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Colorectal cancer (CRC) is the 2nd most common cancer and 3rd most common cause of death in the Middle East and Northern Africa (MENA) region. We aimed to explore CRC stage at diagnosis data from population-based cancer registries in MENA countries. In 2021, we launched a Global Initiative for Cancer Registry Development (GICR) survey on staging practices and breast and CRC stage distributions in MENA. According to the survey results, population-based data on TNM stage for CRC were available from six registries in five countries (Kuwait, Morocco, Oman, Türkiye, UAE). The proportion of cases with unknown TNM stage ranged from 14% in Oman to 47% in Casablanca, Morocco. The distribution of CRC cases with known stage showed TNM stage IV proportions of 26-45%, while the proportions of stage I cancers were lowest in Morocco (≤7%), and highest (19%) in Izmir, Türkiye. Summary extent of disease data was available from six additional registries and four additional countries (Algeria, Bahrain, Iraq, Qatar). In summary, the proportions of CRC diagnosed with distant metastases in Oman, Bahrain and UAE were lower than other MENA countries in our study, but higher than in European and the US populations. Harmonising the use of staging systems and focusing stage data collection efforts on major cancers, such as CRC, is needed to monitor and evaluate progress in CRC control in the region., (© 2024 World Health Organization; licensed by UICC.)

Background: Early diagnosis and treatment of periodontitis, which can cause loss of bone support of the teeth, is of great importance. The use of fractal analysis method is being investigated in order to differentiate periodontal disease radiographically. Fractal analysis presents the degree of complexity in the structure of fractal objects as a numerical data, and has been used to measure changes in trabecular bone. The aim of this study was to compare the trabecular bone fractal dimension (FD) values of patients with periodontitis and gingivitis using panoramic radiographs, and to evaluate the possible relationship between age and gender with fractal dimension., Materials and Methods: Panoramic radiographs of 64 patients with gingivitis and 64 patients with periodontitis were evaluated retrospectively in the study. Using the radiographs of the patients, FD values measured from the trabecular bone were calculated with the box-counting method in the Image J programme. The FD values of both groups were compared. In addition, the relationship between age and gender parameters and FD values was evaluated within the groups., Results: According to the results of the study, the calculated average FD value of the patients in the gingivitis group was 1.195, while the calculated average FD value of the patients in the periodontitis group was 1.196. No statistically significant difference was observed between the FD values of the gingivitis group and the periodontitis group (p > 0.05). No statistically significant correlation was observed between FD values and age and gender (p > 0.05)., Conclusions: No statistically significant results were obtained for the calculated mean FD values of the patients in the gingivitis and periodontitis groups.

Phenomenon: Physician immigration from other countries is increasing as developed countries continue to be desirable destinations for physicians; however, the determinants of Turkish physicians' migration decisions are still unclear. Despite its wide coverage in the media and among physicians in Türkiye, and being the subject of much debate, there is insufficient data to justify this attention. With this study, we aimed to investigate the tendency of senior medical students in Türkiye to pursue their professional careers abroad and its related factors. Approach: This cross-sectional study involved 9881 senior medical students from 39 different medical schools in Türkiye in 2022. Besides participants' migration decision, we evaluated the push and pull factors related to working, social environment and lifestyle in Türkiye and abroad, medical school education inadequacy, and personal insufficiencies, as well as the socioeconomic variables that may affect the decision to migrate abroad. The analyses were carried out with a participation rate of at least 50%. Findings: Of the medical students, 70.7% had emigration intentions. Approximately 60% of those want to stay abroad permanently, and 61.5% of them took initiatives such as learning a foreign language abroad (54.5%) and taking relevant exams (18.9%). Those who wanted to work in the field of Research & Development were 1.37 (95% CI: 1.22-1.54) times more likely to emigrate. The push factor that was related to emigration intention was the "working conditions in the country" (OR: 1.89, 95% CI: 1.56-2.28) whereas the "social environment/lifestyle abroad" was the mere pull factor for the tendency of emigration (OR: 1.73, 95% CI: 1.45-2.06). In addition, the quality problem in medical schools also had a significant impact on students' decisions (OR: 2.20, 95% CI: 1.83-2.65). Insights: Although the percentage of those who want to emigrate "definitely" was at the same level as in the other developing countries, the tendency to migrate "permanently" was higher in Türkiye. Improving working conditions in the country and increasing the quality of medical faculties seem vital in preventing the migration of physicians.

Background: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct tumor biology. Considering it is already known that peripheral immune cells are altered in colorectal cancer (CRC) patients, this study aims to investigate the changes in lymphocyte subsets in SARIFA-positive cases and correlate these changes with the local immune response., Methods: Flow cytometry was performed to analyze B, T, and natural killer (NK) cells in the peripheral blood (PB) of 45 CRC patients. Consecutively, lymphocytes in PB, tumor-infiltrating lymphocytes (TILs), and CD56+ and CD57+ lymphocytes at the invasion front and the tumor center were compared between patients with SARIFA-positive and SARIFA-negative CRCs., Results: Whereas no differences could be observed regarding most PB lymphocyte populations as well as TILs, NK cells were dramatically reduced in the PB of SARIFA-positive cases. Moreover, CD56 and CD57 immunohistochemistry suggested SARIFA-status-dependent changes regarding NK cells and NK-like lymphocytes in the tumor microenvironment., Conclusion: This study proves that our newly introduced biomarker, SARIFA, comes along with distinct immunologic alterations, especially regarding NK cells.

Background/aims: Endoscopic submucosal dissection (ESD) has been established as a treatment modality for superficial esophageal squamous cell carcinoma (ESCC). Long-term follow-up data are lacking in Western countries. The aim of this study was to analyze long-term survival in a Western center., Methods: Patients undergoing ESD for ESCC were included. The analysis was performed retrospectively using a prospectively collected database., Results: R0 resection rate was 96.7% (59/61 lesions in 58 patients). Twenty-seven patients (46.6%) fulfilled the curative resection criteria (M1/M2) (group A), 11 patients (19.0%) had M3 lesions without lymphovascular invasion (LVI) (group B), and 20 patients (34.5%) had lesions with submucosal invasion or LVI (group C). Additional treatment was recommended after non-curative resection. It was not performed in 20/31 patients (64.5%), mainly because of comorbidities (75%). Twenty-nine out of 58 (50.0%) patients died during a mean follow-up of 3.7 years. Death was related to ESCC in 17.2% (5/29) of patients. The disease-specific survival rate after curative resection was 100%. Overall survival rates after 5 years were 61.5%, 63.6% and 28.1% for groups A, B, and C, respectively. The overall survival was significantly worse after non-curative resection (p=0.038)., Conclusion: Non-curative resection is frequent after ESD for ESCC in Western patients. The long-term prognosis is limited and mainly determined by comorbidity. Early diagnosis and pre-interventional assessments need to be improved.

