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REVIEW ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 3  |  Page : 461-468

Review literature on uterine carcinosarcoma


Department of Radiation Oncology, Tarini Cancer Hospital and Research Institute, Alwar, Rajasthan, India

Date of Web Publication14-Oct-2014

Correspondence Address:
Rajendra Singh
C-42 Ambedkar Nagar, Alwar - 301 001, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.138197

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 > Abstract 

Carcinosarcoma of the uterus is a rare gynaecological neoplasm, which is also known as malignant mixed mesodermal tumor. Traditionally this tumour has been regarded as a subtype of uterine sarcoma, and its origin remains controversial. The exact nature and prognosis was not clear in the past. It is believed that uterine carcinosarcoma have a Mullerian duct origin and have a capacity to differentiate into various mesenchymal and epithelial components. Regarding the histogensis, various theories have been given; of which 'conversion theory' was broadly accepted. Carcinosarcoma are mostly of monoclonal origin with the carcinomatous component being the driving force. This type of tumor is broadly divided into two groups, homologous and heterologous, depending on the characteristics of the stroma or mesenchymal components of endometrial tissue. It is more frequent in black women and postmenopausal women. Radiation is a possible etiological factor but the exact etiology is not known yet. However, tamoxifen may induce carcinogenesis in some patients. Its clinical feature is very similar to endometrial carcinoma i.e. postmenopausal vaginal bleeding, have a very aggressive behavior and a poor prognosis. This pelvic malignancy is treated by multimodality therapy including surgery, chemotherapy and radiotherapy. Here we are reviewing old concepts about the disease and modern understandings of the origin, classification, pathogenesis and recent advances in the treatment of the uterine carcinosarcoma.

Keywords: Carcinosarcoma, heterologous, homologous, monoclonal, radiation


How to cite this article:
Singh R. Review literature on uterine carcinosarcoma. J Can Res Ther 2014;10:461-8

How to cite this URL:
Singh R. Review literature on uterine carcinosarcoma. J Can Res Ther [serial online] 2014 [cited 2020 Jun 4];10:461-8. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/461/138197


 > Introduction Top


Carcinosarcomas are most bizarre uterine malignancy in women with diverse origin and histopathological characteristics. It is also known as mixed mesodermal tumor. [1] This tumor has been extensively discussed in literature since the time of Virchow. The exact nature and existence has been of much controversy. It has highly malignant in behavior and generally has a poor prognosis. [2] It accounts for less than 3% of all uterine malignancies. This tumor shows preponderance in postmenopausal women; [3] however, it may occur in premenopausal women as well.

Epidemiology and risk factors

It usually arises from the uterus but may also rarely appear in the ovary,  Fallopian tube More Details, cervix or peritoneum. [4],[5],[6] Occasionally it may develop from benign endometrial polyp. [7] The relative incidence of carcinosarcoma is about 1.5-3% of all uterine malignancies in various clinical series cases. Its incidence begins to increase at approximately 50 years of age and reached a maximum at the age of 75 years, and thereafter plateaus. [8] The median age of diagnosis is 62-67 years. [9] The overall incidence in black is twice as compared with white, but with no differences in survival for women, who received similar therapy.

The most commonly associated etiological factors of carcinosarcoma are previous exposure to radiation. [10] The frequency of carcinosarcoma after radiation exposure increased from a baseline rate as expected. It has been suggested that post-irradiation carcinosarcoma occur at a younger age than those arising de novo. [11] Other risk factors that are associated with the development of carcinosarcoma are exposure to tamoxifen, exogenous estrogen and obesity. Some authors have also suggested that null parity may be one of the risk factors. [12] Compared to endometrial neoplasm, carcinosarcomas are more likely to metastasize to the lungs and lymph nodes. [13] Surgical stage of disease at time of diagnosis is the most important prognostic factors that determine the prognosis of patients of carcinosarcoma. [14]

