TWIST1 Gene Expression as a Biomarker for Predicting Primary Doxorubicin Resistance in Breast Cancer.

Doxorubicin is one of the most commonly used chemotherapeutic agents for adjuvant chemotherapy of breast cancer. In the studies focused on finding biomarkers to predict the response of the patients and tumors to the drugs used, the Twist transcription factor has been suggested as a candidate biomarker for predicting chemo-resistance of breast tumors. In this study, we aimed to investigate the relationship between TWIST transcription factor expression and the effectiveness of doxorubicin treatment on directly taken primary tumor samples from chemotherapy-naive breast cancer patients. Twenty-six primary breast tumor samples taken from 26 different breast cancer patients were included in this study. Adenosine triphosphate tumor chemo-sensitivity assay (ATP-TCA) has been used to determine tumor response to doxorubicin and real-time reverse-transcription polymerase chain reaction (RT-PCR) was used for analyzing the TWIST1 gene expression of tumors. There was a significant difference in TWIST gene expression between responder and non responder tumors (p <0.05). The TWIST gene expression of the drug-resistant group was higher than the responsive group. This difference was not dependent on the histopathological features of tumors. In conclusion, compatible with earlier studies that have been performed with cell lines, the current study supports the role of higher TWIST gene expression as a biomarker for predicting the response of breast tumors to chemo-therapeutic agent doxorubicin.

Is there any diagnostic value of serum protease-activated receptor-1 (PAR1) levels on determination of epithelial ovarian carcinoma?

The role of molecular markers in ovarian cancer is still a matter of debate. Protease-activated receptor-1 (PAR1) might be a good marker in some types of malignant tumors and might provide useful information in diagnosis and prognosis. The objective of this study was to evaluate the serum levels of PAR1 in regard to diagnostic, predictive, and prognostic value in epithelial ovarian cancer (EOC) patients. Forty-four EOC patients were enrolled in this study. Serum PAR1 levels were determined by enzyme-linked immunosorbent assay (ELISA) method. Twenty-five age- and sex-matched healthy controls were included in the analysis. The median age of patients was 58 years old, ranging from 22 to 83 years, where most of them had advanced disease (stage III-IV) (n = 40, 91%). The median serum PAR1 values were significantly elevated in patients compared to healthy controls (1.52 ng/ml vs. 1.13 ng/ml) (p = 0.03), whereas any clinical variables including response to chemotherapy did not associate with serum assay (p > 0.05). Progression-free survival (PFS) and overall survival (OS) of patients who did not respond to chemotherapy nor had platinum resistance in relapsed disease were poorer in the analyses. On the other hand, serum PAR1 levels showed no significant adverse effect on either PFS or OS (p = 0.43 and p = 0.49, respectively). These results proved that baseline serum PAR1 levels of patients with EOC were significantly higher than those of healthy people. However, these assays suggested no predictive or prognostic value in this group of patients.

The diagnostic, predictive, and prognostic role of serum epithelial cell adhesion molecule (EpCAM) and vascular cell adhesion molecule-1 (VCAM-1) levels in breast cancer.

The purpose of this study was to determine the clinical significance of vascular cell adhesion molecule-1 (VCAM-1) and epithelial cell adhesion molecule (EpCAM) in breast cancer (BC) patients. Ninety-six BC patients and 30 age- and sex-matched healthy controls were enrolled into this study. Pretreatment serum markers were determined by the solid-phase sandwich (enzyme-linked immunosorbent assay (ELISA)). The median age at diagnosis was 48 years (range 29-80 years). Majority of the patients (71 %) had luminal subtype, and 38.5 % had metastatic disease. Twenty-nine (30 %) patients showed tumor progression, and 20 (21 %) patients died during follow-up. Median progression-free survival (PFS) and overall survival (OS) were 8.6 ± 1.7 and 35.5 ± 1.5 months, respectively. The baseline serum EpCAM levels of the patients were significantly higher than those of the controls (p < 0.001). There was no significant difference in the serum levels of VCAM-1 between the patients and controls (p = 0.47). No significant correlation was detected between the levels of the serum markers and other clinical parameters (p > 0.05). Patients with HER-2-positive and triple-negative tumors had significantly poorer PFS (p = 0.04 and p = 0.001, respectively), while metastatic disease and chemotherapy unresponsiveness had significantly adverse effect on OS analysis (p < 0.001 and p < 0.001, respectively). Neither serum VCAM-1 levels nor serum EpCAM levels were identified to have a prognostic role on either PFS or OS (VCAM-1 p = 0.76 and p = 0.32; EpCAM p = 0.16 and p = 0.69, respectively). Even though any predictive or prognostic role could not be determined for both markers, serum levels of EpCAM were found to have diagnostic value in BC patients.