Objective: There are many difficulties in diagnosing and treating Stenotrophomonas maltophilia bacteremia. In this study, we aimed to evaluate "true" and "false-positive bacteremia" and assess mortality risk factors and the impact of different treatment regimens., Materials and Methods: Hospitalized adult patients with S. maltophilia -positive blood cultures were assessed by a two-stage analysis. First, the clinical significance of blood cultures was assessed, and patients were divided into "true" and "false-positive bacteremia" groups. Then, excluding false positives, we analyzed the antimicrobial regimens and the factors associated with 28-day mortality in true bacteremia cases performing univariate and multivariate analyses., Results: The study included 127 out of 138 patients with S. maltophilia bacteremia. True bacteremia was identified in 51.2% and false-positive bacteremia in 48.8% of patients. In the true bacteremia group, hypotension, nosocomial bacteremia, concomitant infections, a source of bacteremia, two positive blood culture sets, and 28-day mortality were more common. The 28-day mortality was 50.7% among true bacteremia cases. In multivariate analysis, age and solid tumor were the independent predictors of 28-day mortality. Early effective antimicrobial therapy and different antimicrobial regimens, including trimethoprim-sulfamethoxazole (SXT), fluoroquinolones (FQs), and tigecycline (TGC), did not have any significant impact on survival., Conclusion: Patients with S. maltophilia bacteremia should first be assessed regarding clinical significance. Clinical findings, the presence of multiple positive blood culture sets and the primary sources of bacteremia are useful parameters while discriminating true from false-positive bacteremia. Patients with advanced age and solid tumors should be followed carefully in terms of mortality. Antimicrobial regimens, including SXT, FQs, or TGC, can be preferred in patients with S. maltophilia bacteremia considering antimicrobial resistance and adverse effects or toxicity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Infectious Diseases and Clinical Microbiology.)

Background: Availability of stage information by population-based cancer registries (PBCR) remains scarce for diverse reasons. Nevertheless, stage is critical cancer control information particularly for cancers amenable to early detection. In the framework of the Global Initiative for Cancer Registry Development (GICR), we present the status of stage data collection and dissemination among registries in the Middle East and Northern Africa (MENA) region as well as the stage distribution of breast cancer patients., Methods: A web-based survey exploring staging practices and breast cancer stage was developed and sent to 30 PBCR in 18 countries of the MENA region., Results: Among 23 respondent PBCR, 21 collected stage data, the majority (80%) for all cancers. Fourteen registries used a single classification (9 TNM and 5 SEER), 7 used both staging systems in parallel. Out of 12,888 breast cancer patients (seven registries) 27.7% had unknown TNM stage (11.1% in Oman, 46% in Annaba). When considering only cases with known stage, 65.3% were early cancers (TNM I+II), ranging from 57.9% in Oman to 83.3% in Batna (Algeria), and 9.9% were stage IV cancers. Among the nine registries providing SEER Summary stage for breast cancer cases, stage was unknown in 19% of the cases, (0 in Bahrain, 39% in Kuwait). Stage data were largely absent from the published registry reports., Conclusion: Despite wide stage data collection by cancer registries, missing information and low dissemination clearly limit informing efforts on early detection. The use of two classification systems in parallel implies additional workload and might undermine completeness. The favourable results of early cancer (TNM I+II) in two thirds of breast cancer patients needs to be interpreted with caution and followed up in time. Although efforts to improve quality of stage data are needed, our findings are particularly relevant to the WHO Global Breast Cancer Initiative., Competing Interests: Declaration of interest None; the authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Herat province of Afghanistan is located on the Asian Esophageal Cancer Belt (AECB), a wide area in Central and Eastern Asia where very high rates of esophageal cancer (EC) have been observed. Several risk factors have been reported in the AECB Region by previous studies. Considering lack of information in Afghanistan on this issue, a study was conducted to determine the major risk factors related to EC in order to guide protective measures., Methods: A population-based case-control study was performed from July 2015 to August 2016 among 657 EC patients in the Herat Province and 180 histopathological confirmed cases and 189 controls were interviewed. A structured questionnaire was used and face-to-face interviews were conducted., Results: Low body mass index (BMI), low socio-economic status, family history of EC, consumption of dark tea, very hot beverage and qulurtoroosh were found to be statistically significant for EC and esophageal squamous cell carcinoma (ESCC) in univariate analyses. According to multivariate analyses, sex (OR=2.268; 95% CI=1.238-4.153), very hot beverages (OR=2.253; 95% CI=1.271- 3.996), qulurtoroosh (OR=5.679; 95% CI=1.787-18.815), dark tea (OR=2.757; 95% CI=1.531-4.967), high previous BMI (OR=0.215; 95% CI=0.117-0.431) and low socio-economic status (OR=1.783; 95% CI=1.007-3.177) were associated with ESCC. Being male was found to increase the risk of ESCC with OR=2.268 (95% CI=1.238-4.153)., Conclusion: Consuming very hot beverages dark tea and a local food, qulurtoroosh, were found as important risk factors for EC. Our findings warrant further studies and necessitate the implementation of protective measures for EC which is one of the leading cancers in the region., (© 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Introduction: Cellular immune response to cancer is known to be of great importance for tumor control. Moreover, solid tumors influence circulating lymphocytes, which has been shown for several types of cancer. In our prospective study we elucidate changes in lymphocyte subsets in patients with colorectal carcinoma compared to healthy volunteers., Methods: Flow cytometry was performed at diagnosis of colon carcinoma to analyze B cells, T cells and NK cells including various subtypes of each group. Univariate and multivariate analyses including age, gender, tumor stage, sidedness and microsatellite instability status (MSI) were performed., Results: Forty-seven patients and 50 healthy volunteers were included. Median age was 65 years in patients and 43 years in the control group. Univariate analysis revealed lower total lymphocyte counts, lower CD4 + cells, CD8 + cells, B cells and NKs including various of their subsets in patients. In multivariate analysis patients had inferior values of B cells, CD4 + cells and NK cells and various subsets, regardless of age and gender. Naïve, central memory and HLADR + CD8 + cells showed an increase in patients whereas all other altered subsets declined. MSI status had no influence on circulating lymphocytes except for higher effector memory CD8 + cells in MSI-high patients. Localization in the left hemicolon led to higher values of total cytotoxic T cells and various T cell subsets., Conclusion: We found significant changes in circulating lymphocyte subsets in colon carcinoma patients, independent of physiological alterations due to gender or age. For some lymphocyte subsets significant differences according to tumor localization or MSI-status could be seen., (© 2021. The Author(s).)

Tumor-infiltrating lymphocytes (TILs) correlate with the number and size of the surrounding lymph nodes in patients with colorectal carcinoma (CRC) and reflect the quality of the antitumor immune response. In this prospective study, we analyzed whether this response correlated with the circulating lymphocytes in peripheral blood (PB). In 47 patients with newly diagnosed CRC, flow cytometry was performed to analyze the B cells, T cells, NK cells, and a variety of their subsets in PB. The results were correlated with TILs in the resected tumor and with the number and size of the surrounding lymph nodes in nodal negative (N- patients (LN5: number of lymph nodes measuring ≥5 mm) and the metastasis-to-lymph node size ratio (MSR) in nodal positive patients (N+). Differences between the number of TILs could be seen between N+ and N- patients, dependent on the LN5 and MSR categories, with higher values in N- cases and in patients with a higher LN5 category or a lower MSR. Additionally, higher values of various circulating lymphocyte subgroups were observed in these patients. For the total PB lymphocytes, CD8 cells, and some of their subgroups, a positive correlation with the TILs was found. This study shows that circulating lymphocytes-in particular, cytotoxic T cells-correlate with the local antitumor immune response displayed by TILs and lymph node activation. Our findings indicate that local and generalized antitumor immune responses are concordant with their different components.

Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible toward transformation by activated PIK3CAH1047R but refractory to oncogenic KrasG12D. Using genome-wide transposon screens and genetic loss-of-function experiments, we discover context-dependent genetic interactions that drive extrahepatic cholangiocarcinoma (ECC) and show that PI3K signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts with the pancreas, where oncogenic Kras in concert with p53 loss is a key cancer driver. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development. These studies provide a mechanistic link between PI3K signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor subtype., Significance: We used the first genetically engineered mouse model for extrahepatic bile duct carcinoma to identify cancer genes by genome-wide transposon-based mutagenesis screening. Thereby, we show that PI3K signaling output strength and p27Kip1 function are critical determinants for context-specific ECC formation. This article is highlighted in the In This Issue feature, p. 2945., (©2021 The Authors; Published by the American Association for Cancer Research.)