This tumor shares the risk factors with carcinoma of the endometrium; but the effects of these risk factors are not much stronger than the carcinoma endometrium. [15] However, there is great share of epidemiological risk factor of endometrial type endometrial carcinoma with carcinosarcoma, such as obesity, selective estrogen-receptor modulator. [16],[17],[18] Tamoxifen is also a risk factor for uterine carcinosarcoma but risk is lesser as compared with uterine carcinoma. The incidence of tamoxifen therapy related uterine carcinoma is 160 per hundred thousand per year for endometrial cancer and only 0.5 per lakh per year for uterine sarcoma. [19],[20] The relationship of developing uterine sarcoma due to exposure of tamoxifen has been described in many series but data is limited. However, the period between the exposure of tamoxifen to the patients and development of uterine sarcoma is ranged between 1½ years to 20 years. [21],[22] The endometrial carcinogenesis induced by tamoxifen is assumed to be due to higher concentration of tamoxifen metabolites in the endometrium as compared with serum. [23]

Classification

The classification of this uterine carcinosarcoma has been controversial since Kheres proposed the term mixed mesodermal tumor 1906. By 1935, Mcforland had collected 119 names representing to attempt designation of the gross or microscopic features in individual cases. [24] The basic neoplastic component is mesenchymal sarcoma often called "undifferentiated cellular sarcoma", endometrial sarcoma or fibrosarcoma. Carcinomatous elements are also frequent, out of which the most common is endometrial carcinoma.

Zenker in 1864 classified mesenchymal sarcomas in two groups based on types of cells present in the tissue of neoplasm, one as pure that contains the single cell type and other as mixed that contains more than one cell type. He also divided mesenchymal sarcoma as "homologous", those made up of tissue elements indigenous to the uterus and "heterologous", those containing tissue elements normally foreign to the uterus.

Ober in 1956 proposed an elaborate classification of mesenchymal sarcoma that is primarily based on Zenker classification. According to that classification any tumor of the corpus uteri that contains stromal sarcoma plus one or more heterologous elements or that contains two or more heterologous elements should be coded as "mixed mesodermal tumor". [25] The World Health organization (WHO) classified these uterine neoplasms as carcinosarcomas, an alternative designation is a malignant mixed Mullerian tumor.

Development

How does the tumor develope from different sites of the urogenital system? To understand their origin, first let us consider the embryonic development of the urogenital system. The primitive paramesonephric (Mullerian) duct developed from the mesenchyme of the urogenital ridge and the lining of celomic epithelium. This primitive duct ultimately undergoes differentiation into the body of the uterus, fallopian tubes, cervix and the upper part of vagina. This analog gives rise to all the uterine elements like myometrial smooth muscles, endometrial stroma and endometrial glands. Hence, the term "mixed Mullerian tumor" is applicable to all uterine tumors that are formed from both mesenchymal and epithelial elements. All these components are derived from Mullerian duct. These tumors are more common in uterus as compared to other sites most probably because the epithelial and mesenchymal cells at this site share a common embryonic origin.

The uterus is the most common site of gynecologic sarcoma. Uterine sarcoma can be divided into two general groups with an origin from either the endometrial or the mesenchymal compartment. Endometrial stromal sarcomas are derived only from the endometrial compartment; whereas, leiomyosarcoma is derived solely from the myometrial compartment and the mixed Mullerian malignant tumors have contributed from both compartments. [26]

Pathology

Uterine carcinosarcomas can be divided into homologous and heterologous subtypes depending on the characteristics of the stroma or mesenchymal component of the endometrial tissue. Earlier studies have shown that this has a prognostic importance but recent studies show histological features of stromal component that have no prognostic value. [27],[28] Grossly, the endometrial carcinosarcomas show sessile or polypoid, bulky often hemorrhagic mass usually filling the endometrial cavity or may protrude through the cervical os and fills the vaginal vault. [29] In some instances the tumor infiltrates deeply to myometrium of the uterus that leads to expansion of the walls. Less frequently, it may develop into a large pelvic mass in which uterus cannot be identified. In most cases myometrial invasion is obvious microscopic. The cut surface of this tumor is usually soft and moist and shows extensive necrosis, hemorrhage, grayish whitish or pinkish or purplish in appearance. Occasionally there are gritty or hard areas corresponding to bone and cartilage, and tumor surface is smooth. The size of tumor shows variation range from less than 2.0 cm to over 20 cm in diameter. Microscopically, carcinosarcoma has both the epithelial and mesenchymal elements. The malignant epithelial elements are typically an adenocarcinoma of endometriod type but serous, mucinous, clear cell, squamous cell and differentiated carcinomas are not infrequent. The mesenchymal elements are usually high grade and may be homologous or heterologous. In homologous tumors, it resembles endometrial stromal sarcoma or fibro sarcoma. Alternatively in heterologous tumor, mesenchymal differentiation can be found in association with areas of endometrial, stromal or undifferentiated sarcomas. The most common heterologous sarcoma is rhabdomyosarcoma, chondrosarcoma, osteosarcoma, and liposarcoma in decreasing order of frequency. The pattern of histology of high grade sarcoma is without specific differentiation, which is commonly found.

