Anna Mucha-Małecka

Oxidative damage DNA: 8-oxoGua and 8-oxodG as molecular markers of cancer

Summary Background The broad spectrum of oxidative damage DNA biomarkers: urinary excretion of 8-oxodG (8-oxo-7,8-dihydro-2′-deoxyguanosine), 8-oxoGua (8-oxo-7,8-dihydroguanine) as well as the level of oxidative damage DNA in leukocytes, was analyzed in cancer patients and healthy subjects. Material/Methods 222 cancer patients and 134 healthy volunteers were included in the analysis, using methodologies which involve HPLC (high-performance liquid chromatography) prepurification followed by gas chromatography with isotope dilution mass spectrometry detection and HPLC/EC. Results For the whole patient population (n=222) the median values of 8-oxoGua and 8-oxodG in urine samples were 12.44 (interquartile range: 8.14–20.33) [nmol/24 hr] and 6.05 (3.12–15.38) [nmol/24 hr], respectively. The median values of 8-oxoGua and 8-oxodG in urine samples of the control group (n=85) were 7.7 (4.65–10.15) [nmol/24 hr] and 2.2 (1.7–2.8) [nmol/24 hr], respectively. The level of 8-oxodG in DNA isolated from leukocytes of the patient population (n=179) and of the control group (n=134) was 4.93 (3.46–9.27) per 10’6 dG and 4.46 (3.82–5.31) per 10’6 dG, respectively. Conclusions The results suggest that oxidative stress in cancer patients, demonstrated by augmented amounts of these modifications in urine, could be typical not only for affected tissue but also for other tissues and even the whole organism. An assay that enables the determination of levels of basic markers of oxidative stress might be applied in clinical practice as an additional, helpful marker to diagnose cancer.

Palliative thoracic radiotherapy in non-small cell lung cancer. An analysis of 1250 patients. Palliation of symptoms, tolerance and toxicity

PURPOSE To present our experience with short-time, split-course palliative thoracic radiotherapy (PTR) in patients with advanced non-small cell lung cancer (NSCLC) with special regard to palliation of symptoms, tolerance and toxicity of PTR treatment. PATIENTS AND METHODS Between 1980 and 2005, a group of 1250 patients with locally advanced or metastatic NSCLC was treated with PTR in our Center. All patients presented with moderate or severe symptoms related to local cancer growth. RESULTS The response rate defined as palliation of NSCLC symptoms after PTR was 54.1% for cough, 68% for haemoptysis, 51.1% for thoracic pain, 38.3% for dyspnoea, 12% for hoarseness, and 8% for dysphagia. Tolerance of PTR, expressed in terms of patient compliance to the treatment, was good in 92% of patients (i.e., 2 series of radiotherapy were given at the planned dose and time). Early treatment toxicity was observed in 4.6% of patients and included pneumonitis in 2.3%, intense nausea and vomiting in 0.6%, lung hemorrhage in 0.6%, and severe oesophagitis in 0.5% of patients. Lhermittes syndrome and broncho-oesophageal fistula were observed in 0.4% and 0.2%, respectively. Six out of 70 patients who survived longer than 2 years developed chronic pulmonary fibrosis with respiratory insufficiency and one patient presented symptoms of radiation-induced myelopathy. CONCLUSIONS The analysis of our results and data from the literature show that short-time, split-course PTR is a safe and effective method of palliative treatment in patients with advanced NSCLC.

