W. Tjalma

Trocar implantation metastasis after laparoscopy in patients with advanced ovarian cancer: can the risk be reduced?

OBJECTIVEnThe purpose of this study was to determine risk factors for trocar implantation metastasis after diagnostic laparoscopy in patients with primary or recurrent advanced ovarian cancer.nnnSTUDY DESIGNnEighty-three women with primary advanced ovarian cancer and 21 women with recurrent ovarian cancer undergoing a laparoscopy for a tissue diagnosis and for assessment of operability were included in the study. The occurrence of implantation metastasis at the trocar incision scars was analyzed according to clinicopathologic characteristics.nnnRESULTSnA recurrence developed at the trocar site in 7 (58%) of 12 patients undergoing a laparoscopy in which only the skin was closed at the end of the procedure and in 2 (2%) of 92 patients undergoing a laparoscopy with closure of all layers (odds ratio, 63; 95% confidence interval, 10.3-385; P <.001). The International Federation of Gynecology and Obstetrics stage at initial presentation, tumor histologic type, tumor differentiation, maximal tumor diameter at the time of diagnosis, estimated weight of the metastatic tumor, residual tumor after cytoreductive surgery, surgical characteristics, and type of chemotherapy were well balanced among both groups. Patients with implantation metastasis had significantly more ascites (median, 700 mL vs 300 mL; P =.032) and a longer interval between the start of platinum-based chemotherapy or cytoreductive surgery (median, 6 days vs 17 days; P <.01) compared with patients without abdominal wall recurrence. A palpable abdominal wall metastasis developed in none of the patients undergoing a laparoscopy with closure of all layers of the abdomen followed by cytoreductive surgery or chemotherapy within 1 week after the laparoscopy. Kaplan-Meier survival analysis showed that patients with abdominal wall implantation metastasis had a survival rate similar to that of the other patients.nnnCONCLUSIONSnLaparoscopy with careful closure of the peritoneum, rectus sheath, and skin followed by chemotherapy or cytoreductive surgery with excision of the trocar trajectories within 1 week is safe in patients with disseminated ovarian cancer.

Preoperative breast MRI in patients with invasive lobular breast cancer

To investigate the use of MRI in preoperative characterization of invasive lobular breast cancer (ILC) and in detection of multifocal/multicentric disease. We retrospectively reviewed T1-weighted FLASH 3D precontrast and postcontrast MR images together with subtraction images of 26 women with histopathologically proven invasive lobular cancer. Two experienced radiologists described tumor patterns of ILC independently. MR findings of unifocal, multifocal, single quadrant and multiquadrant disease were correlated with results of other imaging techniques and compared with histopathological findings as gold standard. Most ILC presented on MRI as a single spiculated/irregular, inhomogeneous mass (pattern 1, n=12) or as a dominant lesion surrounded by multiple small enhancing foci (pattern 2, n=8). Multiple small enhancing foci with interconnecting enhancing strands (pattern 3) and an architectural distortion (pattern 4) were both described in three cases. There was one case of a focal area of inhomogeneous enhancement (pattern 5) and one normal MR examination (pattern 6). Unifocal and multifocal lesions were identified on MRI in four patients with normal conventional imaging. In nine women, multiple additional lesions or more extensive multiquadrant disease were correctly identified only on MRI. MRI may play an important role in the evaluation of patients with ILC, which is often difficult to diagnose on clinical examination and conventional imaging and more likely occur in multiple sites and in both breasts. However, false-negative MR findings do occur in a small percentage of ILC.

