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Background: Endocrine treatment and chemotherapy are a treatment options for patients with hormone receptor (HR) positive and HER2-negative metastatic breast cancer (MBC). However, response to first-line hormone treatment could not obtained in all patients, and even patients who havea response will eventually relapse. After disease progression, second-line hormonal treatmentoptions are used sequentially. Everolimus with exemestane has demonstrated promising activity in patients with HR-positive HER2-negative endocrine-resistant MBC with respect to the results of the BOLERO-2 study. In the present study, we aimed to evaluate the efficacy and safety of this combination in the real-life clinical setting for the unselected population in Turkey. Material and Methods: One hundred and one patients with HR-positive HER-2 negative MBC progressing after prior endocrine treatment who were treated with everolimus with exemestane were retrospectively analyzed. The tolerability and efficacy of this combination were evaluated in the unselected Turkish patients. Results: Among 101 patients, 45% of patients had visceral and %50 patients had only bone metastasis. Everolimus with exemestane treatment was administered as a second-line in 21.3% of patients, third-line in 40.4% and forth-line and later in 38.2%. The objective response rate was 24.7% (CR+PR) and stable disease was obtained in 37.7% of patients. At the median follow-up time of 13.5 months, the median progression-free survival (PFS) time and 1-year PFS were 13.8 months and 57.2%, while the median overall survival (OS) interval and 1-year OS were 40 months and 85%. The median treatment duration was 8.3 and 6.5 months for exemestane and everolimus, respectively. The most frequent reason for discontinuation of treatment were disease progression (39%). Moreover, the most common advers events (AE) causing permanent discontinuation were stomatitis (3%) and pneumonitis (3%). A total of 81 % of patients experienced at least one AE of any grade, 25% of patients at least one grade 3 or 4 AE. Due to AEs, everolimus dosage was reduced to 5 mg in 16 (15.8%) of patients. Conclusions: Our findings confirmed that the combination of everolimus with exemestane was the safe and effective treatment options for patients with HR-positive HER-2 negative MBC after second or later lines treatments. Citation Format: Bilici A, Menekse S, Akin S, Degirmenci M, Olmez OF, Avci N, Sakalar T, Tural D, Kaplan MA, Tanriverdi O, Bilgetekin I, Uslu R. The efficacy and safety analysis of the treatments of everolimus and exemestane combination in 101 metastatic breast cancer patients: Real-life experience from Turkey [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-37.

Background The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

Objective In this article, IDAC-Dose2.1 and OLINDA computer codes are compared as they are the most widely used software tools for internal dosimetry assessment at the present time. OLINDA/EXM personal computer code was created as a replacement for the widely used MIRDOSE3.1 code. IDAC-Dose2.1 was developed based on the ICRP specific absorbed fractions and computational framework of internal dose assessment given for reference adults in ICRP Publication 133. IDAC uses cumulated activities per administered activity in hours and calculates the absorbed dose and the effective dose. The program calculates the dose in the Eckerman stylized family phantoms. It is useful in standardizing and automating internal dose calculations, assessing doses in clinical trials with radiopharmaceuticals, making theoretic calculations for existing pharmaceuticals, teaching, and other purposes. Methods To produce such a comparison, the results of this work were compared with available published data in the literature on radiopharmaceuticals. Radiopharmaceuticals with 89Zr, 153Sm, 177Lu radionuclides are used as the basis for the comparison. 89Zr, 153Sm, 177Lu radionuclides are regarded as the future of radiopharmaceutical treatment. For 89Zr, two different labelled carriers, Zr-89_cMAb U36 and Zr-89 Panitumumab, were used on patients. Results The results show a clear difference in terms of absorbed dose of the Zr-89 radiopharmaceuticals for red bone marrow when calculated by IDAC-Dose2.1 (0.76 mGy/MBq), while the estimated absorbed dose in literature results is 0.07 mGy/MBq and 0.14 mGy/MBq when the calculation is done by OLINDA program. In the case of 177Lu-EDTMP, the absorbed dose in red bone marrow is in reasonable agreement (0.63 mGy/MBq and 0.8 mGy/MBq for IDAC-Dose2.1 and OLINDA, respectively). A significant difference was found for the absorbed dose in the bone surface, which was almost twice as high for OLINDA (2.1 mGy/MBq for IDAC-Dose2.1 and 5.4 mGy/MBq for OLINDA). In some direct cases, the calculated absorbed dose in the urinary bladder wall with OLINDA is ten times higher compared to WinAct (which was utilized to calculate the total activity in the organs and tissues) and IDAC 2.1. These results are considered key to greater accuracy in internal dose calculation.

