Atanas Ignatov

An 11-year retrospective study of totally implanted central venous access ports: Complications and patient satisfaction

AIMS We wanted to assess the factors that predict complications and patient satisfaction of totally implanted central venous access ports (TIAP). METHODS We reviewed 550 patients with breast or gynaecological malignancies who had initial port placement for chemotherapy between 1995 and 2006. We retrospectively assessed all TIAP complications, port duration and follow-up care until the TIAPs were removed (or the last known recorded documentation) or until the death of the patient. TIAP-related patient satisfaction was also assessed via a questionnaire-based survey of 356 patients. RESULTS 561 TIAPs were placed in 550 cancer patients (11 patients received 2 TIAPs during the study period); the median time of port duration was 22.5 months. There were 104 complications in this group. Of these, 81 occurred during chemotherapy treatment that lasted a median time of 182 days. Removal secondary to complication was observed in 48 cases. TIAPs placed on the left chest side, through the subclavian vein or with the catheter tip localized in the peripheral part of superior vena cava demonstrated the highest incidence of complications. Patients with a BMI >28.75 had an increased risk for developing complications. Our follow-up questionnaire revealed a 93% patient satisfaction rate with the TIAP. CONCLUSIONS Patients with left-sided ports, catheter tips lying in the upper part of the superior vena cava and implantation via the subclavian vein are at a higher risk for TIAP-associated complications. Being excessively overweight was assessed as another risk factor for developing complications. TIAPs are highly accepted and further recommended by patients.

P16 alterations increase the metastatic potential of endometrial carcinoma.

OBJECTIVE The aim of this study was to investigate the role of p16 in tumorigenesis of endometrial carcinoma (EC). METHODS Expression of p16 protein was analyzed using immunohistochemistry. The methylation status of p16 promoter region was determined by methylation-specific PCR. Deletion analysis of the p16 gene was performed by PCR-analyses. RESULTS Aberrant protein expression of p16 was observed in 18 of 46 (39.2%) ECs and correlated significantly with p16 alterations, including gene deletions in 26 of 46 (56.5%) ECs and promoter hypermethylation in 8 of 46 (17.4%) ECs (p<0.001). A significant increase in the frequency of p16 alterations from early stage (I-II) to advanced stage (III-IV) ECs was observed (p=0.002). There was no significant correlation between p16 protein expression and the clinico-pathological features of EC. The development of metastases correlated significantly with the frequency of p16 alterations: p16 alterations were detected in 14 of 15 (93.3%) PTs with metastases and in only 18 of 31 (58.1%) PTs without metastases (p=0.018). The genetic comparison of 15 primary ECs and their paired metastases revealed that in most of the cases the deleted region of p16 gene remains the same or becomes larger during the progression from primary tumor to its corresponding metastases. CONCLUSION Our results suggest that p16 alterations and particularly p16 gene deletions in ECs are associated with increased incidence of metastases.

Role of GPR30 in endometrial pathology after tamoxifen for breast cancer.

OBJECTIVE This study was undertaken to evaluate the potential role of G-protein-coupled estrogen receptor in endometrial pathology associated with tamoxifen treatment of breast cancer patients. STUDY DESIGN We investigated whether G-protein-coupled estrogen receptor plays a role in mediating proliferating effect of tamoxifen in endometrial carcinoma cells. These results were compared with the G-protein-coupled estrogen receptor expression pattern in endometrial tissue from a cohort of 95 breast cancer patients, who received tamoxifen or another adjuvant therapy. RESULTS In vitro tamoxifen significantly stimulated the mitogen-activated protein kinase phosphorylation and cell proliferation of endometrial cell lines via G-protein-coupled estrogen receptor. In vivo, there was a significant correlation between G-protein-coupled estrogen receptor expression and the tamoxifen-induced endometrial pathology (P = .006). Moreover, G-protein-coupled estrogen receptor positivity was predictive of an earlier development of symptoms, such as bleeding or suspect endometrial thickness, induced by tamoxifen therapy (P = .019). CONCLUSION G-protein-coupled estrogen receptor plays an important role in tamoxifen-induced endometrial abnormalities.