Data from population-based cancer registries (PBCR) are critical for planning, monitoring and evaluation of cancer control programs, but are frequently underutilized by key stakeholders. As part of the ongoing partnership of the International Agency for Research on Cancer (IARC) and the WHO Eastern Mediterranean Regional Office (EMRO) in cancer surveillance, we designed a cancer registry survey to assess the level of involvement of PBCR in national cancer control planning across the region. A questionnaire on registry characteristics, their contribution to cancer control and perceived barriers, was sent to 14 countries with operational PBCR. We obtained replies from Bahrain, Egypt, Iraq, Iran, Jordan, Kuwait, Lebanon, Morocco, Oman, Qatar, Saudi Arabia, Tunisia and the United Arab Emirates. We found a high participation of PBCR in cancer control planning (all registries involved, 46% routinely) and the evaluation of screening (92% registries involved, 46% routinely), but a much lower level of participation in palliative care and rehabilitation activities. Specified barriers included poor governance, a lack of awareness by policy makers, insufficient resources and a limited availability of data electronically, including mortality data. Appropriate planning to ensure the sustainability of PBCR (including the employment of permanent staff), increasing training, building research capacity and ensuring an efficient provision of high-quality data to policymakers, were among the proposed solutions. The results of our study reinforce the need for further tailoring of activities in support of cancer registration and enhanced networking among stakeholders, toward improving quality and use of cancer registry data for cancer control in the EMR., (© 2020 Union for International Cancer Control.)

Season of birth, a surrogate of seasonal variation of environmental exposures, has been associated with increased risk of several cancers. In the context of a Southern-Eastern Europe (SEE) consortium, we explored the potential association of birth seasonality with childhood (0-14 years) central nervous system (CNS) tumors. Primary CNS tumor cases (n = 6,014) were retrieved from 16 population-based SEE registries (1983-2015). Poisson regression and meta-analyses on birth season were performed in nine countries with available live birth data (n = 4,987). Subanalyses by birth month, age, gender and principal histology were also conducted. Children born during winter were at a slightly increased risk of developing a CNS tumor overall [incidence rate ratio (IRR): 1.06, 95% confidence intervals (CI): 0.99-1.14], and of embryonal histology specifically (IRR: 1.13, 95% CI: 1.01-1.27). The winter peak of embryonal tumors was higher among boys (IRR: 1.24, 95% CI: 1.05-1.46), especially during the first 4 years of life (IRR: 1.33, 95% CI: 1.03-1.71). In contrast, boys <5 years born during summer seemed to be at a lower risk of embryonal tumors (IRR: 0.73, 95% CI: 0.54-0.99). A clustering of astrocytomas was also found among girls (0-14 years) born during spring (IRR: 1.23, 95% CI: 1.03-1.46). Although the present exploratory results are by no means definitive, they provide some indications for age-, gender- and histology-related seasonal variations of CNS tumors. Expansion of registration and linkage with cytogenetic reports could refine if birth seasonality is causally associated with CNS tumors and shed light into the complex pathophysiology of this lethal disease., (© 2020 UICC.)

Aim: To investigate the role of dynamic thiol-disulfide homeostasis in preeclamptic and idiopathic fetal growth restricted (FGR) pregnancies. Material and method: In this prospective case-control study, a total of 110 singleton pregnancies with FGR (study group) (51 preeclamptic and 59 idiopathic FGR's cases) were compared with 68 healthy pregnant controls at the same gestational weeks (control group). For serum disulfide-thiol homeostasis, a newly used method described by Erel and Neselioglu was used. Results: Serum native thiol and total thiol levels were lower in FGR pregnancies (285.63 ± 55.92 µmol/L, 324.41 ± 44.18 µmol/L, respectively) than control group (324.41 ± 44.18 µmol/L, 362.98 ± 51.43 µmol/L, p  < .001, p  = .004, respectively). In subgroup analysis, only preeclamptic FGR's have lower native and total thiol levels (254.41 ± 59.55, 324.41 ± 44.18 µmol/L, respectively) compare to both idiopathic FGR's and control's. There was no difference in native and total thiol levels with idiopathic FGR's with controls. Idiopathic FGR's have higher levels of disulfide than preeclamptic FGR's (21.72 ± 17.72 versus 16.80 ± 11.20 µmol/L). The serum albumin and total protein levels were positively and spot urine protein/creatinine ratio, 24-h urine protein levels were negatively correlated with native thiol and total thiol levels. Conclusion: The balance of thiol-disulfide homeostasis was shifted and native and total thiol levels were decreased only in preeclamptic FGR pregnancies. The serum disulfide level was increased in idiopathic FGR pregnancies compare to preeclamptic FGR pregnancies which may be a sign of oxidative stress in idiopathic FGR pregnancies with normal thiol pool.

