Prognostic significance of WNT and hedgehog pathway activation markers in cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) possesses distinct biology and peculiar natural history, in which the roles of the winged and hedgehog signalling pathways are unclear. MATERIALS AND METHODS: We constructed tissue microarrays and studied the immunohistochemical (IHC) expression of ß-catenin, smoothened (SMO) and the transcription factors TCF, LEF, GLI1 in 87 CUP cases for prognostic significance. RESULTS: A low rate of IHC expression of proteins was seen, the cut-off used being any expression in ≥ 1% of tumour cells. At univariate analysis, only nuclear IHC SMO expression displayed a statistically significant association with favourable outcome [median Overall survival (OS) of 19 months in SMO-positive vs. 12 months in SMO-negative cases, P = 0·01]. An activated Wnt pathway, defined as IHC expression of any of nuclear ß-catenin, TCF and LEF, was significantly associated with favourable progression free survival (median 9 vs. 5 months, P = 0·037) and OS (median 19 vs. 13 months, P = 0·04). This prognostic impact on OS was mainly driven by nuclear expression of TCF and/or LEF (P = 0·03). No prognostic significance of the hedgehog pathway activation status, defined as IHC expression of SMO or nuclear GLI1, could be established. A favourable prognostic impact of the concurrent activation of both pathways was observed. A trend for association of activated Wnt with response to chemotherapy (responders 67% among activated Wnt cases vs. 35% among nonactivated Wnt cases, P = 0·07) was observed in CUP adenocarcinomas. CONCLUSIONS: Activation of the Wnt pathway was a positive prognostic factor in a small CUP series, possibly via enhanced chemosensitivity. Independent validation is warranted.

The shape and the thickness of the anterior cruciate ligament along its length in relation to the posterior cruciate ligament: a cadaveric study.

PURPOSE: The purpose of this study was to evaluate the shape of the native anterior cruciate ligament (ACL) along its length in relation to the posterior cruciate ligament (PCL) and compare it with the size of the 3 commonly used autografts (bone-patellar tendon-bone [BPTB], single-bundle hamstring, and double-bundle hamstring). METHODS: With the knee in extension, we filled the intercondylar notch with paraffin, fixing the cruciate ligaments in their natural position, in 8 cadaveric specimens. The ACL-PCL tissue specimen, embedded in paraffin, was removed en bloc. Gross sections were prepared in the coronal plane and were evaluated histologically. The width, thickness, and cross-sectional area of both the ACL and PCL were determined. The dimensions of the semitendinosus tendon (ST), gracilis tendon (GT), and BPTB grafts were measured and compared with those of the native ACL. RESULTS: The PCL occupies the largest part of the intercondylar area, leaving only a small space for the ACL in knee extension. The ACL midsubstance has a width of 5 mm, resembling a band shape. Only before its tibial insertion does the ACL fan out and take the form of its tibial attachment. The BPTB graft has a thickness of 5.8 mm, whereas the ST and GT grafts have a thickness of 6.25 mm and 4.5 mm, respectively, and are comparable to the midsubstance of the ACL but undersized in the tibial insertion (P = .0016 for BPTB graft, P = .002 for ST graft, and P = .0003 for GT graft). A quadruple-looped ST-GT graft, with a diameter of 8 mm, is oversized in the midsubstance (P = .0002) but fits better in the tibial attachment. CONCLUSIONS: The ACL midsubstance has a width of 5 mm, resembling a band shape. Before its tibial insertion, the ACL fans out like a trumpet, taking the form of its wide tibial attachment. CLINICAL RELEVANCE: The dimensions of the native ACL have to be considered in graft selection for anatomic ACL reconstruction.

Can circulated lung cancer cells pass to the urine without apparent urine tract metastases? A single centre series.

Urine cytology has been a useful tool for the diagnosis of urinary tract malignancies. However, the presence of tumor cells in the urine sediment without an obvious urothelial metastatic deposit is a rare phenomenon and in patients with lung cancer has never been reported. We present five cases with metastatic lung cancer and positive urine cytology. The possible mechanisms underlining this phenomenon and its implications are discussed.