Favorable outcome with sentinel lymph node biopsy alone after neoadjuvant chemotherapy in clinically node positive breast cancer at diagnosis: Turkish Multicentric NEOSENTI-TURK MF-18-02-study.

PURPOSE: Factors affecting local outcome were evaluated in patients with clinically node-positive (cN+) breast cancer at diagnosis, who underwent sentinel lymph node biopsy (SLNB) alone after neoadjuvant chemotherapy (NAC). METHODS: Between 2004 and 2018, 303 cytopathology-proven cN (+) patients in a multicentric registry, who received NAC and underwent SLNB alone were analysed. All patients had regional nodal irradiation. RESULTS: Median age was 46 (23-70). Of those, 211 patients had ypN0 disease (69.6%), whereas 92 patients had ypN (+) disease including 19 (20.6%) isolated tumor cells (ITC), 33 micrometastases (35.9%) and 40 macrometastases (43.5%). At a median follow-up of 36 months (24-172), one patient (0.3%) with macrometastatic SLN was found to have locoregional recurrence as chest wall and supraclavicular LN metastases at the 60th month. Five-year disease-free survival (DFS) and disease specific survival (DSS) rates were 87% and 95%, respectively. Patients with cT3/4 (HR = 2.41, 95% CI; 1.14-5.07), non-luminal molecular pathology (HR = 2.60, 95% CI, 1.16-5.82), and non-pCR in the breast (HR = 2.11, 95% CI, 0.89-5.01) were found to have an increased HR compared to others in 5-year DFS. However, no difference could be found between ypN0 and ypN ITC and micrometastasis (HR = 1.23, 95% CI, 0.44-3.47), whereas there was a slight increase in HR of patients with ypN macrometastasis versus ypN0 (HR = 1.91, 95% CI, 0.63-5.79). CONCLUSION: ALND could be avoided in meticulously selected cN (+) patients who underwent SLNB after NAC having breast and/or nodal pCR, cT1-2, or low volume residual nodal disease with luminal pathology, as long as axillary radiotherapy is provided.

Detection of human papillomavirus DNA by polymerase chain reaction and southern blot hybridization in colorectal cancer patients.

PURPOSE: The molecular mechanisms related to colorectal carcinogenesis are controversial. The purpose of this study was to evaluate the possible role of high-risk oncogenic human papillomavirus (HPV) types in the pathogenesis of colorectal cancer. PATIENTS AND METHODS: Tumor, and corresponding normal mucosal tissue specimens were obtained soon after surgery from 56 patients with colorectal adenocarcinoma. We studied both neoplastic and normal colon tissues for the presence of HPV types 6, 11, 16, 18, and 33. After the isolation of DNA, the presence of specific types of HPV DNA was determined by polymerase chain reaction (PCR) and southern blot hybridization. RESULTS: HPV DNA was detected in 46 (82.14 %) of 56 colorectal adenocarcinomas and in 18 (32 %) of 56 normal colonic mucosal tissue samples. Two or more HPV types were detected in 32 carcinoma samples. HPV type 18 (n= 40) and 33 (n= 32) were the most frequently detected types of HPVs in the tumor tissues. None of the normal mucosal specimens revealed HPV 18 DNA. The expression rate of HPV DNA in tumor tissue was significantly higher than that encountered in normal colonic mucosa (p <0.001). CONCLUSION: Detection of HPV DNA types 18 and 33 in most of the colorectal adenocarcinoma specimens suggests that HPVs may be related to carcinogenesis in glandular cells of the colorectal mucosa of our patient population.

