Why are Polish women diagnosed with invasive cervical cancer after negative cytology in the organized screening programme - a pilot reevaluation of negative Pap smears preceding diagnoses of interval cancers.

We have aimed to study reasons for reporting false-negative cytology results preceding diagnosis of interval cervical cancers (CC) in Poland. Data on all Pap smears collected in the organised screening in 2010-2015 were retrieved from the electronic database and linked with Polish National Cancer Registry (PNCR) data. False-negative results were defined as those sampled and assessed normal up to 3.5 years before diagnosis of invasive CC. False-negative slides were then seeded among twice as many randomly selected slides from the same lab and reviewed independently by three expert cytomorphologists. New diagnosis was established when experts agreed on a result. Of 48 selected false-negative slides, 1 case was diagnosed as a low-grade abnormality, 22 cases as a high-grade abnormalities, 3 cases as unsatisfactory for evaluation and 5 as no intraepithelial lesion of malignancy (NILM) by all three experts. There was no agreement in 17 cases. Percentages of agreement between experts was 64.6. Interobserver agreement rate was moderate with Fleiss' κ values. Our pilot study indicates evaluation errors as the main reason of false-negative cytology preceding interval CC in the organized screening programme in Poland. True lack of abnormal cells on the slide is the next reason.

Non-Small Cell Lung Cancer in Countries of Central and Southeastern Europe: Diagnostic Procedures and Treatment Reimbursement Surveyed by the Central European Cooperative Oncology Group.

This article analyzes the availability of different diagnostic procedures of non-small cell lung cancer (NSCLC) and the reimbursement landscape of drugs for NSCLC in countries of central and southeastern Europe (CEE). A survey was conducted by the Central European Cooperative Oncology Group. Results of the survey show that both availability and reimbursement of diagnoses of molecular alterations in NSCLC, the detection of which is essential for therapeutic decisions, varies widely between countries of CEE. Not only is "reflex" testing often substituted by analyses performed only "on demand," but reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. It was concluded that a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. IMPLICATIONS FOR PRACTICE: This article provides an overview of the limitations in lung cancer treatment in countries of central and southeastern Europe, as well as the reimbursement status of various lung cancer treatment regimens in these countries, which directly impacts treatment options.

NSCLC molecular testing in Central and Eastern European countries.

BACKGROUND: The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines. METHODS: A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period. RESULTS: A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers. CONCLUSIONS: Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges.

Assessment of diagnostic value of cytological examination in lung carcinoma in own material obtained by EBUS and EUS methods.

The aim of the study was the evaluation of the efficiency of cytological examination of the material obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound bronchoscope-guided fine needle aspiration (EUSB-FNA) methods in the diagnosis of lung carcinoma. The usefulness was also assessed of the material obtained in that way for immunocytochemical and molecular tests in the diagnosis of non-small cell lung carcinoma. The material included cytological preparations obtained by EBUS and EUS methods. It was demonstrated that the technique made it possible to obtain diagnostic material from 94% of patients. A retrospective thorough analysis of those cases was the basis for the discussion of diagnostic difficulties.

[The role of systemic therapies of non-small cell lung cancer and malignant pleural mesothelioma: updated expert recommendations]. / Rola systemowych metod leczenia u chorych na niedrobnokomórkowego raka pluca i zlosliwego miedzybloniaka oplucnej: uaktualnione zalecenia ekspertów.

Lung cancer is the leading cause of cancer related death in Poland. About 85% of all lung cancer constitutes non-small cancer (NSCLC), in which the role of cytotoxic and molecularly targeted drugs is increasing. This article presents the current evidence- based recommendations for the use of these methods in clinical practice in NSCLC and malignant pleural mesothelioma.

Prognostic value of synaptophysin and chromogranin a expression in patients receiving palliative chemotherapy for advanced non-small-cell lung cancer.

