Sign of efficacy and dose levels in phase 1 oncology trials.

<p>Sign of efficacy and dose levels in phase 1 oncology trials.</p

Sign of efficacy and MTD in 317 phase 1 oncology trials.

<p>MTD: dose maximal tolerated dose;</p><p>*: p<0.05.</p><p>The total of trials within the same treatment categories could differ in the different lines because no data concerning MTD was available in 28 trials and because the first sign of efficacy was not linked to a dose-level in 64 trials.</p

Identification of circulating tumor cells.

<p>a. Representation of the staining of circulating cells using the Cellsearch® assay. CTC are defined as CD45−, DAPI+, and CKPE+ cells. - Upper line: as a positive control, 50 and 500 A549luc cells were analysed in a solution containing 600 µL of medium and 7 mL of healthy human blood. Here, as an example, both CD45−, DAPI+, CKPE+ cells are tumor cells. - Bottom line: representation of the results of the experimental groups. Here, as an example, this CD45−, DAPI+, CKPE+ cell is a CTC. b. Correlation between the Cellsearch ® CTC count and the number of tumor cells in solution. As controls, 0 (negative control), 50 and 500 (positive controls) A549luc cells were analysed in a solution containing 600 µL of medium and 7 mL of healthy human blood. This experiment demonstrated a correlation between the Cellsearch® CTC count and the number of tumor cells in solution (R² = .99857). c. Number of CTC according to the experimental group, CTC group 1 (SC) or CTC group 2 (orthotopic). The overall positivity of the Cellsearch ® assay is comparable in both groups (83%), with a trend toward more CTC in the orthotopic rather than in the subcutaneous model. d. Representation of the bioluminescent signal and number of CTC detected in each of the 12 animals.</p

Pathological examination.

<p>Surgical orthotopic implantation (Group 3) resulted in localized infiltrating tumors, whereas percutaneous orthotopic injection (Group 2) and transpleural orthotopic injection (group 4) resulted in localized rounded nodules. Histological examination revealed a high proportion of undifferentiated carcinoma in group 1-SC tumor, but a low proportion in the 3 experimental groups. Furthermore, the 3 experimental groups were associated with more capsule rupture and vascular emboli than group 1-SC.</p

Follow-up using bioluminescent imaging and survival curves.

<p>a. Evolution of the photons count (expressed as 10⁶ photons/s) over time, from day 0 (implantation) to day 63 (end of the bioluminescent follow up). For each time, the mean and standard deviation of the animals alive are reported. In group 2-POI, percutaneous injection led to pleural seeding in 53% of the cases, as postoperative X-ray showed contrast agent in either left pleural space, right pleural space (anatomical continuum), or both. b. Representative evolution of the bioluminescent signal, from day 14 to day 42. In group 2-POI, pleural seeding created a signal located at the right basis of the thorax, contradicting with the primary goal of this study. No subsequent follow-up as been performed for this group. c. Survival curve from the time of tumor implantation to 2 months using the Kaplan-Meier method and 95% confidence interval bars. The 2-month survival is 100% in group 1-SC, 40% in group 3-SOI, and 65% in group 4-TOI.</p

Per-procedure mortality, tumor engraftment, and tumor extension rates.

*<p>Bone metastasis.</p>**<p>n = 1 false positive (infection); n = 2 false negatives.</p

Pathological examination and CTC levels.

<p>Pathological examination and CTC levels.</p

Otorhinolaryngological Toxicities of New Drugs in Oncology

<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/s12325-017-0512-0"><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

Whole exome sequencing for determination of tumor mutation load in liquid biopsy from advanced cancer patients

<div><p>Tumor mutation load (TML) has been proposed as a biomarker of patient response to immunotherapy in several studies. TML is usually determined by tumor biopsy DNA (tDNA) whole exome sequencing (WES), therefore TML evaluation is limited by informative biopsy availability. Circulating cell free DNA (cfDNA) provided by liquid biopsy is a surrogate specimen to biopsy for molecular profiling. Nevertheless performing WES on DNA from plasma is technically challenging and the ability to determine tumor mutation load from liquid biopsies remains to be demonstrated. In the current study, WES was performed on cfDNA from 32 metastatic patients of various cancer types included into MOSCATO 01 (NCT01566019) and/or MATCHR (NCT02517892) molecular triage trials. Results from targeted gene sequencing (TGS) and WES performed on cfDNA were compared to results from tumor tissue biopsy. In cfDNA samples, WES mutation detection sensitivity was 92% compared to targeted sequencing (TGS). When comparing cfDNA-WES to tDNA-WES, mutation detection sensitivity was 53%, consistent with previously published prospective study comparing cfDNA-TGS to tDNA-TGS. For samples in which presence of tumor DNA was confirmed in cfDNA, tumor mutation load from liquid biopsy was correlated with tumor biopsy. Taken together, this study demonstrated that liquid biopsy may be applied to determine tumor mutation load. Qualification of liquid biopsy for interpretation is a crucial point to use cfDNA for mutational load estimation.</p></div

Translational regulation of the mRNA encoding the ubiquitin peptidase USP1 involved in the DNA damage response as a determinant of Cisplatin resistance

<p>Cisplatin (cis-diaminedichloroplatin (II), CDDP) is part of the standard therapy for a number of solid tumors including Non-Small-Cell Lung Cancer (NSCLC). The initial response observed is in most cases only transient and tumors quickly become refractory to the drug. Tumor cell resistance to CDDP relies on multiple mechanisms, some of which still remain unknown. In search for such mechanisms, we examined the impact of CDDP on mRNA translation in a sensitive and in a matched resistant NSCLC cell line. We identified a set of genes whose mRNAs are differentially translated in CDDP resistant vs. sensitive cells. The translation of the mRNA encoding the Ubiquitin-Specific Peptidase 1 (USP1), a Ubiquitin peptidase with important function in multiple DNA repair pathways, is inhibited by CDDP exposure in the sensitive cells, but not in the resistant cells. This lack of down-regulation of USP1 expression at the translational level plays a primary role in CDDP resistance since inhibition of USP1 expression or activity by siRNA or the small molecule inhibitor ML323, respectively is sufficient to re-sensitize resistant cells to CDDP. We involved the USP1 mRNA translation as a major mechanism of CDDP resistance in NSCLC cells and suggest that USP1 could be evaluated as a candidate predictive marker and as a therapeutic target to overcome CDDP resistance. More generally, our results indicate that analysis of gene expression at the level of mRNA translation is a useful approach to identify new determinants of CDDP resistance.</p