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Morphological transformation, autonomous proliferation and colony formation by chicken heart mesenchymal cells infected with avian sarcoma, erythroblastosis and myelocytomatosis viruses.

Normal chicken heart mesenchymal cells at low density in monolayer culture in plasma-containing medium have a polygonal shape and are proliferatively quiescent. The combination of epidermal growth factor and insulin at hyperphysiological concentration, an insulin-like growth factor surrogate, causes these cells to assume a fusiform shape and to increase 40-fold in number during four days of incubation. These mitogenic hormones do not, however, induce normal chicken heart mesenchymal cells to form colonies in agarose suspension culture. Chicken heart mesenchymal cells infected with the Schmidt-Ruppin or Prague-A strains of Rous sarcoma virus or with the Fujinami or Y73 avian sarcoma viruses assume spindle and round shapes, increase 50-100 fold in number during four days of monolayer culture in the absence of mitogenic hormones and form macroscopic colonies during 3-4 days of agarose suspension culture. The autonomous (mitogenic hormone-independent) proliferation, in monolayer culture, of cells infected with temperature-sensitive transformation mutants of Rous sarcoma virus (tsNY68, tsNY72, tsLA24, tsLA29) is temperature-sensitive. Chicken heart mesenchymal cells infected with avian erythroblastosis virus assume spindle shapes and proliferate in monolayer culture at a rate comparable to that of sarcoma virus-infected cells but do not, however, form colonies in agarose suspension culture. Cells infected with the myelocytomatosis virus MC29 assume stellate shapes and increase 18-fold in number during four days of monolayer culture. Cells infected with the myelocytomatosis virus MH2 assume fusiform shapes and increase fourfold in number during four days of monolayer culture. Neither MC29 nor MH2 renders chicken heart mesenchymal cells capable of colony formation in agarose suspension culture. Infection with avian leukosis viruses (RAV-1, RAV-2, RPL-42) or with transformation-defective mutants of Rous sarcoma virus (tdNY105, 107, 109) does not affect the morphology or proliferative behavior of chicken heart mesenchymal cells. Monolayer culture of chicken heart mesenchymal cells in plasma-containing medium appears, therefore, to define the ability of onc genes of acute transforming avian retroviruses to induce autonomous (mitogenic hormone-independent) cell proliferation, the essential characteristic of neoplasia. The differences in transformed morphology and rates of autonomous proliferation between cells infected with different acute transforming retroviruses probably reflects differences in the modes of action of the transforming proteins encoded by the onc genes of the respective viruses.(ABSTRACT TRUNCATED AT 400 WORDS)

Alpharetrovirus↗

Comparison of features of carcinogen-transformed human cells in vitro with sarcoma-derived cells.

To define characteristics of chemically transformed phenotypes during and after progression to neoplasia and to assess their relationship to those phenotypes expressed by surgically removed sarcoma lesions, we compared the characteristics in the following manner. We investigated: (1) alterations in growth patterns; (2) anchorage-independent growth; (3) reactivity with monoclonal antibodies directed against surface antigen; (4) invasiveness in embryonic chick skin; (5) tumorigenicity in nude mice; and (6) karyology. Fifty different sarcoma cell lines were examined which exhibited different rates and absolute numbers of population doublings. With one exception, all sarcoma cell lines exhibited a finite life span ranging from 60 to 100 population doublings. Populations of these cells that exhibited anchorage-independent growth in soft agar also reacted positively with a monoclonal antibody (MoAb) 345.134S directed against a 115K-GP cell surface glycoprotein. Similarly, chemically transformed cells that grew in soft agar also reacted with the MoAb 345.134S, whereas cells with an inability to grow in soft agar did not. Cell lines established from human sarcoma and from chemically transformed human fibroblasts that reacted positively with the MoAb 345.134S were invasive for embryonic chick skin and formed tumors in nude mice. The selection medium used during culture of the carcinogen-treated cells resulted in the appearance of an altered phenotype that after at least 16 population doublings exhibited characteristics common to those cells derived from human sarcomas.

Animals↗

Vulvar sarcoma: clinical implications.

