The Outcome of Patients with Triple Negative Breast Cancer: The Turkish Oncology Group Experience.

OBJECTIVE: Triple negative breast cancer (TNBC) is generally considered as a poorer prognostic subgroup, with propensity for earlier relapse and visceral involvement. The aim of this study is to evaluate the outcome of non-metastatic TNBC patients from different centers in Turkey and identify clinical and pathologic variables that may effect survival. MATERIALS AND METHODS: Between 1993-2007, from five different centers in Turkey, 316 nonmetastatic triple negative breast cancer patients were identified with follow-up of at least 12 months. The data was collected retrospectively from patient charts. The prognostic impact of several clinical variables were evaluated by the Kaplan-Meier and Cox multivariate anayses. RESULTS: Mean age at diagnosis was 49 years (range: 24-82). The majority of the patient group had invasive ductal carcinoma (n: 260, 82.3%) and stage II disease (n: 164; 51.9%). Majority of the patients (87.7%) received adjuvant chemotherapy. 5 year overall survival (OS) and disease-free survival (DFS) rates were 84.6% and 71.6%, respectively. Univariate analysis revealed locally advanced disease (p: 0.001), advanced pathological stage (p: 0.021), larger tumor size (T1&T2 vs T3&T4) (p<0.001), nodal positivity (p: 0.006), and extensive nodal involvement (p<0.001) as significant factors for DFS; whereas, advanced pathological stage (p: 0.017), extensive nodal involvement (p<0.001) and larger tumor size (p: 0,001) and presence of breast cancer-affected member in the family (p=0.05) were identified as prognostic factors with an impact on OS. Multivariate analysis revealed larger tumor size (T3&T4 vs T1&T2) and presence of lymph node metastases (node-positive vs node-negative) as significant independent prognostic factors for DFS (Hazard ratio (HR): 3.03, 95% CI: 1.71-5.35, p<0.001 and HR: 1.77, 95% CI: 1.05-3.0, p=0.03, respectively). Higher tumor stage was the only independent factor affecting overall survival (HR: 2.81; 95% CI, 1.27-6.22, p=0.01). CONCLUSION: The outcome of patients with TNBC in this cohort is comparable to other studies including TNBC patients. Tumor size and presence of lymph node metastasis are the major independent factors that have effect on DFS, however higher tumor stage was the only negative prognostic factor for OS.

Relationship between antimetabolite toxicity and pharmacogenetics in Turkish cancer patients.

INTRODUCTION: Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration. PATIENTS AND METHODS: Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5' UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms. RESULTS: Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population. CONCLUSION: Pharmacogenetics might contribute to tailored therapy.

Long-term outcome of mesna, ifosfamide, mitoxantrone, etoposide (MINE) regimen as a consolidation in patients with aggressive non-Hodgkin lymphoma responding to CHOP.

In aggressive non-Hodgkin lymphoma (NHL), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) regimen has been standard for decades, and rituximab has increased response rates and survival in CD20 positive patients, recently. The aim of this prospective trial was to evaluate the long-term efficacy and toxicity of MINE as a consolidation treatment in aggressive NHL patients who had achieved CR or unproven CR after six cycles of CHOP in the first line setting. The primary end-point was disease-free-survival (DFS). Thirty-eight patients were enrolled between February 1992 and May 2000. All of the patients received two cycles of MINE (mesna 1.3 g/m(2), ifosfamide 1.3 g/m(2), etoposide 65 mg/m(2) on days 1-3, and mitoxantrone 12 mg/m(2) on day 1, every 3 weeks) following response to CHOP. Initial bulky disease sites were also applied radiotherapy. Male/female ratio was 1.53(23/15). Median age was 49(30-73). Most of the patients had advanced stage (84.2% for stage >3) and high IPI score (79% for IPI score >2). Sixty percent had diffuse large cell histology. Median follow-up time was 118 months (9-195). Actual mean dose intensity was 88%. There were seven febrile neutropenia episodes. Two patients had grade two neuropathy, one had grade three mucositis and another one had non-neutropenic pneumonia. There was no early toxic death. No serious late toxicity was observed during long-term follow-up. Five- and 10-year DFS rates were both 65.3%. DFS rate in the patients with more than two poor prognostic factors according to IPI score is remarkably high (88%). Five- and 10-year OS was 62.5 and 59%, respectively. MINE regimen seems to be effective as a consolidation regimen, especially, in intermediate/high risk patients and has low early and late toxicities, and it warrants to be evaluated in phase III randomised trials with rituximab in CD20 positive aggressive NHL patients.

Fine needle aspiration biopsy features with histologic correlation in mediastinal hepatoid yolk sac tumor presenting with sternum metastasis: a case report.

