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Metallothioneins (MTs) are phylogenetically old cysteine-rich proteins, which are implicated in a variety of physiological and pathological processes. Their growth-regulating, anti-apoptotic and anti-inflammatory functions have been attributed not only to intracellular free radical scavenging and to zinc and copper regulation but also to the ability of secreted MT to bind on surface lipoprotein receptor-megalin/LRP2, which enables the endocytosis of MT-I/II and a wide range of other functionally distinct ligands. In the present study, we analysed the expression pattern of both proteins in 55 cases of premalignant transformation of cervical squamous cells, i.e. in low- and high-grade squamous intraepithelial lesion (LSIL and HSIL). The data showed that in LSIL (cervical intraepithelial neoplasia CIN1; N = 25) MTs were present only in basal and parabasal cells and that megalin was only weakly expressed. In HSIL (CIN2; N = 15 and CIN 3/carcinoma in situ; N = 15), however, overexpression and co-localization of MT with megalin were found in the entire hyperplastic epithelium. Moreover, megalin immunoreactivity appeared on the glandular epithelium and vascular endothelium, as well as on lymphatic cells in stroma. Besides, multiple megalin-positive cells expressed phosphorylated Akt1, implying that MT- and/or megalin-dependent prosurvival signal transduction pathways might contribute to the development of severe cervical dysplasia. The data emphasize the diagnostic power of combined MT/megalin analysis in pre-cancer screening.

Hodgkin lymphoma (HL) is an uncommon malignancy usually limited to the lymph nodes and lymphatic system while extranodal involvement is much less common than in non-Hodgkin lymphoma. The current report presents an unusual case of primary classical HL (cHL), nodular sclerosis type with mixed cellularity in buttock soft tissue of 78-year old man. Primary lymphoma of the gluteal muscle is a rare disease and primary cHL is even rarer. In addition, to this unusual extranodal presentation, the present case highlight a diagnostic challenge in fine-needle biopsy masquerading a low grade sarcoma, primarily myxoinflammatory fibrosarcoma or an inflammatory lesion. However, surgical biopsy and immunohistochemistry guided correct diagnosis that was of major interest for further successful treatment.

The majority of endometrial carcinoma are diagnosed at an early stage and exhibit a favorable prognosis. However, 10% to 15% of ECs recur and the majority are type II tumors which are high-grade carcinomas. The epithelial-mesenchymal transition (EMT) has been considered as a fundamental step for the development of the invasive phenotype of cancer cells. During EMT, many of epithelial surface markers, primarily E-cadherin disappear, and mesenchymal markers including N-cadherin gain. This feature resides predominantly at the invasive front (IF) of the tumor. Therefore, we examined the immunohistochemical expression of E-cadherin and N-cadherin at the IF, in central areas of the tumor and lymphovascular space, in type I and type II endometrial carcinoma. The association of each protein with the clinicopathologic features was also evaluated. Our results confirmed a stronger E-cadherin immunostaining in type I tumors indicating that the loss of E-cadherin may be responsible for a more aggressive behavior of type II ECs. In both types, E-cadherin was strongly expressed in central areas and the reactivity decreased toward the IF. On contrary, N-cadherin was overexpressed at the IF confirming an inverse relationship between these markers. In addition, a decrease in E-cadherin expression was observed in cells within the lymphovascular space. Downregulation of E-cadherin was associated only with high-grade tumors while no correlations between both markers and other clinicopathologic features were found. Our results confirm that EMT occurs at the IF that represents a critical interface between the tumor and the host.

The aim of this report is to present a case of a patient with a recurrent nasal cavity amelanotic melanoma (AM), with emphasis on diagnosis and therapy options of this clinical entity. A 65-year-old female patient presented with pain in the right cheek region and nasal obstruction. In 2013, she was diagnosed with mucosal melanoma (MM) of the left nasal cavity. After endoscopic surgery and radiotherapy, the patient was followed by the oncology team. Five years after the initial diagnosis, rhinoscopy showed a tumorous formation in the right nasal cavity. The tumor mass was without black discoloration and was the same color as the surrounding nasal mucosa. Microscopic examination after biopsy of the tumor confirmed amelanotic MM. The patient underwent an additional endoscopic surgery. A complete standard diagnostic workup for MM found metastases in head and neck lymph nodes, on both sides. MMs of head and neck are uncommon malignancies. Unique biology of MM cells causes a high rate of recurrences. This report presents an example of recurrent AM of the nasal cavity, in treatment with checkpoint inhibitor (pembrolizumab), which could provide a good therapy option for patients with MM., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest.

