Publications by authors named "Maria C Bell"

26 Publications

  • Page 1 of 1

Ex vivo culture of mouse skin activates an interleukin 1 alpha-dependent inflammatory response.

Exp Dermatol 2020 01 16;29(1):102-106. Epub 2019 Oct 16.

Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.

Ex vivo culture of mouse and human skin causes an inflammatory response characterized by production of multiple cytokines. We used ex vivo culture of mouse tail skin specimens to investigate mechanisms of this skin culture-induced inflammatory response. Multiplex assays revealed production of interleukin 1 alpha (IL-1α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during skin culture, and quantitative PCR revealed transcripts for these proteins were also increased. Ex vivo cultures of skin from myeloid differentiation primary response 88 deficient mice (Myd88 ) demonstrated significantly reduced expression of transcripts for the aforementioned cytokines. The same result was observed with skin from interleukin 1 receptor type 1 deficient mice (Il1r1 ). These data suggested the IL-1R1/MyD88 axis is required for the skin culture-induced inflammatory response and led us to investigate the role of IL-1α and IL-1β (the ligands for IL-1R1) in this process. Addition of IL-1α neutralizing antibody to skin cultures significantly reduced expression of Cxcl1, Il6 and Csf3. IL-1β neutralization did not reduce levels of these transcripts. These studies suggest that IL-1α promotes the skin the culture-induced inflammatory response.
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http://dx.doi.org/10.1111/exd.14044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184933PMC
January 2020

Treatment of estrogen-induced dermatitis with omalizumab.

JAAD Case Rep 2019 Jun 25;5(6):481-483. Epub 2019 May 25.

Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana.

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http://dx.doi.org/10.1016/j.jdcr.2019.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536736PMC
June 2019

Phase I Study of an AKT Inhibitor (MK-2206) Combined with Lapatinib in Adult Solid Tumors Followed by Dose Expansion in Advanced HER2+ Breast Cancer.

Clin Cancer Res 2016 06 29;22(11):2659-67. Epub 2016 Mar 29.

University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Purpose: Preclinical data support combining AKT inhibitors with HER2-targeted therapies to overcome resistance to treatment. This phase I study combined the investigational AKT inhibitor, MK-2206, with lapatinib to determine the MTD.

Experimental Design: The dose escalation cohort enrolled adults with advanced solid tumors, who received MK-2206 dosed 30 to 60 mg every other day and lapatinib 1,000 to 1,500 mg daily continuously, escalated using a 3+3 design. Cycles were 28 days except cycle 1 (35 days, including an initial 8 days of MK-2206 alone to evaluate pharmacokinetic interactions). The dose expansion cohort enrolled adults with advanced HER2(+) breast cancer.

Results: Twenty-three participants enrolled in the dose escalation cohort. Dose-limiting toxicities were hyponatremia, fatigue, rash, hypocalcemia, and mucositis. Common toxicities included diarrhea, nausea, and rash. The MTD was reached at MK-2206 45 mg orally every other day and lapatinib 1,500 mg orally daily. Two participants maintained stable disease for >4 months, including a colorectal cancer participant with substantial carcinoembryonic antigen decrease. Of 5 participants in the dose expansion cohort, 2 maintained stable disease for >6 months, including one with prior progression on single-agent lapatinib. Plasma MK-2206 concentrations decreased after addition of lapatinib, but in vitro studies indicate lapatinib increases the intracellular levels of MK-2206.

Conclusions: MK-2206 combined with lapatinib can be tolerated with both drugs above biologically active single-agent doses. Overlapping toxicities result in significant diarrhea and rash, which can be managed medically. Antitumor activity was promising and supports evaluation of AKT inhibitors combined with HER2-targeted therapies. Clin Cancer Res; 22(11); 2659-67. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891227PMC
June 2016

Long-term primary culture of a clear cell ovarian carcinoma reveals an epithelial-mesenchymal cooperative interaction.

Cancer Cell Int 2015 24;15:88. Epub 2015 Sep 24.

Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD USA ; Department of Obstetrics and Gynecology, Sanford School of Medicine, The University of South Dakota, Sioux Falls, SD USA ; Department of Pathology, Faculty of Medicine, McGill University, 3775 University Street, Montreal, QC H3A 2B4 Canada.

Background: We studied a primary culture developed from a biopsy of a clear cell carcinoma of the ovary (O-CCC) by (a) assessing its capacity to retain in vitro pathological features of the tumor of origin; (b) characterizing the main cells released from the complex mass without forced purification of any particular cellular entity; and (c) investigating its long-term proliferative capacity.

Methods: A primary cell culture was developed from a pelvic mass diagnosed as an O-CCC. The morphological analysis of the cell culture was carried out by phase contrast microscopy. Markers of epithelial, mesenchymal, and tumor initiating cells were evaluated by immunocytochemistry. Cell proliferation was studied by detection of bromodeoxyuridine (BrdU) incorporated into newly synthesized DNA. As a biomarker of O-CCC, we assessed the expression of hepatocyte nuclear factor (HNF) 1β.

