer cells are more resistant to metformin treatment when compared with the other breast cancer phenotypes. This drug resistance was associated with the activation of PTK2B/PYK2, a well-known mediator of signalling pathways involved in cell proliferation, migration and invasion. The role of PYK2 in promoting invasion of metformin resistant HER2 breast cancer cells was confirmed through investigating the effect of PYK2 knockdown and metformin on cell invasion and by proteomic analysis of associated cellular pathways. We also reveal a correlation between high level of expression of PYK2 and reduced survival in pure HER2 breast cancer patients. Moreover, we also report a role of PYK2 in tumour initiation and invasion-mediated by pure HER2 breast cancer stem-like cells. This was further confirmed by demonstrating a correlation between reduced survival in pure HER2 breast cancer patients and expression of PYK2 and the stem cell marker CD44. Conclusions We provide evidence of a PYK2-driven pro-invasive potential of metformin in pure HER2 cancer therapy and propose that metformin-based therapy should consider the molecular heterogeneity of breast cancer to prevent complications associated with cancer chemoresistance, invasion and recurrence in treated patients. Electronic supplementary material The online version of this article (10.1186/s13046-019-1221-0) contains supplementary material, which is available to authorized users.

Desmoid tumor is a fibroproliferative neoplasm with an intermediate malignancy and it can be localized in every bodily district: some locations are considered exceptional, like the urogenital localization. The Author point out a rare case of giant idiopathic scrotal fibromatosis that was found during an autopsy. A widower, that lived alone in poor hygienic conditions, was found dead in his house. The Judicial Authority ordered the autopsy, that was performed two days later at the Medico-Legal Section of Milan University. External examinations revealed only the considerable dimension of the scrotum (cm 24 × 41). The cause of death was fixed in a cardiac tamponade due to a natural heart laceration localized in correspondence of a transmural infarction. The toxicological exam resulted negative, while the histopathological and immunohistochemical analysis qualify the scrotal mass as a desmoids tumor. Due to the absence of predisposing conditions and of fibroproliferative infiltration in bladder and retroperitoneal space, the neoplasm was configured as an idiopathic desmoid tumor. The presented case gives the reason for the discussion concerning medico-legal aspects that are typical of rare neoplasms.

Deregulated Notch signaling is associated with T-cell Acute Lymphoblastic Leukemia (T-ALL) development and progression. Increasing evidence reveals that Notch pathway has an important role in the invasion ability of tumor cells, including leukemia, although the underlying molecular mechanisms remain mostly unclear. Here, we show that Notch3 is a novel target protein of the prolyl-isomerase Pin1, which is able to regulate Notch3 protein processing and to stabilize the cleaved product, leading to the increased expression of the intracellular domain (N3IC), finally enhancing Notch3-dependent invasiveness properties. We demonstrate that the combined inhibition of Notch3 and Pin1 in the Notch3-overexpressing human leukemic TALL-1 cells reduces their high invasive potential, by decreasing the expression of the matrix metalloprotease MMP9. Consistently, Pin1 depletion in a mouse model of Notch3-induced T-ALL, by reducing N3IC expression and signaling, impairs the expansion/invasiveness of CD4(+)CD8(+) DP cells in peripheral lymphoid and non-lymphoid organs. Notably, in in silico gene expression analysis of human T-ALL samples we observed a significant correlation between Pin1 and Notch3 expression levels, which may further suggest a key role of the newly identified Notch3-Pin1 axis in T-ALL aggressiveness and progression. Thus, combined suppression of Pin1 and Notch3 proteins may be exploited as an additional target therapy for T-ALL.

