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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background To describe the prognostic value of neutrophil–lymphocyte ratio and its effect on survival in in patients with advanced renal cell carcinoma. Methods We retrospectively analyzed 331 patients. The cut-off value of neutrophil–lymphocyte ratio was specified as “3” which is mostly close—and also clinically easily applicable—to the median neutrophil–lymphocyte ratio level of our study group. High group is identified as neutrophil–lymphocyte ratio >3 (n = 160) and low group is identified as neutrophil–lymphocyte ratio ≤3 (n = 163). Results A total of 331 (with 211 male and 120 female) patients were enrolled to study. The median age of the patients was 58. The International Metastatic RCC Database Consortium risk score is calculated for the 72.8% (n = 241) of the study group and among these patients, favorable, intermediate, and poor risk rates were 22, 45.2, and 32.8%. The total usage of tyrosine kinase inhibitors reached 78% of the patients. The median overall survival was 32 months versus 11 months in the neutrophil–lymphocyte ratio low and high groups, respectively (HR: 0.49 (95% CI 0.37–0.65), p Conclusion In conclusion, the pre-treatment value of elevated neutrophil–lymphocyte ratio might be a predictor of poor overall survival in advanced renal cell carcinoma patients.

Introduction: Impaired DNA damage response (DDR) and subsequent genomic instability are associated with the carcinogenic process itself, but it also results in sensitivity of tumor cells to certain drugs and can be exploited to treat cancer by inducing deadly mutations or mitotic catastrophe. Exploiting DDR defects in breast cancer cells has been one of the main strategies in both conventional chemotherapy, targeted therapies, or immunotherapies. Areas covered: In this review, the authors first discuss DDR mechanisms in healthy cells and DDR defects in breast cancer, then focus on current therapies and developments in the treatment of DDR-deficient breast cancer. Expert opinion: Among conventional chemotherapeutics, platinum-based regimens, in particular, seem to be effective in DDR-deficient patients. PARP inhibitors represent one of the successful models of translational research in this area and clinical data showed high efficacy and reasonable toxicity with these agents in patients with breast cancer and BRCA mutation. Recent studies have underlined that some subtypes of breast cancer are highly immunogenic. Promising activity has been shown with immunotherapeutic agents, particularly in DDR-deficient breast cancers. Chemotherapeutics, DNA-repair pathway inhibitors, and immunotherapies might result in further improved outcomes in certain subsets of patients with breast cancer and DDR.

Little progress has been made, and there is an unmet medical need for treatment of metastatic gastric cancer (MGC). Docetaxel + cisplatin + 5-fluororacil (DCF) combination is an effective regimen with high rate of toxicity and is not well tolerated. We aimed to evaluate the efficacy and toxicity of a modified DCF (mDCF) combination regimen and capecitabine maintenance in MGC.Data of MGC patients were treated with first-line mDCF regimen (two weekly docetaxel 60 mg/mForty patients were included. Mean age was 53 ± 11. Thirty-two patients had de novo metastasis. All patients' performance status was ECOG 1 or 2 (32/8). Median number of mDCF cycles given was 9 (min-max: 1-23). Overall response rate was 47.5%. Ten patients (25%) received capecitabine maintenance. Grade 3/4 toxicity was seen in 20 patients (50%). Hematologic grade 3/4 toxicity occurred in 13 patients (32.5%), and grade 3/4 neutropenia occurred in 11 patients (27.5%) and in 15 cycles. Nonhematologic grade 3/4 toxicity was seen in 7 patients (17.5%). Median follow-up time was 17.2 months. Median time to progression (TTP) was 10.8 ± 1.9 months (95% CI: 6.89-14.64). Median overall survival was 14.7 ± 1.73 months (95% CI: 11.30-18.10).mDCF protocol was a tolerable chemotherapy regimen for the first-line treatment of MGC with higher ORR and longer TTP compared to standard DCF protocol. Capecitabine maintenance might increase TTP.

Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin. In this study, we aimed to evaluate the clinicopathologic characteristics, treatment outcomes, and survival of MCC cases in Turkey. Materials and methods: The patients diagnosed with MCC between 1999 and 2018 at twenty different centers in Turkey were included in the study. Patient and tumor characteristics and adjuvant and metastatis treatment outcomes were analyzed retrospectively. Results: The median age of totally 89 patients was 70 (26-93). The most common primary location was lower limbs (n = 29, 32.5%). Immunohistochemically, CK20 positivity was present in 59 patients (66.3%). Only two patients had secondary malignancy. The majority of the patients (n = 76, 85.4%) were diagnosed at the localized stage. Surgery was performed for all patients in the early stage, and adjuvant radiotherapy or/and chemotherapy was applied to 52.6% (n = 40) of nonmetastatic patients. The median follow-up was 29 months. Recurrence developed in 21 (27.6%) of the 76 patients who presented with local or regional disease. Two-year disease-free survival (DFS) was 68.1% and 5-year DFS was 62.0% for localized stage. The 5-year DFS was similar for patients receiving adjuvant treatment (chemotherapy, radiotherapy, or sequential chemoradiotherapy) and without adjuvant therapy (P > 0.05). Two-year overall survival in patients who presented with localized disease was 71.3% and 18.5% in metastatic patients (P < 0.001). In the metastatic stage, platinum/etoposide combination was the most preferred combination regimen. Median progression-free survival (PFS) in first-line chemotherapy was 7 months (95% confidence interval: 3.5-10.5 months; standart error: 1.78). Conclusions: Although MCC is rare in Turkey, the incidence is increasing. Gender, CK20 status, tumor size, lymph node involvement, and adjuvant treatment were not associated with recurrence.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