MAPK overexpression is associated with anthracycline resistance and increased risk for recurrence in patients with triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer is estimated to account for 15%-20% of all patients with breast cancer and is considered as a prognostically unfavorable subset. The aim of this study is to evaluate the prognostic impact of various molecular factors in patients with triple-negative breast cancer. PATIENTS AND METHODS: Tumor specimens from 109 patients with receptor-negative (estrogen receptor and progesterone receptor) breast cancer were analyzed for mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR) and phosphoinositol-3-kinase (PI3K) expression by immunohistochemistry. The prognostic significance of these molecular factors, in addition to various prognostic variables, was investigated. RESULTS: Fifteen (13.8%), 38 (34.9%) and 33 patients (30.3%) had positive staining for EGFR, MAPK and PI3K, respectively. MAPK was associated with anthracycline resistance (P = 0.008) and lower MAPK score was significantly associated with shorter disease-free survival (P = 0.029). Survival following relapse was significantly worse for those with a higher MAPK score (P = 0.03). CONCLUSION: MAPK is a significant prognostic and predictive factor in patients with triple-negative breast cancer. Furthermore, the level of staining among those with a positive MAPK expression may play a prognostic role at different stages of relapse. Further translational research is required to elucidate molecular mechanisms of tumor proliferation in this subset of patients.

Preoperative chemotherapy for T2 breast cancer is associated with improved surgical outcome.

BACKGROUND: The aim of this study is to compare the clinical outcome in T2 breast cancer patients who underwent preoperative chemotherapy (PC) and who did not. The study also tried to define a subgroup of patients, who are more beneficial after PC in terms of lower re-excision rates, better cosmetic results and local recurrence free survival. MATERIALS AND METHODS: 251 consecutive patients treated for nonmetastatic T2 invasive breast cancer were analyzed retrospectively. Of those; 141 underwent primary surgery (PS) followed by chemotherapy, whereas 110 were treated with combination of PC and surgery. RESULTS: The patients who were treated with PC had a significantly higher incidence of negative margins and lower rate of re-excision (5% vs. 16%, p = 0.02). Of all patients attempted breast conserving surgery (BCS), patients in the PC group were more likely to undergo BCS as their definitive operation compared to patients with PS group (BCS rates; PC group: 99% vs. PS group: 92%, p = 0.05). Multifocal disease (OR: 7, 95% Cl, 2.7-18.4, p = 0.0001) and PC (OR = 0.2; 95% CI, 0.06-0.72, p = 0.01) were factors associated with margin positivity in patients treated with BCS. There was no statistically significant difference in 5 year local-recurrence free survival rates between 2 groups. CONCLUSIONS: Our study shows that PC significantly decreases the re-excision in patients undergoing BCS with primary T2 breast tumors. This data suggests that any patient with a tumor greater than 2 cm might be considered for PC to increase BCS success with final negative margins.

Combined effects of epirubicin and tamoxifen on the cell-cycle phases in estrogen-receptor-negative Ehrlich ascites tumor cells.

Laboratory and clinical data suggest some interactions between cytotoxic agents and tamoxifen. The mechanisms of these interactions differ in estrogen-receptor-negative cell lines. The ability of tamoxifen to modify the effects of epirubicin on the cell-cycle phases of estrogen-receptor-negative Ehrlich's carcinoma ascitic cells (EATC) was studied in mice. The results showed that combination of tamoxifen with epirubicin decreased the thymidine labelling index more effectively than did either drug alone. Adding tamoxifen to epirubicin treatment induced both an early S-phase and G2-M-phase arrest and a later G0-G1-phase arrest in EATC. An increase of S0 cells in the quiescent fraction could play a role in these changes, and some of these quiescent cells may not be viable, causing them to die later. In conclusion, the data suggest that continuous exposure to tamoxifen might modify the effects of epirubicin via cell-cycle perturbations.

