Surgery with hyperthermic intraperitoneal chemotherapy after response to induction chemotherapy in patients with peritoneal metastasis of gastric cancer.

BACKGROUND: Gastric cancer (GC) with peritoneal metastases (PM) has a dismal prognosis and to date only a few management options have been reported. Of those, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after induction bidirectional intraperitoneal and systemic chemotherapy (BIPSC) appear as a promising treatment option for these patients. Outcome data including safety and efficacy of CRS with radical Gastrectomy and HIPEC after response to combination of laparoscopic HIPEC (LHIPEC) with BIPSC as an induction therapy in patients with PM of GC was evaluated in this retrospective observational study. METHODS: Diagnostic Laparoscopy was performed in 53 patients with PM of GC who admitted to the Center for Treatment of Peritoneal Surface Malignancies, Istanbul, between 2013 and 2016. Peritoneal cancer index (PCI), ascites status and cytology were determined. The patients underwent LHIPEC and then, BIPSC induction chemotherapy using intraperitoneal docetaxel (30 mg/m2) and cisplatin (30 mg/m2) and intravenous Docetaxel/Cisplatin/5-Fluorouracil (DCF) for 3 cycles. In selected patients, CRS with radical gastrectomy and HIPEC were performed after the response to induction therapy. BIPSC was continued for 3 more cycles with a dose reduction in an adjuvant setting. RESULTS: All LHIPEC procedures were uneventful with Grade 1-2 side effects (11/53, 20,8%). As a response to induction chemotherapy PCI was reduced from 19.6±8 (range, 6-39) to 13.6±9.8 (range, 1-39) (P<0.001). Ascites was detected in 55% (29 out of 53) and cytology was positive in 51% (27 out of 53) of the patients before induction chemotherapy. Ascites was completely abolished and all cytology became negative. Then, 34 of 53 (64.15%) patients underwent CRS with radical gastrectomy and HIPEC. CC0/1 resection was achieved in 22 (64.70%) of patients (P<0.05). The median survival time was 18.9±13.4 (95% CI: 15.2-22.6 months. Combined surgery and HIPEC related mortality occurred in 1 out of 34 patients (2.9%) due to developed diffuse intravascular coagulation at postoperative day 2. Grade 2 operative complications included biliary fistula in one, and duodenal stump leakage in two patients (8.7%). All of the fistula closed with conservative management. The median survival time was 18.9±13.4 months and the median progression-free survival time was 15.6±12.9 with 1-, 2-, and 5-year survival rates of 82.4%, 59% and 17.6% in patients with PM of GC. Multivariate analysis identified high peritoneal cancer index (P=0.000) and complete resection (P<0.05) as independent predictors for better progression-free and overall survival. CONCLUSIONS: The best outcomes can be expected with optimal cytoreduction and limited peritoneal dissemination in response to induction chemotherapy. Knowledgeable selection of patients with PM of GC is essential to perform surgery with HIPEC safely with acceptable mortality and morbidity.

Curcumin and piperine loaded zein-chitosan nanoparticles: Development and in-vitro characterisation.

Curcumin as the active compound of turmeric has antioxidative, antiinflammatory, antimicrobial and anticancer properties among others. However, its disadvantageous properties like low solubility, poor bioavailability and rapid degradation under neutral or alkaline pH conditions or when exposed to light limit its clinical application. These problems can be solved by a smart combination of using a natural enhancer like piperine and preparing nanoparticles by a proper method like electrospray. Due to these facts it was aimed in this study to develop curcumin and piperine loaded zein-chitosan nanoparticles step by step. For that purpose various formulation parameters like the concentrations of zein, curcumin, piperine and chitosan and the preparation parameters like the applied voltage and the nozzle diameter were investigated step by step. The nanoparticles were characterised by investigating their shapes, morphologies, particle sizes with help of SEM images and the cytotoxicity on neuroblastoma cells. It was succeeded to prepare curcumin and piperine loaded zein-chitosan nanoparticles having a mean particle size of approximately 500 nm and high encapsulation efficencies for curcumin (89%) and piperine (87%). Using a curcumin concentration of 10-25 µg/ml resulted in reduction of the viability of approximately 50% of the neuroblastoma cells. The here developed nanoparticle formulation consisting of solely natural compounds showed good cytotoxic effects and is a promising approach with appropriate properties for final consumption.

