Beyond traditional therapies: clinical significance of complex molecular profiling in patients with advanced solid tumours-results from a Turkish multi-centre study.

OBJECTIVE: The objective of this multi-centre, real-world study was to examine the potential influence of comprehensive molecular profiling on the development of treatment decisions or adjustments for patients with advanced solid malignancies. We then evaluated the impact of these informed choices on patient treatment outcomes. METHODS: The study encompassed 234 adult patients (mean age: 52.7 ± 14.3 years, 54.7% women) who were diagnosed with solid tumours at 21 different medical centres in Turkey. Remarkably, 67.9% of the patients exhibited metastasis at the time of diagnosis. We utilized an OncoDNA (Gosselies, Belgium) platform (OncoDEEP) integrating next-generation sequencing with additional tests to harvest complex molecular profiling data. The results were analyzed in relation with two specific outcomes: (i) the impact on therapeutic decisions, including formulation or modifications, and (ii) associated treatment response. RESULTS: Out of the 228 patients with final molecular profiling results, 118 (50.4%) had their treatment modified, whilst the remaining 110 (47.0%) did not. The response rates were comparable, with 3.9 versus 3.4% for complete response, 13.6 versus 29.3% for partial response, 66.9 versus 51.7% for progressive disease and 15.5 versus 15.5% for stable disease for treatments informed and not informed by complex molecular profiling, respectively (P = 0.16). CONCLUSION: Our real-world findings highlight the significant impact of complex molecular profiling on the treatment decisions made by oncologists for a substantial portion of patients with advanced solid tumours. Regrettably, no significant advantage was detected in terms of treatment response or disease control rates.

Real-Life Analysis of Efficacy and Safety of Everolimus Plus Exemestane in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Patients: A Turkish Oncology Group (TOG) Study.

PURPOSE: This study evaluated the efficacy and safety of everolimus (EVE) plus exemestane (EXE) in hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) patients in real-life settings. METHODS: Overall, 204 HR+, HER2- MBC patients treated with EVE + EXE after progressing following prior endocrine treatment were included. Overall survival (OS) and progression-free survival (PFS) and safety data were analyzed. RESULTS: The objective response rate, median PFS, and median OS were 33.4%, 8.9 months, and 23.4 months, respectively. Multivariate analysis revealed that negative progesterone receptor status was a significant determinant of poor treatment response (p = 0.035) and PFS (p = 0.024). The presence of bone-only metastasis was associated with better treatment response (p = 0.002), PFS (p < 0.001), and OS (p = 0.001). CONCLUSION: We confirmed the favorable efficacy and safety profile of EVE + EXE for HR+, HER - MBC patients.

The Relationship Between Nutritional Status, Performance Status, and Survival Among Pancreatic Cancer Patients.

Aim: The purpose of this study was to identify the nutritional and performance status of Pancreatic Cancer (PanCa) patients and to determine the relationship between these parameters and their survival time.Material and Methods: Ninety-six PanCa patients [59.6% F, 61.4% M; mean age: 60.7 (min:28, max:80) years] were followed up for 6-24 months. The Patient Generated Subjective Global Assessment (PG-SGA) and Eastern Comparative Oncology Group (ECOG) scale were performed. Anthropometric measurements [height, weight, mid-upper arm circumference (MUAC), calf circumference (CC) and triceps skin fold thickness (TSF)], hand grip strength (HGS) were recorded. Survival analyses were conducted using Kaplan-Meier curves.Results: Malnutrition was observed in 85.5% (n = 82) and 54.2% of all patients had poor performance status. A positive correlation was observed between malnutrition and ECOG scale of the patients (P < .01). Antropometric measurements for women and men, respectively, were 34.4 ± 3.03-34.6 ± 3.43 cm for CC; 26.9 ± 3.47-26.05 ± 3.37 cm for MUAC; 20.5 ± 6.3-13.02 ± 7.7 mm for TSF; - 31.02 ± 7.64-20.13 ± 6.04 kg for HGS. Survival time of patients with SGA-A and B was 38.0 ± 6.6 months and of those with SGA-C was 12.0 ± 3.1 months (P = .000).Conclusion: Malnutrition negatively affected both performance status and survival time among PanCa patients.