This is a review of the histories of 47 patients with vulvar sarcoma, consisting of leiomyosarcoma (25), malignant fibrous histiocytoma (5), epithelioid sarcoma (8), dermatofibrosarcoma protuberans (9), including 7 from our own institute. When compared to the biological behaviour of sarcomas from other anatomic sites of the body, no essential differences were found. The prognosis after the appearance of regional or distant recurrence was poor and prevention of local recurrence by wide excision was the best way to improve the prognosis of leiomyosarcoma and dermatofibrosarcoma protuberans. However, the poor prognosis of epitheloid sarcoma did not change. Elective treatment of regional lymph nodes was not indicated in the four tumor types discussed and dissection of metastatic inguinal nodes was rarely beneficial. However, distressing local problems were prevented in a patient with epithelioid sarcoma and lasting benefit was seen in a patient with malignant fibrous histiocytoma who developed an inguinal metastasis after a 3-year disease-free interval. The beneficial effect of resection of pulmonary metastasis needs more attention.

Adolescent↗

Soft-tissue sarcoma of the vagina and vulva: a clinicopathologic study.

OBJECTIVE: To review the clinicopathologic characteristics of vulvovaginal soft-tissue sarcomas, and to correlate these variables with response to treatment. METHODS: We performed a retrospective review of the records of 24 women treated at Memorial Hospital for sarcoma of either the vulva or vagina over 20 years (1974-1993). Archival pathology specimens were reviewed to confirm the diagnosis, histology, and grade of the tumor. RESULTS: Fifteen patients had sarcomas arising from the vagina and nine had primary vulvar tumors. Leiomyosarcoma was the most common histology (n = 13). Twenty-three of 24 women underwent surgical excision as their primary therapy. Twenty-three were available for follow-up, and 16 of them (70%) are free of disease at a median follow-up time of 47 months (range 12-156, mean 59). Five women died of progressive disease and two are currently alive with persistent or recurrent disease. Grade was the most important predictor of outcome; all seven women with low-grade tumors are alive without evidence of disease. CONCLUSION: Soft-tissue sarcomas are rare tumors of the lower genital tract. The primary therapy is surgical; adjuvant radiation therapy is indicated for high-grade tumors and locally recurrent low-grade sarcomas.

Adult↗

Sarcoma-like mural nodules combined with a microfocus of anaplastic carcinoma in mucinous ovarian tumor.

A case of mucinous ovarian tumor with sarcoma-like mural nodules, one of which coexisted with a microfocus of anaplastic carcinoma, was studied by light, electron microscopic, and histochemical examinations. The case suggested that the formation of sarcoma-like mural nodules may be the result of the proliferation of undifferentiated mesenchymal cells which exist beneath the mucinous epithelium by some stimulation like hemorrhage in the cyst wall. Histologically, the mononucleated cells composing the sarcoma-like mural nodules had epithelioid characteristics, particularly at the areas where the covering mucinous epithelium had already detached. The case also suggested that the findings of epithelioid characteristics in the sarcoma-like mural nodules themselves do not imply these nodules to be anaplastic carcinoma, but merely an epithelioid differentiation from undifferentiated mesenchymal cells, namely one of reactive products. However, the existence of a microfocus of anaplastic carcinoma combined with the sarcoma-like mural nodule necessitates a careful histologic analysis of mural nodules for the treatment of patients and the determination of the prognosis.

Adenocarcinoma, Mucinous↗

Endometrial "sarcomas" complicating ovarian thecoma, polycystic ovarian disease and estrogen therapy.

Unopposed endogenous and exogenous estrogenic stimulation has been considered by most investigators to have a role in the pathogenesis of carcinoma of the endometrium. Although a few cases of "sarcomas" of the endometrium that had developed in an estrogenic setting have been reported, a clear-cut association between estrogenic stimulation and these forms of endometrial cancer has not been established. We report six cases of endometrial sarcomas complicating ovarian thecomas, polycystic ovarian disease, or prolonged estrogen therapy. Three ovarian thecomas, which are considered to be estrogenic tumors, were associated with endometrial malignant mullerian mixed tumor, mullerian adenosarcoma, and low-grade stromal sarcoma in postmenopausal women. Polycystic ovarian disease, a condition characterized by unopposed estrinism due to the peripheral conversion of excessive androstenedione to estrone, was found in a 27-year-old infertile woman with an endometrial malignant mullerian mixed tumor. A pure osteogenic sarcoma of endometrial stromal origin developed in a 28-year-old woman with gonadal dysgenesis (Turner's syndrome) who had received estrogens for 18 years. The sixth woman, with an empty sella turcica after radiation therapy of a pituitary adenoma, had an endometrial mullerian adenosarcoma at the age of 40 years after 16 years of estrogen therapy. None of these patients had had pelvic radiation therapy. The evidence from this series of cases and from six additional cases identified in the literature suggests that the risk of endometrial sarcomas may be increased by estrogen therapy or endogenous disorders that lead to unopposed estrogenic stimulation of the uterus.

