An analysis of the prognostic value of IDH1 (isocitrate dehydrogenase 1) mutation in Polish glioma patients.

BACKGROUND AND OBJECTIVE: IDH1 (isocitrate dehydrogenase 1) is a potential biomarker and drug target. Genomic and epigenetic data on astrocytoma have demonstrated that the IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Furthermore, recent studies have also indicated that a mutant IDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. As the presence of the p.R132H mutation in the IDH1 gene seems to be a more powerful prognostic marker than O(6)-methylguanine-DNA methyltransferase promoter status, we evaluated the presence of IDH1 mutation in Polish patients with astrocytoma, glioblastoma, oligoastrocytoma, ganglioglioma, oligodendroglioma, and ependymoma. METHODS: The IDH1 mutation status at codon 132 was determined using a mouse monoclonal antibody specific for the R132H mutation, direct sequencing, and Co-amplification at Lower Denaturation Temperature (COLD) polymerase chain reaction (PCR) high-resolution melting-curve analysis (HRM). RESULTS: Wild-type (WT) IDH1 was detected in cases with a World Health Organization (WHO) grade I astrocytoma. The IDH1 c.G395A; p.R132H mutation was observed in 56 and 94 % of grade II and grade III astrocytoma cases, respectively. Significant differences in the median overall survival were observed in astrocytoma patients grouped on the basis of the presence of IDH1 mutation: survival was 24 months longer in grade II astrocytoma and 12 months longer in glioblastoma. Overall survival was compared between grade II astrocytoma patients with low or high expression of the mutant protein. Interestingly, lower R132H expression correlated with better overall survival. CONCLUSION: Our results indicate the usefulness of assessing the R132H IDH1 mutation in glioma patients: the presence or absence of the R132H mutation can help pathologists to distinguish pilocytic astrocytomas (IDH1 WT) from diffuse ones (R132H IDH1/WT). Moreover, low IDH1 p.R132H expression was related to better prognosis. This clinical implication appears to be important for personalization of prognosis and treatment by oncologists.

Preliminary results of linac-based radiosurgery in arteriovenous malformations and cerebral tumours in the Oncology Centre in Bydgoszcz.

AIM OF THE STUDY: Efficacy of stereotactic radiosurgery (SRS) in the treatment in cerebral AVM's, mennigiomas, metastases, acoustic neuromas and recurrent anaplastic gliomas is well documented. The object of this work was the analysis of the results of the treatment of AVM and selected cerebral lesions with linear accelerator-based stereotactic radiosurgery. MATERIAL AND METHODS: THE LESIONS INCLUDED: 12 AVMs, 2 cavernomas, 27 meningiomas, 16 metastases, 5 acoustic neuromas, 16 gliomas in 78 patients. A mean radiation dose of 16Gy was delivered to the tumour or AVM margin and 12Gy to the tumours located in a ponto-cerebellar angle. Follow-up was 18 months. RESULTS: Control of tumour growth or AVM was achieved in all cases after 6 months and radiological regression was observed in 20 cases after 12 months. The best results were noted in AVM's, meningiomas and neuromas.There were no new permanent deficits nor complications after radiosurgery requiring medicamentation. CONCLUSIONS: Organization of SRS in Oncological Center in Bydgoszcz involving close co-operation of radiotherapist, neurosurgeon and physicist in the process of qualification and treatment planning is based on the best global standards. Preliminary results of treatment are consistent with the literature data. A longer follow-up is required to determine the long term efficacy and the toxicity of this treatment in our institution.

Measurement of primary tumor volume by PET-CT to evaluate risk of mediastinal nodal involvement in NSCLC patients with clinically negative N2 lymph nodes.

