Cell type-dependent HIF1 α-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells.

Tumor hypoxia promotes neoangiogenesis and contributes to the radio- and chemotherapy resistant and aggressive phenotype of cancer cells. However, the migratory response of tumor cells and the role of small GTPases regulating the organization of cytoskeleton under hypoxic conditions have yet to be established. Accordingly, we measured the proliferation, migration, RhoA activation, the mRNA and protein levels of hypoxia inducible factor-1alpha (HIF-1α) and three small G-proteins, Rac1, cdc42 and RhoA in a panel of five human tumor cell lines under normoxic and hypoxic conditions. Importantly, HT168-M1 human melanoma cells with high baseline migration capacity showed increased HIF-1α and small GTPases expression, RhoA activation and migration under hypoxia. These activities were blocked by anti- HIF-1α shRNA. Moreover, the in vivo metastatic potential was promoted by hypoxia mimicking CoCl2 treatment and reduced upon inhibition of HIF-1α in a spleen to liver colonization experiment. In contrast, HT29 human colon cancer cells with low migration capacity showed limited response to in vitro hypoxia. The expression of the small G-proteins decreased both at mRNA and protein levels and the RhoA activation was reduced. Nevertheless, the number of lung or liver metastatic colonies disseminating from orthotopic HT29 grafts did not change upon CoCl2 or chetomin treatment. Our data demonstrates that the hypoxic environment induces cell-type dependent changes in the levels and activation of small GTPases and results in varying migratory and metastasis promoting responses in different human tumor cell lines.

Evaluation of patient knowledge, desire, and psychosocial background regarding postmastectomy breast reconstruction in Hungary: a questionnaire study of 500 cases.

BACKGROUND: According to European guidelines, breast cancer patients requiring mastectomy should be informed about available options regarding breast reconstruction. There are clear differences in the quality standards of oncoplastic care throughout Europe, with slight improvements in Central European countries like Hungary. The aim of the present investigation was to evaluate patients' knowledge and demand for postmastectomy breast reconstruction, as well as their psychosocial background regarding decision-making. MATERIAL AND METHODS: A questionnaire containing 15 structured questions was given to 500 breast cancer patients on the day before undergoing mastectomy. The questions focused on the emotional impact of the malignant disease and the loss of a breast; the importance of environmental conditions; the desire for breast reconstruction; and patients' knowledge and sources of information about the procedure. All answers were statistically analyzed in the context of patient age, marital status, educational level, and place of residence. RESULTS: Descriptive statistical results of the answers to all questions, as well as associations of the different aspects of the decision-making process, are presented. CONCLUSIONS: Hungarian breast cancer patients have very limited knowledge regarding breast reconstruction. We confirmed that patients scheduled for mastectomy have a great degree of anxiety due to their disease and breast loss. Almost 50% of the responders declared their desire for postmastectomy breast reconstruction. Patient's age, residence, educational level, marital status, and profession were confirmed as predictive factors in the decision-making process for breast reconstruction.

Boyden chamber-based method for characterizing the distribution of adhesions and cytoskeletal structure in HT1080 fibrosarcoma cells.

A 2D model was previously presented that describes the gliding motility of human fibrosarcoma cells. The model was based on the observation that adhesions are present only on the outer rim of the leading lamella of the semicircular cell. The present model describes the organization of adhesions and the cytoskeleton of migrating HT1080 fibrosarcoma and LX2 hepatic stellate cells in three dimensions. The migration assays were performed in a modified Boyden chamber using fibronectin, Matrigel, or collagen I as chemoattractants. The distribution of the adhesions was analyzed by confocal laser scanning microscope, and following decoration with heavy meromyosin, the organization of actin filaments was analyzed by electron microscopy. Double labeling was performed to study the relationship of the actin and vimentin filament network in the moving cells. Vinculin containing adhesions were observed only at the front of the cell in the form of a ring while passing through a filter pore of the Boyden chamber. Actin filaments were present only below the plasma membrane, except the very tip of the leading lamella. Vimentin intermediate filaments were localized around the cell nucleus behind the actin filament-rich lamella. This paper describes a model of the organization of adhesions and the cytoskeleton of migrating cells in the Boyden chamber. The model is based on the observation that adhesions are present only at the leading edge of the cell. The results extend the earlier 2D model of cell locomotion into 3D.

