Volume 49 (2015): Edizione 1 (March 2015)

Background. PET-CT is becoming more and more important in various aspects of oncology. Until recently it was used mainly as part of diagnostic procedures and for evaluation of treatment results. With development of personalized radiotherapy, volumetric and radiobiological characteristics of individual tumour have become integrated in the multistep radiotherapy (RT) planning process. Standard anatomical imaging used to select and delineate RT target volumes can be enriched by the information on tumour biology gained by PET-CT. In this review we explore the current and possible future role of PET-CT in radiotherapy treatment planning. After general explanation, we assess its role in radiotherapy of those solid tumours for which PET-CT is being used most.

Conclusions. In the nearby future PET-CT will be an integral part of the most radiotherapy treatment planning procedures in an every-day clinical practice. Apart from a clear role in radiation planning of lung cancer, with forthcoming clinical trials, we will get more evidence of the optimal use of PET-CT in radiotherapy planning of other solid tumours

Background. Whole-body magnetic resonance imaging (WB-MRI) and angiography (WB-MRA) has become increasingly popular in population-based research. We evaluated retrospectively the frequency of potentially relevant incidental findings throughout the body.

Materials and methods. 22 highly health-conscious managers (18 men, mean age 47±9 years) underwent WBMRI and WB-MRA between March 2012 and September 2013 on a Discovery MR750w wide bore 3 Tesla device (GE Healthcare) using T1 weighted, short tau inversion recovery (STIR) and diffusion weighted imaging (DWI) acquisitions according to a standardized protocol.

Results. A suspicious (pararectal) malignancy was detected in one patient which was confirmed by an endorectal sonography. Incidental findings were described in 20 subjects, including hydrocele (11 patients), benign bony lesion (7 patients) and non-specific lymph nodes (5 patients). Further investigations were recommended in 68% (ultrasound: 36%, computed tomography: 28%, mammography: 9%, additional MRI: 9%). WB-MRA were negative in 16 subjects. Vascular normal variations were reported in 23%, and a 40% left proximal common carotid artery stenosis were described in one subject.

Conclusions. WB-MRI and MRA lead to the detection of clinically relevant diseases and unexpected findings in a cohort of healthy adults that require further imaging or surveillance in 68%. WB-MR imaging may play a paramount role in health screening, especially in the future generation of (epi)genetic based screening of malignant and atherosclerotic disorders. Our study is the first which involved a highly selected patient group using a high field 3-T wide bore magnet system with T1, STIR, MRA and whole-body DWI acquisitions as well.

Background. Cetuximab, a monoclonal antibody targeting the Epidermal Growth Factor Receptor (EGFR), has demonstrated activity in various tumor types. Using dynamic contrast-enhanced computed tomography (DCE-CT), we investigated the early activity of cetuximab monotherapy in previously untreated patients with squamous cell carcinoma of the head and neck (SCCHN).

Methods. Treatment-naïve patients with SCCHN received cetuximab for 2 weeks before curative surgery. Treatment activity was evaluated by DCE-CT at baseline and before surgery. Tumor vascular and interstitial characteristics were evaluated using the Brix two-compartment kinetic model. Modifications of the perfusion parameters (blood flow F_p, extravascular space v_e, vascular space v_p, and transfer constant PS) were assessed between both time points. DCE data were compared to FDG-PET and histopathological examination obtained simultaneously. Plasmatic vascular markers were investigated at different time points.

Results. Fourteen patients had evaluable DCE-CT parameters at both time points. A significant increase in the extravascular extracellular space v_e accessible to the tracer was observed but no significant differences were found for the other kinetic parameters (F_p, v_p or PS). Significant correlations were found between DCE parameters and the other two modalities. Plasmatic VEGF, PDGF-BB and IL-8 decreased as early as 2 hours after cetuximab infusion.

