Molecular Targets and Emerging Therapeutic Options for Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is an aggressive malignancy characterized by its early metastasis, high rates of recurrence, and poor prognosis. Multiple obstacles complicate the clinical management of uLMS. These include the fact that most uLMS are typically identified only after a woman has undergone hysterectomy or myomectomy, the limited efficacy of adjuvant therapy for early stage disease, and the poor response of metastatic disease to current treatments. Here, we discuss recent insights into the molecular basis of uLMS and discuss emerging options for its clinical management. Particular attention is given to the biologic basis of these strategies with the goal of understanding the rationale motivating their use.

Adjunct Histamine Blockers as Premedications to Prevent Carboplatin Hypersensitivity Reactions.

OBJECTIVE: The objective of this study was to evaluate the impact of premedications given as an adjunct to carboplatin on the incidence of hypersensitivity reactions in women with ovarian cancer. Medications of interest include a histamine1 (H1 ) and histamine2 (H2 ) blocker in addition to dexamethasone. METHODS: This was a retrospective chart review evaluating the addition of an H1 and H2 blocker in addition to dexamethasone as standard premedications on the incidence of carboplatin hypersensitivity reactions (CHRs) in women with ovarian cancer. MAIN RESULTS: The odds ratio for premedication use was 0.46 with a 95% confidence interval (0.17-1.27), suggesting that patients with premedication use had approximately half the risk of CHR compared with patients without premedication. The overall incidence of CHRs decreased from 7.9% at baseline to 3.2% after the addition of premedications. The incidence of CHRs was 5.2% in 58 patients with recurrent or progressive disease compared with 2.1% in 96 newly diagnosed patients. Lifetime dose greater than 3377 mg, number of cycles more than six, and progressive or recurrent disease were predictive factors of CHR in women with ovarian cancer. PRINCIPAL CONCLUSIONS: Total lifetime exposure to carboplatin remains the greatest predictive factor of CHR in women with ovarian cancer. Although data analysis indicates the addition of premedications for all ovarian cancer patients receiving carboplatin did not result in a statistically significant reduction in CHRs, a patient benefit in CHR reduction was observed. A prospective study is needed to confirm these findings.

Preferences and Outcomes for Chemotherapy Teaching in a Postgraduate Obstetrics and Gynecology Training Program.

PURPOSE: To determine whether chemotherapy teaching is a desired component of postgraduate training programs in obstetrics and gynecology and assess its effect on practicing clinicians. METHOD: After obtaining institutional review board approval, 99 individuals who completed postgraduate training at a single academic medical center between 2005 and 2013 were invited to complete an online survey. Descriptive statistics were used to summarize responses. RESULTS: Of the 99 individuals, 68 (68%) completed the survey. Respondents included physicians currently practicing in both academic medicine (n = 36, 52.9%) and private practice (n = 24, 35.2%). Most respondents (n = 60, 88.2%) indicated that chemotherapy teaching was a desired feature of their training and expressed a preference for both formal didactics and direct clinical involvement (n = 55, 80.2%). Benefits identified by respondents included improved insight into the management of symptoms commonly associated with chemotherapy (n = 55, 82.1%) and an enhanced ability to counsel patients referred for oncology care (n = 48, 70.5%). All respondents who pursued training in gynecologic oncology following residency (n = 6) indicated that chemotherapy teaching favorably affected their fellowship experience. Of the 6 gynecologic oncologists, 3 (50%) who responded also indicated that chemotherapy teaching during residency improved their performance in fellowship interviews. CONCLUSION: Chemotherapy teaching was a desired feature of postgraduate training in general obstetrics and gynecology at the institution studied. Consideration should be given to creating curricula that incorporate the principles and practice of chemotherapy and address the needs of obstetrics and gynecology trainees who intend to pursue both general and subspecialty practice.

Bowel perforation associated with temsirolimus use in a recently irradiated patient.