Background: Despite recent therapeutic advancements, Wilms tumour (WT) presents remarkable survival variations. We explored mortality and survival patterns for children (0-14 years) with WT in 12 Southern and Eastern European (SEE) countries in comparison with the United States of America (USA)., Methods: A total of 3966 WT cases (0-14 years) were registered by a network of SEE childhood cancer registries (N:1723) during available registration periods circa 1990-2016 and surveillance, epidemiology, and end results program (SEER) (N:2243; 1990-2012); mortality data were provided by the respective national statistical services. Kaplan-Meier curves and Cox proportional hazards models were used to assess the role of age, sex, year of diagnosis, urbanisation and Human Development Index (HDI) on overall survival (OS)., Results: Persisting regional variations shape an overall 78% 5-year OS in the participating SEE countries, lagging behind the USA figure (92%, p=0.001) and also reflected by higher SEE mortality rates. Worth mentioning is the gradually escalating OS in SEE (hazard ratio [HR] 5-year increment :0.67, 95% confidence interval [CI]:0.60, 0.75) vs. a non-significant 10% improvement in the SEER data, which had a high starting value. OS differentials [two-fold less favourable among children aged 10-14 years, boys and those living in rural SEE areas (HR:1.37; CI:1.10-1.71) or countries with inferior HDI (2-3-fold)] were minimal in the USA., Conclusions: Children with WT residing in SEE countries do not equally enjoy the substantial survival gains, especially for those living in rural areas and in lower HDI countries. Noteworthy are steep and sizeable survival gains in SEE along with the newly presented Greek data pointing to achievable survival goals in SEE despite the financial crisis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Despite advances in the management of nephroblastoma (Wilms' tumor, WT), the etiology of the tumor remains obscure. We aimed to compare nephroblastoma incidence rates and time trends among children (0-14 years) in 12 Southern and Eastern European (SEE) countries and the Surveillance, Epidemiology, and End Results Program (SEER), USA, in relation to the human development index (HDI)., Methods: In total 1776 WT cases were recorded in 13 SEE collaborating registries (circa 1990-2016), whereas data on 2260 cases (1990-2012) were extracted from the SEER database. Age-standardized incidence rates (AIRs) were calculated and correlated with HDI, whereas temporal trends were evaluated using Poisson regression and Joinpoint analyses., Results: The overall SEE AIR (9.2/10 6 ) was marginally higher than that of the SEER (8.3/10 6 ), whereas significant differences were noted among the 13 SEE registries which comprised mainly Caucasian populations. A statistically significant temporal increase in incidence was noted only in Belarus. Most cases (∼75%) were diagnosed before the fifth year of life, with rates steadily declining thereafter; median age at diagnosis was similar in SEE countries and SEER. A slight male preponderance in the first year of life (male:female = 1.1) was followed by a female preponderance in the older age groups (male:female = 0.7). Lastly, a statistically significant positive association between higher HDI and increasing nephroblastoma incidence was noted (regression coefficient: +3.25, 95%CI: +1.35, +5.15)., Conclusions: Variations in incidence and time trends across the examined registries, changing male-to-female patterns with advancement in age, and positive associations with the HDI imply a plausible role for environmental and genetic factors in disease etiology, and these need to be explored further., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: Neuroblastoma outcomes vary with disease characteristics, healthcare delivery and socio-economic indicators. We assessed survival patterns and prognostic factors for patients with neuroblastoma in 11 Southern and Eastern European (SEE) countries versus those in the US, including-for the first time-the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumours (NARECHEM-ST)/Greece., Methods: Overall survival (OS) was calculated in 13 collaborating SEE childhood cancer registries (1829 cases, ∼1990-2016) and Surveillance, Epidemiology, and End Results (SEER), US (3072 cases, 1990-2012); Kaplan-Meier curves were used along with multivariable Cox regression models assessing the effect of age, gender, primary tumour site, histology, Human Development Index (HDI) and place of residence (urban/rural) on survival., Results: The 5-year OS rates varied widely among the SEE countries (Ukraine: 45%, Poland: 81%) with the overall SEE rate (59%) being significantly lower than in SEER (77%; p < 0.001). In the common registration period within SEE (2000-2008), no temporal trend was noted as opposed to a significant increase in SEER. Age >12 months (hazard ratio [HR]: 2.8-4.7 in subsequent age groups), male gender (HR: 1.1), residence in rural areas (HR: 1.3), living in high (HR: 2.2) or medium (HR: 2.4) HDI countries and specific primary tumour location were associated with worse outcome; conversely, ganglioneuroblastoma subtype (HR: 0.28) was associated with higher survival rate., Conclusions: Allowing for the disease profile, children with neuroblastoma in SEE, especially those in rural areas and lower HDI countries, fare worse than patients in the US, mainly during the early years after diagnosis; this may be attributed to presumably modifiable socio-economic and healthcare system performance differentials warranting further research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neuroblastoma comprises the most common neoplasm during infancy (first year of life). Our study describes incidence of neuroblastoma in Southern-Eastern Europe (SEE), including - for the first time - the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST)/Greece, compared to the US population, while controlling for human development index (HDI). Age-adjusted incidence rates (AIR) were calculated for 1,859 childhood (0-14 years) neuroblastoma cases, retrieved from 13 collaborating SEE registries (1990-2016), and were compared to those of SEER/US (N = 3,166; 1990-2012); temporal trends were assessed using Poisson regression and Joinpoint analyses. The overall AIR was significantly lower in SEE (10.1/million) compared to SEER (11.7 per million); the difference was maximum during infancy (43.7 vs. 53.3 per million, respectively), when approximately one-third of cases were diagnosed. Incidence rates of neuroblastoma at ages <1 and 1-4 years were positively associated with HDI, whereas lower median age at diagnosis was correlated with higher overall AIR. Distribution of primary site and histology was similar in SEE and SEER. Neuroblastoma was slightly more common among males compared to females (male-to-female ratio: 1.1), mainly among SEE infants. Incidence trends decreased in infants in Slovenia, Cyprus and SEER and increased in Ukraine and Belarus. The lower incidence in SEE compared to SEER, especially in infants living in low HDI countries possibly indicates a lower level of overdiagnosis in SEE. Hence, increases in incidence rates in infancy noted in some subpopulations should be carefully monitored to avoid the unnecessary costs health impacts of tumors that could potentially spontaneously regress., (© 2017 UICC.)

Background: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014., Methods: CONCORD-3 includes individual records for 37·5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights., Findings: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89·5% in Australia and 90·2% in the USA, but international differences remain very wide, with levels as low as 66·1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68·9%), colon (71·8%), and rectum (71·1%); in Japan for oesophageal cancer (36·0%); and in Taiwan for liver cancer (27·9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59·9% in South Korea, 52·1% in Taiwan, and 49·6% in China), and for both lymphoid malignancies (52·5%, 50·5%, and 38·3%) and myeloid malignancies (45·9%, 33·4%, and 24·8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49·8% in Ecuador to 95·2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28·9% in Brazil to nearly 80% in Sweden and Denmark)., Interpretation: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer., Funding: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The aim of this paper is to present the validity and reliability of the Turkish version of the add-on module for the WHOQOL measures of quality of life for use with adults having physical or intellectual disabilities known as the WHOQOL-DIS., Methods: Data were collected from 150 Intellectual Disabled (ID) and 157 Physically Disabled (PD) persons in Turkey (Izmir) participating center of the global WHOQOL-DIS project. WHOQOL-DIS module is consisted of 12 disability specific items in addition to 26 generic items of WHOQOL-Bref. The proposed factorial structure (3 factors) of WHOQOL-DIS global study used in the psychometric analyses of the Turkish versions of WHOQOL-DIS. Reliability analyses and construct validity was tested via CFA analyses and convergent and discriminant validity analyses were assessed in relation to SWLS and WHODAS-II respectively., Results: Cronbach alpha values of the WHOQOL-DIS factors were as follows for ID and PD samples respectively: Factor 1 (Discrimination and support)= 0.54 and 0.64; Factor 2 (Independence)= 0.78 and 0.79 ; Factor 3 (Community participation)= 0.88 and 0.83. CFI and RMSEA values were 0.98 and 0.065 for ID sample and 0.98 ve 0.064 for PD sample respectively. Convergent-discriminant validities were satisfactory for all factors in PD group (r= 0.27 - 0.62) whereas Factor 1 was not found discriminative in the ID group (r= 0.09 -0.10)., Conclusion: Psychometric properties provided satisfactory evidence  of reliability and validity of the Turkish version of WHOQOL-DIS. Nevertheless the results of Factor 1 (Discrimination and support) in ID persons should be interpreted with caution.

Aim: Is there any relationship between estrogen and progesterone concentrations during assisted reproductive technology (ART)? Which hormone is the main determinant of impaired endometrial receptivity?, Methods: This study was conducted from July to December 2016 at the in vitro Fertilization/Intracytoplasmic Sperm Injection unit at Zeynep Kamil Women and Children's Health Training and Research Hospital. A total of 289 women who underwent ART were prospectively screened and areas under the curve of temporal estrogen (AUCEM) and progesterone measurements (AUCPM) were calculated for each participant. Women were included if they had regular menstrual cycles, normal serum prolactin levels and had not received hormone treatment within three months. ART was indicated in all patients for unexplained infertility. Patients were divided into two groups: with (n = 90) and without (n = 199) embryo implantation. The relationship between the two AUCs and ART success was assessed in terms of embryo implantation and clinical pregnancy., Results: Implantation was successful in 90 (31.1%) women, and a fetal heart rate was detected in 83 (28.7%) cases. There was a significant correlation between AUCEM and AUCPM (r = 0.525, P < 0.001). Multivariate regression analysis showed significant associations between failure of implantation, lack of clinical pregnancy and AUCEM (beta coefficient = 0.311, P < 0.001; beta coefficient = 0.297, P < 0.001, respectively) after adjusting for AUCPM., Conclusion: Our data showed that the degree of endometrial estrogen exposure is the main factor functioning as a detrimental effect of ovarian stimulation on endometrial receptivity., (© 2017 Japan Society of Obstetrics and Gynecology.)

The Global Initiative for Cancer Registry Development partnership, led by the International Agency for Research on Cancer (IARC), was established in response to an overwhelming need for high-quality cancer incidence data from low-income and middle-income countries. The IARC Regional Hub for cancer registration in North Africa, Central and West Asia was founded in 2013 to support capacity building for cancer registration in each of the countries in this region. In this Series paper, we advocate the necessity for tailored approaches to cancer registration given the rapidly changing cancer landscape for this region, and the challenges faced at a national level in developing data systems to help support this process given present disparities in resources and health infrastructure. In addition, we provide an overview of the status of cancer surveillance and activities country-by-country, documenting tailored approaches that are informing local cancer-control policy, and potentially curbing the growing cancer burden across the region., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras MUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous Kras MUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgfβ-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.