Simultaneous occurrence of T-cell and B-cell neoplasms is rare, and etiologic relationships between these 2 malignancies are poorly understood. We describe the case of a 66-year-old woman who was admitted to the hospital because of fever, hemoptysis, lymphadenopathy, and skin rash. Enlarged lymph nodes in axillary, pectoral, paratracheal, and periportal regions as well as slight hepatomegaly and splenomegaly were confirmed. A peripheral blood smear revealed rouleaux formation and numerous circulating plasma cells, with plasmacytoid lymphocytes. Immunofixation-electrophoresis detected a monoclonal band defined as immunoglobulin (IgG)-lambda light chains with broad-band polyclonal IgA. The patient died from abrupt splenic rupture before diagnostic work-up was finished. Postmortem examination revealed infiltration of atypical lymphoid cells exhibiting high proliferative activity admixed with typical and atypical plasma cells in several organs. Thus, plasma cell leukemia (IgG-lambda) as a rare and aggressive variant of plasma cell myeloma in the present case was associated with aggressive peripheral T-cell lymphoma and polyclonal (IgA) plasmacytosis.

Objective: The aim of the present study was to correlate the level of tumor-infiltrating immune cells with bladder cancer size and T category in patients with solitary low-grade non-muscle invasive bladder cancer (NMIBC)., Patients and Methods: Between 1996 and 2006, 115 patients with solitary low-grade NMIBC after transurethral resection of the bladder without adjuvant therapy were retrospectively identified from the institutional database. Tumor specimens were retrieved and tissue microarrays were constructed. Immunhistochemical staining for tumor-infiltrating immune cells with anti-CD3, CD4, CD8, CD20, CD56, CD68, and granzyme B (Gr B) was performed., Results: Immune cells were predominantly observed within the cancer stroma. Statistically significant higher levels of CD56 cells in small tumors and CD68 cells in T1 tumors (p = 0.0310, 0.0151, respectively) were established., Conclusion: The current study propose a possible correlation of CD56+ and CD68+ cells with bladder cancer size and stage in patients with solitary low-grade NMIBC.

Imperforate hymen is a congenital anomaly of female external genitalia, which is mostly diagnosed in puberty, at the age of 9-13 years, or very rarely at a younger age. Clinical picture varies from abdominal pain and low back pain to acute urinary retention. We describe a case of a 16-month-old female infant where the imperforate hymen presented as a vaginal cyst. The cyst was first observed by the patient's mother, although the child had been examined by a paediatrician on several occasions after birth. Complete workup performed for differential diagnosis, mostly to exclude other reproductive system anomalies, led to the final diagnosis of imperforate hymen. The aim of this report is to emphasise the necessity of thorough examination of genitalia in female newborns in order to avoid possible complications associated with this diagnosis later in life, as well as other, more severe differential diagnostic anomalies., (© The Author(s) 2015.)

A case of a 41-year-old woman with a history of nodular melanoma (NM), associated with an indurated dome-shaped blue-black nodule with a diameter of 1.2 cm in the gluteal region, is presented. Clinical diagnosis of the lesion, present from birth, was blue nevus. Recently, the nodule has been showing a mild enlargement and thus complete resection was performed. Histological analysis revealed a pigmented lesion with an expansive pattern of extension into the dermis and the subcutaneous adipose tissue. The lesion displayed an alveolar pattern as well as a pigmented dendritic cell pattern. The histology was consistent with cellular blue nevus (CBN); however, the history of NM which was excised one year earlier, as well as the clinical information about the slow growing lesion, included a differential diagnosis of CBN, borderline melanocytic tumor, and malignant blue nevus. Additional immunohistochemical (HMB-45, p16, and Ki-67) and molecular (BRAF V600E mutation) analyses were performed on both lesions: the CBN-like and the previously excised NM. Along with lesion history and histological analyses, p16 staining and BRAF were useful diagnostic tools for confirming the benign nature of CBN in this case.

Accurate assessment of HER-2 status is essential for identifying patients who will benefit from HER-2 targeted therapy. The aim of the present study was to show results on the concordance between local and central laboratory testing results in HER-2 positive breast cancer patients. In cases with discordant findings, the immunohistochemical (IHC) and/or in situ hybridization (FISH/SISH) analysis was performed in central laboratories. A total of 104 out of 143 (72.72%) breast carcinoma cases were HER-2 positive (score 3+), while nearly 14% of tumors (20/43) showed weak (score 2+) and 12% (19/143) negative IHC staining (score 0 and 1+). After repeated IHC and ISH, 88% (126/143) were classified as HER-2 positive and 12% (17/143) as HER-2 negative cases. The results obtained are in agreement with many studies that confirmed similar discordance in HER-2 testing by IHC and/or FISH between local and central laboratory. Thus, our findings as well as those from other studies support the importance of regular quality assessment of the staining procedures performed and consistency of interpretation of HER-2 test results.

