Jennifer Y. Wang, MD

All Publications

• Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors. Breast cancer research and treatment Bang, A. S., Fay, C. J., LeBoeuf, N. R., Etaee, F., Leventhal, J. S., Sibaud, V., Arbesman, J., Wang, J. Y., Kwong, B. Y. 2024

  Abstract

  Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management.Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study.Median age of our patients was 55 (range 37-86). Median progression-free survival was 24 months in 5 patients. The median time to rash was 10 months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient.Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

  View details for DOI 10.1007/s10549-023-07217-2

  View details for PubMedID 38224427

  View details for PubMedCentralID 10034067

• What Is Melanoma? JAMA Wang, J. Y., Wang, E. B., Swetter, S. M. 2023

  Abstract

  This JAMA Patient Page describes melanoma, its risk factors, diagnosis, treatment, and prognosis.

  View details for DOI 10.1001/jama.2022.24888

  View details for PubMedID 36867424

• Delays in melanoma presentation during the COVID-19 pandemic: a nationwide multi-institutional cohort study. Journal of the American Academy of Dermatology Trepanowski, N., Chang, M. S., Zhou, G., Ahmad, M., Berry, E. G., Bui, K., Butler, W. H., Chu, E. Y., Curiel-Lewandrowski, C., Dellalana, L. E., Ellis, D. L., Freeman, S. C., Gorrepati, P. L., Grossman, D., Gyurdzhyan, S., Kanetsky, P. A., Loren Ong King, A., Kolla, A. M., Lian, C. G., Lin, J. Y., Liu, V., Lowenthal, A., McCoy, K. N., Munjal, A., Myrdal, C. N., Perkins, S., Powers, J. G., Rauck, C., Smart, T. C., Stein, J. A., Venna, S., Walsh, M. E., Wang, J. Y., Leachman, S. A., Swetter, S. M., Hartman, R. I. 2022

  View details for DOI 10.1016/j.jaad.2022.06.031

  View details for PubMedID 35738513

• Dermatology Advances Into an Era of Precision Medicine. JAMA dermatology Wang, J. Y., Sarin, K. Y. 2021

  View details for DOI 10.1001/jamadermatol.2021.0024

  View details for PubMedID 34076667

• Clinical Characterization of Mogamulizumab-Associated Rash During Treatment of Mycosis Fungoides or Sezary Syndrome. JAMA dermatology Hirotsu, K. E., Neal, T. M., Khodadoust, M. S., Wang, J. Y., Rieger, K. E., Strelo, J., Hong, E., Kim, Y. H., Kwong, B. Y. 2021

  Abstract

  Importance: Mogamulizumab is a monoclonal antibody against CCR4 approved for treatment for mycosis fungoides (MF) and Sezary syndrome (SS). Mogamulizumab-associated rash (MAR) is difficult to differentiate from cutaneous MF or SS, which can lead to unnecessary discontinuation of drug use because of concern for severe drug reaction or incorrect presumption of disease relapse or progression in the skin.Objective: To examine the most common clinical presentations of MAR in patients with MF or SS and the diagnostic and management challenges.Design, Setting, and Participants: This retrospective case series assessed patients from a multidisciplinary cutaneous lymphoma clinic and supportive oncodermatology clinic at a major academic referral center who had a diagnosis of MF or SS and received mogamulizumab from January 1, 2013, to January 1, 2020. Treatment was followed by new or worsening rash with skin biopsy results compatible with drug eruption determined by clinicopathologic correlation and molecular testing to exclude active malignant disease.Exposures: At least 1 dose of mogamulizumab.Main Outcomes and Measures: Mogamulizumab-associated rash was characterized by clinical features, including time to onset, clinical presentation, histopathologic features, and management approach.Results: The study included 19 patients with MF or SS who developed MAR (median age, 65 years; age range, 38-82 years; 10 [52.6%] male). Median time to MAR onset was 119 days (range, 56 days to 3.8 years). Patients with MAR exhibited 4 predominant clinical presentations: (1) folliculotropic MF-like scalp plaques with alopecia, (2) papules and/or plaques, (3) photoaccentuated dermatitis, and (4) morbilliform or erythrodermic dermatitis. The most common anatomical region involved was the head and neck, including the scalp. Histopathologic findings were variable and did not correspond to primary clinical morphologic findings. Immunohistochemistry and T-cell clonality ancillary testing were helpful to distinguish MAR from disease. Most patients with MAR (14 of 19) discontinued mogamulizumab treatment; however, no life-threatening severe cutaneous adverse drug reactions occurred, and the decision for drug therapy cessation was usually multifactorial. Four patients were treated again with mogamulizumab with no life-threatening drug-related events. Approaches to management of MAR include topical corticosteroids, systemic corticosteroids, and/or methotrexate.Conclusions and Relevance: This case series found that mogamulizumab-associated rash had a heterogeneous clinical presentation with variable and delayed onset in patients with MF or SS. Mogamulizumab-associated rash exhibited a predilection for the head and neck and was difficult to clinically distinguish from relapse or progression of disease. Recognition of the most common clinical presentations can help prevent unnecessary discontinuation of mogamulizumab treatment. The presence of MAR does not necessitate permanent discontinuation of or avoidance of retreatment with mogamulizumab.

