Identifying the need to refine the potential patient risk factors for niraparib-induced thrombocytopenia.

OBJECTIVE: Niraparib is a poly (ADP-ribose) polymerase inhibitor (PARP) approved for use in maintenance therapy for ovarian cancer that is associated with the unpredictable grade 3/4 thrombocytopenia. This study was conducted to refine patient dosing recommendations for niraparib based upon clinical practice observations of grade 3/4 thrombocytopenia. METHODS AND MATERIALS: Six patient cases were reviewed to identify similarities in patient factors. An in vitro study was conducted using healthy volunteer blood spiked with Niraparib concentrations ranging from 0 ng/mL to 5000 ng/mL. Manual platelet counts were evaluated at different time intervals for each concentration and compared to untreated controls. Data was then analyzed based on percent change in platelet count versus untreated control for each concentration/time point. RESULTS: In three patients with body weight > 80 kg and platelet count >200 × 109/L, decreased creatinine clearance (CrCl) <60 mL/min was identified as potential signal. An additional three patients with weights below 77 kg and/or baseline platelet counts <150 × 109/L were re-evaluated, and it was observed that all had decreased CrCl of <60 mL/min. Albumin <3.5 g/dL was also observed in some patients with thrombocytopenia. The in vitro study, observed a direct concentration-dependent relationship between niraparib and thrombocytopenia. CONCLUSION: The data suggests that renal insufficiency and hypoalbuminemia may be associated with the development of niraparib-induced thrombocytopenia. Moreover, the preliminary in vitro studies also demonstrated a concentration-dependent relationship between niraparib and direct toxicity to platelets.

Managing Variant Interpretation Discrepancies in Hereditary Cancer: Clinical Practice, Concerns, and Desired Resources.

Variant interpretation is a complex process, and classification may vary between sources. This study aimed to determine the practice of cancer genetic counselors regarding discrepancies in variant interpretation and to identify concerns when counseling these discrepancies. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. The vast majority of counselors (93%) had seen a variant interpretation discrepancy in practice. A large majority (96%) of respondents indicated that they conducted their own research on reported variants. Most respondents cited variant databases as the most common resource utilized in researching variants. Approximately 33% of counselors spent 45 min or more of extra time researching a discrepancy compared to researching a variant with a single classification. When asked how they approached counseling sessions involving variant interpretation discrepancies, the free responses emphasized that counselors considered family history, clinical information, and psychosocial concerns, showing that genetic counselors tailored the session to each individual. Discrepancies in variant interpretation are an ongoing concern for clinical cancer genetic counselors, as demonstrated by the fact that counselors desired further resources to aid in addressing these discrepancies, including a centralized database (89%), guidelines from a major organization (88%), continuing education about the issue (74%), and functional studies (58%). Additionally, most respondents reported that the ideal database would be owned by a non-profit organization (59%) and obtain information directly from laboratories (91%). This investigation was the first to address these discrepancies from a clinical point of view. The study demonstrates that discrepancies in variant interpretation are a concern for clinical cancer genetic counselors and outlines the need for additional support.

Effectiveness of cyanoacrylate microbial sealant in the reduction of surgical site infection in gynecologic oncology procedures: A phase III single institution prospective randomized trial.

