Krzysztof Małecki

Tumor Grade and Matrix Metalloproteinase 2 Expression in Stromal Fibroblasts Help to Stratify the High-Risk Group of Patients With Early Breast Cancer Identified on the Basis of St Gallen Recommendations

BACKGROUND It is still being discussed if the assessment of basal markers or if adhesion molecules expression contributes additional prognostic information to the classic prognostic factors and hence should be included into standard morphologic reports. PATIENTS AND METHODS The aim of the study was to assess the prognostic significance of: (i) classification recommended by St Gallen experts (ii) tumor grade, expression of (iii) basal markers, (iv) adhesion molecules, and (v) matrix metalloproteinase 2 (MMP-2) in patients with T1-T2 N0M0 chemotherapy-naive ductal breast cancer. RESULTS In 79 patients with tumors characterized by estrogen receptor (ER) and progesterone receptor (PgR) positive, human epidermal growth factor receptor 2 negative (HER2) phenotype and MIB-1 labeling index (MIB-l) LI ≤ 15% (low-risk group) cumulative 17-year breast cancer-specific survival probability was 100% and was significantly higher than in 95 patients from the high-risk group (ER(-)/PgR(-)/HER2(-) or HER2(+) or MIB-1 LI > 15%) (72.5%). We found that MMP-2 fibroblast expression indicated 2 subgroups with significantly different survival rates in women with grade 3 tumor (88.9% for MMP-2 positivity and 56.0% for negativity). Cox multivariate analysis revealed that both grade 3 combined with stromal fibroblast MMP-2(-) and a high-risk group according to St Gallen recommendations are independent negative prognostic factors that influence survival of patients with breast cancer. CONCLUSION To the best of our knowledge, we have shown for the first time that MMP-2(-) in stromal fibroblasts might indicate poor survivors in the group of patients with grade 3 tumors and that the cumulative effect of both above-mentioned parameters might be helpful in selecting the high-risk individuals from the group of patients with luminal B subtype/HER2(+)/triple negative phenotype identified according to St Gallen recommendations.

Relationships between immunophenotype, Ki-67 index, microvascular density, Ep-CAM/P-cadherin, and MMP-2 expression in early-stage invasive ductal breast cancer.

There is still a lack of complete consensus on immunohistochemical surrogate markers for luminal A (LA) and luminal B (LB), HER2, and basal-like subtypes of breast carcinomas and their correlation with cancer cell adhesion and invasion-promoting factors. Therefore, early-stage invasive ductal breast cancer patients (N=209) were recruited to the study and divided into 4 subtypes, on the basis of the expression of the estrogen/progesterone receptor and HER2 (LA: 74.4% of cases; LB: 7.8%; HER2: 5.6%; and triple-negative phenotype: 12.2%). Regardless of the above-mentioned classification, we divided all carcinomas into 2 groups: carcinomas expressing at least 1 basal marker [cytokeratine (CK)5/6, CK5, vimentin, epidermal growth factor receptor, or aberrant CK8/18 expression—membranous or in <10% of cells] versus carcinomas negative for basal markers. Then we studied the relationships between the above subtypes (2 classifications) and (i) the expression of adhesion molecules (Ep-CAM, P-cadherin), (ii) matrix metalloproteinases (MMP)-2, (iii) the proliferation index (MIB-1 LI), and (iv) the microvascular density. We confirmed that triple-negative phenotypes are characterized by basal marker expression, a high tumor grade, and high MIB-1 LI. In this subtype, we found MMP-2 expression in stromal leukocytes less frequently. Both LA carcinomas and carcinomas negative for basal markers were more often negative for epithelial cell adhesion molecule (Ep-CAM) and P-cadherin. Moreover, we noted a higher mean value of microvascular density in CK5/6 and Ep-CAM-immunopositive tumors, carcinomas with aberrant CK8/18 expression, and carcinomas with no or strong expression of MMP-2 in stromal fibroblast-like cells. These results might suggest that mechanisms of stroma remodeling and carcinogenesis (Ep-CAM is the suggested marker of breast progenitors) may differ between breast cancer subtypes.

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.

Tracheal cancer: Role of radiation therapy.