Adult↗

Endometrial stromal sarcoma: review of Mayo Clinic experience, 1945-1980.

Uterine sarcomas are uncommon malignancies. We retrospectively examined 24 cases of "high grade" endometrial stromal sarcomas (ESS). The histologic diagnosis was made if there was a high grade sarcoma with a high mitotic index and nuclear anaplasia. Heterologous elements could be present, if focal only. Leiomyosarcomas, mixed mesodermal sarcomas, and carcinosarcomas were excluded. Mitotic index was expressed as the number of mitoses per 10 high-power fields in active areas. Tumor grade was based on nuclear anaplasia. ESS were 5.7% of all uterine sarcomas. Median age was 58.2 years; median duration of symptoms was 67.5 days. Abnormal bleeding was the presenting complaint in 91.7%. Uterine enlargement was seen in 33%; protrusion through the cervical os was seen in 9 cases. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed in 95.8%. Twenty patients had myometrial involvement; 5 patients had serosal spread and extrauterine disease; residual disease was seen in 3 patients. Adjuvant radiation was not beneficial. Ten patients had recurrences: 60% in the pelvis, 50% each with subcomponent of abdominal or distant disease. Overall survival was 3.4 years and was significantly associated with extent of disease, size of the primary tumor, and grade.

Adult↗

Resection of pulmonary metastases from uterine sarcomas.

Long-term survival following resection of pulmonary metastases has been well documented. Variables that are believed to have an effect on survival are site of primary tumor, number and size of metastases, resectability, laterality of the metastases, doubling time, and disease-free interval. Published information regarding resection of pulmonary metastases in patients with gynecologic primary tumors is limited. We reviewed 45 patients whose pulmonary metastases from uterine sarcomas were resected at Memorial Sloan Kettering Cancer Center between 1960 and 1989. All cases met carefully defined criteria at time of thoracotomy: prior hysterectomy for uterine sarcoma, no extrathoracic tumor, known disease thought to be resectable, histology consistent with uterine sarcoma, and no medical contraindication to thoracotomy. Seventy-one percent had unilateral lesions, fifty-one percent had one lesion, and seventy percent had nodules greater than 2 cm. Thirty-six percent had incomplete resection at thoracotomy. Actuarial 5- and 10-year survival from hysterectomy for uterine sarcoma was 65 and 50%, respectively, with a mean follow-up of 89 months. Five- and ten-year survival from resection of pulmonary metastases was 43 and 35%, respectively, with a mean follow-up of 25 months. Unilateral vs bilateral disease was a significant predictor of survival after pulmonary resection (P = 0.02). Metastases size, number of metastases, disease-free interval, and patient age were not significant. Among this carefully selected group of patients undergoing resection of pulmonary metastases from uterine sarcomas, long-term survival was achieved by a substantial proportion of patients. No single risk factor is sufficiently accurate to exclude an individual patient from consideration for pulmonary resection.

Female↗

Cellular regulation of mammalian sarcoma virus expression: a gene regulation model for oncogenesis.

Investigations aimed at defining cellular functions required for expression of transformation by mammalian sarcoma viruses have led to the isolation of a class of revertants that contain biologically active feline sarcoma virus, yet possess in vitro and in vivo properties of normal cells. The block to expression of the transformed state in these cellular revertants was spontaneously reversible at low frequency. Moreover, infection with certain helper viruses reversed the block at very high efficiency. Helper virus complementation was shown not to be a direct effect of helper virus functions expressed in the initially infected revertant cell. Rather, the helper virus acted indirectly by rescuing sarcoma virus and allowing it to infect and transform another cell within the revertant population. Using biochemical and immunologic techniques, it was possible to demonstrate a specific and very marked reduction in transcriptional and translational products of the sarcoma viral genome in the revertant cells. Findings that the reversal of this block was associated with reacquisition of the transformed phenotype, together with other evidence, suggest that reversion results from cellular transcriptional regulation of the integrated sarcoma virus genome. Reversion in this virus transformation system provides a model for oncogenesis resulting from derepression of cellular genes that possess malignant potential.