The efficacy of a five-drug antiemetic combination during chemotherapy regimens containing cisplatin or cyclophosphamide-doxorubicin.

A five-drug combination, including metoclopramide, thiethylperazine, diphenhydramine, dexamethasone, and diazepam, was given to 32 patients during three consecutive treatments with chemotherapy. Eighteen patients (group A) were treated with a cisplatin-containing regimen, and 14 patients (group B) were treated with a cyclophosphamide- and doxorubicin-containing chemotherapy. In group A, complete responses were lower on the first day than on the second and third days (P < 0.015 and P < 0.041, respectively), during the first and second courses. The five-drug antiemetic regimen seems safe and effective. These results show that clinical trials that evaluate antiemetic efficacy in cisplatin-containing chemotherapy regimens should evaluate at least two consecutive courses.

Vascularization pattern of C6 glioma is modified with medroxyprogesterone acetate and ibuprofen in Wistar rat brain.

Beneficial effects of medroxyprogesterone acetate (MPA) in cancer therapy is partly mediated via its antiangiogenic activity. The same is true for the antitumoral action of non-steroidal antiinflammatory drugs. We have studied two liposoluble drugs, MPA and the analgesic ibuprofen, on glioma vascularization in vivo. In this study we have shown that, until the sacrifice at 27. day after tumor inoculation in the right hemisphere, MPA had a slight though insignificant activity to reduce the fatality of C6 glioma, growing in right cerebral hemisphere of male Wistar rats. But ibuprofen both alone or with MPA had no effect on survival with gavage application of a 30 mg/kg/day dosing regime. On histological analysis, intra- and peritumoral vessels were counted. Progesterone seemed to lower intratumoral, but to increase peritumoral vessels, especially glomeruloids, around the tumor mass. Coadministration of ibuprofen acted to suppress the peritumoral vessel increase, and to enhance lymphomonocytic infiltration around tumor vessels.

Acute myocardial infarction in man treated with epirubicin for non-Hodgkin lymphoma.

This article presents a young patient affected with non-Hodgkin lymphoma who developed acute myocardial infarction 7 days after treatment with epirubicin (90 mg/m2, day 1), cyclophosphamide (600 mg/m2, day 1), vincristine (2 mg, day 1), prednisolone (100 mg, days 1-5), and ondansetron (3 x 4 mg/day, days 1-2). Six months after the myocardial infarction the patient had no further cardiac complications after treatment with cylcophosphamide, vincristine, and ondansetron chemotherapy regimen. Epirubicin was considered to play an important role in the production of infarction, and the probable mechanisms of epirubicin-induced myocardial infarction are discussed.

Serum lactate dehydrogenase levels at presentation predict outcome of patients with limited-stage small-cell lung cancer.

Serum lactate dehydrogenase (LDH) is a biochemical parameter that is elevated in the majority of extensive-stage small-cell lung cancer (SCLC). In this study, distribution and prognostic importance of serum LDH in limited-disease SCLC were investigated. Serum concentrations of LDH were measured in 184 patients at initial examination. These results were compared with prospectively recorded clinicopathologic characteristics and patient outcome data. Significant positive association was found between LDH levels and weight loss, performance status, response to chemotherapy, and albumin but not between age, gender, and hemoglobin values. Patients with high concentrations of LDH had a significantly worse prognosis than did patients with normal levels. The probability of overall survival at 1 year was 60.2% in patients with normal serum LDH levels and 33.1% in patients with higher values (p = 0.0017). Also, the prognostic value of LDH on overall survival was shown in multivariate analysis (p = 0.05). At the time of diagnosis, serum levels of LDH appear to have a significant relation to outcome in patients with limited-stage SCLC.

Measurement of serum CA 19-9 may be more valuable than CEA in prediction of recurrence in patients with gastric cancer.

