Roman Makarewicz

Endoglin - a marker of vascular endothelial cell proliferation in cancer.

Endoglin (CD105) is an accessory receptor of transforming growth factor B. The highest synthesis, as well as expression, of endoglin has been found in vascular endothelial cells. The involvement of endoglin in angiogenesis and in angiogenesis-dependent processes has been observed. Endoglin promotes angiogenesis not only by activation of vascular endothelial cell proliferation but also by induction of the antiapoptotic pathway in hypoxic endothelial cells. The potential application of endoglin as a tumour angiogenesis marker, useful for cancer diagnostics and clinical application, is anticipated. Endoglin expression may be useful as an indicator of disease progression and helpful for estimation of recurrence and metastasis risk.

PSA bounces after brachytherapy HDR and external beam radiation therapy for prostate cancer

Summary Background The serum prostate-specific antigen (PSA) test is the most commonly used method for confirming response of prostate cancer after definitive radiation therapy (RT). PSA levels are expected to decrease after radiotherapy but usually remain detectable. Three consecutive PSA rises above the post-treatment nadir have been defined as biochemical failure by the ASTRO consensus panel [1]. Rising serum PSA concentration after RT does not always indicate treatment failure. Some patients have a temporary PSA spike, usually within 12–30 months of radiation therapy [2–4]. Most PSA bounces have a magnitude of 1.0 ng/mL or less. This observation was first described by Wallner and colleagues in 1997 [5]. Although this phenomenon is a source of anxiety for both the patient and the physician, its relevance to biochemical failure is controversial. Aim To determine the clinical and dosimetric factors that predict prostate-specific antigen (PSA) bouncing following brachytherapy HDR and three-dimensional conformal radiation therapy (3D-CRT) for prostate cancer patients. Materials/Methods The evaluated population consisted of 71 hormone-naive patients with a minimum of 2 years of follow-up and at least 6 post-treatment PSA levels. All patients were treated using 3D-CRT combined with brachytherapy HDR. A bounce was defined as a PSA rise of ≥0.2 ng/mL above the nadir followed by a subsequent 120 decline of ≥0.2 ng/mL. Clinical factors evaluated included: patient age, Gleason score, maximum initial pretreatment PSA value (iPSAmax), clinical stage, prostate volume, median time to PSA nadir, median PSA nadir value and patient follow-up in months. Dosimetric factors evaluated included the percentage of the prostate volume receiving 100% (V100), 150% (V150) and 200% (V200) of the prescribed minimal peripheral dose. Results Statistically significant predictive factors for PSA bounce were age, V100, V150, V200, iPSAmax and median time to PSA nadir. Logistic regression model for multivariate analysis revealed that only age, iPSAmax and V200 were statistically significant predictors for PSA bounce. There were no statistical differences between median nadir among patients who exhibited a PSA bounce and those who did not, but non-bouncers reached PSA nadir earlier than bouncers; median time was 12.1 vs 17.2 months respectively. Conclusion PSA bouncing occurs in approximately one third (1/3) of patients treated with 3D-CRT and brachytherapy HDR. Bouncing is associated with age, higher pretreatment PSA level and increased V200 factor.

Pre-irradiation tumour volumes defined by MRI and dual time-point FET-PET for the prediction of glioblastoma multiforme recurrence: A prospective study.