Dental amalgam is one of the most adapted ceramic material which is used in dentistry. On the other hand, they are candidate materials for ionizing radiation exposure during the diagnostic imaging and therapeutic applications. This study is focused on determination of some vital material and physical parameters of dental amalgam composites. The elementary test of the dental amalgam composites have performed using SEM and EDS. On the other hand some significant photon interaction parameters such as mass attenuation coefficients (μ/ρ), half-value layer (HVL), tenth-value layer (TVL), mean free path (MFP), effective atomic number (Zeff) and effective electron density (Nel), energy build up factor (EBF), exposure the factor (EABF) of investigated materials have been determined. The last composition encoded DA5 has obtained with a smooth surface with some small agglomeration. The results showed that DA5 sample has the smallest EABF and EBF values, while DA1 and DA2 own the largest ones. This means that the DA5 sample is more effective than other samples in terms of absorbing gamma radiation.

WOS: 000461694000193, Goals: In the era of neoadjuvant chemotherapy (NAC), the prediction of pathologic response is a major challenge with the potential to modify surgical approach. The aim of the present study was to evaluate the precision of ultrasonography (US) and 18F-FDG-PET/CT for predicting pathologic complete response (ypCR = ypT0, ypN0) after NAC. Methods: A single-institution, retrospective review of a prospectively maintained database was analyzed to identify breast cancer patients treated with NAC. The study included 253 invasive breast cancer patients treated with NAC followed by standard breast and axillary nodal surgery. US and 18F-FDG PET/CT evaluation was done before and after NAC with documentation of clinical complete response. All US studies were interpreted, as “normal” according to the absence of specific characteristics shown to be commonly associated with metastatic involvement both at diagnosis and at the date of operation. 18F-FDG PET/CT scans was termed as negative or positive due to the standardized uptake value. Results: 102 patients (40,3%) achieved pCR and all of whom had a corresponding clinical complete response. Among 134 patients with clinical negative axilla and initial nodal US demonstrating N0 disease, 41.8% had a breast pCR and all of these cases showed no evidence of axillary lymph node metastases after NAC. For 119 patients with initially nod positive disease, 88.2% patients with a breast pCR and 32.3% patients without breast pCR had axillary N0 disease after NAC. Overall sensitivity, specificity, PPV and NPV for prediction of pCR after NAC was found to be 90%, 92%, 90%, 76% for US and 89%, 84%, 81%, 75% for 18F-FDG-PET/CT, respectively. The PPV for predicting axillary status using US alone was 66.1% and for 18 FDG-PET-CT was 55%. Overall accuracy for pCR was found to be 82.6% for US and 78.6% for 18-FDG-PET/CT. The presence of in situ carcinomawas found to be the only significant factor associated with false negative US for pCR. Micrometastatic disease, the size and number of metastatic nodes were significantly associated with false negative PET/CT results for axillary disease. Conclusions: Breast pCR is highly correlated with nodal status after NAC. US is a beneficial tool with the potential of accurate prediction of pCR in up to 80% of patients following NAC. Nevertheless, in cases of rest in situ carcinoma the accuracy of US should be interrogated cautiously. Moreover, in terms of axillary status neither US, nor 18-FDG-PET-CT is highly capable of predicting N0 disease after NAC. Conflict of Interest: No significant relationships.