Objective: To compare embryo transfer (ET) technique based on catheter rotation during its withdrawal in cases with unexplained infertility in a prospective, randomized trial (NCT03097042)., Methods: Two hundred intracytoplasmic sperm injection (ICSI) patients undergoing ET with cleaving or blastocyst-stage fresh embryos were randomized into 2 groups: cases with (n = 100), and without (n = 100) catheter rotation during its withdrawal. Groups were matched for age and some clinical parameters. A soft catheter was used to transfer a single embryo with catheter rotation during its withdrawal in the study group and without rotation in the control. The use of a stiff catheter or tenaculum was not needed in any case. Groups were compared in terms of cycle characteristics and clinical pregnancy rates., Results: Pregnancy rate was significantly higher in the study group (41 vs. 26%, p = 0.04). Clinical pregnancy rate was also significantly higher in the study group (39 vs. 25%, OR 1.9 [1.1-3.5], p = 0.05). On the other hand, the ongoing pregnancy rate was similar between the 2 groups (33 vs. 23%, p = 0.2)., Conclusion: Catheter rotation during its withdrawal may be associated with increased pregnancy and clinical pregnancy rates; however, the difference in ongoing pregnancy rates did not reach statistical significance., (© 2018 S. Karger AG, Basel.)

Background/aims: There are wide variations in colorectal cancer (CRC) incidence across the world. Historically, the highest incidence rates have been reported historically in more developed countries; however, increasing trends have been seen in developing countries. Here, we present the CRC incidence pattern in Cyprus, Israel, Jordan, and İzmir, Turkey, which are countries of the Middle East Cancer Consortium (MECC)., Materials and Methods: We analyzed 2005-2010 CRC data from population-based registries and calculated crude and age standardized rates for CRC, colon and rectum subsites, and annual percent changes (APCs) for trends., Results: The age-adjusted incidence rates (AAIRs) for CRC were the highest in Israeli Jews (IJ) (46.7 for males and 35.5 for females), which exceeded those of the USA Surveillance, Epidemiology, and End Result (SEER) program registries. In both sexes, AAIRs in Cyprus and Israeli Arabs (IA) were close to those in SEER registries. For both sexes, AAIRs in İzmir and Jordan were substantially lower than those in other registries. Statistically significant decreasing trends over time were observed in AAIRs for both sexes in the SEER program (APCs: males, -3.24% and females, -2.54%), whereas the trends varied within the MECC registries. There were decreasing AAIR trends for males in IJ and IA and for females in Cyprus and IJ; APC for females in IJ (-4.29%) was significant. Conversely, increasing trends with the significant APCs were observed in males in İzmir (2.43%) and Jordan (7.57%)., Conclusion: MECC countries comprise both high- and low-risk populations for CRCs. However, increasing trends in low-risk populations have been alarming. Thus, the need for implementing tailored primary and secondary prevention programs in the region is essential.

Childhood (0-14 years) lymphomas, nowadays, present a highly curable malignancy compared with other types of cancer. We used readily available cancer registration data to assess mortality and survival disparities among children residing in Southern-Eastern European (SEE) countries and those in the United States. Average age-standardized mortality rates and time trends of Hodgkin (HL) and non-Hodgkin (NHL; including Burkitt [BL]) lymphomas in 14 SEE cancer registries (1990-2014) and the Surveillance, Epidemiology, and End Results Program (SEER, United States; 1990-2012) were calculated. Survival patterns in a total of 8918 cases distinguishing also BL were assessed through Kaplan-Meier curves and multivariate Cox regression models. Variable, rather decreasing, mortality trends were noted among SEE. Rates were overall higher than that in SEER (1.02/10 6 ), which presented a sizeable (-4.8%, P = .0001) annual change. Additionally, remarkable survival improvements were manifested in SEER (10 years: 96%, 86%, and 90% for HL, NHL, and BL, respectively), whereas diverse, still lower, rates were noted in SEE. Non-HL was associated with a poorer outcome and an amphi-directional age-specific pattern; specifically, prognosis was inferior in children younger than 5 years than in those who are 10 to 14 years old from SEE (hazard ratio 1.58, 95% confidence interval 1.28-1.96) and superior in children who are 5 to 9 years old from SEER/United States (hazard ratio 0.63, 95% confidence interval 0.46-0.88) than in those who are 10 to 14 years old. In conclusion, higher SEE lymphoma mortality rates than those in SEER, but overall decreasing trends, were found. Despite significant survival gains among developed countries, there are still substantial geographic, disease subtype-specific, and age-specific outcome disparities pointing to persisting gaps in the implementation of new treatment modalities and indicating further research needs., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Unique features and worse outcomes have been reported for cancers among adolescents and young adults (AYAs; 15-39 years old). The aim of this study was to explore the mortality and survival patterns of malignant central nervous system (CNS) tumors among AYAs in Southern-Eastern Europe (SEE) in comparison with the US Surveillance, Epidemiology, and End Results (SEER) program., Methods: Malignant CNS tumors diagnosed in AYAs during the period spanning 1990-2014 were retrieved from 14 population-based cancer registries in the SEE region (n = 11,438). Age-adjusted mortality rates were calculated and survival patterns were evaluated via Kaplan-Meier curves and Cox regression analyses, and they were compared with respective 1990-2012 figures from SEER (n = 13,573)., Results: Mortality rates in SEE (range, 11.9-18.5 deaths per million) were higher overall than the SEER rate (9.4 deaths per million), with decreasing trends in both regions. Survival rates increased during a comparable period (2001-2009) in SEE and SEER. The 5-year survival rate was considerably lower in the SEE registries (46%) versus SEER (67%), mainly because of the extremely low rates in Ukraine; this finding was consistent across age groups and diagnostic subtypes. The highest 5-year survival rates were recorded for ependymomas (76% in SEE and 92% in SEER), and the worst were recorded for glioblastomas and anaplastic astrocytomas (28% in SEE and 37% in SEER). Advancing age, male sex, and rural residency at diagnosis adversely affected outcomes in both regions., Conclusions: Despite definite survival gains over the last years, the considerable outcome disparities between the less affluent SEE region and the United States for AYAs with malignant CNS tumors point to health care delivery inequalities. No considerable prognostic deficits for CNS tumors are evident for AYAs versus children. Cancer 2017;123:4458-71. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Aim: To present incidence of central nervous system (CNS) tumours among adolescents and young adults (AYAs; 15-39 years) derived from registries of Southern and Eastern Europe (SEE) in comparison to the Surveillance, Epidemiology and End Results (SEER), US and explore changes due to etiological parameters or registration improvement via evaluating time trends., Methods: Diagnoses of 11,438 incident malignant CNS tumours in AYAs (1990-2014) were retrieved from 14 collaborating SEE cancer registries and 13,573 from the publicly available SEER database (1990-2012). Age-adjusted incidence rates (AIRs) were calculated; Poisson and joinpoint regression analyses were performed for temporal trends., Results: The overall AIR of malignant CNS tumours among AYAs was higher in SEE (28.1/million) compared to SEER (24.7/million). Astrocytomas comprised almost half of the cases in both regions, albeit the higher proportion of unspecified cases in SEE registries (30% versus 2.5% in SEER). Similar were the age and gender distributions across SEE and SEER with a male-to-female ratio of 1.3 and an overall increase of incidence by age. Increasing temporal trends in incidence were documented in four SEE registries (Greater Poland, Portugal North, Turkey-Izmir and Ukraine) versus an annual decrease in Croatia (-2.5%) and a rather stable rate in SEER (-0.3%)., Conclusion: This first report on descriptive epidemiology of AYAs malignant CNS tumours in the SEE area shows higher incidence rates as compared to the United States of America and variable temporal trends that may be linked to registration improvements. Hence, it emphasises the need for optimisation of cancer registration processes, as to enable the in-depth evaluation of the observed patterns by disease subtype., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Marked variations exist in the incidence and mortality trends of major cancers in South-Eastern European (SEE) countries which have now been detailed by age for breast cancer (BC) to seek clues for improvement., Methods: We brought together and analysed data from 14 cancer registries (CRs), situated in SEE countries or directly adjacent. Age-standardised rate at world standard (ASRw) and truncated incidence and mortality rates during 2000-2010 by year, and for four age groups, were calculated. Average annual percentage change of rates was estimated using Joinpoint regression., Results: Annual incidence rates increased significantly in countries and age groups, by 2-4% (15-39 years), 2-5% (40-49), 1-4% (50-69) and 1-6% (at 70+). Mortality rates decreased significantly in all age-groups in most countries, but increased up to 5% annually above age 55 in Ukraine, Serbia, Moldova and Cyprus. The BC data quality was evaluated by internationally agreed indicators which appeared suboptimal for Moldova, Bosnia and Herzegovina and Romania., Conclusion: The observed variations of incidence trends reflect the influence of risk factors, as well as levels of early detection activities (screening). While mortality rates were mostly decreasing, probably due to improved cancer care and introduction of more effective systemic treatment regimens, the worrying increasing mortality trends in the 55-plus age groups in some countries have to be addressed by health professionals and policymakers. In order to assess and monitor the effects of cancer control activities in the region, the CRs need substantial investments., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: The aim of this study was to assess the predictive value of serum substance P (SP) concentrations on oocyte maturation and clinical pregnancy., Methods: Ninety-three women with unexplained infertility underwent intracytoplasmic sperm injection (ICSI) cycles. Antagonist protocol was started for each participant and at the day of oocyte pick up, serum samples were obtained from each participant to assess SP concentrations, and these concentrations were utilized to predict mature/total oocyte ratio and clinical pregnancy., Results: SP concentration was a significant predictor for mature/total oocyte ratio > 0.75 and clinical pregnancy. In correlation analyses, maturation index was significantly correlated with FSH (r= -0.226, p = 0.03), estradiol (r = 0.239, p = 0.021), peak estradiol (r = 0.414, p < 0.001), and substance P (r = 0.796, p < 0.001). In multivariate analyses, number of immature (beta coefficient = -0.379, p < 0.001), mature oocyte (beta coefficient = 0.473, p < 0.001), SP concentration (beta coefficient = 0.723, p < 0.001) and maturation index (beta coefficient = -0.387, p = 0.003) were significantly associated with clinical pregnancy., Conclusion: SP concentrations at the day of oocyte pick up may be used to predict clinical pregnancy and may be an indirect indicator for cycle outcome in assisted reproductive technology (ART).

