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1.  Oral cavity and oropharyngeal squamous cell carcinoma in young adults: a review of the literature 
Radiology and Oncology  2014;48(1):1-10.
Head and neck squamous cell carcinoma (HNSCC) is a disease of middle-aged to elderly adults. However, an increased incidence of HNSCC in young people under 45 years of age has been reported recently. In the present review, we focused on the epidemiology and aetiology of HNSCC in adults under 45 years of age.
We reviewed literature related to HNSCC in adult patients less than 45 years of age and discussed current treatment options and prognosis.
HNSCC in young adults is associated with a higher incidence rate in nonsmokers, lower female-to-male ratio, a higher percentage of oral cavity and oropharynx tumours, and fewer second primary tumours. However, aside from traditional risk factors of tobacco and alcohol exposure, the causes of these cancers in young adults remain unclear. Agents that might contribute to risk include infection with high-risk human papillomavirus subtypes as well as genetic factors or immunodeficiency status. The expected increase in incidence and mortality of the young with HNSCC may become a major public health concern if current trends persist, particularly lifestyle habits that may contribute to this disease.
Given the younger age and potential long-term adverse sequelae of traditional HNSCC treatments, young adults should be treated on a case-by-case basis and post-therapy quality of life must be considered in any treatment-decision making process.
PMCID: PMC3908841  PMID: 24587773
head and neck cancer; squamous cell carcinoma; young adults; quality of life
2.  Pancreatic involvement in small cell lung cancer 
Radiology and Oncology  2014;48(1):11-19.
Few data are available concerning incidence, clinical picture, and prognosis for pancreatic metastases of small cell lung carcinoma. In this paper we review the related literature available in English language.
Although pancreatic metastases are generally asymptomatic, they can rarely produce clinical symptoms or functional abnormalities. The widespread use of multi-detector computerised tomography (CT) in contemporary medical practice has led to an increased detection of pancreatic metastases in oncology patients. Tissue diagnosis is imperative because radiological techniques alone are incapable of differentiating them from primary pancreatic tumours. Pancreatic metastases occur in the relative end stage of small cell lung cancer. The main complications of these lesions, although rare, are acute pancreatitis and obstructive jaundice. Early chemotherapy can provide a survival benefit even in patients with mild acute pancreatitis or extrahepatic biliary obstruction.
PMCID: PMC3908842  PMID: 24587774
lung neoplasms; carcinoma; small cell; neoplasm metastasis; pancreas
3.  Consequence of the introduction of routine FCH PET/CT imaging for patients with prostate cancer: a dual centre survey 
Radiology and Oncology  2014;48(1):20-28.
Fluorocholine(18F) (FCH) was introduced at the beginning of April 2010 in France, Slovenia and three other EU member states for the localisation of bone metastases of prostate cancer with PET. The aim of the study was to compare the evolution of diagnostic imaging in patients with prostate cancer using a new radiopharmaceutical FCH, observed in France and in Slovenia, and to quantify the consequence of the results of new imaging modality on the detection rate of abnormal metastases and recurrences of prostate cancer.
Patients and methods
In two centres (France/Slovenia), a survey of the number of nuclear medicine examinations in patients with prostate cancer was performed, covering 5 quarters of the year since the introduction of FCH. For each examination, the clinical and biological circumstances were recorded, as well as the detection of bone or soft tissue foci.
Six hundred and eighty-eight nuclear medicine examinations were performed impatients with prostate cancer. Nuclear medicine examinations were performed for therapy monitoring and follow-up in 23% of cases. The number of FCH PET/CT grew rapidly between the 1st and 5th period of the observation (+220%), while the number of bone scintigraphies (BS) and fluoride(18F) PET/CTs decreased (−42% and −23% respectively). Fluorodeoxyglucose(18F) (FDG) PET/CT remained limited to few cases of castrate-resistant or metastatic prostate cancer in Paris. The proportion of negative results was significantly lower with FCH PET/CT (14%) than with BS (49%) or fluoride(18F) PET/CT (54%). For bone metastases, the detection rate was similar, but FCH PET/CT was performed on average at lower prostate-specific antigen (PSA) levels and was less frequently doubtful (4% vs. 28% for BS). FCH PET/CT also showed foci in prostatic bed (53% of cases) or in soft tissue (35% of cases).
A rapid development of FCH PET/CT was observed in both centres and led to a higher detection rate of prostate cancer lesions.
PMCID: PMC3908843  PMID: 24587775
prostate cancer; PET/CT; fluorocholine (FCH); fluoride(18F); bone scintigraphy; indication of imaging
4.  The role of ultrasound and ultrasound-guided fine needle aspiration biopsy of lymph nodes in patients with skin tumours 
Radiology and Oncology  2014;48(1):29-34.
The primary aim of this study was to evaluate the diagnostic accuracy of ultrasound (US) in the study of superficial lymph nodes during the follow-up of patients surgically treated for skin tumours. The secondary objective was to compare positive cytological results with histological reports.
