Sitki Tuzlali

CXCL-12/Stromal Cell–Derived Factor-1α Transactivates HER2-neu in Breast Cancer Cells by a Novel Pathway Involving Src Kinase Activation

Experimental evidence suggests that CXCR4, a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), plays a role in breast cancer metastasis. Transactivation of HER2-neu by G protein-coupled receptor activation has been reported as a ligand-independent mechanism of activating tyrosine kinase receptors. We found that SDF-1alpha transactivated HER2-neu in the breast cancer cell lines MDA-MB-361 and SKBR3, which express both CXCR4 and HER2-neu. AMD3100, a CXCR4 inhibitor, PKI 166, an epidermal growth factor receptor/HER2-neu tyrosine kinase inhibitor, and PP2, a Src kinase inhibitor, each blocked SDF-1alpha-induced HER2-neu phosphorylation. Blocking Src kinase, with PP2 or using a kinase-inactive Src construct, and inhibiting epidermal growth factor receptor/HER2-neu signaling with PKI 166 each inhibited SDF-1alpha-stimulated cell migration. We report a novel mechanism of HER2-neu transactivation through SDF-1alpha stimulation of CXCR4 that involves Src kinase activation.

Increased False Negative Rates in Sentinel Lymph Node Biopsies in Patients with Multi-Focal Breast Cancer

There are few data about the reliability of sentinel node biopsy in patients with multi-focal breast cancer. The aim of this study was to determine the factors affecting the identification and accuracy of the sentinel node, comparing multifocality with other variables, using peritumoral isosulfan blue dye injection technique alone. Between 1998 and 2001, 122 patients with clinically negative nodes from a single institute were eligible for sentinel lymph node biopsies (SLNBs). All patients underwent conventional axillary lymph node dissection (ALND). SLNs were identified in 111 of 122 (91%) cases, and analyzed by hematoxylin and eosin. Twenty-one patients with multi-focal breast cancer were determined by clinical or pathologic examination (gross or microscopic). Success in locating the sentinel node was unrelated to patients age, tumor size, type, location, histological or nuclear grade, multifocality, or a previous surgical biopsy. SLNBs accurately predicted the status of the axilla in 104 of the 111 patients (93.7%), while 18 of the 21 patients with multi-focal breast cancer (85.7%) had successful lymphatic mapping. The false negative (FN) rate was 11.3% among patients with successful SLNBs. Multifocality and tumor size (>2 cm) were associated significantly with decreased accuracy and increased FN rates (for multifocality, p = 0.007 and p = 0.006, and for tumor size >2 cm, p = 0.04 and p = 0.05, respectively) in binary logistic regression analysis, whereas excisional biopsy, tumor location in the upper outer quadrant and patients age did not significantly affect the accuracy and FN rates in univariate analysis. These results suggest sentinel lymph node biopsy using peritumoral isosulfan blue injection method alone can accurately predict axillary status in patients with clinically negative nodes, but patients with multi-focal disease and large tumor size may not be ideal candidates.

Increased Lymph Node Positivity in Multifocal and Multicentric Breast Cancer

BACKGROUND Multifocal and multicentric (MF/MC) breast cancers have been reported to be associated with increased lymph node metastases. The limited data on this issue prompted us to investigate the pathologic and clinical differences between unifocal and MF/MC breast cancer. STUDY DESIGN Between 1990 and 2002, 1,322 patients with operable invasive breast cancer underwent a definitive operation at our Breast Clinic. Patients with MF/MC breast cancer (n=147, 11%) were compared with patients with unifocal breast cancer (n=1,175; 89%) in terms of pathologic and clinical characteristics. RESULTS Patients with MF/MC were found to have a higher frequency of lymph node metastases when the largest diameter was used as a tumor size estimate for MF/MC cancer (unifocal T1 and T2, 35% and 49%, respectively, versus MF/MC T1 and T2, 48% and 67%, respectively; p=0.05 and p=0.003, respectively). When the combined diameter assessment was used, the frequency of lymph node positivity was similarly higher in MF/MC patients versus unifocal patients (unifocal T1 and T2, 35% and 49%, respectively, versus MF/MC T1 and T2, 49% and 61%, respectively; p=0.08 and p=0.046, respectively). At a median followup of 55 months (range 12 to 153 months), 5-year disease-free survival (DFS; unifocal, 88% versus MF/MC, 82%, p=0.14) and overall survival (OS) rates (unifocal, 92% versus MF/MC, 93%, p=0.43) did not show any significant difference between two groups. CONCLUSIONS Our data suggest that breast tumors with multiple foci have a different biology, with an increased metastatic potential to axillary lymph nodes, regardless of tumor size, that reflects an advanced stage. The clinical relevance of the currently used TNM classification system, which uses the diameter of the largest nodule, is supported by our findings.