Combination of zoledronic acid and serine/threonine phosphatase inhibitors induces synergistic cytotoxicity and apoptosis in human breast cancer cells via inhibition of PI3K/Akt pathway.

The aim of this study was to investigate the cytotoxic and apoptotic effects of zoledronic acid (ZA) in combination with serine/threonine protein phosphatase inhibitors, calyculin-A (CA) and okadaic acid (OA), in human MCF-7 and MDA-MB-231 breast cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. DNA fragmentation and caspase-3/7 activity assays were performed to evaluate apoptosis. Activities of phosphatase 1 (PP1) and phosphatase 2A (PP2A) were measured by serine/threonine phosphatase ELISA kit. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2, p-Bcl-2, Bad, and p-Bad proteins were evaluated by Western blot analysis. Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis as compared to any agent alone in both MCF-7 and MDA-MB-231 breast cancer cells. Combination treatment also resulted in inhibition of both PP1 and PP2A activities. Both agents used alone or in combination did not induce significant changes in total PI3K, Akt, Bcl-2, and Bad expressions, while p-PI3K, p-Akt, p-Bcl-2, and p-Bad levels were reduced by the combination treatment as compared to agents alone. Moreover, apoptotic effect of combination treatment was significantly inhibited in the presence of LY294002, a specific PI3K inhibitor, in both breast cancer cell lines. In conclusion, synergistic apoptotic effect of the combination treatment is correlated with the block of the PI3K/Akt signal pathway in breast cancer cells.

The Role of Body Mass Index in Triple Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has none of the targeted treatment choices due to its distinct biological property, making this subtype a unique disease. In this study, we evaluated the impact of obesity on clinical outcomes of TNBC. METHODS: The data of breast cancer patients admitted to our department were collected. TNBC was defined as lack of estrogen receptor (ER), progesterone receptor (PR) and HER-2. The body mass index (BMI) of 112 TNBC patients was calculated with weight at the time of diagnosis and height. The patients were classified into groups with a BMI of < 25 (normal/underweight), 25-29.9 (overweight) or ≥ 30 (obese). After a mean follow-up of 23.2 ± 15.5 months, there were 12 recurrences (10.71%) and 6 deaths (5.35%). Disease-free survival (DFS) and overall survival (OS) were assessed. RESULTS: The survival analyses of all the patients did not demonstrate any differences in OS or DFS in obese as compared to non-obese patients. However, we showed that obesity was associated with a poorer OS for postmenopausal TNBC patients (p < 0.05). CONCLUSION: Obesity is related to a poorer OS in postmenopausal TNBC patients. Due to the heterogeneous disease profile of TNBC, larger randomized studies will be needed to clarify the exact role of obesity in TNBC.

Zoledronic acid increases cytotoxicity by inducing apoptosis in hormone and docetaxel-resistant prostate cancer cell lines.

Our aim was to investigate the possible synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and zoledronic acid (ZA), in PC-3 hormone-refractory prostate cancer cells (HRPC), as well as their docetaxel-resistant sublines. We established a docetaxel-resistant cell line (PC-3R) from PC-3 prostate cancer cells, by intermittent exposure to increasing concentrations of docetaxel in vitro. We then examined the effect of ZA and docetaxel on cell proliferation in both PC-3 and PC-3R prostate cancer cells. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 enzyme activity were measured to verify apoptosis. According to our results, docetaxel and ZA were found to be synergistically cytotoxic and apoptotic in both PC-3 and docetaxel-resistant PC-3R cells, in a dose- and time-dependent manner. Combined treatment with docetaxel and ZA synergistically inhibited PC-3 cell growth in vitro through an enhanced induction of cell death, compared with either agent alone; this result was also evident on PC-3R cells. Moreover, we have also demonstrated that apoptosis was induced in prostate cancer cells exposed to these drugs by a concentration-dependent increase in DNA fragmentation and caspase 3/7 enzyme activity. We concluded that ZA, either with docetaxel or not, might still exert some cytotoxicity even in docetaxel-resistant cells. From the clinical perspective, when the clinician decided to change the treatment in the post-docetaxel setting, continuing or combination with ZA may be an effective therapeutic approach for the treatment of HRPC patients.

Nine weeks versus 1 year adjuvant trastuzumab in patients with early breast cancer: an observational study by the Turkish Oncology Group (TOG).