Objective: Pituitary macroadenomas (PAs) are usually defined as benign intracranial tumors. However, they may present local aggressive course. High Ki67 labelling index (LI) values have been related to an aggressive tumor behavior. A recent clinicopathological classification of PA based on local invasiveness and proliferation indexes, divided them in groups with different prognosis. We evaluated the utility of conventional MRI (cMRI) and diffusion-weighted imaging (DWI), in predicting the Ki67- LI according the clinicopathological classification. Methods: 17 patients (12 M and 5 F) who underwent surgical removal of a PA were studied. cMRI features, quantification of T1W and T2W signal intensity, degree of contrast uptake (enhancement ratio, ER) and apparent diffusion coefficient (ADC) values were evaluated by using a 3 T scan. Statistics included Mann–Whitney test, Spearman’s test, and receiver operating characteristic analysis. A value of p ≤ 0.05 was considered significant for all the tests. Results: Negative correlations were observed between Ki-67 LI, ADCm (ρ = - 0.67, p value = 0.005) and ER values (ρ = −0.62; p = 0.008). ER values were significantly lower in the proliferative PA group (p = 0.028; p = 0.017). ADCm showed sensitivity and specificity of 90 and 85% respectively into predict Ki67-LI value. A value of ADCm ≤0, 711 x 10–6 mm2 emerged as a cut-off of a value of Ki67-LI ≥ 3%. Conclusion: Adding quantitative measures of ADC values to cMRI could be used routinely as a non-invasive marker of specific predictive biomarker of the proliferative activity of PA. Advances in knowledge: Routinely use of DWI on diagnostic work-up of pituitary adenomas may help in establish the likely biological aggressive lesions.

Introduction: Metastatic spread in invasive lobular carcinoma (ILC) of breast mainly occurs in bones, gynecological organs, peritoneum, retroperitoneum, and gastrointestinal (GI) tract. Metastases to the GI tract may arise many years after initial diagnosis and can affect the tract from the tongue to the anus, stomach being the most commonly involved site. Clinical presentations are predominantly nonspecific, and rarely asymptomatic. CEA, CA 15–3, and CA 19–9 may be informative for symptomatic patients who have had a previous history of breast cancer. Case presentation: We introduce the case of asymptomatic colonic metastasis from breast carcinoma in a 67-year-old woman followed-up for Luminal A ILC. Diagnosis was performed through positron emission tomography/computed tomography (PET/CT) scan and contrast-enhancement spectral mammography (CESM), steering endoscopist to spot the involved intestinal tract and in ruling out further dissemination in the breast parenchyma. Conclusion: In colonic metastases, tumor markers might not be totally reliable. In asymptomatic cases, clinical conditions might be underappreciated, missing local or distant recurrence. CT and PET/CT scan might be useful in diagnosing small volume diseases, and steering endoscopist toward GI metastasis originating from the breast. CESM represents a tolerable and feasible tool that rules out multicentricity and multifocality of breast localization. Moreover, particular patients could tolerate it better than magnetic resonance imaging (MRI).

Background: A strong, reciprocal crosstalk between inflammation and melanoma has rigorously been demonstrated in recent years, showing how crucial is a pro-inflammatory microenvironment to drive therapy resistance and metastasis. Purpose: We investigated on the effects of Indicaxanthin, a novel, anti-inflammatory and bioavailable phytochemical from Opuntia Ficus Indica fruits, against human melanoma both in vitro and in vivo. Study Design and Methods: The effects of indicaxanthin were evaluated against the proliferation of A375 human melanoma cell line and in a mice model of cutaneous melanoma. Cell proliferation was assessed by MTT assay, apoptosis by Annexin V-Fluorescein Isothiocyanate/Propidium Iodide staining, protein expression by western blotting, melanoma lesions were subcutaneously injected in mice with B16/F10 cells, chemokine release was quantified by ELISA. Results: Data herein presented demonstrate that indicaxanthin effectively inhibits the proliferation of the highly metastatic and invasive A375 cells as shown by growth inhibition, apoptosis induction and cell invasiveness reduction. More interestingly, in vitro data were paralleled by those in vivo showing that indicaxanthin significantly reduced tumor development when orally administered to mice. The results of our study also clarify the molecular mechanisms underlying the antiproliferative effect of indicaxanthin, individuating the inhibition of NF-κB pathway as predominant. Conclusion: In conclusion, we demonstrated that indicaxanthin represents a novel phytochemical able to significantly inhibit human melanoma cell proliferation in vitro and to impair tumor progression in vivo. When considering the resistance of melanoma to the current therapeutical approach and the very limited number of phytochemicals able to partially counteract it, our findings may be of interest to explore indicaxanthin potential in further and more complex melanoma studies in combo therapy, i.e. where different check points of melanoma development are targeted.