Conclusions. Early activity of cetuximab on tumor interstitial characteristics was detected by DCE-CT. Modifications of plasmatic vascular markers are not sufficient to confirm anti-angiogenic cetuximab activity in vivo. Further investigation is warranted to determine to what extent DCE-CT parameters are modified and to evaluate whether they are able to predict treatment outcome.

Background. Hürthle cell neoplasms could be benign (Hürthle cell adenoma) or malignant (Hürthle cell carcinoma). Hürthle cell carcinoma is a rare tumour, representing 5% of all differentiated thyroid carcinomas. The cytological evaluation of Hürthle cell neoplasms by fine needle aspiration biopsy (FNAB) is complicated because of the presence of Hürthle cells in both Hürthle cell adenoma and Hürthle cell carcinoma. Thus, the preoperative distinction between these two entities is very difficult and possible only with pathohistological findings of the removed tumour.

Case report. A 57-year old female patient was admitted at our Department, for investigation of nodular thyroid gland. She was euthyroid and FNAB of the nodules in both thyroid lobes were consistent of Hürthle cell adenoma with cellular atypias. After thyroidectomy the histopathology revealed Hürthle cell adenoma with high cellular content and discrete cellular atypias in the left lobe and follicular thyroid adenoma without cellular atypias in the right lobe. One year after substitution therapy, a palpable tumour on the left side of the remnant tissue was found, significantly growing with time, presented as hot nodule on ^99mTc-sestamibi scan and conclusive with Hürthle cell adenoma with marked cellularity on FNAB. Tumorectomy was performed and well-differentiated Hürthle cell carcinoma detected. The patient received ablative dose of 100 mCi ¹³¹I. No signs of metastatic disease are present up to date.

Conclusions. The differences between Hürthle cell adenomas and Hürthle cell carcinomas could be clearly made only by histopathological evaluation. Patients with cytological diagnosis of Hürthle cell neoplasms should proceed to total thyroidectomy, especially if tumour size is > 1cm, FNAB findings comprise cellular atypias and/or multiple bilateral nodules are detected in the thyroid gland.

Background. Electrochemotherapy is a tumour ablation modality, based on electroporation of the cell membrane, allowing non-permeant anticancer drugs to enter the cell, thus augmenting their cytotoxicity by orders of magnitude. In preclinical studies, bleomycin and cisplatin proved to be the most suitable for clinical use. Intravenous administration of cisplatin for electrochemotherapy is still not widely accepted in the clinics, presumably due to its lower antitumor effectiveness, but adjuvant therapy by immunomodulatory or vascular-targeting agents could provide a way for its potentiation. Hence, the aim of the present study was to explore the possibility of adjuvant tumour necrosis factor α (TNF-α) therapy to potentiate antitumor effectiveness of electrochemotherapy with intravenous cisplatin administration in murine sarcoma.

Materials and methods. In vivo study was designed to evaluate the effect of TNF-α applied before or after the electrochemotherapy and to evaluate the effect of adjuvant TNF-α on electrochemotherapy with different cisplatin doses.

Results. A synergistic interaction between TNF-α and electrochemotherapy was observed. Administration of TNF-α before the electrochemotherapy resulted in longer tumour growth delay and increased tumour curability, and was significantly more effective than TNF-α administration after the electrochemotherapy. Tumour analysis revealed increased platinum content in tumours, TNF-α induced blood vessel damage and increased tumour necrosis after combination of TNF-α and electrochemotherapy, indicating an anti-vascular action of TNF-α. In addition, immunomodulatory effect might have contributed to curability rate of the tumours.

Conclusion. Adjuvant intratumoural TNF-α therapy synergistically contributes to electrochemotherapy with intravenous cisplatin administration. Due to its potentiation at all doses of cisplatin, the combined treatment is predicted to be effective also in tumours, where the drug concentration is suboptimal or in bigger tumours, where electrochemotherapy with intravenous cisplatin is not expected to be sufficiently effective.