In 35 patients with recurrent gastric cancer who had undergone curative gastrectomy, serum carcinoembryonic antigen (CEA) and CA 19-9 (carbohydrate antigen) tumor marker levels were investigated. At least one tumor marker was elevated in 24 (68.6%) patients. The levels of serum CA 19-9 and CEA markers were increased in 20 (57.1%) and 12 (34.3%) patients, respectively. This difference was not statistically significant. However, it may be important in terms of clinical practice.

Stevens-Johnson syndrome in a patient receiving anticonvulsant therapy during cranial irradiation.

A 28-year-old female patient with a recent history of breast carcinoma was referred to our clinic with generalized necrotic skin eruptions and severe mucosal erosions, which developed right after the completion of cranial radiotherapy for brain metastases. She had been receiving prophylactic diphenylhydantoin treatment 100 mg three times daily during radiation therapy. The extensive involvement of the oral mucosa with conjunctivitis and synechiae of the eyelids, facial swelling, and extension of the rash over the trunk and shoulders with bullous detachment of less than 10% of the total body surface strongly suggested Stevens-Johnson syndrome caused by phenytoin treatment in our patient. There has been conflicting evidence on the role of radiotherapy in the increased risk of severe drug reactions. Although various authors have emphasized the augmented rate of severe mucocutaneous reactions caused by anticonvulsants given during radiotherapy and suggested discontinuing the prophylactic use of such drugs in patients with no history of seizures, others have argued in favor of prophylactic anticonvulsants. Given the high risk of seizures, reaching 20% in patients with brain tumors, and the low incidence of drug reactions, the suggestion of refraining from prophylactic anticonvulsants in the setting of primary or metastatic brain tumors is controversial.

Angiogenesis and p53 protein expression in breast cancer: prognostic roles and interrelationships.

The authors have analyzed, on the one hand, the prognostic impact of microvessel density (MVD) and p53 protein expression in patients with breast cancer, and on the other hand, the correlation between the microvascular pattern and the p53 protein expression. Tumors from 120 patients whose paraffin-embedded tissue blocks were available were analyzed using the immunohistochemical method. MVD and p53 protein expression were correlated with histologic grade and tumor size, respectively. The patients with highly vascularized tumor (high MVD) had decreased overall survival (p = 0.04), whereas overexpressed p53 patients did not. In multivariate analysis, axillary lymph node status (p = 0.007), tumor size (p = 0.01), and MVD (p = 0.02) showed important prognostic influence on overall survival. When the simultaneous influence of MVD and p53 protein expression on survival were analyzed, no interrelationship was detected. The results demonstrate the prognostic impact of MVD on overall survival in breast cancer and no association between MVD and p53 protein expression.

The roles of chemotherapy and surgery in gastric carcinoma and the influence of prognostic factors on survival.

In this study, we present the results of surgery and chemotherapy and the impact of various prognostic factors on survival in patients with gastric carcinoma with a follow-up of 6 years. All of the 328 cases were adenocarcinoma histologically and had a median age of 55 years. Median survival was 11 months, and the 5-year survival rate was 18%. Nonmetastatic cases were associated with improved survival as compared with the cases with metastatic disease (p<0.001). Patients with gastrectomy had improved survival (p<0.001). Subtotal gastrectomized patients had better survival rates in comparison to the total gastrectomized patients (p = 0.03). Addition of splenectomy to total gastrectomy and adjuvant chemotherapy did not influence survival rates (p>0.05). In metastatic patients, we determined beneficial effects of gastrectomy and chemotherapy on survival. The benefit was most predominant in chemoresponsive patients (p<0.001). Higher serum CA 19.9 levels in patients without metastases, higher serum lactate dehydrogenase and carcinoembryonic antigen levels in patients with metastases, and lower serum albumin levels in both stages were determined as significant predictors of poor survival. On multivariate analysis, only higher serum CA 19.9 level was the independent unfavorable prognostic factor of survival time in nonmetastatic patients (p = 0.008). In metastatic disease, older age (p = 0.03) and male gender (p = 0.05) were associated with poorer survival. In conclusion, gastric cancer is a great health problem, especially in developing countries, and we need more optimal approaches and treatment modalities for gastric cancer.