BACKGROUND: Chemotherapy is the principal treatment method for patients with advanced non-small-cell lung cancer (NSCLC). Treatment with platinum-based and novel chemotherapeutic regimens, compared to monotherapy, slightly increases the response rates to 20-40%. The predictive and prognostic values of molecular factors are highly variable; however, data on clinical-demographic factors are still burdened by significant limitations. OBJECTIVES: The aim of this study was to assess the prognostic value of synaptophysin and chromogranin A protein expression in patients receiving palliative chemotherapy for advanced NSCLC. METHODS: The study population consisted of 23 women and 116 men. The median age was 57.3 years. Expression of synaptophysin and chromogranin was assessed using a two-step model of immunohistochemical staining. Level 0 represented lack of activity, while level 1 represented its expression. RESULTS: Expression of synaptophysin and chromogranin A was observed in 12 (8.6%) and 5 (3.6%) patients, respectively. The risk of death was significantly lower in patients with expression of synaptophysin (p = 0.008) and chromogranin A (p = 0.014). The 12- and 24-month survival rate of patients with synaptophysin expression was 64% (95% CI 0.35-0.93), while for patients without expression it was 46% (95% CI 0.36-0.56) and 16% (95% CI 0.07-0.25), respectively. The 12- and 24-month survival rate of patients with chromogranin expression was 80% (95% CI 0.44-1.00), while for chromogranin A-negative patients it was 47% (95% CI 0.37-0.57) and 19% (95% CI 0.10-0.28), respectively. We did not observe associations between expression of synaptophysin and chromogranin A and the other typical prognostic factors. CONCLUSIONS: Expression of synaptophysin and chromogranin A was associated with a longer median overall survival and might have prognostic value. These results should be confirmed in a prospective study.

New Genetic Technologies in Diagnosis and Treatment of Cancer of Unknown Primary.

Cancer of unknown primary (CUP) represents a rare oncological and heterogeneous disease in which one or more metastases are present, but the location of the primary site is unknown. Pathological diagnosis, using immunohistochemistry, of such metastatic materials is challenging and frequently does not allow for determining the tissue of origin (ToO). The selection of systemic therapy in patients with CUP is usually based on empiric grounds, and the prognosis is generally unfavourable. New molecular techniques could identify the tissue of origin and be used to select systemic agnostic therapies in various malignancies with specific molecular abnormalities. Targetable driver mutations or gene rearrangements in cancer cells may be identified using various molecular assays, of which particularly valuable are next-generation sequencing techniques. These assays may identify tumour sources and allow personalized treatments. However, current guidelines for CUP management do not recommend routine testing of gene expression and epigenetic factors. This is mainly due to the insufficient evidence supporting the improvement of CUP's prognosis by virtue of this approach. This review summarizes the advantages and disadvantages of new genetic techniques in CUP diagnostics and proposes updating the recommendations for CUP management.

A roadmap for a comprehensive control of cervical cancer in Poland: integration of available solutions into current practice in primary and secondary prevention.

In Poland, cervical cancer incidence and mortality still remain considerably higher than in Western European countries or North America. Recent data indicate decreasing trends in women younger than 60 years and stable trends in older women. In this article, we identified obstacles in primary and secondary prevention of cervical cancer in Poland. We analysed local legislation, management structure and organization of cervical cancer prevention in Poland and reviewed solutions available and implemented in other European countries. The main weaknesses include: (i) very low coverage of organized screening; concurrent unregistered opportunistic screening with unknown coverage and high test consumption (ii) suboptimal quality assurance in organized screening and no external quality assurance in opportunistic screening (iii) very low coverage of human papillomavirus vaccination that is not centrally reimbursed (iv) absence of pilot evaluation of (a) interventions that may improve population coverage and (b) performance of new preventive strategies. The proposed solutions are multifaceted and involve: (i) legislative and organizational regulation of cervical cancer screening aimed at comprehensive registration of procedures, data access and quality assurance (ii) pilot testing and implementation of new ways to increase coverage of cervical cancer screening, in particular among older women (iii) pilot evaluation with possible introduction of human papillomavirus-based screening and (iv) inclusion of human papillomavirus vaccination into the reimbursed national immunization program.