[Oncoplastic versus conventional breast conserving surgery. A comparison of clinicopathological findings, cosmetic results and quality of life in 60 cases]. / Onkoplasztikus versus hagyományos emlomegtartó sebészet. 60 eset összehasonlító klinikopatológiai, kozmetikai és életminoségi vizsgálata.

Oncoplastic surgical techniques seem to be suitable for realizing the goal of retaining cosmesis following radical removal of breast tumors. The purpose of the present study is to provide a clinical and pathological comparison of conventional (BCS) and oncoplastic (OPS) breast-conserving surgeries, supplemented by a subjective assessment of cosmesis and quality of life of patients, the first time on a Hungarian sample. The authors performed a retrospective assessment of clinicopathological data of 60 advanced oncoplastic and 60 conventional breast-conserving surgery cases, and following adjuvant radiotherapy, the authors also surveyed patients for cosmetic results and quality of life (EORTC BR23). Comparison of the results was performed by statistical methods. The two groups did not differ substantially in age, tumor location, breast size, type of axillary surgery (sentinel node biopsy vs. axillary lymphadenectomy), tumor grade and receptor status. Tumor size was significantly greater (p=0.0009), the rate of quadranectomies was higher (p=0.0032), metastases in the regional lymph nodes (p=0.0043) and the administration of adjuvant chemotherapy (p=0.0122) were more frequent in the OPS group. The duration of surgeries was longer (p<0.001), the weight of the specimens was greater (p=0.0308), the rate of completion surgeries due to microscopically positive surgical margins was significantly smaller (p=0.0306) in the OPS than in the BCS group. There was no difference between the two groups in the rate of complications and the time elapsed to the start of adjuvant treatment. The cosmetic outcome was clearly superior in the OPS group (p<0.001), and OPS patients had fewer arm, shoulder (p=0.0399), and chest pain (of the affected side) (p=0.0304), upper limb movements of the operated side were also better (p=0.006). The short follow-up period of the OPS group (mean 32.2 vs. 8.7 months in BCS and OPS, respectively) did not allow a meaningful assessment of oncologic endpoints. When compared to conventional breast conserving surgery, oncoplastic surgery is suitable for microscopically radical tumor removal even in case of larger lesions and true quadranectomy with longer surgical time but lower rate of complications without delaying the adjuvant treatments and thus not increasing the cancer risk. OPS yields better cosmetic results and higher patient satisfaction compared to BCS. More experience and longer follow-up is needed for the assessment of local tumor control achieved by OPS.

[Special aspects of breast cancer surgery in the elderly]. / Az emlorák sebészetének speciális szempontjai idoskorban.

Due to the aging population of Western countries and the high-quality health care system, breast cancer in the elderly generally affects women of good or satisfactory performance status pursuing active lifestyle. Over the last decade, it became evident that, in contrast to previous dogmas, age alone cannot be the contraindication to standard oncological treatment, and adequate multidisciplinary therapy aiming full recovery rather than compromise treatment is required. A number of specific aspects needs to be taken into account regarding surgery, such as life expectancy, co-morbidities, individual mobility, mental and emotional status as well as family background, which may result in changes to the individual treatment plan. Objective evaluation of the above mentioned parameters necessitates a close co-operation of professions. Interestingly, the evidence-based protocols of modern oncology often originate from the generalizations of results from clinical trials representing younger population, due to the typical under representation of elderly patients in clinical studies. Clinical trials should be extended to elderly patients as well or should specifically aim this patient population. The authors of the present paper review the special oncological and reconstructive surgical aspects of breast cancer in the elderly, such as breast conserving surgery versus mastectomia, sentinel lymph node biopsy, axillary lymphadenectomy or the omission of surgery in axillary staging, and questions regarding implant based and autologous reconstructive techniques.

