The role of cytochromes P450 and aldo-keto reductases in prognosis of breast carcinoma patients

Metabolism of anticancer drugs affects their antitumor effects. This study has investigated the associations of gene expression of enzymes metabolizing anticancer drugs with therapy response and survival of breast carcinoma patients.Gene expression of 13 aldo-keto reductases (AKRs), carbonyl reductase 1, and 10 cytochromes P450 (CYPs) was assessed using quantitative real-time polymerase chain reaction in tumors and paired adjacent nonneoplastic tissues from 68 posttreatment breast carcinoma patients. Eleven candidate genes were then evaluated in an independent series of 50 pretreatment patients. Protein expression of the most significant genes was confirmed by immunoblotting.AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control nonneoplastic tissues after correction for multiple testing. Significant association of CYP2B6 transcript levels in tumors with expression of hormonal receptors was found in the posttreatment set and replicated in the pretreatment set of patients. Significantly higher intratumoral levels of AKR1C1, AKR1C2, or CYP2W1 were found in responders to neoadjuvant chemotherapy compared with nonresponders. Patients with high AKR7A3 or CYP2B6 levels in the pretreatment set had significantly longer disease-free survival than patients with low levels. Protein products of AKR1C1, AKR1C2, AKR7A3, CYP3A4, and carbonyl reductase (CBR1) were found in tumors and those of AKR1C1, AKR7A3, and CBR1 correlated with their transcript levels. Small interfering RNA-directed knockdown of AKR1C2 or vector-mediated upregulation of CYP3A4 in MDA-MB-231 model cell line had no effect on cell proliferation after paclitaxel treatment in vitro.Prognostic and predictive roles of drug-metabolizing enzymes strikingly differ between posttreatment and pretreatment breast carcinoma patients. Mechanisms of action of AKR1C2, AKR7A3, CYP2B6, CYP3A4, and CBR1 should continue to be further followed in breast carcinoma patients and models.13-25222J, GACR, Czech Science FoundationCzech Science Foundation [13-25222J]; Internal Grant Agency of the Czech Ministry of Health [NT/14055-3

Paget disease of the breast and bladder cancer in man - rare synchronous multiple cancer

This article refers mammary Paget‘s disease (MPD) in men. It summarizes clinical and pathological presentation, epidemiology, making of diagnosis, appropriate treatment and prognosis. It emphasises common and different findings in male and female patients. In additional case report we present patient with two concomitant malignancies – MPD and bladder cancer. We describe diagnosis procedure and disease management in real clinical setting, which implies in various problems with overlapping of their treatment. © 2020 SOLEN s.r.o.. All rights reserved

Micrometastases in the sentinel lymph node - Necessity of axillar lymph node dissection?

Either radical mastectomy with axillar lymphadenectomy or conservative surgery with axillar lymph node dissection are the standard treatments for patients with breast carcinoma. Sentinel lymph node biopsy is a new method that - if negative - allows axillar lymph node preservation and so minimizes major complications associated with this operation (especially lymphedema of the upper extremity). However, the development of the diagnostic means gave rise to new clinical entities - micrometastases and findings of clusters or solitary cells in the sentinel lymph node. Even though the probability of non-sentinel lymph node metastasis is only 10 %, all patients with the finding of micrometastases in the sentinel lymph node are currently indicated for axillar lymph node dissection. Based on the present retrospective study involving 398 females with breast carcinoma, the authors define a risk group for non-sentinel lymph node metastases. The other patients may be spared from successive axillar dissection

Significance of resection margin as a risk factor for local control of early stage breast cancer

Breast conserving surgery combined with sentinel node biopsy represents currently the gold standard of treatment for early breast cancer. Although breast conserving surgery has been a widely accepted method for many years, there remain some highly controversial unresolved issues. The present analysis focused on the resection margin as one of the key factors for local control of the disease. Methods. Patient disease free survival and overall survival were collected from patients undergoing breast conserving surgery from 2004 to 2009 at the Department of Surgery Atlas hospital Zlin, Czech Republic. All patients with resection margin less then 5 mm were re-resected to achieve this clear resection margin of 5mm or more. Disease free survival (more specifically local relapse free survival, metastasis free survival and regional free survival) and overall survival were assessed. Results. The data on 330 patients were analyzed and 286/330 cases had complete follow-up. After a median follow-up of 70 months, 7 patients with isolated local relapse were identified (2.44%), 13 patients with distant metastasis without local relapse (4.54%) and 2 patients with relapse in the axilla without local relapse in the breast (0.7%). Conclusion. The final decision about the extent of resection margin remains controversial but based on the data on local control presented here it seems reasonable to increase the criteria for a clear resection margin to 5 mm