The characteristics of the sentinel lymph node metastasis in predicting the axillary lymph node status in patients with breast carcinoma.

INTRODUCTION: Lymph node metastases are the most significant prognostic factors in patients with breast carcinoma. A positive sentinel lymph node (SLN) biopsy is followed by an axillary lymph node (ALN) dissection. In sentinel lymph node negative cases the risk of positive non-sentinel ALN is very low though not absent. The aim of this study was to determine predictive factors for non-sentinel lymph node metastases on the basis of sentinel lymph node metastasis characteristics as well as features of the primary tumour. MATERIAL AND METHODS: 128 patients who had a positive SLN biopsy for breast carcinoma in 2005-2007 were identified. The breast carcinoma metastases in each SLN were assessed according to their location within the node (subcapsular, mixed subcapsular and parenchymal, parenchymal, multifocal or extensive) and metastatic infiltration of perinodal tissue was also reported. These data were correlated with the ALN involvement and characteristics of the primary tumour. RESULTS: The strong predictors of the ALN metastasis included the SLN metastasis diameter (7.6 vs. 4.4 mm) and size classified according to WHO classification (ITC 0 vs. 100%, micrometastasis 23.5 vs. 76.5%, macrometastasis 51.9 vs. 48.1%). The SLN metastases with a diameter of above 3 mm were associated with approximately twice more frequent ALN metastases. In an extensive location of SLN metastasis the highest percentage of ALN metastases was found (65 vs. 35%). The weak predictors of ALN metastases were: primary tumor diameter (> 2 cm), immunohistochemical HER2 positive status, infiltration of sentinel perinodal tissue by metastasis, histological primary tumour grade. CONCLUSIONS: Some additional details, which can be easily evaluated in a routine SLN examination in breast carcinoma, have a predictive value of the ALN metastatic status and should be included in the histopathological report.

[Systemic treatment of non-small cell lung cancer--recommendations based on the results of reliable clinical trials]. / Systemowe leczenie niedrobnokomórkowego raka pluca i zlosliwego miedzybloniaka oplucnej: uaktualnione zalecenia oparte na wynikach wiarygodnych badan klinicznych.

Lung cancer is in Poland the most common malignancy. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung tumors. In the multidisciplinary treatment of non-small cell lung cancer patients the role of chemotherapy and, most recently, molecular targeted therapy is increasing. In 2005 we published recommendations for systemic treatment of non-small cell lung cancer and mesothelioma. As many new studies have been published since, it was necessary to update this document. We present here a consensus statement on this topic, prepared by a panel of experts in oncology, thoracic surgery, pathology and pneumonology.

Molecular genetic defects in endometrial carcinomas: microsatellite instability, PTEN and beta-catenin (CTNNB1) genes mutations.

PURPOSE: The present study aims to assess the incidence of microsatellite instability (MSI) and mutations in the PTEN and beta-catenin (CTNNB1) genes in endometrial carcinomas and to analyze the detected defects in these factors in relation to each other and to the clinico-pathological features of tumors. MATERIALS AND METHODS: In a series of 56 endometrioid endometrial carcinomas, the status of MSI was determined using nine polymorphic markers, and mutations in all exons of the PTEN gene and in exon 3 of the CTNNB1 gene were evaluated by SSCP and sequencing methods. RESULTS: Microsatellite instability was found in 18 carcinomas (32.1%, MSI+); the remaining 38 tumors were microsatellite stable (MSI-). In 15 cases (26.8%), a loss of heterozygosity (LOH) at the studied microsatellite markers also occurred. In 29 carcinomas (51.8%), mutations were found in the PTEN gene and in nine tumors (16.1%) in the CTNNB1 gene. PTEN mutations occurred significantly more frequently in MSI+ than in MSI- tumors (77.8 vs. 39.5%, p = 0.007), but, except for one, none of them was attributable to MSI. In contrast, incidence of CTNNB1 mutations in MSI+ and MSI- tumors no significantly differed between themselves (16.7 vs. 15.8%, p = 0.760). Interestingly, mutations in the CTNNB1 gene most frequently coexisted with mutations in the PTEN gene (7/9, 77.8%). However, this finding requires future verification on a larger group of cases. The incidence of MSI and PTEN, but not CTNNB1 mutations, was significantly more common in poorly, than in well-to-moderately, differentiated tumors (G3 vs. G1 + G2; p = 0.042, 0.039 and 0.958, respectively). CONCLUSION: We conclude that most frequently occurring mutations in the PTEN gene may be a key event for the tumorigenesis of endometrioid endometrial carcinomas, while coexistence or absence of microsatellite instability or mutations in the CTNNB1 gene may reflect the heterogeneity of molecular mechanisms contributing to the development of these tumors.