Bone metastases in breast cancer patients are a common clinical problem. Many factors influence the treatment decision, including tumor characteristics, previous treatment and tumor burden in the treatment of metastatic breast cancer.This present review summarizes the new treatment strategies and the chemotherapeutic agents currently available in the management of metastatic breast cancer with bone metastases.Patients with bone metastases more often have hormone receptor-positive tumours. Although new treatment agents for metastatic breast cancer have been investigated, endocrine therapy is still considered as the treatment of choice for patients with bone metastases although chemotherapy still has an important place. In recent years, new chemotherapeutic agents such as etirinotecan and nab-paclitaxel have been established though there are few studies that have looked at particular types of metastases. In the last decade, therapies for bone metastasis resistant to endocrine therapy have predominantly focused on radiotherapy, surgical resection, chemotherapy, bone-targeting radiopharmaceuticals and targeted therapeutics. New targeted agents include: Src inhibitors, cathepsin K inhibitors, CXCR4 inhibitors, TGF-B blockade and integrin antagonists while drug delivery systems for chemotherapy have also been developed. These new treatment options could be future treatment options for bone metastatic disease if early promising results are confirmed by clinical trials.

Introduction and aim To investigate the effect of the prognostic nutritional index on treatment response and survival in patients with metastatic renal cell cancer. Methods We retrospectively analyzed the treatment modalities; the demographic, clinical and pathological features of 396 patients with RCC and prognostic nutritional index. Based on the median value, patients were grouped as having low and high prognostic nutritional index values. Kaplan-Meier method was used for survival analysis, and Cox-regression analysis was used for multivariate analysis. Results The median overall survival was 39 months (95% CI 26.1–51.8), 28 months (95% CI 17.9–38) and 7 months (95% CI 4.7–9.2) in patients with favorable, intermediate and poor International Metastatic Renal Cell Carcinoma Database Consortium risk group, respectively. The difference between the groups was statistically significant (p 38.5) group (p Conclusion In patients with renal cell cancer, prognostic nutritional index is closely related to survival and has prognostic significance.

EgeUn###, BACKGROUND AND AIM: The combination of cetuximab with platinum and 5-fluorouracil (5-FU) chemotherapy prolongs survival in patients with metastatic or recurrent squamous-cell carcinoma of the head and neck (SCCHN). Biweekly (once in 2 weeks) administration of cetuximab requires fewer hospital visits and decreases treatment costs; therefore, it is more convenient both for the patients and for the healthcare providers. Here, we assessed the efficacy, safety, and tolerability of an alternative biweekly regimen of cetuximab in combination with platinum and 5-FU chemotherapy as a first-line treatment for these patients. METHODS AND MATERIALS: Medical records of patients with metastatic or recurrent non-nasopharyngeal SCCHN who were treated with a biweekly regimen of cetuximab (500 mg/m(2) on day 1), cisplatin (40 mg/m(2) on day 1) or carboplatin (target area under the curve 3.5 mg/ml x min on day 1), folinic acid (400 mg/m(2) on day 1), and 5-FU (400 mg/m(2) bolus on day 1 followed by continuous infusion of 2,400 mg/m(2) 5-FU over 46 h) were retrospectively reviewed. Survival estimates were calculated with the Kaplan-Meier method. RESULTS: In total, 60 patients were included. The median age of the patients was 60.5. The objective response rate was 53.3% (95% confidence interval [CI] = 40.7-65.9). The median progression-free survival duration was 6.8 months (95% CI = 5.5-8.1) and the median overall survival duration was 13.3 months (95% CI = 8.4-18.2). The most common grade 3 or 4 adverse events were neutropenia (28.3%) and leucopenia (13.3%). Grade 3 or 4 rash was observed in 3.3% of the patients. CONCLUSION: Biweekly administration of cetuximab, cisplatin, and 5-FU is an effective regimen with a favorable toxicity profile for the first-line treatment of metastatic or recurrent SCCHN. These results warrant further evaluation of this regimen in prospective trials.