Objective: In the era of neoadjuvant chemotherapy (NAC), the most accurate method for axillary staging is a challenge for surgeon. Sentinel lymph node biopsy (SLNB) is the recommended choice of care for axillary staging in clinically node-negative (cN0) disease. Nevertheless, the role of preoperative axillary ultrasound (AUS) or 18F-FDG PET/CT in case of cN0 patients after NAC (ycN0) is controversial. The purpose of the presented study is to assess the correlation between surgeon performed AUS and PET/CT data with SNLB results to further determine the predictive role of AUS in pathologic staging of cN0 axilla after NAC. Materials-Methods: A single institution, retrospective review of a prospectively maintained database was analyzed to identify ycN0 breast cancer patients with AUS and 18F-FDG PET/CT. All AUS studies were interpreted by a dedicated breast surgeon experienced in ultrasound, as "normal" according to the absence of specific characteristics shown to be commonly associated with metastatic involvement at diagnosis and at the date of operation. 18F-FDG PET/CT scans was termed as negative or positive due to the standardized uptake value (SUV). Patient, tumor and operative variables including age, body mass index (BMI), date of diagnosis and surgery, AUS, 18F-FDG PET/CT scans, SLNB results, and final pathology data were evaluated. Results: Of the 69 patients with cN0 axilla after NAC, SNLB was found to be positive in 37 patients (53.6%). 2 (9.5%) out of 21 patients with a normal AUS and 3 (21.4%) out of 14 patients with negative PET/CT were ultimately found to be node-positive on pathologic assessment of SLNB. Intraoperative sonography accurately identified the SLN in 92.7% of cases. The sensitivity, specificity, positive and negative predictive values were 94.5%, 59.3%, 72.9% and 90.5% for surgeon-performed AUS and 91.8%, 34.4%, 61.8% and 78.6% for PET/CT scans, respectively. Overall accuracy was found to be %78.2 for AUS and 65.2.% for PET/CT. The presence of lymphovascular invasion (LVI), micrometastasis, primary tumor size, and body mass index were found to be significantly different between true and false negative AUS. None of the clinicopathological features of the primary tumor were significantly associated with FDG uptake in the axillary lesion. Micrometastatic disease, the size and number of metastatic nodes were significantly associated with FDG uptake leading to a difference between true and false negative PET/CT for axillary disease. No significant difference was noted with regard to patient age, tumor grade, histologic type, hormone receptor status, and time between AUS or PET/CT and axillary surgery. Conclusion: Surgeon performed AUS is a beneficial tool with the potential of accurate prediction of axillary disease in up to 78% of patients after NAC. Nevertheless, the accuracy of AUS findings should be interrogated cautiously particularly for larger tumors with LVI or micrometastasis in overweight patients. Similarly, our data also imply that PET/CT had a limited value in the evaluation of axillary nodes and is not sufficient to predict axillary status particularly in case of micrometastasis after NAC. Citation Format: Karadeniz Cakmak G, Uslu R, Emre AU, Elmas O, Karadere Y, Konuk MB, Engin H, Dogan Gun B. Axillary staging after neoadjuvant chemotherapy: The comparison of surgeon performed axillary ultrasound and 18F-FDG PET/CT with pathologic status of sentinel lymph nodes in clinically node-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-08.

Ilk bakista akut yas, medikal ya da psikiyatrik bir bozukluk olmaktan cok, aci verici bir duruma karsi verilen normal bir tepki gibi gorunur. Ancak Psikiyatrisi icin siniflandirilabilir nevrozlar olmasalar da travmatik yasantilara verilen tepkilerin anlasilmasi onem kazanmistir. Yoksunluk veya sosyal etkilesimin birden kesilmesi gibi gunumuzde cok ilgi ceken durumlar, psikosomatik bozukluklarin basta gelen ruhsal etmenleri arasinda yer almaktadirlar. Savasta yitirdiklerinin yasini tutanlarin sayisindaki buyuk artis, benzer olaylarin toplumun ruhsal ve bedensel sagligi uzerindeki olasi etkisini bilmeyi gerekli kilmaktadir.