Objective To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment. Design Electronic survey to ESE members Dec 2015–Nov 2016. Results Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4–79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%. Conclusion This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.

A previous genome-wide association study (GWAS) identified common variation at the BARD1 locus as being highly associated with susceptibility to high-risk neuroblastoma, but the mechanisms underlying this association have been not extensively investigated. Here, we performed a fine mapping analysis of BARD1 locus (2q35) using GWAS data from 556 high-risk neuroblastoma patients and 2,575 controls of European-American ancestry, and identified two independent genome-wide neuroblastoma-associated loci. Functional single-nucleotide polymorphism (SNP) prioritization identified two causative variants that independently contributed to neuroblastoma risk, and each replicated robustly in multiple independent cohorts comprising 445 high-risk cases and 3,170 controls (rs17489363: combined p = 1.07 × 10 −31 , OR:1.79, 95% CI:1.62–1.98 and rs1048108: combined p = 7.27 × 10 −14 , OR:0.65, 95% CI:0.58–0.73). Particularly, the T risk allele of rs17489363 in the canonical promoter region of full-length BARD1 altered binding site of the transcription factor HSF1 and correlated with low expression of full-length BARD1 mRNA and protein. Low-level expression of full-length BARD1 associated with advanced neuroblastoma. In human neuroblastoma cells, attenuating full-length BARD1 increased proliferation and invasion capacity. In conclusion, we have identified two potentially causative SNPs at the BARD1 locus associated with predisposition to high-risk neuroblastoma, and have shown that full-length BARD1 may act as tumor suppressor.

PURPOSE: To evaluate the oncological impact of postponing radical cystectomy (RC) to allow further conservative therapies prior to progression in a large multicentre retrospective cohort of T1-HG/G3 patients initially treated with BCG. METHODS: According to the time of RC, the population was divided into 3 groups: patients who did not progress to muscle-invasive disease, patients who progressed before radical cystectomy and patients who experienced progression at the time of radical cystectomy. Clinical and pathological outcomes were compared across the three groups. RESULTS: Of 2451 patients, 509 (20.8%) underwent RC. Patients with tumors > 3 cm or with CIS had earlier cystectomies (HR = 1.79, p = 0.001 and HR = 1.53, p = 0.02, respectively). Patients with tumors > 3 cm, multiple tumors or CIS had earlier T3/T4 or N + cystectomies. In patients who progressed, the timing of cystectomy did not affect the risk of T3/T4 or N + disease at RC. Patients with T3/T4 or N + disease at RC had a shorter disease-specific survival (HR = 4.38, p

Background: In this study we investigated the function of the non-catalytic region of tyrosine kinase adaptor protein 2 (NCK2) and its correlation with ITGB1 and ITGB4 integrins in driving ovarian cancer (OvCa) aggressiveness. We also evaluated whether NCK2 may influence prognosis in OvCa patients. Methods: Nanofluidic technology was used to analyze expression of NCK2 in 332 OvCa patients. To evaluate mRNA expression of NCK2, integrins and VEGFA in OvCa cell lines, qRT-PCR was performed. Stable NCK2 overexpression was obtained in OVCAR3. qRT-PCR and Western blot were performed to evaluate expression changes of VEGFA, vimentin, ITGB1, ITGB4, MMP2 and MMP9 under normoxia and hypoxia conditions. Coimmunoprecipitation (Co-IP) was performed in the A2780 cell line to study the interaction between NCK2 and proteins of interest. To investigate whether NCK2 can influence anchorage-independent growth, a soft agar assay was completed. Transwell invasion assay was performed on stable-transfected OVCAR-3 cell lines. Results: Nanofluidic data showed NCK2 can play an important role as a factor promoting tumor aggressiveness and survival in OvCa. This role was also linked to the behaviors of ITGB1 and ITGB4. Moreover, in cells overexpressing NCK2, the expression of vimentin, MMP2, MMP9, VEGFA and ITGB1, but not of ITGB4 was induced by hypoxia. Co-IP showed that NCK2 can directly bind ITGB1, but not VEGFA. NCK2 may be involved in mediating cell-extracellular matrix interactions in OvCa cells by influencing tumor aggressiveness. Conclusions: This study provides evidence of a possible role of NCK2 as biomarker of OvCa progression.