AIM: The study aimed to determine a prognostic value of primary tumor volume measured on the basis of integrated positron emission tomography-computerized tomography (PET-CT) in terms of mediastinal nodal metastases (N2) prediction in non-small-cell lung cancer (NSCLC) patients with PET-CT N2 negative lymph nodes. METHODS: The records of 70 potentially operable NSCLC patients treated with surgical resection were analyzed. All patients underwent diagnostic, preoperative PET-CT, which was the basis for tumor volume calculations as well as the evaluation of N2 nodes status. The logistic regression analysis was employed to determine correlation between mediastinal nodal involvement and volume of primary tumor (izoSUV2.5 volume), that is the volume of primary tumor inside SUV 2.5 line, tumor histology, location (peripheral vs. central), hilar node status. RESULTS: A statistically significant correlation between mediastinal node involvement and izoSUV2.5 volume, tumor histology, locations peripheral vs. central and hilar node status was found. The risk of mediastinal lymph node metastasis is 24% for tumor volume of 100 cm(3) and increases up to 40% for tumor volume of 360 cm(3). An increase of tumor volume by 1 cm(3) increases the risk of lymph node disease by 0.3%. Tumor histology adenocarcinoma vs. squamous cell carcinoma increases the risk of mediastinal lymph node involvement by 195%, location central vs. peripheral by 68% and hilar node involvement by 166%. CONCLUSIONS: The study demonstrates that izoSUV2.5 volume of primary tumor may be considered as a prognostic factor in NSCLC patients, since it strongly correlates with mediastinal lymph node pathological status. This correlation is modified by primary tumor location, histology and hilar node involvement.

The role of postoperative radiotherapy in prostate cancer patients.

AIM OF THE STUDY: The aim of the study was to evaluate the effectiveness of postoperative radiotherapy in prostate cancer patients with unfavorable prognostic factors. MATERIAL AND METHODS: In the years 2002-2008, 121 consecutive prostate cancer patients underwent radical prostatectomy and postoperative radiotherapy. The median dose was 64 Gy (range: 60-72 Gy). Biochemical and clinical progression-free survival were estimated. Univariate and multivariate analyses were used to analyze clinicopathological variables associated with treatment failure. RESULTS: The median follow-up was 27 months. Three-year bPFS was 72%. On univariate analysis it was influenced by: extracapsular tumor extension (60% vs. 75%, p = 0.0232), seminal vesicles invasion (52% vs. 85%, p = 0.00041), Gleason score ≥ 7 (65% vs. 86%, p = 0.044) and the use of hormonal therapy (50% vs. 80%, p = 0.0058). On multivariate analysis bPFS was associated with: TNM stage (HR = 3.19), postoperative hormonal therapy (HR = 2.6), total irradiation dose (HR = 0.82) and the maximum pretreatment level of prostate-specific antigen (PSA) (HR = 0.95). Three-year cPFS was 84%. On univariate analysis it was influenced by: preoperative PSA level > 10 ng/ml (75% vs. 90%, p = 0.04), vascular-nerve bundles involvement (63% vs. 88%, p = 0.0031), adjacent organs infiltration (50% vs. 85%, p = 0.018) and the use of postoperative hormonal therapy (62% vs. 90%, p = 0.02). On multivariate analysis cPFS was associated with: TNM stage (HR = 2.68), postoperative hormonal therapy (HR = 3.61) and total irradiation dose (HR = 0.78). CONCLUSIONS: Postoperative radiotherapy in patients with unfavorable prognostic factors provides good biochemical and local control. Total irradiation dose and postoperative hormonal therapy are important treatment factors influencing prognosis.

[The involvement of RCAS1 in creating a suppressive tumor microenvironment in patients with pharyngeal squamous cell carcinoma]. / Udzial bialka RCAS1 w tworzeniu supresyjnego profilu mikrosrodowiska raka plaskonablonkowego gardla srodkowego.