PURPOSE To assess the results of tracheal cancer patients treatment and factors influencing prognosis. BACKGROUND Primary malignant neoplasms of the trachea are rare. The treatment of choice for tracheal carcinomas is resection. Radiation therapy is recommended as a part of radical treatment or for palliation of symptoms. MATERIALS AND METHODS Between 1962 and 2006, 50 patients diagnosed with tracheal cancer were treated at the Centre of Oncology in Krakow. The analysis focused on locoregional recurrence-free survival (LRRFS), disease free survival (DFS) and overall survival (OS). Survival rates, univariate and multivariate analyses of prognostic factors were performed using the Kaplan-Meier method, the log rank test and Coxs proportional hazard method, respectively. For over 40 years, patients were treated using different modalities: surgery followed by radiotherapy (6%), radiotherapy (78%), chemoradiotherapy (8%), and symptomatic treatment (8%). RESULTS The 5-year LRRFS was 18%, DFS was 15% and OS was 17%. gender (favoured females) was the only prognostic factor for LRRFS. For OS, the independent prognostic factors were performance status (favoured Karnofsky higher than 80), stage and year of start of the treatment (later than 1988 vs. earlier - 5-year OS 20% vs. 12%). 5-year OS in the following (strongly differentiated over the time) treatment modalities were: surgery followed by radiotherapy (66%), radiotherapy (16%), chemoradiotherapy (0%), and symptomatic treatment (0%). Of 44 patients treated with radiotherapy symptomatic partial response was observed in 32 patients and follow-up imaging studies revealed complete response in 5 patients, partial response in 25, stable disease in 4 or progressive disease in 4. CONCLUSIONS Radical treatment in patients in early stage and good performance status seems to be correlated with the improvement of survival. However, despite the fact that results of treatment are poor, radiotherapy offers symptomatic improvement.

85/Czynniki prognostyczne i predykcyjne u chorych na zaawansowanego raka krtani i krtaniowej części gardła napromienianych po indukcyjnej chemioterapii

Cel pracy Skojarzenie indukcyjnej chemioterapii (CHT) i radioterapii (RT) u chorych na zaawansowanego raka krtani i krtaniowej cześci gardla daje szanse na poprawe wynikow leczenia i zachowanie narządu glosu. Brak jednak czynnikow predykcyjnych mogących pomoc w doborze pacjentow do takiego sposobu leczenia. Celem pracy jest proba oceny klinicznych, histologicznych i molekularnych czynnikow prognostycznych i predykcyjnych u chorych na zaawansowanego raka krtanii i krtaniowej cześci gardla napromienianych po indukcyjnej chemioterapii. Material i metodyka W latach 1988 – 1997 u 108 chorych na zaawansowanego raka krtani i krtaniowej cześci gardla zastosowano CHT: cisplatyna + 5FU. Grupa obejmowala 101 mezczyzn i 7 kobiet. Mediana wieku wynosila 57 lat (zakres 36–80 lat). U 7 chorych stwierdzono II° zaawansowania klinicznego, u 27 – III°, u 74 −IV°. Sześciu chorych otrzymalo tylko jedną serie CHT. U 102 chorych podano 2–4 serii CHT. Nastepową RT zastosowano u 95 chorych. Wyniki leczenia analizowano w odniesieniu do czynnikow klinicznych, terapeutycznych, histologicznych i molekularnych. Archiwalny material histologiczny byl dostepny jedynie u 38 chorych. W tej grupie przeprowadzono retrospektywną ocene stopnia zroznicowania histolo-gicznego raka, ocene ekspresji EGFr, p53, Ki-67. Za kryteria oceny wynikow przyjeto odpowiedź na CHT (CR+PR), przezycie bez wznowy lokoregionalnej (LRRFS) i przezycie calkowite (OS). Wyniki Mediana okresu obserwacji wynosila 20 miesiecy. Odpowiedź na CHT uzyskano u 62% chorych. LRRFS i OS w odniesieniu do czynnikow klinicznych, terapeutycznych, histologicznych i molekularnych przedstawiono w Tabeli 1. Najwyzsze odsetki odpowiedzi na CHT uzyskano u chorych na raka w stopniu zroznicowania G3 oraz u chorych, u ktorych nie stwierdzono ekspresji EGFr. Wnioski Czynnikami predykcyjnymi odpowiedzi na CHT są: stopien zroznicowania histologicznego G3 oraz brak ekspresji EGFr. Zachowanie narządu glosu uzyskano u 46% chorych, ktorzy odpowiedzieli na CHT. Czynnikami prognostycznymi dla przezyc są: odpowiedź na CHT i ekspresja EGFr. Tabela 1 Czynnik N chorych Odpowiedź naCHT (%) (PR+CR) LRRFS (%) OS(%) Zaawansowanie kliniczne II 7 57 36 38 III 27 60 32 33 IV 74 64 33 23 Liczba seriiCHT 1 6 0 33 40 2–4 102 66 32 26 Odpowiedź na CHT yes 67 − 45 31 no 41 − 13 19 Zroznicowanie histol. G1+G2 18 56 39 27 G3 18 83 39 24 EGFr − 20 85 44 29 + 13 39 15 10 Ki-67 14 64 48 37 >54 24 70 30 17 p53 − 12 67 46 9 + 23 70 17 31