Therapeutic plasma exchange (TPE) is an extracorporeal treatment with reported beneficial as well as detrimental effects on circulation. However, there is a lack of data using advanced hemodynamic monitoring during TPE. Therefore, we investigated the effects of TPE on hemodynamic parameters derived from transpulmonary thermodilution (TPTD) as well as the risk for transfusion-related acute lung injury (TRALI). We compared hemodynamic parameters obtained before and after a total of 30 sessions of TPE treatment in 10 intensive care unit patients. Among standard hemodynamic parameters, heart rate (P < 0.012) and systolic blood pressure (P < 0.008) significantly increase, whereas neither mean arterial pressure nor diastolic blood pressure was altered after TPE. The TPTD-derived cardiac function parameters, cardiac index (CI; P = 0.035), cardiac power index (CPI; P = 0.008), global ejection fraction (GEF; P = 0.002), and stroke volume index (SVI; P = 0.014), were significantly higher after TPE. Furthermore, systemic vascular index significantly increased (P < 0.042). Among the cardiac preload parameters, central venous pressure was significantly lower after TPE (P < 0.001), while the global end-diastolic volume index (GEDVI) did not change. Contractility marker dPmax did not change. Finally, TPE application did not significantly alter the pulmonary hydration and permeability parameters, extravascular lung water index (EVLWI) and pulmonary vascular permeability index. Vasopressor dose was not statistically significantly altered. Considering increases in SVI, CI, GEF, and CPI and stable values for GEDVI, EVLWI, and dPmax, our data do not give any hint for hemodynamic impairment or TRALI., (© 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Pilocytic astrocytomas (PA) comprise the most common childhood central nervous system (CNS) tumor. Exploiting registry-based data from Southern and Eastern Europe (SEE) and SEER, US, we opted to examine incidence, time trends, survival and tentative outcome disparities of childhood PA by sociodemographic and clinical features. Childhood PA were retrieved from 12 SEE registries (N = 552; 1983-2014) and SEER (N = 2723; 1973-2012). Age-standardized incidence rates (ASR) were estimated and survival was examined via Kaplan-Meier and Cox regression analysis. ASR of childhood PA during 1990-2012 in SEE was 4.2/10 6 , doubling in the USA (8.2/10 6 ). Increasing trends, more prominent during earlier registration years, were recorded in both areas (SEE: +4.1 %, USA: +4.6 %, annually). Cerebellum comprised the most common location, apart from infants in whom supratentorial locations prevailed. Age at diagnosis was 1 year earlier in SEE, whereas 10-year survival was 87 % in SEE and 96 % in SEER, improving over time. Significant outcome predictors were age <1 year at diagnosis diagnosis (hazard ratio, HR [95% confidence intervals]: 3.96, [2.28-6.90]), female gender (HR: 1.38, [1.01-1.88]), residence in SEE (HR: 4.07, [2.95-5.61]) and rural areas (HR: 2.23, [1.53-3.27]), whereas non-cerebellar locations were associated with a 9- to 12-fold increase in risk of death. The first comprehensive overview of childhood PA epidemiology showed survival gains but also outcome discrepancies by geographical region and urbanization pointing to healthcare inequalities. The worse prognosis of infants and, possibly, females merits further consideration, as it might point to treatment adjustment needs, whereas expansion of systematic registration will allow interpretation of incidence variations.