INTRODUCTION: Tumor microenvironment makes up the stroma of the neoplasm and is the tissue that determines the growth and progression of the tumor and its ability to create metastases. THE AIM OF THE PRESENT STUDY: has been to evaluate the potential role of RCAS1 protein in creating the suppressive tumor microenvironment in pharyngeal squamous cell carcinomas. The immunoreactivity of RCAS1, CD3, CD25, CD68, CD69 and Foxp3 was assessed in the tissue samples of the tumor, in tumor microenvironment and in the reference samples of palatine tonsils in chronic inflammation. RESULTS: A statistically significantly higher RCAS1 antigen immunoreactivity was identified in pharyngeal cancer samples than in the stromal samples, the presence of RCAS1 positive macrophages infiltrating the tumor and its stroma was also noticed. The statistically significantly higher RCAS1 antigen immunoreactivity level was identified in the pharyngeal cancer samples in patients with the presence of lymph node metastases in comparison to patients without metastases. The infiltration of CD68 positive cells (macrophages) was significantly higher in the stromal tissue samples than in cancer samples and it was in both, the tumor and the stroma, significantly higher in patients with the presence of lymph node metastases than in patients without metastases. Additionally the presence of CD3 positive TILs was noticed in the tissue of the tumor and in its stroma, the cells were activated, typified by CD69 immunoreactivity which was higher than in the reference samples, and impaired cytotoxicity with low CD25 antigen immunoreactivity. This observation confirmed the presence of selective immune suppression within the tumor and the stroma. CONCLUSION: RCAS1, an active factor secreted by the tumor and present in its stroma may play an important role in the phenomenon of tumor escape from host immunological surveillance and in creating the immune tolerance for the tumor cells, as well as in the tumor microenvironment remodeling with creating its suppressive profile enabling the further tumor growth and metastases.

The immunohistochemical analysis of antigens such as RCAS1 and B7H4 in the cervical cancer nest and within the fibroblasts and macrophages infiltrating the cancer microenvironment.

INTRODUCTION: The presence of the aggressive phenotype of the tumor seems to be indicated by the local infiltration of cancer cells and by the development of metastases in the lymph nodes. This phenotype is related to the intensity of the suppressive profile of the tumor microenvironment. The aim of our study has been to gather information about the expression of both RCAS1 and B7H4 proteins in the macrophages and fibroblasts present within both the microenvironment of cervical cancer tumors and the cancer cells present on the front of the cancer nest. METHODS: We analyzed the immunoreactivity levels of such antigens as B7H4 and RCAS1 in the macrophages and fibroblasts of the cancer microenvironment and within the cancer nest in the tissue samples derived from patients on whom both a radical hysterectomy and a lymphadenectomy had been performed following a diagnosis of uterine cervical carcinoma. These patients were then divided into two subgroups according to the extent of the local and distant advancement of the cancer - that is, according to the FIGO stage and the presence or absence of lymph node metastases. RESULTS: RCAS1 immunoreactivity levels on the front of the cancer nest statistically significantly increase according to the FIGO stage or the extent of the local spread of the disease while B7H4 immunoreactivity levels on the tumor front increase in relation to the extent of the distant spread of the disease or the presence of lymph nodes metastases. CONCLUSION: The intensity of the suppressive profile of the cervical cancer microenvironment indicated by the presence of both RCAS1 and B7H4 on the front of the tumor and in the macrophages and fibroblasts infiltrating the cancer stroma seems to correlate with the extent of both the local and distant advancement of the disease.

Acute pulmonary embolus in the course of cancer.

Risk of pulmonary embolism (PE) is relatively high in patients with advanced chronic diseases, particularly with malignancies. Most patients with cancer have blood coagulation test abnormalities indicative of up-regulation of the coagulation cascade, increased platelet activation and aggregation. Pulmonary thromboembolism is common in patients with any cancer and incidence is increased by surgery, chemotherapy, radiotherapy and disease progression. Manifestations range from small asymptomatic to life-threatening central PE with subsequent hypotension and cardiogenic shock. Diagnostic algorithms utilizing various noninvasive tests have been developed to determine the pretest probability of PE results of D-dimer assay, chest radiography ECG and computed tomography. The mortality in untreated PE is high (30%) but appropriate treatment may decrease it to 2-18%. The current recommended treatment for massive pulmonary embolus is either thrombolytic therapy or surgical embolectomy.

The analysis of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) immunoreactivity within the microenvironment of the ovarian cancer lesion relative to the applied therapeutic strategy.