Human breast cancer tissue expresses high level of type 1 5'-deiodinase.

Type 1 5'-deiodinase is one of two isoenzymes that participate in conversion of prohormone thyroxine into triiodothyronine (T3). A decrease in type 1 5'-deiodinase expression was observed in renal clear cell carcinoma, thyroid cancer, and lung cancer. The aim of this study was to evaluate type 1 5'-deiodinase activity and mRNA level in breast cancer tissue and non-cancerous surrounding breast tissue. Material was collected from 36 patients undergoing radical mastectomy or local tumor resection. In all non-cancerous breast tissues, type 1 50-deiodinase activity was found to be at a very low or immeasurable level, and type 1 5'-deiodinase mRNA was detected only in 2 out of the 36 samples. By contrast, 20 out of the 36 breast cancer tissues, mainly grades G1 and G2, expressed abundant type 1 5'-deiodinase activity and/or a high mRNA level. Our data demonstrated the presence of type 1 5'-deiodinase in well-differentiated breast cancer tissue. High enzymatic activity of type 1 50-deiodinase can potentially lead to an increase in the production of T3, which may affect target gene transcription, including genes responsible for energy expenditure, growth, differentiation, and proliferation.

Incidence of lymphomas in Poland. The national register data for 2006.

In Poland, data on the incidence and mortality associated with malignancies are collected by the National Cancer Register (NCR). The Register is based on the International Classification of Diseases (ICD-10), which does not allow for assessing the incidence of lymphatic neoplasms classified according to the WHO classification system enforced since 2001. Under the National Program of Combating Neoplastic Diseases that focuses on detection and diagnosing malignant lymphomas in Poland in order to record and precisely classify lymphatic neoplasms, in 2006, the Haematopathological Section of the Polish Society of Pathologists, acting in collaboration with the Polish Lymphoma Study Group, initiated a nationwide register of lymphatic malignancies, a continuation of the Register of Lymphomas for the Province of Malopolska. The register not only renders epidemiological data more specific, but also allows for a comprehensive quality control.

[Small-cell lung cancer diagnostic and therapeutic recommendations of Polish Lung Cancer Group]. / Drobnokomórkowy rak pluca - zalecenia diagnostyczno-terapeutyczne Polskiej Grupy Raka Pluca.

Small-cell lung cancer is characterized by an aggressive clinical course with high tendency for early dissemination. At presentation, patients are usually symptomatic and with hilar or mediastinal mass at radiography. Staging should be focused on identifying any evidence of distant spread. Chemotherapy including cisplatin and etoposide is a cornerstone of treatment for all patients. Limited-stage disease should be managed by chemotherapy combined with concurrent chest irradiation. All patients who achieve complete response should be considered for elective cranial irradiation. Surgical treatment may be used in highly selected patients with TNM stage I disease, and surgery should always be combined with chemotherapy. Extensive-stage disease should be managed by multi-agent chemotherapy alone. Long-term survivors should undergo careful monitoring for development of a second primary tumour.

Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland.