OBJECTIVES: Surgery is a cornerstone for patients with gynecologic malignancies. Surgical site infections (SSI) remain a source of post-operative morbidity. Consequences range from escalated costs, delay in adjuvant therapy, and increased morbidity. Our primary objective was to evaluate the effectiveness of a cyanoacrylate microbial sealant (CMS) to reduce post-operative SSI following laparotomy for suspected gynecologic malignancy. METHODS: Patients were randomized using a 1:1 allocation to receive either standard skin preparation or standard preparation with CMS and stratified by BMI. Patients were followed for 6weeks for SSI. Demographic data was collected through the EMR. Associations between SSI, use of CMS, and clinicopathologic factors were explored using descriptive statistics, chi-square and multivariate analysis. RESULTS: 300 patients underwent randomization. Median age of the cohort was 58. Arms were matched and there was no difference in rate of medical comorbidities. Mean BMI was 38.8kg/m2 in patients randomized to BMI≥30 and 26.3kg/m2 randomized to BMI<30. Surgical characteristics for the entire cohort: 66% malignancy, 91% clean-contaminated, 21% bowel surgery, 25% transfusion. Seventy-six (25%) patients developed a SSI: 43 patients (28%) treated with CMS, compared to 33 (21%) patients treated without CMS (p=0.18). Multivariate model demonstrated that BMI≥30 (p<0.005), surgery for malignancy (p=0.010), transfusion in the OR (p<0.001), and closure with staples (p=0.0005) were associated with post-operative SSI. CONCLUSIONS: Patients presenting to a gynecologic oncologist for surgery frequently present with multiple risk factors for SSI and laparotomy is complicated by surgical-site complications in up to 30% of cases. The addition of CMS alone does not appear to reduce risk of overall SSI. Additional risk-reducing strategies including use of antimicrobial agents and optimization of modifiable risk factors prior to surgery should be explored as pathways for reducing this significant post-operative morbidity.

Chemotherapy Response Rates Among Patients With Endometrial Cancer Who Have Elevated Serum Platelets.

OBJECTIVE: This retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer. METHODS: From 3 separate cancer centers, a total of 318 patients with endometrial cancer who received postoperative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Patients were classified as having an elevated platelet count if their serum platelet count was greater than 400 × 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease-free and disease-specific survival. χ² Test and Student t test were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival. RESULTS: There were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (hazard ratio [HR], 2.8; 95% 95% confidence interval [CI], 1.46-5.38; P < 0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased disease-free survival (HR, 2.24; 95% CI, 1.26-3.98; P < 0.01) but not disease-specific survival (HR, 1.03; 95% CI, 0.56-1.88, P = 0.93). CONCLUSIONS: Patients with endometrial cancer who have an elevated serum platelet count greater than 400 × 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared with patients with a count within the reference range.

Referrals to phase I clinical trials in a gynecologic oncology unit.

OBJECTIVES: Previous reviews of phase I clinical trials report limited response rates. Development of novel biologic agents and trials designs have increased these rates. A contemporary appraisal of phase I clinical trials in gynecologic malignancies could help validate these findings. METHODS: Retrospectively reviewed records for 410 patients with gynecologic malignancies treated in a phase I unit, January 1999 to October 2012. Patient characteristics and treatment outcomes were abstracted and analyzed. RESULTS: Patients enrolled in 43 different phase I trials, 17 phase Ia, 17 phase Ib dose escalation and 9 dose expansion. 9 trials (21%) investigated unique cytotoxic delivery methods, 15 (35%) conventional cytotoxic plus novel agents and 19 (44%) novel agents alone. For patients treated in the first-line setting, 90 (74.4%) achieved CR, 20 (16.5%) PR, 9 (7.4%) SD and 2 (1.7%) PD, yielding an overall response rate of 90.9%. In patients treated for recurrent disease, 2 (1.6%) achieved CR, 11 (8.9%) PR, 57 (46.0%) SD and 54 (43.5%) PD, yielding a response rate of 11% and an overall clinical benefit rate of 57%. Response rate for molecular targeted therapies was 11.5% with an overall clinical benefit rate of 46.2%. Patients with prior anti-angiogenic exposure had comparable median PFS to those who had not been previously exposed (3.5 vs. 4.0 months, p = 0.29). CONCLUSIONS: Results support referral of gynecologic cancer patients for phase I clinical trials. Patients with advanced, heavily pretreated disease fare at least as well as they do on phase II trials and a proportion of them can attain an objective response or stabilization of their disease.

Phase II trial of vaginal cuff brachytherapy followed by chemotherapy in early stage endometrial cancer patients with high-intermediate risk factors.