Associations of angiogenesis-related proteins with specific prognostic factors, breast cancer subtypes and survival outcome in early-stage breast cancer patients. A Hellenic Cooperative Oncology Group (HeCOG) trial.

Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 µm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values <0.05), with the exception of the one between VEGF-C and VEGFR1 (chi-square test, p = 0.15). Tumors with high VEGF-A protein expression, as compared to tumors with low expression were more frequently ER/PgR-negative (33.3% vs. 20.8%, chi-square test, p = 0.009) and HER2-positive (44.8% vs. 20.6%, p<0.001). In addition, tumors with high VEGFR1 expression, were more frequently HER2-positive (32.8% vs. 19.6%, p<0.001), while tumors with high VEGFR3 expression were more frequently ER/PgR-negative (24.9% vs. 17.0%, p = 0.024) and HER2-positive (26.9% vs. 14.8%, p = 0.001). High VEGF-A and VEGF-C protein expression was associated with increased DFS in the entire cohort (HR = 0.57, 95% CI 0.36-0.92, Wald's p = 0.020 and HR = 0.71, 95% CI 0.52-0.96, p = 0.025, respectively), as well as in specific subtypes/subgroups, such as HER2-positive (VEGF-A, HR = 0.32, 95% CI 0.14-0.74, p = 0.008) and triple-negative (VEGF-C, HR = 0.44, 95% CI 0.21-0.91, p = 0.027) patients. High vs. low VEGFR1 expression was an unfavorable factor for DFS in triple-negative patients (HR = 2.74, 95% CI 1.26-5.98, p = 0.011), whereas the opposite was observed among the ER/PgR-positive patients (HR = 0.69, 95% CI 0.48-0.98, p = 0.041). Regarding OS, high VEGF-C protein expression was associated with increased OS in the entire cohort (HR = 0.64, 95% CI 0.46-0.89, Wald's p = 0.008), as well as in in specific subtypes/subgroups, such as ER/PgR-negative (HR = 0.37, 95% CI 0.20-0.71, p = 0.003) and triple-negative (HR = 0.42, 95% CI 0.19-0.90, p = 0.026) patients. In conclusion, high expression of angiogenesis-related proteins is associated with adverse clinicopathological parameters in early-stage breast cancer patients and may be surrogate markers of biologically distinct subgroups of ER/PgR-negative or triple-negative tumors with superior outcome. Further validation of our findings in independent cohorts is needed.

Global profiling of EGFR gene mutation, amplification, regulation and tissue protein expression in unknown primary carcinomas: to target or not to target?

INTRODUCTION: Epidermal growth factor receptor (EGFR) signalling contributes to malignant transformation and survival. We studied molecular predictors of benefit from EGFR-modulating therapies in patients with cancer of unknown primary (CUP). MATERIALS AND METHODS: Tumours from paraffin-embedded biopsies of 50 patients with CUP were stained for EGFR protein by immunohistochemistry. Polymerase chain reaction amplification, single-strand conformational polymorphism and direct sequencing were used to study EGFR intron 1 cytosine-adenosine (CA) repeat length as well as exon 18, 19, 21 activating mutations and amplification. RESULTS: Thirty-seven tumours (74%) expressed EGFR protein but only six (12%) strongly. Regarding intron 1 CA repeat length, we detected five alleles with CA repeat numbers 16-20, allele 16 being the most common (39%). All samples were heterozygous, the commonest genotype consisting of 16/18 dinucleotides (78%). Five samples had three intron 1 alleles and were associated with EGFR overexpression in 40% of cases. There was no evidence of EGFR exon 18, 19, 21 amplification. Two mutations were detected: Exon 21 2508 C > T, a silent nucleotide polymorphism (R836R) and a G > A substitution in sequences flanking exon 19 (IVS19 + 24G > A) resulting in aberrant mRNA splicing. Neither EGFR protein expression nor CA repeat length were prognostic factors for survival. CONCLUSIONS: Our data depict absence of molecular predictors of benefit from EGFR modulation in patients with CUP. Study of its molecular pathophysiology and targeting other molecular pathways may be warranted instead.

Prognostic significance of HER-2, p53 and Bcl-2 in patients with epithelial ovarian cancer.