The carcinomatous components correspond to any Mullerian type. Commonly there is a sharp demarcation between the epithelial and mesenchymal components. The epithelial proportion in tumors varies from less to more and in some instances the sarcomatous components are predominant to such an extent that carcinoma may be difficult to identify. In such condition, extensive sampling is required to demonstrate the carcinoma. However, in some cases the carcinoma is predominant. The most common heterologous elements present in striated muscles, is identifiable, if the rhabdoblast has well differentiated and cross striated cells. For the staining and recognition of cross-striation, hematoxylin and eosin (H and E) and phosphotingstic acid hematoxylin or immunohistochemistry are required, respectively. The rhabdoblast appear as large cells with strap like, round or oval atypical nuclei and granular eosinophilc cytoplasm (racket cells). They are more difficult to recognize if single and sparse. Their presence is confirmed by immunohistochemistry using antibody against myoglobin, desmin, sarcomin and c-actin. Other rare elements are neuroectodermal tissue, melanoid and neuroendocrine elements. [30],[31] Whenever, serum α-fetoprotein is elevated, it is usually associated with yolk sac components or elements. [32],[33] Carcinomatous cells usually show a marked degree of anaplasia with variable size and shape of the nucleus, bizarre mitotic figure often giant cells i.e. pleomorphic cells.

Metastasis

The pattern of metastasis in carcinosarcoma depends on dominancy of the type of elements. Most studies suggest that the behavior of carcinosarcomas is governed by the carcinomatous element. Carcinoma typically spread through the lymphatic channels to nearby lymph nodes, while sarcoma frequently metastasize to the peritoneal cavity or hematogenously to the lungs. In sarcoma, lymph node metastasis is very uncommon. A study conducted by a Gynecologic oncology group (GOG) has shown that when extra uterine metastasis is found, only the epithelial component of the tumor is present. [34] Another study analyzed 22 cases of uterine carcinosarcoma where it was found that carcinosarcoma metastasize mainly to lymph nodes, ovaries, fallopian tubes and omentum and uncommonly to parametrium, bowels, liver and tonsils. All metastatic foci have only carcinomatous component. [35] This shows that the carcinomatous component has predominantly responsible for most metastasis and sarcomatous component has only a minor role. This view is supported by a number of studies conducted by different groups. [36],[37]

The patients of carcinosarcomas behave much like as high grade endometrial adenosarcoma and commonly metastasize to pelvic or par aortic lymph nodes. Leiomyosarcoma rarely involves nodal sites. When metastatic foci analyzed histologically, most often neoplastic nests in lymph vascular spaces were present and this mimics the epithelial component of neoplasm. [38],[39] One of the recent study (Ferguson et al.) have concluded that most carcinosarcoma have myometrial invasion (85%) mostly in less than half of the wall, lymhovascular invasion present in (60%) and carcinomatous component mostly invading the myometrium and lymhovascular spaces. [40] While studying the histological feature of 62 metastasis of uterine carcinosarcomas, Sreeman and Hart observed carcinoma only in 43, both carcinoma and sarcoma in 15 and 4 had only sarcoma. Based on these finding, authors speculated that the potential for sarcomatous in metastatic lesion is enhanced in anatomic sites with hollow space that allow polypoid growth such as peritoneal cavity and vagina. In view of this observation, we can say that primary carcinosarcoma in the genital tract and non-genital tract areas (for e.g. as an esophagus) are usually have polypoid neoplasm that tend to grow intraluminally in organ with hollow space. Finally, we conclude that sarcomatoid differentiation may be a marker of more aggressive behavior and of regression to more primitive stem cell like phenotype with the ability to give rise to epithelial or stromal progenitor cells. Usually the epithelial is the main component driving metastasis.