RCAS1 is involved in generating the suppressive profile of the tumor microenvironment that helps cancer cells evade immune surveillance. The status of the cells surrounding the cancer nest may affect both the progression of the cancer and the development of metastases. In cases of ovarian cancer, a large number of patients do not respond to the applied therapy. The patient's response to the applied therapy is directly linked to the status of the tumor microenvironment and the intensity of its suppressive profile. We analyzed the immunoreactivity of RCAS1 on the cells present in the ovarian cancer microenvironment in patients with the disease; these cells included macrophages and carcinoma-associated fibroblasts. Later we analyzed the immunoreactivity levels within these cells, taking into consideration the clinical stage of the cancer and the therapeutic strategy applied, such as the number of chemotherapy regiments, primary cytoreductive surgery, or the presence of advanced ascites. In the patients who did not respond to the therapy we observed significantly higher immunoreactivity levels of RCAS1 within the cancer nest than in those patients who did respond; moreover, in the non-responsive patients we found RCAS1 within both macrophages and carcinoma-associated fibroblasts. RCAS1 staining may provide information about the intensity of the immuno-suppressive microenvironment profile found in cases of ovarian cancer and its intensity may directly relate to the clinical outcome of the disease.

Analysis of Treg cell population alterations in the peripheral blood of patients treated surgically for ovarian cancer - a preliminary report.

PROBLEM: Treg cells constitute the main cell population that enables cancer cells to evade immune surveillance. An alteration in the Treg cell population might correspond to the diminishment of the tumour mass in patients with cancer and could therefore be a useful marker of the intensity of the selective suppression of the host immune system and also of the degree of radicalism of a procedure. Certainly, it is well known that in order for anti-cancer therapy to succeed the proper immune response against cancer cells must be restored. Furthermore, monitoring the level of selective immune system suppression during cancer therapy might yield information that would support a decision to supplement standard therapy by immunotherapy or to increase the degree of radicalism of the applied therapy. METHOD OF STUDY: We examined the Treg cell populations in the peripheral blood of a group of patients treated surgically for ovarian cancer. In each patient, the peripheral blood samples were collected both prior to and 1 day after the surgical procedure, and then again 5 days after the procedure. The presence of regulatory T cells in the samples was analyzed by means of flow cytometry. RESULTS: In our study, the percentages of FOXP3(+) cells in the subpopulation of CD4(+) T lymphocytes found in the peripheral blood of the patients before the surgical intervention were statistically significantly higher than those observed in the peripheral blood of these same patients after the surgical procedure. CONCLUSION: It would seem that the alteration in the Treg cell subpopulation could be a key factor in determining the status of the tumour microenvironment. Most likely, it could provide information about whether the proper level of anti-cancer immune response could be restored. The possibility of restoring the immune response may directly correspond to the degree of radicalism of the surgical intervention.

Randomized clinical trial on 7-days-a-week postoperative radiotherapy for high-risk squamous cell head and neck cancer.

PURPOSE: To evaluate the normal tissue reactions and loco-regional control rates (LRC) in patients treated with 7-days-a-week postoperative continuous irradiation (p-CAIR) compared to conventionally fractionated 5-days-a-week postoperative radiotherapy (CF). MATERIALS/METHODS: Between 2001 and 2004, 279 patients with high-risk squamous cell cancer of the larynx (158 pts.) or cancer of the oral cavity/oropharynx (121 pts.) were enrolled. They were stratified according to the primary cancer site (larynx vs. others) and the treating center and randomized to receive 63 Gy in fractions of 1.8 Gy given 5-days-a-week (140 pts: CF) or 7-days-a-week (139 pts: p-CAIR). RESULTS: The acute and late toxicity was considered acceptable, although the proportion of patients with confluent mucositis was higher in p-CAIR compared to CF (60.0 vs. 33.3%). The actuarial 3-year LRC were 64 vs. 70% for CF and p-CAIR, respectively, p=0.32. A statistically significant improvement in 3-year LRC in p-CAIR arm appeared in a subset of the patients with cancer of the oropharynx/oral cavity (74% p-CAIR vs. 53% CF, p=0.02). By contrast, there was no improvement in LRC in a subset of the patients with cancer of the larynx (p=0.46). CONCLUSION: An improvement in LRC attributable to acceleration of postoperative radiotherapy appeared restricted to the patients with cancer of the oropharynx/oral cavity. In patients with cancer of the larynx acceleration of postoperative radiotherapy did not have any beneficial effect.