Animals↗

Translocation involving chromosome 22 in Ewing's sarcoma. A cytogenetic study of four fresh tumors.

Ewing's sarcoma was described in 1921 by James Ewing as a diffuse endothelioma of bone and, for some time, was believed to be an undifferentiated type of Parker's sarcoma. At present, these two entities are thought to be distinct, the macroscopic and microscopic aspects of Ewing's sarcoma being very characteristic, although the exact cell type of this tumor remains unknown. This has lead many workers to study this sarcoma in order to recognize its origin. We thought it of interest to carry out cytogenetic investigations of our cases of Ewing's sarcoma, since very few chromosomal data on this malignancy exist in the literature [1-3].

Aneuploidy↗

Significance of both numerical and structural chromosomal abnormalities in clear cell sarcoma.

We analyzed cytogenetically two cases of clear cell sarcoma. The t(12;22)(q13;q13) hypothesized to be characteristic of clear cell sarcoma was detected in one of the two cases. Although this translocation was not observed in the other case; trisomy of chromosome 22 was, as were other numerical abnormalities. This latter observation has also been described in other reported studies of clear cell sarcoma. These findings confirm the nonrandomness of t(12;22)(q13;q13) in clear cell sarcoma, but also suggest that in its absence other abnormalities of chromosome 22 are significant. Trisomy 8, noted in both cases we report, as well as in previous studies, also appears to play an important role in clear cell sarcoma.

Adult↗

Complete remission of metastasised clear cell sarcoma of tendons and aponeuroses.

Clear cell sarcoma of tendons and aponeuroses is a rare disorder which originates from migrated neural crest cells. It tends to local recurrences and dissemination and the prognosis has to be considered as poor. Based on a small series of patients, a wide surgical excision of the primary tumour or amputation are the therapies of choice. Radiotherapy might be of some value as an adjuvant treatment but radiotherapy and chemotherapy are of little value in the treatment of the advanced disease. Because of the lack of treatment alternatives we treated a 40-year-old female patient with disseminated clear cell sarcoma with interferon-alpha 2b (IFN-alpha 2b) perilesionally after several courses of systemic chemotherapy and radiotherapy had failed. After 4 months of therapy the patient came into a complete pathological remission which lasted for 17 months. A relapse of round cell sarcoma on both tumour sites was then noted. This outcome shows that IFN-alpha 2b was able to induce a complete remission in clear cell sarcoma and might have altered the natural course of the disease. IFN-alpha should be studied as adjuvant therapy after surgery of primary clear cell sarcoma and as a first-line palliative treatment in disseminated disease.

Adult↗

In vitro radiation studies on Ewing's sarcoma cell lines and human bone marrow: application to the clinical use of total body irradiation (TBI).

Patients with Ewing's sarcoma who present with a central axis or proximal extremity primary and/or with metastatic disease have a poor prognosis despite aggressive combination chemotherapy and local irradiation. In this high risk group of patients, total body irradiation (TBI) has been proposed as a systemic adjuvant. To aid in the design of a clinical TBI protocol, we have studied the in vitro radiation response of two established cell lines of Ewing's sarcoma and human bone marrow CFUc. The Ewing's lines showed a larger Do (1.26 Gy, 2.04 Gy) and n (6.0, 3.2) compared to the bone marrow CFUc (Do = 0.86 Gy, n = 1.2). No repair of potentially lethal radiation damage (PLDR) was found after 4.5 Gy in plateau phase Ewing's sarcoma cells. A theoretical split dose survival curve for both the Ewing's sarcoma lines and human bone marrow CFUc using this TBI schedule shows a significantly lower surviving fraction (10(-4)-10(-5] for the bone marrow CFUc. Based on these in vitro results, two 4.0 Gy fractions separated by 24 hours is proposed as the TBI regimen. Because of the potentially irreversible damage to bone marrow, autologous bone marrow transplantation following the TBI is felt to be necessary. The details of this clinical protocol in high risk Ewing's sarcoma patients are outlined.