Novel systemic therapies and modern surgical and ablative approaches have improved the survival rates for the patients with metastatic colorectal cancer. However, there are still patients with poor prognosis and underlying mechanisms that could not be defined clearly. Metastatic colorectal cancer patients with skin metastasis have a poor prognosis. A 45-year-old man, who presented with large bowel obstruction, was diagnosed with metastatic rectal adenocarcinoma. Unresectable liver metastases were found at diagnosis. FOLFOX plus bevacizumab treatment was started, but the patient developed bowel obstruction after the third cycle. Therefore, ileostomy was performed. Multiple skin, lung, liver and bone metastases appeared during that time. Bone marrow biopsy demonstrated diffuse infiltration by adenocarcinoma cells. Even though partial remission was achieved after 4 cycles of FOLFIRI-cetuximab, the disease progressed after the 8th cycle. The patient lost his life due to disease progression 8 months after the diagnosis. Bone marrow and skin are unusual sites of metastasis for colorectal carcinoma. Metastases in bone marrow and skin develop at later stages of metastatic disease. This patient lived only 4 months after the development of skin and bone marrow metastases. Skin and bone marrow metastases may be the harbingers of short survival. Biopsy of metastatic sites is crucial for diagnosis and detailed molecular analysis. Molecular pathway alterations underlying worse disease course may be found, and hence probable targets for drug improvement may be indicated.

The effects of inflammation on the prognosis, life expectancy and several parameters such as response to treatment of breast cancer have been previously studied. The purpose of this study was to investigate the effect of inflammatory markers on prognosis in patients with metastatic breast cancer.This study was conducted on 81 patients with metastatic breast cancer who have been followed up at the Department of Medical Oncology, Hacettepe University Institute of Oncology, between December, 2009 and March, 2014. For all studied parameters Kaplan-Meier survival estimates and p values computed by log-rank test were calculated. A p value0.05 was considered statistically significant.Median follow-up time was 26 months. There were 38 deaths due to disease progression during the follow up. The levels of serum albumin, and erythrocyte sedimentation rate (ESR) were not associated with a significant effect on overall survival (OS). Among patients with a higher serum C-reactive protein (CRP), the estimated mean survival was 84±36 months, compared to 278±113 months among patients with a normal serum CRP (p=0.032). When patients with higher and normal lactate dehydrogenase (LDH) levels were compared, their 2-year OS survival rates were 68.2 and 87.7%, respectively (p=0.034). Among patients with higher serum ferritin levels, the estimated mean survival was 29±10 months, compared to 212±113 months for normal serum ferritin (p=0.01). Among patients with higher serum beta-2 microglobulin (β2-M), the estimated mean OS survival was 28±8 months, compared to 84±57 months for those with normal levels (p0.01).Serum CRP, ferritin and β2-M can be useful prognostic factors for OS in patients with metastatic breast cancer.

Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life.Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC.Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies, lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine. Novel agents are currently investigated.

Purpose Excision repair cross-complementation group 1 enzyme (ERCC1) plays a key role in the removal of platinum induced DNA adducts and cisplatin resistance. Prognostic role of ERCC1 expression in the neoadjuvant setting in bladder cancer has not been reported before. We evaluated the prognostic role of ERCC1 expression in bladder cancer receiving platinum-based neoadjuvant chemotherapy. Materials and methods Thirty-eight patients with muscle invasive bladder cancer who received neoadjuvant platinum-based chemotherapy were included. Clinical and histopathologic parameters along with immunohistochemical ERCC1 staining were examined and correlated with response rates and survival. Results Pathologic complete response rates were similar between patients with low and high ERCC1 expression. Median disease-free survival (DFS) was 9.3 vs. 20.5 months ( P = 0.186) and median overall survival (OS) was 9.3 vs. 26.7 months ( P = 0.058) in patients with high ERCC1 expression compared with those with low expression, respectively. In multivariate Cox regression analysis: pathological complete response (pCR) after chemotherapy (hazard ratio (HR) 0.1, 95% CI 0.012–0.842, P = 0.034) and high ERCC1 expression (HR 3.7, 95% CI 1.2–11.2, P = 0.019) were significantly associated with DFS. Patient age (>60 vs. ≤60 years) (HR 3.4, 95% CI 1.2–9.4, P = 0.018), the presence of pCR (HR 0.11, 95% CI 0.014–0.981, P = 0.048) and high ERCC expression (HR 6.1, 95 CI 1.9–19.9, P = 0.002) were significantly associated with OS. Conclusions Our results showed that high ERCC1 expression was independently associated with shorter disease-free and overall survival in patients with bladder cancer who received neoadjuvant platinum-based chemotherapy. ERCC1 may represent a potential predictive marker for platinum-based treatment in bladder cancer.

Recently, it has been shown that androgen and androgen receptor (AR) also have an important role in the pathogenesis and outcome of breast cancer. However, their significance in different subtypes of breast cancer is still under investigation. The aim of this study was to study the effects of AR on clinicopathological features and prognosis in patients with estrogen and progesterone receptor (ER/PR)-negative, HER2-positive breast cancer. Tumor paraffin-embedded blocks from archives were used for AR study. Data of patients with ER/PR-negative and HER2-positive breast cancer diagnosed at our institute between 1999 and 2010 were recorded and analyzed retrospectively. We studied 36 patients with ER/PR-negative and HER2-positive breast cancer for AR status. Sixteen of them (44.4%) showed AR positivity. The median age was 47 and 56 years for AR-negative and -positive patients, respectively ( P = 0.03). The number of postmenopausal patients was higher in the AR-positive than -negative group (56 vs 30%) ( P = 0.01). Other demographic data were similar in both group. Histopathological parameters and tumor and nodal stages were similar in both groups. Trastuzumab treatment was more frequently given to AR-positive than -negative patients (94 vs 44%) ( P = 0.01). Median follow-up was 47.1 and 34.7 months in AR-negative and -positive groups, respectively ( P = 0.03). Relapse occurred in six and four patients in AR-negative and -positive groups. Median progression-free survival (PFS) was similar in both groups (15.7 and 19.6 months in AR-negative and -positive patients, respectively; P = 0.56). Two patients died at 23.4 and 46 months of follow-up in the AR-negative group. There were no deaths in the AR-positive group. Overall survival analyses were not done as a result of an unmet number of events. Median PFS was similar in AR-positive and -negative in that group of patients with ER/PR-negative and HER2-positive breast cancer. However AR-positive patients were more frequently postmenopausal, older, and positive for lymphovascular space invasion. More frequently applied trastuzumab in the AR-positive group might have an effect on the similarity of PFS between the two groups. Studies with higher numbers in this subset of patients with breast cancer will give more robust data.