The aim of this study was to explore the effects of exercise on angiogenesis and apoptosis-related molecules, quality of life, fatigue and depression in patients who completed breast cancer treatment. Sixty breast cancer patients were randomised into three groups, as supervised exercise group, home exercise group and education group. Angiogenesis and apoptosis-related cytokine levels and quality of life (EORTC QOL-C30: European Organisation for Research and Treatment of Cancer Quality of Life C30), fatigue (Brief Fatigue Inventory) and depression (BDI: Beck Depression Inventory) scores were compared before and after a 12-week exercise programme. After the exercise programme, statistically significant decreases were found in interleukin-8 and neutrophil activating protein-78 levels in the home exercise group (P0.05). The education group showed a statistically significant increase in monocyte chemoattractant protein-1 level (P0.05). Functional score and global health score of EORTC QOL-C30 in the supervised exercise group and functional score of EORTC QOL-C30 in the home exercise group increased significantly after exercise programme (P0.05). BDI score was significantly lower in the supervised exercise group after the exercise programme (P0.05). Changes in angiogenesis and apoptosis-related molecules in the study groups suggest a possible effect of exercise on these parameters. Exercise programmes are safe and effective on quality of life and depression in breast cancer patients whose treatments are complete.

The coexistence of two different malignancies in the same patient is a very rare entity. It is highly possible to see secondary malignancies in survivors of cancer after chemotherapy or radiotherapy, especially in breast cancer and Hodgkin lymphoma since the life expectancy in these disorders is quite long. The drugs or the radiation given during the treatment could provide the etiopathological basis for development of secondary cancers. However, the exact mechanisms underlying the coexistence of two different cancers in the same patients have not yet been clarified. In this article, we summarize two patients with simultaneous breast cancer and chronic myeloid leukemia., Aynı hastada 2 ayrı malinitenin eş zamanlı saptanması çok nadir bir durumdur. Özellikle meme kanseri ya da Hodgkin lenfoma tanısı için kemoterapi ve/veya radyoterapi alan ve kür elde edilen insanlarda beklenen yaşam süresi yeterince uzun olduğu için, bu tedavilere bağlı ikincil kanser görme şansı fazladır. Burada etiyolojik ajan olarak verilen kemoterapi ya da radyoterapi suçlanabilir. Ama aynı hastada 2 ayrı malinitenin eş zamanlı saptanmasının mekanizması tam olarak aydınlatılamamıştır. Bu yazıda, meme kanseri ve kronik myeloid lösemi tanısı alan 2 olgu sunulmaktadır.

There are very few randomized controlled studies on exercise in cancer patients. Consequently, there are no guidelines available with regard to the exercises that can be recommended and difficulties are encountered in the clinical practice as to which exercise is more suitable to the patients.The purpose of this study was to investigate the impact of pilates exercises on physical performance, flexibility, fatigue, depression and quality of life in women who had been treated for breast cancer.Randomized controlled trial.Out patient group, Department of Physical Medicine and Rehabilitation and Medical Oncology Department, University Hospital.Fifty-two patients with breast cancer were divided into either pilates exercise (group 1) and control group (group 2).Patients in Group 1 performed pilates and home exercises and patients in group 2 performed only home exercises. Pilates exercise sessions were performed three times a week for a period of eight weeks in the rehabilitation unit.Subjects were assessed before and after rehabilitation program, with respect to, 6-min walk test (6MWT), modified sit and reach test, Brief Fatigue Inventory (BFI), Beck Depression Index (BDI) and the European Organisation for Research and Treatment of Cancer Quality of Life C30 (EORTC QLQ-C30) and EORTC QLQ BR23.After the exercise program, improvements were observed in Group 1 in 6-minute walk test, BDI, EORTC QLQ-C30 functional, and EORTC QLQ-C30 BR23 functional scores (P0.05). In contrast, no significant improvement was observed in Group 2 after the exercise program in any of parameters in comparison to the pre-exercise period (P0.05). When the two exercise groups were compared, there were significant differences in 6MWT in pilates-exercise group (P0.05).Pilates exercises are effective and safe in female breast cancer patients. There is a need for further studies so that its effect can be confirmed.This study addressed the effects of pilates exercise, as a new approach, on functional capacity, fatigue, depression and quality of life in breast cancer patients in whom there are doubts regarding the efficacy and usefulness of the exercise.