Bone Marrow↗

Conformal radiotherapy for unresectable retroperitoneal soft tissue sarcoma.

Local tumor control remains a continuing challenge in the treatment of retroperitoneal soft tissue sarcoma. Though complete resection by means of wide excision or excisional biopsy can be performed in a minority of patients only, aggressive surgical approach remains the treatment of choice. Unresectable sarcoma can rarely be controlled by conventionally applied radiotherapy--only a few percent of patients survive. A superior dose distribution of external radiation is demanded in order to spare healthy tissue. The presumably greatest advantage will occur when radiotherapy is used preoperatively. The possible clinical gain of superior dose distribution is demonstrated by results of the dynamic, 3-D conformal pion radiotherapy at PSI. Between April 1983 and June 1988 a total of 21 patients were treated with high doses (greater than or equal to 30 Gy) for unresectable retroperitoneal soft tissue sarcoma. The follow-up time is 13-74 months, median 24. Fifteen patients were treated with 20 fx, and 19 patients were treated with fraction sizes of 150 or 165 cGy. Except for one patient with thrombocytopenia after chemotherapy, no treatment interruption was necessary. Five patients developed late reactions, caused also by surgery and chemotherapy: two intestinal obstructions, one liver abscess, one leg edema, and one superficial skin necrosis. Nine patients had laparotomy after pion irradiation, five for resection of the previous unresectable tumor; 3/5 sarcoma were completely resected. Morbidity rate after post-pion laparotomy did not increase. Three patients had local tumor progression, 1/3 inside the treatment volume. The actuarial five-year local tumor control rate of these unresectable retroperitoneal sarcoma is 60%, the actuarial five-year survival rate is 33%. Out of the 21 patients, 15 are alive, two have died from local progression, one from peritoneal progression, and three from metastases.

Humans↗

Radiation therapy for non-AIDS associated (classic and endemic African) and epidemic Kaposi's sarcoma.

PURPOSE: A retrospective analysis of patients with non-AIDS and AIDS-related Kaposi's sarcoma, who were treated with radiation therapy. METHODS AND MATERIALS: Between 1978 and 1992, 56 patients with one of the three major types (classical, endemic, epidemic) of Kaposi's sarcoma received radiation therapy as their sole treatment modality. Extent of fields, daily fractionation, and total dose were applied on a clinical basis. These lesions received superficial x-ray therapy, Co-60 teletherapy, or 6-8 MeV electron beams. Field sizes depended on extent of the lesion. Total dose administration ranged from 8-12 Gy in one exposure, or a total of 24-30 Gy fractionated over 2-3 weeks. RESULTS: The majority of patients responded to radiation therapy. Symptomatic relief was achieved in 80-100% of patients irrespective of the type of Kaposi's sarcoma, treatment modality, or schedule. Side effects were tolerable in all but three patients with epidemic type Kaposi's sarcoma, who developed severe mucositis. CONCLUSION: Radiotherapy is the most useful mode of palliative treatment for all forms of Kaposi's sarcoma in southern African patients.

Acquired Immunodeficiency Syndrome↗

Radiotherapy in the management of epidemic Kaposi's sarcoma.