Results: We show that cells with epithelial morphological features express E-cadherin and expand with time in culture, a fact that the incorporation of BrdU confirms. Cells with mesenchymal-like characteristics that express the mesenchymal marker vimentin, however, allocate to the edges of the epithelial compartment. Moreover, we found that some cells with epithelial features also expressed vimentin. At the beginning of incubation, over 60 % of primary cells expressed the O-CCC marker HNF1β; such percentage declined upon passaging. We show that epithelial not mesenchymal cells undergo DNA replication, and that few cells in both epithelial and mesenchymal compartments express the stem-like tumor antigen CD133.

Conclusions: We provide proof-of-principle that cells separated in bulk from a biopsy of an O-CCC can be maintained in culture for several months, and that two consistent cellular compartments-one epithelial that retains the O-CCC marker HNF1β, and another mesenchymal-persist, and seem to have a cooperative interaction leading to the multiplication of epithelial cells within a mesenchymal cellular environment.
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http://dx.doi.org/10.1186/s12935-015-0243-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581082PMC
September 2015

Teleoncology for gynecologic cancers.

Gynecol Oncol 2015 Oct 5;139(1):172-7. Epub 2015 Jul 5.

Division of Gynecologic Oncology, Billings Clinic, Billings, MT, United States.

Teleoncology describes cancer care provided remotely to improve access to care in rural or underserved areas. In the United States, 14.8 million women live more than 50 miles away from the closest gynecologic oncologist; 4.3 million women live more than 100 miles distant. Teleoncology may therefore partially relieve the geographic barriers to high-quality gynecologic cancer care these women experience. Little has been published on the feasibility of remote provision of high-quality care for gynecologic cancers, perhaps owing to the particular difficulties inherent in remote management of patients who may require both medical and surgical intervention. In this article, we review the data supporting the use of telemedicine in the treatment of cancer patients with a specific focus on applicability to management of gynecologic malignancies. We further add our group's experience with the treatment of rural, underserved gynecologic cancer patients. We believe that development of teleoncologic systems is critical to ensure that all women have access to high-quality gynecologic cancer care, regardless of where they reside.
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http://dx.doi.org/10.1016/j.ygyno.2015.06.042DOI Listing
October 2015

Ormeloxifene efficiently inhibits ovarian cancer growth.

Cancer Lett 2015 Jan 13;356(2 Pt B):606-12. Epub 2014 Oct 13.

Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address:

Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of p27, cyclin E, cyclin D1, and CDK2. In a pre-clinical xenograft mouse ORM treatment significantly reduces tumorigenesis and metastasis. These results indicate that ORM effectively inhibits the growth of cisplatin resistant ovarian cancer cells. ORM is currently in human use and has an established record of patient safety. Our encouraging in vitro and pre-clinical in vivo findings indicate that ORM is a promising candidate for the treatment of ovarian cancer.
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http://dx.doi.org/10.1016/j.canlet.2014.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391643PMC
January 2015

Pathologic findings at risk-reducing salpingo-oophorectomy: primary results from Gynecologic Oncology Group Trial GOG-0199.

J Clin Oncol 2014 Oct 8;32(29):3275-83. Epub 2014 Sep 8.

Mark E. Sherman, Phuong L. Mai, Lori Minasian, and Mark H. Greene, National Cancer Institute, Rockville; Olga B. Ioffe, University of Maryland Medical Center; Brigitte M. Ronnett, Johns Hopkins Medical Institutions, Baltimore; Chad A. Hamilton, Walter Reed National Military Medical Center, Bethesda, MD; Marion Piedmonte, Roswell Park Cancer Institute, Buffalo; Stephanie V. Blank, New York University School of Medicine; Noah D. Kauff, Memorial Sloan Kettering Cancer Center; New York, NY; Linda Van Le, University of North Carolina at Chapel Hill, Chapel Hill, NC; Iouri Ivanov, Columbus Cancer Council, Columbus, OH; Maria C. Bell, Sanford University of South Dakota Medical Center, Sioux Falls, SD; Paul DiSilvestro, Women and Infants Hospital, Providence, RI; Krishnansu S. Tewari, University of California Medical Center Irvine, Orange, CA; Katie Wakeley, Tufts University; Steven J. Skates, Massachusetts General Hospital, Boston, MA; S. Diane Yamada, University of Chicago, Chicago; Gustavo Rodriguez, North Shore University Health System, Evanston, IL; David S. Alberts, University of Arizona Cancer Center, Tucson, AZ; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; and Karen Lu, MD Anderson Cancer Center, Houston, TX.

Purpose: Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study.