Patients and methods
From 2004 to 2011, 480 patients (male/female: 285/195; median age 57 years; prevalent skin tumour: melanoma) underwent US-guided fine-needle aspiration biopsy (FNAB) of suspicious recurrent lymph nodes. An expert radiologist first performed US testing of the lymph nodes, expressing either a negative or positive outcome of the test. Subsequently, US-guided FNAB was performed. FNAB positive patients were subjected to lymphadenectomy; the patients who tested negative underwent the follow-up.
The size of lymph nodes was ≤ 2 cm in 90% of cases. Out of the 336 (70%) US “positive” patients, 231 (68.8%) were FNAB positives. Out of the 144 (30%) US “negatives”, 132 (91.7%) were FNAB negatives. The sensitivity and specificity of the US were 95% and 55.7%, respectively; the negative predictive value was 91.7% and the positive predictive value was 68.8%. Definitive histological results confirmed FNAB positivity in 97.5% of lymphadenectomies.
US is a sensitive method in the evaluation of superficial lymph nodes during the follow-up of patients with skin tumours. High positive predictive value of cytology was confirmed.
PMCID: PMC3908844  PMID: 24587776
skin tumours; ultrasound; fine needle aspiration biopsy, follow-up
5.  Minimally invasive CT guided treatment of intraspinal synovial cyst 
Radiology and Oncology  2014;48(1):35-39.
Intraspinal synovial cysts of vertebral facet joints are uncommon cause of radicular pain as well as neurological deficits. They can be managed both conservatively and surgically.
Case report
A 77-year old polymorbid patient presented with bilateral low back pain which worsened during the course of time and did not respond to the conservative treatment. A diagnosis of intraspinal synovial cyst was made using the magnetic resonance imaging (MRI). Percutaneous computed tomography (CT) guided injection with installation of local anesthetic together with corticosteroid and rupture of the cyst was successfully used. A month after the procedure his pain improved, the usage of analgesics diminished and his over-all quality of life improved.
Percutaneous CT guided lumbar synovial cyst treatment is safe and reliable alternative to the surgical treatment in polymorbid patients with radiculopathy who are not able to tolerate general anesthesia and operation.
PMCID: PMC3908845  PMID: 24587777
intraspinal synovial cyst; polymorbid patient; radiculopathy; pain; percutaneous CT guided treatment
6.  Increased expression of SHP-1 is associated with local recurrence after radiotherapy in patients with nasopharyngeal carcinoma 
Radiology and Oncology  2014;48(1):40-49.
Nasopharyngeal carcinoma (NPC) is a major cancer in southern China. Src homology phosphatase-1 (SHP-1) is a tyrosine phosphatase that regulates growth, differentiation, cell cycle progression, and oncogenesis. We determined the clinical significance of SHP-1 expression in the tumours of NPC patients from southern China who were treated with radiotherapy.
Patients and methods.
SHP-1 expression was determined by real-time polymerase chain reaction (PCR) and western blotting of NPC tissue samples of 50 patients and nasopharyngeal tissues of 50 non-NPC patients who had chronic nasopharyngeal inflammation. SHP-1 expression was measured in NPC tissue samples of 206 patients by immunohistochemistry and survival analysis was performed.
The tumours of NPC patients had significantly increased expression of SHP-1 at mRNA and protein levels relative to patients with chronic nasopharyngeal inflammation. Survival analysis of NPC patients indicated that SHP-1 expression was significantly associated with poor local recurrence-free survival (p = 0.008), but not with nodal recurrence-free survival, distant metastasis-free survival, or overall survival.
SHP-1 appears to be associated with radiation resistance of NPC cells and can be considered as a candidate marker for prognosis and/or therapeutic target in patients with this type of cancer.
PMCID: PMC3908846  PMID: 24587778
SHP-1; nasopharyngeal carcinoma; real-time quantitative PCR; Western blotting; immunohistochemistry; radiation resistance
7.  Evaluation of undiagnosed solitary lung nodules according to the probability of malignancy in the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines 
Radiology and Oncology  2014;48(1):50-55.
This study retrospectively investigated the clinical significance of undiagnosed solitary lung nodules removed by surgical resection.
Patients and methods
We retrospectively collected data on the age, smoking, cancer history, nodule size, location and spiculation of 241 patients who had nodules measuring 7 mm to 30 mm and a final diagnosis established by histopathology. We compared the final diagnosis of each patient with the probability of malignancy (POM) which was proposed by the American College of Chest Physicians (ACCP) guidelines.
Of the 241 patients, 203 patients were diagnosed to have a malignant lung tumor, while 38 patients were diagnosed with benign disease. There were significant differences in the patients with malignant and benign disease in terms of their age, smoking history, nodule size and spiculation. The mean value and the standard deviation of the POM in patients with malignant tumors were 51.7 + 26.1%, and that of patients with benign lesions was 34.6 + 26.7%. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.67. The best cut-off value provided from the ROC curve was 22.6. When the cut-off value was set at 22.6, the sensitivity was 83%, specificity 52%, positive predictive value 90%, negative predictive value 36% and accuracy 77%, respectively.
The clinical prediction model proposed in the ACCP guidelines showed unsatisfactory results in terms of the differential diagnosis between malignant disease and benign disease of solitary lung nodules in our study, because the specificity, negative predictive value and AUC were relatively low.