OBJECTIVE: To determine the progression free survival (PFS), toxicity, and patterns of failure for early stage, high-intermediate risk (H-IR) patients in a phase II trial with adjuvant vaginal cuff brachytherapy (VCB) and three cycles of carboplatin and paclitaxel. METHODS: Surgically staged patients with stage I-IIb endometrial cancer with H-IR factors were treated with VCB (2100cGy) followed by three cycles of carboplatin (AUC 6) and paclitaxel (175 mg/m(2)). The primary endpoint was PFS at 2 years, with toxicity and sites of failure as secondary endpoints. Toxicity was assessed by patient report (CTCAE v. 3) as well as by delays or dose modifications in treatment. RESULTS: All patients completed VCB and 19/23 (83%) completed both VCB and 3 cycles of chemotherapy. Mean time to complete VCB was 14.5 days with minimal acute toxicity noted. At 6 months, all toxicity related to VCB had resolved. In total 60 cycles of chemotherapy were given, with one dose reduction (1.6%) for grade 2 neuropathy and seven delays (11.6%) in treatment due to hematologic toxicity. At a median follow-up of 44.5 months, 91% of patients remained progression free at 2 years. Four patients experienced a recurrence; they recurred both locally and distant. CONCLUSIONS: Adjuvant therapy with VCB and chemotherapy is well tolerated in a population of patients with H-IR endometrial carcinoma and provides 2 year PFS of 91%. A randomized trial is currently underway to assess whether combined VCB and chemotherapy reduces the rate of recurrence compared to external beam radiation therapy (EBRT) in this patient population.

A contemporary analysis of epidemiology and management of vaginal intraepithelial neoplasia.

OBJECTIVE: The purpose of this study was to review a large cohort of patients with vaginal intraepithelial neoplasia (VAIN) and to analyze the epidemiology and outcomes with various treatment modalities. STUDY DESIGN: A retrospective chart review was performed that encompassed patients who were treated for VAIN at a single center from 1990-2007. Demographics, disease characteristics, referring cytology, and histologic information were recorded. Primary outcome was recurrence or progression to carcinoma. Statistical analyses were performed with statistical software. RESULTS: One hundred sixty-three women were included in the study: median age, 50 years (range, 21-84 years); white, 87%; current or previous smokers, 35%. At the time of diagnosis, 23% of the women had VAIN1; 37% of the women had VAIN2, and 35% of the women had VAIN3. Referral Papanicolaou smear results of high-grade squamous intraepithelial lesion or atypical glandular cells revealed VAIN2 or VAIN3 in 89% of cases (P = .0019) vs 53% of cases with low-grade squamous intraepithelial lesion. The median follow-up period was 18 months (range, 1-194 months). VAIN1 was observed in 70% of cases; 71% of patients who were treated for VAIN1 had recurrence or progression. VAIN2 was treated in 77% of patients; 53% of those who were treated had recurrence or progression. VAIN3 was treated in 94% of cases; 31% of them had recurrence or progression. Risk of recurrence was not correlated to VAIN type (P = .3). Six carcinomas were discovered in patients with VAIN2 and VAIN3. Median time to progression was 17 months for VAIN1, 11 months for VAIN2, and 11 months for VAIN3 (P = .036). CONCLUSION: Despite the subtype, VAIN often recurs but does so more quickly with higher grade dysplasia.

Distance traveled for treatment of cervical cancer: who travels the farthest, and does it impact outcome?