BACKGROUND: Several oncogenes and onco-suppressor genes have been implicated in epithelial ovarian carcinogenesis, but their clinical significance is not clear and conflicting data have been found in various studies. PATIENTS AND METHODS: The immunohistochemical expression of HER-2, p53 and Bcl-2 proteins was investigated in a cohort of 95 patients with advanced epithelial ovarian cancer (stages IIc-IV). These patients participated in a phase III randomized clinical trial and were treated either with paclitaxel/carboplatin, orpaclitaxel/carboplatin alternating with paclitaxel/cisplatin. RESULTS: Positive immunostaining for HER-2, p53 and Bcl-2 proteins was found in 18%, 70.5% and 69.5% of the cases, respectively. In multivariate analysis, older patients (< 63 vs. > or = 63 years, p < 0.001), worse grade (I-II vs. III, p = 0.04) and p53 expression (negative vs. positive, p = 0.002) were significant prognostic factors independently associated with survival. CONCLUSION: p53 status along with age and grade appear to be independent prognostic factors for survival in patients with epithelial ovarian cancer.

Subcutaneous metastasis of peritoneal mesothelioma diagnosed by fine-needle aspiration.

Mesothelioma is a rare malignant neoplasm of the serosal membranes, which can give distant metastases in various organs in advanced stages of its course. Subcutaneous tissue is an unusual metastatic site. In the literature, only one case of metastatic mesothelioma to the skin of the face has been reported. We present a case of a 60-year-old female with a prior history of peritoneal malignant mesothelioma, who 6 months after the initial diagnosis presented with a subcutaneous nodule in the lateral chest wall. Cytological examination of the material obtained by FNA from the nodule revealed metastatic mesothelioma. Although subcutaneous metastasis of malignant mesothelioma is a rare entity, one must always keep this possibility in mind and proceed to further investigation of such lesions. In these cases, FNA is a simple diagnostic procedure for the identification of metastatic disease in patients with a prior history of malignancy.

The expression levels of JunB, JunD and p-c-Jun are positively correlated with tumor cell proliferation in diffuse large B-cell lymphomas.

We analyzed the expression of Jun family in relation to CD30 expression, cell proliferation and B-cell differentiation immunophenotypes [Germinal Center and non-Germinal Center] in diffuse large B-cell lymphomas (DLBCL). Expression and high expression of phosphorylated-c-Jun (p-c-Jun), JunB, JunD and CD30 (cut-off scores 20% and 50%, respectively) was found in 18/103, 49/103, 72/101 and 26/102 cases, respectively, and in 6/103, 27/103, 60/101 and 21/102 cases, respectively. The following significant positive correlations were observed: (a) JunB with cyclin A (p = 0.046), cyclin B1 (p = 0.033), cyclin E (p = 0.003), MUM-1 (p = 0.002) and CD30 (p < 0.001), (b) JunD with Ki67 (p = 0.002) and cyclin E (p = 0.014), (c) p-c-Jun with CD30 (p = 0.015), and (d) high p-c-Jun with cyclin A (p = 0.034). The positive correlation between expression of JunB, JunD and p-c-Jun and tumor cell proliferation in DLBCL, suggests that increased JunB, JunD and p-c-Jun expression may be involved in the pathogenesis of DLBCL by increasing tumor cell proliferation.

Intrapericardial drug delivery: pharmacologic properties and long-term safety in swine.

BACKGROUND: Intrapericardial drug delivery is a promising new technique, but the pharmacologic properties of various agents delivered via this route are not known. Furthermore, the long-term safety of intrapericardial catheters has not been previously examined. METHODS: Using a pericardial access device, a catheter connected to a drug-delivery system was implanted in five pigs. Plasma levels and electrocardiographic measurements were obtained after intravenous and intrapericardial administration of digoxin and procainamide. Histological examination was performed after the device had been implanted for a total of 6 months. RESULTS: The QTc interval did not change significantly after digoxin or procainamide intravenous administration. QTc decreased by 47+/-23 ms (p=0.046) 8 h after digoxin intrapericardial administration and increased by 128+/-60 ms (p=0.002) 1 h after procainamide intrapericardial administration. The QRS duration did not change significantly after intravenous administration of either agent, but it increased by 17+/-9 ms (p=0.004) 1 h and by 15+/-4 ms (p=0.01) 8 h after procainamide intrapericardial administration. After intravenous procainamide the RR interval decreased, but it did not change significantly after intrapericardial administration of either agent. Histology showed moderate inflammatory infiltration and fibrosis adjacent to the catheter. CONCLUSIONS: Intrapericardial delivery of digitalis and procainamide produces unique electrophysiological properties. In contrast to satisfactory success of the implantation technique, long-term dwell of the catheter in the pericardium induces moderate, albeit probably clinically significant, fibrosis.