  View details for DOI 10.1001/jamadermatol.2021.0877

  View details for PubMedID 33881447

• Next generation sequencing confirms T-cell clonality in a subset of pediatric pityriasis lichenoides. Journal of cutaneous pathology Raghavan, S. S., Wang, J. Y., Gru, A. A., Marqueling, A. L., Teng, J. M., Brown, R. A., Novoa, R. A., Kim, Y., Zehnder, J., Zhang, B. M., Rieger, K. E. 2021

  Abstract

  Pityriasis lichenoides (PL) is a papulosquamous disease that affects both adults and children. Previous studies have shown a subset of this entity to have clonal T-cell populations via PCR based assays. In this study, we sought to implement next generation sequencing as a more sensitive and specific test to examine for T-cell clonality within the pediatric population.We identified 18 biopsy specimens from 12 pediatric patients with clinical and histopathologic findings compatible with PL. Patient demographics, clinical features, management, and histopathologic findings were reviewed. All specimens were analyzed for clonality with next generation sequencing of T-cell receptor beta (TRB) and gamma (TRG) genes.Of the 12 patients, 9 (75%) had complete resolution of lesions at the time of data collection (mean follow up 31 months). The remaining three patients significantly improved with methotrexate (with or without acitretin). Interestingly, 7 of 12 patients (58%) and 9 of 17 biopsy specimens (53%) showed evidence of T-cell clonality. Two patients showed matching TRB clones from different anatomic sites.T-cell clonality is a common finding in PL, likely representing a "reactive clonality" rather than a true lymphoproliferative disorder. Clonality alone cannot be used as a means to distinguish PL from lymphomatoid papulosis or cutaneous lymphoma. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.14143

  View details for PubMedID 34614220

• Concurrent Trypanosoma cruzi and Cytomegalovirus Reactivation in an Immunosuppressed Patient With Limited Cutaneous Systemic Sclerosis. The American Journal of dermatopathology Chang, M. S., Bae, G. H., Almazan, T., Raghavan, S. S., Wang, J. Y., Czech, M. M., Wang, H., Banaei, N., Blackburn, B. G., Novoa, R. A., Rieger, K. E. 2020

  Abstract

  Chagas disease, a multisystem infection caused by the protozoan Trypanosoma cruzi, is primarily found in Latin America. In recent years, prevalence has increased in the United States, where reactivation is the most common clinical scenario. Here, we describe cutaneous reactivation of T. cruzi in a patient with limited cutaneous systemic sclerosis on immunosuppression therapy who simultaneously presented with cytomegalovirus reactivation. Histopathology showed parasitized histiocytes in the superficial and deep dermis. Occasional epidermal keratinocytes were also parasitized, and rare organisms were also seen in the walls of blood vessels. Also noted were viral cytopathic changes within the vascular endothelium, and immunostaining confirmed cytomegalovirus. In this report, we describe the difference in cutaneous findings between reactivated and acute Chagas disease, and we also review the histopathologic features that help distinguish T.cruzi from other intracellular organisms.

