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Cancer Statistics
Population in 2012: 7.4m
People newly diagnosed with cancer (excluding NMSC) / yr: 32,100
Age-standardised rate, incidence per 100,000 people/yr: 234.8
Risk of getting cancer before age 75:23.8%
People dying from cancer /yr: 18,100
Data from IARC GlobalCan (2012)
Bulgarian Cancer Resources
Latest Research Publications from Bulgaria

Bulgarian Cancer Resources (12 links)

Latest Research Publications from Bulgaria

Sedloev T, Vlahova A, Usheva S, et al.
Long-Term Survival and Complete Response to
Anticancer Res. 2019; 39(8):4393-4398 [PubMed] Related Publications
BACKGROUND/AIM: Metastatic breast cancer (MBC) represents a wide spectrum of heterogeneous conditions with different secondary spread sites, time to relapse and biology. MBC is still considered an incurable disease despite the fact that survival rates have improved in the last years. Cutaneous metastases are a rare site for metastatic spread and indicate advanced disease. The aim of this study is to demonstrate the excellent therapeutic result following endocrine therapy only in MBC with just skin involvement.
CASE REPORT: We present a case of an 82-year-old woman with no family history of breast cancer (BC), who was diagnosed with de novo metastatic estrogen/progesterone receptor-positive and HER2-negative invasive lobular BC. The only site of secondary spread was the skin. She was treated with just endocrine therapy for 116 months with which she achieved and maintained long-term complete clinical response (CR).
DISCUSSION: To our knowledge this is the only case of lobular BC with de novo metastatic manifestation as multiple skin metastases, which achieved CR following the aromatase inhibitor treatment (anastrozole) with such impressive long-term overall survival.

Ivanova D, Zhelev Z, Semkova S, et al.
Resveratrol Modulates the Redox-status and Cytotoxicity of Anticancer Drugs by Sensitizing Leukemic Lymphocytes and Protecting Normal Lymphocytes.
Anticancer Res. 2019; 39(7):3745-3755 [PubMed] Related Publications
BACKGROUND/AIM: The study is directed to the effect of resveratrol on the redox-status and viability of leukemic and normal lymphocytes, as well as its ability to sensitize leukemic lymphocytes to anticancer drugs.
MATERIALS AND METHODS: Cytotoxicity was analyzed by trypan blue staining, apoptosis - by Annexin V test, and oxidative stress - by the intracellular levels of reactive oxygen species (ROS) and protein-carbonyl products.
RESULTS: Incubation of resveratrol in combination with the majority of anticancer drugs resulted in higher toxicity than resveratrol or drug alone. In the case of leukemic lymphocytes treated with barasertib and everolimus in the presence of resveratrol, synergistic cytotoxicity was accompanied by strong induction of apoptosis, increased levels of hydroperoxides and insignificant changes in protein-carbonyl products. None of these parameters changed in normal lymphocytes.
CONCLUSION: Resveratrol is a promising supplementary compound for anticancer therapy, that may allow reduction of the therapeutic doses of barasertib and everolimus, minimizing their side-effects.

Nikolov S, Dimitrov A, Vera J
Hierarchical Levels of Biological Systems and their Integration as a Principal Cause for Tumour Occurrence.
Nonlinear Dynamics Psychol Life Sci. 2019; 23(3):315-329 [PubMed] Related Publications
The development of new theories, mathematical methods and models for effective control of complex systems is one of the main problems for modern science. Biological systems are complex and hierarchically organized, with the behaviour of higher levels influencing the dynamics of the lower ones and vice versa. Hierarchical organization can be observed from subcellular to supercellular levels. When biological systems are far from their steady states, then nonlinear dependences take place, and a slight external impact can cause unexpected and unpredictable (chaotic, irregular) behaviour in these systems, resulting in fractal hierarchical structures. By examining tumours as strange (chaotic) attractors, we define in this article the hypothesis that the cause of their occurrence, development and spread (metastasis) is due to disorders in the hierarchical structure and integration of cell signalling pathways in tumour cells. An essential point in this article is the thesis (contrary to the view that the only causality in hierarchical systems is physical causality, i.e. there is no "top-down,' "holistic causality,' "intelligent causality,' etc.) that hierarchical systems are built on the principle of communication. Intelligent systems (in particular biological) that do not interact as mechanical objects, but on the basis of different meanings of biochemical signals obtained after their interpretation, participate in this communication.