Hematogenous Metastases in Patients with Stage I or II Endometrial Carcinoma

AimsThe aim of this study was to present the characteristics, methods of treatment, and the survival of patients with hematogenous metastases from endometrial carcinoma, free from local and other distant recurrences.Patients and MethodsIn 1,610 endometrial carcinoma patients managed with surgery and postoperative radiotherapy, we defined hematogenous metastases as a tumor spread to the lung or other sites via hematogenous routes.ResultsA total of 110 patients with stage I and II endometrial carcinoma, presenting with 134 metastases sites (69 in the lungs, 32 in the liver, 23 in the bones, and 10 in the brain), were observed. Progestin and combination chemotherapy were the most commonly used therapies. Primary treatment consisted of surgery in patients with solitary metastases to the lung (30 patients), liver (2 patients), and brain (2 patients). Radiotherapy was performed in 32 patients with metastases to the brain and bones. Presenting with a 36-month survival rate were 11.6% (8/69) of patients with metastases to the lungs, 6.3% (2/32) of patients with metastases to the liver, 8.7% (2/23) of patients with metastases to the bones, and 20.0% (2/10) of patients with metastases to the brain.ConclusionsHormonal therapy and chemotherapy play a major role in the palliative management of patients with hematogenous metastases from endometrial carcinoma to the liver, lungs, and bones. Radical treatment in patients with metastases to the lung or liver consists of resection of the metastasis combined with chemo- and/or hormonotherapy for metastases to the bones treatment consists of radiotherapy + chemotherapy, for metastasis to the brain treatment consists of resection combined with radiotherapy.ZusammenfassungZielDarstellung von Charakteristika, Behandlungsmethoden und Überleben von Patientinnen mit hämatogenen Metastasen des Endometriumkarzinoms ohne lokalen und Fernrezidive.Patienten und MethodenBei 1610 Patientinnen mit Endometriumkarzinom, die mit Operation und postoperativer Strahlentherapie behandelt worden waren, definierten wir hämatogene Metastasen als Ausbreitung bösartiger Tumoren in die Lungen oder andere Regionen über die Blutbahn.ErgebnisseWir beobachteten 110 Endometriumkarzinom-Patientinnen, Stadien I und II, bei denen 134 Metastasenlokalisatione festgestellt wurden: 69 in den Lungen, 32 in der Leber, 23 in den Knochen und 10 im Gehirn. Die am häufigsten eingesetzten Behandlungsregime waren Progestine und Kombinationschemotherapie. Erstbehandlung waren Operationen bei Patientinnen mit einzelnen Lungenmetastasen (30 Fälle), Lebermetastasen (2 Fälle) und Gehirnmetastasen (2 Fälle). Eine Strahlentherapie wurde bei 32 Patienten mit Gehirnmetastasen und mit Knochenmetastasen durchgeführt. Nach 36 Monaten betrug die Überlebensrate 11,6% (8/69) der Patientinnen mit Lungenmetastasen, 6,3% (2/32) der Patientinnen mit Lebermetastasen, 8,7% (2/23) der Patientinnen mit Knochenmetastasen und 20,0% (2/10) der Patientinnen mit Gehirnmetastasen.SchlussfolgerungHormon- und Chemotherapie spielen eine wesentliche Rolle in der palliativen Behandlung von Patientinnen mit hämatogenen Leber-, Lungen- und Knochenmetastasen des Endometriumkarzinoms. Die radikale Behandlung bei Lungen- oder Lebermetastasen umfasst chirurgische Metastasenresektion und adjuvante Chemo- und/oder Hormontherapie, bei Knochenmetastasen Strahlen- plus Chemotherapie und bei Gehirnmetastasen chirurgische Metastasenresektion und adjuvante Strahlentherapie.

Prognostic value of the interval from surgery to initiation of radiation therapy in correlation with some histo-clinical parameters in patients with malignant supratentorial gliomas

Aim of the study To determine the relationship between the interval from surgery to initiation of radiation therapy (ISRT) and prognostic factors, such as age, performance status, tumour location, extent of surgical resection and tumour histology in patients with malignant gliomas. Materials and methods From 1995 to 2005, 308 adults patients with supratentorial malignant gliomas (198 glioblastomas, and 110 anaplastic astrocytomas) received postoperative radiotherapy with radical intent. A total tumour dose of 60 Gy in 30 fractions in 6 weeks was delivered. ISRT varied from 15 to 124 days, with median time of 37 days, and it was a cut-off value to assess the results. The end point in our study was two-year overall survival. Results The two-year overall survival rate in the whole group was 17%, with 24% for patients with ISRT value ≤ 37 days, and 14% for patients with an interval longer than 37 days (p = 0.042). Univariate analysis showed that delayed initiation of radiotherapy influenced the outcome of patients with glioblastoma older than 40 years, and with other than frontal location of tumour. Two-year overall survival rates for ISRT ≤ 37 days were 15%, 18% and 22% respectively, compared to 8%, 4% and 11% for ISRT > 37 days. In a multivariate analysis (Coxs model) the only variables that were significantly associated with worse survival were older age and ISRT prolonged for more than 37 days. Conclusion The study showed longer than 37 days waiting time from surgery to initiation of radiotherapy to be a significant predictor of overall survival for adult patients with malignant supratentorial gliomas.