  View details for DOI 10.1097/DAD.0000000000001842

  View details for PubMedID 33201010

• ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism. Journal of cutaneous pathology Brown, R. A., Wang, J. Y., Raghavan, S. S., Zhang, J., Wan, D. C., Born, D., Koo, M., Hazard, F. K., Novoa, R. A., Rieger, K. E. 2020

  View details for DOI 10.1111/cup.13890

  View details for PubMedID 33034114

• Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis. Pediatric dermatology Wu, T. T., Goodarzi, H., Wang, J., Novoa, R., Teng, J. M. 2020

  Abstract

  Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.

  View details for DOI 10.1111/pde.14327

  View details for PubMedID 32970342

• PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features. Journal of cutaneous pathology Raghavan, S. S., Wang, J. Y., Kwok, S., Rieger, K. E., Novoa, R. A., Brown, R. A. 2020

  Abstract

  BACKGROUND: PRAME (PReferentially expressed Antigen in MElanoma) has shown utility in distinguishing melanoma from benign melanocytic lesions, but knowledge of its expression pattern in intermediate melanocytic and spitzoid proliferations is limited.METHODS: Immunohistochemical expression of PRAME was examined in 112 melanocytic proliferations with intermediate histopathologic or spitzoid features.RESULTS: Any intensity of PRAME staining in at least 60% of lesional melanocytes was determined as the best threshold for diffuse staining in this cohort. Nearly all non-spitzoid melanomas (23/24; 95.8%) demonstrated diffuse PRAME expression. PRAME was completely negative in 95.6% (43/45) of mitotically-active nevi, traumatized nevi, nevi with persistent/recurrent features, and dysplastic nevi. Most Spitz nevi (15/20) and atypical Spitz tumors (10/13) entirely lacked PRAME expression. One Spitz nevus, one atypical Spitz tumor, and one case of spitzoid melanoma (1/2) demonstrated diffuse PRAME expression.CONCLUSIONS: Although diffuse PRAME expression is generally limited to malignant melanoma, benign Spitz nevi and atypical Spitz tumors can infrequently express diffuse PRAME. PRAME immunohistochemistry can be useful in the evaluation of atypical melanocytic proliferations with intermediate histopathologic features but should be interpreted with caution in the setting of spitzoid neoplasms. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13818

  View details for PubMedID 32700786

• Diagnostic Utility of LEF1 Immunohistochemistry in Differentiating Deep Penetrating Nevi From Histologic Mimics. The American journal of surgical pathology Raghavan, S. S., Saleem, A., Wang, J. Y., Rieger, K. E., Brown, R. A., Novoa, R. A. 2020

  Abstract

  Deep penetrating nevi (DPNs) are intermediate grade lesions which have the capacity to recur, metastasize, or progress to melanoma. Differentiating DPN from other melanocytic lesions including blue and cellular blue nevi can be diagnostically challenging, and markers to distinguish these entities can be useful. Mutations of the beta-catenin and mitogen-activated protein kinase pathways have recently been elucidated as distinctive of DPN. This pathway can subsequently activate lymphoid enhancer-binding factor 1 (LEF1), a transcription factor shown to facilitate the epithelial-mesenchymal transition to propagate tumorigenesis. Seventy-two cases in total were examined on hematoxylin and eosin sections and with beta-catenin and LEF1 immunohistochemistry. This included: DPN (14), cellular blue nevi (19), blue nevi (15), congenital melanocytic nevi (12), and melanoma (12). Nuclear expression of LEF1, present throughout the entire depth of the lesion, was noted in 13/14 (93%) of DPN, 0/19 (0%) of cellular blue nevi, 0/15 (0%) of blue nevi, 1/12 (8%) of congenital melanocytic nevi, and 9/12 (75%) of melanoma cases. Nuclear expression of beta-catenin, present throughout the entire depth of the lesion, was noted in 14/14 (100%) of DPN, 0/18 (0%) of cellular blue nevi, 0/15 (0%) of blue nevi, 1/12 (8%) of congenital melanocytic nevi, and 1/12 (8%) of melanoma cases. A majority of congenital melanocytic nevi demonstrated a gradient of LEF1 and beta-catenin expression with more intense staining superficially and loss of staining with increasing depth. Deep, uniform nuclear LEF1 combined with beta-catenin immunohistochemical staining can be useful in distinguishing DPN from histologic mimics.