WOS: 000309472300069, PubMed ID: 22938467, Background: This study aimed to research the awareness of screening colonoscopy (SC) among patients with colorectal cancer (CRC) and their relatives. Methodology: A questionnaire form including information and behavior about colonoscopic screening for CRCs of patients and their first-degree relatives (FDRs) was prepared. Results: A total of 406 CRC patients were enrolled into the study, with 1534 FDRs (siblings n: 1381 and parents n: 153). Positive family history for CRC was found in 12% of the study population. Previous SC was performed in 11% of patients with CRC. Mean age of the patients whose FDRs underwent SC was lower than the patients whose FDRs did not (52 vs 57 years; p

Aims and Background Capecitabine, as all fluoropyrimidines, interferes with vitamin metabolism and may thus have an impact on hematopoiesis. It is metabolized to its active form 5-fluoruracil by the enzyme thymidine phosphorylase, which exists in higher concentrations in tumor tissue and liver than in normal tissues. In the study, we investigated the changes in mean corpuscular volume (MCV) of red blood cells and the possible correlation of these changes with the clinical outcome of capecitabine treatment in women with metastatic breast cancer. Methods and Study Design Data from 75 metastatic breast cancer patients were analyzed retrospectively. Capecitabine was used at a dose of 2500 mg/m2 daily for 14 days of every 3-week period. Mean corpuscular volume of red blood cells and other parameters of complete blood count were recorded at the beginning of the treatment, in the ninth week, and periodically thereafter. Results Mean age was 51.5 ± 10.8 and 61.3% of the patients were premenopausal. Capecitabine was administered as the median 3rd line (min-max: 1–9) treatment and a median of 6 cycles (min-max: 1–24) for metastatic breast cancer. Median ΔMCV level (post-treatment values at ninth week - baseline) was 8. ΔMCV was ≥8 in 37 patients and Conclusions Capecitabine increases the mean corpuscular volume levels of red blood cells by a yet unidentified mechanism. Early increment of mean corpuscular volume levels is higher than 8, i.e. by the 9th week, might predict clinical benefit from the treatment.

Chronic infections with hepatitis C virus (HCV) are frequently pronounced in the etiology of malignancies especially in hepatocellular carcinoma. The association between HCV and risk of renal cell carcinoma (RCC) development has been stated recently. The authors retrospectively evaluated hepatitis serology for HCV and HBV in patients who had RCC diagnosis between 2005 and 2010 in six oncology centers. Control group was also included from the three different published studies that hepatitis serology studied in healthy people that has been living in the same geographic regions. Histologically confirmed 903 RCC cases and 5,267 healthy subjects were included the study. Median age at diagnosis of RCC was 58 (range: 26-89). There was no increase in HCV positivity in RCC patients compared to healthy control group (1.7 vs. 1.5%; P = 0.77). Frequency of HBsAg positivity was 4.4 and 4.1% in RCC and control groups, respectively (P = 0.65). There is no increase in frequency of HCV and HBsAg positivity in RCC patients. HCV positivity in RCC patients were not different from the healthy people.

Breast cancer is the second most common cause of CNS metastasis, following lung cancer. With better control of systemic disease, the CNS is emerging as a sanctuary site of relapse in patients with otherwise controlled cancer.Standard therapy for brain metastasis is currently whole-brain radiotherapy. Other treatment modalities include surgery and radiosurgery in selected cases, corticosteroids, and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of brain metastases, partly because tumors develop brain metastases at a stage when they become totally chemoresistant. Nevertheless, new treatment choices have emerged considering cytotoxic and biological agents for the treatment of CNS metastases in patients with breast cancer.In this review, we aimed to review current and future treatment options in the systemic treatment of brain metastases of breast cancer.Corticosteroids, anti-epileptic drugs, and radiotherapy remain the cornerstones of management. The efficacy of conventional cytotoxic chemotherapeutics is limited. Novel biologic agents, lapatinib being the most promising, are currently investigated in the treatment of brain metastases of breast cancer with promising results.