BACKGROUND AND PURPOSE The diagnostic accuracy of magnetic resonance imaging (MRI) for glioblastoma multiforme (GBM) is suboptimal. We analysed pre-treatment MRI- and dual time-point 18F-fluoroethylthyrosine-PET (FET-PET)-based target volumes and GBM recurrence patterns following radiotherapy with temozolomide. MATERIALS AND METHODS Thirty-four patients with primary GBM were treated according to MRI-based treatment volumes (GTVRM). Patients underwent dual time-point FET-PET scans prior to treatment, and biological tumour volumes (GTVPET) were contoured but not used for target definition. Progressions were classified based on location of primary GTVs. Volume and uniformity of MRI- vs. FET-PET/CT-derived GTVs and progression patterns assessed by MRI were analysed. RESULTS FET-based GTVs measured 10min after radionuclide injection (a.r.i.; median 37.3cm(3)) were larger than GTVs measured 60min a.r.i. (median 27.7cm(3)). GTVPET volumes were significantly larger than corresponding MRI-based GTVs. MRI and PET concordance for the identification of glioblastoma GTVs was poor (mean uniformity index 0.4). 74% of failures were inside primary GTVPET volumes, with no solitary progressions inside the MRI-defined margin +20mm but outside the GTVPET detected. CONCLUSIONS The size and geometry of GTVs differed in the majority of patients. The GTVPET volume depends on time after radionuclide injection. FET-PET better defined failure site than MRI alone.

Angiogenesis and lymphangiogenesis as prognostic factors after therapy in patients with cervical cancer

Aim of the study This retrospective study attempts to evaluate the influence of serum vascular endothelial growth factor C (VEGF-C), microvessel density (MVD) and lymphatic vessel density (LMVD) on the result of tumour treatment in women with cervical cancer. Material and methods The research was carried out in a group of 58 patients scheduled for brachytherapy for cervical cancer. All women were patients of the Department and University Hospital of Oncology and Brachytherapy, Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń. VEGF-C was determined by means of a quantitative sandwich enzyme immunoassay using a human antibody VEGF-C ELISA produced by Bender MedSystem, enzyme-linked immunosorbent detecting the activity of human VEGF-C in body fluids. The measure for the intensity of angiogenesis and lymphangiogenesis in immunohistochemical reactions is the number of blood vessels within the tumour. Statistical analysis was done using Statistica 6.0 software (StatSoft, Inc. 2001). The Cox proportional hazards model was used for univariate and multivariate analyses. Univariate analysis of overall survival was performed as outlined by Kaplan and Meier. In all statistical analyses p < 0.05 (marked red) was taken as significant. Results In 51 patients who showed up for follow-up examination, the influence of the factors of angiogenesis, lymphangiogenesis, patients’ age and the level of haemoglobin at the end of treatment were assessed. Selected variables, such as patients’ age, lymph vessel density (LMVD), microvessel density (MVD) and the level of haemoglobin (Hb) before treatment were analysed by means of Cox logical regression as potential prognostic factors for lymph node invasion. The observed differences were statistically significant for haemoglobin level before treatment and the platelet number after treatment. The study revealed the following prognostic factors: lymph node status, FIGO stage, and kind of treatment. No statistically significant influence of angiogenic and lymphangiogenic factors on the prognosis was found. Conclusion Angiogenic and lymphangiogenic factors have no value in predicting response to radiotherapy in cervical cancer patients.

Results of interstitial HDR brachytherapy for cancer of the lower lip

Summary Background HDR brachytherapy has been employed in the treatment of cancers in numerous locations around the body, however, few publications have dealt with primary carcinomas of the head and neck. To our knowledge, only one paper concerns the use of this technique in the treatment of cancers of the lower lip. Furthermore, the recommendations given by the American Association of Brachytherapy do not appear to elaborate on the subject. Aim To analyse the treatment of lower lip carcinoma by interstitial HDR brachytherapy. Materials/Methods Retrospective analysis of the results of treatment was carried out among a group of 24 consecutive patients, of whom 18 were treated by brachytherapy alone while 6 others were treated after surgery. Fifteen patients were classified as T1, nine patients as T2. 23 patients were classified as N0 and one as N1. Each patient had histologically confirmed squamous cell carcinoma. Radiotherapy involved interstitial, high dose rate brachytherapy with an iridium-192 source. Post-operative brachytherapy was indicated in cases of microscopically incomplete excision. The dose was determined using the Paris method, the reference dose being 80% or at a point 3–5 mm from the macroscopic lesion or tumour bed. The mean total dose was 35 Gy, the mean number of fractions was 7, and the mean fraction dose was 5.7 Gy. The total treatment time was 12 days, on average, whereas the mean follow-up was 32 months. Results Local control was obtained after 24 months in 21 patients (87.5%). All patients developed a severe early reaction. Three patients with mouth corner infiltration (100%) failed to show complete regression. Two of these patients underwent additional irradiation to the residual lesion, resulting in cures. The third patient underwent successful surgical treatment. The cosmetic and functional effect was very good. Conclusuions Interstitial HDR brachytherapy is an effective and safe method for the treatment of carcinoma in the lower lip.