APC promoter hypermethylation is an early event in endometrial tumorigenesis

The aim of the current study was to investigate the role of promoter methylation of adenomatous polyposis coli (APC) and epithelial cadherin (E‐cadherin) genes in endometrial tumorigenesis. The methylation status of both genes was investigated in 43 cases of normal endometrium, 21 simple hyperplasia, 17 atypical hyperplasia, and 86 endometrial carcinoma (EC). Additionally, the methylation pattern of both genes was analyzed in 24 primary ECs and their corresponding metastases. DNA methylation of the APC gene increased from atypical hyperplasia (23.5%) to endometrial carcinoma, reaching its highest level of 77.4% in early stage cancer (FIGO I and II) and decreasing stepwise to 24.2% in advanced stage carcinomas (FIGO III and IV). No methylation of APC was found in normal endometrium or simple hyperplasia. Methylation of E‐cadherin was found only in EC (22.1%). The mean age of the patients with aberrant APC methylation was 68.8 years and was significantly higher compared to the mean age (60.9 years) of the patients without methylation of APC promoter (P = 0.02). APC promoter methylation significantly correlated with decreased protein expression of APC (P = 0.039), with increased expression of the Ki‐67 proliferative marker (P = 0.006) and decreased metastatic potential (P = 0.002). There was no correlation between APC and E‐cadherin methylation patterns and the other clinicopathologic features, nor with patient outcome. Our results suggest that hypermethylation of APC promoter region is an early event in endometrial tumorigenesis. (Cancer Sci 2009)

GPER-1 Expression Decreases During Breast Cancer Tumorigenesis

GPER-1 protein expression was immunohistochemically examined in 164 primary breast cancer specimens and their matched normal breast epithelium. GPER-1 down-regulation correlated significantly with increased histological grading (p = .015), lymph node metastases (p = .032), and negative estrogen receptor status (p = .018). The decrease of GPER-1 expression in breast cancer tissue, relative to normal tissue, was associated with poor overall survival (p = .043) and disease-free survival (p = .037) and remained a significant unfavorable factor in multivariate analysis for DFS (HR = 1.569; 95% CI, 1.024–2.797; p = .041) and OS (HR = 2.082; 95% CI, 1.248–4.773; p = .039). Thus aberrant GPER-1 expression seems to be an important factor in breast cancer progression.

GPER functions as a tumor suppressor in triple-negative breast cancer cells

AbstractBackground The orphan, membrane-bound estrogen receptor (GPER) is expressed at high levels in a large fraction of breast cancer patients and its expression is favorable for patients’ survival.MethodsWe investigated the role of GPER as a potential tumor suppressor in triple-negative breast cancer cells MDA-MB-231 and MDA-MB-468 using cell cycle analysis and apoptosis assay. The constitutive activity of GPER was investigated.Results GPER-specific activation with G-1 agonist inhibited breast cancer cell growth in concentration-dependent manner via induction of the cell cycle arrest in G2/M phase, enhanced phosphorylation of histone H3 and caspase-3-mediated apoptosis. Analysis of the methylation status of the GPER promoter in the triple-negative breast cancer cells and in tissues derived from breast cancer patients revealed that GPER amount is regulated by epigenetic mechanisms and GPER expression is inactivated by promoter methylation. Furthermore, GPER expression was induced by stress factors, such as radiation, and GPER amount inversely correlated with the p53 expression level.ConclusionsOverall, our results establish the protective role in breast cancer tumorigenesis, and the cell surface expression of GPER makes it an excellent potential therapeutic target for triple-negative breast cancer.

Interval between Port Catheter Flushing Can Be Extended to Four Months

Background: Little is known about proper interval periods between the flushings of totally implantable access ports after completion of chemotherapy. Manufacturer guidelines recommend flushing catheters every 4 weeks. Methods: This retrospective study examined whether flushing less than every 4 weeks conferred any benefit. Results: 349 totally implanted access ports were divided into four groups based on the different durations of the intervals between flushings. Sixteen (4.6%) complications were observed in the study population. Conclusion: Our results demonstrate that extending the flushing interval to up to 4 months remains medically safe and drastically reduces the costs.

GPER functions as a tumor suppressor in MCF-7 and SK-BR-3 breast cancer cells.

AbstractPurposeThe orphan, membrane-bound estrogen receptor (GPER) is expressed at high levels in a large fraction of breast cancer patients, and its expression is favorable for patients’ survival. We investigated the role of GPER as a potential tumor suppressor in MCF-7 and SK-BR-3 breast cancer cells.MethodsThe effect of GPER agonist G-1 in cell culture was used to determine whether GPER inhibit cell growth. The methylation status of GPER promoter was investigated by methylation-specific PCR.Results GPER-specific agonist G-1 inhibited breast cancer cell proliferation in concentration-dependent manner via induction of the cell cycle arrest in M-phase, enhanced phosphorylation of histone 3 and cell apoptosis. Analysis of the methylation status of the GPER promoter in MCF-7 and SK-BR-3 cells revealed that GPER expression is regulated by epigenetic mechanisms and GPER expression is inactivated by promoter methylation. Overall, our results are consistent with our recent findings in triple-negative breast cancer cells, and the cell surface expression of GPER makes it an excellent potential therapeutic target for non-triple-negative breast cancer.

Acute hepatic failure following monotherapy with sunitinib for ovarian cancer.