Fischer K, Al-Sawaf O, Bahlo J, et al.
Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.
N Engl J Med. 2019; 380(23):2225-2236 [PubMed] Related Publications
BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.
METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.
RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with
CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).

Cornelio B, Laronze-Cochard M, Miambo R, et al.
5-Arylisothiazol-3(2H)-one-1,(1)-(di)oxides: A new class of selective tumor-associated carbonic anhydrases (hCA IX and XII) inhibitors.
Eur J Med Chem. 2019; 175:40-48 [PubMed] Related Publications
Sixteen 5-aryl-substituted isothiazol-3(2H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2H)-one-1-oxide or -1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N-tert-butylisothiazolone series, the 5-phenyl-substituted analog (1a) excelled in the inhibition of tumor-associated hCA IX and XII (K

Yeung AWK, Horbańczuk M, Tzvetkov NT, et al.
Curcumin: Total-Scale Analysis of the Scientific Literature.
Molecules. 2019; 24(7) [PubMed] Free Access to Full Article Related Publications
The current study aimed to provide a comprehensive bibliometric overview of the literature on curcumin, complementing the previous reviews and meta-analyses on its potential health benefits. Bibliometric data for the current analysis were extracted from the Web of Science Core Collection database, using the search string TOPIC=("curcumin*"), and analyzed by the VOSviewer software. The search yielded 18,036 manuscripts. The ratio of original articles to reviews was 10.4:1. More than half of the papers have been published since 2014. The major contributing countries were the United States, China, India, Japan, and South Korea. These publications were mainly published in journals representing the following scientific disciplines: biochemistry, chemistry, oncology, and pharmacology. There was a significant positive correlation between the total publication count and averaged citations per manuscript for affiliations, but not for countries/regions and journals. Chemicals that were frequently mentioned in the keywords of evaluated curcumin publications included curcuminoids, resveratrol, chitosan, flavonoids, quercetin, and polyphenols. The literature mainly focused on curcumin's effects against cancer, inflammation, and oxidative stress. Cancer types most frequently investigated were breast, colon, colorectal, pancreatic, and prostate cancers.

Hu T, Linghu K, Huang S, et al.
Flaxseed extract induces apoptosis in human breast cancer MCF-7 cells.
Food Chem Toxicol. 2019; 127:188-196 [PubMed] Related Publications
Significant evidence indicated that flaxseed (Linum usitatissimum) possesses various positive health aspects such as reducing the risk of cancer and cardiovascular diseases. The fatty acids are considered to be responsible for these benefits of flaxseed. Herein, the in vitro effects of flaxseed extract on the growth and apoptosis of human breast cancer MCF-7 cells were investigated. The MCF-7 cells treated with flaxseed extract showed a dose-dependent decrease in cell viability. The flaxseed extract induced reactive oxygen species and the flow cytometric analysis demonstrated that flaxseed fatty acids triggered apoptosis of MCF-7 cells, which was also shown by the loss of mitochondrial membrane potential and caspase cascade reaction. Thus, the flaxseed extract regulated the growth of MCF-7 cells and induced apoptosis. Eventually, the flaxseed could be used as a dietary supplement to prevent breast cancer.

Ulisse S, Tuccilli C, Sorrenti S, et al.
PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.