Melanoma ulceration is the third most powerful survival predictor in the analysis for the currently valid 2010 AJCC melanoma staging system. However, there is still no detailed explanation for melanoma ulceration mechanism. Although thicker tumors are more commonly ulcerated, ulceration is a factor that predicts the disease outcome independently of melanoma thickness. It is our hypothesis that EGFR activates melanoma cell mobility. Melanoma cells with increased mobility move through tissue in diverse direction. Cells moving toward the epithelium weaken the intercellular bonds between the cells causing the loss of epithelium and subsequently ulceration., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim of the present study was to correlate tumor-infiltrating lymphocytes (TIL) with bladder cancer recurrence in patients with solitary low-grade non-muscle-invasive bladder cancer (NMIBC). We retrospectively identified from the institutional database 115 patients with solitary low-grade NMIBC after transurethral resection (TURBT) without adjuvant therapy and with complete follow-up, between 1996 and 2006. Tumor specimens were retrieved and tissue microarrays were constructed. Patients were divided in two groups: those who developed recurrent disease (n = 69) and those without recurrence (n = 46) during a follow-up period of a minimum of 5 years. Immunohistochemical staining for TIL with anti-CD3, CD4, CD8, CD20, CD56, CD68, and granzyme B (GrB) was performed. Student's t test, Mann-Whitney U test, as well as uni- and multivariate analyses were applied to compare the two patient groups. TIL were predominantly observed in cancer stroma. The number of CD3+ and CD8+ lymphocytes observed in the non-recurrent group of patients was lower than that in recurrent patients (p = 0.0001, p = 0.0002, respectively). Also, in uni- and multivariate analyses, levels of CD3+ TIL (OR = 5.4035; p = 0.0001 and OR = 5.8280; p = 0.0102) and CD8+ TIL (OR = 3.2857; p = 0.0036 and OR = 5.3257; p = 0.0092) showed prognostic value with regard to NMIBC recurrence. Our results suggest that CD3+ and CD8+ TIL are predictive of bladder cancer recurrence in patients with solitary low-grade NMIBC which might facilitate identification of patients with higher risk of recurrence. However, prospective validating studies have to confirm these results before immunohistochemical staining for CD3 and CD8 TIL can be included in the clinical workup of these patients.

Three case reports on conservative treatment of posttraumatic open conquassant wounds in children are presented. In 2 cases, the wounds opened after rejection of a previously applied skin graft, whereas in the third case, the wound was consequential to toe amputation and treated conservatively. Based on the authors' long-standing favorable experience with this type of dressing in healing of deep burns in children, treatment was continued with the use of a hydrofiber supportive silver-containing dressing (AQUACEL Ag, ConvaTec, Bridgewater, NJ). From the beginning of treatment, wound dressing was performed on an outpatient basis and without antibiotic therapy. The wounds healed within 4-8 weeks. The process of wound healing and treatment, the mechanisms that may compromise it, and the possibilities offered by hydrofiber silver dressing in conservative treatment of posttraumatic conquassant skin wounds are discussed.

Dirofilariasis is a zoonotic infection caused by worms belonging to the genus Dirofilaria. The disease is transmitted by mosquitoes and the hosts are usually dogs. Infections in humans are rare and they usually manifest as a subcutaneous nodule or a conjunctival form. We present a 10-year-old boy with a subcutaneous nodule on his left forearm, who was admitted to the hospital. On examination, the only significant findings were high levels of eosinophils. The pediatrician suspected dirofilariasis and the boy was referred to pediatric surgery. The whole lesion was surgically removed and histopathologic examination confirmed parasitic infection by Dirofilaria repens. Although human dirofilariasis is a rare disease, the number of reported cases has recently increased worldwide. The disease mainly occurs in southern European countries, but has also been described in eastern Europe, Central Asia and Sri Lanka. Croatia is one of the endemic areas for dirofilariasis, especially in the region of the Istria Peninsula. The case presented highlights the requirement for further monitoring of endemic areas in order to establish effective preventive measures.

Multiple myeloma (MM) shows great variability in clinical course of the disease, and survival varies between a few months and more than 10 years. Myeloma plasma cells (PCs) can appear completely "normal" in morphology, but can also be overtly atypical, polymorphic, immature, as well as in all transitional forms. The aim of this investigation was to analyze the relationship between various morphological and morphometric parameters of myeloma cells, common staging/prognostic systems and survival in patients with MM. Sixty newly diagnosed MM patients were included in the study. Morphologic as well as basic morphometric features of myeloma PCs were analyzed in bone marrow (BM) aspirates, and compared with patient's clinical stage determined by Durie-Salmon and International Staging System, and with survival. We conclude that myeloma cell morphology has a prognostic potential. The most significant morphologic characteristics indicating shorter survival are: finding of >15% atypical PCs in BM aspirate, largest nuclear diameter/largest cytoplasmatic diameter of PCs ratio (maxND/maxCD)≥0.65, and anisocytosis expressed as standard deviation of maxCD ≥4.2 µm. Furthermore, PCs with irregular nuclei and absence of paranuclear clearing of the cytoplasm indicate more advanced stage of disease and worse prognosis. This preliminary results obtained on myeloma cells morphology and morphometry should be confirmed in the larger study which will include cytogenetic data as well as a therapeutic protocols applied., (Copyright © 2013 Wiley Periodicals, Inc.)