OBJECTIVE: To evaluate the impact of distance from residence to treatment center on disease characteristics and recurrence of cervical cancer. MATERIALS AND METHODS: A single-institution retrospective chart review of patients treated for cervical cancer during 2006-2011 was performed. Demographic, socioeconomic, and clinicopathologic characteristics were recorded. Distance traveled from home to treatment facility was calculated and categorized. Recurrence and follow-up data were extracted; progression-free survival and overall survival were calculated. SAS version 9.2 was used for statistical analysis. RESULTS: Two hundred nineteen patients met the study criteria; 75% were Caucasian. Forty-nine percent used tobacco. Twenty-five percent had stage III/IV disease. Insurance type was 46% private, 25% Medicaid, 20% Medicare, and 9% uninsured. Distance between residence and hospital was less than 15 miles (29%), 15 to 30 miles (21%), 30 to 50 miles (17%), and more than 50 miles (33%). Median follow-up period was 23 months (range, 1-65). Caucasians were more likely to travel more than 30 miles to a treatment center (P = 0.018) Non-Caucasians were less likely to have private insurance (P = 0.0005) and more likely to recur (P = 0.0045). Recurrence was highest (50%) in African Americans. Travel of more than 30 miles was not associated with age, stage, histology, tobacco abuse, employment, clinical trial enrollment, primary chemoradiation for stage IB disease, or delayed radiation. Travel of more than 30 miles was associated with government insurance (P = 0.029) and a trend toward unemployment (P = 0.059). Four-year progression-free survival (53% vs 52%; P = 0.992) and overall survival (57% vs 62%; P = 0.73) were similar between less than or more than 30-mile travel. CONCLUSIONS: Fifty percent of the patients reside more than 30 miles from treating hospital. Despite farther travel, stage of disease, clinical trial enrollment, treatment type, radiation completion, and recurrence rates were similar among patients with cervical cancer. Non-Caucasians are less likely to travel more than 30 miles.

Vaginal cancer: the experience from 2 large academic centers during a 15-year period.

OBJECTIVE: Limited data regarding the natural history, management, and prognosis of vaginal cancer exist owing to the relative disease rarity. MATERIALS AND METHODS: A retrospective chart review was performed at 2 institutions to identify women receiving treatment for vaginal cancer between 1990 and 2004. Demographics, risk factors, histology, International Federation of Gynecology and Obstetrics stage, treatment, and treatment-related complications were recorded. Statistical Analysis Software (SAS) version 9.2 was used. RESULTS: A total of 110 patients were identified in the 2 university databases. Median age was 63 years (range = 36-93 years), and 84% were white; 73% had squamous cell carcinoma, 40% were ever users of tobacco, and 64% had no abnormal Pap smear results. Of the patients, 83% had early-stage (I or II) disease. Treatment varied by stage with increasing use of radiation with advancing stage. Recurrence was 24%, 32%, and 53% for stage I, II, and III/IV disease, respectively. After a median follow-up of 21 months, progression-free survival was 59, 35, and 23 months for stage I, II, and III/IV disease, respectively. Overall survival was 106, 58, and 34 months for stage I, II, and III/IV disease, respectively. Age greater than 60 years (p = .0339; hazard ratio [HR] = 2.162), advanced stage (p = .0004; HR = 2.475), and tobacco use (p = .0004; HR = 1.02) were negatively associated with survival. Thirty percent developed a significant complication (fistula, stricture, cystitis, or proctitis), and 21% developed a vesicovaginal and/or rectovaginal fistula. There was no association of fistula development with age, stage, tobacco use, histological finding, or treatment history (including radiation therapy). CONCLUSIONS: Age, stage, and tobacco abuse seem to be negatively associated with survival in vaginal cancer. However, no risk factors were associated with fistula development.

Wound complications after gynecologic cancer surgery.