Waller CF, Ranganna GM, Pennella EJ, et al.
Randomized phase 3 efficacy and safety trial of proposed pegfilgrastim biosimilar MYL-1401H in the prophylactic treatment of chemotherapy-induced neutropenia.
Ann Hematol. 2019; 98(5):1217-1224 [PubMed] Free Access to Full Article Related Publications
Pegfilgrastim is indicated for reducing the duration of neutropenia and incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy. Here, safety and efficacy of MYL-1401H, a proposed pegfilgrastim biosimilar, were investigated as prophylaxis for chemotherapy-induced neutropenia. This was a phase 3, multicenter, randomized, double-blind, parallel-group equivalence trial of MYL-1401H vs European Union-sourced reference pegfilgrastim. Patients with newly diagnosed stage II/III breast cancer eligible to receive (neo) adjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide every 3 weeks for 6 cycles were enrolled and randomized 2:1 to 6 mg of MYL-1401H or reference pegfilgrastim 24 h (+ 2-h window after the first 24 h) after the end of chemotherapy. The primary efficacy endpoint was the duration of severe neutropenia in cycle 1 (i.e., days with absolute neutrophil count (ANC) < 0.5 × 10

Jiang X, Cao C, Sun W, et al.
Scandenolone from Cudrania tricuspidata fruit extract suppresses the viability of breast cancer cells (MCF-7) in vitro and in vivo.
Food Chem Toxicol. 2019; 126:56-66 [PubMed] Related Publications
Scandenolone, an isoflavone, has shown anti-cancer potential. In this study, we extracted scandenolone from Cudrania tricuspidata fruit and evaluated its anti-breast cancer effects as well as toxicity in cell and animal models. In cell model, scandenolone suppressed the breast cancer MCF-7 cells viability, ceased mitotic cell cycle, decreased mitochondrial membrane potential, up-regulated cleaved caspase-3 and promoted the phosphorylation of p53. Additionally, this isoflavone promoted cell apoptosis and induced a sustained activation of the phosphorylation of p38 and ERK, but not JNK and Akt. The effects were further verified in a human MCF-7 breast cancer xenograft model, where scandenolone efficiently suppressed the cancer growth and increased apoptotic cells in tumor tissue. However scandenolone has also shown certain toxicity to normal hepatocytes and breast epithelial cells. It could be concluded that scandenolone suppressed the growth of breast cancer cells, but its toxicity towards normal cells might limit its potential clinical use.

Dukov N, Bliznakova K, Feradov F, et al.
Models of breast lesions based on three-dimensional X-ray breast images.
Phys Med. 2019; 57:80-87 [PubMed] Related Publications
This paper presents a method for creation of computational models of breast lesions with irregular shapes from patient Digital Breast Tomosynthesis (DBT) images or breast cadavers and whole-body Computed Tomography (CT) images. The approach includes six basic steps: (a) normalization of the intensity of the tomographic images; (b) image noise reduction; (c) binarization of the lesion area, (d) application of morphological operations to further decrease the level of artefacts; (e) application of a region growing technique to segment the lesion; and (f) creation of a final 3D lesion model. The algorithm is semi-automatic as the initial selection of the region of the lesion and the seeds for the region growing are done interactively. A software tool, performing all of the required steps, was developed in MATLAB. The method was tested and evaluated by analysing anonymized sets of DBT patient images diagnosed with lesions. Experienced radiologists evaluated the segmentation of the tumours in the slices and the obtained 3D lesion shapes. They concluded for a quite satisfactory delineation of the lesions. In addition, for three DBT cases, a delineation of the tumours was performed independently by the radiologists. In all cases the abnormality volumes segmented by the proposed algorithm were smaller than those outlined by the experts. The calculated Dice similarity coefficients for algorithm-radiologist and radiologist-radiologist showed similar values. Another selected tumour case was introduced into a computational breast model to recursively assess the algorithm. The relative volume difference between the ground-truth tumour volume and the one obtained by applying the algorithm on the synthetic volume from the virtual DBT study is 5% which demonstrates the satisfactory performance of the proposed segmentation algorithm. The software tool we developed was used to create models of different breast abnormalities, which were then stored in a database for use by researchers working in this field.

Jiang X, Finucane HK, Schumacher FR, et al.
Shared heritability and functional enrichment across six solid cancers.
Nat Commun. 2019; 10(1):431 [PubMed] Free Access to Full Article Related Publications
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r

Rich A, Baldwin D, Alfageme I, et al.
Achieving Thoracic Oncology data collection in Europe: a precursor study in 35 Countries.
BMC Cancer. 2018; 18(1):1144 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire.
METHODS: Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months.
RESULTS: Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses.
CONCLUSION: Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research.