  View details for DOI 10.1097/PAS.0000000000001513

  View details for PubMedID 32520758

• Disseminated Tuberculosis Presenting as Medium-Vessel Vasculitis in an Immunocompromised Host. Journal of cutaneous pathology Wang, J. Y., Brown, R. A., Pugliese, S., Kwong, B. Y., Novoa, R. A. 2020

  Abstract

  Cutaneous tuberculosis is an uncommon entity with several clinical forms recognized. Histopathologically, most cases are characterized by granulomatous inflammation and caseating necrosis, though less common findings, including vasculitis, have also been described. We report a 55-year-old male with a history of recently diagnosed dermatomyositis receiving immunosuppression with mycophenolate mofetil and prednisone, who developed multifocal soft tissue abscesses and an indurated erythematous plaque on the back. Skin biopsy of the back revealed a necrotizing medium-vessel vasculitis. M. tuberculosis was detected in the skin via acid-fast bacilli stain and confirmed by tissue culture and polymerase chain reaction. Cutaneous findings improved rapidly with anti-tuberculosis therapy. This case illustrates an uncommon clinical and histopathologic presentation of disseminated tuberculosis. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13678

  View details for PubMedID 32133689

• Reticulohistiocytoma (solitary epithelioid histiocytoma) with mutations in RAF1 and TSC2. Journal of cutaneous pathology Bahrani, E. n., Fernandez-Pol, S. n., Wang, J. Y., Aasi, S. Z., Brown, R. A., Novoa, R. A. 2020

  View details for DOI 10.1111/cup.13727

  View details for PubMedID 32342514

• Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma. Journal of the American Academy of Dermatology Hirotsu, K. E., Rana, J. n., Wang, J. Y., Raghavan, S. S., Rieger, K. E., Srinivas, S. n., Fan, A. C., Kwong, B. Y., Novoa, R. A., Zaba, L. n. 2020

  View details for DOI 10.1016/j.jaad.2020.11.067

  View details for PubMedID 33301805

• Histopathologic Characterization of Mogamulizumab-associated Rash. The American journal of surgical pathology Wang, J. Y., Hirotsu, K. E., Neal, T. M., Raghavan, S. S., Kwong, B. Y., Khodadoust, M. S., Brown, R. A., Novoa, R. A., Kim, Y. H., Rieger, K. E. 2020

  Abstract

  Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.

  View details for DOI 10.1097/PAS.0000000000001587

  View details for PubMedID 32976123

• Diffuse PRAME expression is highly specific for malignant melanoma in the distinction from clear cell sarcoma. Journal of cutaneous pathology Raghavan, S. S., Wang, J. Y., Toland, A. n., Bangs, C. D., Rieger, K. E., Novoa, R. A., Charville, G. W., Brown, R. A. 2020

  View details for DOI 10.1111/cup.13812

  View details for PubMedID 32681554

• Fitzpatrick Phototype Disparities in Identification of Cutaneous Malignancies by Google Reverse Image. Journal of the American Academy of Dermatology Jia, J. L., Wang, J. Y., Mills, D. E., Shen, A. n., Sarin, K. Y. 2020

  View details for DOI 10.1016/j.jaad.2020.05.005

  View details for PubMedID 32389713

• Epidermolysis bullosa with pyloric atresia consistently demonstrates concurrent low intra-basal epidermal and lamina lucida cleavage planes: a survey of six cases. Journal of the European Academy of Dermatology and Venereology : JEADV Wang, J. Y., Marinkovich, M. P., Rieger, K. E. 2019

  Abstract

  Epidermolysis bullosa with pyloric atresia (EB-PA) is a rare, autosomal recessive form of epidermolysis bullosa characterized by mucocutaneous fragility, intestinal obstruction, and frequent urologic and renal abnormalities. The clinical course is typically lethal in the first few weeks of life, with an overall mortality of nearly 80%.1 Mutations in ITGB4, ITGA6, and PLEC1, which encode hemidesmosome components beta4 integrin, alpha6 integrin, and plectin, respectively, are most commonly implicated.