To the editor Sunitinib (Sutent; PWzer Pharmaceuticals Group, New York, NY, USA) is an orally administered vascular endothelial growth factor (VEGF) receptor tyrosine-kinase inhibitor (RTK) with demonstrated cytotoxic activity against various malignant diseases [1, 2]. We present the case of a 49-year-old patient who died of fulminant hepatic failure following third-line monotherapy with sunitinib for ovarian cancer. The patient was diagnosed with stage IIb ovarian cancer in 2002 and after R0 surgery; she received Wrst-line chemotherapy. In 2006, second-line chemotherapy was started for disease recurrence, leading to a complete remission after six cycles. Nine months later, a tumor measuring 37 £ 42 £ 50 mm in the area of the left iliac vein was diagnosed again by CT scan. An explorative laparotomy was performed revealing an entirely inconspicuous abdominal cavity except for a tumorous lesion on the left pelvic wall, about 50 mm cranial of the inguinal ligament. The tumor was removed and histology revealed a lymph node metastasis of the ovarian cancer. Additional lymph nodes, multiple biopsies of the abdominal cavity and diaphragm, as well as peritoneal Xuid cytology showed no evidence of metastatic disease. Since recurrence occurred nine months after second-line therapy, necessity of third-line chemotherapy was discussed with the patient, but she refused due to toxicities experienced with the previous treatments. At this point, the possibility of oral therapy with sunitinib was discussed. Sunitinib inhibits, amongst others, the RTKs: platelet derived growth factor (PDGF), VEGF c-KIT (produced by the KIT gene) and colony stimulating factor (CSF)-1 whose expression has been reported in ovarian cancer [1, 3]. The risks and possible complications due to side eVects of sunitinib were explained to the patient and she was thoroughly informed about prohibited co-medication during the treatment. Sunitinib therapy was started, at a dose of 50 mg given orally once daily for 4 weeks every 6 weeks. Vital signs and laboratory analysis at the start of therapy were within normal limits. No toxicities except common terminology criteria for adverse events (CTCAE) grade 2 fatigue occurred during the Wrst 4 weeks of therapy. On day 26 of the treatment, the patient presented with CTCAE grade 4 fatigue and an Eastern Cooperative Oncology Group (ECOG) performance status of 3 and was hospitalized. Abnormal laboratory reports included bilirubin 1.1 mg/dl; alanine aminotransferase (ALT) 52.5 U/l; aspartate aminotransferase (AST) 49.2 U/l; gamma glutamyl transpeptidase ( GT) 83.4 U/l; and thyroidea stimulating hormone (TSH) 27.22 mIU/l. She received 75 g Levothyroxin daily for hypothyroidism as concomitant medication. A cranial CT scan did not reveal any abnormality. Therapy with sunitinib was stopped. Twelve hours after admission, the physical condition of the patient and laboratory results had dramatically worsened. Her conscious state deteriorated, she became hypoxic and was transferred to the Intensive Care Unit for intubation and supportive measures. Liver function deteriorated rapidly (Fig. 1), hepatitis serology was negative for HBsAg, and AntiHCV, AntiHBs was 281.2 IU/l. The patient died of liver failure 29 h after hospitalization, despite maximum supportive therapy measures. Immediate family members did not agree with an autopsy. Nevertheless, we believe that the liver failure was associated A. Taran · A. Ignatov · B. Smith · S. D. Costa · J. BischoV Women’s Clinic, Otto-von-Guericke University, Magdeburg, Germany

The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer

To date, blockade of growth factor receptors is the mainstay of targeted therapy in metastatic breast cancer (mBC). Monoclonal antibodies such as trastuzumab and bevacizumab represent the first generation of molecular-based therapies. Both the HER2 inhibitors and the vascular endothelial growth factor (VEGF) antagonists have shown synergism with a broad spectrum of established cytotoxins, thus being approved for first-line treatment of mBC in combination with taxanes. As a next step, tyrosine kinase inhibitors (TKIs) have been integrated into daily routine as an alternative approach for targeting HER2: The dual HER1/2 inhibitor lapatinib demonstrated activity in trastuzumab-pretreated mBC patients in combination with capecitabine. Furthermore, chemotherapy-free regimens (trastuzumab or lapatinib plus aromatase inhibitors) have been identified as additional options for hormone receptor (HR)- and HER2-positive patients. Recently published data indicate that a combination of two biologicals such as lapatinib and trastuzumab can be effective as a treatment beyond trastuzumab related progression. Multitarget TKIs have the potential to inhibit several signaling pathways involved in breast cancer-related angiogenesis. Until now, they have failed to show a clear benefit in mBC. On the other hand, poly(ADP-ribose) polymerase (PARP) inhibition, mediated by a new class of small molecules, is an interesting area of investigation. Future directions of research in HER2-positive breast cancer focus on the evaluation of novel antibodies (pertuzumab, T-DM1), and irreversible TKIs (neratinib, BIBW 2992) and inhibitors of HER2-related downstream signaling (mTOR, TORC 1/2, PI3K/Akt) and of receptor cross-talk (IGFR).