Pathology in Practice

Krystal J. Vail from the Departments of Veterinary Patho-biology (Vail, Edwards, Rech, Delgado) and Large Animal Clinical Sciences (Madrigal, Washburn, Romano), College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, TX 77843; Equine Sports Medicine and Surgery, Weatherford, TX 76087 (Madrigal); and Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX 77843 (Delgado).

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Rodolfo Madrigal from the Departments of Veterinary Patho-biology (Vail, Edwards, Rech, Delgado) and Large Animal Clinical Sciences (Madrigal, Washburn, Romano), College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, TX 77843; Equine Sports Medicine and Surgery, Weatherford, TX 76087 (Madrigal); and Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX 77843 (Delgado).

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Kevin Washburn from the Departments of Veterinary Patho-biology (Vail, Edwards, Rech, Delgado) and Large Animal Clinical Sciences (Madrigal, Washburn, Romano), College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, TX 77843; Equine Sports Medicine and Surgery, Weatherford, TX 76087 (Madrigal); and Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX 77843 (Delgado).

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Juan Romano from the Departments of Veterinary Patho-biology (Vail, Edwards, Rech, Delgado) and Large Animal Clinical Sciences (Madrigal, Washburn, Romano), College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, TX 77843; Equine Sports Medicine and Surgery, Weatherford, TX 76087 (Madrigal); and Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX 77843 (Delgado).

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John F. Edwards from the Departments of Veterinary Patho-biology (Vail, Edwards, Rech, Delgado) and Large Animal Clinical Sciences (Madrigal, Washburn, Romano), College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, TX 77843; Equine Sports Medicine and Surgery, Weatherford, TX 76087 (Madrigal); and Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX 77843 (Delgado).

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Raquel Rech from the Departments of Veterinary Patho-biology (Vail, Edwards, Rech, Delgado) and Large Animal Clinical Sciences (Madrigal, Washburn, Romano), College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, TX 77843; Equine Sports Medicine and Surgery, Weatherford, TX 76087 (Madrigal); and Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX 77843 (Delgado).

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Josue Delgado from the Departments of Veterinary Patho-biology (Vail, Edwards, Rech, Delgado) and Large Animal Clinical Sciences (Madrigal, Washburn, Romano), College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, TX 77843; Equine Sports Medicine and Surgery, Weatherford, TX 76087 (Madrigal); and Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX 77843 (Delgado).

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History

An 8-year-old 412-kg (906-lb) female dromedary camel was evaluated because of intermittent vaginal discharge of several months’ duration and multiple abortions.

Clinical Findings

During the examination, rectal ultrasonography and vaginoscopy exposed a large extramural mass pushing inward on the uterus. A CBC and serum biochemical profile revealed anemia, neutrophilia, lactic acidosis, and azotemia. Serum progesterone concentration was 0.76 ng/mL, indicative of the presence of a nongravid uterus (serum progesterone concentration is typically < 1 ng/mL in female camels in a non-pregnant reproductive state and peaks at 3 to 5 ng/mL in pregnant camels1). Findings of an abdominal laparotomy confirmed a right uterine mass and enlarged left ovary; an incisional biopsy specimen was collected from the uterine mass. Following surgery, the camel died and a necropsy was performed.

Gross Findings

On necropsy, a V-shaped, 7-cm-long, transmural, dark pink mass on the ventral aspect of the uterine body extended 13 cm into each uterine horn (Figure 1). The uterus contained necrotic exudate, and the peritoneal cavity contained 15 L of serosanguineous, malodorous fluid. There was bilateral thrombosis of the uterine arteries, and the lymphatic vessels were dilated. The pancreatic and retroperitoneal and lumbar lymph nodes were enlarged (≤ 7 × 4 × 3.5 cm), and the parenchyma was effaced by pale pink, firm coalescing nodules with necrotic exudate. Multiple 0.3- to 3-cm-diameter, well-demarcated, pale tan, firm nodules were visible in the lungs. Additional gross findings included moderate bilateral renal hydronephrosis and ventrally bridging spondylosis of the T6-T8 vertebral bodies.