Background: Although the impact of oral hygiene on head and neck cancer risk has been investigated, few studies have been conducted among the Asian population. Methods: We conducted a multicenter case-control study to investigate this potential association. We performed unconditional multiple logistic regression models adjusted by potential confounders. Results: We observed an inverse association of frequency of dental visits with head and neck cancer risk, with an adjusted odds ratio (OR) of 3.70 (95% CI 2.51-5.45) for never dental visits compared with ≥1 time/year (Ptrend

Summary Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m 2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1–21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5–14·1) in the ipatasertib group and 10·2 months (6·0–13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8–9·0) with ipatasertib versus 4·9 months (3·6–5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37–0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6–9·1) with ipatasertib versus 3·7 months (1·9–7·3) with placebo (stratified HR 0·59, 95% CI 0·26–1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. Funding F Hoffmann-La Roche.

Background/aim Occult cancers' reported rates vary from 2-12% and serous tubal intraepithelial carcinomas (STICs) have been identified in 3-12% of the prophylactically removed tubes of women carrying a BRCA mutation. The aim of this study was to evaluate the incidence of tubal minor epithelial atypia (STIL), STIC, and occult invasive cancer and to evaluate the cancer-specific mortality in a prospective series of women at higher risk of ovarian and breast cancer undergoing risk-reducing salpingo-oophorectomy (RRSO) n a tertiary cancer center. Patients and methods A series of RRSO specimens (including endometrial biopsy) from women carrying a BRCA mutation, BRCA-unknown and BRCA-negative were collected between January 1998 and April 2016 at the Division of Gynecology at the European Institute of Oncology. Inclusion criteria were: asymptomatic women who had a negative gynecologic screening within 3 months prior to RRSO. Exclusion criteria were: women with ovarian/tubal cancer prior to RRSO. Results A total of 411 women underwent RRSO. Median age at RRSO was 47.0 years (range=32-70 years); 75.2% had a history of breast cancer. Fifteen women were diagnosed with an occult cancer (7 STIC, 4 invasive cancers, 2 breast cancers metastatic to the adnexa, 2 endometrial cancer) (3.6%). Sixteen showed a STIL (3.9%). When excluding cases with preoperative positive markers, the occult invasive cancer rate drops to 1.5%. Conclusion Our study, covering an 18-year period, shows a substantial low risk of occult cancer among a high-risk population of women undergoing RRSO. Our data still support the indication for RRSO in higher-risk patients. An endometrial biopsy should also be routinely obtained as it raises the chances of detecting occult endometrial cancers that may be otherwise missed.

Background Identification of factors associated with dismal survival after surgery in resectable pancreatic ductal adenocarcinoma is important to select patients for neoadjuvant treatment. The present meta-analysis aimed to compare the results of distal pancreatectomy for resectable adenocarcinoma of the pancreatic body-tail with and without splenic vessels infiltration. Methods A systematic search was performed of PubMed, Embase and the Cochrane Library in accordance with PRISMA guidelines. The inclusion criteria were studies including patients who underwent distal pancreatectomy for pancreatic cancer with or without splenic vessels infiltration. 5-year overall survival (OS) was the primary outcomes. Meta-analysis was carried out applying time-to-event method. Results Six articles with 423 patients were analysed. Patients with pathological splenic artery invasion had a worse survival compared with those without infiltration (Hazard ratio 1.76, 95% CI 1.36–2.28; P < 0.0001). A similar results was found when considering pathological splenic vessels infiltration, showing that survival was significantly poorer when splenic vein infiltration was present (Hazard ratio 1.51, 95% CI 1.19–1.93; P = 0.0009). Conclusions This meta-analysis showed worse survival for patients with splenic vessels infiltration undergoing distal pancreatectomy for pancreatic cancer. Splenic vessels infiltration represents the stigmata of a more aggressive disease, although resectable.