Ruscelli P, Renzi C, Polistena A, et al.
Clinical signs of retroperitoneal abscess from colonic perforation: Two case reports and literature review.
Medicine (Baltimore). 2018; 97(45):e13176 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Retroperitoneal colonic perforation is a rare cause of retroperitoneal abscess. It presents, more frequently in frail elderly patients, with heterogeneous signs and symptoms which hamper the clinical diagnosis. Subcutaneous emphysema with pneumomediastinum and iliopsoas muscle abscess are unusual signs. Colonic retroperitoneal perforation may be consequent to diverticulitis or locally advanced colon cancer. Due to the anatomy of the retroperitoneal space and different physiopathology, diverticular perforation may present with air and pus collection; on the other hand perforated colon cancer may cause groin mass and psoas abscess. We reported 2 cases of colonic retroperitoneal perforation from diverticulitis and locally advanced colon cancer, respectively. Aim of this report is to improve differential diagnosis based on clinical signs.
PATIENTS' CONCERNS: A 71-year-old man presented with pain in his left side, fatigue, fever, nausea, massive subcutaneous emphysema of the neck, and Blumberg sign in the left iliac fossa. A 67-year-old man presented with abdominal pain, sub-occlusion, left groin mass, left groin, and lower limb pain during walking, negative Blumberg sign.
DIAGNOSIS: In the first patient the computerized tomography revealed pneumoperitoneum, gas in the mesosigma, pneumomediastinum, wall thickening of the descending colon, and retroperitoneal collection from diverticular perforation. In the second patient abdominal CT scan found thickening of the sigmoid colon adherent to the iliopsoas and fluid collection.
INTERVENTIONS: In the first patient, a left hemicolectomy extending to the transverse colon, followed by a toilette and debridement of the retroperitoneum were performed. In the second patient, tumor of descending colon perforated in the retroperitoneum with iliopsoas abscess was treated with left hemicolectomy and a drainage of the abscess.
OUTCOMES: The first patient underwent right colectomy with ileostomy in the 7 postoperative day for large bowel necrosis. He died of sepsis 2 days after. The second patient had regular postoperative and he is still alive.
LESSONS: The spread of retroperitoneal abscess in complicated colonic diverticulitis is different from that in advanced colonic cancer. The former can present with a subcutaneous emphysema, the latter with a groin mass. Hence a thorough clinical examination and radiological studies are needed to diagnose these conditions.

Matejcic M, Saunders EJ, Dadaev T, et al.
Germline variation at 8q24 and prostate cancer risk in men of European ancestry.
Nat Commun. 2018; 9(1):4616 [PubMed] Free Access to Full Article Related Publications
Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10

Li JW, Zuo WJ, Ivanova D, et al.
Metronomic capecitabine combined with aromatase inhibitors for new chemoendocrine treatment of advanced breast cancer: a phase II clinical trial.
Breast Cancer Res Treat. 2019; 173(2):407-415 [PubMed] Related Publications
PURPOSE: This study was designed to determine the safety and clinical efficacy of metronomic chemotherapy combined with aromatase inhibitors (AIs) for hormone receptor (HR)-positive advanced breast cancer (ABC) patients who cannot tolerate conventional-dose chemotherapy.
METHODS: Postmenopausal patients with HR-positive ABC, who exhibited disease progression after first-line AIs treatment and who could not tolerate or rejected conventional chemotherapy, were enrolled in this study. Patients received capecitabine 500 mg PO TID (could be reduced to 500 mg QD in case of adverse effects) and exemestane 25 mg QD (after PD with letrozole) or letrozole 2.5 mg QD (after PD with exemestane). The primary endpoints were safety and tolerance, the secondary endpoints were objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and time to treatment failure (TTF).
RESULTS: In our analysis of 44 patients, the median age was 64 years (range 38-90) and 68.2% patients had at least two recurrences or metastatic lesions. Grade 3 toxicities (hand-foot syndrome) were observed only in 4 of the patients. Most patients exhibited no or mild toxicities. After a median follow-up of 14.8 months, ORR was 70.5%, CBR-77.3%, PFS-16.2 months, and TTF-14.4 months.
CONCLUSIONS: Metronomic oral capecitabine combined with AIs showed good efficacy, minimal toxicities, and good tolerance in HR-positive patients with ABC. It is a potential treatment option especially for postmenopausal HR-positive ABC patients in poor general condition who cannot tolerate conventional chemotherapy.
TRIAL REGISTRATION: Clinicaltrials.gov NCT01924078.

