Focal dose escalation using FDG-PET-guided intensity-modulated radiation therapy boost for postoperative local recurrent rectal cancer: a planning study with comparison of DVH and NTCP

<p>Abstract</p> <p>Background</p> <p>To evaluate the safety of focal dose escalation to regions with standardized uptake value (SUV) >2.0 using intensity-modulated radiation therapy (IMRT) by comparison of radiotherapy plans using dose-volume histograms (DVHs) and normal tissue complication probability (NTCP) for postoperative local recurrent rectal cancer</p> <p>Methods</p> <p>First, we performed conventional radiotherapy with 40 Gy/20 fr. (CRT 40 Gy) for 12 patients with postoperative local recurrent rectal cancer, and then we performed FDG-PET/CT radiotherapy planning for those patients. We defined the regions with SUV > 2.0 as biological target volume (BTV) and made three boost plans for each patient: 1) CRT boost plan, 2) IMRT without dose-painting boost plan, and 3) IMRT with dose-painting boost plan. The total boost dose was 20 Gy. In IMRT with dose-painting boost plan, we increased the dose for BTV+5 mm by 30% of the prescribed dose. We added CRT boost plan to CRT 40 Gy (<it>summed plan 1</it>), IMRT without dose-painting boost plan to CRT 40 Gy (<it>summed plan 2</it>) and IMRT with dose-painting boost plan to CRT 40 Gy (<it>summed plan 3</it>), and we compared those plans using DVHs and NTCP.</p> <p>Results</p> <p>D_meanof PTV-PET and that of PTV-CT were 26.5 Gy and 21.3 Gy, respectively. V₅₀of small bowel PRV in <it>summed plan 1 </it>was significantly higher than those in other plans ((<it>summed plan 1 </it>vs. <it>summed plan 2 </it>vs. <it>summed plan 3</it>: 47.11 ± 45.33 cm³vs. 40.63 ± 39.13 cm³vs. 41.25 ± 39.96 cm³(p < 0.01, respectively)). There were no significant differences in V₃₀, V₄₀, V₆₀, D_meanor NTCP of small bowel PRV.</p> <p>Conclusions</p> <p>FDG-PET-guided IMRT can facilitate focal dose-escalation to regions with SUV above 2.0 for postoperative local recurrent rectal cancer.</p

Bipartite life cycle of coral reef fishes promotes increasing shape disparity of the head skeleton during ontogeny: an example from damselfishes (Pomacentridae)

Background: Quantitative studies of the variation of disparity during ontogeny exhibited by the radiation of coral reef fishes are lacking. Such studies dealing with the variation of disparity, i.e. the diversity of organic form, over ontogeny could be a first step in detecting evolutionary mechanisms in these fishes. The damselfishes (Pomacentridae) have a bipartite life-cycle, as do the majority of demersal coral reef fishes. During their pelagic dispersion phase, all larvae feed on planktonic prey. On the other hand, juveniles and adults associated with the coral reef environment show a higher diversity of diets. Using geometric morphometrics, we study the ontogenetic dynamic of shape disparity of different head skeletal units (neurocranium, suspensorium and opercle, mandible and premaxilla) in this fish family. We expected that larvae of different species might be relatively similar in shapes. Alternatively, specialization may become notable even in the juvenile and adult phase. Results: The disparity levels increase significantly throughout ontogeny for each skeletal unit. At settlement, all larval shapes are already species-specific. Damselfishes show high levels of ontogenetic allometry during their postsettlement growth. The divergence of allometric patterns largely explains the changes in patterns and levels of shape disparity over ontogeny. The rate of shape change and the length of ontogenetic trajectories seem to be less variable among species. We also show that the high levels of shape disparity at the adult stage are correlated to a higher level of ecological and functional diversity in this stage. Conclusion: Diversification throughout ontogeny of damselfishes results from the interaction among several developmental novelties enhancing disparity. The bipartite life-cycle of damselfishes exemplifies a case where the variation of environmental factors, i.e. the transition from the more homogeneous oceanic environment to the coral reef offering a wide range of feeding habits, promotes increasing shape disparity of the head skeleton over the ontogeny of fishes

Vicrostatin – An Anti-Invasive Multi-Integrin Targeting Chimeric Disintegrin with Tumor Anti-Angiogenic and Pro-Apoptotic Activities

Similar to other integrin-targeting strategies, disintegrins have previously shown good efficacy in animal cancer models with favorable pharmacological attributes and translational potential. Nonetheless, these polypeptides are notoriously difficult to produce recombinantly due to their particular structure requiring the correct pairing of multiple disulfide bonds for biological activity. Here, we show that a sequence-engineered disintegrin (called vicrostatin or VCN) can be reliably produced in large scale amounts directly in the oxidative cytoplasm of Origami B E. coli. Through multiple integrin ligation (i.e., αvβ3, αvβ5, and α5β1), VCN targets both endothelial and cancer cells significantly inhibiting their motility through a reconstituted basement membrane. Interestingly, in a manner distinct from other integrin ligands but reminiscent of some ECM-derived endogenous anti-angiogenic fragments previously described in the literature, VCN profoundly disrupts the actin cytoskeleton of endothelial cells (EC) inducing a rapid disassembly of stress fibers and actin reorganization, ultimately interfering with EC's ability to invade and form tubes (tubulogenesis). Moreover, here we show for the first time that the addition of a disintegrin to tubulogenic EC sandwiched in vitro between two Matrigel layers negatively impacts their survival despite the presence of abundant haptotactic cues. A liposomal formulation of VCN (LVCN) was further evaluated in vivo in two animal cancer models with different growth characteristics. Our data demonstrate that LVCN is well tolerated while exerting a significant delay in tumor growth and an increase in the survival of treated animals. These results can be partially explained by potent tumor anti-angiogenic and pro-apoptotic effects induced by LVCN

Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage

Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P=0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up

Three genes that escape X chromosome inactivation are clustered within a 6 Mb YAC contig and STS map in Xp11.21-p11.22.

In order to study the distribution of genes that escape X chromosome inactivation, a high density yeast artificial chromosome (YAC) contig and STS map spanning approximately 6 Mb has been constructed in Xp11.21-p11.22. The contig contains 113 YACs mapped with 53 markers, including 10 genes. Four genes have been assayed for their expression status on both the active and inactive human X chromosomes, and these data have been combined with previous results on two other genes in the contig. Three of these genes escape X inactivation and have been localized to a single YAC clone of approximately 1075 kb. The other three genes are subject to inactivation, with two of them lying among the genes that escape inactivation. These results suggest that there are both regional control signals as well as gene-specific elements that determine the X inactivation status of genes on the proximal short arm of the human X chromosome