[Sentinel lymph node biopsy in pregnancy-associated breast cancer]. / Orszemnyirokcsomó-biopszia terhességi emlorákban.

The incidence of pregnancy-associated breast cancer is rising. Sentinel lymph node biopsy is the method of choice in clinically node negative cases as the indicated minimally invasive regional staging procedure. Some reports have linked radioisotope and blue dye required for lymphatic mapping to teratogenic effects, the idea of which has become a generalized statement and, until recently, contraindication for these agents was considered during pregnancy. Today, there are many published reports of successful interventions with low-dose 99mTc-labeled human albumin nanocolloid, based on dosimetric modeling demonstrating a negligible radiation exposure of the fetus. These results contributed to the seemingly safe and successful use of sentinel lymph node biopsy during pregnancy, though generally it can not replace axillary lymphadenectomy in the absence of high-quality evidence. The possibility of sentinel lymph node biopsy should be offered to pregnancy-associated early breast cancer patients with clinically negative axilla, and patients should be involved in the decision making following extensive counselling. This paper presents the successful use of sentinel lymph node biopsy with low-dose tracer during two pregnancies (in the first and third trimesters) and, for the first time in Hungarian language, it offers a comprehensive literature review on this topic. Orv. Hetil., 154(50), 1991-1997.

[Autologous fat transplantation in the modern reconstructive surgery of breast cancer]. / Autológ zsírátültetés az emlorák modern rekonstrukciós sebészetében.

Autologous fat transplantation is often used in aesthetic plastic surgery, and is recently becoming increasingly popular in the reconstruction of soft tissue defects following oncological surgery. A still not standardized technique of fat transplantation for breast cancer reconstruction is rapidly getting popular. The procedure is not a passive volume replacement, but transplantation of biologically active tissue bearing endocrine, paracrine, exocrine functions and containing fat-derived stem cells, which in the tumorous environment raises many questions in relation to the oncological safety and diagnostic follow-up. Although long-term results based on prospective, randomized studies are not yet available, published clinical experience is promising and reveals an effective and surgically safe procedure if used with appropriate indications and techniques. The authors conducted a broad review of the literature, presenting indications, technique, molecular interactions, and potential risks of the clinical results of autologous fat transplantation in the breast cancer reconstructive surgery. The authors initiated that breast and plastic surgeons should promote adequate long term follow-up of breast cancer patients who underwent breast reconstruction with autologous fat transplantation by the establishment of national registries.

[Breast care nurse. A new specialist in the multidisciplinary care of breast cancer patients]. / Az emlorák-terápiás novér. Új szakember az emlorák multidiszciplináris ellátásában.

The uniform European structure and professional standards for high quality breast cancer care were established in conjunction with the European Organisation for Research and Treatment, the European Society of Mastology and the European Breast Cancer Coalition with the support of the European Parliament. Well-prepared professional teams including a new member called the breast care nurse serve as ground for special breast cancer centers with international accreditation that provide modern, evidence based, patient centered multidisciplinary oncological care. The responsibilities of the new qualified professional staff member include the psycho-social support of the patient and carers from the moment of diagnosis throughout the whole oncological treatment, the fostering of delivering information and communication between patients and specialists. As a result of the curriculum founded by the European Oncology Nursing Society, breast care nurses have become key members of the practice of holistic breast cancer care in countries where the European recommendations have already been implemented. Considering the expected rearrangement of national oncological care, the new sub-specialty is outlined for the first time in the light of the experiences gained at the National Institute of Oncology, Budapest, a comprehensive cancer center.

[Novel oral anticancer drugs: a review of adverse drug reactions, interactions and patient adherence]. / Az újabb orális tumorellenes készítmények mellékhatásprofiljának, interakcióinak és az adherencia problémáinak áttekintése.