The correlation of preoperative CT, MR imaging, and clinical staging (FIGO) with histopathology findings in primary cervical carcinoma

The aim of this study was to compare the preoperative findings of abdominal/pelvic CT and MRI with the preoperative clinical International Federation of Obstetrics and Gynecology (FIGO) staging and postoperative pathology report in patients with primary cancer of the cervix. Thirty-six patients with surgical–pathological proven primary cancer of the cervix were retrospectively studied for preoperative staging by clinical examination, CT, and MR imaging. Studied parameters for preoperative staging were the presence of tumor, tumor extension into the parametrial tissue, pelvic wall, adjacent organs, and lymph nodes. The CT was performed in 32 patients and MRI (T1- and T2-weighted images) in 29 patients. The CT and MR staging were based on the FIGO staging system. Results were compared with histological findings. The group is consisted of stage 0 (in situ):1, Ia:1, Ib:8, IIa:2, IIb:12, IIIa:4, IVa:6, and IVb:2 patients. The overall accuracy of staging for clinical examination, CT, and MRI was 47, 53, and 86%, respectively. The MRI incorrectly staged 2 patients and did not visualize only two tumors; one was an in situ (stage-0) and one stage-Ia (microscopic) disease. The MRI is more accurate than CT and they are both superior to clinical examination in evaluating the locoregional extension and preoperative staging of primary cancer of the cervix.

The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer

Vascular endothelial growth factor (VEGF)-A inhibitors exhibit unseen high responses and toxicity in recurrent epithelial ovarian cancer suggesting an important role for the VEGF/VEGFR pathway. We studied the correlation of VEGF signalling and AKT/mTOR signalling. Using a tissue microarray of clinical samples (N=86), tumour cell immunohistochemical staining of AKT/mTOR downstream targets, pS6 and p4E-BP1, together with tumour cell staining of VEGF-A and pVEGFR2 were semi-quantified. A correlation was found between the marker for VEGFR2 activation (pVEGFR2) and a downstream target of AKT/mTOR signalling (pS6) (R=0.29; P=0.002). Additional gene expression analysis in an independent cDNA microarray dataset (N=24) showed a negative correlation (R=−0.73, P<0.0001) between the RPS6 and the VEGFR2 gene, which is consistent as the gene expression and phosphorylation of S6 is inversely regulated. An activated tumour cell VEGFR2/AKT/mTOR pathway was associated with increased incidence of ascites (χ2, P=0.002) and reduced overall survival of cisplatin–taxane-based patients with serous histology (N=32, log-rank test, P=0.04). These data propose that VEGF-A signalling acts on tumour cells as a stimulator of the AKT/mTOR pathway. Although VEGF-A inhibitors are classified as anti-angiogenic drugs, these data suggest that the working mechanism has an important additional modality of targeting the tumour cells directly.

Enhancing area surrounding breast carcinoma on MR mammography: comparison with pathological examination

The enhancing area surrounding breast carcinoma on MR mammography is correlated with findings from pathological examination. We studied 194 patients with breast cancer who underwent preoperative MR mammography. Of all malignant lesions presenting with an enhancing surrounding area on MR mammography, morphologic features including long spicules, a ductal pattern, diffuse enhancement or nodules were evaluated and compared with histopathological examination. A double breast coil was used; we performed a 3D FLASH sequence with contiguous coronal slices of 2xa0mm, before and after injection of 0.2xa0mmol/kg GD-DTPA, and subtraction images were obtained. In total, 297 malignant lesions were detected at MR mammography and 101 of them had one or more types of enhancing surrounding area. In 49 of the 53 cancers with long spicules and in 49 of the 55 cancers with surrounding ductal pattern of enhancement, pathological examination showed in situ and/or invasive carcinoma. Multiple nodules adjacent to the carcinoma were seen in 20 patients and corresponded with six cases of invasive and ten cases of ductal in situ carcinoma. A diffuse enhancing area next to a mass was seen in ten patients and consisted of carcinoma in all cases: seven in situ and three invasive carcinomas. Enhancing areas including long spicules, a ductal pattern, noduli, or diffuse enhancement surrounding a carcinoma corresponded with in situ or invasive extension of the carcinoma in 92.5, 89, 80 and 100% of cases, respectively.

A phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancer

The majority of patients with hormone receptor-positive metastatic breast cancer die from disease progression despite different types of anti-hormonal treatments. Preclinical studies have indicated that resistance to anti-hormonal therapies may be the result of an activated NF-κB signalling pathway in breast cancer. Bortezomib is a proteasome inhibitor that blocks the NF-κB pathway. Recent pharmacodynamic and pharmaco-kinetic xenograft studies have shown that drug exposure may be a crucial factor for the efficacy of bortezomib in solid tumours. The aim was to investigate whether the addition of bortezomib to anti-hormonal therapy would result in regained antitumour activity in patients with progressive and measurable disease being treated with an endocrine agent. Clinical benefit was defined as patients obtaining stable disease, partial response or complete response after 2 cycles, lasting for at least another five weeks. Bortezomib was administered on days 1, 8, 15 and 22 of a 5-week regimen (1.6xa0mg/m2). Eight patients received an aromatase inhibitor and bortezomib, while one received tamoxifen and bortezomib. There were 3 grade 3 gastrointestinal toxicities. Median time to treatment failure was 69 days (range, 35-140). Two out of the 9 patients had stable disease for more than 10 weeks. Despite an effective target inhibition, suggested in peripheral blood mononuclear cells and available tumour samples, no objective antitumour responses were observed. Addition of a proteasome inhibitor to anti-hormonal therapy resulted in a clinical benefit rate of 22% in a limited number of patients with endocrine resistant and progressive metastatic breast cancer. The demonstrated proteasome inhibition in tumour tissue provides evidence that the lack of clinical responses is not attributed to deficient drug exposure.

Invasive papillary carcinoma of the male breast

Abstract. Intracystic papillary carcinoma of the male breast is a very rare disease with only a few cases reported in the literature. A case is described and the additional value of MRI is discussed. To our knowledge, this is the first report regarding the MRI findings of an intracystic papillary carcinoma of the male breast.

Angiogenic escape and tumour progression in two patients with metastatic breast cancer receiving bevacizumab treatment.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 AbstractsnnAbstract #1029 nnBackground: Vascular endothelial growth factor A (VEGF-A) has an important role in tumour progression by promoting angiogenesis. VEGF-A inhibitors, such as bevacizumab (Bev) and VEGF-Trap are being introduced into the treatment of breast cancer in order to target angiogenesis by inhibiting VEGF-A. Material and Methods: Two patients with metastatic breast cancer are described having tumour progression while being treated with single agent Bev. Both patients participated in the AVADO clinical phase III study, where shown to have received Bev in combination with docetaxel (D) as first line treatment for metastatic breast cancer. The first patient (A) had received 6 cycles of D and Bev and was for 4 months on single agent Bev (15mg/kg/3wk) before progressing. Pt B had received 9 cycles of D and Bev and was on 7 months of single agent Bev (15mg/kg/3wk) before disease progression. Tumour biopsies of progressing lesions were obtained after informed consent. Routine histological assessment and a CD34/Ki67 double staining were performed on their primary tumour as well as on the newly developed metastasis (A+B). Chalkley counts (CC) and endothelial cell proliferation fractions (ECP) were assessed by two independent observers. RT-PCR Taqman low density arrays with a gene panel of 94 angiogenesis related genes were performed in triplicate on both metastasis and compared to 10 other primary breast tumours. Results: Both lesions showed a high CC, respectively 7.5±0.62 (A) and 4.8±0.2 (B). Both lesions had elevated ECP values of 14% (A) and 8% (B). Using the 2 (-__CT) method and 18S as an internal control, the VEGFR1 mRNA was highly overexpressed in both A (25.18±0.12 fold change) and B (38.60±0.07 fold change) compared to the mean of 10 unselected primary breast tumours serving as controls (p<10-7). Similarly, in metastasis B, VEGF-B, TGFB1 and PDGFRA were found to be overexpressed, i.e. out of range [min-max] of the 10 primary breast tumours. A had out of range overexpression of VEGF-C. The gene expression of VEGF-A, VEGF-D, VEGFR2, VEGFR3, PDGFB and PDGFRB in both A and B were found to be in the range of the 10 controls. Conclusion: We describe two patients with progressive disease while being treated with Bev after an initial response on the combination of D and Bev. These new sites of disease showed a highly angiogenic and apparently vascular dependent growth pattern, in spite of high dosed anti-VEGF-A regimen. This suggests the existence of an important VEGF-A independent alternative modality of the tumour to promote angiogenesis. VEGFR1 was remarkably overexpressed in both metastases compared to controls. The expression of placental growth factor, a VEGFR1 specific ligand is further being explored. Knowledge of the biology of Bev resistance is essential since it could be useful in designing well considered combinations of targeted therapies.nnCitation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1029.

