Rafał Matkowski

ABCC2 (MRP2, cMOAT) Localized in the Nuclear Envelope of Breast Carcinoma Cells Correlates with Poor Clinical Outcome

Nuclear expression of ABCC2 can be specific for lower differentiated cells and stem cells. The study aimed at examination of ABCC2 expression in breast cancers. The immunohistochemical analyses were performed on 70 samples of breast cancer. We have also studied prognostic value of the ABCC2 mRNA expression using the KM plotter which assessed the effect of 22,277 genes on survival in 1809 breast cancer patients. Immunohistochemical studies demonstrated that ABCC2 expression may be manifested in nuclear envelope of neoplastic cells (ABCC2n) as well as in their cell membrane and cytoplasm (ABCC2c). The univariate and multivariate analyses showed that higher expression of ABCC2n and ABCC2c was typical for cases of a shorter overall survival time. Higher ABBC2n expression was also typical for cases of a shorter disease-free survival and a shorter progression-free time. The KM plotter analysis of the prognostic value of ABCC2 mRNA expression showed that elevated ABCC2 expression was specific for cases of a shorter relapse-free survival only in the estrogen receptor-negative subgroup. The study demonstrated hat breast cancers manifest ABCC2 expression and that it is linked to a less favourable prognosis. Our results suggested that immunohistochemical tests represent a reliable way to detect prognostic value of ABCC2 expression, allowing to demonstrate differences related to subcellular localization of the protein. Cases with nuclear expression of ABCC2 manifested a more aggressive clinical course, which might reflect a less advanced differentiation of neplastic cells, resistance to the applied cytostatic drugs and tamoxifen.

HER-2 Expression in Immunohistochemistry Has No Prognostic Significance in Gastric Cancer Patients

The role of HER-2 expression as a prognostic factor in gastric cancer (GC) is still controversial. The aim of the study was to asses HER-2 status, its correlations with clinicopathological parameters, and prognostic impact in GC patients. Tumor samples were collected from 78 patients who had undergone curative surgery. In order to evaluate the intensity of immunohistochemical (IHC) reactions two scales were applied: the immunoreactive score according to Remmele modified by the authors and standardised Hercep test score modified for GC by Hofmann et al. The HER-2 overexpression was detected by IHC in 23 (29.5%) tumors in Hercep test (score 2+/3+) and in 24 (30.7%) in IRS scale (IRS 4–12). The overexpression of HER-2 was associated with poorly differentiated tumors, but this correlation was not significant (P = 0.064). No relationship was found between HER-2 expression and primary tumor size and degree of spread to regional lymph nodes. Both univariate and multivariate analyses revealed that TNM stage and patients age were the crucial negative prognostic factors. No correlation was observed between patient survival and expression of HER-2 estimated using both scales. This research did not confirm HER-2 expression (evaluated with immunohistochemistry) value as a prognostic tool in GC.

Elevated BUBR1 Expression Is Associated with Poor Survival in Early Breast Cancer Patients: 15-Year Follow-up Analysis

BUBR1 (budding uninhibited by benzimidazole-related 1) represents the component of a controlling complex in mitosis. Defects in mitotic control complex result in chromosomal instability and, as a result, disturb the mitotic process. This study was aimed at examining the prognostic value linked to the expression of BUBR1 in a group of patients with breast cancer. We analyzed the expression of BUBR1 in 98 stage II breast cancer patients with a median follow-up of 15 years. Immunohistochemical reactions were performed using monoclonal antibodies against BUBR1. We also studied the prognostic value of BUBR1 mRNA expression using the Kaplan-Meier (KM) plotter, which assessed the effect of 22,277 genes on survival in 2422 breast cancer patients. A background database was established using gene expression data and survival information on 2422 patients downloaded from the Gene Expression Omnibus (GEO; Affymetrix HGU133A and HGU133+2 microarrays). The median relapse-free survival was 6.43 years. Univariate and multivariate analyses showed that higher expression of BUBR1 was typical for cases of shorter overall survival, disease-free time, and disease-specific survival. KM plotter analysis showed that elevated BUBR1 mRNA expression had a negative impact on patients’ relapse-free, distant metastases–free, and overall survival. Elevated BUBR1 expression was associated with poor survival in early stage breast cancer patients.