Evaluation of sarcopenia, sarcopenic obesity, and phase angle in geriatric gastrointestinal cancer patients: before and after chemotherapy

Background/aim: The purpose of this study was to determine sarcopenia, sarcopenic obesity and phase angle (PA) and the influence of chemotherapy (CT) on anthropometric measurements and and the PA in in geriatric patients with gastrointestinal (GI) cancer. Materials and methods: The anthropometric measurements, calf circumference (CC), upper midarm circumference (UMAC), and hand grip strength (HGS), have been measured to understand muscle function of 153 patients (mean age of 70.5 ± 5.6 years, 28.8% female, 71.2% male). Sarcopenia and PA measurements have been evaluated by bioelectrical impedance analyses. The same evaluations were checked again after 1 cycle of CT (min: 4, max: 6 weeks). Results: Patient population consisted of colorectal (51,6%), gastric (26.8%), pancreas (11.8%), liver (7.2%), and biliary tract cancer (2%). UMAC (28.5 ± 4.4 before, 28.1 ± 4.9, P = 0.034 after CT), and HGS measurements (27.5 ± 8.6 before, 26.8 ± 8.8 after CT, P = 0.007) have significantly decreased after CT. CC measurement < 31 cm at first visit was seen in 13.1% of patients, but the ratio raised to 20.3% after CT (χ², P = 0.003). Severe sarcopenia was determined in 33% of all patients, and 30.0% of them have been considered as sarcopenic obese. Conclusion: Sarcopenia and sarcopenic obesity were prevalent in this group patients. The CT caused a decrease in muscle functions, UMAC, and CC. Patients should be followed up carefully for sarcopenia, sarcopenic obesity, and nutritional aspect and it would be proper to intervene before sarcopenia has not occurred yet.

Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study.

BACKGROUND: Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy. METHODS: JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing. FINDINGS: Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes. INTERPRETATION: Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile. FUNDING: Merck and Pfizer.

Risk factors for poor mobilization in solid tumors: How effectively can we mobilize patients with solid tumors?

BACKGROUND: In the literature, risk factors for poor mobilization were tried to identify. However, most of the studies consisted heterogeneous group of patients including both hematologic and oncologic malignancies. In this study, we aimed to identify the risk factors for poor mobilization in adults with solid tumors. METHODS: We enrolled 49(47 men, 2 women) adult patients with solid tumor who were mobilized between September 2007 and February 2017. All the mobilization procedures were performed with G-CSF(10µg/kg/day) with chemotherapy. Mobilization insufficiency was defined as peripheral blood CD34+stem cell number less than 10/µl and/or total collected CD34+cells less than 2.5×10 6/kg. RESULTS: The patients were divided into two groups, patients with successful mobilization at the first attempt(group 1, 36 patients,73.5%) and poor mobilizers (group 2, 13 patients 26.5%). Second and third mobilization attempt was needed in 11 and 2 patients, respectively. The median number of CD34+cells collected was 7,08×106/kg(0,6-19) with a median 4(1-6) apheresis. There was no statistical difference between two groups in terms of patient's and mobilization characteristics. Only number of CD 34+stem cells collected was statistically different (median 9,07×106/kg CD34+cells in group 1 versus 2,14×106/kg in group 2, p<0.05). The only possible risk factor that we could define was presence of organ metastasis. CONCLUSIONS: Since several methods and new drugs are available for peripheral stem cell collecting, risk factors should be identified clearly in adult population with solid tumors. So multicenter studies should be constructed for resolving this problem.

Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells.

Prostate cancer (PCa) is the most common type of cancer among males. Although survival rate of early-stage PCa is high, treatment options are very limited for recurrent disease. In this study, the possible synergistic cytotoxic and apoptotic effect of octreotide in combination with AT-101 was investigated in DU-145 hormone and drug refractory prostate cancer cell line. To enlighten the action mechanisms of the combination treatment, expression levels of somatostatin receptors 2 and 5 (SSTR2 and SSTR5) were also investigated. Cell viability was measured by XTT assay. Apoptosis was assessed through DNA fragmentation analysis and caspase 3/7 assay. mRNA and protein levels of SSTR2 and SSTR5 were evaluated by qRT-PCR and western blot analysis, respectively. Octreotide in combination with AT-101 inhibited cell viability and induced apoptosis synergistically in DU-145 cells as compared to any agent alone. Combination treatment increased both SSTR2 and SSTR5 mRNA and protein levels in DU-145 cells. The data suggest that this combination therapy may be a good candidate for patients with advanced metastatic PCa do not respond to androgen deprivation.