Participants And Methods: This analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression.

Results: Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign.

Conclusion: Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer.
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http://dx.doi.org/10.1200/JCO.2013.54.1987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178524PMC
October 2014

A phase II trial of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube.

Gynecol Oncol 2014 Mar 27;132(3):517-25. Epub 2014 Jan 27.

Sanofi U.S., Bridgewater, NJ, USA.

Objective: To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery.

Methods: Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m(2)), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS).

Results: A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response+partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months.

Conclusions: This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.
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http://dx.doi.org/10.1016/j.ygyno.2014.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718618PMC
March 2014

Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173.

Gynecol Oncol 2013 Feb 29;128(2):155-9. Epub 2012 Nov 29.

The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Objective: To determine which patients with near midline lesions may safely undergo unilateral groin dissection based on clinical exam and lymphoscintigraphy (LSG) results.

Methods: Patients participating in GOG-173 underwent sentinel lymph node (SLN) localization with blue dye, and radiocolloid with optional LSG before definitive inguinal-femoral lymphadenectomy (LND). This analysis interrogates the reliability of LSG alone relative to primary tumor location in those patients who had an interpretable LSG and at least one SLN identified. Primary tumor location was categorized as lateral (>2cm from midline), midline, or lateral ambiguous (LA) if located within 2cm, but not involving the midline.

Results: Two-hundred-thirty-four patients met eligibility criteria. Sixty-four had lateral lesions, and underwent unilateral LND. All patients with LA (N=65) and midline (N=105) tumors underwent bilateral LND. Bilateral drainage by LSG was identified in 14/64 (22%) patients with lateral tumors, 38/65 (58%) with LA tumors and in 73/105 (70%) with midline tumors. At mapping, no SLNs were found in contralateral groins among those patients with LA and midline tumors who had unilateral-only LSGs. However, in these patients groin metastases were found in 4/32 patients with midline tumors undergoing contralateral dissection; none were found in 27 patients with LA tumors.

Conclusion: The likelihood of detectable bilateral drainage using preoperative LSG decreases as a function of distance from midline. Patients with LA primaries and unilateral drainage on LSG may safely undergo unilateral SLN.
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http://dx.doi.org/10.1016/j.ygyno.2012.11.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638213PMC
February 2013

Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study.

J Clin Oncol 2012 Nov 2;30(31):3786-91. Epub 2012 Jul 2.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 440, Houston, TX 77030, USA.

Purpose: To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer.

Patients And Methods: Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed.

Results: In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%).

Conclusion: Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.
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http://dx.doi.org/10.1200/JCO.2011.41.2528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478573PMC
November 2012

HPV infection among rural American Indian women and urban white women in South Dakota: an HPV prevalence study.

BMC Infect Dis 2011 Sep 24;11:252. Epub 2011 Sep 24.

Avera Cancer Institute, Sioux Falls, SD, USA.

Background: High-risk strains of human papillomavirus (HPV) cause cervical cancer. American Indian (AI) women in the Northern Plains of the U.S. have significantly higher incidence and mortality rates for cervical cancer than White women in the same geographical area. We compared HPV prevalence, patterns of HPV types, and infection with multiple HPV types in AI and White women living in South Dakota, U.S.

Methods: We analyzed the HPV status of cervical samples collected in 2006-2008 from women aged 18-65 years who attended two rural AI reservation clinics (n = 235) or an urban clinic in the same area serving mostly White women (n = 246). Data collection occurred before HPV vaccination was available to study participants. HPV DNA was amplified by using the L1 consensus primer system and an HPV Linear Array detection assay to identify HPV types. We used chi-square tests to compare HPV variables, with percentages standardized by age and lifetime number of sexual partners.

Results: Compared to White women, AI women were younger (p = 0.01) and reported more sexual partners (p < 0.001). A lower percentage of AI women tested negative for HPV infection compared to Whites (58% [95% CI = 51-65] vs. 77% [95% CI = 71-82]; p < 0.001), and a higher percentage of AI women were infected by oncogenic types (30% [95% CI = 25-36] vs. 16% [95% CI = 11-21]; p = 0.001). Infections among AI women showed a wider variety and very different pattern of HPV types, including a higher prevalence of mixed HPV infections (19% [95% CI = 26-38] vs. 7% [95% CI = 4-11]; p = 0.001). AI women had a higher percentage of HPV infections that were not preventable by HPV vaccination (32% [95% CI = 26-38] vs. 15% [95% CI = 11-21]; p < 0.001).

Conclusions: A higher HPV burden and a different HPV genotyping profile may contribute to the high rate of cervical cancer among AI women.
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http://dx.doi.org/10.1186/1471-2334-11-252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3190376PMC
September 2011

Clinical and cost comparisons for hysterectomy via abdominal, standard laparoscopic, vaginal and robot-assisted approaches.