Chlamydia trachomatis is the most prevalent infection of the genital tract in women worldwide. C. trachomatis has a tendency to cause persistent infection and induce a state of chronic inflammation, which has been reported to play a role in carcinogenesis. We report that persistent C. trachomatis infection increases the expression of inflammatory tumour cytokines and upregulates molecular biomarkers such as podoplanin, Wilms' tumour gene 1 and osteopontin in primary cultures of mesothelial cells (Mes1) and human mesothelioma cells (NCI). Infection experiments showed that Mes1 and NCI supported the growth of C. trachomatisin vitro, and at an m.o.i. of 4, the inclusion-forming units/cell showed many intracellular inclusion bodies after 3 days of infection. However, after 7 days of incubation, increased proliferative and invasive activity was also observed in Mes1 cells, which was more evident after 14 days of incubation. ELISA analysis revealed an increase in vascular endothelial growth factor, IL-6, IL-8, and TNF-α release in Mes1 cells infected for a longer period (14 days). Finally, real-time PCR analysis revealed a strong induction of podoplanin, Wilms' tumour gene 1 and osteopontin gene expression in infected Mes1 cells. The aim of the present study was to investigate the inflammatory response elicited by C. trachomatis persistent infection and the role played by inflammation in cell proliferation, secretion of proinflammatory cytokines and molecular biomarkers of cancer. The results of this study suggest that increased molecular biomarkers of cancer by persistent inflammation from C. trachomatis infection might support cellular transformation, thus increasing the risk of cancer.

Purpose To assess the role of N-cadherin as a prognostic biomarker in patients with non–muscle-invasive bladder cancer (NMIBC) treated with transurethral resection with or without adjuvant intravesical therapy. Patients and methods Immunohistochemistry using monoclonal mouse antibody was used to evaluate the expression status of N-cadherin in 827 patients with NMIBC. N-cadherin was considered positive if any immunoreactivity with membranous staining was detected. Multivariable Cox regression models were performed to evaluate the prognostic effect of N-cadherin on survival outcomes. Results N-cadherin expression was observed in 333 patients (40.3%); it was associated with pT1 stage and high tumor grade (both were P

Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996–1007. ©2016 AACR.

Anaplastic seminoma (AS) is an uncommon histological variant of classical seminoma of the testis and account for 5%-15% of cases. It is poorly described in the scientific literature. We present the case of a 50-years-old homeless man presenting with fever, marked left scrotal hardness and a fungating left scrotal lesion. He underwent left orchiopexy 40 years before. A computed tomography with contrast media showed a suspect testis cancer with scrotal involvment, extensive intralesional necrosis and multiple systemic metastases. A wide excision of the left hemiscrotum including the testis was performed in order to prevent severe local and systemic infectious complications. Histological examination revealed an AS. General conditions showed a rapid deterioration and the patient died on post operative day 10.

Purpose Despite documented oncologic benefit, use of postoperative adjuvant radiotherapy (aRT) in patients with prostate cancer is still limited in the United States. We aimed to develop and internally validate a risk-stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Patient and Methods Our cohort included 512 patients with prostate cancer treated with radical prostatectomy at one of four US academic centers between 1990 and 2010. All patients had ≥ pT3a disease, positive surgical margins, and/or pathologic lymph node invasion. Multivariable Cox regression analysis tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk-stratification tool. Our study adhered to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for development of prognostic models. Results Overall, 21.9% of patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT versus initial observation ( P < .001). Pathologic T3b/T4 stage, Gleason score 8-10, lymph node invasion, and Decipher score > 0.6 were independent predictors of CR (all P < .01). The cumulative number of risk factors was 0, 1, 2, and 3 to 4 in 46.5%, 28.9%, 17.2%, and 7.4% of patients, respectively. aRT was associated with decreased CR rate in patients with two or more risk factors (10-year CR rate 10.1% in aRT v 42.1% in initial observation; P = .012), but not in those with fewer than two risk factors ( P = .18). Conclusion Using the new model to indicate aRT might reduce overtreatment, decrease unnecessary adverse effects, and reduce risk of CR in the subset of patients (approximately 25% of all patients with aggressive pathologic disease in our cohort) who benefit from this therapy.