Axillary sentinel node biopsy after neoadjuvant chemotherapy

INTRODUCTION The role of sentinel lymph node biopsy (SLNB) in patients with locally advanced breast cancer (LABC) with potentially sterilized axillary lymph nodes after neoadjuvant chemotherapy (NAC) remains unclear. PATIENTS AND METHODS Between 2002 and 2008, SLNB with both blue-dye and radioisotope injection was performed in 77 patients with LABC whose cytopathologically confirmed positive axillary node(s) became clinically negative after NAC. Factors associated with SLN identification and false-negative rates, presence of non-sentinel lymph node (non-SLN) metastasis were analyzed retrospectively. RESULTS SLNB was successful in 92% of the patients. Axillary status was predicted with 90% accuracy and a false-negative rate of 13.7%. Patients with residual tumor size >2 cm had a decreased SLN identification rate (p=0.002). Axillary nodal status before NAC (N2 versus N1) was associated with higher false-negative rates (p=0.04). Positive non-SLN(s) were more frequent in patients with multifocal/multicentric tumors (versus unifocal; p=0.003) and positive lymphovascular invasion (versus negative; p=0.0001). SLN(s) positive patients with pathologic tumor size >2 cm (versus <or=2 cm; p=0.004), positive extra-sentinel lymph node extension (versus negative; p=0.002) were more likely to have metastatic non-SLN(s). CONCLUSIONS SLNB has a high identification rate and modest false-negative rate in LABC patients who became clinically axillary node negative after NAC. Residual tumor size and nodal status before NAC affect SLNB accuracy. Additional involvement of non-SLN(s) increases with the presence of multifocal/multicentric tumors, lymphovascular invasion, residual tumor size >2 cm, and extra-sentinel node extension.

Comparison of different injection sites of radionuclide for sentinel lymph node detection in breast cancer: single institution experience.

Background: There are still ongoing controversies about several aspects of lymphatic mapping and sentinel lymph node biopsy for breast cancer, including injection site of radioisotope and blue dye. This study aims to evaluate the success rate of different radiocolloid injection techniques in the detection of sentinel lymph nodes (SLN) in early breast cancer. Study Design: One hundred ninety-two women with early breast cancer were included. For SLN mapping with lymphoscintigraphy (LSG), 5 different injections were used. Group A (36 patients) had 4 peritumoral (PT), group B (n = 36) had 1 subdermal (SD) injection of Tc-99m rhenium sulfide colloid over the tumor quadrant. Group C (59 patients) had 1 PT and 1 SD combined injections. In group D (56 patients), lymphatic mapping was performed with 2 intradermal periareolar (ID-PA) injections. In group E (n = 41), 2 ID-PA and 1 PT combined injections were performed. Early dynamic and delayed images were obtained. A surgical gamma probe was used to explore the SLNs. Surgical specimens were evaluated histopathologically. The SLN identification rate, false negative rate, and comparison of groups were evaluated by statistical methods. Results: The SLN identification rate by LSG in groups A, B, C, D, and E were 72%; 92%, 93.2%, 98%, and 95%, respectively. The highest detection rates for the axilla (98%) and mammary internal (MI) drainage (22%) were obtained with ID-PA injections and a peritumoral injection, respectively. Seventy of 192 patients (36.4%) had positive axillary lymph nodes. The only statistically significant difference was between the PT and SD injection groups in axillary SLN identification rate by LSG (P = 0.016). Conclusion: The success rate was superior with intradermal periareolar injection compared with PT and SD injection to visualize the axillary SLN. However, PT deep injection combined with ID-PA injections may be more favorable to demonstrate the primary internal mammary (IM) lymphatic drainage.

Comparison of subdermal and peritumoral injection techniques of lymphoscintigraphy to determine the sentinel lymph node in breast cancer

Purpose: The purpose of this study was to evaluate 2 different injection techniques for lymphoscintigraphy to determine the axillary sentinel lymph node (SLN) in patients with breast cancer. Methods: Thirty-six patients with early breast cancer were studied prospectively. Both peritumoral (PT) and subdermal (SD) injections were performed on each patient with Tc-99m rhenium sulfide colloid. PT injections were done 1 to 8 days before surgery and SD injections were done on the day of operation. An intraoperative gamma probe was used to explore the axillary SLNs prior to tumor excision and axillary dissection. All surgical specimens were evaluated histopathologically. Results: In 19 of 36 patients, the same lymphatic drainage sites were observed with both techniques. Of these, 17 patients showed only axillary, 1 showed axillary and internal mammary (IM), and 1 showed axillary and subclavicular drainage sites. With PT injections 26 of 36 patients (72%), and with SD injections 33 of 36 patients (92%), showed axillary drainage and axillary SLNs. With PT injections 9 patients, and with SD injections only 2 patients, did not show any drainage site. During the operation with a gamma probe, axillary SLNs were excised in 35 patients (success rate, 97%). IM drainage was seen in 8 of 36 patients who underwent PT injections and in 3 of 36 with SD injections. Conclusion: The success rate was found to be higher with the SD injection technique than with PT injections to visualize the axillary SLN. To increase the visualization of both axillary and IM SLNs, it may be useful to perform lymphoscintigraphy with SD and PT injections together.