S D Med 2011 Jun;64(6):197-9, 201, 203 passim

Introduction: The goal of this study was to compare outcomes and costs of four methods of hysterectomy: abdominal, standard laparoscopic, vaginal and robot-assisted approaches.

Methods: We conducted a retrospective medical chart review of 1474 consecutive hysterectomy patients with benign indications.

Results: Implementation of a robotics program at our institution resulted in reductions in abdominal (33 percent to 8 percent) and laparoscopic (29 percent to 5 percent) hysterectomies. Robotic surgery demonstrated the least blood loss and shortest hospital stays (both p < 0.0001), despite greater case complexity. Overall complication rates were highest for abdominal procedures (14 percent) and similar across minimally invasive approaches (8 to 9 percent). Conversion rates were four times greater in laparoscopic than vaginal or robotic hysterectomy (p = 0.01). Vaginal hysterectomy, performed in the least complex cases, had the lowest major complication rate (1.5 percent) and lowest costs. Costs for robotic surgery were similar to abdominal and laparoscopic approaches when robots were not depreciated as direct surgical expenses.

Conclusions: Vaginal hysterectomy was the least expensive surgical option. Robotic surgery reduced morbidity, conversions and hospital stays even in complex cases, without incurring additional costs beyond purchase of the robotic system.
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June 2011

Uterine pleomorphic rhabdomyosarcoma: a case report and review of literature.

S D Med 2011 Feb;64(2):47-9

Sanford School of Medicine, The University of South Dakota Pathology Residency, Lenoir, NC, USA.

Primary pleomorphic rhabdomyosarcoma of the uterus is a very rare neoplasm. We describe a 65-year old female with this diagnosis, who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy and lymph node dissection. Also included is a discussion on the different types of rhabdomyosarcoma with reviews of their histological features, epidemiology and common sites of origin.
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February 2011

Risk factors for HPV infection among American Indian and white women in the Northern Plains.

Gynecol Oncol 2011 Jun 17;121(3):532-6. Epub 2011 Mar 17.

Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD, USA.

Objective: American Indian (AI) women living in the Northern Plains have high incidence and mortality rates for cervical cancer. We assessed risk factors for human papillomavirus (HPV) infection among AI and White women.

Methods: We tested cervical samples for HPV infection obtained from women ages 18-65 years attending 2 rural AI reservation clinics in South Dakota (n=235) and an urban clinic serving predominantly White women (n=246). Patients self-reported information on HPV risk factors. We used percentages and chi-square tests to compare risk factors, and logistic regression with HPV status as the outcome to quantify the association between HPV and risk factors.

Results: AI women had more risk factors than White women, including younger age, less education, less vegetable consumption, more sexual partners, younger age at first sexual experience and first pregnancy, and more pregnancies (p values≤0.003). AI women more often endorsed recreational drug use, history of sexually transmitted diseases, and current smoking; White women reported more alcohol consumption (p values<0.001). In multivariate analysis, younger age and current smoking were associated with higher odds of HPV infection in AI women, whereas a higher number of sexual partners was associated with higher odds of HPV infection in White women.

Conclusions: AI women have a high burden of risk factors for HPV disease, and associations with HPV infection appear to differ by community. Knowledge of specific risk factors in AI populations may provide targets for public health officials to decrease HPV infection and disease.
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http://dx.doi.org/10.1016/j.ygyno.2011.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498572PMC
June 2011

Ovarian small cell carcinoma, hypercalcemic type exhibiting a response to high-dose chemotherapy.

S D Med 2010 Nov;63(11):375-7

Sanford School of Medicine Pathology Residency, The University of South Dakota, USA.

A gravida 2, para 2 25-year-old woman three months post-partum presented to her primary physician with abdominal pain and bloating; a 20-cm complex cystic pelvic mass was identified by ultrasound. No ovarian masses were noted during ultrasound exam at the prior pregnancy, less than one year earlier. Her labs included hypercalcemia (11.8 mg/dL, normal less than 10.5) and an elevated CA 125 (160 U/mL, normal less than 35). An exploratory laparotomy revealed a 20-cm right ovarian mass. Frozen section was performed and a sex cord-stromal tumor was favored. Permanent sections of the specimen, however, revealed round, closely packed neoplastic cells with a high nuclear to cytoplasm ratio and high mitotic rate growing in a diffuse pattern with scattered follicle-like, ill-defined microcystic spaces. Immunohistochemical stains revealed the neoplasm to be focally positive for keratin and negative for inhibin. The final diagnosis rendered was small cell carcinoma of the ovary, hypercalcemic type. Further staging revealed para-aortic lymph node involvement (stage IIIC). Current literature suggests a very poor prognosis for these neoplasms despite aggressive therapy, with an overall survival rate of 10 percent. Rare response has been noted, however, with high-dose chemotherapy followed by autologous peripheral blood stem cell transplant. Our patient underwent a rigorous chemotherapeutic regimen followed by peripheral blood stem cell transplant, and as of August 2010, (17 months after initial diagnosis), the patient has had no recurrence.
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November 2010

Curcumin suppresses human papillomavirus oncoproteins, restores p53, Rb, and PTPN13 proteins and inhibits benzo[a]pyrene-induced upregulation of HPV E7.