Survival of breast cancer patients according to changes in expression of selected markers between primary tumor and lymph node metastases

BACKGROUND The differences between primary and metastatic tumor cells might be important for treatment selection and prognostication. MATERIALS & METHODS Expression of ER, PR, HER2, CK5/6, EGFR, Ki-67, Ep-CAM, P-cadherin, CD24, CD44, ALDH was assessed immunohistochemically in primary tumor (T) and corresponding synchronous nodal metastases (LNM) in 156 invasive ductal breast cancer patients (T ≥1, N ≥1, M0). RESULTS Independent negative prognostic factors for disease-free survival were pN3, ALDH immunopositivity in LNM, nonluminal A subtype in LNM, reduction of Ep-CAM expression in LNM, lack of changes or enhancement of CK5/6 and ALDH expression in LNM. DISCUSSION Our results suggest that in some cases expression of markers in lymph node metastases might bring additional prognostic information to that obtained from primary tumor.

BGX-Ki-67 index as a supplementary marker to MIB-1 index, enabling more precise distinction between luminal A and B subtypes of breast carcinoma and eliminating the problem of membranous/cytoplasmic MIB-1 staining.

OBJECTIVES We compared clinical utility of MIB-1 and BGX-Ki-67 clones of anti-Ki-67 antibody in a group of 156 patients with invasive ductal breast cancer. METHODS MIB-1 labeling index (MIB-1LI) and BGX labeling index (BGXLI) were evaluated immunohistochemically both in primary tumors (T) and synchronous lymph node metastasis (LNM). RESULTS In addition to nuclear MIB-1 staining, in 23 of 145 and 19 of 144 T and LNM, respectively, membranous/cytoplasmic labeling was found. In these cases, BGX-Ki-67 showed exclusively nuclear labeling and presented significantly higher labeling index. High BGXLI(T) was a significant independent negative prognostic factor for disease-free survival. Moreover, based on BGXLI(T)/BGXLI(LNM), patients with high MIB-1LI(T) were stratified into low- and high-risk carriers. CONCLUSIONS In carcinomas with membranous/cytoplasmic MIB-1 staining, additional assessment of BGXLI is recommended. It may help in defining breast cancer subtype and in selection of individuals at risk who, despite appropriate therapy, would benefit from more frequent controls aimed at earlier implementation of second-line treatment.

Distribution of Podoplanin-Positive Tumor Vessels Predicts Disease-Specific Survival of Node-Positive Breast Cancer Patients Treated with Anthracyclines and/or Taxanes

We analyzed survival of 102 invasive ductal, node positive breast cancer patients, treated with surgery and adjuvant chemotherapy (anthracyclines and/or taxanes) with relation to: (a) well-known clinicopathological parameters, (b) MIB-1 labeling index (LI), (c) the distribution of podoplanin-positive vessels (DPV), expression of: (d) basal markers, and (e) fascin. Lower progression risk was found for patients with tumors characterized by (i) pN1 + pN2, (ii) MIB-1LI ≤ 28%, (iii) lack of lymphatic vessels or high tumor DPV than for patients with pN3, MIB-1LI > 28%, low DPV, respectively. Cox multivariate analysis revealed that both pN3 and low DPV were negative prognostic indicators.

Methods and results of locoregional treatment of brain metastases in patients with non-small cell lung cancer

This article presents methods and results of surgery and radiotherapy of brain metastases from non-small cell lung cancer (BMF-NSCLC). Patients with single BMF-NSCLC, with Karnofsky score ≥ 70 and controlled extracranial disease are the best candidates for surgery. Stereotactic radiosurgery (SRS) is recommended in patients with 1–3 BMF-NSCLC below 3–3.5 cm, with minor neurological symptoms, located in parts of the brain not accessible to surgery, with controlled extracranial disease. Whole brain radiotherapy (WBRT) following SRS reduces the risk of local relapse; in selected patients median survival reaches more than 10 months. Whole brain radiotherapy alone is a treatment in patients with multiple metastases, poor performance status, uncontrolled extracranial disease, disqualified from surgery or SRS with median survival 3 to 6 months. There is no doubt that there are patients with BMF-NSCLC who should receive only the best supportive care. There is a debate in the literature on how to select these patients.