Locoregional Recurrence after Conservative Surgery by Early Breast Carcinoma

Konzervativní výkony u karcinomu prsu jsou alternativou mastektomie, avšak počet lokálních recidiv je větší. Cílem prospektivní studie bylo zjistit počet lokálních recidiv v prsu po konzervativních výkonech a určit rizikové faktory, které se na vzniku podílí, se zvláštním zaměřením na rozsah resekce. Do studie bylo zařazeno 330 pacientek. Lokální recidivy byly diagnostikovány 5x (1,51%). Dvě recidivy byly prvními známkami generalizace procesu. Tři byly velikosti 8 mm až 20 mm a nebyla prokázána generalizace. Doporučujeme dodržet vzdálenost 5 mm resekční linie od nádoru.Conservative surgery is considered as standard and alternative mastectomy in early stage breast cancer but number of local recurrence is higher. Aim of the study was to detect number of local recurrence after conservative surgery and to identify risk faktors of local recurrence especially importance of resection margins. Conservative surgery was performed in 330 patients. In breast local recurrence appeared in 5 (1,51%) patients and one had regional recurrence without in breast recurrence. We recommend keeping this resection distance

Distribution of metastatic affection in colorectal carcinoma using lymphatic mapping and radiation-navigated biopsy of the sentinel lymph node

AIM: The aim is to define distribution of the lymphonode metastatic affection in colorectal carcinoma and to evaluate a new methodology of lymphatic mapping and the sentinel lymphonode detection during colorectal carcinoma procedures in practice. USED METHODS: A method of peroperative lymphatic mapping using a Patentblue method in vivo. Rectoscopic peritumoral application of a radiocoloid in a two-day or a single-day protocol, scintigraphy, peroperative quants of radioactivity detection using a gamma probe. Radical or paliative tumor resection. Detection of the sentinel and non-sentinel nodes on a preparation ex vivo, divided according to levels. The metastatic affection distribution is assessed in three levels, marked U1 - U3, a S1 - S3. Histopathological examination of the nodes on series sections and, event, immunohistochemistry. RESULTS: The methods were used in 66 patients. A total of 970 nodes have been examined, with an average of 14.6 nodes/ patient. The metastases quantity decreases with distance from the tumor. The peritumoral levels (U1a S1) record the highest rates of metastases. In our patient group, 92% of the metastases were recorded in the S1 level, 4% in the S2 level and 4 % in the S3 level. CONCLUSIONS: The highest rate of metastases was recorded in the levels, closest to the tumor, therefore, in case of negative findings of sentinel nodes in the S1 level, the nodes from this level may be closely examined (using the method of series sections and immunhistochemistry) and the staging be established more precisely

Significance of the resection margin and risk factors for close or positive resection margin in patients undergoing breast-conserving surgery

Purpose: While positive resection margin (RM) in women undergoing breast-conserving surgery (BCS) represents a clear indication for re-resection, there is no unequivocal recommendation regarding the extent of the clear RM. The aim of this study was to define the optimal extent of the RM and the risk factors for close or positive RM. Methods: Patients scheduled for BCS had diagnosis confirmed before BCS (lumpectomy and quadrantectomy) by core biopsy. Sentinel lymph node biopsy followed BCS, and in case of positive findings axillary lymph node dissection followed. According to RM patients were categorized into 4 groups: 1) Patients with positive RM; 2) Clear RM 5 mm. In the first 3 groups where re-resection was indicated, the presence of tumor cells in the re-resection specimen was determined. All patients were followed for local recurrence. Results: 330patients undergoing BCS were studied. Median follow up was 39.6 months (range 12-70). Lumpectomy was performed in 111 cases and quadrantectomy in 219. In 19 cases the final procedure was mastectomy due to the impossibility to achieve negative RM. In 78 cases re-resection followed the primary procedure due to close or positive RM. Clear RM was < 2 mm in 12 cases (15%), 2-5 mm in 56 (72%) and positive margin in 10 (13%). Positive re-resection specimen was detected in 31 cases (39.7%) (in 10 cases with positive RM after primary procedure, in 3 with negative margin < 2 mm and in 18 with 2-5 mm margin). The re-resection rate according to the location of the primary tumor was 77% (n=60) in the upper outer quadrant, 8% (n=6) in the lower outer quadrant, 6% (n=5) in the upper inner quadrant, 4% (n=3) in the lower inner quadrant, and 5% (n=4) in centrally located tumors. Multicentric/multifocal tumor was diagnosed in 16 cases from which re-resection was indicated in 12 cases (75%). The number of re-resection according to tumor size was as follows: Tis 8 cases (30.7%), T1a none, T1b 14 (20.2%), T1c 34 (22.5%), T2 22 (28%). Re-resection was performed in 8 cases (31%) of ductal carcinoma in situ (DCIS), in 53 (22%) of ductal carcinoma, in 10 (37%) of lobular carcinoma, and in 7 (15%) of other histology. Five cases with local relapse were detected during follow up. Conclusion: The generally recommended clear RM of 1-5 mm is not sufficient because of the high number of positive specimens in the case of clear RM of 2-5 mm. The risk factors for close or positive RM are multicentric tumors and upper outer location of the primary tumor. Longer follow up will be needed to analyze local relapse rate according to RM status