Mol Carcinog 2011 Jan;50(1):47-57

Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota 57105, USA.

Curcumin has great potential as a chemopreventive and chemotherapeutic agent; however, its effects on human papillomavirus (HPV)-associated molecular events are inadequately explored. This study examined the effects of curcumin on HPV-associated pathways involved in developing cervical cancer. We demonstrate for the first time that curcumin treatment suppresses cervical cancer cell growth in a three-dimensional raft culture system. Curcumin also inhibits tumorigenic characteristics as shown by decreases in both clonogenic potential and cell motility. Additionally, our findings show that curcumin treatment inhibits the transcription of HPV16 E6/E7 as early as 6 h posttreatment and restores the expression of tumor suppressor proteins p53, retinoblastoma protein, and PTPN13. While smoking is a recognized risk factor for cervical cancer, the molecular effects of smoke carcinogens on the expression of HPV E6/E7 oncogenes are not well known. We show for the first time that exposure to benzo[a]pyrene (BaP), a tobacco carcinogen, increases the expression of HPV E7 oncoprotein suggesting a molecular link between smoking and cervical cancer. Importantly, curcumin decreases the BaP induced increase in the expression of HPV E7 oncoprotein. The results of this study clearly demonstrate that curcumin alters HPV-associated molecular pathways in cervical cancer cells. These novel findings imply that curcumin may be an effective chemopreventive and therapeutic agent for cervical cancer prevention and treatment.
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http://dx.doi.org/10.1002/mc.20695DOI Listing
January 2011

Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth.

J Ovarian Res 2010 Apr 29;3:11. Epub 2010 Apr 29.

Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57105, USA.

Background: Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, we demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin resistant ovarian cancer cells. To improve the efficacy and specificity of curcumin induced chemo/radio sensitization, we developed a curcumin nanoparticle formulation conjugated with a monoclonal antibody specific for cancer cells.

Methods: Cisplatin resistant A2780CP ovarian cancer cells were pre-treated with curcumin followed by exposure to cisplatin or radiation and the effect on cell growth was determined by MTS and colony formation assays. The effect of curcumin pre-treatment on the expression of apoptosis related proteins and beta-catenin was determined by Western blotting or Flow Cytometry. A luciferase reporter assay was used to determine the effect of curcumin on beta-catenin transcription activity. The poly(lactic acid-co-glycolic acid) (PLGA) nanoparticle formulation of curcumin (Nano-CUR) was developed by a modified nano-precipitation method and physico-chemical characterization was performed by transmission electron microscopy and dynamic light scattering methods.

Results: Curcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. During the 6 hr pre-treatment, curcumin down regulated the expression of Bcl-XL and Mcl-1 pro-survival proteins. Curcumin pre-treatment followed by exposure to low doses of cisplatin increased apoptosis as indicated by annexin V staining and cleavage of caspase 9 and PARP. Additionally, curcumin pre-treatment lowered beta-catenin expression and transcriptional activity. Nano-CUR was successfully generated and physico-chemical characterization of Nano-CUR indicated an average particle size of ~70 nm, steady and prolonged release of curcumin, antibody conjugation capability and effective inhibition of ovarian cancer cell growth.

Conclusion: Curcumin pre-treatment enhances chemo/radio-sensitization in A2780CP ovarian cancer cells through multiple molecular mechanisms. Therefore, curcumin pre-treatment may effectively improve ovarian cancer therapeutics. A targeted PLGA nanoparticle formulation of curcumin is feasible and may improve the in vivo therapeutic efficacy of curcumin.
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http://dx.doi.org/10.1186/1757-2215-3-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880315PMC
April 2010

Cervical cancer prevention: new tools and old barriers.

Cancer 2010 Jun;116(11):2531-42

Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-4410, USA.