Stavrev P, Stavreva N, Penev D, et al.
Investigation of the effect of natural tumor cell death on radiotherapy outcomes.
Phys Med Biol. 2018; 63(20):205001 [PubMed] Related Publications
The aim of the work is to investigate the impact of radiation-independent (natural or spontaneous) tumor cell death on tumor control probability (TCP) during and following fractionated external-beam radiotherapy employing both analytical and numerical methods. The analytical method solves a TCP model accounting for tumor repopulation and non-radiation tumor cell death during fractionated external-beam radiotherapy. The numerical method is based on a Monte Carlo simulation of the processes of radiation-induced cell kill, as well as cell division and natural cell death randomly taking place in the time interval between fractions. Distributions of the number of surviving cells are constructed using the Monte Carlo method for cases with and without natural cell death. The analytically and numerically calculated values of TCP were found to be in excellent agreement (as shown in the Method and materials section), thereby validating both methods. The TCP model is then fitted to two different experimental data sets with the aim of determining the model parameter values, primarily the natural death rate. Two versions of the linear-quadratic model of cell damage-with and without assumed re-sensitization of the tumor cells during treatment-are used. In two of the fits a strong correlation between the repopulation and spontaneous cell death rates is observed. It was possible to determine separately the values of the two rates only in the fit of the model with resensitization to the most diversified data set consisting of seven different fractionation regimes. The observed correlation together with a theoretical consideration leads to the conclusion that in most cases it is the net effect of the two processes of birth and death rather than the processes separately that determines treatment outcome. However, depending on the values of the rates of the two processes and the duration of the treatment, the treatment outcome may be more accurately determined by the absolute values of the two rates rather than just by their difference.

Uzunova KH, Filipova EP, Vekov TY
Bosutinib: Valuable therapeutic option for the Bulgarian market.
J Cancer Res Ther. 2018 Jul-Sep; 14(5):909-915 [PubMed] Related Publications
Aim of Study: This review aims to highlight that bosutinib represents a valuable alternative for patients already treated unsuccessfully with one or more other tyrosine kinase inhibitors (TKIs). Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm associated with a specific genetic abnormality resulting in a fusion protein with an active tyrosine kinase region. Therefore, TKIs were developed as a suitable treatment option.
Methods: Full-text articles, abstracts, and meta-analysis comparing the efficacy and safety of the five TKIs were included in the review. Efficacy of these enhanced therapies is estimated on the basis of achievement of a complete cytogenetic response (CCyR) and this outcome is an important goal as a surrogate marker for improved survival.
Results: Bosutinib's efficacy is comparable to that of imatinib in the first-line setting and with dasatinib and nilotinib as second-line therapy, while its safety profile is distinctly different. Most therapeutic guidelines for CML recommend an initiation of therapy with imatinib and application of dasatinib and nilotinib as subsequent lines.
Conclusion: Bosutinib is generally not recommended despite its demonstrated efficacy and manageable toxicity. However, resistance, intolerance, specific mutations, as well as disease progression are often the reasons for the lack of sufficient response to therapy registered by the lower rates or complete absence of CCyR. Treatment options are limited for these patients.