Traditionally carcinosarcoma considered as a subtypes of uterine sarcoma and oncological treatment have often been similar to those used for high grade uterine sarcoma, but patients failed to respond such treatment. This occurred due to different histology and the origin of tumors than the counterpart high grade uterine sarcoma. Therefore, four main theories regarding the histogensis of uterine carcinosarcoma are put forward, namely:

  • The collision theory suggests that the epithelial and mesenchymal elements have arisen independently and collided to give the impression of single mixed tumor
  • The combination theory suggests that both the components are derived from a single stem cell that has undergone diverge differentiation in the early evolution of tumors
  • The conversion theory suggests that the sarcomatous element is derived from carcinoma during the evolution of the tumor
  • Composition tumor is an endometrial carcinoma with reactive, atypical stroma.


The composition theory can be easily excluded because in these neoplasms, the sarcomatous component shows malignant histological feature. At present, there has been ample evidence that most but not all carcinosarcomas are of monoclonal origin i.e. being derived from single stem cell and the carcinomatous component is the driving force. [41],[42]

However, collision tumors rarely occur, but these are easily identified in the hysterectomy specimen where separate areas of carcinoma and sarcoma are present. Rarely carcinoma arises from pre-existing adenosrcoma. [43],[44],[45] The combination and conversion theory are not mutually exclusive in the prime nodes of histogensis of these neoplasms. To date, the conversion theory is broadly accepted, in which the sarcomatous component is derived from carcinoma.

Clinical characteristics

The carcinosarcoma arise mostly in the uterus and the majority of patients are presented with postmenopausal vaginal bleeding, and in some patient it is associated with a protuberant fleshy mass from the cervix. [28],[46] The presentation of uterine carcinosarcoma is based on the site of origin. Most patients present with irregular vaginal bleeding that may be slight or profuse. [47] The discharge may be bloody or watery. The patient could also complain gradual weakness, abdominal swelling, pain or abdominal mass and sometime increased abdominal girth. In advanced stages, the patient could complain of urinary tract or gastrointestinal symptoms.

Prognosis

Uterine carcinoma has a poor prognosis despite different treatment modalities used. It is usually worse than the corresponding set of high grade endometrial carcinoma, mainly in type I carcinoma with median survival of 18-36 months. For women with carcinosarcoma, their prognosis vary inversely with the initial stage at presentation, which include tumor size, lymph node metastasis, adenexal spread, lymphovascular invasion, histological grade, cell type and depth of myometrial invasion. Other factors also influence the prognosis of carcinosarcoma patients, like types of surgery, chemotherapy doses and regimens, adjuvant radiotherapy and patients' characteristics. Gloria et al., studied the serum CA125 levels in patients of carcinosarcoma and has shown that the preoperative elevation is a marker of extra uterine disease and deep myometrial invasion. [48] Postoperative CA125 elevation is an independent prognostic factor for poor survival.

Some studies have shown that hormonal receptor status may have prognostic value and help in determining the treatment modalities. One of the studies that was performed by Ansink et al., investigated the role of estrogen receptor (ER) and progesterone receptor (PR) receptor status in uterine carcinosarcomas and they concluded that the hormone receptor positivity may have associated with clinical outcome. They also drawn the conclusion, on the basis of receptor positivity in four patients out of 11 patients, three out of 11 patients were alive, and two of these had hormone receptor positivity in the epithelial sarcoma patients. [49] George et al., has shown that the prognosis is correlated with the type and degree of differentiation of the epithelial component of uterine carcinosarcoma. [50] Michel et al., study has shown the women who were postmenopausal or had a history of prior pelvic radiation, pain at presentation, clinical stage (II-III disease), uterine enlargement (>12 weeks) or an abnormal papnicolaou finding had a significant poor prognosis that those without these factors. [51]

Management

Surgery is often the principal means of diagnosis and is the primary treatment for all patients with uterine sarcoma. Uterine carcinosarcoma required combined modality approach which includes surgery, chemotherapy, radiotherapy and sometimes hormonal therapy. However, standard treatment is surgery which includes hysterectomy, bilateral salpingoophrectomy, lymph node dissection and resection of all gross disease. The stage of disease is important for the selection of type of treatment modality to be used. For e.g. if patients are in stage I and II, they are usually treated by total abdominal hysterectomy, and the bilateral salpingoophrectomy and omentectomy are also performed due to the propensity for abdominal dissemination. But patients may need adjuvant radiotherapy and chemotherapy. While in advanced stages (III, IV) tumors are treated by debulking surgery, chemotherapy, and adjuvant radiation.