OBJECTIVE: To explore clinical correlates of wound complications in high-risk women undergoing abdominal gynecologic surgery in a tertiary referral center. METHODS: Retrospective analysis of patient demographics, pre-operative and intra-operative information, and outcomes was performed in a cohort of patients who underwent abdominal surgery for suspected gynecologic malignancy between 1/2005 and 6/2008. The primary outcome was wound complication within 6 weeks of surgery. Univariate and multivariate logistic regression analyses were employed. A nomogram predicting post-operative wound complications was created and validated by receiver operating characteristic (ROC) curve analysis and 10-fold cross-validation. RESULTS: Median age of 373 women analyzed was 57years (range 25-88), median body mass index (BMI) 32.3kg/m(2) (range 14.0-70.7). A total of 150 patients (40%) had prior abdominal surgery; 40 (11%) had a pre-operative serum albumin <3.5g/dl; and 78 (21%) had pulmonary disease. Wound complications occurred in 125 patients (34%). In multivariate analysis wound complications were correlated with BMI of 30-39.9kg/m(2) (OR=5.62, 95% CI 2.08-15.19, p<0.0001) and BMI≥40kg/m(2) (OR=10.27, 95% CI 3.66-28.88, p<0.0001), prior abdominal surgery (OR 3.28, 95%CI1.89-5.70, p<0.0001), serum albumin≤3.5g/dl (OR 4.24, 95%CI 1.87-9.61, p=0.0005), pulmonary disease (OR 2.22, 95%CI 1.09-4.51, p=0.03), lysis of adhesions (OR 3.57, 95%CI 1.04-12.26, p=0.04), and length of surgery (OR 2.42, 95%CI 1.35-4.35, p=0.003). Risk for wound complication was lower with pelvic drain placement (OR 0.26, 95%CI 0.11-0.64, p=0.003). CONCLUSIONS: Wound complications are common in gynecologic oncology. Further studies should explore whether risk factor modification decreases complications.

Clinical and pathologic features of vulvar intraepithelial neoplasia in premenopausal and postmenopausal women.

OBJECTIVE: To explore the clinical and pathologic differences between vulvar intraepithelial neoplasia (VIN) in premenopausal and postmenopausal women cared for in a tertiary referral center. METHODS: Between January 1997 and June 2008, 145 women received care at our institution for VIN and VIN-associated squamous cell carcinoma (SCC). All patients' demographic characteristics and recurrence histories were recorded throughout the study period and were retrieved retrospectively. Menopausal status was self-reported at the time of initial diagnosis. χ, odds ratio, and logistic regression analyses were used. RESULTS: The median age was 50 years (range = 19-91 y) with 77% (111/145) of patients white, 20% (29/145) African American, and 3% (5/145) other ethnicity. Sixty percent of patients diagnosed with VIN were current smokers, 18% (26/145) were immunocompromised (positive for human immunodeficiency virus/transplant/steroids), and 30% (44/145) had concomitant or previous lower genital tract dysplasia. Vulvar intraepithelial neoplasia or VIN-related cancer recurred in 57 (39%) of 145 patients; of these, 40 (71%) had recurrence of VIN and 18 (29%) had recurrence of cancer. Fifty-one percent (74/145) of patients were menopausal at initial VIN diagnosis. Among women with VIN, the odds of initially presenting with a VIN-related SCC was 3.2 times greater in postmenopausal than in premenopausal women (confidence interval = 1.5-7.1, p < .01), and postmenopausal women were more likely to present with stage II to IV SCC (p = .021). Recurrence risk of SCC, but not VIN, was associated with menopause status (p < .05). CONCLUSIONS: Among women with VIN, the risk of SCC is higher in postmenopausal than in premenopausal women both initially and at recurrence. Excisional therapies to identify occult invasion are especially important for postmenopausal women with VIN.

Chemoradiation in locally advanced cervical carcinoma: an analysis of cisplatin dosing and other clinical prognostic factors.

OBJECTIVES: The aim of this study was to evaluate the effect of number of chemotherapy cycles and other clinical and pathologic factors on progression-free (PFS) and overall survival (OS) in patients with newly diagnosed cervical cancer. METHODS: We identified 118 patients with locally advanced cervical cancer (stages IB2-IVA) treated with combination weekly cisplatin (40 mg/m(2)) and radiation therapy (RT) between 2003 and 2007. Kaplan-Meier and Cox proportional hazard models were utilized to evaluate PFS and OS for associations with number of chemotherapy cycles and other factors. RESULTS: The majority of patients had stage IB2 or II disease (70%), squamous histology (91%), and size <6 cm (65%). Median RT duration was 50 days and 95% received brachytherapy. Thirty percent of patients completed <6 cycles of chemotherapy, and estimated PFS and OS were 63% and 75%, respectively. In multivariate analyses, the number of chemotherapy cycles was independently predictive of PFS and OS. Patients who received <6 cycles of cisplatin had a worse PFS (HR 2.65; 95% CI 1.35-5.17; p=0.0045) and OS (HR 4.47; 95% CI 1.83-10.9; p=0.001). Advanced stage, longer time to RT completion, and absence of brachytherapy were also associated with decreased OS and PFS (p<0.05). Similar results were found when analysis was conducted using a breakpoint of at least five but not less than five chemotherapy cycles. Higher grade was associated with decreased PFS (p=0.03) but not OS. Age, race, BMI, tumor size, smoking, histology, and IMRT were not statistically significant for OS or PFS. CONCLUSIONS: Aggressive supportive care to minimize missed chemotherapy treatments may improve survival after chemoradiation.