BACKGROUND: Optimal duration of adjuvant trastuzumab in early breast cancer is an unresolved issue. In this observational study, we compared the outcome of 9 weeks and 1 year adjuvant trastuzumab in early breast cancer patients in Turkey. METHODS: Records of 680 patients with HER2-positive early breast cancer who received adjuvant trastuzumab plus chemotherapy were obtained and patients were followed up to compare the disease-free survival (DFS) outcome of 9 weeks versus 1 year trastuzumab. RESULTS: Nine weeks and 1 year trastuzumab was given to 202 (29.7 %) and 478 (70.3 %) patients, respectively. There was a significantly lower rate of patients with negative lymph nodes in the 9-week trastuzumab group. At median 3 years of follow-up from the date of starting trastuzumab, the DFS rates were 88.6 and 85.6 %, respectively (p = 0.670). When adjusted for all the prognostic factors that were significant on univariate analysis, again there was no significant difference in DFS between the groups (HR 0.675; 95 % CI 0.370-1.231; p = 0.200). Cardiac toxicity defined as a ≥15 % decrease in LVEF was significantly higher in the 1-year trastuzumab group (1.88 % versus none for 1-year and 9-week trastuzumab groups, respectively; p = 0.050). CONCLUSION: The results of this observational study suggest that DFS outcome of 9 weeks of adjuvant trastuzumab may be comparable to 1 year adjuvant trastuzumab: this needs confirmation by randomized trials.

Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells.

We investigated the effects of AT-101/cisplatin combination treatment on the expression levels of apoptotic proteins and epigenetic events such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme activities in OVCAR-3 and MDAH-2774 ovarian cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase 3/7 activity measurements were performed. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. DNMT and HDAC activities were evaluated by ELISA assay and mRNA levels of DNMT1 and HDAC1 genes were quantified by qRT-PCR. Combination of AT-101/cisplatin resulted in strong synergistic cytotoxicity and apoptosis in human ovarian cancer cells. Combination treatment reduced some pivotal anti-apoptotic proteins such as Bcl-2, HIF-1A, cIAP-1, XIAP in OVCAR-3 cells, whereas p21, Bcl-2, cIAP-1, HSP27, Clusterin and XIAP in MDAH-2774 cells. Among the pro-apoptotic proteins, Bad, Bax, Fas, phospho-p53 (S46), Cleaved caspase-3, SMAC/Diablo, TNFR1 and Cytochrome c were induced in OVCAR-3 cells, whereas, Bax, TRAILR2, FADD, p27, phospho-p53 (S46), Cleaved caspase-3, Cytochrome c, SMAC/Diablo and TNFR1 were induced in MDAH-2774 cells. Combination treatment also inhibited both DNMT and HDAC activities and also mRNA levels in both ovarian cancer cells. AT-101 exhibits great potential in sensitization of human ovarian cancer cells to cisplatin treatment in vitro, suggesting that the combination of AT-101 with cisplatin may hold great promise for development as a novel chemotherapeutic approach to overcome platinum-resistance in human ovarian cancer.

Comparing time to disease progression of irinotecan and oxaliplatin-based chemotherapies in colorectal cancer patients with liver only metastasis.

OBJECTIVES: The liver is the most common metastatic site in colorectal cancer (CRC). In this study, we evaluated if there is any difference between first-line irinotecan-based and oxaliplatin-based chemotherapies in the duration of time to disease progression (TTP) in CRC patients with only liver metastasis. METHODS: We retrospectively reviewed the medical records of patients with metastatic CRC referred to the Medical Oncology Department at the Faculty of Medicine of Ege University, between January 2002 and December 2010. Seventy-seven patients had only liver metastasis and completed their first-line chemotherapy. Forty-two patients had oxaliplatin-based treatments while 12 also had bevacizumab therapy, and 35 patients had irinotecan-based treatments while 16 also had bevacizumab therapy. RESULTS: Median TTP was 6.70 ± 0.29 months for patients treated with oxaliplatin+5-fluorouracil (5-FU) and 8.33 ± 1.15 months for patients treated with oxaliplatin+5-FU+bevacizumab. TTP was significantly improved for patients who received irinotecan+5-FU+bevacizumab (median TTP, 13.73 ± 2.10 mo) when compared with irinotecan+5-FU (median TTP, 5.13 ± 0.70 mo). CONCLUSIONS: Although previous studies showed no survival difference between these 2 chemotherapeutic agents in metastatic CRC, there might be differences in the benefit of delaying the disease progression in subgroup populations. Irinotecan+5-FU with bevacizumab combination chemotherapy may be superior in the first-line treatment of CRC with hepatic only metastasis.