Background. Mild hyperthermia (mHT) increases the tumor perfusion and vascular permeability, and reduces the interstitial fluid pressure, resulting in better intra-tumoral bioavailability of low molecular weight drugs. This approach is potentially also attractive for delivery of therapeutic macromolecules, such as antibodies. Here, we investigated the effects of mHT on the stability, immunological and pharmacological properties of Herceptin^®, a clinically approved antibody, targeting the human epidermal growth factor receptor 2 (HER-2) overexpressed in breast cancer.

Results. Herceptin^® was heated to 37°C (control) and 42°C (mHT) for 1 hour. Formation of Herceptin^® aggregates was measured using Nile Red assay. mHT did not result in additional Herceptin^® aggregates compared to 37°C, showing the Herceptin^® stability is unchanged. Immunological and pharmacological properties of Herceptin^® were evaluated following mHT using HER-2 positive breast cancer cells (BT-474). Exposure of Herceptin^® to mHT preserved recognition and binding affinity of Herceptin^® to HER-2. Western-blot and cell proliferation assays on BT-474 cells showed that mHT left the inhibitory activities of Herceptin^® unchanged.

Conclusions. The stability, and the immunological and pharmacological properties of Herceptin^® are not negatively affected by mHT. Further in-vivo studies are required to evaluate the influence of mHT on intra-tumoral bioavailability and therapeutic effectiveness of Herceptin^®.

Background. There is limited effect of tyrosine kinase inhibitors or “naked” antibodies binding EGFR or HER2 for therapy of metastasized urinary bladder cancer and these methods are therefore not routinely used. Targeting radionuclides to the extracellular domain of the receptors is potentially a better possibility.

Methods. EGFR- and HER2-expression was analyzed for primary tumors and corresponding metastases from 72 patients using immunohistochemistry and the internationally recommended HercepTest. Intracellular mutations were not analyzed since only the receptors were considered as targets and intracellular abnormalities should have minor effect on radiation dose.

Results. EGFR was positive in 71% of the primary tumors and 69% of corresponding metastases. Local and distant metastases were EGFR-positive in 75% and 66% of the cases, respectively. The expression frequency of HER2 in related lesions was slightly higher (data from previous study). The EGFR-positive tumors expressed EGFR in metastases in 86% of the cases. The co-expression of EGFR and HER2 was 57% for tumors and 53% for metastases. Only 3% and 10% of the lesions were negative for both receptors in tumors and metastases, respectively. Thus, targeting these receptors with radionuclides might be applied for most patients.

Conclusions. At least one of the EGFR- or HER2-receptors was present in most cases and co-expressed in more than half the cases. It is therefore interesting to deliver radionuclides for whole-body receptor-analysis, dosimetry and therapy. This can hopefully compensate for resistance to other therapies and more patients can hopefully be treated with curative instead of palliative intention.

Background. Gastroesophageal reflux is suspected to be an etiological factor in laryngeal and pharyngeal cancer. The aim of this study was to establish, using a non-invasive method, whether laryngopharyngeal reflux (LPR) appears more often in patients with early laryngeal cancer than in a control group.

Patients and methods. We compared the pH, the level of bile acids, the total pepsin and the pepsin enzymatic activity in saliva in a group of 30 patients with T1 laryngeal carcinoma and a group of 34 healthy volunteers.

Results. The groups differed significantly in terms of levels of total pepsin and bile acids in the saliva sample. Higher levels of total pepsin and bile acids were detected in the group of cancer patients. No significant impact of other known factors influencing laryngeal mucosa (e.g. smoking, alcohol consumption, and the presence of irritating substances in the workplace) on the results of saliva analysis was found.

Conclusions. A higher level of typical components of LPR in the saliva of patients with early laryngeal cancer than in the controls suggests the possibility that LPR, especially biliary reflux, has a role in the development of laryngeal carcinoma.