Enhanced Immunoreactivity of TIMP-2 in the Stromal Compartment of Tumor as a Marker of Favorable Prognosis in Ovarian Cancer Patients

Degradation of the extracellular matrix and basement membrane is a critical step in tumor progression. Matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP 2) act in a coordinated manner to form an integrated system involved in ovarian cancer (OC) progression. In this study, the authors describe the expression of TIMP-2 detected by immunohistochemistry in 6 OC cell lines and in 43 malignant epithelial ovarian tumors (in tumor and stromal compartments) in sections originating from primary laparotomies. No significant correlations between overall and progression-free survival and TIMP-2 expression in tumor compartment were observed. The analysis demonstrated a significant association between enhanced stromal expression of TIMP-2 and better clinical response to cisplatin- and paclitaxel-based chemotherapy. Increased expression of TIMP-2 in the stromal compartment and simultaneous overexpression in both stromal and tumor compartments strongly correlated with increased survival. No significant correlations were found in vitro between resistance to cisplatin, paclitaxel, or topotecan and the expression of TIMP-2 in the OC cell lines, suggesting stromal influences on tumor chemoresistance in the physiological environment. This study supports the concept of TIMP-2 expression in the stromal compartment of OC as a promising marker of prognosis and response to cisplatin- and paclitaxel-based chemotherapy in OC patients.

Golgi-Related Proteins GOLPH2 (GP73/GOLM1) and GOLPH3 (GOPP1/MIDAS) in Cutaneous Melanoma: Patterns of Expression and Prognostic Significance

GOLPH2 and GOLPH3 are Golgi-related proteins associated with aggressiveness and progression of a number of cancers. Their prognostic significance in melanoma has not yet been analyzed. We performed immunohistochemical analysis for GOLPH2 and GOLPH3 in 20 normal skin, 30 benign nevi and 100 primary melanoma tissue samples and evaluated their expression in three compartments: cancer cells, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). High levels of both proteins in melanoma cells were associated with characteristics of aggressive disease, and shorter disease-free survival (DFS) and cancer-specific overall survival (CSOS). On the contrary, increased numbers of GOLPH2-positive and GOLPH3-positive TAMs were observed in thinner, non-ulcerated tumors, with brisk lymphocytic reaction and absent lymphangioinvasion. Distant metastases were not observed among patients with high numbers of GOLPH2-positive TAMs. Increased expression of either protein in TAMs was related to prolonged CSOS and DFS. Similarly, GOLPH3-expressing CAFs were more frequent in thin melanomas with low mitotic rate, without ulceration and lymphangioinvasion. Moreover, increased GOLPH3-positive CAFs correlated with the absence of regional or distant metastases, and with longer CSOS and DFS. GOLPH2 expression was not observed in CAFs. Our results suggest that GOLPH2 and GOLPH3 play a role in melanoma progression and are potential targets for molecular-based therapies.

Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: a 5-year survival analysis.

The presence of ulceration has been considered as one of the most important primary tumor characteristics of cutaneous malignant melanoma (CMM) for predicting patient outcome. Yet recently, scientific attention has been drawn towards another microscopic feature of primary tumors, the mitotic rate (MR). The present study aimed to examine the relationship between the presence of ulceration and the mitotic rate and clinicopathological characteristics and melanoma patient survival, and to discuss the results in the context of AJCC melanoma staging recommendations. Tissue samples were obtained from 104 patients treated for CMM. In classical H&E staining, the mitotic rate and the presence of ulceration were evaluated. Non-mitogenic tumors were defined as having 0 mitoses/mm2, low mitogenic potential, 1-2 mitoses/mm2 and highly mitogenic tumors, ≥3 mitoses/mm2. In the entire group of 104 patients, a high mitotic rate (hMR) and ulceration were highly negative prognostic factors, and indicated considerably shorter overall survival, cancer-specific overall survival and disease-free survival. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in both the pT1 (P=0.001) and pT2 subgroups (P=0.006). Kaplan‑Meier analysis of the remaining subsets (pT3 and pT4) did not reveal any important differences in the 5-year survival with regard to MR values. The presence of ulceration also had a prognostic significance for early melanomas, but only for pT1 tumors (P=0.05). Multivariate analysis confirmed that hMR was strongly associated with an unfavorable prognosis. Ulceration had no prognostic significance in the Cox proportional hazards model. Considering the biology of melanoma, hMR seems to be a more reliable parameter than the presence of ulceration. The value of MR categorizes melanomas into tumors with low or high proliferative potential, thus giving direct information concerning their capacity to infiltrate deeper layers of the dermis and, potentially, to generate regional lymph node and distant metastases.

Urinary complications in rectal cancer patients are related to the dissection tool.