The Management of Women's Health Care by Internists With a Focus on the Utility of Ultrasound.

Adult women require routine care for the acute and chronic health problems found in both sexes, and they require specialized care for women's health problems, including disease prevention, disease screening, and disease management. Internists should direct primary care and participate in specialized care and to the extent possible follow guidelines published by various professional organizations. They should understand the use of ultrasound in breast cancer screening, the management of pregnancy, and other gynecologic problems, including vaginal bleeding, pelvic pain, and investigation for pelvic malignancy. Finally, all management decisions need discussions on the potential benefit or harm in each step of a woman's care with an emphasis on personal preferences.

The value of perioperative imaging in patients with uterine sarcomas.

OBJECTIVE: To explore the yield and impact of perioperative imaging on management among patients undergoing surgical resection and treatment of uterine sarcomas. METHODS: A retrospective chart review was done for women with histologically confirmed uterine sarcomas treated at Barnes Jewish Hospital/Washington University from 2001 to 2007. Descriptive statistics, Cox multivariate models, and Kaplan-Meier plots were used to evaluate associations and survival. RESULTS: A total of 92 patients were identified and 55 (60%) were diagnosed with stage III-IV disease. Perioperative imaging was obtained in 84 (91%) cases, including chest X-ray in 66 (72%), computerized tomography (CT) of the abdomen and pelvis in 59 (64%), chest CT in 33 (36%), positron emission tomography (PET) in 8 (9%), and CT of the head, pelvic magnetic resonance imaging (MRI), or bone scan in a total of 2 (2.2%). Imaging identified abnormalities concerning for metastases in 30 (32%) studies. Thirty-four recurrences have been documented, and 21 (62%) of these treatment failures were extrapelvic. Multivariate analysis of this series noted that tomographic evidence of extrauterine disease predicted recurrence (p=0.028) and incomplete surgical resection (p=0.003, HR 6.0 95% CI 1.9-19.9) predicted disease-free survival. Imaging contributed to change in surgical and post-surgical treatment decisions in 8 (9%) patients. CONCLUSION: Pretreatment imaging studies change management in a minority of patients with newly diagnosed uterine sarcomas.

Quality Improvement to Demonstrate the Lack of Reliability of the Human Papillomavirus mRNA Assay to Identify Women With Latent Human Papillomavirus Infections.

OBJECTIVE: To assess the consistency between human papillomavirus (HPV) mRNA testing in women with a history of previous HPV infections diagnosed by HPV DNA assay and the potential effects on follow-up HPV screening. METHODS: This was a quality improvement study that used data from a pathology laboratory software database reviewed from November 2014 to June 2016 to identify female patients aged 30 years or older with greater than one HPV-positive result, including one or more HPV mRNA assay results and one or more documented HPV DNA assay results for comparison. Previous correlative cytology and colposcopic histopathology were also documented. American College of Obstetricians and Gynecologists' cervical cancer screening guidelines were used to compare potential differences in follow-up recommendations. RESULTS: Four hundred twenty-five charts for female patients 30 years of age or older were identified with one or more prior high-risk HPV infections by DNA assay. There was a 69.3% difference in HPV mRNA results compared with previous HPV DNA-positive results. There was a potential change in follow-up for 71.7% of patients with one prior high-risk-HPV-positive result and 60.0% of patients with two or more prior high-risk HPV-positive results. There were 231 colposcopy reports evaluated in this study. Of these, 62 (26.8%) were abnormal colposcopy reports, including 45 low-grade squamous intraepithelial lesions, 15 high-grade squamous intraepithelial lesions, and two cancers. Twenty-five (40.3%) abnormal colposcopy findings were in patients with a history of at least than two prior HPV DNA-positive results and a report of currently being HPV-negative with the mRNA assay. CONCLUSION: The HPV mRNA assays are less sensitive for detection of latent HPV infections compared with HPV DNA assays. Based on these data and the potential change in follow-up care, the HPV mRNA assay should not be used for a primary screening tool for cervical cancer. Many pathology laboratories have shifted to using the HPV mRNA assay without clear discussion with gynecologists about the effects on patient follow-up. The type of HPV assay being used should be documented and any HPV mRNA result confirmed by HPV DNA assay.