Background. Ovarian cancer is usually diagnosed in an advanced stage and the present clinical and diagnostic molecular markers for early OC screening are insufficient. The aim of this study was to identify potential relationship between the hypodontia and epithelial ovarian cancer (EOC).

Patients and methods. A retrospective study was conducted on 120 patients with EOC treated at the Department of Gynaecologic and Breast Oncology at the University Clinical Centre and 120 gynaecological healthy women (control group) of the same mean age. Women in both groups were reviewed for the presence of hypodontia and the patients with EOC also for clinicopathological characteristics of EOC according to hypodontia phenotype.

Results. Hypodontia was diagnosed in 23 (19.2%) of patients with EOC and 8 (6.7%) controls (p = 0.004; odds ratio [OR] = 3.32; confidence interval [CI], 1.42-7.76). There was no statistically significant difference in patients with EOC with or without hypodontia regarding histological subtype (p = 0.220); they differed in regard to FIGO stage (p = 0.014; OR =3.26; CI, 1.23-8.64) and tumour differentiation grade (p = 0.042; OR = 3.1; CI, 1.01-9.53). Also, bilateral occurrence of EOC was more common than unilateral occurrence in women with hypodontia (p = 0.021; OR = 2.9; CI, 1.15-7.36). We also found statistically significant difference between the ovarian cancer group and control group in presence of other malignant tumours in subjects (p < 0.001).

Conclusions. The results of the study suggest a statistical association between EOC and hypodontia phenotype. Hypodontia might serve as a risk factor for EOC detection.

Background. Small molecules that inhibit V600 mutated BRAF protein, such as vemurafenib and dabrafenib, are effective in treatment of metastatic melanoma.

Case report. We here describe the clinical course of a V600E BRAF mutated metastatic melanoma patient with systemic disease, who developed tumor progression on superficial soft-tissue metastases during treatment with dabrafenib. Bleomycin electrochemotherapy during dabrafenib treatment was administered to control the soft-tissue progressing metastases and ensured sustained local control without significant toxicity.

Conclusions. The new combined approach maintained the patient quality of life and allowed for the prosecution of the target therapy, which proved to be still effective on systemic disease, up to 17 months

Background. Haemangiomas of tongue are rare type of malformations. They can be treated mostly conservatively but in some cases they need more aggressive treatment with preoperative intra arterial embolization and surgical resection. Lesions of tongue that are localized superficially can also be treated with direct puncture and injection of sclerosing agent (absolute ethanol).

Case report. We present a case of a 48 years old female patient, where we performed embolization of cavernous haemangioma with mixture of absolute ethanol and oil contrast. After the procedure the patient received analgetics and antioedematous therapy. After the sclerotization the planed surgery was abandoned. Control MRI examinations 6 and 12 months after the procedure showed only a small remnant of haemangioma and no signs of a larger relapse.

Conclusions. In our case the direct puncture of haemangioma and sclerotherapy with ethanol proved to be a safe and effective method to achieve preoperative devascularization of the lesion. Direct puncture of the lesion is not limited by the anatomy of the vessels or vasospasm, which can occur during the intra-arterial approach.

Background. Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial. Patients and methods. The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m² or 125 mg/m²) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated.

Results. Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0-2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3-8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6-8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1-2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed.

Conclusions. In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity.

Background. This study was initiated to create a predictive instrument for estimating the survival of patients with metastatic epidural spinal cord compression (MESCC) from esophageal cancer.

Methods. In 27 patients irradiated for MESCC from esophageal cancer, the following nine characteristics were evaluated for potential impact on survival: age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, histology, number of involved vertebrae, ambulatory status before irradiation, further bone metastases, visceral metastases, and dynamic of developing motor deficits before irradiation. In addition, the impact of the radiation regimen was investigated. According to Bonferroni correction, p-values of < 0.006 were significant representing an alpha level of < 0.05.