Sentinel lymph node (SLN) biopsy is an accurate method for the detection of axillary metastases in early breast cancer patients and is of value as a replacement for axillary dissection. However, variations in the methods and protocols used for the pathological evaluation of SLN exist in everyday practice. Therefore, standardization how to detect, dissect, process, stain, assess and report SNL is required in order to stratify patients into adequate prognostic groups. The aim of this study was to present our experience in SLN analysis in patients with early breast cancer and clinical stage T1-2 and N0. In the period between 2003 and 2011, 1071 consecutive patients or 1915 SLN were analyzed. The protocol included intraoperative analysis of histological frozen sections and cytological imprint, followed by analysis of paraffin sections according to the protocol that included sections of whole SLN with the interval of 250 prm. According to the accepted protocol 75% of SLN were negative. The obtained results were correlated with literature data.

Plasmacytoid urothelial carcinoma (PUC) is a very rare variant of urothelial carcinoma with an aggressive clinical course. According to small series reported to date, it is a high grade cancer usually diagnosed at an advanced stage, and with poor prognosis. Descriptions of the cytologic features of this type of carcinoma in literature are limited. Plasmacytoid appearance of tumor cells could cause diagnostic dilemma and potential incorrect diagnosis as multiple myeloma (MM). This report describes cerebrospinal fluid, bone marrow, and urine sediment cytomorphologic and immunocytochemical findings in a patient with meningeal carcinomatosis as the first manifestation of a PUC, initially misdiagnosed as MM with a brief review of the literature., (Copyright © 2012 Wiley Periodicals, Inc.)

There is a global rising incidence of melanoma. For different reasons, the patterns of the incidence, appearance, gender, anatomical distribution and outcome vary among different geographic areas. Screening programs have led to better early detection of melanoma in Australia and some world areas. National Cancer Registry and practice data show the incidence in Croatia to be constantly rising. Despite public education programs about early detection, at clinical departments there are still many new advanced stage melanoma patients. We analyzed data on 157 patients treated and followed up for 10 years for T1b-T4aN0 skin melanoma. There was a difference in anatomical distribution of melanoma lesions in correlation with patient age (ANOVA test, F=3.51, p=0.009). A higher prevalence of shoulder melanoma was found in young people and of head/neck melanoma in the elderly (post-hoc Sheffe test, p=0.038). T4 lesions were more commonly found in men and T1 mainly in women (Pearson χ(2)-test, χ(2)=12.08, p=0.016). There was no difference in Clark level, but a significantly higher Breslow stage was found in men (t=-2.52, p=0.013). Men were much more prone to have head and neck, body and shoulder melanoma, whereas women had more melanoma on their legs and arms. Clark and Breslow levels were strongly correlated in leg melanoma; head localization showed no correlation at all. In conclusion, more attention should be devoted to improve the results in melanoma detection in men, especially considering the prevalence of body (back) and head/neck localizations, sometimes not readily accessible for visual detection. The pattern of distribution also pointed to the need for more attention to pay to shoulder melanoma in younger people.

The aim of this study is to investigate the differences of clinical and laboratory parameters between patients with JAK2-V617F positive myeloproliferative neoplasms (MPNs) and JAK2 wild type MPNs. DNA was isolated from peripheral blood granulocytes of 106 patients treated at Rijeka University Hospital Center: 41 with polycythemia vera (PV), 43 with essential thrombocythemia (ET), 9 with primary myelofibrosis (PMF) and 13 with myeloproliferative neoplasm--unclassifiable (MPN-u). The JAK2-V617F mutation was detected using allele specific PCR. Laboratory and clinical parameters were obtained from patient's medical records. The JAK2-V617F mutation was detected in 69% (73/106) patients with MPNs. The results revealed significantly different prevalence of JAK2-V617F mutation, between MPNs entities: 88% in PV 58% in ET, 56% in PMF and 54% in MPNs-unclassified disorders. The JAK2-V617F mutation significantly correlated with higher leukocyte count and alkaline phosphatase co re in ET group and with higher platelets count, leukocyte alkaline phosphatase score and serum lactate dehydrogenase in PV group. Vascular events were associated with elevated platelets count in whole MPNs group, with higher platelets and leukocyte count in ET and with splenomegaly in PVpatients. Clinical and laboratory data revealed significant contribution ofJAK2-V617F mutation to the development of clinical phenotype in patients with distinct subgroups of MPNs.