PMCID: PMC3908847  PMID: 24587779
inflammatory lung nodule; undiagnosed lung nodule; surgical resection; non-small cell lung cancer; solitary pulmonary nodules; computed tomography
8.  Results of photon radiotherapy for unresectable salivary gland tumors: is neutron radiotherapy’s local control superior? 
Radiology and Oncology  2014;48(1):56-61.
The results of RTOG-MRC randomized trial of photon (n=15) versus neutron (n=17) therapy in the 1980’s reported an improved local control (LC) with neutron radiotherapy for unresectable salivary gland tumors. Due to increased severe toxicity with neutron radiotherapy and the paucity of neutron-therapy centers, we analyzed our institution’s results of photon radiotherapy for unresectable salivary gland tumors.
Patients and methods
From 1990 to 2009, 27 patients with unresectable salivary gland cancer underwent definitive photon radiotherapy at our institution. Nodal involvement on presentation was found in 9 patients. Median dose of radiotherapy was 70 Gy. Chemotherapy was given to 18 patients, most being platinum-based regimens. Local control (LC), locoregional control (LRC), distant metastasis-free survival (DMFS), overall survival (OS), and toxicity outcomes were assessed.
With a median follow-up of 52.4 months, the 2/5-year actuarial LC was 69% (95%CI ± 21.0%)/55% (± 24.2%), LRC was 65% (± 21.4%)/47% (± 21.6%), and DMFS was 71% (± 21.8%)/51% (± 22.8%), respectively using competing risk analysis. The median OS was 25.7 months, and the 2/5-year OS rates were 50% (± 19.0%)/29% (± 16.6%), respectively. Higher histologic grade was significant for an increased rate of DM (intermediate grade vs. low grade, p=0.04, HR 7.93; high grade vs. low grade, p=0.01, HR 13.50). Thirteen (48%) patient’s experienced acute grade 3 toxicity. Late grade 3 toxicity occurred in three (11%) patients.
Our data compares favorably to neutron radiotherapy with fewer late complications. Photon radiotherapy is an acceptable alternative to neutron radiotherapy in patients who present with unresectable salivary gland tumors.
PMCID: PMC3908848  PMID: 24587780
photon; neutron; radiotherapy; salivary gland cancer; IMRT
9.  Balloon aortic valvuloplasty (BAV) as a bridge to aortic valve replacement in cancer patients who require urgent non-cardiac surgery 
Radiology and Oncology  2014;48(1):62-66.
Balloon aortic valvuloplasty (BAV) is a percutaneous treatment option for severe, symptomatic aortic stenosis. Due to early restenosis and failure to improve long term survival, BAV is considered a palliative measure in patients who are not suitable for open heart surgery due to increased perioperative risk. BAV can be used also as a bridge to surgical or transcatheter aortic valve implantation (TAVI) in haemodinamically unstable patients or in patients who require urgent major non-cardiac surgery.
Patients and methods.
We reported on 6 oncologic patients with severe aortic stenosis that required a major abdominal and gynaecological surgery. In 5 cases we performed BAV procedure alone; in one patient with concomitant coronary artery disease we combined BAV and percutaneous coronary intervention (PCI).
With angioplasty and BAV we achieved a good coronary artery flow and an increase in aortic valve area without any periprocedural complications. After the successful procedure, we observed a hemodynamic and symptomatic improvement. As a consequence the operative risk for non-cardiac surgery decreased and the surgical treatment of cancer was done without complications in all the 6 cases.
BAV can be utilized as a part of a complex therapy in severe aortic stenosis aimed to improve the quality of life, decrease the surgical risk for major non-cardiac surgery or as a bridge to surgical or transcatheter aortic valve implantation.
PMCID: PMC3908849  PMID: 24587781
aortic valve stenosis; balloon dilatation; angioplasty; heart valve prosthesis implantation; elderly; comorbidities; coronary artery disease
10.  Semirigid thoracoscopy: an effective method for diagnosing pleural malignancies 
Radiology and Oncology  2014;48(1):67-71.
Thoracoscopy with a semirigid instrument is a recent technique for diagnosing pleural diseases. The purpose of this study was to report diagnostic yield and complications of the method.
Patients and methods.
Patients with pleural effusion of unknown origin and/or pleural irregularities suspicious for pleural malignancy were included after less invasive means of diagnosis had failed. All procedures were performed under local anaesthesia with intravenous sedation/analgesia with a single point of entry with a semirigid thoracoscope (Olympus LTF-160). Data were collected prospectively between 2008 and 2012.
One hundred fifteen thoracoscopies were performed on 111 patients. The median age was 65 years (range 28–86 years), 14.4% were female and 85.6% male. Seventy-three (65.8%) patients had malignant pleural disease (malignant mesothelioma, metastatic cancer) and 38 (34.2%) had benign disease. The sensitivity, negative predictive value, and accuracy of the procedure for malignancy were 96.0%, 93.0%, and 97.4% respectively. Pleurodesis was carried out in 34 patients; in 32 (94.1%) it was assessed as successful after 1 month. There were 24 adverse events: three empyemas/pleural infections, three bronchopleural fistulae after chest tube placement and lung re-expansion, five patients had excessive pain after pleurodesis, six patients had sedation-associated hypotension, and seven patients had self-limited fever after plerodesis. One patient died 11 days after a procedure for advanced carcinoma.