Figure 1
Figure 1
Figure 1

Photographs of the reproductive organs from a dromedary camel that had intermittent vaginal discharge of several months’ duration and multiple abortions. A—In dorsal view, the uterine body is thickened and infiltrated by a V-shaped mass (asterisk). There is thrombosis of the ovarian arteries (white arrowheads). Inset—Cross section of left uterine horn at the level of the striped line in the main image. The uterine wall is markedly thickened by pale pink, firm, nodular foci. There is superficial necrosis (black arrowhead) and hemorrhage in the endometrium. Bar = 1 cm. B—The ovarian artery is occluded by a thrombus (arrow). Cv = Cranial portion of the vagina. Cx = Cervix. Lo = Left ovary. Luh = Left uterine horn. Ro = Right ovary. Ruh = Right uterine horn.

Citation: Journal of the American Veterinary Medical Association 259, 1; 10.2460/javma.259.1.45

Histopathologic Findings

Sections of the mass were examined. Microscopically, the uterine endometrium was effaced, and the myometrium and serosa were infiltrated by a densely cellular, poorly demarcated, highly infiltrative epithelial neoplasm supported by preexisting stroma with necrotic foci. Neoplastic cells transitioned from individual and necrotic cells in the endometrium to pleomorphic flattened to cuboidal to columnar epithelial cells, arranged in variably dilated tubules, nests, and solid aggregates in the myometrium and serosa (Figure 2). These cells each had a scant to moderate amount of eosinophilic cytoplasm and a round to pleomorphic, central nucleus with coarsely stippled chromatin and a prominent nucleolus. Binucleation and bizarre mitoses were common, and there were 4 mitoses/hpf (400X). Similar neoplastic cells extensively infiltrated the uterine lymphatic vessels; mesenteric, retroperitoneal, and periaortic lymph nodes; lungs; and mesentery. Neoplastic cells within lymph nodes were arranged in papillary projections, solid aggregates, and small nests and had frequent necrotic foci. Interestingly, several of the lymph node metastases contained scattered trabeculae of variably mineralized immature woven bone. Approximately 95% of neoplastic cells had uniform, diffuse, strong membranous and cytoplasmic immunoreactivity for cytokeratin AE1/AE3. Neoplastic cells were negative for vimentin. Additional relevant histopathologic findings included bilateral ovarian artery thrombosis, focal mycotic pneumonia, and mild focal hepatic fibrosis.

Figure 2
Figure 2
Figure 2

Photomicrographs of sections of the camel's uterine mass and a mesenteric lymph node. A—A highly infiltrative epithelial neoplasm with solid areas (arrow) and dilated tubules filled with necrotic debris (asterisks) has effaced the endometrium and subendometrial connective tissue. H&E stain; bar = 50 [.proportional]m. Inset—Neoplastic epithelial cells have strong diffuse cytoplasmic and membranous labeling for cytokeratin AE1/AE3. Cytokeratin-specific immunohistochemical reaction; bar = 20 [.proportional]m. B—Within a mesenteric lymph node, metastatic epithelial neoplastic cells form papillary structures, often arranged around trabeculae of immature woven bone (asterisks) with areas of mineralization (arrow). H&E stain; bar = 200 [.proportional]m.

Citation: Journal of the American Veterinary Medical Association 259, 1; 10.2460/javma.259.1.45

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: endometrial adenocarcinoma with anaplastic areas and distant metastasis.

Case summary: reproductive failure caused by metastatic endometrial adenocarcinoma in a female dromedary camel.

Comments

Common reproductive abnormalities of female camels described in the veterinary medical literature include ovarian hypoplasia, follicular cysts, segmental cervical aplasia, acute cervicitis, early embryonic death, fetal maceration, endometrial erosions and hemorrhage, and endometritis.24 To our knowledge, only 1 report5 mentions endometrial adenocarcinoma in camels. The frequency of reproductive neoplasms in New World camelids is also relatively low, with few reports6,7 of uterine neoplasms, including adenocarcinomas and a uterine leiomyosarcoma.