Poly(ADP-Ribose) polymerases (PARPs) are one of the important components of base excision repair pathway for single strand DNA breaks. Currently accepted hypothesis for the mechanism of action for PARP inhibitors in tumors with homologous recombination deficiency is synthetic lethality, as the simultaneous blockage of both pathways prevents the tumor cells from repairing DNA damage. Other proposed mechanisms include PARP trapping, defective BRCA1 and POLQ recruitment to sites of DNA repair. Breast cancer subgroups with germline BRCA mutations or non-mutational functional defects in BRCA proteins exemplify potential targets for PARP inhibitors.Promising results have been achieved with PARP inhibitors in BRCA associated cancers, particularly in ovarian and breast cancer. Olaparib is the only PARP inhibitor approved by FDA in the treatment of patients with germline BRCA mutated advanced ovarian cancer pretreated with ≥3 prior lines of chemotherapy. In this article, we reviewed the current status of PARP inhibitors, completed and ongoing trials, safety and resistance issues in patients with breast cancer.PARP inhibitors show promise in cancers with BRCA mutation and in the treatment of sporadic cancers with defective homologous recombination. Predictors of response, strategies to overcome resistance, combination with other chemotherapies and targeted agents, optimum dose and schedule of administration should be investigated in future trials.

A 31-year-old patient with multiple sclerosis (MS), treated with interferon beta-1b (IFNB-1b) for two years, presented with fatigue and dizziness. Coombs' positive autoimmune hemolytic anemia (AIHA) was found. Other potential etiologies of AIHA were ruled out. An association with IFNB-1b was highly suspected. Interferon therapy was discontinued and prednisone therapy instituted. There was resolution of the hemolytic anemia, and prednisone therapy was tapered gradually. To the best of our knowledge, there is no reported case of the development of AIHA associated with IFNB-1b use in MS patients. We conclude that if an unexplained drop in hematocrit occurs with a MS patient receiving IFNB-1b, autoimmune mediated hemolysis should also be considered. Multiple Sclerosis 2007; 13: 683-685. http://msj.sagepub.com

Aims and background Breast cancer is a heterogeneous disease with various pathological and molecular subtypes. This study aims to determine the association between BMI and the distribution of breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2/neu) expression in pre- and postmenopausal breast cancers. Methods and study design A total of 1847 female breast cancer patients were involved. After the exclusion of 457 patients due to missing subtype information (n = 400) or benign histology (n = 57), 1390 were included in the analyses. The histological type of the tumor, ER and PR expression, HER2/neu with immunohistochemistry and HER2/neu gene evaluation with interphase fluorescence in situ hybridization (if necessary), age, body weight, height and menopausal status at diagnosis were investigated retrospectively. The patients were stratified as having a normal body weight if BMI was ≤24.9 kg/m2, as being overweight if BMI was between 25.0 and 29.9 kg/m2, and as being obese if BMI was ≥30.0 kg/m2. Results Median BMI was 28.7 kg/m2 (17.6–55.6) in the postmenopausal and 25.6 kg/m2 (16.4–51.1) in the premenopausal group ( P 2 showed a tendency towards ER– tumors when compared to premenopausal women with a BMI of 2 ( P = 0.009). Conclusions The risk of specific breast cancer subtypes may not be associated with BMI in pre- and postmenopausal breast cancer. However, obesity might be related to an increased risk of premenopausal hormone receptor-negative breast cancer. Further studies are needed for clarification of the probable mechanisms in the pathogenesis of premenopausal hormone receptor-negative breast cancer.

The incidence of breast cancer at an advanced stage has decreased in the modern world due to screening programs and usage of novel chemotherapy agents at an adjuvant setting. Recurrence is the major problem seen in50% of breast cancer patients diagnosed at an early stage. Developing new drugs for metastatic breast cancer is a huge and challenging research area.Emerging drugs showed positive results in clinical studies and agents in routine clinical usage are updated. Current treatment strategies as a combination of biologic agents and overcoming drug resistance are discussed. Literature search is made from PubMed, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts.A number of drugs caused survival benefit for advanced breast cancer. Hundreds of new studies with tens of agents are conducted for treatment of metastatic breast cancer. Tumor resistance and treatment related toxicities are unavoidable which are two main search areas for improving metastatic breast cancer management. Understanding the pathways of genesis and progression yielded many targets for treatment. However, cure in metastatic breast cancer is still a far aim and new agents and treatment strategies are needed.

The risk of malignancy in transplant patients is higher than in the general population. The risk is increased mostly due to immune alteration and viral infections. While the most common cancers following liver transplantation include skin cancers, lymphoma and Kaposi's sarcoma, gastric cancer is uncommon. Herein, we report a case of gastric adenocarcinoma developing three years after cadaveric liver transplantation in a patient with autoimmune hepatitis. The patient was successfully operated. The patient did not receive any adjuvant therapy, and is free of disease at 9 months' follow-up.