Local recurrences after conservative surgery in breast carcinoma

Východisko: Lokální recidivy v prsu po konzervativní chirurgické terapii musíme hodnotit jako selhání primární léčby. Ve studii jsme sledovali počet lokálních recidiv po konzervativních chirurgických výkonech i ve vztahu k relapsům a úmrtí na karcinom. Metoda a výsledky: V období od 1.12. 1998 do 30.06.2004 bylo na chirurgickém oddělení nemocnice Atlas ve Zlíně léčeno 143 pacientů s karcinomem prsu, které podstoupily konzervativní výkon. U všech následovala radioterapie prsu a boost. Minimální makroskopická vzdálenost byla l,0 cm. Reexcise následovala, když minimální mikroskopická vzdálenost byla pod 5mm. Minimální dávka na lůžko tumoru a na celý prs byla 50Gy během 5-6 týdnů, denně 2Gy. Vždy byla nasazena brachyterapie. Kombinace chemoterapie s hormonální terapií následovala u 56x, jen chemoterapie 31x, jen hormonální terapie 31x, bez adjuvantní terapie 25x. Výsledky: Medián sledování byl 32 měsíců. Velikost nádoru dle TNM klasifikace: TIS 10, pT1a 1x, pTb 28x, pTc 55x, pT2 44x, pT3 5x. Stadium: 0 1x, I 58x, IIA 56x, IIB 24x, IIIA 4x. Lokální recidiva v prsu se objevila 5x, (3, 49%). Vzdálené metastázy byly registrovány 6x, (4,1%) a z nich 3x(2,09%) došlo k úmrtí základní onemocnění. Lokální recidiva byla pouze jedenkrát následována vznikem vzdálených metastáz a úmrtím na karcinom a to v intervalu 12 měsíců. Velikost primárního tumoru, který recidivoval, se pohybovala od l0mm do 45mm a recidivy objevily se v intervalu od 12 do 42 měsíců. Lokální recidivy byly řešeny mastektomií 4x, jedenkrát reresekcí. Závěr: Počet lokálních recidiv v souboru je v souladu s mezinárodním doporučením a je výsledkem moderní multimodální léčby.Backgrounds: Local recurrences in breast after conservative surgery are failure of primary therapy. The aim of the study was monitoring of local recurrences after conservative surgery and also relationships of local recurrences with disease free interval and survival. Materials and Methods: Between 1.12. 1998 and 30.06.2004, 143 patients with breast carcinoma were treated at Department of Surgery Atlas Hospital Zlin by conservative surgery. All patients received radiotherapy and boost in breast. Macroscopic free margins were l0 mm and reexcision were done in all patients with free margins less than 5mm. Dose of the radiotherapy whole breast and cavity were 50Gy, interval 5-6 weeks, daily 2Gy. Brachytherapy received all patients, combination of chemotherapy and hormonal therapy were 56x, only chemotherapy 31x, only hormonal therapy 31x and without adjuvant therapy 25x. Results: Median follow-up was 32 month. Tumor size according to TNM classification: TIS 10, pT1a 1x, pTb 28x, pTc 55x, pT2 44x, pT3 5x. Stage: 0 1x, I 58x, IIA 56x, IIB 24x, IIIA 4x. Local recurrences in breast were 5x, (3, 49%), distant metastases 6x, (4, 1%) and 3x (2, 09%) appeared distant metastases and death at breast carcinoma without local recurrence. Only in one patient local recurrence were followed by distant metastases and death. Interval from local recurrence and death was 12 month. Size of the original tumor with local recurrences was from 10mm to 45 mm. Interval from the time of initial treatment to local recurrences was from12 to 42 month. Surgical treatment of local recurrences included mastectomy 4x and conservative surgery 1x. Conclusion: Number of local recurrences is in correspondence with international guideline and results of modern multimodal therapy