Randomized clinical trial on continuous 7-days-a-week postoperative radiotherapy for high-risk squamous cell head-and-neck cancer: a report on acute normal tissue reactions.

BACKGROUND AND PURPOSE: To analyse acute mucosal reactions in patients treated with continuous accelerated postoperative irradiation (p-CAIR) compared to conventionally fractionated postoperative radiotherapy (p-CF). PATIENTS AND METHODS: The patients were randomly assigned to receive 63 Gy in 1.8 Gy fractions 7-days-a-week given over a period of 5 weeks (n=88), or 63 Gy in 1.8 Gy fractions given 5-days-a-week over 7 weeks (n=87). It represents 65% of an overall trial size. Acute mucosal reactions were scored using modified Dische system. Polychotomous logistic regression was used to estimate the influence of the selected variables on maximum grade of mucositis, and percent of the body weight loss during radiotherapy. RESULTS: The average maximum Dische score and percent of the patients with confluent mucositis were higher in patients treated with p-CAIR, compared to p-CF (13.3 vs. 10.8 and 54 vs. 27%). Polychotomous logistic regression analysis revealed that fractionation scheme and tumour site have significantly influenced maximum Dische score. Tumour site (laryngeal vs. other) had even stronger influence on maximum Dische score than fractionation scheme. The average residual Dische score 8 weeks after radiotherapy was higher in p-CAIR compared to p-CF (2.1 vs. 1.4), and was, most frequently, related to persistent mucosal erythema (70 vs. 57% of pts.). No severe consequential toxicity of radiotherapy was observed, so far, in the trial. CONCLUSIONS: While the incidence, intensity and duration of mucosal reactions was higher in p-CAIR than in p-CF the accelerated treatment can be considered tolerable with respect to acute toxicity. In both arms of the trial slight or moderate mucosal erythema was the most frequent acute side effect, which did not completely subside within 8 weeks after irradiation.

[Reactive oxygen species as an inducing factor of neoplasms of female reproductive organs ]. / Reaktywne formy tlenu jako jeden z czynników rozwoju nowotworów narzadów plciowych kobiet.

AIM: In our study we measured selenium concentration in the blood of women with diagnosed cancer and benign tumors. The results were compared with healthy women. Some other parameters of the antioxidant system in all studied groups were also investigated, namely, activity of glutatione peroxidase, superoxide dismutase, as well as the levels of glutathione and malondialdehyde. MATERIAL AND METHODS: All parameters were determined in peripheral blood of (a) 47 women with diagnosed cancer (b) 46 women with diagnosed benign tumors, and (c) 20 healthy women (control group). Statistical analysis of the results was performed using "Statistica" software. RESULTS: Our results showed lower selenium concentration in the whole blood and plasma of cancer and benign tumor patients as compared to healthy women. An activity of glutathione peroxidase in erythrocytes and plasma were also lower in both patients' groups than in the control group. Statistical analysis of data revealed a positive correlation between selenium concentration and glutathione peroxidase activity in plasma. Lower activity of superoxide dismutase and increased concentration of malondialdehyde was noted in plasma of cancer patients as compared to healthy women. CONCLUSIONS: 1. A status of antioxidant systems plays an important role in carcinogenesis. 2. The antioxidant system of the women suffering from cancer is deficient. 3. A capacity of that system depends greatly on the concentration of antioxidants and activity of antioxidant enzymes, among them glutathione peroxidase.

Radiotherapy in the prevention of heterotopic ossification after arthroplasty.

Heterotopic ossification (HO) is defined as the formation of mature lamellar bone in nonosseous tissues. HO is a common problem following total hip replacement (THR) and surgical repair of traumatic acetabular fracture (TAF). Without receiving any kind of prophylaxis the incidence of HO in patients with THR is about 30-80%. The etiology of this disorder is not well understood. The treatment of symptomatic HO is excision of heterotopic bone. Radiation therapy is a safe and effective metod for prevention of HO. The present article extensively reviews the clinical studies to define the role of radiotherapy for prevention of HO.