PURPOSE: This study is presented to help define the role of radiotherapy in the management of epidemic Kaposi's sarcoma. METHODS AND MATERIALS: Between June 1986 and June 1993, we treated 453 patients who had acquired immunodeficiency syndrome related Kaposi's sarcoma. Two hundred fifty-two patients (55.6%) had received previous treatment for their Kaposi's sarcoma: 228 (55.3%) with interferon, and 116 (25.6%) with Vinblastine. Depending on both tumour size and location, patients were treated with extended cutaneous irradiation using 4 MeV electron beam energy and/or localized irradiation using 45-100 kV x-ray (cutaneous lesions), or 4 MV x-ray (oral tumours). A total of 5015 courses of radiation therapy was given. The intention of the treatment was closely linked to the anatomic sites. Multiple courses of treatment ranging from 10 to 20 Gy (2.5 Gy/fraction, 4 times/week) were used for Kaposi's sarcoma involving conjunctiva (n = 32 treatments), eyelids (n = 306), lips (n = 170), hands (n = 208), feet (n = 417), penis (n = 131), oral mucosa (n = 43), and anal region (n = 5). A second group including other cutaneous sites (face, trunk, limbs) was treated with a dose of 30 Gy (20 Gy in 2 weeks followed by 2 weeks rest and then a second series of 10 Gy in 1 week). RESULTS: For the first group, tolerance was generally good excluding oral cavity irradiation, with an effective palliation of symptoms (87.8% overall rate of objective responses); an enhanced mucosal reactions was noted in patients receiving oropharyngeal irradiation. For the second group, a complete regression rate of 85% was observed; tolerance was acceptable: complications were severe epidermitis with skin ulceration (5%), exsudative epidermitis (26%), dry epidermitis (60%), and varying degrees of erythema (9%). There was a significant correlation between risk of recurrence (overall recurrence rate of 71% after an average of 7.5 months) and occurrence of opportunistic infections: 85% of recurrences appeared concomitantly with accelerated course of acquired immunodeficiency syndrome. CONCLUSIONS: We conclude that radiotherapy is an efficient treatment for epidemic Kaposi's sarcoma (EKS): doses of 15.2 Gy for oral lesions and 20 Gy for lesions involving conjunctiva, eyelids, lips, hands, feet, penis, and anal region were sufficient to produce shrinkage of the tumour and good palliation of symptoms. For the other cutaneous sites, 30 Gy local field irradiation could be safely given with better short-term response. Prophylactic measures with antifungal treatment should be systematically associated with oropharyngeal irradiation, to improve tolerance to the treatment.

Acquired Immunodeficiency Syndrome↗

Management of retroperitoneal sarcomas: does dose escalation impact on locoregional control?

PURPOSE: Only 50% of patients with retroperitoneal sarcomas undergo complete resection and of these, 47% develop local tumor recurrence. To determine whether irradiation with dose escalation improves locoregional control, we reviewed the experience with adjuvant radiotherapy in the treatment of retroperitoneal sarcomas at the Fox Chase Cancer Center and the Hospital of the University of Pennsylvania. METHODS AND MATERIALS: Twenty-one patients with retroperitoneal sarcomas were treated with curative intent with surgical resection and radiation therapy at Fox Chase Cancer Center or the Hospital of the University of Pennsylvania between May 1965 and July 1992. Follow-up ranged from 14-340 months. Nineteen patients were treated postoperatively and 2 preoperatively. Radiation doses were between 36.0 Gy and 90.0 Gy (median 54.0 Gy). RESULTS: The 2-year rates of local control and survival were 72% and 69%, respectively. Tumor size, stage, grade, and histology did not influence local control. Two of eight patients (25%) who received a total dose of > 55.2 Gy experienced local failure compared to 5 of 13 (38%) who received < or = 55.2 Gy. One patient experienced a small bowel obstruction that required surgical intervention. There were no other severe complications. CONCLUSION: Postoperative treatment with radiotherapy using a dose > 55.0 Gy is recommended for patients with retroperitoneal sarcomas following surgical resection due to the significant likelihood of local recurrence. Innovative adjuvant radiation techniques to escalate doses to greater than 55.0 Gy including intraoperative radiation therapy, brachytherapy, or use of small bowel exclusion devices to reduce small bowel toxicity should be considered for retroperitoneal sarcomas.

Adult↗

Sarcomas following radiation therapy for breast cancer: a report of three cases and a review of the literature.

PURPOSE: First to describe clinical and pathologic features of sarcomas arising after radiation therapy for breast cancer and to report three cases of sarcoma arising 7, 15, and 20 years following radiation therapy for breast cancer. Second, to review the literature on this treatment complication. METHODS AND MATERIALS: Medline literature search. RESULTS: The most frequent histology is osteosarcoma and bone is affected more commonly than soft tissue at a median latency of 11 years. The scapula is the most frequently affected bone. The most frequently affected soft tissue site is now the conserved breast with a median latency of 5.5 years. The aetiologic factors relating to these sarcomas are not fully defined with factors of beam energy, radiation dose, chemotherapy and regional edema being inconsistently reported. CONCLUSION: The frequency of radiation-induced sarcoma at 10 years of follow-up is approximately 0.2%. This is an overestimate by an unknown factor because of the description of sarcomas arising metachromously in breast cancer patients, in nonirradiated areas.

Adult↗