Zoledronic acid in combination with serine/threonine phosphatase inhibitors induces enhanced cytotoxicity and apoptosis in hormone-refractory prostate cancer cell lines by decreasing the activities of PP1 and PP2A.

UNLABELLED: What's known on the subject? and What does the study add? Prostate cancer is the second most common cancer diagnosed among elderly men. Current standard of care with surgery, chemotherapy or radiation in prostate cancer patients are of limited efficacy, especially in the androgen refractory state of the disease, and unfortunately metastatic disease remains incurable. Skeletal metastases are the most common site for metastases for prostate cancer and bisphosphonates have been widely used for the treatment of morbidity due to skeletal related events. Zoledronic acid (ZA) is the most potent member of the nitrogen containing new generation bisphosphonate (N-BPs) family. Okadaic acid (OA) and Calyculin A (CA) are the most commonly used inhibitors of PP1 and 2A. OA, extracted from common black sponge Halachondria okaddai is a potent inhibitor of protein phosphatases, PP1 and PP2A, and CA was isolated from another marine sponge, Discodermia calyx. Therapies based on combinations of chemotherapeutics with phosphatase inhibitors that target signaling pathways within the cell with different mechanisms of action, may be useful for increasing therapeutic effect and also diminish toxic side effects by decreasing the doses of conventional chemotherapeutics. Although clinically well known, the in vitro effects of ZA on cancer cells and the underlying mechanisms are not well elucidated. In our previous studies, we have already shown anticancer effect of ZA in hormone-and drug refractory prostate cancer cells, PC-3 and DU-145. In addition to this, we have also shown that this anticancer effect may be augmented with some cytotoxic agents in prostate cancer. Now, in our present study, we have investigated whether ZA induced growth inhibition and apoptosis in PC-3 and DU-145 may be enhanced by the combination with CA or OA, through inhibition of serine/threonine phosphatases in prostate cancer cells. Both ZA/CA and ZA/OA combinations inhibited the cell viability of hormone-and drug refractory prostate cancer cells at in vivo achievable therapeutic concentrations. Moreover, a potentiation of the apoptotic effects of the combinations was also observed in the same experimental conditions. This is the first report of a synergistic combination of ZA with phosphatase inhibitors CA and OA which inhibits cell viability and induces apoptosis in human hormone and drug refractory prostate cancer cells. OBJECTIVES: • To investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the serine/threonine protein phosphatase inhibitors calyculin A (CA) and okadaic acid (OA) in hormone and drug refractory prostate cancer cells, PC-3 and DU-145. • To discover the effect of these combination treatments on phosphatase 1 (PP1) and PP2A protein expression levels in prostate cancer cells. MATERIALS AND METHODS: • An XTT cell viability assay was used to determine cytotoxicity. • Apoptosis was evaluated by enzyme-linked immunosorbent assay (ELISA) using a Cell Death Detection ELISA Plus Kit and verified by measuring caspase 3/7 enzyme activity. • The PP1 and PP2A enzyme activities were evaluated by serine/threonine phosphatase ELISA and expression levels of PP1 and PP2A proteins were then re-assessed by Western blot analysis. RESULTS: • Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis compared with any agent alone in both PC-3 and DU-145 prostate cancer cells. • The combination of ZA with phosphatase inhibitors resulted in enhanced suppression of both PP1 and PP2A enzyme activity and protein levels, which was more overt with the ZA/CA combination. CONCLUSION: • Results from our study increase the translational potential of our in vitro findings and offer the basic rationale for the design of new combinatory strategies with ZA and phosphatase inhibitors for the treatment of prostate cancer, which may become resistant to conventional therapy.

The frequency and significance of radiologically detected indeterminate pulmonary nodules in patients with colorectal cancer.