Among domestic animals, endometrial adenocarcinomas are rare, except in rabbits and cattle.8,9 Endometrial hyperplasia is thought to precede the development of endometrial adenocarcinoma in women and is potentially caused by prolonged exposure to circulating estrogen in the face of insufficient progesterone.10 In rabbits, approximately half of endometrial adenocarcinomas are associated with endometrial hyperplasia, but it is uncertain whether endometrial hyperplasia is a preneoplastic change in that species.11 In rabbits, which are induced ovulators, the development of endometrial adenocarcinomas may be promoted by administration of exogenous estrogens, and those neoplasms often metastasize to the lungs.8 Camels have a short breeding season during the cooler months and are also induced ovulators, typically ovulating only after the stimulus of mating.12 In the absence of mating, female camels undergo continuous follicular waves with high serum estrogen and testosterone concentrations and low progesterone concentration.13 It is possible that prolonged periods of exposure to estrogen stimulation might predispose induced ovulators to develop endometrial adenocarcinoma.14

In the uterus of healthy rabbits, endometrial glandular epithelium, stromal cells, and myometrial smooth muscle express estrogen and progesterone receptors.11 Immunohistochemically, cells of the luminal and glandular epithelia, stroma, and myometrial smooth muscle in the uterus of camels have nuclear but not cytoplasmic immunolabeling for progesterone receptors; the immunolabeling has uniform distribution and moderate to strong intensity.13,15 To our knowledge, no reports describe estrogen receptor expression in camels. Although well-differentiated endometrial adenocarcinomas typically retain expression of both estrogen and progesterone receptors, expression of 1 or both receptors is often lost in poorly differentiated neoplasms.9,10 In a study of rabbit endometrial adenocarcinomas, 4 of 6 tumors had immunolabeling for progesterone receptors.9 In another study, estrogen and progesterone receptor expression in rabbits varied on the basis of subclassification of endometrial adenocarcinomas; 12 of 16 (75%) tubular or solid adenocarcinomas had expression of both estrogen and progesterone receptors, whereas 5 of 26 (19.2%) papillary adenocarcinomas were positive for 1 or both receptors.11 In the case described in the present report, attempts to immunolabel uterine adenocarcinoma tissue sections for both estrogen and progesterone receptors were unsuccessful, as were attempts to validate the use of test antibodies in normal camelid tissue.

The etiopathogenesis of endometrial adenocarcinoma is largely unknown. Estrogens and progestogens appear to have major roles, and testing for these hormones in humans facilitates tumor subtype classification with prognostic and therapeutic implications. In this regard, there are 2 major types of endometrial adenocarcinoma, namely type I, which is estrogen dependent and develops through the endometrial hyperplasia–carcinoma sequence, and type II, which is not estrogen dependent and develops independently of endometrial hyperplasia. Estrogen-dependent endometrial adenocarcinoma is most common among women in developed countries and is often linked to obesity, diabetes mellitus, nulliparity, hypertension, or menopause.16 Additionally, viral infections, medications, chemical pollutants, and spontaneous mutations occasionally have been linked to endometrial adenocarcinomas.1721 Although the cytomorphology and cytokeratin immunoprofile of the tumor in the case described in the present report were sufficient to reach a final diagnosis, there was a lack of demonstrable immunoexpression of estrogen and progesterone receptors. Without better characterization of estrogen and progesterone receptors in genital tissues and neoplasms of female camels, the usefulness of receptor analysis for accurate subtyping of endometrial adenocarcinomas in that species remains undetermined.

Although uterine neoplasia develops infrequently in captive and wild camelid species, it should be considered as a differential diagnosis for reproductive failure or uterine masses with or without regional lymphadenopathy in female camels. Future studies are required to characterize the influence of prolonged exposure to circulating estrogen on the development of uterine neoplasms in this species.

Acknowledgments

The authors declare no conflicts of interest with respect to the research, authorship, or publication of this article.

The authors thank Dr. Andy Ambrus for technical help with immunohistochemical analyses and the reviewers for their thoughtful feedback.

References

  • 1.