Cervical cancer is the second most common female tumor worldwide, and its incidence is disproportionately high (>80%) in the developing world. In the United States, in which Papanicolaou (Pap) tests have reduced the annual incidence to approximately 11,000 cervical cancers, >60% of cases are reported to occur in medically underserved populations as part of a complex of diseases linked to poverty, race/ethnicity, and/or health disparities. Because carcinogenic human papillomavirus (HPV) infections cause virtually all cervical cancer, 2 new approaches for cervical cancer prevention have emerged: 1) HPV vaccination to prevent infections in younger women (aged < or =18 years) and 2) carcinogenic HPV detection in older women (aged > or =30 years). Together, HPV vaccination and testing, if used in an age-appropriate manner, have the potential to transform cervical cancer prevention, particularly among underserved populations. Nevertheless, significant barriers of access, acceptability, and adoption to any cervical cancer prevention strategy remain. Without understanding and addressing these obstacles, these promising new tools for cervical cancer prevention may be futile. In the current study, the delivery of cervical cancer prevention strategies to these US populations that experience a high cervical cancer burden (African-American women in South Carolina, Alabama, and Mississippi; Haitian immigrant women in Miami; Hispanic women in the US-Mexico Border; Sioux/Native American women in the Northern Plains; white women in the Appalachia; and Vietnamese-American women in Pennsylvania and New Jersey) is reviewed. The goal was to inform future research and outreach efforts to reduce the burden of cervical cancer in underserved populations.
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http://dx.doi.org/10.1002/cncr.25065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876205PMC
June 2010

The first 100 da Vinci hysterectomies: an analysis of the learning curve for a single surgeon.

S D Med 2009 Mar;62(3):91, 93-5

Sanford School of Medicine, University of South Dakota, Sioux Falls, USA.

Background: Robotic gynecologic procedures were FDA-approved in March 2005. Published average times for robotic hysterectomies vary from 192 minutes to 242 minutes and one report indicated operative times ranging from 4.5 to ten hours. Many critics cite learning curves and increased operative times as a deterrent to performing robotic hysterectomies.

Methods: This is a retrospective review of surgical times (learning curve) for the first 100 consecutive extrafascial hysterectomies with or without salpingo-oophorectomy for a single surgeon. Operating times were recorded by operating room nursing staff for each case. The times reported are from "skin to skin," which is defined as from when the surgeon started to place anything vaginally until the last suture was placed to close the trocar sites. We report average times for hysterectomy per 20 cases.

Results: The average time for hysterectomies was as follows: First 20 cases--124 minutes, second 20 cases--94 minutes, third 20 cases--85 minutes, fourth 20 cases--88 minutes, fifth 20 cases--81 minutes. Age, body mass index and uterine weights were comparable between groups. Complications were highest in the first 20 at 15 percent, compared with 5 percent for the remaining groups, but this did not reach statistical significance.

Conclusions: The learning curve for da Vinci hysterectomies is steep, with the maximum improvement in surgical times in the first 20 cases. Minimal improvement was demonstrated after this.
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March 2009

Expression and functions of transmembrane mucin MUC13 in ovarian cancer.

Cancer Res 2009 Feb 27;69(3):765-74. Epub 2009 Jan 27.

Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, South Dakota 57105, USA.

MUC13, a transmembrane mucin, is normally expressed in gastrointestinal and airway epithelium. Its aberrant expression has been correlated with gastric colon and cancer. However, the expression and functions of MUC13 in ovarian cancer are unknown. In the present study, the expression profile and functions of MUC13 were analyzed to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. A recently generated monoclonal antibody (clone PPZ0020) was used to determine the expression profile of MUC13 by immunohistochemistry using ovarian cancer tissue microarrays and 56 additional epithelial ovarian cancer (EOC) samples. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with the normal ovary/benign tissues. Among all ovarian cancer types, MUC13 expression was specifically present in EOC. For the functional analyses, a full-length MUC13 gene cloned in pcDNA3.1 was expressed in a MUC13 null ovarian cancer cell line, SKOV-3. Here, we show that the exogenous MUC13 expression induced morphologic changes, including scattering of cells. These changes were abrogated through c-Jun NH(2) kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Additionally, a marked reduction in cell-cell adhesion and significant (P < 0.05) increases in cell motility, proliferation, and tumorigenesis in a xenograft mouse model system were observed upon exogenous MUC13 expression. These cellular characteristics were correlated with up-regulation of HER2, p21-activated kinase 1, and p38 protein expression. Our findings show the aberrant expression of MUC13 in ovarian cancer and that its expression alters the cellular characteristics of SKOV-3 cells. This implies a significant role of MUC13 in ovarian cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-0587DOI Listing
February 2009

Epidemiology of Human Papilloma Virus (HPV) in Cervical Mucosa.

Methods Mol Biol 2009 ;471:439-56

Department of Obstetrics and Gynecology, Sanford School of Medicine, The University of South Dakota, Sioux Falls, SD, USA.