OBJECTIVE: To investigate the frequency and significance of pulmonary nodules in patients with colorectal cancer (CRC). SUBJECTS AND METHODS: Medical records of 1,344 patients with CRC who underwent thoracic computerized tomography scans between January 2003 and December 2009 were reviewed. Those with any distant metastatic disease or who were already known to have pulmonary malignancies were excluded. Number, size, shape and location of the nodules were evaluated. A multivariate analysis was performed to determine the predictive factors for evidence of metastases. RESULTS: Of the 1,344 patients, 55 (4.09%) had nodules that met the criteria of an indeterminate pulmonary nodule. The mean follow-up time was 25 ± 17.9 months and the mean time to develop pulmonary metastasis was 15.5 ± 6.4 months. The nodules of 17 (30.9%) patients showed progression at follow-up; 8 had metastasized. Multivariate analysis showed multiple indeterminate pulmonary nodules (p = 0.006) of parenchymal localization (p = 0.016) with an irregular border (p = 0.002), which is predictive of metastatic disease. CONCLUSION: Our study has shown that multiple indeterminate pulmonary nodules with an irregular border in a parenchymal location were more likely to represent metastatic disease. However, the frequency of the occurrence of indeterminate pulmonary metastases of CRC was low.

Pretreatment with AT-101 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of breast cancer cells by inducing death receptors 4 and 5 protein levels.

PURPOSE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has been shown to induce extrinsic pathway of apoptosis in many types of cancer cells. AT-101, an (-)-enantiomer of gossypol, is a potent anticancer agent that is shown to be an inhibitor of Bcl-2/Bcl-XL. In this study, we searched whether pretreatment with either of these drugs would result in the enhancement of apoptosis through induction of death receptors and activation of mitochondrial pathways within breast cancer cells. METHODS: Human breast cancer (MCF-7 and MDA-MB-231) and normal breast cells (MCF-10A) were treated with drugs alone/in combination/sequentially. XTT cell viability assay was used to evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase 3/7 activity measurements were done. ELISA and Western blot analysis were done to assess DR4 and DR5 protein levels. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. RESULTS: The sequential treatment of AT-101 followed by TRAIL resulted in significant synergistic cytotoxicity and apoptosis. Moreover, pretreatment of breast cancer cells with AT-101 and then with TRAIL caused enhancement of the expression levels of DR4 and DR5 in both cancer cell lines, suggesting that these cells were under strong apoptotic stimuli. CONCLUSIONS: These findings all together, strongly suggest that pretreatment with AT-101 enhances TRAIL-induced death-inducing signaling complex resulting in the engagement of the mitochondrial pathway to apoptosis in breast cancer cells. These promising, preliminary results make AT-101 and TRAIL a novel combination treatment candidate for breast cancer.

p53 protein accumulation and presence of visceral metastasis are independent prognostic factors for survival in patients with metastatic inflammatory breast carcinoma.

OBJECTIVE: The aim of this study was to determine the markers of prognosis in metastatic inflammatory breast cancer (IBC). SUBJECTS AND METHODS: The prognostic value of patients' clinical characteristics and expression of c-erbB-2, p53, Ki-67, ER and PgR were assessed in the 45 patients with IBC who had developed distant metastasis. Immunohistochemical methods were used to detect the expression of c-erbB-2, p53, Ki-67, ER and PgR in surgical resection specimens of the patients' primary tumor. RESULTS: The median overall survival (OS) measured from the diagnosis of metastatic disease was 23 months. In the univariate analysis, p53 protein accumulation and the presence of visceral metastasis were predictive of poor survival (p = 0.01 and 0.003, respectively). In the multivariate analysis, accumulation of p53 protein and the presence of visceral metastasis correlated with OS (p = 0.02 and 0.008, respectively). CONCLUSION: In metastatic IBC, accumulation of p53 protein and presence of visceral metastasis are independent prognostic factors for OS. Established prognostic factors in non-IBC patients such as patient age, histologic grade, hormone receptor status and c-erbB-2 status did not have independent significance in IBC in this study.

Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines.

We report that all-trans retinoic acid (ATRA) in combination with zoledronic acid has strong synergistic cytotoxic and apoptotic effects against human hormone- and drug-refractory prostate cancer cells, PC-3 and DU-145, in a time- and dose-dependent manner. We further investigated the effect of the combination treatment on the apoptotic process by both oligoarray and protein array analysis in DU-145 cells, in which the drug combination shows much more strong synergistic effects, as compared to PC-3 cells. Moreover, we have also performed real time-PCR array analysis to validate oligoarray results. We demonstrated that the combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in human androgen-and drug refractory prostate cancer cells DU-145, at either transcriptional or translational levels. While expression of proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), Bad, Bax, Fas, FADD are induced with the exposure of the combination, expression of antiapoptotic genes or proteins such as members of inhibitor apoptosis family (IAPs), MCL-1, LTBR, p53 and bcl-2 are reduced. Because this novel combination treatment has fewer side effects than is generally the case with conventional cytotoxic agents, this regimen may be a good option for treatment of elderly prostate cancer patients.