Semirigid thoracoscopy is an accurate and safe method for evaluation of pleural diseases and useful for therapeutic talc pleurodesis.
PMCID: PMC3908850  PMID: 24587782
flex-rigid pleuroscopy; pleural biopsy; pleural effusion; safety; thoracoscopy
11.  Glioblastoma patients in Slovenia from 1997 to 2008 
Radiology and Oncology  2014;48(1):72-79.
Glioblastoma is the most common primary brain tumour. It has a poor prognosis despite some advances in treatment that have been achieved over the last ten years. In Slovenia, 50 to 60 glioblastoma patients are diagnosed each year. In order to establish whether the current treatment options have any influence on the survival of the Slovenian glioblastoma patients, their data in the period from the beginning of the year 1997 to the end of the year 2008 have been analysed.
Patients and methods
All patients treated at the Institute of Oncology Ljubljana from 1997 to 2008 were included in the retrospective study. Demographics, treatment details, and survival time after the diagnosis were collected and statistically analysed for the group as a whole and for subgroups.
From 1997 to 2008, 527 adult patients were diagnosed with glioblastoma and referred to the Institute of Oncology for further treatment. Their median age was 59 years (from 20 to 85) and all but one had the diagnosis confirmed by a pathologist. Gross total resection was reported by surgeons in 261 (49.5%) patients; good functional status (WHO 0 or 1) after surgery was observed in 336 (63.7%) patients, radiotherapy was performed in 422 (80.1%) patients, in 317 (75.1%) of them with radical intent, and 198 (62.5 %) of those received some form of systemic treatment (usually temozolomide). The median survival of all patients amounted to 9.7 months. There was no difference in median survival of all patients or of all treated patients before or after the chemo-radiotherapy era. However, the overall survival of patients treated with radical intent was significantly better (11.4 months; p < 0.05). A better survival was also noticed in radically treated patients who received additional temozolomide therapy (11.4 vs. 13.1 months; p = 0.014). The longer survival was associated with a younger age and a good performance status as well as with a more extensive tumour resection. In patients treated with radical intent, having a good performance status, and receiving radiotherapy and additional temozolomide therapy, the survival was significantly longer, based on multivariate analysis.
We observed a gradual increase in the survival of glioblastoma patients who were treated with radical intent over the last ten years. Good functional surgery, advances in radiotherapy and addition of temozolomide all contributed to this increase. Though the increased survival seems to be more pronounced in certain subgroups, we have still not been able to exactly define them. Further research, especially in tumour biology and genetics is needed.
PMCID: PMC3908851  PMID: 24587783
glioblastoma; treatment; survival; surgery; radiotherapy; temozolomide
12.  Individual radiosensitivity in a breast cancer collective is changed with the patients’ age 
Radiology and Oncology  2014;48(1):80-86.
Individual radiosensitivity has a crucial impact on radiotherapy related side effects. Our aim was to study a breast cancer collective for its variation of individual radiosensitivity depending on the patients’ age.
Materials and methods
Peripheral blood samples were obtained from 129 individuals. Individual radiosensitivity in 67 breast cancer patients and 62 healthy individuals was estimated by 3-color fluorescence in situ hybridization.
Breast cancer patients were distinctly more radiosensitive compared to healthy controls. A subgroup of 9 rather radiosensitive and 9 rather radio-resistant patients was identified. A subgroup of patients aged between 40 and 50 was distinctly more radiosensitive than younger or older patients.
In the breast cancer collective a distinct resistant and sensitive subgroup is identified, which could be subject for treatment adjustment. Preliminary results indicate that especially in the range of age 40 to 50 patients with an increased radiosensitivity are more frequent and may have an increased risk to suffer from therapy related side effects.
PMCID: PMC3908852  PMID: 24587784
individual radiosensitivity; chromosomal aberrations; age; fluorescence in situ hybridization; radiotherapy; breast cancer
13.  Evaluation of a software system for estimating planned dose error in patients, based on planar IMRT QA measurements 
Radiology and Oncology  2014;48(1):87-93.
Intensity modulated radiation therapy (IMRT) dosimetry verification is routinely conducted via integrated or individual field dosimetry using film or a matrix of detectors. Techniques and software systems are commercially available which use individual field dosimetry measurements as input into algorithms that estimate 3D patient dose distributions on CT scan derived target volumes and organs at risk (OARs), thus allowing direct dose-volume histogram (DVH) analysis vs. treatment planning system (TPS) DVH. The purpose of this work is to present a systematic benchmarking technique to evaluate the accuracy and consistency of such a software system.
A MapCheck2 diode array and 3DVH™ software from Sun Nuclear were used for this study. Delivered planar dose was measured with the diode array as an input to 3DVH™ software that was used to estimate the 3D dose matrix. Accuracy of the output of 3DVH™ is tested by comparing measured planar doses over a range of depths to the same planes reconstructed by 3DVH™. Different fields from complex IMRT cases were selected and examined in this study. The sensitivity to depth of measurement was evaluated.