Çocuk ve ergen intiharları son yıllarda giderek artmaktadır.Çocuk ve ergenlerde intihar girişimi ve tamamlan mamış intiharlar ile ilgili yüksek risk etkenleri tartışılmış ailelerin tepkileri ve terapi sürecinde bu tepkilerin geçirdiği aşamalar verilmiştir

The symptoms and survival of patients with advanced pancreatic cancer show great variability according to tumor localization. The main purpose of this study was to see for any differences between the intensity of symptoms, mainly pain, and the need for analgesic treatment in advanced pancreatic cancer patients with different (head vs. body-tail) tumor localizations.Ninety-six patients with histologically confirmed pancreatic cancer were enrolled in the study. The patients were divided into 2 subgroups according to tumor localization: group 1 (n=50) with head tumors and group 2 (n=46) with body and tail tumors. The demographic features of the patients as well as disease stages, onset of symptoms and necessity and consumption of analgesics were recorded. Patients were followed-up until death, and survival data was also analysed.At the time of diagnosis, patients with body and tail tumors had more advanced disease stages compared to head tumors (p=0.006). While jaundice was the most common initial symptom in head tumors (p0.0001), it was pain in body and tail tumors (p0.001). Patients with body and tail tumors had more analgesics consumption as compared to those with head tumors (p=0.009). No statistically significant difference in survival was detected between the 2 groups (p0.05).We believe that pancreatic cancer should be accepted as two diverse disease types according to tumor localization, and pain and symptom management should be organized based on this fact.

To evaluate the necessity and direct cost effectiveness of screening and staging procedures in breast cancer patients having ≥4 positive axillary lymph nodes and to identify further possible biopathological risk factors associated with increased risk of metastasis.We reviewed the demographic and clinicopathological data from the medical records of 1897 newly diagnosed breast cancer patients. Patients having ≥4 positive axillary lymph nodes after primary surgery for breast cancer and who had staging examinations for metastasis were eligible. The impact of staging procedures (thoracoabdominal CT, bone scan etc.) for detecting metastasis, decision of adjuvant treatment and direct costs were analyzed in 329 patients with operable breast cancer.Thirty-five (10.6%) patients were found with metastasis at diagnosis. Seven (20.0%) among them had multiple metastases. Eighteen (51.4%) had lung, 17 (48.6%) bone, and 7 (20.0%) liver metastasis. Twenty-one (60.0%) patients needed further radiological investigation for metastasis confirmation. Treatment decision was changed in 27 (77.1%) patients. No statistically significant risk factor was identified among the metastatic patients by means of conventional demographic and biopathological parameters. The cost of screening was lower when compared to the cost of treatment without any screening procedure.Since the conventional clinicopathological data seems not sufficient to define the risk of developing metastasis in breast cancer patients with ≥4 axillary lymph node involvement, all of them should undergo full staging examinations until new parameters based on genomic level are defined. Staging procedures need modification for high risk breast cancer patients.

Cancer patients encounter many problems in the post-diagnosis period and they want to establish a good contact with the treatment team in order to get better information about their condition. This study attempted to investigate in patients with completed treatment the level of satisfaction they derived from the treatment and the treatment team.The archive of medical records of the Medical Oncology Department comprising 4622 patients was randomly screened between the years 2000 and 2006. Charts of 528 patients were reached via phone and analysed for clinical data.Approximately 78.8% of the patients had been informed about their malignant diseases. The rates of satisfaction from the treatment team, the treatment itself, and communication with the physician was higher among informed patients compared to uninformed ones (p0.05). Of all the evaluated patients, 38.5% had been recommended to practise general exercises.The great majority of our patients were informed about their diseases and treatments, although without being given adequate importance, and the satisfaction rates were higher among informed patients. We believe that our study will provide new approaches in relation to the importance and methods of communicating with and informing patients.