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.

Adjuvant chemotherapy may contribute to an increased risk for metabolic syndrome in patients with breast cancer.

PURPOSE: Cytotoxic treatment may cause weight gain and important alterations in the metabolic status of breast cancer (BC) patients. The aim of this study was to investigate the changes in metabolic and anthropometric parameters of patients with BC who received adjuvant chemotherapy. METHODS: All consecutive women treated with adjuvant TAC (docetaxel 75 mg/m(2), doxorubicine 50 mg/m(2), cyclophosphamide 500 mg/m(2)) chemotherapy for node-positive breast carcinoma at our Institution between 2008 and 2010 were included. RESULTS: Among 104 patients, 84 of them were stage II and 20 of them were stage III. When we compared the measurements between 1(st) and 6(th) adjuvant chemotherapy, we observed statistically significant increases in weight and serum triglyceride levels, and decreases in high density lipoprotein, apolipoprotein A-1, transferrin, albumin and prealbumin levels. An elevation of follicle stimulating hormone, luteinizing hormone together with the decrease of estradiol was detected. Waist-to-hip ratio has also increased significantly. In subgroup analyses, we observed dramatic changes in body mass index in pre-menopausal women whereas no significant change was seen in the post-menopausal group. CONCLUSIONS: Adjuvant chemotherapy may contribute to an increased risk for metabolic syndrome in patients with BC and these changes are more profound in pre-menopausal patients.

Reliability and validity of the Turkish version of the EORTC QLQ-C15-PAL for patients with advanced cancer.

OBJECTIVE: Assessing quality of life, which is the main focus of palliative care, is highly important. The number of available, specific, simple, and valid assessment instruments for patients with advanced cancer in Turkey is limited. The aim of our study was to perform a psychometric evaluation of the Turkish version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-PAL (EORTC QLQ-C15-PAL). METHOD: The study was conducted in Izmir with patients who had received treatment in the palliative care unit of a university hospital between November of 2011 and December of 2013. Sociodemographic and disease characteristics forms, the Karnofsky Performance Status (KPS) Scale, and the EORTC QLQ-C15-PAL Scale were employed in order to gather data. RESULTS: A total of 150 patients completed the study: 55.3% of participants were female, 80.7% were married, and the average age was 52.76 ± 14.55. The value of Cronbach's α in the analyses ranged from 0.93 to 0.98. Most questionnaire areas had low to moderate correlations with the others. The moderate correlations were between fatigue and physical function (-0.41) and between insomnia and emotional function (-0.53). Conversely, weak correlations were found between nausea/vomiting and appetite loss (0.31) and between insomnia and pain (0.22). KPS scores decreased, patient physical and emotional function were diminished, global QoL declined, and patients' symptoms became more frank. SIGNIFICANCE OF RESULTS: We concluded that the EORTC QLQ-C15-PAL is a valid and reliable tool to determine the quality of life of advanced cancer patients who are undergoing palliative treatment in Turkey.

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.

Hypersensitivity to chemotherapeutics: a cross sectional study with 35 desensitisations.