An unusual presentation of a patient with advanced prostate cancer, massive ascites and peritoneal metastasis: Case report and literature review.

We describe the case of a patient with prostate cancer, ascites, omental and bone metastases, an extremely rare clinical variant that warrants further investigation, and review the relevant literature.

Superiority of early relative to late ischemic preconditioning in spinal cord protection after descending thoracic aortic occlusion.

OBJECTIVE: We previously showed that ischemic preconditioning significantly reduced spinal cord injury caused by 35-minute aortic occlusion. In this study we investigated the effect of ischemic preconditioning on spinal cord injury after 45-minute aortic occlusion. METHODS: Thirty-two pigs were divided as follows: group 1 (n = 6) underwent sham operation, group 2 (n = 6) underwent 20 minutes of aortic occlusion, group 3 (n = 6) underwent 45 minutes of occlusion, group 4 (n = 6) underwent 20 minutes of occlusion and 48 hours later underwent an additional 45 minutes, and group 5 (n = 8) underwent 20 minutes of occlusion and 80 minutes later underwent an additional 45 minutes. Aortic occlusion was accomplished with two balloon occlusion catheters placed fluoroscopically after the origin of the left subclavian artery and at the aortic bifurcation. Neurologic evaluation was by Tarlov score. The lower thoracic and lumbar spinal cords were harvested at 120 hours and examined histologically with hematoxylin-eosin staining. The number of neurons was counted, and the inflammation was scored (0-4). Statistical analysis was by Kruskal-Wallis and 1-way analysis of variance tests. RESULTS: Group 5 (early ischemic preconditioning) had better Tarlov scores than group 3 ( P < .001) and group 4 (late ischemic preconditioning, P < .001). The histologic changes were proportional to the Tarlov scores, with the least histologic damage in the animals of group 5 relative to group 3 (number of neurons P < .001, inflammation P = .004) and group 4 (number of neurons P < .001, inflammation P = .006). CONCLUSION: Early ischemic preconditioning is superior to late ischemic preconditioning in reducing spinal cord injury caused by the extreme ischemia of 45 minutes of descending thoracic aortic occlusion.

Early ischemic preconditioning without hypotension prevents spinal cord injury caused by descending thoracic aortic occlusion.

OBJECTIVE: Postoperative neurologic deficits after thoracic aortic reconstruction vary widely. Our previous study showed that delayed ischemic preconditioning could prevent spinal cord injury caused by occlusion of the descending thoracic aorta in pigs. We investigated early ischemic preconditioning in the same model. METHODS: Twenty-eight pigs were divided into 4 groups: group 1 (n = 6) underwent a sham operation, group 2 (n = 6) underwent aortic occlusion for 20 minutes, group 3 (n = 8) underwent aortic occlusion for 35 minutes, and group 4 (n = 8) underwent aortic occlusion for 20 minutes and underwent aortic occlusion 80 minutes later without hypotension for 35 minutes. Aortic occlusion was accomplished by using 2 balloon occlusion catheters placed fluoroscopically at T6 to T8 above the diaphragm and at the aortic bifurcation. Neurologic evaluation was performed by an independent observer according to the Tarlov scale (0-4). The lower thoracic and lumbar spinal cords were harvested at 120 hours and examined histologically with hematoxylin-and-eosin stain. Histologic results (number of neurons and grade of inflammation) were scored (0-4) and were similarly analyzed. Statistical analysis was by means of the Kruskal-Wallis test. RESULTS: Group 4 had a better neurologic outcome at 24, 48, and 120 hours in comparison with group 3 (P <.001). The histologic changes were proportional to the neurologic test scores, with the more severe and extensive gray matter damage in animals of group 3 (number of neurons, P <.001; grade of inflammation, P <.001). CONCLUSION: Early ischemic preconditioning without hypotension protects against spinal cord injury after aortic occlusion, as confirmed by using the Tarlov score and histopathology.

