Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin

<p><strong>Article full text</strong></p> <p><br> The full text of this article can be found <a href="https://link.springer.com/article/10.1007/s12325-017-0561-4"><b>here</b>.</a><br> <br> <strong>Provide enhanced digital features for this article</strong><br> If you are an author of this publication and would like to provide additional enhanced digital features for your article then please contact <u>[email protected]</u>.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br> <br> Other enhanced features include, but are not limited to:<br> • Slide decks<br> • Videos and animations<br> • Audio abstracts<br> • Audio slides<u></u></p

Efficacy of fulvestrant 500 mg in Japanese postmenopausal advanced/recurrent breast cancer patients and factors associated with prolonged time-to-treatment failure

<div><p><b><i>Objective</i>:</b> We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation.</p><p><b><i>Research design and methods</i>:</b> This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014.</p><p><b><i>Main outcome measures</i>:</b> TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated.</p><p><b><i>Results</i>:</b> The median age was 65 (42 – 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), <i>de novo</i> metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder.</p><p><b><i>Conclusions</i>:</b> Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, <i>de novo</i> metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.</p></div

Production of Kinanthraquinone D with Antimalarial Activity by Heterologous Gene Expression and Biotransformation in Streptomyces lividans TK23

Two new compounds, kinanthraquinone C (1) and kinanthraquinone D (2), were isolated along with two known compounds, kinanthraquinone (3) and kinanthraquinone B (4), produced by the heterologous expression of the kiq biosynthetic gene cluster and its pathway-specific regulator, kiqA, in Streptomyces lividans TK23. The chemical structures of compounds 1 and 2 were determined using mass spectrometry and nuclear magnetic resonance analyses. To examine a biosynthetic pathway of compounds 1 and 2, incubation experiments were conducted using S. lividans TK23 to supply the compounds 3 and 4. These experiments indicated that compounds 3 and 4 were converted to compounds 2 and 1, respectively, by the endogenous enzymes of S. lividans TK23. Compounds 2, 3, and 4 had antimalarial activities at half-maximal inhibitory concentration values of 0.91, 1.2, and 15 μM, respectively, without cytotoxicity up to 30 μM

Development of a Terpenoid-Production Platform in <i>Streptomyces reveromyceticus</i> SN-593

Terpenoids represent the largest class of natural products, some of which are resources for pharmaceuticals, fragrances, and fuels. Generally, mass production of valuable terpenoid compounds is hampered by their low production levels in organisms and difficulty of chemical synthesis. Therefore, the development of microbial biosynthetic platforms represents an alternative approach. Although microbial terpenoid-production platforms have been established in <i>Escherichia coli</i> and yeast, an optimal platform has not been developed for <i>Streptomyces</i> species, despite the large capacity to produce secondary metabolites, such as polyketide compounds. To explore this potential, we constructed a terpenoid-biosynthetic platform in <i>Streptomyces reveromyceticus</i> SN-593. This strain is unique in that it harbors the mevalonate gene cluster enabling the production of furaquinocin, which can be controlled by the pathway specific regulator Fur22. We simultaneously expressed the mevalonate gene cluster and subsequent terpenoid-biosynthetic genes under the control of Fur22. To achieve improved <i>fur22</i> gene expression, we screened promoters from <i>S. reveromyceticus</i> SN-593. Our results showed that the promoter associated with <i>rvr2030</i> gene enabled production of 212 ± 20 mg/L botryococcene to levels comparable to those previously reported for other microbial hosts. Given that the <i>rvr2030</i> gene encodes for an enzyme involved in the primary metabolism, these results suggest that optimized expression of terpenoid-biosynthetic genes with primary and secondary metabolism might be as important for high yields of terpenoid compounds as is the absolute expression level of a target gene(s)

Patient characteristics and EPN distribution.

<p>Patient characteristics and EPN distribution.</p

Kaplan-Meier plots for TTF according to subtypes.

<p>Among the four subtypes, TTF was 10.0 months in the EPN group and 3.7 months in the non-EPN group in the luminal type (p = <0.001); 31.7 months in the EPN group and 17.5 months in the non-EPN group in the luminal-HER2 type (p = 0.270); 15.9 months in the EPN group and 9.5 months in the non-EPN group in the HER2 type (p = 0.029); and 6.1 months in the EPN group and 3.7 months in the non-EPN group of the triple negative type (p = 0.043).</p

Patient characteristics and EPN distribution.

<p>Patient characteristics and EPN distribution.</p

Cumulative dose, dose intensity and response rate.

<p>Cumulative dose, dose intensity and response rate.</p

The early onset of peripheral neuropathy might be a robust predictor for time to treatment failure in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel

<div><p>Background</p><p>Paclitaxel plays a central role in chemotherapy for breast cancer. Peripheral neuropathy, a well-known toxicity with paclitaxel, may be of interest in predicting the efficacy of paclitaxel therapy for patients with metastatic breast cancer. We performed a retrospective analysis assessing whether the early occurrence of peripheral neuropathy (EPN) was a predictive marker for better efficacy in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel.</p><p>Patients and methods</p><p>Between January 2000 and August 2008, we examined the records of 168 patients with metastatic breast cancer treated with paclitaxel in our hospital. EPN was defined as a symptom of Grade 2 or more during first three months of treatment. The overall response rate (ORR) and time to treatment failure (TTF) in each group were analyzed retrospectively.</p><p>Results</p><p>Of 168 patients with metastatic breast cancer who were treated with paclitaxel, EPN was documented in 101 patients (60.1%). The clinical benefit rate (CR, PR, and SD ≥ 6 months) was 72.3% in the EPN group and 49.3% in the non-EPN group (p = 0.002). The TTF of the EPN group (median 11.2 months, 95% CI: 9.5–12.9) was significantly longer than that of the non-EPN group (5.7 months, 95% CI: 4.6–6.8) (p<0.001). Multivariate analysis demonstrated that EPN (p<0.001), dose intensity of less than 70% (p<0.001), and the history of microtubule agents (p = 0.001) were the significant favorable prognostic factors for TTF.</p><p>Conclusion</p><p>The early onset of peripheral neuropathy might be a robust predictor for TTF in patients with metastatic breast cancer treated with paclitaxel.</p></div

Univariate and multivariate analysis of prognostic factors.

<p>Univariate and multivariate analysis of prognostic factors.</p