Prognostic factors in pancreatic carcinoma: serum LDH levels predict survival in metastatic disease.

In this study, our aim was to investigate the impact of various prognostic factors on survival in patients with pancreatic carcinoma. The group consisted of 127 cases with adenocarcinoma histologically. The patients had a median age of 58 years, and 81 (64%) were male. The median survival time of the whole group was 7 months, and the 4-year survival rate was 18%. The median survival duration of the patients without metastases was 8 months, and the survival rate at 1 year was 37.5% and 7.2% at 5 years. It was associated with improved survival compared with the cases with metastatic disease (p < 0.0001). In univariate analysis, decreased performance status (p = 0.0009) and unresectability of tumor (p < 0.0001) were associated with poor outcome. However, only surgery was found to be a statistically significant parameter in multivariate analysis (p = 0.002). The median survival duration of patients with metastases was 5 months, and the 1-year survival rate was 10%. Age younger than 60 years (p = 0.04), decreased serum hemoglobin levels (p = 0.04), and elevated lactic dehydrogenase (LDH) levels (p = 0.0001) were associated with a significantly shorter survival rate. In the Cox model, a high serum LDH level was the only independent unfavorable prognostic factor (p = 0.001). In conclusion, surgical intervention in the group without metastases and serum LDH levels in the group with metastases were the most important prognostic factors influencing survival. Pretreatment serum LDH determinations may provide a useful means of stratifying patient populations when comparing treatment programs for advanced pancreatic cancer.

Multiple primary neoplasms at a single institution: differences between synchronous and metachronous neoplasms.

During the 10-year period (1987-1996) of our study, 26,255 patients with cancer were admitted to our clinic and, of these, 271 (1%) patients had multiple primary malignant tumors. Ninety-two (34%) patients had synchronous tumors (synchronous group), and 179 (66%) patients had metachronous tumors (metachronous group). The mean age at first diagnosis was higher in the former group. The ratio of men to women was 1.36 in the synchronous group and 0.74 in the metachronous group (p = 0.018). Smokers and drinkers were more common in the synchronous group. Breast cancer and lung cancer were most prevalent, and associations between head/neck and lung cancer and between breast and breast cancer were the most frequent associations in both the synchronous and the metachronous group. The frequency of aerodigestive tumors was higher and that of mesenchymal tumors was lower in the synchronous group than in the metachronous group. Localization in the medial region and in the head/neck was more frequent in the synchronous group than in the case of metachronous secondary tumors.

5-fluorouracil-induced balanitis in a patient with oesophageal carcinoma.

We have reported the case history of a patient with balanitis, who was treated with 5-FU. Although 5-FU has a wide toxicity profile, balanitis has not been reported in association with this therapy.

Combination chemotherapy with docetaxel and irinotecan in metastatic malignant melanoma.

AIM: The aim of the current trial was to assess the efficacy and toxicity of 3-weekly intravenous docetaxel and irinotecan in the treatment of patients with metastatic malignant melanoma. MATERIALS AND METHODS: Sixteen patients with no history of previous cytotoxic agents or immunological treatment for advanced disease were treated with docetaxel 50 mg/m2 and irinotecan 150 mg/m2 intravenously over 60 min every 21 days. Prior immunotherapy with interferon and chemotherapy for adjuvant therapies were accepted provided there was a minimum 4-week treatment-free interval. Response evaluation was performed after two cycles. RESULTS: None of the patients had chemotherapy-induced tumour response. Eight patients achieved stable disease and others had progression of disease. The median survival time was 136 days (95% CI: 30.2-241.8), and the 3-month survival rate was 62.5%. Patients with stable disease (n = 8) had a longer survival than non-responders (P = 0.023, Breslow test). Generally side effects were mild and tolerable. Grade III-IV haematological toxicity occurred in approximately 10%. Severe emesis, stomatitis and diarrhoea was seen in less than 20% of the patients. Alopecia was observed in all patients. CONCLUSION: A 3-weekly intravenous docetaxel and irinotecan combination appears to be inactive in the treatment of patients with malignant melanoma and has not been recommended.