Systemic Treatment of Metastatic/Recurrent Uterine Leiomyosarcoma: A Changing Paradigm.

The treatment of metastatic and recurrent uterine leoimyosarcoma (uLMS) has evolved rapidly in the past several years. Leoimyosarcoma is extremely aggressive and responds poorly to traditional chemotherapeutics. Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these new compounds. Additionally, the potential role of immunotherapy is being assessed in current uLMS clinical trials. Given the increasing number of agents available both in the U.S. and globally, a treatment template that addresses optimal sequencing based upon expert consensus would be useful. Current guidelines, although listing various options, lack granularity by line of therapy. Most patients with leiomyosarcoma, even in early stage, are treated with surgery followed by adjuvant chemotherapy despite uLMS being relatively chemoresistant. Adjuvant chemotherapy often includes the combination of gemcitabine and docetaxel with or without doxorubicin in first-line systemic therapy, but these cytotoxic agents only provide patients with advanced disease a 5-year survival <30%. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uLMS. Critical ongoing studies investigating novel approaches including immunotherapeutics and genetic alterations also will be discussed. IMPLICATIONS FOR PRACTICE: Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these compounds. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uterine leoimyosarcoma.

Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma.

While high-grade serous ovarian carcinoma (HGSOC) is the most common histologic subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants [by DNA next-generation sequencing (NGS) using a 50 gene Ion Torrent panel] and gene expression (using the NanoString PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT). NGS was performed on plasma cell free DNA (cfDNA) on a select group of patients (n = 14) to assess the utility of using cfDNA to monitor these changes. A total of 86 genes had significant changes in RNA expression after NACT. Thirty-eight genetic variants (including SNPs) from 6 genes were identified in tumors pre-NACT, while 59 variants from 19 genes were detected in the cfDNA. The number of DNA variants were similar after NACT. Of the 59 variants in the plasma pre-NACT, only 6 persisted, whereas 33 of 38 specific variants in the tumor DNA remained unchanged. Pathway analysis showed the most significant alterations in the cell cycle and DNA damage pathways.Implications: Gene expression profiles at the time of interval debulking provide additional genetic information that could help impact treatment decisions after NACT; although, continued collection and analysis of matched tumor and cfDNA from multiple time points are needed to determine the role of cfDNA in the management of HGSOC. Mol Cancer Res; 16(5); 813-24. ©2018 AACR.

Sublethal effects of atrazine and glyphosate on life history traits of Aedes aegypti and Aedes albopictus (Diptera: Culicidae).

Although exposure of mosquito larvae to agricultural chemicals such as herbicides is common and widespread, our understanding of how these chemicals affect mosquito ecology and behavior is limited. This study investigated how an environmentally relevant concentration of two herbicides, atrazine and glyphosate, affects mosquito life history traits. One hundred and fifty (150) first instar Aedes (Stegomyia) aegypti (L.) or Aedes (Stegomyia) albopictus (Skuse) larvae were reared in 1.6 L of live oak leaf (Quercus virginiana) infusion in the presence (5 mg/L) or absence (0 mg/L) of atrazine or glyphosate. The containers were monitored daily to determine the emergence rates, sex ratio, male and female emergence times, and female body size. Emergence rates of A. aegypti from atrazine treatment were significantly higher relative to either glyphosate or control treatments (A. aegypti: atrazine = 93 ± 6% (±95% CI), glyphosate = 82 ± 5%, control = 78 ± 5%), while emergence rates of A. albopictus in atrazine treatments were significantly higher than in glyphosate treatments but not in controls (A. albopictus: atrazine = 84 ± 5 %, glyphosate = 76 ± 4%, control = 78 ± 4%). For both mosquito species, a sex ratio distortion with male bias was observed in control and glyphosate treatments, but not in atrazine treatments (A. aegypti: atrazine = 0.90 ± 0.17 (±SE), glyphosate = 1.63 ± 0.21, control = 1.69 ± 0.26; A. albopictus: atrazine = 1.09 ± 0.08, glyphosate = 1.88 ± 0.12, control = 1.37 ± 0.11). Emergence times for both sexes of the two mosquito species were significantly longer in atrazine treatments compared to glyphosate or control treatments (A. aegypti: females: atrazine = 11.20 ± 0.50 (days ± 95 % CI), glyphosate = 9.71 ± 0.23, control = 9.87 ± 0.21; males: atrazine = 9.46 ± 0.27, glyphosate = 8.80 ± 0.25, control = 8.85 ± 0.24; A. albopictus: females: atrazine = 17.40 ± 1.70, glyphosate = 12.4 ± 0.40, control = 12.5 ± 0.30; males: atrazine = 12.96 ± 0.41, glyphosate = 10.48 ± 0.24, control = 10.64 ± 0.37). For A. albopictus but not A. aegypti, adult females from atrazine treatment had significantly longer wing lengths compared to those from glyphosate or control treatments (A. albopictus: atrazine = 3.06 ± 0.07 (mm ± 95% CI), glyphosate = 2.80 ± 0.07, control = 2.83 ± 0.06). These results demonstrate the potential for atrazine, a widely used herbicide, to influence epidemiologically relevant life history traits of mosquitoes.

Temperature and density-dependent effects of larval environment on Aedes aegypti competence for an alphavirus.

Mosquito larvae experience multiple environmental stressors that may modify how subsequent adults interact with pathogens. We evaluated the effect of larval rearing temperature and intraspecific larval competition on adult mosquito immunity and vector competence for Sindbis virus (SINV). Aedes aegypti larvae were reared at two intraspecific densities (150 and 300 larvae) at 20° C and 30° C and the adults were fed artificially on citrated bovine blood containing 10(5) plaque forming units of SINV. Expression of cecropin, defensin, and transferrin was also evaluated in one- and five-day-old female adults. There was a direct relationship between larval density and SINV infection and dissemination rates at low temperature (20° C) and an inverse relationship between larval density and SINV infection rate at high temperature (30° C). Cecropin was only expressed in five-day-old adults that were raised at high temperature as larvae and was 20-fold over-expressed at low compared to high density treatments. Defensin and transferrin were under-expressed in one-day-old adults and over-expressed in five-day-old adults in all competition-temperature combinations relative to low density treatments at 20° C. These findings suggest that interaction between biotic and abiotic conditions of the larval environment may alter adult mosquito immunity resulting in enhanced vector competence for arboviruses.