The role of circulating tumor cells (CTCs) in the management of colorectal cancer has not yet established. In present study, we aimed to investigate the relationship between clinicopathological characteristics and CTC levels in patients with colorectal carcinoma. The isolation of CTCs in blood was performed with the semi-automated CellSearch System (Veridex TM). Ninety-three patients were analyzed. Median age of patients at the time of diagnosis was 56 (24-78). Total number of blood samples collected for CTCs were 130. CTCs were detected in 46 patients (or =1 per 7.5 mL), but only thirty (32%) patients were interpreted as positive (or = 3/7.5 mL). In the 27 patients in whom 2 blood samples were taken, levels of CTCs were found to be decreased in 8 patients, increased in 14 patients and did not change in 5 patients after therapy. Although only 2 (25%) of 8 patients in whom CTCs decreased after therapy had disease progression, 13 (93%) of 14 patients with increased CTCs had disease progression (p = 0.001). Similarly, 4 (80%) of 5 patients with stable CTCs had also disease progression. Our findings indicate that decreased CTCs after therapy is related with remission while increased CTC level is associated with disease recurrence or progression.

We investigate retrospectively the demographic and clinico-pathological characteristics of patients with triple-negative breast cancer (TNBC) compared to those with non-TNBC. Patients with breast cancer diagnosed from 1981 to 2008 in our clinic were retrospectively analyzed. Patient demographics including survival data and tumor characteristics were obtained from charts. A total of 795 patients were assessed in the study, including 140 patients (17.6%) with TNBC and 655 patients (82.4%) with non-TNBC. Patients with non-TNBC were further classified into 3 groups according to hormone receptor (HR) and HER-2 status. Median age was 49 (range 38–60 years) and similar between patients with TNBC and non-TNBC. Patients with TNBC had an increased likelihood of a higher histological grade III compared with HR(+) HER-2(−) subgroup (P > 0.001) and lower stage compared with HR(+)/HER2(+) and HR(−)/HER2(+) subgroups (P < 0.001 and P = 0.002, respectively). In patients with TNBC, the disease-free survival (DFS) rate was 66% at 5 years. In subgroup analysis of non-TNBCs, 5-year-DFS rates of the patients in HR(+)/HER2(−), HR(+)/HER2(+) and HR(−)/HER2(+) subgroups were 59, 66, and 57%, respectively. There was no significant difference between the TNBC and non-TNBC subgroups (P = 0.238). In multivariate analysis, nodal involvement (RR = 2.8, 95% CI: 0.99–8.3, P = 0.052) and the presence of lymphovascular invasion (RR = 3.2, 95% CI: 1.1–9.2, P = 0.029) were significantly associated with increased recurrence risk in patients with TNBC. Although there are differences in patient and tumor features, patients with TNBC had similar clinical course with those with non-TNBC.

WOS: 000274653200032, PubMed ID: 20085931, …

Treatment with a bisphosphonate was found to be associated with a significantly increased risk for atrial fibrillation (AF) in a few studies. A recent study showed that once-yearly infusions of intravenous zoledronic acid (ZA) significantly increased the risk of serious AF in postmenopausal women with osteoporosis. This study was conducted to determine the frequency of atrial fibrillation among cancer patients receiving the standard treatment of ZA.Patients with bone metastases who presented to our outpatient clinic for any reason (routine control, chemotherapy, or ZA administration) were included in the study. All patients had been receiving 4 mg ZA at 4-week intervals, with each dose administered over 15 min. A short survey was completed and standard 12-lead ECG recordings were obtained.One hundred and twenty-four cancer patients with documented bone metastases were evaluated. Mean age of the patients was 55 ± 13.0 years, 60% of the patients were female. Forty-one percent of the patients had breast cancer, 18% had non-small cell lung cancer, and the remainder had other solid tumors. Mean duration of ZA administration was 13.4 ± 15.0 months. Mean total cumulative dose was 54 ± 15.0 mg per patient. Sixty patients (48%) had previously been treated with anthracycline-containing regimens, and 37 (30%) had received chest radiotherapy that might affect the heart. Twenty-three percent of the patients had hypertension, 10% had diabetes mellitus, 3.7% had myocardial infarction history, 1.9% had congestive heart failure, and 1% had valvular disease; 10.5% were current smokers and 32% ex-smokers. On ECG evaluation, we observed normal sinus rhythm in 58%, sinus tachycardia in 15%, sinus bradicardia in 3.2%, and ventricular extrasystole in 5.7% of the patients. There was no AF in any of the cases.There was no increase in the risk of AF frequency in cancer patients who were treated with intravenous ZA, although most of the patients had additional risk factors including previous treatment with cardiotoxic agents or with chest radiotherapy. We believe that the risk of AF is negligible in this patient population and does not affect treatment decisions.

To the Editor, Cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) are often used in follow up care of breast cancer and provide important clues to the clinicians for disease progression in metastatic and recurrent breast cancer. However, use of CA 15-3 and CEA levels are not recommended for surveillance after primary therapy of breast cancer at ASCO guideline [1]. Triple-negative breast cancers (TNBC) are frequently defined as a single group identifiable using routine clinical tests. They are negative for estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2), the so-called ‘triple-negative’ breast cancers. We retrospectively analyzed serum CEA and CA 15-3 levels of 544 consecutive non-metastatic breast cancer patients presenting at Hacettepe University Institute of Oncology. The 15.1% of the patients were TNBC. There were no statistically significant differences in clinical characteristics of the disease between TNBC and non-TNBC patients. At the time of diagnosis TNBC group have lower serum CEA (2.5 ± 5.9 vs. 4.0 ± 16.4; P = 0.35) and CA 15-3 (23.7 ± 14.6 vs. 37.1 ± 117; P = 0.021) levels compared to non-triple negative (non-TN) group (3). This may be explained in part by undifferentiated characteristics of triple negative breast cancers. In conclusion, serum levels of CEA and CA 15-3 may be different in breast cancer subgroups. Our findings need to be confirmed in further studies.