Background: The role of epidermal growth factor (EGF) and its receptor (EGFR) in the pathogenesis and progression of various malignant tumors has long been known, but there is still disagreement concerning prognostic significance of EGFR expression in clear cell renal cell carcinoma (CCRCC). The present study was designed to analyze more objectively the protein EGFR expression in CCRCC and to compare its value with EGFR gene copy number changes and clinicopathologic characteristics including patient survival., Methods: The protein EGFR expression was analyzed immunohistochemically on 94 CCRCC, and gene copy number alterations of EGFR by FISH analysis on 41 CCRCC selected according to distinct membrane EGFR staining., Results: Membrane EGFR expression in tumor cells was heterogeneous with respect to the proportion of positive cells and staining intensity. FISH analysis did not reveal EGFR gene amplification, while polysomy of chromosome 7 found in 41% was associated with higher EGFR membrane expression. Moreover, EGFR overexpression was associated with a higher nuclear grade, larger tumor size and shorter patient's survival, while there was no connection with pathological stage., Conclusion: In conclusion, the protein expression of EGFR had an impact on prognosis in patients with CCRCC, while an increased copy number of chromosome 7 could be the possible reason for EGFR protein overexpression in the absence of gene amplification.

Background: Prognostic and predictive significance of epidermal growth factor receptor (EGFR) in colorectal carcinomas (CRCs) is still controversial. The aim of the present study was to explore and correlate membrane and nuclear EGFR and cyclin-D1 protein expression with EGFR gene status of tumor cells., Methods: Immunohistochemical and FISH analysis was performed on 135 archival formalin fixed and paraffin embedded CRCs., Results: Strong membrane and strong nuclear EGFR staining was detected in 16% and 57% of cases, respectively, and strong cyclin-D1 expression in 57% samples. Gene EGFR amplification was identified in 5.9% and polysomy in 7.4% of cases, while 87% showed no EGFR gene changes. A statistically significant difference was only found between tumor grade and expression of membrane EGFR, while nuclear EGFR and cyclin-D1 expression was not associated with the clinicopathologic characteristics analyzed. Tumor cells displaying gene amplification and strong protein membrane EGFR expression overlapped, while EGFR gene status showed no correlation with nuclear EGFR and cyclin-D1. There was no association between membrane EGFR and cyclin-D1, whereas nuclear EGFR expression was strongly related to cyclin-D1 expression., Conclusions: Study results revealed heterogeneity among CRCs, which could have a predictive value by identifying biologically and probably clinically different subsets of tumors with the possibly diverse response to anti-EGFR therapies., (© 2011 Dekanićć et al; licensee BioMed Central Ltd.)

In Croatia, lung cancer is the most common malignant disease among male population and the third common among female population where 85% of patients have non-small cell lung cancer. Due to significance of this disease it is necessary to define and implement standardized approach for diagnostic and treatment algorithm as well to patients monitoring. Several multidisciplinary sessions were organized in achieving this goal. The sessions' results are given in the form of the Clinical guidelines.

Epithelioid hemangioendothelioma (EHE) is a rare tumor of the vascular origin. It was first described in its pulmonary form by Dail and Leibow in 1975 and named "intravascular bronchioalveolar tumor" (IVBAT). Since then, reports of occurrences of the tumor have been made for number of locations, but most often tumor can be found in soft tissues, liver, lungs, bone and skin. It is considered to be a low or borderline malignant tumor with, usually, slow progression, but aggressive forms have been described. We here report a case of a 46-year old female patient with multifocal malignant tumor spreading to lungs, liver, spleen and with synchronous involvement of lumbal vertebrae, illiac bones and central nervous system dissemination. To the best of the authors knowledge, no case of malignant EHE with multiorgan involvement of this proportions and synchronous central nervous system and bone involvement in one patient has been reported to this date in English-speaking literature.

Determination of hormone receptors is of utmost importance in planning therapy in patients with breast cancer. The aim of the study was to assess the expression of estrogen (ER) and progesterone (PR) receptors in ductal invasive breast carcinoma not otherwise specified (NOS) according to patient menopausal state and tumor histopathology. The study included 549 patients treated at University Department of Surgery, Rijeka University Hospital Center, between January 1, 2000 andJanuary 1, 2005. The patients were diagnosed with breast cancer and underwent mastectomy. ER and PR status was determined by immunohistochemistry. Study results showed no statistically significant differences in the expression of ER and PR, tumor size and grade of histologic differentiation between premenopausal and postmenopausal women. However, tumor size and grade of histologic differentiation differed significantly according to the expression of hormone receptors. Tumors greater than 5 cm in size were mostly ER- in premenopausal (P = 0.012) and PR- in postmenopausal (P = 0.044) patients. Poorly differentiated cancers were associated with ER-PR-status in both premenopausal and postmenopausal patients (P < 0.001). Hormone dependent tumors (ER+PR+) were of smaller diameter and lower histologic grade, while hormone independent tumors (ER-PR-) had greater diameter and higher histologic grade, the difference being statistically significant (P = 0.004 and P < 0.001, respectively). Study results on the characteristics of ductal invasive carcinoma according to hormone status were consistent with those described in the literature. Considering controversies about the role of steroid receptors in endocrine therapy response, our future objective is assessment of the 5-year prognosis in our patients.