Aim: To assess trends in survival and geographic disparities among children (0-14 years) with chronic myeloid leukaemia (CML) before and after the introduction of molecular therapy, namely tyrosine kinase inhibitors (TKIs) in Southern-Eastern European (SEE) countries and the USA., Methods: We calculated survival among children with CML, acute lymphoblastic (ALL) and acute myeloid leukaemia (AML) in 14 SEE (1990-2014) cancer registries and the U.S. Surveillance, Epidemiology and End Results Program (SEER, 1990-2012). We used Kaplan-Meier curves and multivariate Cox regression models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: Among 369 CML cases, substantial improvements were noted in 2-year survival during the post-TKI (range: 81-89%) compared to pre-TKI period (49-66%; HR: 0.37, 95% CI: 0.23-0.60). Risk of death was three times higher for <5-year-old children versus those aged 10-14 years (HR: 3.03, 95% CI: 1.85-4.94) and 56% higher for those living in SEE versus SEER (HR: 1.56, 95% CI: 1.01-2.42). Regardless of geographic area and period of TKI administration, however, age seems to be a significant determinant of CML prognosis (pre-TKI period, HR 0-4y : 2.71, 95% CI: 1.53-4.79; post-TKI period, HR 0-4y : 3.38, 95% CI: 1.29-8.85). Noticeably, post-TKI survival in CML overall approximates that for ALL, whereas therapeutic advancements for AML remain modest., Conclusion: Registry data show that introduction of molecular therapies coincides with revolutionised therapeutic outcomes in childhood CML entailing dramatically improved survival which is now similar to that in ALL. Given that age disparities in survival remain substantial, offering optimal therapy to entire populations is an urgent priority., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To describe epidemiologic patterns of childhood (0-14 years) lymphomas in the Southern and Eastern European (SEE) region in comparison with the Surveillance, Epidemiology and End Results (SEER), USA, and explore tentative discrepancies., Methods: Childhood lymphomas were retrieved from 14 SEE registries (n = 4,702) and SEER (n = 4,416), diagnosed during 1990-2014; incidence rates were estimated and time trends were evaluated., Results: Overall age-adjusted incidence rate was higher in SEE (16.9/10 6 ) compared to SEER (13.6/10 6 ), because of a higher incidence of Hodgkin (HL, 7.5/10 6 vs. 5.1/10 6 ) and Burkitt lymphoma (BL, 3.1 vs. 2.3/10 6 ), whereas the incidence of non-Hodgkin lymphoma (NHL) was overall identical (5.9/10 6 vs. 5.8/10 6 ), albeit variable among SEE. Incidence increased with age, except for BL which peaked at 4 years; HL in SEE also showed an early male-specific peak at 4 years. The male preponderance was more pronounced for BL and attenuated with increasing age for HL. Increasing trends were noted in SEER for total lymphomas and NHL, and was marginal for HL, as contrasted to the decreasing HL and NHL trends generally observed in SEE registries, with the exception of increasing HL incidence in Portugal; of note, BL incidence trend followed a male-specific increasing trend in SEE., Conclusions: Registry-based data reveal variable patterns and time trends of childhood lymphomas in SEE and SEER during the last decades, possibly reflecting diverse levels of socioeconomic development of the populations in the respective areas; optimization of registration process may allow further exploration of molecular characteristics of disease subtypes.

Objective: One of the most common encountered problems in free flap surgeries is anastomotic thrombosis. The mean platelet volume (MPV) may indicate the concentration of intra-platelet proactive substances and the thrombogenic potential of the platelets. MPV is used as a clinical monitoring index in routine blood counts, it has not yet been effectively used in free flap surgery., Methods: This study evaluates the relationship between the preoperative MPV value and anastomotic thrombus formation during the postoperative 48 hours in 32 free flap operations from September 2013 to September 2014. The mean patient age was 36.75 years. The preoperative MPV value, which was obtained from the complete blood count, was recorded and correlation of MPV and postoperative thrombus formation was investigated., Results: Four anastomotic thrombus were encountered in 34 free flaps during the postoperative 48 hours. Two of them were salvaged by performing thrombectomy and/or administration of i.v. heparin. There was no statistical relationship between MPV value and postoperative thrombus formation during 48 hours follow-up (p = 0.925)., Conclusion: Even though this study didn't find a correlation between preoperative MPV value and postoperative early anastomotic thrombus, it would be helpful to validate the results using multi-centre and comprehensive studies with larger patient cohorts.

It is important that population-based cancer registries provide accurate and reliable data for public health purposes. These data are essential data for planning of cancer control and prevention. In this study, we examined cancer incidence rates (year 2005-2010) in four MECC registries (Cyprus, Jordan, Israel, Izmir (Turkey)) and compared with the rates in the US. The overall age-standardized incidence rates for males were highest in the US followed by Israeli Jews, Izmir (Turkey), Cyprus, Israeli Arabs, and lowest in Jordan. In women the rates of cancer of all sites were also highest in US women followed by Israeli Jews, Cyprus, Israeli Arabs, Izmir (Turkey), and lowest in Jordan. It is of interest that although site-specific cancer rates differ between the countries studied, prostate, lung and colorectal cancers are within the five most common cancers males in all countries studied. In females, breast colorectal and endometrium cancers are three of the five most common cancers in females in all countries studied. The results presented in this paper can have implications for opportunities in cancer control and prevention in these countries. Future studies on individual cancer sites with highest rates in these Countries are currently underway., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-D-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.

Introduction: Most countries in South-Eastern Europe (SEE) have lower incidence, but higher mortality rates of malignant melanoma (MM) of the skin compared to North-Western Europe (NWE). We explored trends in MM incidence and mortality in SEE countries by sex and age and compared them with the trends in NWE., Methods: We obtained data on incident cases and deaths from MM (ICD-10 code C43) from 11 population-based cancer registries in Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Malta, Romania, Serbia, Slovakia, Slovenia and Turkey. We calculated age-specific rates for 25-49 ('young'), 50-69 ('middle aged') and 70+ years ('older') and estimated the average annual percent of change in incidence and mortality trends 2000-2010 according to age group and sex, using joinpoint regression analysis., Findings: The incidence rates of MM across the region were uniformly increasing. Significant increases in mortality rates were observed in middle aged men in Serbia and Bulgaria, middle aged women in Slovenia, older men in the Czech Republic, Serbia and Turkey, and older women in Slovenia and Serbia., Interpretation: While MM incidence rates were still increasing across SEE, mortality trends diverged and were less favourable than in NWE. Empowering cancer registration and improving the quality of incidence and mortality data will be essential for monitoring progress in MM control. In the context of prevention of melanoma, disparities in early detection appear to be widening the gap between SEE and NWE, while the provision of care to patients with advanced disease is likely to prove a challenge for regional healthcare budgets., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: The aim of the present study was to evaluate the pregnancy rates of intrauterine insemination (IUI) and controlled ovarian hyperstimulation (COH) in patients with one-sided tubal occlusion on hysterosalpingography (HSG)., Materials and Methods: Patients who underwent COH/IUI were enrolled into this retrospective cohort study. The patients with one-sided tubal occlusion diagnosed under HSG who met the inclusion criteria were accepted into the study group. The control group consisted of patients with unexplained infertility. The outcomes of COH/IUI were compared between the study and control groups., Results: Ninety-seven patients in the study group (n=44) and control group (n=53) who underwent COH/IUI treatment were included into study. The biochemical, clinical, and ongoing pregnancy rates were similar between patients with unilateral occlusion diagnosed under HSG and those with unexplained infertility. The spontaneous pregnancy rate within one year was higher in patients with normal HSG than in patients with unilateral tubal occlusion, but the difference did not show statistical significance., Conclusion: Infertile patients with one-sided tubal occlusion in HSG can be managed as with patients with unexplained infertility and normal HSG findings. In addition, COH/IUI may be considered as the first-line treatment option in the management of these patients., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