Dose estimation for different skin models in interstitial breast brachytherapy

Purpose Skin is a major organ at risk in breast-conserving therapy (BCT). The American Brachytherapy Society (ABS) recommendations require monitoring of maximum dose received, however, there is no unambiguous way of skin contouring provided. The purpose of this study was to compare the doses received by the skin in different models. Material and methods Standard treatment plans of 20 patients who underwent interstitial breast brachytherapy were analyzed. Every patient had a new treatment plan prepared according to Paris system and had skin contoured in three different ways. The first model, Skin 2 mm, corresponds to the dermatological breast skin thickness and is reaching 2 mm into an external patient contour. It was rejected in a further analysis, because of distinct discontinuities in contouring. The second model, Skin 4 mm, replaced Skin 2 mm, and is reaching 2 mm inside and 2 mm outside of the External contour. The third model, Skin EXT, is created on the External contour and it expands 4 mm outside. Doses received by the most exposed 0.1 cc, 1 cc, 2 cc, and the maximum doses for Skin 4 mm and Skin EXT were compared. Results Mean, median, maximum, and standard deviation of percentage dose difference between Skin EXT and Skin 4 mm for the most exposed 0.1 cc (D0.1cc) of skin were 18.01%, 17.20%, 27.84%, and 4.01%, respectively. All differences were statistically significant (p < 0.05). Conclusions Monitoring of doses received by skin is necessary to avoid complications and obtain a satisfactory cosmetic effect. It is difficult to assess the compatibility of treatment plans with recommendations, while there is no unambiguous way of skin contouring. Especially, if a mean difference of doses between two models of skin contouring is 18% for the most exposed 0.1 cc and can reach almost 28% in some cases. Differences of this magnitude can result in skin complications during BCT.

Time-Dependent Changes of Plasma Concentrations of Angiopoietins, Vascular Endothelial Growth Factor, and Soluble Forms of Their Receptors in Nonsmall Cell Lung Cancer Patients Following Surgical Resection

Even when patients with nonsmall cell lung cancer undergo surgical resection at an early stage, recurrent disease often impairs the clinical outcome. There are numerous causes potentially responsible for a relapse of the disease, one of them being extensive angiogenesis. The balance of at least two systems, VEGF VEGFR and Ang Tie, regulates vessel formation. The aim of this study was to determine the impact of surgery on the plasma levels of the main angiogenic factors during the first month after surgery in nonsmall cell lung cancer patients. The study group consisted of 37 patients with stage I nonsmall cell lung cancer. Plasma concentrations of Ang1, Ang2, sTie2, VEGF, and sVEGF R1 were evaluated by ELISA three times: before surgical resection and on postoperative days 7 and 30. The median of Ang2 and VEGF concentrations increased on postoperative day 7 and decreased on day 30. On the other hand, the concentration of sTie2 decreased on the 7th day after resection and did not change statistically later on. The concentrations of Ang1 and sVEGF R1 did not change after the surgery. Lung cancer resection results in proangiogenic plasma protein changes that may stimulate tumor recurrences and metastases after early resection.