The term 'triple-negative breast cancer' defines tumors that do not express estrogen receptors, progesterone receptors or Her2 on immunohistochemical analysis. This subgroup accounts for 15% of all types of breast cancer. Histologically, triple-negative breast cancers are poorly differentiated and are characterized by an aggressive clinical history. A significant overlap exists in biological and clinical characteristics of basal-like breast cancer and triple-negative breast cancer. Treatment options are limited, as these tumors lack a therapeutic target and are naturally resistant to existing targeted therapies, i.e., endocrine treatment and trastuzumab. As there are no specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, local and systemic relapse rates are high due to the adverse biology of the disease. Triple-negative breast cancer has many histological and genetic similarities with BRCA-1-associated breast cancer, suggesting a common pathogenesis and the potential use of common chemotherapeutics in both cancers. This review discusses current and future treatment options in the light of the new insights in major proliferative pathways active in the pathogenesis of triple-negative breast cancer.

Background: Oxidative stress (OS) may result in damage to critical macromolecules, and an association between lead (Pb) toxicity and OS is a matter of research. Therefore, the aim of the present study was to investigate the effect of Pb on the oxidative system in indirectly Pb-exposed male apprentices. Methods: Established parameters of Pb toxicity (aminolevulinic acid dehydratase index [ALAD index], zinc-protoporphyrin [ZPP]) as well as Pb-level in blood were determined in Pb-exposed apprentices (n > 25) and controls (n > 24). Enzymatic (glutathione peroxides [GPx], superoxide dismutase [SOD], catalase [CAT]) and non-enzymatic (α-tocopherol, β-carotene) indices of OS, and malondialdehyde (MDA) level were also determined. Results: There was a statistically significant increase in Pb level, ALAD index, ZPP concentration, GPx activity and MDA concentration in Pb-exposed apprentices when compared to controls. Although a statistically significant decrease in α-tocopherol and β-carotene levels was seen, SOD and CAT activities were unaltered in Pb-exposed apprentices. Pb level and duration of Pb exposure were correlated with each other, as well as various indices of OS and MDA concentration. Conclusions: Chronic indirect Pb exposure results in lipid peroxidation in erythrocytes of apprentices via OS, and duration of Pb exposure is a reliable marker of Pb toxicity.

Behcet's disease (BD) has been known for many years, yet the etiology of the systemic vasculitis remains unknown. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. ADMA is involved in endothelial dysfunction in various vascular diseases and its level in BD is unclear. This study was performed to evaluate the relationship between ADMA and NO levels in plasma of patients with BD. There were 3 groups of 30 subjects: (a) controls, (b) BD patients with mucocutaneous involvement, and (c) BD patients with vascular involvement. Plasma NO levels were assayed by spectrophotometry and plasma ADMA levels were assayed by an ELISA test. Plasma ADMA levels were higher in both groups of BD patients than in the controls; the ADMA levels were higher in the BD patients with vascular involvement than in the mucocutaneous group. Plasma NO levels were lower in both groups of BD patients than in controls; plasma NO levels were lower in the BD patients with vascular involvement than in mucocutaneous group. In the combined groups of 60 BD patients, there was significant inverse correlation between the plasma concentrations of ADMA and NO (r = -0.570, p0.001). Plasma lipid profiles did not differ significantly between the BD patients and the controls. These results are evidence for increased plasma ADMA levels and decreased plasma NO levels as risk factors for cardiovascular events in BD patients. Inhibition of NO synthesis by ADMA may contribute to vascular involvement in BD.

Behcet's disease BD may involve in any large or small artery, vein. We present a case of BD with multiple venous thromboses, cardiac and pulmonary involvements, and renal failure. A 22-year-old man admitted with progressive dyspnea and edema on his face and neck. He had the history of recurrent oral and genital ulcers, and pustular skin lesions for 4 years. Doppler ultrasonography revealed right internal jugular vein thrombosis. Transthoracic echocardiography showed a pericardial effusion, decreased left ventricular ejection fraction. While his symptoms were regressing moderately with a pulse cyclophosphamide, prednisolone, and low molecular weight heparin treatment, new thromboses occurred in vena cava inferior, and bilateral renal veins after the third and 7th dosages of pulse cyclophosphamide. Creatinine levels increased progressively, which required hemodialysis. However, he died after the second session of hemodialysis. Patients with BD should be followed up for new developing thrombosis even during an immunosuppressive treatment.