The Gamma Index analysis, comparing calculated 3D dose with measured 3D dose with 2% and 2mm distance-to-agreement (DTA) criteria returned a pass rate of > 90% for all patient cases calculated by the treatment planning system and it returned a pass rate of > 96% in 9 out of 10 cases calculated by 3DVH™. Extracted computed dose planes with 3DVH™ software at different depths in the flat phantom passed all gamma evaluation analyses when compared to measured planes at different depths using MapCheck2.
Studying complex head and neck IMRT fields, it was shown that the 3D dose distribution predicted by the planned dose perturbation (PDP) algorithm is both accurate and consistent.
PMCID: PMC3908853  PMID: 24587785
intensity modulated radiation therapy; quality assurance; 3D dosimetry; planar dosimetry; MapCheck; 3 dose-volume histogram
14.  Impact of respiratory motion on breast tangential radiotherapy using the field-in-field technique compared to irradiation using physical wedges 
Radiology and Oncology  2014;48(1):94-98.
This study aimed to evaluate whether the field-in-field (FIF) technique was more vulnerable to the impact of respiratory motion than irradiation using physical wedges (PWs).
Patients and methods
Ten patients with early stage breast cancer were enrolled. Computed tomography (CT) was performed during free breathing (FB). After the FB-CT data set acquisition, 2 additional CT scans were obtained during a held breath after light inhalation (IN) and light exhalation (EX). Based on the FB-CT images, 2 different treatment plans were created for the entire breast for each patient and copied to the IN-CT and EX-CT images. The amount of change in the volume of the target receiving 107%, 95%, and 90% of the prescription dose (V107%, V95%, and V90%, respectively), on the IN-plan and EX-plan compared with the FB-plan were evaluated.
The V107%, V95%, and V90% were significantly larger for the IN-plan than for the FB-plan in both the FIF technique and PW technique. While the amount of change in the V107% was significantly smaller in the FIF than in the PW plan, the amount of change in the V95% and V90% was significantly larger in the FIF plan. Thus, the increase in the V107% was smaller while the increases in the V95% and V90% were larger in the FIF than in the PW plan.
During respiratory motion, the dose parameters stay within acceptable range irrespective of irradiation technique used although the amount of change in dose parameters was smaller with FIF technique.
PMCID: PMC3908854  PMID: 24587786
breast cancer; radiotherapy; field-in-field technique; respiratory motion
15.  MicroRNAs and long non-coding RNAs: prospects in diagnostics and therapy of cancer 
Radiology and Oncology  2013;47(4):311-318.
Non-coding RNAs (ncRNAs) are key regulatory molecules in cellular processes, and are potential biomarkers in many diseases. Currently, microRNAs and long non-coding RNAs are being pursued as diagnostic and prognostic biomarkers, and as therapeutic tools in cancer, since their expression profiling is able to distinguish different cancer types and classify their sub-types.
There are numerous studies confirming involvement of ncRNAs in cancer initiation, development and progression, but have only been recently identified as new diagnostic and prognostic tools. This can be beneficial in future medical cancer treatment options, since ncRNAs are natural antisense interactors included in regulation of many genes connected to survival and proliferation. Research is directed in development of useful markers for diagnosis and prognosis in cancer and in developing new RNA-based cancer therapies, of which some are already in clinical trials.
PMCID: PMC3814275  PMID: 24294175
microRNAs; long non-coding RNAs; diagnosis; therapy; biomarker
16.  Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies 
Radiology and Oncology  2013;47(4):319-329.
Tumor tissue-associated KLKs (kallikrein-related peptidases) are clinically important biomarkers that may allow prognosis of the cancer disease and/or prediction of response/failure of cancer patients to cancer-directed drugs. Regarding the female/male reproductive tract, remarkably, all of the fifteen KLKs are expressed in the normal prostate, breast, cervix uteri, and the testis, whereas the uterus/endometrium and the ovary are expressing a limited number of KLKs only.
Most of the information regarding elevated expression of KLKs in tumor-affected organs is available for ovarian cancer; depicting them as valuable biomarkers in the cancerous phenotype. In contrast, for breast cancer, a series of KLKs was found to be downregulated. However, in breast cancer, KLK4 is elevated which is also true for ovarian and prostate cancer. In such cases, selective synthetic KLK inhibitors that aim at blocking the proteolytic activities of certain KLKs may serve as future candidate therapeutic drugs to interfere with tumor progression and metastasis.
PMCID: PMC3814276  PMID: 24294176
cancer, proteases; endometrium; ovary; uterus; prostate; testis; cervix; breast
17.  Expansive growth of two glioblastoma stem-like cell lines is mediated by bFGF and not by EGF 
Radiology and Oncology  2013;47(4):330-337.
Patient-derived glioblastoma (GBM) stem-like cells (GSCs) represent a valuable model for basic and therapeutic research. GSCs are usually propagated in serum-free Neural Basal medium supplemented with bFGF and EGF. Yet, the exact influence of these growth factors on GSCs is still unclear. Recently it was suggested that GBM stem-like cells with amplified EGFR should be cultured in stem cell medium without EGF, as the presence of EGF induced rapid loss of EGFR amplification. However, patient biopsies are usually taken into culture before their genomic profiles are defined. Thus, an important question remains whether GBM cells without EGFR amplification also can be cultured in stem cell medium without EGF.