Sentinel lymph node biopsy in the breast carcinoma in clinical practice

Cíl: V chirurgickém léčení časného karcinomu prsu biopsie sentinelové uzliny postupně nahradila disekci axilárních uzlin I. a II. etáže. Cílem studie je ověřit proveditelnost a spolehlivost metody v našich podmínkách. Metoda: V období od června 1998 do června 2007 bylo provedeno 458 biopsií sentinelové uzliny (SLNB). Ke značení uzlin byla nejdříve použita Patentblue a od roku 2000 kombinace radiokoloidu s gama sondou a Patentblue. Po SLNB následovala vždy disekce axily, od které bylo upuštěno u negativních sentinelových uzlin v roce 2002. Výsledky: Z celkového počtu 458 SLNB bylo do souboru zařazeno 382 pacientek. Pouze SLNB bez současné disekce axily byla provedena 170x. V 70 případech byla sentinelová uzlina pozitivní a následovala disekce axily. Non-sentinelové uzliny byly pozitivní 17x. Celkem bylo v základním souboru 382 biopsií vyšetřeno 899 sentinelových uzlin. Průměr byl 2,35. Falešně negativní uzliny byly zaznamenány u pacientek se SLNB a následnou disekcí axily 3x (4,6 %.) Nebyla registrována lokální recidiva v axile u negativní sentinelové uzliny bez následné disekce axily. Závěr: Biopsie sentinelové uzliny je bezpečná alternativa axilární disekce v chirurgické léčbě časného karcinomu prsu.Aim: In the management of early breast carcinoma, biopsy of sentinel lymph nodes has gradually replaced dissection of Level I and II axillary nodes. The aim of the study is to assess feasibility and reliability of the method in our conditions. Method: From June 1998 to June 2007, a total of 458 sentinel no de biopsies (SLNB) were performed. Originally, patent blue sentinel node mapping was used. Since 2000, a combination of radiocolloid application and a gamma- probe (detector), as well as the patent blue, has been used. Originally, SLNBs were followed by axi1lary dissections, however, in 2002, the procedure was waived in cases of negative sentinel nodes findings. Results: Out of the total of 458 SLNB patients, 382 female patients were inc1uded in the study. SLNB, without concomitant axi1lary dissection, was performed in 170 subjects. In 70 subjects, the sentinel node was positive and they were indicated for axillary dissections. Positive non-sentinel nodes were detected 17 times. In total, 899 sentinel nodes were examined in the study group of 382 biopsies. The mean was 2.35. False negative nodes were recorded in three cases in female patients with SLNB and axi1lary dissection (4.6%). No local relapses in the axi1la were recorded in negative sentinel node findings without subsequent axi1lary dissections. Conclusion: Sentinel node biopsy is a safe alternative to axi1lary dissection in the surgical management of ear1y breast carcinoma

Targeted axillary dissection with preoperative tattooing of biopsied positive axillary lymph nodes in breast cancer

Sentinel lymph node biopsy (SLNB) has emerged as an alternative to axillary lymph node dissection during breast cancer surgery during the last 2 decades. However, there are several controversies regarding the indication of the sentinel node biopsy after neoadjuvant chemotherapy which can convert positive lymph nodes to negative. The false-negative rate after neoadjuvant chemotherapy is unacceptably high. This high false-negative rate can be decreased by marking of the positive lymph nodes and removal during sentinel lymph node biopsy procedure in addition to the sentinel lymph nodes. The aim of this study was to investigate the possibility of carbon tattooing of the positive sentinel lymph nodes before neoadjuvant chemotherapy. In 2016, a prospective protocol was launched investigating the black carbon tattooing procedure of the suspective and positive axillary lymph nodes by injecting 0.1-0.5 carbon ink in normal saline under ultrasound guidance. All patients underwent black carbon tattooing of the suspected or positive axillary lymph nodes before the chemotherapy or one week before the primary surgery when chemotherapy was not indicated in the neoadjuvant setting. Sentinel lymph nodes together with lymph nodes marked by the black carbon ink were removed and histologically evaluated. So far 27 patients were treated under this protocol. Breast saving surgery was performed in 22 cases and mastectomy in 5 cases. All patients had invasive ductal carcinoma. In 20 patients neoadjuvant chemotherapy was indicated and in 7 patients primary surgery was performed. All lymph nodes marked by black carbon ink were successfully identified and removed. Sentinel lymph node biopsy was performed in 8 cases and sentinel lymph node biopsy followed by axillary dissection in 15 cases. Axillary dissection alone was performed in 4 cases. In 19 cases, the black carbon ink was present in the sentinel lymph node at the same time and in 4 cases carbon dye was present in other lymph nodes than the lymph node identified during SLNB, which corresponds to 17.4%. In the group of patients undergoing primary surgery, in one case from six, the sentinel lymph node was negative and the lymph node marked with carbon ink positive which represents false-negative lymph node and failure of the SLNB procedure. After neoadjuvant chemotherapy, there was no false-negative lymph node identified, but the conversion of the positive lymph nodes to negative was present in 10 cases (50%). There were no complications attributed to carbon ink tattooing. The results of positive sentinel lymph nodes tattooing have confirmed that this method is safe and allows a decrease in the false negativity rate during the sentinel node biopsy procedure