Endemic water borne fluorosis is a public health problem in Isparta, a city located in southern Turkey. In order to investigate the association between osteosclerosis and fluorosis, we retrospectively screened the results of lumbar spine and femur neck bone mineral density (BMD) of 1500 patients who were examined before, for any reason in between 2001-2003. Sixty nine patients (67 females and 2 males, mean age 52.6+/-10.2) with vertebra T-scores>or=+2 were found only except a patient with osteoid osteoma in the femur neck (femur T-score+6.64). Thirty-four of the patients could be reexamined with lateral vertebra BMD and investigated for fluorosis and the other etiologic causes of osteosclerosis. Of 34 patients, 14 had either mottled tooth enamel or urine fluoride level greater than 1.5 mg/l. Other etiologic causes were hypothyroidism (2), hypoparathyroidism (1), history of lumbar fracture (1), use of retinoids (1), vitamin D (7), oral calcium preparations (9), and bisphosphanates (3). Lateral lumbar vertebral T-score was greater than+2 in 12 patients (35.3%). Femur T-score was greater than+2 in 7 patients (20.6%). Fourteen patients (41.2%) had lateral vertebral or femur T-score>or=+2. Five (35.7%) of these patients had signs of fluorosis, as discussed before. Mean body mass index of individuals with fluorosis was 36.4+/-7.9 and this result was significantly higher than other osteosclerotic subjects (31.6+/-4.4). In conclusion we believe that approximately one third of the osteosclerosis in our region was due to endemic skeletal fluorosis and obesity may enhance this osteosclerotic type bone changes in endemic fluorosis.

Background: Behcet's disease is a systemic vasculitis in which studies have given conflicting results about ventricular diastolic functions. However, tissue Doppler echocardiography has never been used in any of these studies. Aortic stiffness, a cardiovascular risk factor, may also precede ventricular dysfunction. Objectives: The aim of this study was to assess aortic stiffness and biventricular diastolic functions in patients with Behcet's disease. Methods: A total of 26 patients with Behcet's disease (mean age; 33 +/- 10 years) and 20 age- and sex-matched controls (mean age; 33 +/- 7 years) were included. Aortic stiffness was evaluated by aortic strain and distensibility. Ventricular diastolic functions were evaluated with both conventional and tissue Doppler echocardiography. Mitral E and A wave, E/A ratio of E wave, deceleration time, and isovolumic relaxation time were calculated. Results: There was no significant difference in diastolic Doppler parameters between patients and controls. Similarly, there was no significant difference in mitral annular E and A velocities between these two groups. Aortic strain in patients with Behcet's disease was found to be significantly less than in the controls (8.3 +/- 4.9% and 15.7 +/- 2.7% respectively, p < 0.001). Aortic distensibility was also significantly low in patients with Behcet's disease when compared to controls (0.45 +/- 0.28 and 0.78 +/- 0.13 respectively, p < 0.001). Beta index values were significantly high in Behcet's patients (7.23 +/- 5.93 and 2.69 +/- 0.55 respectively, p < 0.001). Conclusion: No significant diastolic dysfunction was found in left and right ventricles in patients with Behcet's disease by using both conventional and tissue Doppler echocardiography. However, an increase in aortic stiffness was found, suggesting an inflammatory involvement of proximal aorta.

This study investigated blood lead (Pb-B) levels and Pb-B effects on thyroid functions in long-term low-level-lead-exposed male adolescents who work as auto repairers. Pb-B and ALAD index (logarithm of activated delta-aminolaevulinic acid dehydratase/nonactivated delta-aminolaevulinic acid dehydratase) were measured as indicators of exposure to lead. Thyroid function tests including free thyroxine (FT4). free triiodothyronine (FT3), and thyrotrophin (TSH) were conducted and thyroid ultrasounds were performed in 42 lead-exposed adolescents and 55 healthy control subjects. Mean Pb-B levels and ALAD index were found significantly higher in the study group than in the normal. control group (7.3 +/- 2.92 mu g/dl vs. 2.08 +/- 1.24 mu g/dl P < 0.001 and 0.44 +/- 0.26 vs. 0.29 +/- 0.23, P < 0.05, respectively). FT4 levels were found significantly lower in the study group (1.02 +/- 0.18 mI/mL and 1.12 +/- 0.14 mIU/mL, P < 0.05). No subject in the control group had an abnormal FT4 level, but FT4 levels were found under normal limits in 11 subjects (26%) in the study group. FT3 and TSH levels in the study and control groups did not differ (P > 0.05). Thyroid volumes in the study and control groups did not exhibit any significant differences (P > 0.05). Pb-B was found to be negatively correlated to FT4 levels (r = -0.20, P = 0.044). This study revealed that long-term low-level lead exposure may lead to reduced FT4 level without significant changes in TSH and T3 levels in adolescents even at low Pb-B levels. (c) 2005 Elsevier Inc. All rights reserved.

We report two cases of paraneoplastic remitting seronegative symmetrical synovitis with pitting edema (RS3PE) associated with prostatic adenocarcinoma. One of the patients was positive for Helicobacter pylori and the other had secondary bone metastases. In the latter, the clinical picture of RS3PE developed after surgical intervention for the primary lesion. On physical examination, while the hands and feet were swollen in the first patient, pitting edema was present only at the feet of the other. All joints of the affected hands and feet were painful. Serological tests including rheumatoid factor, antinuclear antibody, and human leukocyte antigen B27 were all negative. Response to low-dose corticosteroid treatment was delayed in the first patient, but the symptoms were relieved better in the second one.