Abstract P1-01-24: Preoperative ultrasound staging of the axilla superfluous peroperative examination of the sentinel node

Background: Axillary surgery in breast cancer is tailored. The current standard is to perform a frozen section or dep examination of the sentinel node during surgery. If the sentinel node is found positive (≥ macrometastases) a complete axilliary resection is recommended. Preoperative identification of positive nodes will lead to a further improvement of the tailored therapy. Hypothesis: A percentage of less than 5% of patients who would needed an additional operation is considered acceptable. Material and Method: From 2010 – 2012 all breast cancer patients of the Multidisciplinary Breast Clinic Antwerpen had an ultrasound evaluation of the axilla as part of their staging. Fine needle aspiration cytology was performed of suspicious lymph nodes. If this showed to be positive, sentinel node biopsy was bypassed. Patients with normal nodes or benign/non diagnostic biopsy had removal of the sentinel node(s) without peroperative pathological examinations. Results: A total of 275 breast patients had an ultrasound staging (table 1). The sensitivity, specificity, positive predictive value and negative predictive value was respectively 90%, 85%, 77% and 94%. Ten of the 275 patients (3.6%) needed an axillary clearance as a second procedure. Discussion Preoperative detection of invaded lymph nodes has several advantages. First of all it will allow you to identify patients with positive nodes, who can participate in neoadjuvant trial. Secondly it will save operating time and avoid overloading of the system for direct examination and reduces tissue loss. This approach will reduce costs for the health system and anesthetic time for the patient, with an acceptable reoperation rate. Conclusion Preoperative evaluation ultrasound staging of the axillare lymph nodes will avoid peroperative examination of the sentinel node at an acceptable reoperation rate. It is better for the patient, the physicians and the health care system. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-24.

Oncogenic Pathway Signatures and Survival Outcome

Recent microarray technology and bioinformatics have shown the ability of analysing oncogenic cellular signalling pathways based upon gene signatures in cancers. (Bild et al., 2006; Dressman et al., 2007; Gatza et al., 2010) Epithelial ovarian cancer (EOC) is the most important cause of mortality among gynaecological cancers. Patients with EOC often present in an advanced stage. Treatment modalities consist in general of the sequence of surgical cytoreduction and platinum-taxane based chemotherapy. (Cannistra, 2004) Although the disease is relatively sensitive to cytotoxics, relapses occur in a majority of patients with advanced stage. (Cannistra, 2004) The emergence of resistance to conventional chemotherapeutics is an often-deadly event in the management of ovarian cancer patients. There is an urgent need for additional therapies that increase survival and/or quality of life in these patients. The objective of our study was to look for cellular pathways that have an effect on survival outcome by a bioinformatical approach. (Trinh et al., 2011) These pathways may guide us to find interesting targets in ovarian cancer. Survival can be used as a measure to quantify the biological relevance in this disease. Ideally, evaluation of survival outcome should be made in a homogenous population with a uniform treatment to avoid treatment-induced biases and uniform histology to find subtler differences independent from histology. Another methodology of estimating prognostic value may be the correlation with documented prognostic gene signatures that have shown to be of prognostic value in breast cancer and other types of cancer. The invasiveness gene signature (IGS) was generated using stem celllike or tumorigenic breast cancer cells.(Liu et al., 2007) This signature has shown prognostic value in lung cancer, medulloblastoma and prostate cancer. The Wound healing response (WHR) signature, based upon genes induced by wound healing, also has shown its prognostic value in breast cancer, NSLC and bladder cancer. (Chang et al., 2005; Lauss, Ringner, & Hoglund, 2010; Mostertz et al., 2010) The genomic grade index (GGI) is a signature that divides low-grade versus high-grade breast carcinomas. (Sotiriou et al., 2006) Interestingly, using this signature, histological intermediate-grade tumours could be classified as lowor high-grade tumours with the preservation of the gene signatures’ prognostic value.