Groen JV, Sibinga Mulder BG, van Eycken E, et al.
Differences in Treatment and Outcome of Pancreatic Adenocarcinoma Stage I and II in the EURECCA Pancreas Consortium.
Ann Surg Oncol. 2018; 25(12):3492-3501 [PubMed] Related Publications
BACKGROUND: The EUropean REgistration of Cancer CAre (EURECCA) consortium aims to investigate differences in treatment and to improve cancer care through Europe. The purpose of this study was to compare neo- and adjuvant chemotherapy (ACT) and outcome after tumor resection for pancreatic adenocarcinoma stage I and II in the EURECCA Pancreas consortium.
METHODS: The eight, collaborating national, regional, and single-center partners shared their anonymized dataset. Patients diagnosed in 2012-2013 who underwent tumor resection for pancreatic adenocarcinoma stage I and II were investigated with respect to treatment and survival and compared using uni- and multivariable logistic and Cox regression analyses. All comparisons were performed separately per registry type: national, regional, and single-center registries.
RESULTS: In total, 2052 patients were included. Stage II was present in the majority of patients. The use of neo-ACT was limited in most registries (range 2.8-15.5%) and was only different between Belgium and The Netherlands after adjustment for potential confounders. The use of ACT was different between the registries (range 40.5-70.0%), even after adjustment for potential confounders. Ninety-day mortality was also different between the registries (range 0.9-13.6%). In multivariable analyses for overall survival, differences were observed between the national and regional registries. Furthermore, patients in ascending age groups and patients with stage II showed a significant worse overall survival.
CONCLUSIONS: This study provides a clear insight in clinical practice in the EURECCA Pancreas consortium. The differences observed in (neo-)ACT and outcome give us the chance to further investigate the best practices and improve outcome of pancreatic adenocarcinoma.

Pisano M, Zorcolo L, Merli C, et al.
2017 WSES guidelines on colon and rectal cancer emergencies: obstruction and perforation.
World J Emerg Surg. 2018; 13:36 [PubMed] Free Access to Full Article Related Publications

Stanilova S, Stanilov N, Julianov A, et al.
Transforming growth factor-β1 gene promoter -509C/T polymorphism in association with expression affects colorectal cancer development and depends on gender.
PLoS One. 2018; 13(8):e0201775 [PubMed] Free Access to Full Article Related Publications
It is widely known that sporadic colorectal cancer (CRC) is age-related diseases with higher incidence rate among men. Transforming growth factor-β1 (TGF-β1) is a major immune regulatory cytokine with a great impact and dual role in gastrointestinal carcinogenesis. In this context, the aim of the study was to explore the role of circulating TGF-β1 and the -509C/T functional promoter polymorphism (rs1800469) within the TGF-β1 gene (TGFB1) in the susceptibility, progression, and prognosis of CRC among Bulgarian male and female patients. Patients with sporadic CRC and healthy controls were genotyped by polymerase-chain reaction-restriction fragment length polymorphism. Serum TGF-β1 levels before and after curative surgery were determined by ELISA. Total RNA was extracted from paired tumor, normal mucosa and distant metastasis samples and was used for quantitative detection of TGFB1 mRNA by TaqMan qPCR.We observed that TGF-β1 serum levels depend on the -509C/T genotype in combination with gender. TGF-β1 serum levels in CRC patients were decreased compared to controls, but statistical significance was reached only for men. In the stratified analysis by gender and genotype, a significant association was found for the CC genotype. Overall, our results indicate that the -509C allele increased the cancer risk, particularly for advanced stages (OR = 1.477; p = 0.029). The results from the relative mRNA quantification showed a significant upregulation of TGFB1 in distant metastases compared to primary tumor tissues and higher TGFB1 mRNA levels in men (RQ = 4.959; p = 0.022). In conclusion, we present data that diminished circulating TGF-β1 due to the CC genotype could be a possible risk factor for tumor susceptibility and progression. This association is more pronounced in males than in females. Colorectal cancer tissue expression of TGFB1 gene mRNA correlates with tumor progression and metastasis.