The natural history of HPV infection of the uterine cervix. Long-term observational and histological data.

BACKGROUND: To investigate the natural history of HPV infection of the uterine cervix following a 10-year prospective observational study. PATIENTS AND METHODS: Three hundred and thirty women with cytological and colposcopic features of HPV infection +/- CIN 1 were recruited into the study. These women were followed up for a period of 10 years, during which time they had repeated colposcopic assessments and cytological monitoring Those women with evidence of high-grade disease at any stage of follow-up were treated by Large Loop excision of the transformation zone (LLETZ) and excluded from the study. At the end of the surveillance period, 179 women with evidence of persistent HPV infection alone or in conjunction with low-grade disease underwent a shallow diagnostic LLETZ. In total, 51 women defaulted from follow-up. RESULTS: Thirty-three per cent of the women with cytological and colposcopic features suggestive of persistent HPV infection alone during the 10-year follow-up period had histological evidence of CIN at the end of the study. Two thirds of this disease was graded as CIN 2 or 3. Nineteen per cent of the women with cytological and colposcopic features suggestive of persistent HPV infection and CIN 1 actually had high-grade CIN at histology (CIN 2 and 3). Only 6.1% of the study population had normal histological findings. CONCLUSION: The finding that a relatively large percentage of high-grade lesions might have been masked for anything up to a decade by a low-grade phenotype, coupled with the worrying percentage of defaulters from follow-up, indicate that an early decision for intervention (diagnostic and/or therapeutic) may be appropriate if a low-grade abnormality persists after a short surveillance period.

The contribution of aqueous humor cytology in the differential diagnosis of anterior uvea inflammations.

BACKGROUND: Cytology of the aqueous humor can confirm the diagnosis of many intraocular conditions by revealing inflammatory cells, ghost red cells, lens material, and microorganisms. PURPOSE: The purpose of this study was to emphasize the contribution of aqueous humor fine needle aspiration cytology in cases where there is a clinical diagnostic dilemma whether an infectious or a noninfectious inflammatory process of the uvea is present. METHODS: Collection of 0.15-0.2 ml aqueous humor was carried out with an insulin needle. The aspirated aqueous was then prepared for examination using either the Cytospin or the Thin-Prep technique and smears were stained with modified Papanikolaou and May-Grünwald-Giemsa stains. RESULTS: Cytology of the aqueous humor essentially facilitated the differential diagnosis in 16 cases with an anterior uveal inflammation clinical picture. The cases included phacoanaphylactic endophthalmitis (n = 6), chronic postoperative bacterial endophthalmitis (n = 3), phacolytic glaucoma (n = 2), ghost cell glaucoma (n = 2), metastatic endophthalmitis (n = 1), post-traumatic lenticular abscess (n = 1), and iridocyclitis (n = 1). Treatment of the cases was successful. CONCLUSIONS: In selected cases, cytology of the aqueous humor reveals specific, with regard to the clinical entity, cell populations and other elements and thus contributes effectively to the differential diagnosis and therapeutic approach to some anterior uvea inflammations.

Fine-needle aspiration of secondary malignancies of the penis: a report of three cases.

Metastatic malignancy to the penis is an uncommon clinicopathologic entity, with only 300 cases reported since 1870. Of the reported cases, 75% were secondary to genitourinary primary tumors. Priapism is the most frequent symptom, although dysuria, ulceration, and node formation have also been described. We report three cases of penile metastatic involvement from primary tumors in the urinary bladder (two cases) and prostate (one case), respectively. Fine-needle aspiration (FNA) cytology from the penile nodules was performed in each case. The smears in all cases were highly cellular, and atypical neoplastic cells were observed singly, in clusters, or in papillary formations. The cells were pleomorphic with hyperchromatic nuclei and prominent nucleoli. Immunocytochemistry was performed for keratin 8 and 18 and prostatic-specific antigen (PSA). In conclusion, although it has rarely been used as a diagnostic tool, FNA of the penis can be proved effective and safe in diagnosing a suspected secondary malignancy.