PURPOSE: A probable case of bowel perforation associated with temsirolimus use in a patient with uterine leiomyosarcoma is reported. SUMMARY: A 45-year-old Hispanic woman reported acute abdominal pain one day after receiving her third weekly i.v. infusion of temsirolimus, a mammalian target of rapamycin inhibitor increasingly used against a variety of cancers, including renal cell carcinoma and soft tissue sarcomas. Temsirolimus had been initiated three weeks previously in an attempt to control retroperitoneal metastases of uterine leiomyosarcoma, which had progressed despite surgical resection, six cycles of adjuvant chemotherapy, and pelvic irradiation. A computed tomography scan revealed a large pelvic mass with foci of gas, fluid collection, and other findings highly suggestive of an abscess due to bowel perforation. Application of the adverse drug reaction probability scale of Naranjo et al. in this case indicated a probable relationship between the bowel perforation and temsirolimus use; a literature search identified no other reported cases of temsirolimus-associated bowel perforation in association with uterine leiomyosarcoma. It is suspected that the patient's recent course of pelvic radiotherapy may have played a role in predisposing her to bowel perforation during temsirolimus use. While the mechanism of bowel perforations associated with temsirolimus therapy remains unclear, it is possible that due to its inhibitory effects on vascular endothelial growth factor (VEGF), temsirolimus use may result in gastrointestinal stresses and weaknesses similar to those attributed to bevacizumab, a VEGF-targeted angiogenesis inhibitor that has been linked to chemotherapy-induced bowel perforation. CONCLUSION: A woman who recently received pelvic radiation experienced a bowel perforation after three infusions of temsirolimus for the treatment of metastatic leiomyosarcoma.

On the reproducibility of TCGA ovarian cancer microRNA profiles.

Dysregulated microRNA (miRNA) expression is a well-established feature of human cancer. However, the role of specific miRNAs in determining cancer outcomes remains unclear. Using Level 3 expression data from the Cancer Genome Atlas (TCGA), we identified 61 miRNAs that are associated with overall survival in 469 ovarian cancers profiled by microarray (p<0.01). We also identified 12 miRNAs that are associated with survival when miRNAs were profiled in the same specimens using Next Generation Sequencing (miRNA-Seq) (p<0.01). Surprisingly, only 1 miRNA transcript is associated with ovarian cancer survival in both datasets. Our analyses indicate that this discrepancy is due to the fact that miRNA levels reported by the two platforms correlate poorly, even after correcting for potential issues inherent to signal detection algorithms. Corrections for false discovery and microRNA abundance had minimal impact on this discrepancy. Further investigation is warranted.

MicroRNAs and Recent Insights into Pediatric Ovarian Cancers.

Ovarian cancer is the most common pediatric gynecologic malignancy. When diagnosed in children, ovarian cancers present unique challenges that differ dramatically from those faced by adults. Here, we review the spectrum of ovarian cancers found in young women and girls and discuss the biology of these diseases. A number of advances have recently shed significant new understanding on the potential causes of ovarian cancer in this unique population. Particular emphasis is placed on understanding how altered expression of non-coding RNA transcripts known as microRNAs play a key role in the etiology of ovarian germ cell and sex cord-stromal tumors. Emerging transgenic models for these diseases are also reviewed. Lastly, future challenges and opportunities for understanding pediatric ovarian cancers, delineating clinically useful biomarkers, and developing targeted therapies are discussed.

Novel MicroRNAs regulating proliferation and apoptosis in uterine papillary serous carcinomas.

MicroRNAs (miRNAs) are endogenous, non-coding RNA transcripts that regulate gene expression. Here, we report 175 putative novel miRNAs identified in uterine cancers profiled by Next Generation Sequencing. Our data indicate that one of these putative miRNAs (BCM-173) is conserved across multiple species and is expressed at levels similar to known human miRNAs. Functionally, this miRNA promotes the growth and migration of uterine cancer cell lines by targeting vinculin and altering the distribution of focal adhesions. These results expand our insight into the repertoire of human miRNAs and identify novel pathways by which dysregulated miRNA expression promotes uterine cancer growth.

Evaluation of liposomal curcumin cytochrome p450 metabolism.

BACKGROUND: Curcumin (diferuloylmethane) is a commonly used spice and nutritional supplement that has demonstrated potential anti-tumor and anti-inflammatory activity. There is limited information regarding curcumin metabolism and the potential for drug-drug interactions. The objective of this study was to characterize the hepatic metabolism of synthetic curcumin used in the liposomal curcumin formulation. MATERIALS AND METHODS: High-throughput cytochrome P450 (CYP450) metabolism inhibition assays were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6. An ex vivo model of cryopreserved human hepatocytes was used to evaluate the CYP450 metabolism induction potential of curcumin for CYP P450 3A4, 2C8/2C9, and 2D6. RESULTS: In the in vitro CYP450 inhibition studies, curcumin at any concentration did not inhibit CYP450 3A4 or CYP450 2D6 activity. At a curcumin concentration of 58.3 microM, 10.5% and 22.5% inhibition of CYP450 2C9 and CYP450 2C8 activity, respectively, was observed. In the ex vivo hepatocyte inductions studies, minimal to no induction of CYP450 3A4, CYP450 2C8/2C9 or CYP450 2D6 was observed. Rifampicin did not induce the metabolism of curcumin and curcumin did not induce its own metabolism. CONCLUSION: There is low potential for CYP450 mediated drug interactions at physiologic serum concentrations of liposomal curcumin. Based on preliminary data, liposomal curcumin will not interact with other chemotherapy agents that are metabolized and/or eliminated via the primary drug metabolizing CYP450 pathways.