Irimie AI, Braicu C, Cojocneanu R, et al.
Differential Effect of Smoking on Gene Expression in Head and Neck Cancer Patients.
Int J Environ Res Public Health. 2018; 15(7) [PubMed] Free Access to Full Article Related Publications
Smoking is a well-known behavior that has an important negative impact on human health, and is considered to be a significant factor related to the development and progression of head and neck squamous cell carcinomas (HNSCCs). Use of high-dimensional datasets to discern novel HNSCC driver genes related to smoking represents an important challenge. The Cancer Genome Atlas (TCGA) analysis was performed in three co-existing groups of HNSCC in order to assess whether gene expression landscape is affected by tobacco smoking, having quit, or non-smoking status. We identified a set of differentially expressed genes that discriminate between smokers and non-smokers or based on human papilloma virus (HPV)16 status, or the co-occurrence of these two exposome components in HNSCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways classification shows that most of the genes are specific to cellular metabolism, emphasizing metabolic detoxification pathways, metabolism of chemical carcinogenesis, or drug metabolism. In the case of HPV16-positive patients it has been demonstrated that the altered genes are related to cellular adhesion and inflammation. The correlation between smoking and the survival rate was not statistically significant. This emphasizes the importance of the complex environmental exposure and genetic factors in order to establish prevention assays and personalized care system for HNSCC, with the potential for being extended to other cancer types.

Hristova MG
Neuroendocrine and immune disequilibrium as a probable link between metabolic syndrome and carcinogenesis.
Med Hypotheses. 2018; 118:1-5 [PubMed] Related Publications
Numerous investigations prove a higher incidence of carcinogenesis in metabolic syndrome (MetS). They indicate the important role of obesity, elevated inflammatory biomarkers, hyperinsulinemia, hyperglycemia, and dyslipidemia as well. Elevated plasma insulin and free insulin-like growth factor-1 (IGF-1) levels stimulate cell proliferation. The present publication considers the role of neuroendocrine and immune disequilibrium in MetS as a reason for transition to carcinogenesis. It emphasizes the role of hormonal disbalance, i.e. hyperleptinemia, hyperinsulinemia, hypercortisolemia, hypercatecholaminemia, hyperestrogenemia and hyperandrogenemia in MetS. It is presumed that these important components modify cellular microenvironment towards carcinogenesis. The interactions between neurotrophins, leptin, and mast cells and the alterations in the hypothalamo-hypophyseal-adrenal axis in MetS are discussed. It is assumed that they are the consequence of inflammatory distress followed by hormonal and immune disbalance at a central level as well as of enlarged adipose tissue and changed adipocyte microenvironment leading, finally, to carcinogenesis.

Pashov A, Hernandez Puente CV, Ibrahim SM, et al.
Thinking Cancer.
Monoclon Antib Immunodiagn Immunother. 2018; 37(3):117-125 [PubMed] Related Publications
Evolutionary theories are necessarily invoked for understanding cancer development at the level of species, at the level of cells and tissues, and for developing effective therapies. It is crucial to view cancer in a Darwinian light, where the differential survival of individual cells is based on heritable variations. In the process of this somatic evolution, multicellularity controls are overridden by cancer cells, which become increasingly autonomous. Ecological epigenetics also helps understand how rogue cells that have basically the same DNA as their normal cell counterpart overcome the tissue homeostasis. As we struggle to wrap our minds around the complexity of these phenomena, we apply often times anthropomorphic terms, such as subversion, hijacking, or hacking, to describe especially the most complex among them-the interaction of tumors with the immune system. In this commentary we highlight examples of the anthropomorphic thinking of cancer and try to put into context the relative meaning of terms and the mechanisms that are oftentimes invoked to justify those terms.