  View details for DOI 10.1111/jdv.16153

  View details for PubMedID 31851393

• Pityriasis rubra pilaris-like graft-vs-host disease following allogeneic stem cell transplant in two patients. Clinical case reports Wang, J. Y., Tabata, M. M., Pugliese, S., Phillips, D., Kim, J., Weng, W. K., Kwong, B. Y. 2019; 7 (12): 2491-2494

  Abstract

  Chronic cutaneous graft-vs-host disease (GVHD) has several atypical variants. We describe two cases of GVHD with clinical and histopathologic features of pityriasis rubra pilaris (PRP), which responded to additional immunosuppression. Recognition of this newly described PRP-like clinical presentation of GVHD may prompt early consideration of additional steroid-sparing therapies.

  View details for DOI 10.1002/ccr3.2458

  View details for PubMedID 31893086

  View details for PubMedCentralID PMC6935619

• Pityriasis rubra pilaris-like graft-vs-host disease following allogeneic stem cell transplant in two patients CLINICAL CASE REPORTS Wang, J. Y., Tabata, M. M., Pugliese, S., Phillips, D., Kim, J., Weng, W., Kwong, B. Y. 2019

  View details for DOI 10.1002/ccr3.2458

  View details for Web of Science ID 000496342800001

• Persistent Upper Lip Swelling in a Young Woman: Answer. The American Journal of dermatopathology Wang, J. Y., Rieger, K. E. 2019; 41 (5): 386–87

  View details for PubMedID 31009412

• Persistent Upper Lip Swelling in a Young Woman: Answer AMERICAN JOURNAL OF DERMATOPATHOLOGY Wang, J. Y., Rieger, K. E. 2019; 41 (5): 386–87

  View details for DOI 10.1097/DAD.0000000000001048

  View details for Web of Science ID 000480719200015

• Persistent Upper Lip Swelling in a Young Woman: Challenge AMERICAN JOURNAL OF DERMATOPATHOLOGY Wang, J. Y., Rieger, K. E. 2019; 41 (5): E43–E44

  View details for DOI 10.1097/DAD.0000000000001047

  View details for Web of Science ID 000480719200001

• Headache with Midline Shift: An Uncommon Presentation of Sarcoidosis. Journal of general internal medicine Wang, J. Y., Jacobson, D. F. 2017; 32 (3): 363-364

  View details for DOI 10.1007/s11606-016-3807-y

  View details for PubMedID 27431385

• Persistent Upper Lip Swelling in a Young Woman. The American Journal of dermatopathology Wang, J. Y., Rieger, K. E. 2017

  View details for PubMedID 29140807

• Is a Career in Medicine the Right Choice? The Impact of a Physician Shadowing Program on Undergraduate Premedical Students ACADEMIC MEDICINE Wang, J. Y., Lin, H., Lewis, P. Y., Fetterman, D. M., Gesundheit, N. 2015; 90 (5): 629-633

  Abstract

  Undergraduate (i.e., baccalaureate) premedical students have limited exposure to clinical practice before applying to medical school-a shortcoming, given the personal and financial resources required to complete medical training.The Stanford Immersion in Medicine Series (SIMS) is a program that streamlines the completion of regulatory requirements for premedical students and allows them to develop one-on-one mentor-mentee relationships with practicing physicians. The program, offered quarterly since 2007, is an elective available for Stanford University sophomores, juniors, and seniors. Participants apply to the program and, if accepted, receive patient rights and professionalism training. Students shadow the physician they are paired with at least four times and submit a reflective essay about their experience.SIMS program coordinators administered surveys before and after shadowing to assess changes in students' perceptions and understanding of medical careers.The authors observed, in the 61 Stanford premedical students who participated in SIMS between March and June 2010 and completed both pre- and postprogram questionnaires, significant increases in familiarity with physician responsibilities and in understanding physician-patient interactions. The authors detected no significant changes in student commitment to pursuing medicine. Student perceptions of the value of shadowing-high both pre- and post shadowing-did not change.Physician shadowing by premedical baccalaureate students appears to promote an understanding of physician roles and workplace challenges. Future studies should identify the ideal timing, format, and duration of shadowing to optimize the experience and allow students to make informed decisions about whether to pursue a medical career.