BACKGROUND/AIMS To assess the incidence and risk of urinary complications after anterior rectal cancer resection with regard to the surgical device used for total mesorectal excision (TME). METHODOLOGY During the years 2004-2009 we operated 374 rectal cancer patients with TME and the intent of autonomic nerves sparing intent. Seventeen patients underwent mesorectal dissection with ultrasound scalpel (US). They were compared to the control series of 35 cases selected from the patients for whom electrocautery was used. Selection was done in the manner to eliminate any other significant differences between groups. RESULTS Intraoperative complications, postoperative mortality, anastomotic leakage and infectious complications did not occur. Urinary bladder disturbances developed in US group in 1 patient (6%) while in 12 patients (34%) in EC group (p<0.05). In US group the character of complication was transient stress incontinence with symptoms being significantly reduced during six postoperative months. In EC group two patients had dysuria, two nycturia, one had both. Stress incontinence occurred in six patients, complete incontinence requiring catheterization in one. CONCLUSIONS When compared to EC, TME with US is related to lower risk of urinary complications and facilitates autonomic nerve preservation due to minimized thermal lateral tissue damage.

Prognostic significance of immunohistochemical epithelial–mesenchymal transition markers in skin melanoma patients

AIM To investigate secreted protein acidic and rich in cystein (SPARC) and neural cadherin (NCAD), which are associated with epithelial-mesenchymal transition in primary skin melanoma and nodal metastases and their prognostic impact in melanoma patients. METHODS Expression of proteins was assessed by immunochemistry in archival paraffin samples from 103 primary melanoma tumors and 16 nodal metastases. RESULTS Increased expression of SPARC and NCAD in primary skin melanoma was associated with decreased overall survival, adverse clinicopathological features and particularly with microsatellitosis (SPARC) and ulceration (NCAD). In univariate Cox regression analysis, both biomarkers were significantly associated with the risk of death; the multivariate Cox regression analysis identified no significance. CONCLUSION The most important result of our study was that we confirmed the strict correlation between SPARC and NCAD expression and clinicopathological parameters related with melanoma progression, which is a specific clinical equivalent of the molecular mechanisms of epithelial-mesenchymal transition process and confirms its key role in the disease outcome.

High Percentage of ADAM-10 Positive Melanoma Cells Correlates with Paucity of Tumor-Infiltrating Lymphocytes but Does Not Predict Prognosis in Cutaneous Melanoma Patients

ADAM-10 (CDw156, CD156c, and kuzbanian) is a protein belonging to a superfamily of metalloproteases, enzymes capable of degrading the extracellular matrix. ADAMs have also been shown to be primarily involved in ectodomain cleavage. The aim of the study was to assess the expression and intracellular location of ADAM-10 in 104 primary skin melanomas and 16 metastatic lesions from regional lymph nodes. Also, prognostic significance of ADAM-10 expression in primary tumor cells and metastatic lesion cells was evaluated during 5-year observation. It was revealed that high expression of ADAM-10 positive cells was strictly related with lower intensity of tumor-infiltrating lymphocytes (P = 0.037), which suggests that ADAM-10 regulates immunoresponse in melanoma initiation and progression. No statistically significant correlations were found between ADAM-10 expression in primary tumor cells and nodal metastases and other histopathological parameters analyzed. Decreased immunoreactivity of ADAM-10 in cancer cells from regional lymph nodes was correlated with worse prognosis; however this correlation was statistically nonsignificant (P = 0.065). Review of the literature shows that our study is the first one ever to describe the significance of ADAM-10 expression in correlation with detailed histopathological parameters of the primary tumor and data on long-term survival of cutaneous melanoma patients.

Mastectomy approach with Y-shaped incision: a technique designed for women with obesity.

Objective: To evaluate the access to axilla, postoperative complications, and cosmetic results of the modified radical mastectomy with a Y-shaped approach especially designed for women with obesity. Methods: One hundred seventeen consecutive women with obesity with infiltrating breast cancer were studied. All of them were not eligible for breast-conserving therapy and underwent modified radical mastectomy. Operation was performed using a surgical technique designed to improve the axillary clearance and to eliminate the lateral dog ear deformity. Two oblique incisions were added to the traditional transverse Stewart incision at the lateral part forming the Y-shaped approach. After lateral flap retraction, the axillary dissection was done. Before closing the wound, the triangular flap was advanced medially, whereas superior and inferior areas of redundant skin overlying the latissimus dorsi muscle were excised. Results: No intraoperative complications were observed. In each case, the axillary dissection (with level 3 node clearance when needed) was performed with ease. The wound was healed by primary adhesion, giving an excellent cosmetic result without lateral dog ear deformity. Skin flap necrosis was found in 2 elderly patients. Wound hematoma and surgical site infection developed in 1 patient each. Necrosis of the apex of axillary triangle occurred in one woman with diabetes. These rare complications were managed successfully in all the cases. Conclusions: The Y-shaped approach for modified radical mastectomy is a simple and safe technique. It facilitates the wide access to axilla and improves cosmesis in women with obesity by eliminating lateral dog ear deformity.