In the past treatment approach for patients of uterine sarcoma was surgery and adjuvant radiation. At that time, chemotherapy was not used but adjuvant radiation was given infrequently both in pre and post operative stages. Controversy exsits regarding the effectiveness of radiation for improvement of survival. Some authors had reported that some patients showed improvement but others did not. [52] Carcinosarcoma staging to be performed in the same manner as endometrial carcinoma. One study has established that very good survival can be achieved in patients with carcinosarcoma, if they undergo surgical staging and post-operative radiation therapy, based on surgical finding followed by adjuvant chemotherapy with cisplatin and epirubicin. [53]

The role of radiation therapy as an adjuvant for the treatment of carcinosarcoma depends on post-operative residual disease or surgical inaccessible sites as well as lymph node status. Most of the studies have shown that radiotherapy reduces local recurrence. [54],[55] Callister et al., reported that radiotherapy reduced risk of local recurrence from 48% to 28% and prolonged the time to distant relapse but did not improve overall survival. One of the retrospective review was carried out in Canada, in patients of early stage uterine carcinosarcoma and their analysis report have suggestedthat the patient with poor histological prognostic factor may be benefited with adjuvant radiation therapy, which consequently improve in progression free and overall survival. [56] Piver et al., reported that only an estimated five year survival rate of 36% in surgically treated patients in early stage uterine carcinosarcoma. [57] While Gadduci et al., obtained a five year survival rate of 33% in early stage patients with uterine carcinosarcoma treated with a combination of radiotherapy and surgery. [58] The role of radiotherapy is controversial as different conclusions were reached by different small series. [59],[60],[61]

Radiation therapy has been most commonly used as an treatment effort to reduce pelvic failure. It has been advocated that radiation therapy to be given in doses of 5000-6000 cGy to the pelvis. Some authors also recommend intravaginal brachytherapy to deliver a boost to the vaginal cuff. Preoperative radiation is infrequently used and typically given in patients with bulky cervical involvement or parametrial extension. One of the recent data has reported that there has been a significant improvement in survival of the patients of uterine carcinosarcoma, who had received radiation. [62] Though the above study suggested benefit of pelvic radiation but it is limited to stage II, III, IV. While on stage I there was no statistically significant difference in survival between surgery-alone and in combination of surgery plus adjuvant radiation. [63]

The adjuvant radiation reduced chances of local recurrences as depicted by the number of trials like Major et al., [64] has found that pelvic radiation reduced recurrence rate in patients as compared with those who had not received radiation. It appears that patients treated with radiation have a greater degree of local tumor control, i.e. pelvic control, than without radiation. The majority of patients treated with radiation had recurrences or failure in site distant from the pelvis. This indicates patients require a systemic agent, which will reduce distant site of failure. Several published retrospective reports suggesting that combined adjuvant radiation and chemotherapy may impart an even longer survival mainly in stages I and II of the disease. [54],[65],[66] Uterine sarcoma has a high rate of distant metastasis even in the absence of intraperitonial or lymph node metastasis. It has been concluded that this is due to the high rate of hematogenous and lymphatic dissemination. [67] Even for surgical stage I disease, the recurrence rate is high. [34]