A chromium(I) dinitrogen complex reacts rapidly with O2 to form the mononuclear dioxo complex [Tp(tBu,Me)Cr(V)(O)2] (Tp(tBu,Me) = hydrotris(3-tert-butyl-5-methylpyrazolyl)borate), whereas the analogous reaction with sulfur stops at the persulfido complex [Tp(tBu,Me)Cr(III)(S2)]. The transformation of the putative peroxo intermediate [Tp(tBu,Me)Cr(III)(O2)] (S = 3/2) into [Tp(tBu,Me)Cr(V)(O)2] (S = 1/2) is spin-forbidden. The minimum-energy crossing point for the two potential energy surfaces has been identified. Although the dinuclear complex [(Tp(tBu,Me)Cr)2(μ-O)2] exists, mechanistic experiments suggest that O2 activation occurs on a single metal center, by an oxidative addition on the quartet surface followed by crossover to the doublet surface., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Fungal infections present a constant risk to critically ill and immunocompromised patients. Therefore, treatment guidelines recommend echinocandins as first-line antifungals in critically ill patients to improve patient outcomes. Echinocandins are usually well tolerated; nevertheless, rare adverse events can occur. There are reports of temporary deterioration of hemodynamic parameters during loading doses, especially in critically ill patients. The objective of this study is to analyze the hemodynamic changes during administration of the echinocandin antifungals, caspofungin and anidulafungin, in medical intensive care unit patients., Methods: A prospective study in medical ICU patients receiving echinocandins was monitored using single-indicator transpulmonary thermodilution (TPTD). TPTD measurements were performed immediately before, directly after, and 4 h after echinocandins on two following days., Results: Mean arterial pressure and also diastolic blood pressure showed significant changes (p < 0.042 and p < 0.007) after echinocandin application in the measurement immediately after application, but not after 4 h. Basic hemodynamic parameters as well as the TPTD-derived cardiac function parameters did not significantly change after echinocandin application at all. In patients with the need for norepinephrine therapy, the vasopressor dose was not statistically significantly altered., Conclusion: To conclude, administration of echinocandins in this observed study population is safe, even in severely critically ill patients if application rules of these agents are followed. However, adverse effects could be observed and practitioners should be cognizant of these effects. These observations can be optimized by high-level assessments, such as the pulse contour cardiac output monitoring, and clinicians should continue to be vigilant with cardiac monitoring of patients receiving echinocandin antifungals.

Aim: Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region., Methods: Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan-Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants., Results: Variations in mortality (8-16 per million) and survival (5-year: 35-69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (-2.4%, p=0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1-1.4)., Conclusion: Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: Following completion of the first 5-year nationwide childhood (0-14 years) registration in Greece, central nervous system (CNS) tumour incidence rates are compared with those of 12 registries operating in 10 Southern-Eastern European countries., Methods: All CNS tumours, as defined by the International Classification of Childhood Cancer (ICCC-3) and registered in any period between 1983 and 2014 were collected from the collaborating cancer registries. Data were evaluated using standard International Agency for Research on Cancer (IARC) criteria. Crude and age-adjusted incidence rates (AIR) by age/gender/diagnostic subgroup were calculated, whereas time trends were assessed through Poisson and Joinpoint regression models., Results: 6062 CNS tumours were retrieved with non-malignant CNS tumours recorded in eight registries; therefore, the analyses were performed on 5191 malignant tumours. Proportion of death certificate only cases was low and morphologic verification overall high; yet five registries presented >10% unspecified neoplasms. The male/female ratio was 1.3 and incidence decreased gradually with age, apart from Turkey and Ukraine. Overall AIR for malignant tumours was 23/10(6) children, with the highest rates noted in Croatia and Serbia. A statistically significant AIR increase was noted in Bulgaria, whereas significant decreases were noted in Belarus, Croatia, Cyprus and Serbia. Although astrocytomas were overall the most common subgroup (30%) followed by embryonal tumours (26%), the latter was the predominant subgroup in six registries., Conclusion: Childhood cancer registration is expanding in Southern-Eastern Europe. The heterogeneity in registration practices and incidence patterns of CNS tumours necessitates further investigation aiming to provide clues in aetiology and direct investments into surveillance and early tumour detection., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large "areas" of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths)., (© 2014 UICC.)

Here we describe a conditional piggyBac transposition system in mice and report the discovery of large sets of new cancer genes through a pancreatic insertional mutagenesis screen. We identify Foxp1 as an oncogenic transcription factor that drives pancreatic cancer invasion and spread in a mouse model and correlates with lymph node metastasis in human patients with pancreatic cancer. The propensity of piggyBac for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a Cdkn2a cis-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including Fign insertions in hepatoid pancreatic cancer. Our studies demonstrate the power of genetic screening to discover cancer drivers that are difficult to identify by other approaches to cancer genome analysis, such as downstream targets of commonly mutated human cancer genes. These piggyBac resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer.

Purpose: The present study was carried out to measure knowledge level and behavior of family health personnel (FHP) in Izmir on early diagnosis of breast and cervical cancers., Materials and Methods: The study population of this cross-sectional study was not selected. A questionnaire was applied to all FHP to measure knowledge level and behavior about cancer. The participation rate was 88%. Breast examination, mammography analysis, Papanicolaou smear applications were determined as dependent variables, and knowledge level about breast and cervical cancer, age, professional time as FHP as independent variables. Data were evaluated using definitive statistics, chi-square and logistic regression tests in SPSS software package for Windows 15.0., Results: A total of 970 family health personnel participated in the research. The age range was 20-45 years (82.4%). Mean age was 37.9±7.4. Response rate was 87.3%. Of the participants, 88.4% performed breast self-examination. Rate of performing mammography at least once was 24.1%. Rate of performing Pap-smear examination at least once was 61.0%. In logistic regression analyses, it was determined that people with knowledge on breast and cervical cancer were those performing breast self-examination, mammography and Pap-smear examinations (p<0.05., Conclusions: It is essential that the knowledge, behavior and manners of health providers on early diagnosis for cancer increases awareness in the general population and provides information on execution ofthe most effective methods for generating a healthy society.

Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.

Background: This study aimed to determine the incidence of prostate cancer in Turkey in a population-based sample, and to determine clinical and pathological characteristics of the cases., Materials and Methods: All newly diagnosed prostate cancer patients were included in this national, multi-centered, prospective and non- interventional epidemiological registry study conducted in 12 cities representing the 12 regions of Turkey from July 2008 to June 2009. The population-based sample comprised 4,150 patients with a recent prostate cancer diagnosis., Results: Age-adjusted prostate cancer incidence rate was 35 cases per 100,000 in Turkey. At the time of diagnosis, median age was 68, median PSA level was 10.0 ng/mL. Digital rectal examination was abnormal in 36.2% of 3,218 tested cases. Most patients had urologic complaints. The main diagnostic method was transrectal ultrasound guided biopsy (87.8%). Gleason score was ≤6 in 49.1%, 7 in 27.8% and >7 in 20.6% of the cases. There was a statistically significant positive correlation between serum PSA level and Gleason score (p=0.000). The majority of patients (54.4%) had clinical stage T1c., Conclusions: This is the first population-based national data of incidence with the histopathological characteristics of prostate cancer in Turkey. Prostate cancer remains an important public health concern in Turkey with continual increase in the incidence and significant burden on healthcare resources.

Improvements in the syntheses of the carboxamide-substituted tris(pyrazolyl)borate ligands Tp(CONHPh,Me) [tris(3-anilinocarbonyl-5-methylpyrazol-1-yl)borate] and Tp(CONHt-Bu,Me) [tris(3-tert-butylaminocarbonyl-5-methylpyrazol-1-yl)borate] are reported. Their Tl(I) salts, namely [tris(3-anilinocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]thallium(I), [Tl(C33H31BN9O3)], (II), and [tris(3-tert-butylaminocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]thallium(I), [Tl(C27H43BN9O3)], (III), as well as the Cu(I) carbonyl complexes (Tp(CONHPh,Me))Cu(CO), namely carbonyl[tris(3-anilinocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]copper(I) tetrahydrofuran trisolvate, [Cu(C33H31BN9O3)(CO)]·3C4H8O, (IV), and (Tp(CONHt-Bu,Me))Cu(CO), namely carbonyl[tris(3-tert-butylaminocarbonyl-5-methylpyrazol-1-yl-κN(2))borato]copper(I) tetrahydrofuran hemisolvate, [Cu(C27H43BN9O3)(CO)]·0.5C4H8O, (V), have been prepared. Their spectroscopic properties and structures are compared with those of related compounds. The molecules of (II)-(V) show hydrogen bonding to either solvent molecules or neighboring complex molecules via amide groups. The title compounds feature the ability to engage other ligands in hydrogen bonding and they show strong electron-withdrawing character. Compound (V) displays voids of ca 800 Å(3) in the crystal structure.