BACKGROUND: Chemotherapy is one of the main treatments for lung cancer, and in these patients, discontinuation of treatment due to uncontrollable hypersensitivity reactions (HSRs) is an important problem. AIM: To determine the frequency of HSRs during chemotherapy and to review current approaches. METHODS: We did a cross sectional study in patients undergoing chemotherapy for lung cancer in a reference chemotherapy unit from January 2012 to January 2013. Patients who developed immediate-HSRs or delayed-HSRs to chemotherapeutics and gave consent were included into study. The effectiveness of a standardised 12-step "rapid drug desensitisation" (RDD) procedure was investigated in patients with immediate-HSRs. RESULTS: In total, 1,099 cycles of chemotherapy were administered to 292 patients in 1 year. We observed ten HSRs, during ten cycles in ten patients (~3 % of the patients). Two HSRs were delayed-type, eight were immediate-type at grade 1-3. Of those with immediate-type HSR, five patients with grade 2-3, and additional two referred patients with grade 4 HSRs were successfully given their culprit drug in 35 cycles of chemotherapy with 12-step or modified 20-step RDD protocol. CONCLUSIONS: HSRs to chemotherapeutics are not so rare. Premedication alone does not prevent such reactions. The results of RDD treatment look promising for continuing treatment with the culprit chemotherapeutic agent.

Determining the satisfaction levels of the family members of patients with advanced-stage cancer.

OBJECTIVE: The objective of our study was to determine the satisfaction levels of family members of patients with advanced-stage cancer. METHOD: This descriptive study was conducted in the palliative care and medical oncology clinics of a university hospital in the province of Izmir between April of 2011 and January of 2012. The study sample consisted of a total of 145 family members, who were selected from among the family members of patients with advanced-stage cancer receiving palliative treatment. The study data were obtained using the Patient Description Form and Family Satisfaction Scale during face-to-face interviews with patients. RESULTS: Some 67% of patients were female and 33% male, 70% were married, 35% were high school graduates, and 34.5% were housewives. The average total family satisfaction score was 76.87 ± 1.14, and the average scores for the component variables were as follows: information giving 74.37 ± 1.28, availability of care 78.40 ± 1.17, physical care 78.99 ± 1.09, and psychosocial care 74.52 ± 1.30. We found a relationship between the level of satisfaction of family members and (1) gender, (2) occupation, (3) presence of someone supporting the care, and (4) possession of sufficient information about the patient (p < 0.05). SIGNIFICANCE OF RESULTS: Satisfaction levels of participants were determined to be high. We found that family member satisfaction levels were affected by gender and occupation, the existence of someone supporting the care, and possession of sufficient information about the patient.

WNT1 gene expression alters in heterogeneous population of prostate cancer cells; decreased expression pattern observed in CD133+/CD44+ prostate cancer stem cell spheroids.

PURPOSE: Established cancer cell lines contain cancer stem cells (CSCs) which can propagate to form three dimensional (3D) tumor spheroids in vitro. Aberrant activation of WNT signaling is strongly implicated in the progression of cancer and controls CSCs properties. In this study we hypothesized that when cells were maintained as spheroids, the structure of CSCs could show differentiation between CSCs and non- CSCs. METHODS: CD133+/CD44+ cancer-initiating cells were isolated from DU-145 human prostate cancer cell line monolayer cultures, propagated as tumor spheroids and compared with the remaining heterogeneous cancer cells bulk population. The expression levels of WNT1, FZD1, ADAR, APC, AXIN, BTRC, FRAT1 and PPARD genes were measured by polymerase chain reaction (PCR) array assay and the protein expression levels of WNT1, FZD and AXIN by immunohistochemistry. RESULTS: The expression levels of WNT pathway-related molecules were found to increase in both CSCs and non- CSCs when CSCs were maintained as spheroids. However, different expression profiles were observed when CSCs and non-CSCs were compared. In spheroids, the expression levels of FZD1, APC, ADAR, WNT1, PPARD genes in CSCs decreased when compared to non-CSCs. Interestingly, when CSCs from spheroids were compared with CSCs from monolayers the most significant decrease was observed in FZD1 and increase in APC genes. CONCLUSION: It is possible to assume that intracellular signaling of WNT-related molecules in the nucleus and/or cytoplasm might play an important role but it is independent from increased ligand expression and this expression strongly differentiate CSCs and non-CSCs population. This unexpected expression could be important for CSCs behavior and targeting this pathway could have therapeutic implications in cancer.

Enhanced cytotoxicity and apoptosis by thymoquinone in combination with zoledronic acid in hormone- and drug-resistant prostate cancer cell lines.