BACKGROUND: The hepatoid variant of yolk sac tumor (H-YST) is an exceedingly rare and highly malignant neoplasm. We present and discuss our experience with cytologic and histopathologic features of a mediastinal H-YST presenting with sternum metastasis, which to the best of our knowledge has not been previously reported. CASE: A 38-year-old man presented with a large mass on the sternum. Computed tomography of the thorax showed a large anterior mediastinal mass with sternum metastsis and multiple lung metastases. Laboratory examination revealed elevated serum alpha-fetoprotein (60,000 IU/mL). No tumor was found in the other organ systems. A percutaneous fine needle aspiration biopsy and subsequent open surgical biopsy were performed on the sternum metastasis. Cytologically, the tumor was composed of monotonous, large, round to polygonal hepatoid cells forming solid sheets and trabeculae entrapped with endothelial cells resembling hepatocellular carcinoma. Histopathologic sections of tumor showed tumor cells with eosinophilic to clear cytoplasm arranged in a solid, trabecular growth pattern, with some acinar formations. Immunohistochemical study supported the hepatoid origin. CONCLUSION: Fine needle aspiration cytology, together with the characteristic clinical presentations and specific tumor markers, is crucial to the initial diagnosis of H-YST.

Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer.

BACKGROUND: In this non-randomized study we aimed to assess the efficacy of the addition of low molecular weight heparin (LMWH) to gemcitabine (GEM) plus cisplatinum (CDDP) combination chemotherapy on survival by prevention of thromboembolic complications in patients with advanced pancreatic cancer (APC). PATIENTS AND METHODS: Between November 1999 and February 2004, 69 consecutive patients with APC were treated with GEM (800 mg/m2, day 1, day 8) plus CDDP (35 mg/m2, day 1, day 8) every 21 days +/-LMWH (nadroparine calcium, 2,850 IU/day until disease progression). Ten out of 35 patients in LMWH group and 10 out of 34 patients in chemotherapy alone group had primary inoperable locally advanced disease and the rest of the patients had metastatic disease. RESULTS: Total response rate was 58.8% (11.7% CR) for the patients treated with LMWH and 12.1% for those treated without LMWH (P = 0.0001). LMWH group had a better median time to progression (TTP) and survival when compared to control group (7.3 vs. 4.0 months, P = 0.0001; 13.0 vs. 5.5 months, P = 0.0001). The toxicity was similar and acceptable in both groups. CONCLUSION: Addition of LMWH to GEM plus CDDP combination significantly improved the response and survival in patients with APC and the current schedule deserves to be tested in phase III trials.

Alpha fetoprotein producing gastric hepatoid adenocarcinoma.

Gastric carcinoma generally as presents adenocarcinoma and rarely shows a hepatoid pattern, it may or not produce alpha-fetoprotein. The interpretation of the lesion may be difficult in a patient with a hepatic mass and raised alpha-fetoprotein level. A 51 year old man with hepatoid adenocarcinoma in stomach, producing alpha-fetoprotein is presented.

Divided dose of cisplatin combined with gemcitabine in malignant mesothelioma.

Malignant mesothelioma is a rare but notoriously chemoresistant tumor. An impressive activity of gemcitabine and cisplatin combination in malignant mesothelioma has been shown. However, the hematological toxicity and nephrotoxicity related to this regimen affect the patient's life negatively. The aim of this study is to investigate the efficacy and toxicity of divided dose of cisplatin combined with gemcitabine in chemo-naïve patients with malignant mesothelioma. Twenty-six eligible patients with malignant mesothelioma were enrolled onto the study. Cisplatin 35 mg/m(2) and gemcitabine 800 mg/m(2) were administered on days 1 and 8 as intravenous infusion in a 3-week cycle, up to maximum 6 cycles. Response and toxicity evaluations were performed in 26 patients. Male-female ratio was 11/15 with a mean age of 50.5 years (37-70). Locations of tumor were pleura in 16 patients, and peritoneum in 10 patients. All patients had epitheloid subtype of malignant mesothelioma. The partial response and stable disease were observed in 6 patients (23.1%) and in 13 patients (50%), respectively, with an overall tumor control rate of 73.1%. Seven patients (26.9%) had progressive disease. Median time to disease progression and survival were 4 and 19.5 months, respectively. Grade 3 nausea and vomiting were observed in one patient (3.8%), grade 4 neutropenia developed in one patient (3.8%) and grades 3-4 thrombocytopenia and nephrotoxicity did not develop. There was no treatment related death. Divided dose of cisplatin combined with gemcitabine, at the current dosage and schedule, appears to be an active regimen in chemotherapy-naïve patients with malignant mesothelioma, and well-tolerated.

Significance of inducible nitric oxide synthase expression in benign and malignant breast epithelium: an immunohistochemical study of 151 cases.

The role of calcium independent inducible nitric oxide synthase (iNOS) in breast carcinoma is controversial, and the implications of iNOS expression on prognosis are not known. In this study, we aimed to investigate the significance of immunohistochemical iNOS expression in 100 invasive ductal carcinomas. In addition, 11 normal breast tissues, 20 cases of usual ductal hyperplasias (UDHs) and 20 fibroadenomas were included. We found that 78% of malignant and 75% of benign cases showed iNOS immunoreactivity. However, the intensity and the quantity of iNOS expression were significantly higher in the cancer group when compared with benign breasts (P<0.001), suggesting a role of iNOS in breast carcinogenesis. We were unable to show a correlation between iNOS expression and tumor grade, axillary lymph node status, and estrogen receptor expression. In 50 axilla negative cases having 5--12 years follow-up, disease free survival (DFS) rate was significantly lower in cases showing strong iNOS expression (P=0.05). As strong iNOS expression was correlated with short DFS, we concluded that further studies would be necessary to elucidate if iNOS expression might be a useful prognostic marker in breast carcinoma, especially in the axilla negative group.