Henoch-Schönlein purpura (HSP) is the most common childhood systemic small-vessel vasculitis with skin, joint, gastrointestinal (GI) and renal involvement. Uncommon GI complications are intussusception, bowel perforation and rarely reported appendicitis. HSP-associated stenosing ureteritis represents a rare and potentially serious complication. We present a 5-year-old boy with severe and prolonged course of HSP and three very rare complications that occurred sequentially: appendicitis, intussusception and ureteritis. Only three days after admission, he developed clinical signs of acute appendicitis indicating surgical intervention. Histological analysis of excised appendix showed inflammation but without signs typical for vasculitis. Two weeks later, with the reccurence of HSP he again developed clinical picture of acute abdomen. Ultrasound and radiologic evaluation demonstrated ileo-ileal intussusception and the second laparotomy was undertaken. Histological analysis of the resected bowel tissue showed typical signs of leucocytoclastic vasculitis. In the fourth week of his illness, serial urinalysis showed nephritic urinary sediment indicative of renal involvement. Unexpectedly, control abdominal ultrasound demonstrated mild hydronephrosis of the left kidney, not seen on previous ultrasound evaluations. Undertaken excretory urography and computed tomography (CT) scan showed stenosis of upper/ midureter with mild dilation of upper part of the left ureter suggesting unilateral HSP-associated stenosing ureteritis. Eventually, the patient was discharged and closely followed-up for the next two years. He had no further reccurence of HSP, the urinalysis normalized after six months, while mild unilateral hydronephrosis remained unchanged. Our search of the literature did not show reports of HSP complicated by appendicitis, intussusception and ureteritis, and to our knowledge this is the first case with three different illness events that occured sequentially. We emphasize the necessity of repeated ultrasound evaluations in the course of HSR especially in cases with severe GI and renal invovement.

The epidermal growth factor receptor (EGFR)-family and cyclin-D1 have been extensively studied in breast cancer; however systematic studies that examine protein expression and gene status in the same cohort of patients are lacking. Also emerging evidences suggest existence of a direct EGFR-signaling pathway, which involves cellular transport of EGFR from cell membrane to the nucleus, and transcriptional regulation of the target genes. Thus, we examined the protein expression of membrane EGFR, nuclear EGFR, cyclin-D1 and the corresponding gene status in 113 breast carcinomas by immunohistochemistry and fluorescence in situ hybridization using tissue microarrays. Membrane EGFR overexpression and EGFR gene amplification were detected in 2% cases, while nuclear EGFR was detected in 40% of cases, with 12% having high nuclear EGFR staining. Nuclear EGFR correlated with tumor size (P=0.0005), lymph node metastasis (P=0.0288), Nottingham prognostic index (P=0.0011) and estrogen receptor (ER) expression (P=0.0258) but the letter correlation was observed only in premenopausal group of patients. Strong cyclin-D1 expression and cyclin-D1 gene (CCND1) amplification were found in 64 and 13% of the cases, respectively. Cyclin-D1 expression showed positive correlation with ER (P=0.0113) and inverse correlation with Nottingham prognostic index (P=0.0309) and membrane EGFR (P=0.0201). CCND1 amplification also showed inverse correlation with membrane EGFR (P=0.0420). A strong correlation between membrane EGFR expression and gene amplification (P=0.0035), as well as cyclin-D1 overexpression and gene amplification (P=0.0362), was demonstrated. On univariate analysis cyclin-D1 expression showed a correlation with longer overall survival in the premenopausal group and nuclear EGFR correlated with shorter overall survival in whole cohort as well in the premenopausal group of patients. Multivariate analysis revealed nuclear EGFR to be an independent prognostic factor and showed 3.4 times greater mortality risk for nuclear EGFR+++ patients as compared with nuclear EGFR negative patients (hazard ratio =3.402; P=0.0026).

Axillary lymph node dissection (ALND) is an important procedure in the staging of breast cancer patients. However, it is associated with a significant morbidity rate. In addition, using early diagnosis a high number of cases with negative lymph nodes can be identified. A lymph node defined as sentinel lymph node (SLN) would be the first to receive tumoral drainage. A less morbid but accurate staining procedure using mapping and SLN biopsy has been introduced. The aim of this study was to estimate the likelihood of additional disease in the axilla after SLN analysis. A total of 259 breast carcinomas and SLN biopsies followed by ALND were examined. The patient median age was 59 years, approximately 75% of them postmenopausal. Tumor size was 1.4 +/- 0.8 cm (almost 80% in pT1). SLNs were positive in 59 of 259 (22.8%) carcinomas, 30 (11.6%) with micrometastases (<2.0 mm) and 29 (11.2%) with metastases. Tumor size ( P = .004) and presence of lymphovascular invasion (LVI; P = .034) were found to be significant predictors of pathologically positive SLN. Following ALND, positive non-SLNs were present mostly in patients with metastasis >2 mm in SLN (P = .003), in carcinoma with higher nuclear grade ( P = .044), decreased estrogen receptor (ER; P = .042), and progesterone receptor (PR; P = .042). Finally, lymph node status (pN) following SLN and ALND was found to be significantly associated with tumor size ( P = .006), LVI (P = .037), PR (P = .023), and Her-2 status (P < .001). These results point to detailed analysis of primary tumor and SLN that may increase the precision of patient selection for further axillary surgery or radiotherapy.