To compare the effect of racemic gossypol with its (-)/(-) enantiomer (AT-101) on expression profiles of angiogenic molecules by mRNA levels in human ovarian cancer cell line OVCAR-3.Cell viability assay (2,3-bis (2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) was used to detect cytotoxicity of gossypol enantiomers. DNA fragmentation by an enzyme-linked immunosorbent (ELISA) assay was used to evaluate the rate of apoptosis. The mRNA expression levels of angiogenic molecules were investigated by Human Angiogenesis RT2 ProfilerTM PCR Array (SuperArray, Frederick, MD).Both racemic form and AT-101 resulted in a significant cytotoxicity and induced apoptosis. This effect was observed in a dose- and time dependent manner. However, AT-101 was much more potent. In addition, the treatment of 10 microM of racemic gossypol alone and 3 microM of AT-101 alone resulted in significant down-regulation (or= 3 fold) in mRNA levels of some pivotal angiogenic molecules in OVCAR-3, but altered gene profiles were different by the treatment of each enantiomer.The efficacy of two gossypol enantiomers in OVCAR-3 cells showed distinction. AT-101 was much more potent than racemic gossypol, not only by means of cell death and apoptosis, but also by modulation of angiogenic molecules released from OVCAR-3 cells. Further studies with endothelial cells should be done to verify the anti-angiogenic effect of gossypol enantiomers in cancer treatment.

To assess the efficacy and toxicity of the docetaxel and platinum combination in patients with locoregionally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN).A total of 24 patients with metastatic or locoregionally advanced SCCHN treated with docetaxel and platinum combination chemotherapy were retrospectively reviewed. All of them had histologically proven SCCHN, measurable disease and ECOG performance status of 2 or less, and were treated with docetaxel 75 mg/m(2) as a 60 min i.v. infusion on day 1, followed by cisplatin 75 mg/m(2) or carboplatin AUC 6 as a 60 min i.v. infusion on day 1 every 3 weeks, until disease progression or unacceptable toxicity. Patients were evaluated for response, survival and toxicity.Seven (29%) patients showed partial response (PR) and 1 (4%) complete response (CR) for an overall response rate of 33%. Twelve (50%) patients had stable disease (SD). Disease control rate was 83%. The median follow-up time was 26.4 months (range 2-127), the median time to progression 16 months (range 2-20), and the median overall survival 19 months (range 2-22). Grade 3-4 hematologic toxicity occurred in 13 (54%) patients. Febrile neutropenia was seen in 5 (21%) patients.Docetaxel plus cisplatin or carboplatin is an effective regimen with acceptable safety profile for palliation of locally advanced or metastatic SCCHN.

Lack of effective treatment for surgically unresectable hepatocellular carcinoma has made this disease dismal. Although, systemic and/or locoregional chemotherapy and chemo-embolization are among the established treatment options, the results of these modalities are still far from being satisfactory. Systemic interferon administration is also used for the treatment of this disease however it has high toxicity rates. We conducted a pharmacology guided phase I/II study with the aim to explore the effect of hypoxy and interferon alpha-2a in vitro using the HepG2 Hepatoma cell line. We then translated the in-vitro results to the clinical setting and designed a treatment protocol. This schema consisted of lipiodol embolisation via a hepatic artery port in between two sets of seven loco-regional injections of IFNalpha-2a, 3 MU every other day. The in-vitro study revealed the best sequence of hypoxy and IFN as IFN-Hypoxy-IFN. Based on this finding, ten patients with HCC were treated with loco-regional IFN and lipiodolisation. Seven of them achieved partial response and the mean duration of response was 10 months. There was no Grade 4 toxicity. In conclusion, our preliminary clinical results suggest that the combined use of IFN and lipiodolisation in the optimal sequence may provide a new therapeutic option for patients with HCC.