In a worldwide scenario, human papillomavirus (HPV) infection is the second leading cause of cancer-related morbidity and mortality among women due to its very close association with cervical cancer. More than 100 different types of HPV genotypes have been characterized to date. Among these, approximately 24 HPV genotypes specifically infect the genital and oral mucosal system. The mucosal HPVs are most frequently sexually transmitted, and they are responsible for the most common sexually transmitted diseases throughout the world. In a majority of the cases, oncogenic/nononcogenic HPV infections spontaneously clear by themselves without any medical intervention. However, a persistent and long-term HPV infection usually leads to cervical cancer, which remains difficult to treat. In recent years, advance understanding of the structure of HPV and its pathogenesis has led to a variety of new treatments to combat HPV-related diseases, including a Food and Drug Administration-approved HPV vaccine that is very effective in young women. To effectively use this HPV vaccine worldwide, a clear understanding of HPV genotypes in different geographical populations is imperative. In this chapter, we have focused briefly on HPV genotypes and HPV prevalence in the women of different geographical populations.
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http://dx.doi.org/10.1007/978-1-59745-416-2_22DOI Listing
March 2009

Comparison of outcomes and cost for endometrial cancer staging via traditional laparotomy, standard laparoscopy and robotic techniques.

Gynecol Oncol 2008 Dec 1;111(3):407-11. Epub 2008 Oct 1.

Department of Obstetrics and Gynecology, Sanford Women's Health, Sanford Clinic, Sioux Falls, SD 57105, USA.

Objectives: The study purpose was to compare hysterectomy and lymphadenectomy completed via robotic assistance, laparotomy, and laparoscopy for endometrial cancer staging with respect to operative and peri-operative outcomes, complications, adequacy of staging, and cost.

Methods: One hundred and ten patients underwent hysterectomy with bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy for endometrial cancer staging. All cases were performed by a single surgeon, at a single institution (40 robotic, 40 laparotomy, and 30 laparoscopic) and were retrospectively reviewed to compare demographics and peri-operative variables including, operative time, estimated blood loss, lymph node count, hospital stay, complications, and return to normal activity. Additionally, a cost comparison between all three modalities was performed.

Results: Patients undergoing robotic assisted hysterectomy and staging experienced longer operative time than the laparotomy cohort with no difference in comparison to the laparoscopic cohort (184 min, 108.6 min, 171 min, p<0.0001, p=0.14). Estimated blood loss was significantly reduced for the robotic cohort in comparison to the laparotomy cohort and comparable to laparoscopic cohort (166 cc, 316 cc, 253 cc, p=0.01, p=0.25). The complication rate was lowest in the robotic cohort (7.5%) relative to the laparotomy (27.5%) and laparoscopic cohorts (20%) (p=0.015, p=0.03). Average return to normal activity for the robotic patients was significantly shorter than those undergoing laparotomy (24.1 days versus 52 days, p<0.0001) and those undergoing laparoscopy (31.6 days, p=0.005). Lymph node retrieval did not differ between the 3 groups (robotic 17 nodes, laparotomy 14 nodes, laparoscopic 17 nodes). The total average cost for hysterectomy with staging completed via laparotomy was $12,943.60, for standard laparoscopy $7569.80, and for robotic assistance $8212.00. The difference in cost between laparotomy and robotic cohorts was significant p=0.0001 while there was no statistically significant difference in cost between laparoscopy and robotic cohorts p=0.06.

Conclusions: Robotic hysterectomy provides comparable node retrieval to laparotomy and laparoscopic procedures in the case of the experienced laparoscopic surgeon. While robotic hysterectomy takes longer to perform than hysterectomy completed via laparotomy, it is equivalent to laparoscopic hysterectomy and provides the patient with a more expeditious return to normal activity with reduced post-operative morbidity. Additionally, the average cost for hysterectomy and staging was highest for laparotomy, followed by robotic, and least for standard laparoscopy.
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http://dx.doi.org/10.1016/j.ygyno.2008.08.022DOI Listing
December 2008

A rare case of squamous cell carcinoma arising in a mature cystic teratoma of the ovary.

S D Med 2007 Oct;60(10):401-3

Sanford School of Medicine, University of South Dakota Residency Program, Sioux Falls, USA.

Mature cystic teratoma is a common benign adnexal tumor in females. We describe a 43-year-old female with a 10 cm left ovarian mature cystic teratoma with the rare finding of squamous cell carcinoma. The clinical evaluation with ultrasound and serologic markers is discussed. Treatment typically consists of surgical resection with adjuvant chemotherapy using platinum-based agents. Prognosis is extremely poor in most cases.
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October 2007

There is a high prevalence of human papillomavirus infection in American Indian women of the Northern Plains.

Gynecol Oncol 2007 Nov 30;107(2):236-41. Epub 2007 Jul 30.

Cancer Biology Research Institute, Sanford Research, Sanford School of Medicine, The University of South Dakota, Sioux Falls, SD, USA.

Objectives: Cervical cancer is the leading gynecological malignancy worldwide, and the incidence of this disease is very high in American Indian women. Infection with the human papillomavirus (HPV) is responsible for more than 95% of cervical squamous carcinomas. Therefore, the main objective of this study was to analyze oncogenic HPV infections in American Indian women residing in the Northern Plains.