Determination of minimum effective dose and optimal dosing schedule for liposomal curcumin in a xenograft human pancreatic cancer model.

BACKGROUND: Curcumin is a food chemical present in tumeric (Curcuma longa) that has pharmacological activity to suppress carcinogenesis and inhibits multiple signaling pathways such as nuclear factor kappaB (NF-kappaB), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral bioavailability limiting its clinical activity; however, a patent pending liposomal formulation of curcumin was developed to improve drug delivery and has demonstrated activity in multiple cancers. This study was designed to determine the minimum effective dose (MED) as well as the optimal dosing schedule of liposomal curcumin in a xenograft mouse model of human pancreatic cancer. MATERIALS AND METHODS: The MED determination and optimal schedule was evaluated in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells. Dosing was initiated at an average tumor size of 5mm. For the MED, mice were treated with the following dose levels of liposomal curcumin: no treatment, liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg given by tail vein injection three times weekly for 28 days. For the optimum dosing schedule, three additional schedules were evaluated and compared to the control of three times weekly; daily (five days per week), every four days, and weekly for 28 days. All mice were weighed and tumor measurements taken three times weekly to evaluate toxicity and efficacy. RESULTS: The 20 mg/kg dose had the greatest decrease in tumor growth at 52% decrease in tumor growth when compared to no treatment control mice. MED was determined to be 20 mg/kg and was used for the optimal dosing schedule determination. Daily dosing and three times per week dosing had greater inhibition of tumor growth with no discernable difference than once weekly or every 4 day dosing. No toxicity was observed at any dose or schedule. CONCLUSION: The MED for liposomal curcumin is 20 mg/kg given once daily three times per week to achieve optimal tumor growth inhibition. This was dose recommended for additional preclinical studies to define safety and tolerability of liposomal curcumin in rat and dog models.

Evaluation of active hexose correlated compound hepatic metabolism and potential for drug interactions with chemotherapy agents.

Active hexose correlated compound (AHCC), a Basidiomycotina extract, is a well-tolerated nutritional supplement with no reported adverse effects. It has demonstrated potential antitumor activity and immune modulator activity. However, there is no current information regarding its metabolism and the potential for drug-drug interactions for AHCC in combination with chemotherapy. The objective of this study was to characterize AHCC hepatic metabolism, specifically involving the potential for drug interactions with selected chemotherapy agents. High-throughput cytochrome P-450 (CYP450) metabolism inhibition experiments were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6 followed by an evaluation of AHCC as a substrate of these same isoenzymes. An ex vivo model of cryopreserved human hepatocytes was used to evaluate the CYP450 metabolism induction potential of AHCC for CYP450 3A4, 2C8/2C9, and 2D6. No inhibition of CYP450 activity was observed in presence of AHCC; however, AHCC was a substrate of CYP450 2D6. The CYP450 induction metabolism assays indicate that AHCC is an inducer of CYP450 2D6. AHCC does have the potential for drug-drug interactions involving CYP450 2D6, such as doxorubicin or ondansetron; however, the overall data suggest that AHCC would be safe to administer with most other chemotherapy agents that are not metabolized via the CYP450 2D6 pathway.

The Small RNA gene activator protein, SphI postoctamer homology-binding factor/selenocysteine tRNA gene transcription activating factor, stimulates transcription of the human interferon regulatory factor-3 gene.

Many small nuclear RNA gene promoters are activated by SphI postoctamer homology (SPH)-binding factor/selenocysteine tRNA gene transcription activating factor (SBF/Staf). Whereas this transcription factor was initially identified by its ability to bind to SPH elements in such promoters, it was more recently shown to have the capacity to activate transcription of a synthetic mRNA gene promoter through a distinct activation domain. Here, we show that the human interferon regulatory factor-3 (IRF-3) gene promoter contains a functional SPH element that is bound by SBF/Staf in vitro and in transfected cells.