Targeted therapy of non-small cell lung cancer (NSCLC) patients with mutations in the epidermal growth factor receptor (EGFR) gene has been associated with improved prognosis. However, there is a shortage on data from real-world clinical practice in management of EGFR-positive NSCLC patients in Poland. The present study retrospectively analyzed data from the INSIGHT study to evaluate the incidence and clinical management of EGFR-positive NSCLC in Poland. The authors additionally aimed to identify predictors of the EGFR mutation and factors associated with clinical stage of the tumor at diagnosis. Incidence of EGFR mutations was 11.8% and the most common mutations were a deletion on exon 19 and an L858R substitution on exon 21. Mutations were strongly associated with female gender [male vs. female odds ratio (OR): 0.51; P=0.004] and never having smoked (current/past smoker vs. never smoked OR: 0.16; P<0.001), and advanced clinical stage (stage IV vs. stage I/II OR: 2.89; P=0.029). Patients with EGFR mutation were also observed to have a greater propensity to develop bone metastasis (OR: 11.62; P=0.008). Multivariate regression analysis demonstrated that patients with past or current smoking history or a poor performance on the Eastern Cooperative Oncology Group (ECOG) scale were less likely to have the EGFR mutation. Furthermore, EGFR-positive patients with greater ECOG scores and a tumor other than adenocarcinoma or squamous cell carcinoma were more likely to present advanced tumors. Early screening for EGFR mutation and the use of EGFR-targeting therapies as first-line agents may lead to better prognosis and successful clinical management of EGFR-positive NSCLC patients.

Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer in the Real-World Setting in Central Europe: The INSIGHT Study.

The ImplementatioN of perSonalized medicine In NSCLC in Central Europe: EGFR testing, Histopathology, and clinical feaTures (INSIGHT) observational study assessed both implementation of epidermal growth factor receptor (EGFR) mutation testing and treatment of patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) in a real-world setting in Central Europe. A total of 1785 patients from 14 cancer centers of six Central European countries were enrolled. EGFR mutations were detected in tumors of 13.8% of the patients. More than 70% of patients with advanced EGFR mutation-positive NSCLC received EGFR tyrosine kinase inhibitors as first-line therapy. The INSIGHT study demonstrated the establishment of EGFR mutation testing, a mutation rate consistent with other Caucasian patients populations, and adherence to current guidelines regarding treatment of patients with EGFR mutation-positive tumors in Central Europe.

HER2 status in breast cancer determined by IHC and FISH: comparison of the results.

HER2 (human epidermal growth factor receptor 2) status became an important prognostic and predictive factor in breast carcinoma clinical management. There are two main techniques of evaluation of HER2 status: immunohistochemistry (IHC) for the protein expression and fluorescence in situ hybridization (FISH) for amplification of HER2 gene. The aim of the study was to compare the results obtained by IHC and FISH methods in determination of HER2 status in breast cancer. Three hundred and sixty breast cancer specimens were examined. Patients were operated in the Oncology Centre in Warsaw. IHC and FISH were performed in every case. IHC was performed with DAKO HercepTest and FISH with Oncor-QBiogene reagents. IHC results were classed into 4 groups, accordingly to the four-tier DAKO criteria system (0, 1+, 2+, 3+). FISH results were divided into three main categories: NA--no amplification, LA--low amplification and HA--high amplification. The number of copies of chromosome 17 was also assessed. Over 90% of cases described by IHC as 3+ exhibited amplification of HER2/neu gene. Remaining cases were positive with IHC, but presented no gene amplification. This might be due to the subjective assessment of the membrane staining. Another possibility is that overexpression of the protein was caused by mRNA stability or disorders in receptor degradation. The majority of cases classed by IHC as 2+ were also negative by FISH (80%). One fifth of IHC 2+ tumours were found to exhibit gene amplification. Remaining cases showed no amplification of HER2/neu gene, combined with aneuploidy of chromosome 17. All cases described by IHC as 0/1+ were also HER2-negative by FISH. IHC is well-established method of assessing HER2 status in breast cancer. Nonetheless, a group of cases described as 2+ should be additionally examined using FISH. The results obtained by the latter method are more reliable. In order to improve accuracy and gain the highest quality of HER2 status evaluation, in 2+ cases both methods should be applied.