Methods: Cervical samples were collected from 287 women attending a Northern Plains American Indian reservation outpatient clinic. DNA was extracted from the cervical samples and HPV-specific DNA was amplified by polymerase chain reaction (PCR) using the L1 consensus primer sets. The PCR products were hybridized with the Roche HPV Line Blot assay for HPV genotyping to detect 27 different low- and high-risk HPV genotypes. The Chi-squared test was performed for statistical analysis of the HPV infection and cytology diagnosis data.

Results: Of the total 287 patients, 61 women (21.25%) tested positive for HPV infection. Among all HPV-positive women, 41 (67.2%) were infected with high-risk HPV types. Of the HPV infected women, 41% presented with multiple HPV genotypes. Additionally, of the women infected with oncogenic HPV types, 20 (48.7%) were infected with HPV16 and 18 and the remaining 21 (51.3%) were infected with other oncogenic types (i.e., HPV59, 39, 73). Women infected with oncogenic HPV types had significantly higher (p=0.001) abnormal Papanicolaou smear tests (Pap test) compared to women who were either HPV negative or positive for non-oncogenic HPV types. The incidence of HPV infection was inversely correlated (p<0.05) with the age of the patients, but there was no correlation (p=0.33) with seasonal variation.

Conclusions: In this study, we observed a high prevalence of HPV infection in American Indian women residing on Northern Plains Reservations. In addition, a significant proportion of the oncogenic HPV infections were other than HPV16 and 18.
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http://dx.doi.org/10.1016/j.ygyno.2007.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2396448PMC
November 2007

Combined staining of TAG-72, MUC1, and CA125 improves labeling sensitivity in ovarian cancer: antigens for multi-targeted antibody-guided therapy.

J Histochem Cytochem 2007 Aug 3;55(8):867-75. Epub 2007 May 3.

Cancer Biology Research Institute, Sanford Research/USD, Department of Obstetrics and Gynecology and Basic Biomedical Science Division, Sanford School of Medicine, The University of South Dakota, Sioux Falls, SD 57105, USA.

Single antigen-targeted intraperitoneal radioimmunotherapy for ovarian cancer has shown limited success. Due to the heterogeneous expression of tumor antigens on cancer cells, a multi-antigen targeting approach appears logical to augment the therapeutic efficacy of antibody-guided therapy. In the interest of developing this novel approach, ovarian cancer tissue microarray slides containing cancer and benign/non-neoplastic tissue samples (n=92) were processed for single-, double-, and triple-antigen labeling using antibodies for the tumor-associated antigens TAG-72, MUC1, and CA125. Among all ovarian cancer types, 72%, 61%, and 50% of the samples showed immunolabeling for TAG-72, MUC1, and CA125, respectively. Expression level of these antigens was significantly (p<0.005) higher in advanced stage carcinomas compared with early stage. Of the 48 epithelial ovarian cancer samples, individual anti-TAG-72, MUC1, and CA125 antibody probing showed labeling in 89.5%, 87.5%, and 73.0% of the cases, respectively. In the majority of the cancer samples (>70%), a heterogeneous labeling pattern was observed (only 30-40% of the cancer cells within the sample were labeled). However, upon combining the three antigens (triple-antigen labeling), 98% of the epithelial ovarian cancer samples were labeled and >95% of the cancer cells within each sample were labeled. Our data indicate that the heterogeneous expression of cancer antigens appears to be a major obstacle in antibody-guided therapy, and this can be overcome by multiple antigen targeting. Therapeutic efficacy of antibody-guided therapy for ovarian cancer treatment will be enhanced by the combined targeting of TAG-72, MUC1, and CA125.
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http://dx.doi.org/10.1369/jhc.7A7213.2007DOI Listing
August 2007

Cervical cancer chemoprevention, vaccines, and surrogate endpoint biomarkers.

Cancer 2003 Nov;98(9 Suppl):2044-51

Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

At the Second International Conference on Cervical Cancer, held April 11-14, 2002, experts in cervical cancer prevention, detection, and treatment reviewed the need for more research in chemoprevention, including prophylactic and therapeutic vaccines, immunomodulators, peptides, and surrogate endpoint biomarkers. Investigators and clinicians noted the need for more rigorous Phase I randomized clinical trials, more attention to the risk factors that can affect study results in this patient population, and validation of optical technologies that will provide valuable quantitative information in real time regarding disease regression and progression. They discussed the role of the human papillomavirus (HPV) in cervical cancer development and the importance of developing strategies to suppress HPV persistence and progression. Results in Phase I randomized clinical trials have been disappointing because few have demonstrated statistically significant regression attributable to the agent tested. Researchers recommended using a transgenic mouse model to test and validate new compounds, initiating vaccine and immunomodulator trials, and developing immunologic surrogate endpoint biomarkers.
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http://dx.doi.org/10.1002/cncr.11674DOI Listing
November 2003
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