Background: The role of angiogenesis in the pathogenesis of renal cell carcinoma is well recognized, however, the influence of tumor cells in this activity has not yet been fully clarified. The aim of this study was to analyze the expression of hypoxia inducible factor-1alpha (HIF-1alpha), a regulatory factor of angiogenic switch, in comparison to vascular endothelial growth factor A and C (VEGF-A and VEGF-C), recognized to be involved in blood and lymph vessel neoangiogenesis, with potential association in the prognosis of patients with renal cell carcinoma., Methods: Ninety-four patients with diagnosis of clear cell renal cell carcinomas (CCRCC), all clinicopathological characteristics and overall survival were unrolled in this study. Immunohistochemicaly VEGF-A, VEGF-C, HIF-1alpha and Ki67 were detected on tumor cells and the staining was performed on tissue microarrays (TMA). The staining was evaluated as a percentage of cytoplasmic or nuclear positive tumor cells., Results: Variable expression of all three proteins was confirmed. Both angiogenic factors demonstrated perimembranous or diffuse cytoplasmic staining, with diffuse pattern positively associated (p < 0.001). Nuclear HIF-1alpha expression (nHIF-1alpha) showed inverse correlation with diffuse cytoplasmic VEGF-A (p = 0.002) and VEGF-C (p = 0.053), while cytoplasmic HIF-1alpha expression (cHIF-1alpha) showed positive correlation with diffuse staining of both angiogenic factors (p < 0.001; p < 0.001, respectively). In comparison to clinicopathological characteristics, a higher nuclear grade (p = 0.006; p < 0.001, respectively), larger tumor size (p = 0.009; p = 0.015, respectively), higher stage (p = 0.023; p = 0.027, respectively) and shorter survival (p = 0.018; p = 0.024, respectively) were associated with overexpression of cHIF-1alpha and diffuse cytoplasmic VEGF-A expression. In contrary, overexpression of nHIF-1alpha was associated with better diagnostic parameters i.e. lower nuclear grade (p = 0.006), smaller tumor size (p = 0.057), and longer survival (p = 0.005)., Conclusion: Overexpression of VEGF-A and cHIF-1alpha in tumor cells highlights a more aggressive subtype of CCRCC that might have some clinical implications. The significance of nHIF-1alpha expression associated with better differentiated tumors should be further elucidated.

Aim: To assess the relationship between protein and messenger RNA (mRNA) levels of vascular endothelial growth factor (VEGF) and subcellular localization of nuclear factor-kappa B (NF-kappaB), proliferation rate of tumor cells, and clinicopathological characteristics of renal cell tumors., Methods: We analyzed 31 one renal cell tumors - 22 clear cell renal cell carcinomas (CCRCC) and 9 other histologic types (non-CCRCC). VEGF expression and subcellular localization of p65 member of NF-kappaB and Ki67 were immunohistochemically evaluated for the proliferation rate of tumor cells. Expression of VEGF mRNA was assessed using quantitative real-time polymerase chain reaction after total RNA extraction from snap-frozen tumor tissue samples., Results: Cytoplasmic localization of VEGF protein in renal cell tumors showed a perimembranous and diffuse pattern, the former being more evident in CCRCC (27.1 -/+ 18.9 vs 3.3 -/+ 10 % tumors, P<0.001) and the latter in non-CCRCC type (71.7 -/+ 23.2 vs 31.1 -/+ 22.1 % tumors, P<0.001). Heterogeneity in VEGF gene expression was more pronounced in CCRCC type than in non-CCRCC type (P=0.004). In addition, perimembranous VEGF pattern was associated with higher VEGF mRNA levels (P=0.006) and diffuse VEGF pattern with lower VEGF mRNA levels (P<0.001). Nuclear and cytoplasmic staining of NF-kappaB/p65 was observed in the majority of tumor cells. A significant association was recorded between cytoplasmic NK-kappaB/65 staining and VEGF staining of diffuse pattern (P=0.026). Association between NF-kappaB/65 and proliferation rate of tumor cells was significant for cytoplasmic staining (P=0.039) but not for nuclear NFkB/p65 staining (P=0.099)., Conclusion: Higher but inhomogeneous expression of VEGF in tumor cells, especially in CCRCCs, is associated with NF-kappaB/65 activity. This indicates that both VEGF and NF-kappaB/65 may be important in renal carcinogenesis, representing a possible molecular target in the treatment of renal cell carcinoma.