Meterials and methods
To address this question, we used two heterogeneous glioblastoma GSC lines (NCH421k and NCH644) that lack EGFR amplification.
Although both cell lines showed very low EGFR expression under standard growth conditions, bFGF stimulation induced higher expression of EGFR in NCH644. In both cell lines, expression of the stem cell markers nestin and CD133 was higher upon stimulation with bFGF compared to EGF. Importantly, bFGF stimulated the growth of both cell lines, whereas EGF had no effect. We verified that the growth stimulation by bFGF was either mediated by proliferation (NCH421k) or resistance to apoptosis (NCH644).
We demonstrate that GSC cultures without EGFR amplification can be maintained and expanded with bFGF, while the addition of EGF has no significant effect and therefore can be omitted.
PMCID: PMC3814277  PMID: 24294177
glioblastoma; bFGF; EGF; EGFR; stem cell cultures
18.  Heterogeneity of uroplakin localization in human normal urothelium, papilloma and papillary carcinoma 
Radiology and Oncology  2013;47(4):338-345.
Uroplakins are differentiation-related membrane proteins of urothelium. We compared uroplakin expression and ultrastructural localization in human normal urothelium, papilloma and papillary carcinoma. Because of high recurrence rate of these tumours, treated by transurethral resection, we investigated urothelial tumour, resection border and uninvolved urothelium.
Patients and methods
Urinary bladder samples were obtained from tumour free control subjects and patients with papilloma and papillary carcinoma. Immunohistochemical and immunoelectron labelling of uroplakins were performed.
In normal human urothelium with continuous uroplakin-positive superficial cell layer uroplakins were localized to flattened mature fusiform vesicles and apical plasma membrane of umbrella cells. Diverse uroplakin expression was found in papilloma and papillary carcinoma. Three aberrant differentiation stages of urothelial cells, not found in normal urothelium, were recognized in tumours. Diverse uroplakin expression and aberrant differentiation were occasionally found in resection border and in uninvolved urothelium.
We demonstrated here that uroplakin expression and localization in urothelial tumours is altered when compared to normal urothelium. In patients with papilloma and papillary carcinoma immunolabelling of uroplakins at ultrastructural level shows aberrant urothelial differentiation. It is possible that aberrant differentiation stages of urothelial cells in resection border and in uninvolved urothelium contribute to high recurrence rate.
PMCID: PMC3814278  PMID: 24294178
human urothelium; papilloma; papillary carcinoma; uroplakins; immunoelectron microscopy; immunohistochemistry
19.  Biological evaluation of transdichloridoplatinum(II) complexes with 3- and 4-acetylpyridine in comparison to cisplatin 
Radiology and Oncology  2013;47(4):346-357.
In our previous study we reported the synthesis and cytotoxicity of two trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] (1) and trans-[PtCl2(4-acetylpyridine)2] (2), revealing significant cytotoxic potential of 2. In order to evaluate the mechanism underlying biological activity of both trans-Pt(II) isomers, comparative studies versus cisplatin were performed in HeLa, MRC-5 and MS1 cells.
Materials and methods.
The cytotoxic activity of the investigated complexes was determined using SRB assay. The colagenolytic activity was determined using gelatin zymography, while the effect of platinum complexes on matrix metalloproteinases 2 and 9 mRNA expression was evaluated by quantitative real-time PCR. Apoptotic potential and cell cycle alterations were determined by FACS analyses. Western blot analysis was used to evaluate the effect on expression of DNA-repair enzyme ERCC1, and quantitative real-time PCR was used for the ERCC1 mRNA expression analysis. In vitro antiangiogenic potential was determined by tube formation assay. Platinum content in intracellular DNA and proteins was determined by inductively coupled plasma-optical emission spectrometry.
Compound 2 displayed an apparent cytoselective profile, and flow cytometry analysis in HeLa cells indicated that 2 exerted antiproliferative effect through apoptosis induction, while 1 induced both apoptosis and necrosis. Action of 1 and 2, as analyzed by quantitative real-time PCR and Western blot, was associated with down-regulation of ERCC1. Both trans-complexes inhibited MMP-9 mRNA expression in HeLa, while 2 significantly abrogated in vitro tubulogenesis in MS1 cells.
The ability of 2 to induce multiple and selective in vitro cytotoxic effects encourages further investigations of trans-platinum(II) complexes with substituted pyridines.
PMCID: PMC3814279  PMID: 24294179
angiogenesis; apoptosis; MMPs; MRC-5; trans-platinum(II)
20.  Dual time point imaging fluorine-18 flourodeoxyglucose positron emission tomography for evaluation of large loco-regional recurrences of breast cancer treated with electrochemotherapy 
Radiology and Oncology  2013;47(4):358-365.
Electrochemotherapy is a local anticancer treatment very efficient for treatment of small cutaneous metastases. The method is now being investigated for large cutaneous recurrences of breast cancer that are often confluent masses of malignant tumour with various degrees of inflammation. To this end 18-Flourine-Flourodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) could be a method for response evaluation. However, a standard FDG-PET/CT scan cannot differentiate inflammatory tissue from malignant tissue. Dual point time imaging (DTPI) FDG-PET has the potential of doing so. The purpose of this study was to investigate if DTPI FDG-PET/CT could assess response to electrochemotherapy and to assess the optimal timing of imaging.