    Elias E, Bedrak E, Yagil R. Peripheral blood levels of progesterone in female camels during various reproductive stages. Gen Comp Endocrinol 1984;53:235240.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    El-Wishy AB. Genital abnormalities of the female dromedary (Camelus dromedurius). An abattoir survey. Reprod Domest Anim 1989;24:8487.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Mshelia GD, Abba Y, Voltaire YAC, et al. Comparative uterine bacteriology and pathology of camels (Camelus dromedarius) and cows in north-eastern Nigeria. Comp Clin Pathol 2013;22:11951200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Ribadu AY, Ogwu D, Njoku CO, et al. An abattoir survey of female genital disorders of imported camels (Camelus dromedarius) in Kano, Nigeria. Br Vet J 1991;147:290292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Al-Afaleq AI, Hegazy AA, Hussein MF, et al. Pathological disorders of the female reproductive system in slaughtered camels (Camelus dromedarius) in Saudi Arabia. Comp Clin Pathol 2012;21:245251.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Hardefeldt LY, Poulsen KP, McGuirk SM, et al. Urogenital leiomyosarcoma in an alpaca. Can Vet J 2010;51:13871390.

  • 7.

    Klopfleisch R, van der Grinten E, Gruber AD. Metastatic uterine adenocarcinoma and hepatic lipomatosis in a llama (Lama glama). J Vet Diagn Invest 2009;21:280282.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Elsinghorst TA, Timmermans HJ, Hendriks HG. Comparative pathology of endometrial carcinoma. Vet Q 1984;6:200208.

  • 9.

    Vinci A, Bacci B, Benazzi C, et al. Progesterone receptor expression and proliferative activity in uterine tumours of pet rabbits. J Comp Pathol 2010;142:323327.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Kreizman-Shefer H, Pricop J, Goldman S, et al. Distribution of estrogen and progesterone receptors isoforms in endome-trial cancer. Diagn Pathol 2014;9:7784.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Asakawa MG, Goldschmidt MH, Une Y, et al. The immunohistochemical evaluation of estrogen receptor-α and progester-one receptors of normal, hyperplastic, and neoplastic endometrium in 88 pet rabbits. Vet Pathol 2008;45:217225.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Skidmore JA. Reproductive physiology in female Old World camelids. Anim Reprod Sci 2011;124:148154.

  • 13.

    Emam MA. Immunohistochemical localization of androgen and progesterone receptors in the uterus of the camel (Camelus dromedarius). Acta Histochem 2014;116:12251230.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Miller MA, Ramos-Vara JA, Dickerson MF, et al. Uterine neoplasia in 13 cats. J Vet Diagn Invest 2003;15:515522.

  • 15.

    Abd-Elnaeim MM, Al-Kheraije KA. Immunohistochemical localization of progesterone receptors in the non-pregnant one-humped camel uterus. J Adv Vet Res 2012;2:188191.

    • Search Google Scholar
    • Export Citation
  • 16.

    Setiawan VW, Yang HP, Pike MC, et al. Type I and II endome-trial cancers: have they different risk factors? J Clin Oncol 2013;31:26072618.

  • 17.

    Bernstein L, Deapen D, Cerhan JR, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999;91:16541662.

  • 18.

    Bergman L, Beelen ML, Gallee MP, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;356:881887.

  • 19.

    Dunnick JK, Sanders JM, Kissling GE, et al. Environmental chemical exposure may contribute to uterine cancer development: studies with tetrabromobisphenol A. Toxicol Pathol 2015;43:464473.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    de Vivo I, Huggins GS, Hankinson SE, et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A 2002;99:1226312268.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Church DN, Briggs SEW, Palles C, et al. DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer. Hum Mol Genet 2013;22:28202828.

  • Figure 1

    Photographs of the reproductive organs from a dromedary camel that had intermittent vaginal discharge of several months’ duration and multiple abortions. A—In dorsal view, the uterine body is thickened and infiltrated by a V-shaped mass (asterisk). There is thrombosis of the ovarian arteries (white arrowheads). Inset—Cross section of left uterine horn at the level of the striped line in the main image. The uterine wall is markedly thickened by pale pink, firm, nodular foci. There is superficial necrosis (black arrowhead) and hemorrhage in the endometrium. Bar = 1 cm. B—The ovarian artery is occluded by a thrombus (arrow). Cv = Cranial portion of the vagina. Cx = Cervix. Lo = Left ovary. Luh = Left uterine horn. Ro = Right ovary. Ruh = Right uterine horn.