Tumour surface area as a prognostic factor in primary and recurrent glioblastoma irradiated with 192Ir implantation

Summary Background To evaluate the impact of tumour surface area (TSA) on survival of patients treated with 192 Ir implantation for glioblastoma multiforme (GBM). Methods/Materials The analysis of survival and prognostic factors was performed based on a retrospective study group of 120 patients (74 males and 46 females; mean age 53 years; mean KPS score 74.6) irradiated with 192 Ir for GBM between 1999 and 2003. There were 72 (60%) patients with recurrent and 48 (40%) with primary inoperable tumour. Patients with recurrences were initially treated with surgery and external beam radiotherapy (EBRT; mean total dose (MTD) 53.5Gy). Individuals with primary inoperable glioblastoma underwent EBRT (MTD 37.2Gy) after brachytherapy completion. All patients were irradiated with 192 Ir with a total dose of 15Gy given in 5 fractions. Results For the total group of patients 1-year and 2-year survival were 22% and 11%, respectively, with a median survival time (MST) of 6.1 months. The multivariate Cox analysis of the best fit (Chi 2 =22.98, p=0.000041) distinguished such variables as: patient age (p=0.002), performance status (p=0.04) and tumour surface area (p=0.04) to significantly affect survival. Patients with TSA 2 had better prognosis compared to those with TSA≥90cm 2 (p Conclusions Tumour surface area is an independent prognostic factor in patients irradiated with 192 Ir for glioblastoma multiforme. TSA less than 90cm 2 predicts significantly longer survival and appears to be a more powerful prognostic variable than tumour volume.

Does interstitial HDR brachytherapy for breast cancer increase soft tissue fibrosis

Summary Aim To analyze the physical parameters of interstitial HDR brachytherapy and their influence on the risk of soft tissue fibrosis. Materials/Methods A retrospective analysis of 54 breast cancer patients treated between 1994–1999 in the Brachytherapy Department of the Oncological Centre in Bydgoszcz was performed. Minimum follow up period was 41 months and the maximum was 89 months. The mean follow up period was 65 months. Owing to statiscally significant differences between the groups, when compared to a normal distribution, the U Mann-Whitney non-parametrical test was used as the method for comparison. Results Out of the nine parameters analysed, three were found to be associated with increased risk of fibrosis occurrence. Reference volumes V100, V150 and V200 showed statistically significant differences (p Conclusions In breast conserving therapy a number of parameters influence the results of treatment. Our own studies have shown that among the risk factors responsible for fibrosis are: reference volume V100 (the volume of tissue surrounded by 100% isodose), V150 (volume of tissue surrounded by 150% isodose) and V200 (volume of tissue surrounded by 200% isodose).

Indications for postoperative radiotherapy in patients with prostate cancer after surgery with positive surgical margins

Aim of the study Prostate cancer is the second most prevalent cancer among men in Poland. The main methods of radical treatment are radical prostatectomy and radiotherapy. In patients who have been correctly qualified for surgery, a positive surgical margin is always an unexpected and undesirable factor. The aim of this prospective study was to evaluate the incidence of positive margins in more than 100 consecutive patients with prostate cancer undergoing radical prostatectomy. Material and methods The study included 114 patients aged 44–78 years (mean 61.5 years) who underwent surgery for prostate cancer in stage cT1-3N0/M0 (according to the TNM staging system) in the years 2010-2011 in the Clinical Department of Oncological Urology in the Center of Oncology in Bydgoszcz. Results The presence of positive surgical margins was found in 45 (39.47%) patients, and in 20 (17.54%) margins were assessed as close (1–2 mm). Among the patients with positive surgical margins about 22% had biochemical recurrence. Among patients with negative surgical margins 13% of pT2c and 12.5% of pT3a had biochemical recurrence. Patients with positive surgical margins, along with patients diagnosed with tumor extending beyond the prostate (pT3a) or invading seminal vesicles (pT3b), are at an increased risk of recurrence and progression, reaching up to 30–50% over 10 years. The risk is 2–4 times higher than in patients without positive operating margins.