Introduction Patients with clinical T4 (cT4) bladder cancer (BCa) infrequently undergo radical cystectomy (RC). We investigated the reliability of preoperative clinical staging, perioperative and survival outcomes in patients treated with RC due to cT4a-b BCa disease at a single tertiary care institution. Methods The study relied on 917 BCa patients treated with RC and pelvic lymph node dissection (PLND) at a single institution between January 1995 and December 2012. We compared the accuracy of the clinical assessment with final pathology results. Moreover, we evaluated perioperative outcomes, complication rates and survival after surgery. Results The median follow-up was 62 months. Overall, 74 (8.1%) patients presented cT4 stage at preoperative evaluation. Conversely, a pathological T4 disease was confirmed only in 68.9% patients staged initially as cT4. No differences were recorded in complications, 30 days readmission or 30 days death rates between cT1–T3 vs. cT4a vs. cT4b (p > 0.1). At multivariable Cox regression analyses predicting cancer specific mortality, clinical T4 stage vs. clinical T1–2, clinical T3 stage vs. clinical T1–2 and age were predictors of worst survival after RC (all p Conclusions We recorded poor concordance between preoperative imaging and pathology in cT4 patients. No differences in major perioperative outcomes and acceptable survival expectancies were reported in patients treated for cT4 disease.

Few data exist on stage migration in bladder cancer and trends in survival after radical cystectomy. We evaluated the changes in clinical, pathologic, and oncologic outcomes for patients treated with radical cystectomy for bladder cancer. In context, the body mass index and the presence of carcinoma in situ increased over the years and stage pT3-T4 bladder cancer disease decreased. An improvement in overall survival was reported for patients treated in recent years compared with historical controls. Introduction We evaluated the effect of the year of surgery on the clinical, pathologic, and oncologic outcomes of patients with bladder cancer (BCa) treated with radical cystectomy (RC) at a single institution. Materials and Methods The present study included 1253 consecutive patients with BCa treated with RC and extended pelvic lymphadenectomy at a single institution from January 1990 to December 2014. Analysis of variance and χ2trend tests were used to report the clinical and pathologic characteristics of the cohort over time. Multivariable Cox regression analysis was used to test the relationship between the year of surgery and recurrence, cancer-specific mortality (CSM) and overall mortality (OM). Results Considering the clinical characteristics, patient age (P = .1) and gender (P = .2) remained steady during the study period. In contrast, the body mass index (P < .005) increased. Also, of the pathologic features, carcinoma in situ detection (P < .001) showed an increasing rate, and pathologic stage T3-T4 (P = .005) showed a decreasing trend. The number of lymph nodes removed increased during the study period (P < .001), resulting in an increased number of positive nodes (P < .001). However, the rate of lymph node invasion (P = .1) remained stable in the overall population. Multivariable Cox regression analyses revealed the year of surgery as a predictor of recurrence (hazard ratio [HR], 0.97), CSM (HR, 0.97), and OM (HR, 0.98), with a slight, but constant, reduction in all survival outcomes (P < .04 for all). Conclusion Changes were recorded considering the patient and tumor characteristics across the previous 25 years. These variations directly reflect the differences in long-term survival expectations we recorded.