Evaluation Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus in Combination With Anticancer Drugs in Human Cancer Orthotopic Mouse Models.

OBJECTIVE: To determine the activity of fucoidan from Undaria pinnatifida (UPF) and Fucus vesiculosus (FVF) when given in combination of chemotherapy drugs using selected human breast or ovarian cancer orthotopic mouse models. METHODS: Mice were inoculated with 1 × 106 cells of TOV-112d, MCF-7, or ZR-75 subcutaneously or SKOV3-GFP-Luc intraperitoneally on day 0. MCF-7 and ZR-75 mice were administered with estradiol valerate 2 mg/kg in 0.2 mL castor oil subcutaneously two days prior to cell inoculation. Mice were randomized to one of six arms (N = 10/arm) paclitaxel, UPF/paclitaxel, FVF/paclitaxel, tamoxifen, UPF/tamoxifen, or FVF/tamoxifen. Tumors were measured three times per week for 28 days. RESULTS: Improved activity was observed with UPF or FVF in combination with tamoxifen in both the MCF-7 and ZR-75D breast cancer mouse models. Decreased activity of paclitaxel was observed when given in combination with UPF or FVF in both breast cancer mouse models. The combination of FVF/tamoxifen in the TOV-112d ovarian cancer mouse model had improved activity but no there was difference observed with the UPF/tamoxifen in either ovarian cancer mouse model. No difference was observed with combination of UPF or FVF with paclitaxel in human ovarian cancer SKOV3 or TOV-112d orthotopic mouse models. CONCLUSION: This study did confirm that UPF/FVF in combination with tamoxifen did not decrease tamoxifen activity in both breast and ovarian cancer, with some potential to improve activity compared to tamoxifen alone in breast cancers. Previous in vitro studies had suggested UPF and FVF had overall synergistic activity with paclitaxel; however, in the current in vivo human cancer mouse model studies there was no change in paclitaxel activity when given in combination with UPF or FVF in either of the two human ovarian cancer models. Furthermore, this study demonstrated that UPF or FVF given in combination with paclitaxel had a potential antagonistic effect in breast cancer models. Additional studies are warranted to delineate mechanisms contributing to variation in the in vivo activity when given in combination with paclitaxel. As a first step, a clinical pharmacokinetic study evaluating impact of FVF/UPF given in combination with chemotherapy in patients with solid tumors is underway.

Evaluation of Active Hexose Correlated Compound (AHCC) in Combination With Anticancer Hormones in Orthotopic Breast Cancer Models.

