Ewa Chmielik

Is the 1-cm Rule of Distal Bowel Resection Margin in Rectal Cancer Based on Clinical Evidence? A Systematic Review

Background Distal intramural spread is present within 1 cm from visible tumor in a substantial proportion of patients. Therefore, ≥1 cm of distal bowel clearance is recommended as minimally acceptable. However, clinical results are contradictory in answering the question of whether this rule is valid. The aim of this review was to evaluate whether in patients undergoing anterior resection, a distal bowel gross margin of <1 cm jeopardizes oncologic safety.

High frequency of recurrent mutations in BRCA1 and BRCA2 genes in Polish families with breast and ovarian cancer

Germ‐line mutations in BRCA1 and BRCA2 genes result in a significantly increased risk of breast and ovarian cancer. Other genes involved in an increased predisposition to breast cancer include the TP53 gene, mutated in Li‐Fraumeni syndrome. To estimate the frequency of germ‐line mutations in these three genes in Upper Silesia, we have analyzed 47 breast/ovarian cancer families from that region. We found five different disease predisposing mutations in 17 (36%) families. Twelve families (25.5%) carried known BRCA1 mutations (5382insC and C61G), four families (8.5%) carried novel BRCA2 mutations (9631delC and 6886delGAAAA), and one family (2%) harbored novel mutation 1095del8 in the TP53 gene, which is the largest germline deletion in coding sequence of this gene identified thus far. The 5382insC mutation in BRCA1 was found in 11 families and the 9631delC mutation in BRCA2 occurred in three families. These two mutations taken together contribute to 82% of all mutations found in this study, and 30% of the families investigated harbor one of these mutations. The very high frequency of common mutations observed in these families can only be compared to that reported for Ashkenazi Jewish, Icelandic, and Russian high‐risk families. This frequency, however, may not be representative for the entire Polish population. The observed distribution of mutations will favor routine pre‐screening of predisposed families using a simple and cost‐effective test. Hum Mutat 16:482–490, 2000.

Tumour regression grading in patients with residual rectal cancer after preoperative chemoradiation

BACKGROUND AND PURPOSE To explore the utility of tumour regression grading (TRG, the amount of residual tumour cells in relation to extension of fibrosis) after chemoradiation of rectal cancer. MATERIALS AND METHODS Of 131 patients who received preoperative chemoradiation in the frame of the randomized trial, pathological complete response (pCR, TRG0), good regression (TRG1), moderate regression (TRG2), and poor regression (TRG3) were recorded in 17%, 31%, 31%, and 22% of patients, respectively. RESULTS The rates of ypN-positive category for TRG0, TRG1, TRG2, and TRG3 groups were 5%, 23%, 45%, and 46%, respectively, p=0.001. When ypT-category and TRG were evaluated by the logistic regression analysis, only ypT-category remained significant for independent prediction of the risk for mesorectal nodal metastases, p=0.006. The 4-year (median follow-up) disease-free survival (DFS) for TRG0, TRG1, TRG2, and TRG3 groups were 91%, 67%, 54%, and 47%. When patients with persistent disease (TRG1 vs. TRG2 vs. TRG3) were analyzed separately, TRG had no prognostic value for DFS, p=0.402. CONCLUSIONS TRG in patients with residual cancer had no prognostic value for the incidence of nodal disease and for DFS. Our findings and literature data question the need for the inclusion of TRG assessment into a routine pathological report.

The Risk of Relapse in Papillary Thyroid Cancer (PTC) in the Context of BRAFV600E Mutation Status and Other Prognostic Factors.

Introduction The risk of over-treatment in low-advanced PTC stages has prompted clinicians to search for new reliable prognostic factors. The presence of BRAF mutation, the most frequent molecular event in PTC, seems to be a good candidate. However, there is still lack of randomised trials and its significance has been proved by retrospective analyses, involving a large group of patients. The question arises whether this factor is useful in smaller populations, characterised for specialised centres. Thus, the aim of the study was to evaluate the use of BRAF mutation as a potential predictive marker in PTC patients. Material 233 PTC subjects treated between 2004-2006, were retrospectively analysed. Stage pT1 was diagnosed in 64.8% patients and lymph node metastases in 30.9%. Median follow-up was 7.5 years. BRAFV600E mutation was assessed postoperatively in all cases. Results BRAF V600E mutation was found in 54.5%. It was more frequent in patients > 45 years (p=0.0001), and associated with larger tumour size (p=0.004). Patients with tumours <= 10 mm were over-represented among BRAF negative population (p=0.03). No association between BRAF mutation and other clinicopathological factors was observed. BRAF status was associated neither with relapse nor with disease-free survival (DFS) (p=0.76). Nodal status, extrathyroidal invasion and tumour size significantly influenced DFS. Conclusion The risk of PTC recurrence is mainly related to the presence of lymph node metastases and extrathyroidal invasion, whereas no impact of BRAF V600E mutation has been demonstrated.

Identifying clinically relevant prognostic subgroups in node-positive postmenopausal HR+ early breast cancer patients treated with endocrine therapy: A combined analysis of 2,485 patients from ABCSG-8 and ATAC using the PAM50 risk of recurrence (ROR) score and intrinsic subtype.