We studied the effect of arsenic trioxide (As2O3) on prostate and ovarian carcinoma cell lines. As2O3 has been shown to be effective in leukemia, and acute promyelocytic leukemia in particular, both in vitro and in vivo. As model cell lines, we used DU145 and PC-3 for prostate cancer and MDAH 2774 for ovarian cancer. New modalities of treatment are essential in these kinds of cancers, which produce a high death toll. The 3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to evaluate cytotoxicity. Flow cytometric analysis and mono-oligo nucleosome detection-based ELISA were used to determine the apoptosis. Isobologram analysis was used to evaluate synergism and/or the additive effects of As2O3 and conventional chemotherapeutic agents. We clearly demonstrated that As2O3 has significant cytotoxic effect on both prostate and ovarian carcinoma cell lines. The dose range of As2O3 in all three cell lines was approximately 10(-6) M. The mechanism underlying cytotoxicity of As2O3 was shown to be apoptosis. The experiments by butylated hydroxyanisole showed that the cytotoxic effect of As2O3 was not through superoxide generation. There was no synergism, but the additive effects of As2O3 were demonstrated with cisplatin, adriamycin, and etoposide. We strongly suggest that As2O3 alone or in combination with conventional chemotherapeutic agents be evaluated further as a new agent for the treatment of prostate and ovarian cancers.

Serine/threonine protein phosphatase 2A (PP2A) may play a role in leukaemic cell differentiation of the HL-60 myeloid leukaemic cell-line after methylprednisolone induction. We have investigated the specific enzyme activity and expression of catalytic and regulatory subunits of PP2A. The resulting specific enzyme activity and immunoblots showed an increase in enzyme activity and the expression of regulatory subunits after methylprednisolone treatment. There was no change in the expression of PP2A catalytic subunits. It is suggested that the effect of methylprednisolone on leukaemic differentiation may be the result of PP2A upregulation.

To determine the sensitivity of drug-resistant prostate cancer cell lines to doxazosin-mediated cell death, and the effects of combining doxazosin and chemotherapeutic agents on these cell lines. Materials and methods The cytotoxic effect of doxazosin was initially evaluated in the prostate carcinoma cell lines DU145 and PC-3. Doxazosin was combined either with adriamycin, etoposide or paclitaxel after its cytotoxic effects were detected in these cell lines. The tetrazolium dye (MTT) assay and trypan blue dye-exclusion tests were used to determine drug-mediated cytotoxicity. Experiments were performed at least three times and representative data are presented.Both cell lines were sensitive to doxazosin-mediated cytotoxicity and the maximum cytotoxicity was achieved after 72 h. While cell death increased with increasing concentrations of doxazosin, 60 micromol/L doxazosin killed more than half of the cells in these cell lines. The combination of doxazosin with both adriamycin and etoposide resulted in significant synergistic cytotoxic activity at subtoxic concentrations of the drugs. Interestingly, the combination of doxazosin and paclitaxel resulted in antagonistic activity.Doxazosin-mediated cytotoxicity in the drug-resistant human prostate carcinoma cell lines was confirmed. Combinations of doxazosin with either adriamycin and etoposide, but not paclitaxel, had synergistic cytotoxic activity in these tumour cell lines. These results suggest that doxazosin could be a new cytotoxic agent, either used alone or combined, in the treatment of prostate cancer.