Comparison of XTT and Alamar blue assays in the assessment of the viability of various human cancer cell lines by AT-101 (-/- gossypol).

This study compared the two different commercially available in vitro viability assays: XTT and Alamar blue (AB), to detect anti-proliferative effects of AT-101, a cotton plant extract, on six different human carcinoma cell lines including: prostate (PC-3 and DU-145), breast (MCF-7 and MDA-MB-231), and ovary (OVCAR-3 and MDAH 2774) in a time- and dose-dependent manner. Cells were exposed to AT-101 in the concentration range of 2.5-40 µM for 24, 48, and 72 h. The AB assay was slightly more sensitive than the XTT assay in the evaluation of AT-101 at 24 h, suggesting that the AB assay might be used for detecting early changes in cell viability as compared to the XTT assay. Moreover, the AB assay showed less intra-assay variability as compared to the XTT. The non-toxic, non-radioactive AB metabolism assay allows rapid assessment of large numbers of samples, with simple equipment and at reduced cost for continuous monitoring of cancer cell viability, and, thus, should be accepted as a suitable alternative viability method.

Gossypol exerts its cytotoxic effect on HL-60 leukemic cell line via decreasing activity of protein phosphatase 2A and interacting with human telomerase reverse transcriptase activity.

In this study, we aimed to investigate the potential relationship between gossypol-induced cytotoxicity of human promyelocytic leukemia cell line (HL-60) leukemic cells and intracellular serine/threonine protein phosphatase (PP) dynamics and human telomerase reverse transcriptase (hTERT) activity. Gossypol was found to be cytotoxic in HL-60 cells with the IC(50) dose of 4.5 microM. The combination of gossypol and okadaic acid in IC(50) doses revealed the increased cytotoxicity in a time-dependent manner. Treatment of cells with gossypol has shown significant decrease in PP2A activity. The expression of the PP2A catalytic subunit was downregulated in gossypol-treated cells with 24 hours' intervals. hTERT mRNA levels were gradually decreased. In conclusion, during gossypol-induced cytotoxicity, intracellular activity and expression of PP2A was decreased as well as the activity of hTERT. The variation of hTERT activity in gossypol-treated HL-60 cells may be the potential reason for the phosphatase interaction during the gossypol treatment of leukemic cells resulting in cellular cytotoxicity.

Comparison of inflammatory breast cancer and noninflammatory breast cancer in Western Turkey.

OBJECTIVE: The study was aimed at investigating the clinical and biological features and survival outcomes of patients who were treated for metastatic inflammatory and noninflammatory breast carcinoma. SUBJECTS AND METHODS: One hundred and sixty-seven metastatic breast cancer patients were enrolled into this study and divided into two groups: inflammatory (n = 46) and noninflammatory (n = 121). The clinical and hormone receptor status, c-erbB-2, Ki-67, and p53 expression, based on the immunohistochemical staining patterns, were compared between the two groups. RESULTS: The inflammatory breast carcinoma group had a younger patient population, higher rate of adjuvant anthracycline therapy, number of lymph node metastases, rates of extranodal extension and c-erbB-2 overexpression than noninflammatory breast cancer patients (p < 0.05). With regard to survival, there were slightly better outcomes in the noninflammatory breast carcinoma group (30 months) compared to the inflammatory breast carcinoma group (23 months), but the difference was not statistically significant (p = 0.08). While survival results of p53-negative inflammatory and noninflammatory breast carcinoma patients were similar, p53-positive survival was significantly worse (p < 0.05) in inflammatory breast cancer carcinoma patients. CONCLUSION: Because of c-erbB-2 overexpression in inflammatory breast carcinoma patients, treatment options including trastuzumab could have given better survival outcomes. Survival of inflammatory breast carcinoma patients with a low p53 immunohistochemistry staining appeared similar to that for noninflammatory breast carcinoma. For this reason, new treatment options are needed especially in inflammatory breast carcinoma patients with high p53 positivity.

Comparison of the clinical and pathological features between patients with recurrent metastatic breast carcinoma and patients with initially metastatic breast carcinoma.