Each aspect of oncological care is widely affected by the spread of oral anticancer agents, which raises several questions in terms of safe medication use and patient adherence. Over the past decade targeted therapies have appeared in clinical practice and revolutionized the pharmacological treatment of malignancies. Regular patient - doctor visits and proper patient education is crucial in order to comply with the therapy previously agreed upon with the oncologist, to increase patient adherence, to detect and to treat adverse effects in early stages. Since the information on the new medicines in Hungarian language is sparse it is the intention of the authors to give an overview of the basic knowledge, patient safety issues, adverse effects and interactions. Official drug information summaries and data on pharmacokinetics, interactions and adverse effects from the literature are reviewed as the basis for this overview.

[The place of skin-sparing mastectomy in oncoplastic breast surgery]. / A bõrtakarékos mastectomia helye a modern onkoplasztikus emlõsebészetben.

Despite its ever increasing popularity, there is no evidence-based confirmation so far on the results of skin-sparing mastectomy, introduced 20 years ago. However, the results of countless published retrospective, long-term trials seem to underpin the ability of the precisely implemeted procedure in early stage invasive and in situ breast cancers to yield the oncological results of modified radical mastectomy. As a result of the procedure involving special surgical techniques, the skin not affected by cancer can be preserved, which facilitates immediate reconstruction and improves cosmetic outcome. The effect of postmastectomy radiotherapy on the reconstruction needs to be considered at the time of the multidisciplinary design of the surgical procedure. The authors give a detailed description of the surgical techniques, and provide a wide review of the literature, for the first time in Hungarian language.

[Special considerations in breast cancer treatment of an augmented breast]. / Emlonagyobbító mutét után kialakult emlorákok ellátásának speciális megfontolásai.

Breast augmentation surgery involving the use of implants has been one of the most popular plastic surgical procedures for decades. As the multi-million female population who received breast implants ages, the risk of cancer is increasing rapidly, therefore the incidence of malignant disease in association with breast implants will increase as well. Although there is no relationship between tumor development and implants, these cases require special considerations in diagnostics, therapy and follow-up methods. Appropriate multidisciplinary treatment of tumors in augmented breasts corresponding with modern oncoplastic principles can only be accomplished based on adequate oncological, breast and plastic surgical knowledge. Supposing a possible increase of this condition in Hungary, too, authors provide a wide review of the literature on the special oncological and esthetic considerations, for the first time in Hungarian language.

[The role of ductoscopy in the modern diagnostics and therapy of breast diseases]. / A duktoszkópia szerepe az emlobetegségek modern diagnosztikájában és kezelésében.

Mammary ductoscopy is a modern, minimally invasive procedure that enables direct, in vivo observation of the mammary ductal system, primarily by nipple discharge. The rapidly developing device is suitable for aimed biopsy for further cytological or molecular examinations. High-tech equipments facilitate polypectomy or laser vaporization of certain intraluminal lesions, and play an important role in the direct surgical excision of the duct or the so-called terminal duct-lobular unit. The above listed facilitate the early diagnosis of malignancies even before imaging could detect them, and the control of high risk patients. Ductoscopy can foster surgical removal of ductal in situ tumors as anatomical units, thus enabling the optimization of radicality of breast conserving surgeries. Authors give a detailed description of the surgical techniques, and provide a wide review of the literature, for the first time in the Hungarian language. Orv. Hetil., 2011, 152, 1284-1293.

[Role of nipple sparing mastectomy in modern breast surgery]. / Az emlobimbó-megtartó mastectomia lehetséges helye a modern emlosebészetben.

Recently an increasing number of reports of clinical experience have been published on nipple-sparing mastectomy. By the preservation of uninvolved skin and the nipple areola complex, this surgical technique greatly facilitates immediate reconstruction and optimal aesthetic outcome. However, the procedure raises serious oncologic concerns regarding the risk of an occult or a newly formed primary tumor due to parenchyma left behind in the nipple and the retroareola. Despite the ever increasing popularity of the method, there is still no evidence based confirmation to it. According to data from scientific literature on nipple-sparing mastectomy, there is no straightforward consequence to be drawn on oncologic safety; therefore the procedure is not generally considered to be alternative to standard mastectomy. In the indication of risk reduction, justification of the intervention seems to be well supported, and is expected to foster a greater rate of acceptance of surgical prophylaxis in patients with higher risk diseases. The procedure should be carried out possibly in the framework of clinical trials, in well selected patients with suitable preoperative and postoperative examinations, applying precise techniques and adequate patient education, according to international guidelines. Further long-term results are needed to form a substantive expert opinion. Authors give a detailed description of the surgical techniques, and provide a wide review of the literature, for the first time in Hungarian language.

[Sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer]. / Orszemnyirokcsomó-biopszia neoadjuváns kemoterápiát igénylõ emlõrákoknál.

The indication of neoadjuvant chemotherapy has been recently extended; it is now applied not only in locally advanced breast cancer but in primarily resecable tumours as well, in order to promote breast conservation. Based on recent clinical results, the reconsideration of traditional lymph node dissection in axillary staging is timely in patients receiving neoadjuvant chemotherapy. Precise axillary staging needs surgical removal of lymph nodes. Based on prospective randomised trials, sentinel lymph node biopsy appears to be appropriate for axillary staging even in tumours requiring neoadjuvant treatment. The extended indication of sentinel lymph node biopsy raises several questions and problems. In the present paper the authors review the results and possible limitations of sentinel lymph node biopsy in relation to neoadjuvant chemotherapy.

[Main treatment and preventive measures for hand-foot syndrome, a dermatologic side effect of cancer therapy]. / A daganatterápia egyik dermatológiai mellékhatása, a kéz-láb szindróma fõbb kezelési és megelõzési elvei.

Hand-foot syndrome is a highly unpleasant adverse reaction caused by treatment protocols containing capecitabine (an orally administered drug), docetaxel, liposomal doxorubicin infusions or continuously infused 5-fluorouracil. It affects the skin of the palms and soles manifesting characteristic symptoms like erythema, inflammation, dysesthesia, pain, thickening, desquamation and cracking of the skin that may progress to cause wounds and ulceration, negatively influencing quality of life, psychological state and belief in recovery, which often result in the need of permanent or temporary interruption of the oncologic treatment and are potential sources of danger to the completion of the therapy. Adequate provision of the syndrome is of particular importance since a decline in adherence due to adverse events endangers precise maintenance of the self-sufficient oral treatment at home. Early recognition of symptoms, regular oncologic checkups and patient education on how to prevent or soothe the unpleasant skin toxicities could ensure a more successful treatment.

[Introduction of a clinical protocol for extravasation at the National Institute of Oncology, Budapest, Hungary]. / Extravazációs protokoll bevezetése az Országos Onkológiai Intézetben.

Extravasation of cytostatics occurs when an infusion containing a cytotoxic drug leaks into the surrounding perivascular and subcutaneous tissues. Incidence of cytostatic extravasation is found to be 0.1-6% according to the literature. Depending on the severity of complications, pain, loss of function in the extremities, or in extreme cases tissue necrosis necessitating an amputation may develop, drawing consequences like delay or interruption of the chemotherapy. Extent of complications is greatly influenced by the type of medication administered, general condition of the patient, and professional preparedness of staff providing the oncological health service. The protocol recently implemented in the National Institute of Oncology is a short, compact guidance for physicians and nurses providing oncological care, so by quick and adequate management of extravasation cases, severe complications could be prevented. More complex practical guidelines including algorithms could be created as a result of a wider collaboration, with the help of which oncological health professionals could easily cope with this rare problem. The authors describe in their review the implementation of the use of dry warm and cold packs, dymethylsulfoxide and hyaluronidase and their function within the algorithm of extravasation treatment.

[The potential role of SPECT/CT in the preoperative detection of sentinel lymph nodes in breast cancer]. / A SPECT/CT szerepe az orszemnyirokcsomó preoperatív meghatározásában, emlorákban.