Patients and methods
Within a phase II clinical trial 11 patients with cutaneous recurrences had FDG-PET/CT scans at three time points: 60 min, 120 min and 180 min after FDG injection. The scans were performed before and 3 weeks after electrochemotherapy.
A significant reduction in maximum standard uptake value at 60 min post injection was seen after treatment. Furthermore a change in the FDG uptake pattern was observed; from increasing uptake in up to 180 min post injection before treatment to stabilization of FDG uptake at 120 min post injection after treatment. The change in FDG uptake pattern over time lead to change of response in three target lesions; two lesions changed from stable metabolic disease to partial metabolic response and one lesion changed from partial metabolic response to stable metabolic disease. To ensure detection of the change in uptake pattern, scanning 60 and 180 min post injection seems optimal.
The present study shows that FDG-PET/CT 60 and 180 min after tracer injection is a promising tool for response evaluation of cutaneous recurrences of breast cancer treated with electrochemotherapy.
PMCID: PMC3814280  PMID: 24294180
dual time point FDG PET; breast cancer; electrochemotherapy; response assessment; cutaneous metastases
21.  Electrochemotherapy as a new therapeutic strategy in advanced Merkel cell carcinoma of head and neck region 
Radiology and Oncology  2013;47(4):366-369.
Merkel Cell Carcinoma (MCC) is a rare and aggressive tumour, arising from a cutaneous mechanoceptor cell located in the basal layer of epidermis, with poor prognosis. The treatment of choice for the initial stage of the disease is surgery and/or radiotherapy. The treatment of recurrent or advanced disease is still controversial.
Case report
We report a case of 84 years old woman with a recurrent MCC of the chin treated with electrochemotherapy (ECT). During the period of 20 months, four sessions of ECT were employed, which resulted in an objective response of the tumour and good quality of residual life.
Our case shows the effectiveness of ECT in the treatment of locally advanced MCC of the head and neck region in a patient not suitable for standard therapeutic options.
PMCID: PMC3814281  PMID: 24294181
electrochemotherapy; head and neck cancer; Merkel cell carcinoma; palliative treatment
22.  Minimally invasive treatment of peristomal metastases from gastric cancer at an ileostomy site by electrochemotherapy 
Radiology and Oncology  2013;47(4):370-375.
Peristomal metastases are rare, but potentially associated with relevant morbidity. Surgical resection, followed by stoma relocation, represent the gold standard in most patients. We describe electrochemotherapy (ECT), a minimally invasive method for locally-enhancing drug delivery by means of electric pulses, as an alternative approach.
Patient and methods
A 49-year-old man with advanced gastric cancer developed skin metastases around an ileostomy site. The ulcerated and oozing tumor growth impaired patient’s quality of life due to continuous trouble in fitting the ostomy appliance, its poor adherence and consequent stools spillage. ECT consisted of a 20-minute course under mild general sedation. A bleomycin bolus of 15 000 IU/m2 was followed by the percutaneous application of multiple, 1.5 ms -long electric pulses by means of a needle electrode.
Post ECT course was uneventful and the patient was discharged on the same day. After one week, tumor nodules were flattened and partial tumor regression was appreciable at one-month follow-up. More importantly, peristomal skin conditions significantly improved, thus allowing for an effective application of the ostomy appliance during the following moths, until patient’s death.
This report suggests the feasibility of ECT as a minimally invasive approach for peristomal tumors. In selected cases, ECT, by achieving a rapid tumor control, may ensure effective ostomy management and preserve patients’ quality of life.
PMCID: PMC3814282  PMID: 24294182
stomach neoplasms; ileostomy; electrochemotherapy; skin care; palliative care
23.  Effect of ionizing radiation on human skeletal muscle precursor cells 
Radiology and Oncology  2013;47(4):376-381.
Long term effects of different doses of ionizing radiation on human skeletal muscle myoblast proliferation, cytokine signalling and stress response capacity were studied in primary cell cultures.
Materials and methods
Human skeletal muscle myoblasts obtained from muscle biopsies were cultured and irradiated with a Darpac 2000 X-ray unit at doses of 4, 6 and 8 Gy. Acute effects of radiation were studied by interleukin – 6 (IL-6) release and stress response detected by the heat shock protein (HSP) level, while long term effects were followed by proliferation capacity and cell death.
Compared with non-irradiated control and cells treated with inhibitor of cell proliferation Ara C, myoblast proliferation decreased 72 h post-irradiation, this effect was more pronounced with increasing doses. Post-irradiation myoblast survival determined by measurement of released LDH enzyme activity revealed increased activity after exposure to irradiation. The acute response of myoblasts to lower doses of irradiation (4 and 6 Gy) was decreased secretion of constitutive IL-6. Higher doses of irradiation triggered a stress response in myoblasts, determined by increased levels of stress markers (HSPs 27 and 70).