OBJECTIVE: To compare initial metastatic breast carcinoma (MBC) with recurrent MBC and assess their biologic phenotypes and clinical behaviors. METHODS: A comparison of clinical and biological characteristics and median overall survival times were assessed in the 251 patients with MBC at the Division of Medical Oncology, Ege University School of Medicine, and the Division of Radiation Oncology, Tepecik Government Hospital, Izmir, Turkey between 1995 and 2004. Hormone receptors, c-erbB-2, Ki-67, and p53 expressions were performed by immunohistochemistry. RESULTS: Out of 251 MBC patients, 206 patients had recurrent MBC, and 45 had initial MBC. Regarding survival, there was no difference between the recurrent MBC group and the initial MBC group. The initial MBC group had a higher proportion of T4 tumors (46% versus 27%), a lower proportion of T1-2 tumors (31% versus 55%; p=0.01), and a higher percentage of patients with high Ki-67 expression (64% versus 49%; p=0.05). Multivariate analysis showed that T stage was an independent prognostic factor (p=0.02). CONCLUSION: Patients with initial MBC tended to present with larger tumors. This relationship can be explained by delayed diagnosis. The potential for reducing death rates from breast cancer is contingent on educational improvement and increased screening rates.

Risk factors for central nervous system metastasis in patients with metastatic breast cancer.

AIMS: Patients with metastatic breast cancer (MBC) and central nervous system (CNS) involvement have an impaired survival and quality of life. In this study, we investigated the risk factors for CNS metastasis among patients with MBC. METHODS: The risk factors for development of CNS metastasis were analyzed in 154 patients with MBC. Expression of c-erbB-2, Ki-67, p53, and hormone receptors was examined by immunohistochemistry (IHC) in breast cancer tissue samples from the 154 patients. Kaplan-Meier and log-rank tests were used for the analysis of overall survival (OS). Chi-square test was used for univariate analysis. RESULTS: Median OS was significantly poorer for patients with CNS metastasis as compared with patients with no CNS metastasis (OS, 23 mo vs 30 mo, respectively;p = 0.03). Ki-67 and p53 overexpressions by IHC, and lung metastasis as the first site of relapse, were associated with a higher risk of developing CNS metastasis in the univariate analysis (p

Efficacy of lower dose capecitabine in patients with metastatic breast cancer and factors influencing therapeutic response and outcome.

OBJECTIVE: Capecitabine exerts considerable therapeutic efficacy in metastatic breast cancer (MBC) patients previously treated with anthracyclines and taxanes. MATERIALS AND METHODS: In this study, the efficacy and safety of lower dose capecitabine (2000 mg/m(2)/d) in patients with anthracycline- and taxane-pretreated MBC were studied with a special emphasis on the potential predictors of time to tumor progression (TTP) and response to the capecitabine treatment. RESULTS: The overall response rate (ORR) was 17%. The median TTP was 5 months. Among various factors analyzed, univariate analysis showed that a performance status (PS) of 2 and the presence of visceral metastases were inversely correlated with TTP. Multivariate analysis showed that a poor PS score was associated with impaired TTP. CONCLUSIONS: Our study indicates that lower dose capecitabine has substantial antitumor activity and a favorable safety profile in the treatment of anthracycline- and taxane-pretreated MBC. Also, only performance score was demonstrated to be a significant parameter affecting TTP.

Gemcitabine treatment in patients with inoperable locally advanced/metastatic pancreatic cancer and prognostic factors.

OBJECTIVE: Most patients with pancreatic cancer show an inoperable locally advanced/ metastatic tumour at the time of diagnosis. The present study was aimed at determining the prognostic factors in patients with advanced pancreatic carcinoma treated with gemcitabine. MATERIAL AND METHODS: Sixty-seven unresectable or metastatic pancreatic cancer patients treated with gemcitabine were included in the study and a total of 258 cycles of treatment were applied. RESULTS: The overall response rate was 5%. Thirty-one percent of the patients had stable disease, whereas progressive disease was seen in 49%. Clinical benefit response rate was 15%. The median duration of response was 7.3 months. Median progression-free survival was 3 months, while median overall survival was 9 months. Univariate analysis revealed that worse results were found in patients with performance status (PS) = 2, and in patients with primary tumour location in the body or tail of the pancreas (p<0.05). Multivariate analysis of data revealed that the most important factor was PS of the patient, as the patients with PS = 2 had worse results than the patients with PS = 0-1 (p<0.05). CONCLUSIONS: Low PS is a negative predictive factor for the survival of patients with advanced pancreatic carcinoma treated with gemcitabine.