  • Figure 2

    Photomicrographs of sections of the camel's uterine mass and a mesenteric lymph node. A—A highly infiltrative epithelial neoplasm with solid areas (arrow) and dilated tubules filled with necrotic debris (asterisks) has effaced the endometrium and subendometrial connective tissue. H&E stain; bar = 50 [.proportional]m. Inset—Neoplastic epithelial cells have strong diffuse cytoplasmic and membranous labeling for cytokeratin AE1/AE3. Cytokeratin-specific immunohistochemical reaction; bar = 20 [.proportional]m. B—Within a mesenteric lymph node, metastatic epithelial neoplastic cells form papillary structures, often arranged around trabeculae of immature woven bone (asterisks) with areas of mineralization (arrow). H&E stain; bar = 200 [.proportional]m.

  • 1.

    Elias E, Bedrak E, Yagil R. Peripheral blood levels of progesterone in female camels during various reproductive stages. Gen Comp Endocrinol 1984;53:235240.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    El-Wishy AB. Genital abnormalities of the female dromedary (Camelus dromedurius). An abattoir survey. Reprod Domest Anim 1989;24:8487.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Mshelia GD, Abba Y, Voltaire YAC, et al. Comparative uterine bacteriology and pathology of camels (Camelus dromedarius) and cows in north-eastern Nigeria. Comp Clin Pathol 2013;22:11951200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Ribadu AY, Ogwu D, Njoku CO, et al. An abattoir survey of female genital disorders of imported camels (Camelus dromedarius) in Kano, Nigeria. Br Vet J 1991;147:290292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Al-Afaleq AI, Hegazy AA, Hussein MF, et al. Pathological disorders of the female reproductive system in slaughtered camels (Camelus dromedarius) in Saudi Arabia. Comp Clin Pathol 2012;21:245251.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Hardefeldt LY, Poulsen KP, McGuirk SM, et al. Urogenital leiomyosarcoma in an alpaca. Can Vet J 2010;51:13871390.

  • 7.

    Klopfleisch R, van der Grinten E, Gruber AD. Metastatic uterine adenocarcinoma and hepatic lipomatosis in a llama (Lama glama). J Vet Diagn Invest 2009;21:280282.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Elsinghorst TA, Timmermans HJ, Hendriks HG. Comparative pathology of endometrial carcinoma. Vet Q 1984;6:200208.

  • 9.

    Vinci A, Bacci B, Benazzi C, et al. Progesterone receptor expression and proliferative activity in uterine tumours of pet rabbits. J Comp Pathol 2010;142:323327.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Kreizman-Shefer H, Pricop J, Goldman S, et al. Distribution of estrogen and progesterone receptors isoforms in endome-trial cancer. Diagn Pathol 2014;9:7784.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Asakawa MG, Goldschmidt MH, Une Y, et al. The immunohistochemical evaluation of estrogen receptor-α and progester-one receptors of normal, hyperplastic, and neoplastic endometrium in 88 pet rabbits. Vet Pathol 2008;45:217225.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Skidmore JA. Reproductive physiology in female Old World camelids. Anim Reprod Sci 2011;124:148154.

  • 13.

    Emam MA. Immunohistochemical localization of androgen and progesterone receptors in the uterus of the camel (Camelus dromedarius). Acta Histochem 2014;116:12251230.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Miller MA, Ramos-Vara JA, Dickerson MF, et al. Uterine neoplasia in 13 cats. J Vet Diagn Invest 2003;15:515522.

  • 15.

    Abd-Elnaeim MM, Al-Kheraije KA. Immunohistochemical localization of progesterone receptors in the non-pregnant one-humped camel uterus. J Adv Vet Res 2012;2:188191.

    • Search Google Scholar
    • Export Citation
  • 16.

    Setiawan VW, Yang HP, Pike MC, et al. Type I and II endome-trial cancers: have they different risk factors? J Clin Oncol 2013;31:26072618.

  • 17.

    Bernstein L, Deapen D, Cerhan JR, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999;91:16541662.

  • 18.

    Bergman L, Beelen ML, Gallee MP, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;356:881887.

  • 19.

    Dunnick JK, Sanders JM, Kissling GE, et al. Environmental chemical exposure may contribute to uterine cancer development: studies with tetrabromobisphenol A. Toxicol Pathol 2015;43:464473.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    de Vivo I, Huggins GS, Hankinson SE, et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A 2002;99:1226312268.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Church DN, Briggs SEW, Palles C, et al. DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer. Hum Mol Genet 2013;22:28202828.

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