HER-2, TOP2A and chromosome 17 alterations in breast cancer

HER-2 amplification is a biomarker for identifying patients who respond to trastuzumab and has been evaluated as a factor predicting the response to anthracyclines. The relationship between HER-2 and response to anthracycline therapy may also be the result of the close localization of TOP2A on 17q. It has been a matter of debate whether these two genes, HER-2 and TOP2A, behave separately on different amplicons or act together thus making it possible to predict the TOP2A status from the HER-2 status. In this study TOP2A, HER-2 and chromosome 17 aneusomy were investigated by fluorescent in situ hybridization (FISH) in 50 consecutive breast cancer patients. HER-2 amplification was detected in 11 patients (22%) and TOP2A changes were seen in 6 patients (12%); two amplifications and two deletions were observed in HER-2-amplified cases and two deletions in HER-2-nonamplified cases. Three of the TOP2A-deleted cases had polysomy 17. HER-2 copy number was higher than the TOP2A copy number in one patient with co-amplification. Polysomy was observed in 9 cases (18%) and monosomy in 6 cases (12%). Aneusomy was the sole anomaly in 11 patients (22%). We conclude that the TOP2A status cannot be predicted from the HER-2 status and evaluation of the TOP2A status only in patients with HER-2 overexpression may lead to missing cases with TOP2A deletion with possible resistance to therapy. Other factors modulating topo IIα activity may also affect the response to therapy. Studies evaluating different parameters that can modulate topo IIα activity and the response to the drugs targeting the enzyme are necessary.

Prognostic role of nm23 gene expression in patients with ovarian cancer.

The aim of the study was to define the prognostic role of the metastasis suppressor gene, nm23, in 50 patients with primary ovarian cancer. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded specimens by the primary nm23 monoclonal antibody (Novocastra, NCL-nm23 clone 37.6). Forty-two specimens (84%) showed a positive nm23 staining. The nm23 staining was more intensive in patients with normal serum CA19.9 levels, patients with nonrecurrent disease, and alive patients (p < 0.05). Nm23 expression did not correlate with common clinicopathologic parameters such as histology, grade of differentiation, International Federation of Gynecology and Obstetrics stage, and CA-125. Although the difference was not statistically significant (p = 0.11), we found that nm23 may have a favorable prognostic factor in ovarian cancer. To clarify this subject further, prospective studies on a larger population are needed.

Positive or close margins in breast conserving surgery: Is re-excision always necessary?

BACKGROUND More than half of re-excision specimens after breast conserving surgery (BCS) are found to be free of residual tumor at definitive histology. The aim of this study was to identify clinicopathological factors along with intrinsic subtypes of the tumor (luminal A, luminal B, HER2-overexpressing, triple-negative) associated with residual tumor in re-excision or mastectomy specimen. METHODS Two hundred forty-eight patients with initial BCS, who underwent one or more re-excisions or mastectomy because of close or positive margins were reviewed. RESULTS Residual cancer was found in 50% of re-excision(s) or mastectomy specimens. Patients with multifocality (vs unifocality; OR = 5.2; 95% CI, 2.6-10.4) or positive nodes (vs negative nodes; OR = 2.5; 95% CI, 1.4-4.4), or positive margins (vs close margins; OR = 1.7; 95% CI = 1.0-2.9) were more likely to have residual tumor in re-excision or mastectomy specimen compared to others. CONCLUSION Our results suggest that further surgery is often indicated in patients with node positive or multifocal cancers or positive margins after BCS since residual disease cannot be ruled out. Re-excision or mastectomy could be omitted in patients with close margins with favorable factors such unifocal tumor or node negative disease.

Siegfried Oberndorfer: a tribute to his work and life between Munich, Kiel, Geneva, and Istanbul

In 1907 Siegfried Oberndorfer published his observations and interpretations on tumorlets (“Geschwulstchen”) in the small intestine, which he called carcinoids (“karzinoide Tumoren”). This article pursues the questions why this discovery was so unique and what role it played in the later life of Siegfried Oberndorfer.