Cytokines play important roles in the pathogenesis of lymphomas. This study aimed to determine the relationship(s) between serum levels of interleukin (IL)-6, IL-8 and IL-10, measured by enzyme-immunoassay, and the clinical characteristics and outcomes in 46 untreated patients with diffuse large B-cell lymphoma (DLBCL). Serum IL-6, IL-8 and IL-10 levels were higher in DLBCL patients than in control subjects. Elevated levels of IL-6, IL-8 and IL-10 correlated with more adverse disease features. Consequently, patients with elevated IL-6, IL-8 and IL-10 levels prior to treatment had a lower response to therapy. Furthermore, those with elevated IL-6 and IL-10 levels had poor median, 3-year and 5-year survival, while elevated serum IL-8 level did not correlate with overall survival. Worse survival was also confirmed in patients with combined elevated pretreatment serum levels of IL-6, IL-8 and IL-10 (none, one, two or three elevated). Multivariate analysis identified elevated values of IL-6 and IL-10 and response to therapy as significant predictors for overall survival. Serum levels of IL-6, IL-8 and IL-10 before treatment of patients with newly diagnosed DLBCL may give some insight into the possible prognosis and thus facilitate the decisions regarding therapeutic approaches for individual patients.

Tenascin-C (TN-C) is an extracellular matrix protein which participates in different processes like normal fetal development, wound healing, inflammation, keloids and rheumatoid arthritis. Furthermore, the immunostaining for TN-C is seen in the stroma of various malignant tumors as in glioblastoma multiforme (GBM), however, the significance of these findings is still not clear. In this study 62 GBM samples were analyzed immunohistochemically for distribution patterns of TN-C and correlated with angiogenesis and tumor cell proliferation. Tenascin-C in GBM localizes in two compartments, perivascular and intercellular space. Intercellular tenascin-C (TN-C ic) showed focal distribution in 66%, and diffuse one in 34% of cases. Perivascular tenascin-C (TN-C pv) showed strong correlation with microvascular density (MVD) and vascular endothelial growth factor (VEGF) expression. Moreover, it seems that TN-C pv enhanced the effect of VEGF. Intercellular TN-C did not correlate with MVD and VEGF expression, but showed strong correlation with proliferation index. Furthermore, tumors with diffuse TN-C ic expression had higher proliferation indices than tumors with focal TN-C expression. Our results indicate that TN-C plays a role in angiogenesis and tumor cell proliferation, but beside the intensity of expression, the distribution patterns are also important in these processes. This study also suggests that perivascular and intercellular TN-C compartments have probably different sources and different roles in GBM.

Urinary bladder cancers can be grouped into three general categories: superficial, invasive and metastatic. Approximately 90% of malignant tumors of the urinary bladder are of epithelial origin and the majority of them are transitional cell carcinomas (TCC). Metastatic spread of urinary bladder cancers usually includes regional lymph nodes, the lung, the liver and the bones. The presence of metastasis tends to correlate with muscular wall invasion as often demonstrated at the initial diagnosis; consequently clinical bladder cancer represents a late phase of the disease. Although skeletal metastases of bladder cancers are rather common, they have been rarely described to occur in distal bones. For that reason, we report metatarsal metastasis from transitional cell cancer of the urinary bladder in a 59-year-old woman.

Angiogenic and anti-angiogenic factors, secreted by tumor, inflammatory, and stromal cells play an important role in regulation of neovascularization. Among the most important of these is vascular endothelial growth factor (VEGF), a specific mitogen for endothelium, which increases vascular permeability and induces proteolytic enzymes necessary for vascular remodeling. Tumor-associated macrophages (TAMs) can express complex functions related to tumor biology, including growth, proliferative rate, stroma formation and dissolution, and neovascularization. The aim of this study was to define, using immunohistochemical analysis, the microvessel density (MVD), VEGF expression, and TAMs level in 97 human invasive ductal breast carcinomas not otherwise specified (NOS), investigate a possible relationship between them and then correlate their values with tumor grade, mitotic activity index (MAI), tumor size and lymph-node status. Statistical analysis showed a strong positive relationship between MVD and VEGF expression ( P<0.001). Furthermore, both MVD and VEGF expression were significantly correlated with tumor grade and lymph-node status, and TAMs infiltration with MAI. TAM level showed a significant positive connection with VEGF expression and MVD. These in situ observations suggest that VEGF stimulates angiogenesis in human invasive ductal breast carcinoma NOS and attracts macrophages to the tumor locus, which then may be involved in angiogenesis promotion. The expression of this angiogenic molecule, and MVD and TAM level, can provide additional prognostic significance and help in the identification of patients who need postoperative adjuvant therapy.