317. Prognostyczne i predykcyjne czynniki u chorych na zaawansowanego płaskonabłonkowego raka regionu głowy i szyi (HNSCC) napromienianych (RT) po indukcyjnej chemioterapii (CT)

Cel Zbadanie prognostycznej i predykcyjnej wartości wybranych czynnikow klinicznych, histopatologicznych i molekularnych poprzez określenie ich wplywu na szanse uzyskania odpowiedzi na CT i szanse uzyskania wyleczenia. Material i metody W latach 1988–1997 198 chorych otrzymalo indukcyjną CT (cisplatyna + fluorouracyl). Grupa skladala sie ze 184 mezczyzn i 14 kobiet, średni wiek 57 lat, zakres 36–80 lat. Drugi stopien zaawansowania klinicznego stwierdzono u 7 chorych, III-45, IV-146. 18 chorych otrzymalo 1 serie chemioterapii, 180 – 2–4 serii. RT zastosowano nastepnie u 156 chorych. Wyniki leczenia analizowano w zalezności od czynnikow klinicznych, terapeutycznych, histologicznych i molekularnych. U 77 chorych, w oparciu o archiwalny material histologiczny, dokonano ponownej oceny stopnia zroznicowania histologicznego oraz wykonano oznaczenia EGFr, p53, MIB1. Wyniki Mediana czasu obserwacji wynosila 16 miesiecy. Odpowiedz na CT uzyskano u 46%. Wyleczenia loko-regionalne (LRC) i przezycia calkowite (OS) w zalezności od czynnikow klinicznych, terapeutycznych, histologicznych i molekuarnych przedstawiono w tabeli. Najwyzszy odsetek odpowiedzi na CT uzyskano u chorych na raka krtani i gardla dolnego, chorych na raki o niskim stopniu zroznicowania (G3) oraz u chorych bez ekspresji EGFr. Wnioski Czynniki rokownicze odpowiedzi na CT to: niski stopien zroznicowania histologicznego oraz brak ekspresji EGFr. Czynniki prognostyczne wplywające na szanse uzyskania wyleczenia to: odpowiedz na CT oraz lokalizacja guza pierwotnego.

CONCURRENT CHEMORADIOTHERAPY IN LIMITED-STAGE SMALL-CELL LUNG CANCER. RESULTS OF A PILOT STUDY

Abstract Between January 1994 and February 1998, 32, limited-stage small-cell lung cancer patients were treated with concurrent chemoradiotherapy. Follow-up time ranged from 4 to 34 months, (median 14 months). Complete regression was obtained in 22 of the 30 patients, who received at least four courses of EP chemotherapy and a tumour dose of 50 Gy or more. In all, 2-year actuarial disease-free survival was 21 %. Brain metastases occurred in 8 (36.4 %) patients with CR, in 5/7 (71.4 %) patients without prophylactic cranial irradiation (PCI) and in 3/15 (20 %) patients after PCI. The survival rate was lower in patients with PCI, in Whom chest irradiation was started later than one month from the beginning of course 1 of EP chemotherapy. We have suggested a modification of the treatment protocol.