Regional lymph node status is the most important prognostic factor in breast cancer. Sentinel lymph node biopsy is the standard method of axillary staging in early breast cancer patients with clinically negative nodes. Preoperative lymphoscintigraphy might support refining biopsy findings by determining the number and location of sentinel lymph nodes. In aged or overweight patients, in the presence of atypical or extra-axillary lymphatic drainage, non-visualized lymph nodes, or sentinel lymph nodes close to the isotope injection site, detection could be aided by a new, hybrid imaging tool: the single-photon emission computed tomography combined with computed tomography (3D SPECT/CT). For the first time in Hungarian language, authors overview the literature: all 14 English-language articles on the implementation of 3D SPECT/CT in sentinel lymph node detection in breast cancer are included. It is concluded that 3D SPECT/CT increases the success rate and quality of preoperative sentinel node identification, and is capable of providing a more accurate staging of breast cancer patients in routine clinical practice.

[Surgical challenges of chest wall and intra-thoracic desmoid tumors]. / Mellkasfali és intrathoracalis desmoid tumorok sebészi kezelésének kihívásai.

Chest wall desmoids are rare, borderline tumors. Radical surgical excision is considered to be the primary treatment. Tendency of desmoids to infiltrate the chest wall, the shoulder girdle, lung parenchyma, brachial plexus and vital components of the mediastinum provides a difficult surgical challenge in the efforts of achieving microscopically negative margins. Implantation of synthetic meshes and reconstructive plastic surgical techniques might be necessary to perform in order to preserve stability of the thorax, and to achieve optimal functional and aesthetic results. Multidisciplinary surgeries may result in a high rate of morbidity even in specialized centers. Within the framework of a retrospective multicenter review, authors assessed surgical techniques implemented in the case of patients who underwent surgical management for sporadically appearing chest-wall and intra-thoracic desmoids, and reviewed the relevant literature.

[Breast conserving oncoplastic surgery in the treatment of centrally located malignant breast tumors]. / Emlomegtartásos onkoplasztikai sebészi lehetoségek centrális elhelyezkedésu malignus emlotumorok kezelésében.

Central breast neoplasms account for 5 to 20% of breast cancer cases. For decades, they have been traditionally treated with mastectomy. The high incidence of involvement associated with these tumors necessitates nipple and areola resection. Oncoplastic surgical techniques, in well selected cases, enable the achievement of adequate cosmetic results following a radical central quadrantectomy along with the Nipple-Areola Complex. The present paper summarizes the indications, techniques and results of breast conserving surgeries of central breast tumors.

[Long-term experience with multidisciplinary therapy of twenty-six patients with dermatofibrosarcoma protuberans]. / Dermatofibrosarcoma protuberans multidiszciplináris kezelésével szerzett hosszú távú eredmények 26 betegnél.

UNLABELLED: Dermatofibrosarcoma protuberans is a low or moderate grade malignant, uncommon soft tissue tumor. The tumor is characterized by slow, but locally aggressive growth, low metastatic potential and high recurrence rate. Initial treatment is the radical surgical excision, using traditional wide excision or Mohs surgery. In case of positive surgical margin or local recurrence, radio-chemotherapy and recently imatinib mesylate is used as adjuvant therapy. AIMS: Twenty-six patients treated multidisciplinary for dermatofibrosarcoma protuberans were followed up. METHODS AND RESULTS: Mean age of the patients was 44.7 years; mean follow-up time was 60.57 months. In fifteen cases (57.7%) R0 resection was performed, while eleven patients (42,3%) received only R1 resection. An average of 1.87 resections was necessary in order to achieve R0 resection. Six patients (23%) received adjuvant radiotherapy and two patients (7.6%) adjuvant chemotherapy following the removal of the primary tumor. Sixteen patients had no local recurrence. Ongoing treatments were needed in the case of ten patients (38.4%) who developed local recurrence. One patient has deceased due to distant metastases. Using statistical methods we examined the effects indicated as prognostic factors in the literature on local recurrence, precisely, the effect of age above 50 years and surgical radicalism. CONCLUSIONS: Dermatofibrosarcoma protuberans can be successfully treated with multidisciplinary therapy. A larger number of cases and randomized multicenter investigations are needed in order to reach more accurate conclusion.