OBJECTIVE: To determine the impact on antitumor activity when active hexose correlated compound (AHCC) in combination with anticancer hormonal agents in orthotopic mouse models of human estrogen receptor positive breast cancer and evaluate impact of AHCC on aromatase activity. METHODS: The study consisted of 7 treatment arms (n=10) conducted in 2 breast cancer mouse models: MCF-7 and ZR-75. Treatment groups included untreated, vehicle, AHCC 50 mg/kg, AHCC 50 mg/kg + tamoxifen 10 mg/kg, tamoxifen 10 mg/kg, AHCC 50 mg/kg + letrozole 10 µg/mouse, or letrozole 10 µg/mouse. All treatments were administered daily by oral gavage for 12 weeks. Tumors were measured 3 times a week. In vitro estrone and 17ß-estradiol enzyme immunoassay was used to evaluate aromatase activity. RESULTS: There was no difference in the activity with the combination of AHCC + tamoxifen compared with tamoxifen ( P = 0.29). In the ZR-75 model (catechol- O-methyltransferase [COMT] wild-type), there was no difference in activity with the letrozole + AHCC compared with letrozole. However, in the MCF-7 model (COMT variant), AHCC + letrozole resulted in a decrease in activity compared with letrozole ( P < 0.01). Immunoassay data suggested that AHCC is a potential inducer of aromatase activity. In both tumor models, there was cytotoxicity observed with AHCC compared with untreated ( P < 0.02). CONCLUSION: AHCC did not change the activity of tamoxifen. AHCC may have some interaction with letrozole in patients with COMT variant genotype. AHCC had cytotoxicity that warrents additional studies to evaluate its potential role for consolidation/prevention of breast cancer.

Zika Virus: Epidemiology, Pathogenesis and Human Disease.

The Zika virus is a positive sense, single-stranded RNA arbovirus in the Flaviviridae family, genus Flavivirus. This virus was initially isolated in Africa and is transmitted to nonhuman primates and humans by mosquitoes. Initial reports describe sporadic mild viral infection with fever, arthralgia, myalgia and conjunctivitis in Africa and Asia. However, its geographic distribution has significantly increased, and it has caused large outbreaks in the Yap Islands in 2007, in French Polynesia in 2013 and in Brazil in 2015. Multiple cases of Guillain-Barre´ syndrome occurred in French Polynesia and Columbia during outbreaks, and infections in pregnant women in Brazil have been associated with microcephaly and fetal loss. The viremic phase in humans is short, and diagnosis usually depends on positive immunoglobulin M titers with serum neutralization tests for confirmation. Treatment is directed at symptoms; there are no antiviral drugs available. Transmission can also occur through sexual contact with infected men and through blood transfusion. Prevention is important in women and includes limiting travel to endemic areas when possible, control of mosquito populations and condom use when appropriate. The Centers for Disease Control and Prevention is actively involved in tracking these infections and providing up-to-date information.

Preclinical Evaluation of Safety of Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus for Use in Cancer Treatment.

OBJECTIVES: To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo studies were done to confirm safety and investigate fucoidan-mediated immune modulation. METHODS: Cytochrome P450 (CYP450) 3A4, 2C8, 2C9, and 2D6 inhibition experiments were conducted in vitro followed by an ex vivo human hepatocytes model to evaluate the CYP450 induction potential of each fucoidan at highest theoretical concentrations. Four hepatic metabolism phase II pathways-glutathione S transferase (GST), quinone oxidoreductase (QOR), catechol-O-methyltransferases (COMT), and uridine di-phosphate (UDP)-glucuronosyltransferase (UGT)-were evaluated with validated immunoassays. Growth inhibition assays were performed with each fucoidan alone and in combination with chemotherapy agents in a panel of human cancer cell lines. In vivo studies evaluated safety and immune modualtion. RESULTS: CYP450 inhibition was observed with FVF. The GST, QOR, and UGT pathways had no changes. UPF and FVF both interacted with COMT. No growth inhibitory activity in cancer cell lines was observed. UPF and FVF had synergistic activity with paclitaxel or tamoxifen and additive activity with topotecan. In vivo, FVF decreased HeLa human cervical tumor growth and both FVF and UPF decreased TOV-112D human ovarian tumor growth. Otherwise, no significant change in tumor growth was observed. FVF immune modulation of IgG and IL-6 was observed (p<0.03). CONCLUSION: At higher doses, UPF and FVF may have limited potential for drug-supplement interactions, with either CYP450 or COMT hepatic metabolism pathways. Additional studies are warranted to evaluate to confirm findings of fucoidans in combination with chemotherapy.