A number of drugs have been tried but only three chemotherapeutic agents have demonstrated effectiveness against the disease. These are ifosfamide, cisplatin and paclitaxel. [68],[69],[70],[71],[72],[73] Out of the three drugs, ifosfamide is the most active agent studied to date. It produced 25 complete responses and 12 partial responses (overall responses 36%) among 102 patients with no prior chemotherapy. Several reports have demonstrated the combination chemotherapy usually results in a higher response rate than single agent treatment. [74],[75] However, all combination regimens have had an impact upon survival. [76] A phase III trial carried out by GOG has shown greater response in patients who received a combination regimen (paclitaxel plus ifosfamide) than single drug chemotherapy. This also demonstrated that the addition of paclitaxel significantly improved overall survival and response rate. [69] One of the studies performed by GOG in patients of carcinosarcomas was to compare the effects of whole abdominal irradiation and cisplatin -ifosfamide based chemotherapy between two groups and to see the pattern of failure. On analysis it was found that only vaginal recurrence appeared to be increased in the chemotherapy cohort vs radiotherapy cohort. Other sites of relapse were similar except for a notable reduction in abdominal failure in the chemotherapy treated group as compared with radiotherapy treated group. Based on these patterns of recurrences the vaginal brachytherapy may be required for chemotherapy treated patients. [77] Recent studies have shown that ifosfamide based combination chemotherapy significantly improved progression-free survival and overall survival over ifosfamide alone in advanced persistent or recurrent uterine carcinosarcomas. [70] But this drug also gives better response in the early stage of disease. Several drugs have been tried in patients who have relapsed or persisting disease. These are cisplatin, doxorubicin, paclitaxel, ifosfamide, cyclophosphamide, liposomal doxorubicin, docetexel, gemcitabine, imitinib mesylate etc. All these drugs are usually given in various combinations and show a variable rate of response. Two recent phase II trials have been performed, that shows not much activity against the persistent or recurrent disease. One of them was based on gemicitabine and docetaxel drugs, which was given weekly in combination. The result indicated that this regimen is not active in patients with recurrent carcinosarcoma of uterus as second-line chemotherapy. [78]

The role of hormonal therapy has not been studied extensively in mesenchymal uterine tumors. One trial by Wang et al., [79] on recurrent uterine high-grade carcinosarcomas has shown that the dramatic response rate with letrazole therapy. For the possible role of hormonal therapy more trial will be needed to reach to any conclusion. Because of the aggressive nature of this disease and poor response rate to radiotherapy and chemotherapy biologic agents may have promising role to overcome the problem of treatment. The recent advances in the biology of uterine sarcoma made possible to define the treatment target. These are tyrosine kinase receptors and vascular endothelial growth factors. Some investigators have studied the biologic agents. Emoto et al., demonstrated the inhibition of vascular endothelial growth factor (VEGF) expressing malignant mixed tumor line by TNP-470 (an angiogenesis inhibitor). [80] Thalidomide was studied in recurrent or persists mixed malignant Mullerian tumor of the uterus by GOG, with no activity seen. Likewise, a trial conducted by Warner et al., in 2010 to assess the efficacy and safety of imatinib mesylate (Gleevec) in women with recurrent or persistent carcinosarcoma of the uterus concluded that imatinib mesylate was generally well tolerated but had minimal activity as a single agent in unscreened patients. In this study, sample size was very small giving the study a very limited power. To further explore the relationship between imitinib mesylate and clinical outcome in patients, the multi institutional collaborative trials are required. [81]


 > Summary Top


The carcinosarcomas are a biphasic malignancy consists of malignant epithelial and mesenchymal components, which usually appear to arise from transformation of pleuoripotent stem cell that have the potential to produce cells with divergent differentiation. Most but not all uterine carcinosarcomas are monoclonal in origin, rather than true collision tumor and should be regarded as metaplastic carcinosarcomas and adjuvant treatment should probably be similar to that directed against aggressive high grade endometrial sarcoma, rather than being sarcoma-based. This tumor warrants compressive surgical staging to assess tumor dissemination followed by systemic therapy in both early and advance stage diseases excluding patients with non -invasive disease. Chemotherapy is effective in advanced and metastatic stage of disease and is ineffective as adjuvant for most early stage uterine sarcoma and there is no proven role for chemotherapy in stage I disease following complete surgical resection. Enough evidence is present to support the use of pelvic radiation or vaginal brachytherapy with or without chemotherapy for surgical I and II stage patients of uterine carcinosarcoma.


 > Acknowledgment Top


I would like to gratefully thank Dr. Shyam Singh (clinical assistant in department of radiation oncology, Medcity, Gurgaon, Haryana) for valuable suggestion during writing of review article.

 
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