  View details for DOI 10.1097/ACM.0000000000000615

  View details for Web of Science ID 000353879700026

  View details for PubMedID 25565263

• Combination of calcitriol and dietary soy exhibits enhanced anticancer activity and increased hypercalcemic toxicity in a mouse xenograft model of prostate cancer PROSTATE Wang, J. Y., Swami, S., Krishnan, A. V., Feldman, D. 2012; 72 (15): 1628-1637

  Abstract

  The potential role of vitamin D and soy in prostate cancer (PCa) prevention/treatment has gained much attention in recent years. In this study, we evaluated the anticancer activity of calcitriol, the active form of vitamin D, dietary soy, and their combinations in a mouse model of PCa.Athymic male nude mice bearing PC-3 human PCa xenografts received diets containing 10 or 20 kcal% soy, calcitriol injections, or a combination of dietary soy and calcitriol. Changes in tumor growth, serum levels of 1,25(OH)(2)D and calcium, and regulation of tumor gene expression were examined.The combination treatments resulted in substantially greater inhibition of tumor growth than either agent alone. Soy diets alone caused a modest elevation in serum 1,25(OH)(2)D, whereas the calcitriol-soy combinations led to substantially elevated serum 1,25(OH)(2) D, hypercalcemia, and in some cases lethal toxicity. The combinations enhanced calcitriol activity in regulating target gene expression, including greater up-regulation of anti-proliferative (p21, IGFBP-3) and pro-apoptotic (Bax) genes, increased inhibition of anti-apoptotic (Bcl-2) and cell cycle promoting (cyclin D1) genes, and suppression of prostaglandin (PG) synthesis and signaling (COX-2, 15-PGDH, PG receptors). Increases in serum calcium were accompanied by elevated expression of intestinal calcium absorption genes (TRPV6, calbindin-9k).Soy increases the bioavailability of endogenous and administered calcitriol, thereby enhancing its anticancer effects and risk of hypercalcemia. Since both agents are easily available as dietary supplements, the increased potential for hypercalcemic toxicity becomes an important factor when considering the combined use of vitamin D and soy in PCa therapy.

  View details for DOI 10.1002/pros.22516

  View details for Web of Science ID 000309405800004

  View details for PubMedID 22457201

  View details for PubMedCentralID PMC3389566

• Dietary Vitamin D-3 and 1,25-Dihydroxyvitamin D-3 (Calcitriol) Exhibit Equivalent Anticancer Activity in Mouse Xenograft Models of Breast and Prostate Cancer ENDOCRINOLOGY Swami, S., Krishnan, A. V., Wang, J. Y., Jensen, K., Horst, R., Albertelli, M. A., Feldman, D. 2012; 153 (6): 2576-2587

  Abstract

  1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer. Because CYP27B1 (1α-hydroxylase), the enzyme catalyzing 1,25(OH)(2)D(3) formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D(3) will be converted to 25(OH)D(3) in the body and then to 1,25(OH)(2)D(3) locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions. Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D(3)-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D(3) inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 μg/mouse, three times a week). Both treatments equivalently inhibited PC-3 prostate cancer xenograft growth but to a lesser extent than the MCF-7 tumors. Calcitriol at 0.05 μg and 0.1 μg caused modest but statistically significant increases in serum calcium levels indicating that the dietary vitamin D(3) comparison was to a maximally safe calcitriol dose. Dietary vitamin D(3) did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D(3) diet raised circulating 1,25 dihydroxyvitamin D levels and did not alter CYP27B1 mRNA in the kidney but increased it in the tumors, suggesting that extrarenal sources including the tumors contributed to the elevated circulating 1,25 dihydroxyvitamin D(3). Both calcitriol and dietary vitamin D(3) were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D(3) supplementation in cancer prevention and therapy.

  View details for DOI 10.1210/en.2011-1600

  View details for Web of Science ID 000304370700010

  View details for PubMedID 22454149

  View details for PubMedCentralID PMC3359605

• Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo. Hormones & cancer Swami, S., Krishnan, A. V., Wang, J. Y., Jensen, K., Peng, L., Albertelli, M. A., Feldman, D. 2011; 2 (3): 190-202

  Abstract

  Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ERα levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa.

  View details for DOI 10.1007/s12672-011-0073-7

  View details for PubMedID 21686077

  View details for PubMedCentralID PMC3114631