Results. ECOG performance score (p < 0.001), number of involved vertebrae (p = 0.005), and visceral metastases (p = 0.004) had a significant impact on survival and were included in the predictive instrument. Scoring points for each characteristic were calculated by dividing the 6-months survival rates (in %) by 10. The prognostic score for each patient was obtained by adding the scoring points of the three characteristics. The prognostic scores were 4, 9, 10, 14 or 20 points. Three prognostic groups were formed, 4 points (n = 11), 9-14 points (n = 12) and 20 points (n = 4). The corresponding 6-months survival rates were 0%, 33% and 100%, respectively (p < 0.001). Median survival times were 1 month, 5 months and 16.5 months, respectively.

Conclusions. This new instrument allows the physician estimate the 6-months survival probability of an individual patient presenting with MESCC from esophageal cancer. This is important to know for optimally personalizing the treatment of these patients.

Background. The aim of the study was to evaluate the dosimetric benefit of applying volumetric modulated arc therapy (VMAT) on the post-mastectomy left-sided breast cancer patients, with the involvement of internal mammary nodes (IMN).

Patients and methods. The prescription dose was 50 Gy delivered in 25 fractions, and the clinical target volume included the left chest wall (CW) and IMN. VMAT plans were created and compared with intensity-modulated radiotherapy (IMRT) plans on Pinnacle treatment planning system. Comparative endpoints were dose homogeneity within planning target volume (PTV), target dose coverage, doses to the critical structures including heart, lungs and the contralateral breast, number of monitor units and treatment delivery time.

Results. VMAT and IMRT plans showed similar PTV dose homogeneity, but, VMAT provided a better dose coverage for IMN than IMRT (p = 0.017). The mean dose (Gy), V₃₀ (%) and V₁₀ (%) for the heart were 13.5 ± 5.0 Gy, 9.9% ± 5.9% and 50.2% ± 29.0% by VMAT, and 14.0 ± 5.4 Gy, 10.6% ± 5.8% and 55.7% ± 29.6% by IMRT, respectively. The left lung mean dose (Gy), V₂₀ (%), V₁₀ (%) and the right lung V₅ (%) were significantly reduced from 14.1 ± 2.3 Gy, 24.2% ± 5.9%, 42.4% ± 11.9% and 41.2% ± 12.3% with IMRT to 12.8 ± 1.9 Gy, 21.0% ± 3.8%, 37.1% ± 8.4% and 32.1% ± 18.2% with VMAT, respectively. The mean dose to the contralateral breast was 1.7 ± 1.2 Gy with VMAT and 2.3 ± 1.6 Gy with IMRT. Finally, VMAT reduced the number of monitor units by 24% and the treatment time by 53%, as compared to IMRT.

Conclusions. Compared to 5-be am step-and-shot IMRT, VMAT achieves similar or superior target coverage and a better normal tissue sparing, with fewer monitor units and shorter delivery time.

Background. The aim of the study was to systematically evaluate population exposure from diagnostic and interventional radiological procedures in Slovenia.

Methods. The study was conducted in scope of the “Dose Datamed 2” project. A standard methodology based on 20 selected radiological procedures was adopted. Frequencies of the procedures were determined via questionnaires that were sent to all providers of radiological procedures while data about patient exposure per procedure were collected from existing databases. Collective effective dose to the population and effective dose per capita were estimated from the collected data (DLP for CT, MGD for mammography and DAP for other procedures) using dose conversion factors.

Results. The total collective effective dose to the population from radiological in 2011 was estimated to 1300 manSv and an effective dose per capita to 0.6 mSv of which approximately 2/3 are due to CT procedures.

Conclusions. The first systematic study of population exposure to ionising radiation from radiological procedures in Slovenia was performed. The results show that the exposure in Slovenia is under the European average. It confirmed large contributions of computed tomography and interventional procedures, identifying them as the areas that deserve special attention when it comes to justification and optimisation.