PURPOSE: Thymoquinone (TQ), an active ingredient of black seed oil (Nigella Sativa), has been shown to possess cytotoxic activity against a variety of cancer cell lines. Our purpose was to investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the TQ in hormone- and drug-refractory prostate cancer cells PC-3 and DU-145. METHODS: XTT cell proliferation assay was used to assess cytotoxicity; DNA fragmentation and caspase 3/7 activity were also measured. RESULTS: The combination of TQ and ZA resulted in a significant synergistic cytotoxic activity and DNA fragmentation when compared to any single agent alone, in a dose- and time-dependent manner. In addition, TQ and ZA combination increased the caspase 3/7 activity in PC-3 cell line, while this activity could not be demonstrated in DU-145 cell line. CONCLUSION: TQ and ZA had minimal hematological and non-hematological toxicity profile compared to cytotoxic agents. So, this combination may be an alternative approach for patients who are unable to be treated by conventional treatments because of poor performance status.

Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group Trial.

OBJECTIVE: It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin (XELOX) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer (mCRC). METHODS: Patients received either bevacizumab (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m(2) twice daily on days 1-14 + oxaliplatin 130 mg/m(2) on day 1 every 3 weeks) until disease progression (arm A) or the same doses of bevacizumab + XELOX for 6 cycles followed by bevacizumab + capecitabine until disease progression (arm B). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. RESULTS: One hundred and twenty-three patients were randomized. Treatment compliance was similar in both groups. Median PFS was significantly longer for arm B than for arm A (11.0 vs. 8.3 months; p = 0.002). There was no significant difference between the two arms for ORR (66.7 vs. 59.0%; p = 0.861) or median OS (23.8 vs. 20.2 months; p = 0.100). Tolerability was acceptable in both treatment arms; the most frequent grade 3/4 treatment-related adverse events (arm B vs. arm A) were fatigue (6.6 vs. 16.1%), diarrhoea (3.3 vs. 11.3%), anorexia (3.3 vs. 11.3%), and neuropathy (1.6 vs. 8.1%). CONCLUSIONS: Maintenance therapy with bevacizumab + capecitabine can be considered an appropriate option following induction bevacizumab + XELOX in patients with mCRC instead of continuation of bevacizumab + XELOX.

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.

Examination of pain experiences of cancer patients in western Turkey: a phenomenological study.

This study aims to explore the individual experience of living with cancer pain. This qualitative study was performed by using a phenomenological research design. In-depth and open interviews with participants were conducted to collect the data and a qualitative Colaizzi method of analysis was performed. Following the analysis of the data, the expressions made by the cancer patients during the interviews were grouped under 5 themes. Consistent with the questionnaire format, 5 themes and 19 subthemes of responses were determined describing the pain of the cancer patients. The results of our study have demonstrated that cancer patients go through negative physical, psychological, and social experiences due to the pain they suffered.

Effects of Thymus serpyllum extract on cell proliferation, apoptosis and epigenetic events in human breast cancer cells.

Thymus (T.) serpyllum (wild thyme) is an aromatic medicinal plant due to its several biological properties, including anticancer activity. Breast cancer is one of the most common malignancies and increasing evidence supports that it is not only a genetic but also an epigenetic disease. Epigenetics investigates changes in gene expression caused by mechanisms that do not involve alterations in DNA sequence. DNA methylation and histone acetylation are the most widely studied epigenetic changes in cancer cells. This study evaluated the effects of T. serpyllum on apoptosis and epigenetic events in breast cancer cells. XTT cell viability assay was used to determine cytotoxicity. DNA fragmentation and caspase 3/7 activity assays were used in the assesment of apoptosis. DNA methyltransferase (DNMT) and histone deacetylase (HDAC) activities were evaluated by ELISA and verified by qRT-PCR. T. serpyllum extract induced significant cytotoxicity in breast cancer cells (MCF-7 and MDA-MB-231) but not in normal cells. It also induced apoptosis and inhibited the DNMT and HDAC activities in MDA-MB-231 cells. In the present study, the first preliminary data on the effects of the methanolic extract of T. serpyllum in normal and breast cancer cells were obtained and suggest that T. serpyllum may be a promising candidate in the development of novel therapeutic drugs for breast cancer treatment.

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.