A rare case of primary malignant melanoma of the scrotum diagnosed by fine-needle aspiration.

We report a case of a 55-yr-old man with malignant melanoma of scrotum. He was referred to our Hospital with a complaint of gradual focal enlargement of the scrotum in a period of 3 yr. On physical examination, a pigmented, poorly marginated mass, with central necrosis was observed. A fine-needle aspiration (FNA) of the lesion was performed. Cytological examination revealed highly cellular smears, containing malignant cells, dispersed or arranged in loose aggregates. Cellular morphology and characteristics were identical to those of malignant melanoma arising elsewhere in the skin. The immunocytochemical study revealed positivity of neoplastic cells for anti-melanoma monoclonal antibody (HMB-45) antigen. Histological confirmation finally was provided after wide excision of the lesion. We emphasize the difficulties in differential diagnosis considerations and diagnostic pitfalls of scrotal lesions.

Relapsing Episodes of Loss of Consciousness in a Patient With Hepatocellular Carcinoma.

Hypoglycemia is common in people with diabetes treated with insulin or oral medications such as sulphonylureas or other secretagogues, and constitutes a relatively rare paraneoplastic syndrome in patients with a variety of mesenchymal or epithelial tumors. In this case report we present a 51-year-old patient with metastatic hepatocellular carcinoma and persistent, severe, symptomatic hypoglycemia and we discuss management options and review the relevant medical literature.

Evaluation of current prognostic and predictive markers in breast cancer: a validation study of tissue microarrays.

BACKGROUND: Tissue microarrays (TMAs) are an attractive alternative to analysis of whole sections (WS). For breast carcinomas, the recent recommendations for cut-offs (i.e. Ki67, H-score) have necessitated the re-evaluation of TMAs. MATERIALS AND METHODS: TMA results of immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) testing for Estrogen receptors (ER), Progesterone receptors (PgR), Ki67 and HER2 were compared against the results of WS for 88 breast carcinomas. RESULTS: We found excellent agreement between the two methods for ER and PgR IHC evaluation, using the H-score (Kappa coefficient 0.972 and 0.9, respectively). There was also excellent correlation for HER2 IHC (Kappa coefficient 1) and amplification (Kappa coefficient 0.933). Furthermore, scoring of Ki67 was highly-correlated between TMAs and WS (Kappa coefficient 0.954). The latter excellent correlation has not, to our knowledge, been previously reported. CONCLUSION: For breast cancer, TMAs are an efficient and reliable alternative to the use of WS, using the currently recommended markers, evaluation protocols and cut-off values.

Global microRNA profiling in favorable prognosis subgroups of cancer of unknown primary (CUP) demonstrates no significant expression differences with metastases of matched known primary tumors.

No data exist on biologic differences between Cancer of unknown primary (CUP) and metastatic solid tumors of known primary site. We assigned a primary tissue of origin in 40 favorable CUP patients (A: serous peritoneal carcinomatosis n = 14, B: axillary adenocarcinoma n = 8, C: upper squamous cervical adenopathy n = 18) by means of a 64-microRNA assay. Subsequently, we profiled the expression of 733 microRNAs (miRs) in the CUP cases and compared results with metastases from 20 ovarian carcinomas, 10 breast adenocarcinomas, 20 squamous head neck or lung tumors. In the Peritoneal CUP versus Ovarian (Known Primary Metastases) KPM comparison, a total of 12 miR were significantly differentially expressed: higher than twofold expression difference in CUP was seen only for miR-513a-5p (3.7-fold upregulated) and miR-483-5p (2.5-fold upregulated), while miR-708 exhibited a twofold downregulation. In the Breast CUP versus Breast KPM comparison, only miR-29c that were downregulated in CUP by 2.7-fold satisfied the FDR threshold. miR-30e and miR-27b, downregulated in ovarian CUPs versus KPMs, were also non-significantly downregulated in breast CUP by 2.0- and 1.4-fold respectively. Six miRs, which belong to the 17-92 oncocluster showed a trend of upregulation in Breast CUP versus Breast KPM cases. A CUP signature remains elusive.