506 Background: The aim of the study is to verify hypothesis that accelerated hyperfractionated preoperative radiotherapy for rectal cancer (HART) may provide a favorable long-term tolerance compared to treatment given in higher fraction (fx) doses (HYPO). This report focuses on early outcomes of the study. Comparison of late tissue reactions, evaluation of QLQ and long-term outcome in both trial arms is the ultimate goal. Methods: Between 2005 and 2011, 238 patients (pts) with cT3-4 resectable adenocarcinoma of the rectum were enrolled, which represents app. 70% of an overall trial size. The pts were randomly assigned to HART (n=122) or HYPO (n=116). The pelvis was irradiated 2x/day to the total dose of 42 Gy in 1.5 Gy/fx over 18 days (HART). Patients in HYPO received 39 Gy in 3.0 Gy/fx over 17 days. Postoperative chemotherapy (PCT) was given to ypN+ pts. Results: The actuarial perioperative complication rate at 1 year after treatment was 24.4% vs. 33.4% for HART and HYPO resp. (RR=0.69, p=0.13). The cru...

BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma

Background The molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation–its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior. Methods In order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset. Results Most of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(−) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project. Conclusion The study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.

Gene Expression Profiling in Hereditary, BRCA1-linked Breast Cancer: Preliminary Report

Global analysis of gene expression by DNA microarrays is nowadays a widely used tool, especially relevant for cancer research. It helps the understanding of complex biology of cancer tissue, allows identification of novel molecular markers, reveals previously unknown molecular subtypes of cancer that differ by clinical features like drug susceptibility or general prognosis. Our aim was to compare gene expression profiles in breast cancer that develop against a background of inherited predisposing mutations versus sporadic breast cancer. In this preliminary study we analysed seven hereditary, BRCA1 mutation-linked breast cancer tissues and seven sporadic cases that were carefully matched by histopathology and ER status. Additionally, we analysed 6 samples of normal breast tissue. We found that while the difference in gene expression profiles between tumour tissue and normal breast can be easily recognized by unsupervised algorithms, the difference between those two types of tumours is more discrete. However, by supervised methods of data analysis, we were able to select a set of genes that may differentiate between hereditary and sporadic tumours. The most significant difference concerns genes that code for proteins engaged in regulation of transcription, cellular metabolism, signalling, proliferation and cell death. Microarray results for chosen genes (TOB1, SEPHS2) were validated by real-time RT-PCR.

The prevalence of somatic RAS mutations in medullary thyroid cancer — a Polish population study

INTRODUCTION Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer (MTC). Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours, which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis. Thus, the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations. MATERIAL AND METHODS Somatic mutations (RET, RAS genes) were evaluated in 78 snap-frozen MTC samples (57 sporadic and 21 hereditary) by direct sequencing. Next, three randomly selected RET-negative MTC samples were analysed by the next generation sequencing. RESULTS RAS mutation was detected in 26.5% of 49 sporadic MTC tumours. None of all the analysed samples showed N-RAS mutation. When only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%, compared to 6% observed in RET-positive samples. Most of these mutations were located in H-RAS codon 61 (72%). None of 21 hereditary MTC samples showed any RAS mutations. CONCLUSIONS RAS mutations constitute a frequent molecular event in RET-negative sporadic medullary thyroid carcinoma in Polish patients. However, their role in MTC tumorigenesis remains unclear.

Dynamic risk stratification in the follow-up of thyroid cancer: what is still to be discovered in 2017?

The adequate risk stratification in thyroid carcinoma is crucial to avoid on one hand the overtreatment of low-risk and on the other hand the undertreatment of high-risk patients. The question how to properly assess the risk of relapse has been discussed during recent years and resulted in a substantial change in our approach to risk stratification in differentiated thyroid cancer, proposed by the newest ATA guidelines. First initial risk stratification, based on histopathological data is carried out just after primary surgery. It should be emphasized, that a high quality of histopathological report is crucial for proper risk stratification. Next, during the follow-up, patients are restratified considering their response to treatment applied and classified to one of the following categories: excellent response, biochemical incomplete response, structural incomplete or indeterminate response. This new approach is called dynamic risk stratification as, in contrary to the previous rigid evaluation performed at diagnosis, reflects a real-time prognosis and thereby substantially influences and personalizes disease management. In this review, we raise some unresolved questions, among them the lack of prospective studies, fulfilling evidence-based criteria, necessary to validate this model of risk stratification. We also provided some data concerning the use of dynamic risk stratification in medullary thyroid cancer, not yet reflected in ATA guidelines. In conclusion, dynamic risk stratification allows for better prediction of the risk of recurrence in thyroid carcinoma, what has been demonstrated in numerous retrospective analyses. However, the validation of this approach in prospective studies seems to be our task for near future.

An assessment of computed tomography laser mammography in breast cancer diagnosis

1 Department of Radiology, Medical University of Silesia, Katowice, Poland 2 Department of Radiology, Center of Oncology Institute, Gliwice Branch, Poland 3 Department of PET Diagnostics, Center of Oncology Institute, Gliwice Branch, Poland 4 Tumor Pathology Department, Center of Oncology Institute, Gliwice Branch, Poland 5 Department of Laboratory Medicine, University of Warmia and Mazury in Olsztyn, Poland 6 Department of Medical Physics, Center of Oncology Institute, Gliwice Branch, Poland