Yancheva N, Strashimirov D, Hrischev V, et al.
Three cases of non-Hodgkin's lymphoma in HIV-infected Bulgarian patients.
Infez Med. 2018; 26(2):155-159 [PubMed] Related Publications
HIV-associated lymphoma was first classified as an AIDS-defining disease by the American Center for Disease Control and Prevention (CDC) in 1985. Non-Hodgkin's lymphomas (NHLs) are frequent malignancies in AIDS patients. The risk of NHL in the case of an underlying HIV infection is estimated to be 100 times greater than in the general population, and it increases with the progression of the retrovirus-related immunosuppression. Cases of HIV-related non-Hodgkin's lymphoma are widely documented in the literature. In this article we present three cases of NHL and HIV hospitalized over a period of three years (2013-2016) at our specialized department for AIDS patients. Two of them were initially diagnosed with NHL and then with HIV infection. In one patient, NHL developed despite the patient's taking background antiretroviral therapy. The first case was a 38-year-old male diagnosed previously with HIV, who developed a palpable mass in the left zygomatic bone. The second case was a 52-year-old male who was first diagnosed with a cutaneous lymphoma, and subsequently with HIV infection. The third patient was a 63-year-old male who presented with two palpable masses: one in the left part of the mandible, and the other in the right inguinal region, the latter subsequently diagnosed as lymphoma. Following the latter diagnosis, the patient tested positive for HIV. The histological findings of the three lymphomas were as follows: an NHL plasmoblastic lymphoma, a cutaneous large B-cell anaplastic lymphoma, and a diffuse large B-cell lymphoma. The first patient received antiretroviral therapy (ART) and EPOCH (etoposide, pharmarubicin, vincristin, endoxane, uromitexan) plus radiotherapy, while the second received ART and CHOEP (endoxan, epirubicin, vincristin, etoposide, prednisolone). The third patient died a few days after beginning antiretroviral therapy.

Glushkova M, Bojinova V, Koleva M, et al.
Molecular genetic diagnostics of tuberous sclerosis complex in Bulgaria: six novel mutations in the
J Genet. 2018; 97(2):419-427 [PubMed] Related Publications
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of hamartomas localized in various tissues which can occur in the skin, brain, kidney and other organs. TSC is caused by mutations in the

Sarafian VS, Koev I, Mehterov N, et al.
LAMP-1 gene is overexpressed in high grade glioma.
APMIS. 2018; 126(8):657-662 [PubMed] Related Publications
High-grade gliomas (HGG) are the most frequent brain tumors in adults. Glioblastoma multiforme (GBM) is their most aggressive form resistant to therapy. It was shown that inhibition of autophagy reduced GBM development and autophagy interfering agents are regarded as a new strategy to fight glioma cells. The lysosome-associated membrane proteins (LAMPs) display differential expression particularly in cancer. There are few data on their expression and especially on their molecular profile. The aim of the present study is to investigate the expression of LAMP-1 and LAMP-2 genes and proteins in HGG. Newly diagnosed patients with HGG and healthy controls were examined by immunohistochemistry and qPCR for both protein and mRNA levels of LAMP-1 and LAMP-2. The transcriptional activity of LAMP-1 in HGG was significantly higher compared to normal brain and to LAMP-2. The two glycoproteins were detected in the cytosol of tumor cells with varying intensity, LAMP-1 showing again enhanced expression. In conclusion, novel data on LAMP-1 overexpression in HGG are presented suggesting involvement of this gene and protein in cell adhesion and tumor progression. These findings might help the elucidation of the complex biological role of the multifunctional LAMPs proteins and to predict novel therapeutic targets in lysosomes.

Chobanova N, Ivanova K, Stojanovska Z, Atanasov T
Radiat Prot Dosimetry. 2018; 181(1):52-55 [PubMed] Related Publications
The indoor radon concentrations and lung cancer incidence in Eleshnitza village and Blagoevgrad district of Bulgaria were examined in the study reported here. The Eleshnitza was the second largest uranium mining and milling region of the country. The geometric mean of indoor radon concentration in Eleshnitza (465 Bq/m3) was higher than the geometric mean of Blagoevgrad district (78 Bq/m3). Retrospective analyses on lung cancer incidence, covering the period 1995-2012 have been shown the same trend. The results were suggestive of an existing relationship between the two variables. Possible effects attributable to age and gender on lung cancer incidence were examined and found to be significant.

Dadaev T, Saunders EJ, Newcombe PJ, et al.
Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.
Nat Commun. 2018; 9(1):2256 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Schumacher FR, Al Olama AA, Berndt SI, et al.
Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.
Nat Genet. 2018; 50(7):928-936 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10

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