Previous studies have demonstrated that treatment of human tumor cell lines with a combination of cis-diamminedichloroplatinum (CDDP) and tumor necrosis factor-alpha (TNF-alpha) results in additive/synergistic cytotoxic effects and reverses tumor cell resistance to TNF drugs. Free radical intermediates are induced by both TNF-alpha and CDDP; however, the role of free radicals in synergy is not known. This study investigated the effect of two inhibitors on synergy, phenoxan (Phe) and butylated hydroxyanisole (BHA), which inhibit Complex I and Complex I and II of the mitochondrion respiratory chain, respectively.Three human ovarian carcinoma cell lines of different sensitivity to TNF-alpha and/or CDDP were selected for the study and consisted of 222, a TNF/CDDP-sensitive line, 222TR (TNF-resistant), a TNF-resistant, CDDP-sensitive line, and AD10, a TNF-sensitive, CDDP-resistant line. Cytotoxicity was determined by the microculture tetrazolium dye assay.Synergy in cytotoxicity was achieved in all three lines treated with a combination of TNF-alpha and CDDP. Cytotoxicity by either TNF-alpha or CDDP or by both TNF-alpha and CDDP was inhibited in the presence of either Phe or BHA. Pretreatment of tumor cells with either Phe or BHA for up to 4 hours, washed and followed by the addition of the cytotoxic agents (alone or combined), resulted in no inhibitory effect. Pretreatment of the cells with the cytotoxic agent for up to 2 hours, washed and then followed by the addition of Phe, resulted in significant inhibition of cytotoxicity. In contrast to Phe, the addition of BHA as late as 12 hours post pretreatment of the cells with the cytotoxic agent(s) still inhibited cytotoxicity. These results demonstrated that free radicals are involved in cytotoxicity mediated by a single agent, and in synergy with both agents. Further, the results demonstrated that Phe acts at an early stage of the cytotoxic pathway and that BHA acts at both an early and a late stage of the cytotoxic pathway.These results demonstrated that both TNF-alpha and CDDP rapidly stimulate the induction of free radicals but a lag of several hours was necessary to initiate the irreversible program of cell death. Further, the studies demonstrated that synergy and reversal of drug resistance in ovarian tumor cells by TNF-alpha and CDDP, used in combination, share the same pathway of cytotoxicity as that mediated by TNF-alpha or CDDP used as a single agent.

Endocrine resistance is a major clinical issue. AP-1 is a transcription factor downstream of different growth factor receptors (GFR) and stress-related signaling cascades implicated in endocrine resistance. We have previously shown that acquired endocrine resistance is associated with increased AP-1 activity. Moreover, AP-1 modulates the estrogen receptor (ER) transcriptional program, especially upon high GFR signaling. We therefore hypothesized that interfering with AP-1 could circumvent endocrine resistance. Methods and results AP-1 was genetically inhibited by siRNA or by stable expression of an inducible dominant-negative (DN) c-Jun in MCF7 cells. In vitro, siRNA c-Jun significantly inhibited the growth of acquired tamoxifen resistant (TamR) MCF7 derivatives (>95% inhibition, p = .001) but not of parental cells (p = .06). Xenografts of two inducible DN c-Jun clones were established in nude mice. Mice were randomized to continued estrogen (E2) supplementation or to either estrogen deprivation (ED) or Tam, all in the presence or absence of DN c-Jun. AP-1 blockade significantly reduced time to tumor response (p = .014 and p = .006 for the two clones) and time to tumor disappearance (p = .001 and p = .0034) in the Tam group, with similar results in the ED group. In addition, AP-1 blockade significantly delayed TamR by increasing time to tumor doubling (p = .002). Furthermore, induction of DN c-Jun resulted in dramatic tumor shrinkage after long-term Tam treatment, suggesting reversal of endocrine resistance with AP-1 blockade. Interestingly, no significant effect was observed on E2-stimulated tumor growth. Immunohystochemistry showed that AP-1 blockade reduced proliferation and induced apoptosis. A gene signature of our TamR MCF7 xenografts significantly overlapped (p Conclusions We show that AP-1 blockade increases tumor sensitivity and circumvents resistance to endocrine therapy. We suggest that AP-1 is critical in a switch in the ER transcriptional program and may be a new hallmark of endocrine resistance. Disclosure All authors have declared no conflicts of interest.