Our results show that myoblasts are sensitive to irradiation in terms of their proliferation capacity and capacity to secret IL-6. Since myoblast proliferation and differentiation are a key stage in muscle regeneration, this effect of irradiation needs to be taken in account, particularly in certain clinical conditions.
PMCID: PMC3814283  PMID: 24294183
myoblasts; irradiation; proliferation; interleukin 6; muscle regeneration; apoptosis
24.  Recombinant human erythropoietin alters gene expression and stimulates proliferation of MCF-7 breast cancer cells 
Radiology and Oncology  2013;47(4):382-389.
Functional erythropoietin (EPO) signaling is not specific only to erythroid lineages and has been confirmed in several solid tumors, including breast. Three different isoforms of erythropoietin receptor (EPOR) have been reported, the soluble (EPOR-S) and truncated (EPOR-T) forms acting antagonistically to the functional EPOR. In this study, we investigated the effect of human recombinant erythropoietin (rHuEPO) on cell proliferation, early gene response and the expression of EPOR isoforms in the MCF-7 breast cancer cell line.
Materials and methods
The MCF-7 cells were cultured with or without rHuEPO for 72 h or 10 weeks and assessed for their growth characteristics, expression of early response genes and different EPOR isoforms. The expression profile of EPOR and EPOR-T was determined in a range of breast cancer cell lines and compared with their invasive properties.
MCF-7 cell proliferation after rHuEPO treatment was dependent on the time of treatment and the concentration used. High rHuEPO concentrations (40 U/ml) stimulated cell proliferation independently of a preceding long-term exposure of MCF-7 cells to rHuEPO, while lower concentrations increased MCF-7 proliferation only after 10 weeks of treatment. Gene expression analysis showed activation of EGR1 and FOS, confirming the functionality of EPOR. rHuEPO treatment also slightly increased the expression of the functional EPOR isoform, which, however, persisted throughout the 10 weeks of treatment. The expression levels of EPOR-T were not influenced. There were no correlations between EPOR expression and the invasiveness of MCF-7, MDA-MB-231, Hs578T, Hs578Bst, SKBR3, T-47D and MCF-10A cell lines.
rHuEPO modulates MCF-7 cell proliferation in time- and concentration-dependent manner. We confirmed EGR1, FOS and EPOR as transcription targets of the EPO-EPOR signaling loop, but could not correlate the expression of different EPOR isoforms with the invasiveness of breast cancer cell lines.
PMCID: PMC3814284  PMID: 24294184
breast cancer; erythropoietin; erythropoietin receptor isoforms; proliferation; gene expression
25.  The usefulness of F-18 FDG PET/CT-mammography for preoperative staging of breast cancer: comparison with conventional PET/CT and MR-mammography 
Radiology and Oncology  2013;47(4):390-397.
The objective of the study was to compare the diagnostic efficacy of an integrated Fluorine-18 fluorodeoxyglucose (F-18 FDG) PET/CT-mammography (mammo-PET/CT) with conventional torso PET/CT (supine-PET/CT) and MR-mammography for initial assessment of breast cancer patients.
Patients and methods
Forty women (52.0 ± 12.0 years) with breast cancer who underwent supine-PET/CT, mammo-PET/CT, and MR-mammography from April 2009 to August 2009 were enrolled in the study. We compared the size of the tumour, tumour to chest wall distance, tumour to skin distance, volume of axillary fossa, and number of meta-static axillary lymph nodes between supine-PET/CT and mammo-PET/CT. Next, we assessed the difference of focality of primary breast tumour and tumour size in mammo-PET/CT and MR-mammography. Histopathologic findings served as the standard of reference.
In the comparison between supine-PET/CT and mammo-PET/CT, significant differences were found in the tumour size (supine-PET/CT: 1.3 ± 0.6 cm, mammo-PET/CT: 1.5 ± 0.6 cm, p < 0.001), tumour to thoracic wall distance (1.8 ± 0.9 cm, 2.2 ± 2.1 cm, p < 0.001), and tumour to skin distance (1.5 ± 0.8 cm, 2.1 ± 1.4 cm, p < 0.001). The volume of axillary fossa was significantly wider in mammo-PET/CT than supine-PET/CT (21.7 ± 8.7 cm3 vs. 23.4 ± 10.4 cm3, p = 0.03). Mammo-PET/CT provided more correct definition of the T-stage of the primary tumour than did supine-PET/CT (72.5% vs. 67.5%). No significant difference was found in the number of metastatic axillary lymph nodes. Compared with MR-mammography, mammo-PET/CT provided more correct classification of the focality of lesion than did MR-mammography (95% vs. 90%). In the T-stage, 72.5% of cases with mammo-PET/CT and 70% of cases with MR-mammography showed correspondence with pathologic results.
Mammo-PET/CT provided more correct definition of the T-stage and evaluation of axillary fossa may also be delineated more clearly than with supine-PET/CT. The initial assessment of mammo-PET/CT would be more useful than MR-mammography because the mammo-PET/CT indicates similar accuracy with MR-mammography for decision of T-stage of primary breast tumour and more correct than MR-mammography for defining focality of lesion.
PMCID: PMC3814285  PMID: 24294185
breast cancer; fluorodeoxyglucose; positron emission tomography; MRI; mammography

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