Background and purpose: The aim of this study was to perform a head-to-head comparison of the Roach formula vs. two other newly developed prediction tools for lymph node invasion (LNI) in prostate cancer, namely the Nguyen and the Yu formulas. Material and methods: We included 3115 patients treated with radical prostatectomy and extended pelvic lymph node dissection (ePLND), between 2000 and 2010 at a single center. The predictive accuracy of the three formulas was assessed and compared using the area-under-curve (AUC) and calibration methods. Moreover, decision curve analysis compared the net-benefit of the three formulas in a head-to-head fashion. Results: Overall, 10.8% of patients had LNI. The LNI-predicted risk was >15% in 25.5%, 3.4%, and 10.2% of patients according to the Roach, Nguyen and Yu formula, respectively. The AUC was 80.5%, 80.5% and 79%, respectively (all p > 0.05). However, the Roach formula demonstrated more favorable calibration and generated the highest net-benefit relative to the other examined formulas in decision curve analysis. Conclusions: All formulas demonstrated high and comparable discrimination accuracy in predicting LNI, when externally validated on ePLND treated patients. However, the Roach formula. showed the most favorable characteristics. Therefore, its use should be preferred over the two other tools. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Background: To assess the long-term patency of the biologic prosthetic conduit used for reconstruction of the superior vena cava (SVC) by magnetic resonance imaging (MRI). Methods: Patients undergoing oncologic resection and reconstruction of the SVC by a bovine pericardial prosthesis (January 2003 to April 2010) have been studied after 1 year (if surviving) by MRI for the assessment of the conduit long-term patency. Results were compared with those of a control group of patients with normal SVC. Blood flow and area of lumen section at 3 different levels (proximal, middle, distal) were analyzed. Results: Sixteen consecutive patients surviving after 1 year from surgery out of 17 (9 lung cancer, 8 mediastinal malignancy) undergoing SVC reconstruction were included. One patient died postoperatively and was not included. Sixteen patients with similar demographic characteristics were studied in the control group. Mean blood flow was 18.4 ± 3.5 mL/sec (range 14.3 to 25.7) in patients with reconstructed SVC and 20.8 ± 4.1 mL/sec (range 15.3 to 27.7) in the control group. Mean area of the conduit lumen section was 2.2 ± 0.6 cm2 (range 1.6 to 3.6) at proximal level, 2.9 ± 1.3 cm2 at middle level (range 1.3 to 5.7), and 2.1 ± 0.9 cm2 (range 0.5 to 4) at distal level in the reconstructed group, and 2.6 ± 0.7 cm2 (range 1.8 to 4.2), 2.7 ± 0.7 cm 2 (range 1.9 to 4.3), and 2.4 ± 0.3 cm2 (range 1.8 to 3.1), respectively, at proximal, middle, and distal levels in the control group. Differences between the 2 groups were not significant (p > 0.05). Conclusions: The MRI assessment in terms of blood flow and area of lumen section at 3 different levels confirms that bovine pericardial conduit used for SVC replacement shows an optimal patency over the long term. © 2013 by The Society of Thoracic Surgeons.

In renal cell carcinoma (RCC), lymph node status at preoperative imaging is affected by a non-negligible false-positive rate. We aimed to investigate which factors are related to a concordance between clinical suspicion and pathological confirmation of lymph node invasion (LNI). At a single tertiary care institution, 2954 RCC patients underwent either partial or radical nephrectomy. For the aim of the study, only clinically positive lymph node cases were included (cN1). Statistical analyses assessed the concordance between preoperative and pathological nodal status. Preoperative axial CT scans revealed 424 (14.4 %) patients showing at least one enlarged lymph node suspected for LNI (cN1). All lymphadenopathies were removed at surgery, and LNI was pathologically confirmed (pN1) in 122 patients (28.8 %). When focusing the analyses on clinical characteristics (variables known before surgery), metastases at diagnosis [OR 3.0 (95 %1.9–4.8), p

Background Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. Methods and Findings Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child–Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26–106 mo) and 39 mo for Taiwanese patients (interquartile range, 12–61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score ≤ 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2–3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4–5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score’s prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. Conclusions The ITA.LI.CA prognostic system includes both a tumor staging—stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)—and a prognostic score—integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations.