Postoperative treatment of patients with anaplastic oligodendrogliomas. Thirty years' experience of the Maria Sklodowska-Curie Memorial Centre in Kraków, 1975–2000

Summary Background Anaplastic oligodendrogliomas (AO) are infiltrative, mostly supratentorial tumours, often bilaterally affecting the white matter. Radiotherapy alone or in combination with chemotherapy have a role in the adjuvant treatment of AO, but currently the efficacy of various treatment modalities could not be definitively determined because of the heterogeneity of the therapies used. Aim Assessment of the efficacy of altered therapy schedules in postoperative treatment of patients with anaplastic oligodendrogliomas Materials/Methods Between 1975 and 2000, 101 adult patients with anaplastic oligodendrogliomas were postoperatively treated in our institution. During this period patients received conventional radiation therapy and chemotherapy (CRT/CH), conventional radiation therapy (CRT), and split course hypofractionated radiation therapy (SCHRT). Between 1975 and 1985, CRT/CH was applied in 42 patients. Whole brain irradiation was delivered; the tumour dose of 5Gy in 25 fractions over 5 weeks was calculated at the midplane of the skull. Then treatment fields were reduced and a 10Gy boost was given in 5 fractions over 5 days to the known tumour bearing area. On the last day of irradiation patients began the first of six planned series of chemotherapy with CCNU, given 100mg/ 2 , orally every 8 weeks. From 1986 to 1990, CRT was received by 27 patients. Irradiation was only as described above. Between 1991 and 2000, 32 patients were given SCHRT. There were 3 courses of irradiation separated by a one-month interval. In each of the two first series patients received 20Gy in 5 fractions in five days to the whole brain, and in the third course a 20Gy boost in 5 fractions over 5 days was given as in the CRT regimen. Results Actuarial overall survival rates at two and five years were 38% and 10% respectively for patients treated with CRT/CH, 36% and 11% for the CRT group, and 23% and 6% for the SCHRT option. Multivariate analysis revealed that only age was a significant factor. Patients aged 45 years or less carried the best prognosis. Conclusions The efficacy of different postoperative treatments administered to our patients with anaplastic oligodendrogliomas gave approximately comparable and unrewarding poor results.

82/Wielopostaciowy żółtako-gwiaździak – opis przypadku

Wielopostaciowy zoltako-gwiaździak (Pleomorphic xantho-astrocytoma – PXA) jest rzadko wystepującą postacią glejaka mozgu. Wystepuje najcześciej u ludzi mlodych (do 30 roku zycia), lokalizuje sie glownie powierzchownie w placie skroniowym i ciemieniowym mozgu. Podstawową metodą leczenia jest operacja, natomiast radioterapia (zwykle dawką rzedu 30–60 Gy) jest stosowana u chorych po nieradykalnym leczeniu chirurgicznym. Wyniki leczenia są z reguly dobre i zalezą glownie od radykalności przeprowadzonego leczenia operacyjnego. Prezentowany przypadek to 28 letnia pacjentka, u ktorej w marcu 2004 r. z powodu narastającego bolu glowy, nudności i zaburzen świadomości wykonano TK mozgu. W wykonanym badaniu stwierdzono obecnośc rozleglego, torbielowatego guza o wymiarach 83×68 mm, polozonego nadnamiotowo w okolicy czolowo-skroniowo-ciemieniowej prawej polkuli mozgu. 11 marca 2004 r. w Klinice Neurochirurgii Szpitala Uniwersyteckiego w Krakowie wykonano kraniotomie czolową prawostronną, usuwając subtotalnie guz. W badaniu histopatologicznym guz odpowiadal pleomorficznemu zoltako-gwiaździakowi o nieco bardziej agresywnym charakterze, w klasyfikacji WHO określanym jako: pleomorphic xantoastrocytoma with anaplastic features – WHO II/III. W maju 2004 r. w Centrum Onkologii w Krakowie przeprowadzono uzupelniającą radioterapie, podano na obszar lozy po guzie z resztkową zmianą dawke calkowitą 50.4 Gy w 30 frakcjach, frakcjonując dwa razy dziennie. W wykonanym w czerwcu 2004 r. badaniu KT nie stwierdzono wznowy guza. Pacjentka w stanie ogolnym dobrym, bez pogorszenia stanu neurologicznego pozostaje w kontroli.