Objective: To validate the impact of lymphovascular invasion (LVI) on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) in a large multiinstitutional cohort. Material and methods: Retrospective data from 6,678 patients treated with a RP and bilateral lymphadenectomy for prostate cancer (PC) from 8 centers were collected. The primary endpoint was BCR. Results: Overall, 767 patients (11.5%) had LVI. Patients with LVI had significantly higher Gleason scores (P = 0.01). After a median follow-up of 28 months (interquartile range: 21-44), patients with LVI had a 1.66 fold increased risk of BCR (P

Purpose The aim of this study was to evaluate the overexpression of human epidermal growth factor receptor 2 (HER2) in patients with bladder cancer (BCa) and to assess its association with oncological outcomes. Methods This retrospective single-center study included 354 patients with BCa treated with radical cystectomy (RC). HER2 status was assessed with immunohistochemistry and scored according to HercepTest. Conditional survival and competing risk regression were performed to assess the association between HER2 expression and survival outcomes. Results HER2 was overexpressed in 36% of patients. HER2 overexpression was associated with features of tumor aggressiveness such as lymph-node metastases ( P = 0.002). At a median follow-up of 123 months (interquartile range: 79–180), 160 patients (45%) experienced disease recurrence, 263 patients (74%) died and 157 (44%) died of cancer. On multivariable analyses, HER2 overexpression was not significantly associated with any oncological outcomes. Adding HER2 status to a model for the prediction of survival outcomes did not change the accuracy of the model for any of the outcomes. Interestingly, HER2 status significantly affected late disease recurrence ( P = 0.05 for conditional survival at 24 months). Conclusions More than one third of RC patients overexpress HER2 in their tumors. HER2 overexpression was associated with features of biological and clinical aggressiveness. HER2 did not add prognostic significance to the standard established predictors of survival outcomes after RC. However, due to the high overexpression rate, it could represent a target for therapy in select advanced BCa tumors.

Objective Patients treated with radical cystectomy (RC) due to bladder cancer (BCa) face high risk of clinical recurrence. The aim of our study was to describe recurrence patterns and characteristics related to survival in patients treated with RC due to BCa. Methods Years 1992–2012 of a prospectively maintained institutional RC registry were queried for clinical localized urothelial BCa patients. Clinical recurrences were categorized as local, distant or secondary urothelial recurrences. Kaplan Meier analysis assessed time to cancer specific mortality (CSM). Multivariable Cox regression models were constructed to predict recurrence and CSM after recurrence. Results Data from 1110 patients with urothelial non-metastatic BCa at RC were analyzed with 7.5 years of median follow up. Overall, 324 patients experienced recurrence and 200 (61.7%) were single site recurrence. The locations were: 43 local (22 cystectomy bed and 21 pelvic lymph node dissection template), 138 distant (36 lung, 19 liver, 52 bone, 17 extra pelvic LN, 7 peritoneal, 4 brain and 3 others) and 19 secondary urothelial carcinoma (11 upper urinary tract, 8 urethra). Significant independent predictors of overall recurrence were pathological stage pT3/T4 vs. pT0-2, pathological N positive status and positive surgical margin. Median overall survival after recurrence was 18 months. At multivariate analysis, pathological T3 (Hazard ratio [HR]: 1.62), T4 (HR: 1.58), interval from RC to recurrence (HR: 0.92) and distant (HR: 2.57) recurrences were independently associated with CSM (all p Conclusions Overall, one out of three patients treated with RC face recurrence during follow up. Early and distant recurrences are associated with shortest survival expectancies.

A 3-year-old boy presented with an asymptomatic intertesticular mass increasing in size. Plasma tumor markers ( α -fetoprotein and β -human chorionic gonadotrophin) were negative. The mass had a pattern similar to testicular parenchyma but no discernable blood flow on scrotal Doppler ultrasound. Magnetic resonance imaging scan showed that it reached the posterior urethra after passing through the right corpus cavernosum with a progressive tapering extending into the pelvis. The mass was excised surgically and histologically found to be consistent with a dermoid cyst. Such rare benign lesions should be considered in the differential diagnosis of painless scrotal masses in children. Its anatomy was accurately defined by magnetic resonance imaging and was essential to minimize the risk to adjacent structures.