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Wafik S. El-Deiry MD PhD FACP Richard M. Goldberg MD Heinz-Josef Lenz MD FAPC Anthony F. Shields MD PhD Geoffrey T. Gibney MD Antoinette R. Tan MD MHSc Jubilee Brown MD Burton Eisenberg MD Elisabeth I. Heath MD FACP Surasak Phuphanich MD Edward Kim MD FACP FASCO Andrew J. Brenner MD PhD John L. Marshall MD 《CA: a cancer journal for clinicians》2019,69(4):305-343
The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up-to-date sources to ensure he or she provides optimum care. In this review, the authors provide the current state of the art for molecular profiling/precision medicine, practice standards, and a view into the future ahead. 相似文献
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Mohamed E. Salem J. Nicholas Bodor Alberto Puccini Joanne Xiu Richard M. Goldberg Axel Grothey W. Michael Korn Anthony F. Shields William M Worrilow Edward S. Kim Heinz-Josef Lenz John L. Marshall Michael J. Hall 《International journal of cancer. Journal international du cancer》2020,147(10):2948-2956
Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI. 相似文献
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Reisa A. Sperling Elizabeth C. Mormino Aaron P. Schultz Rebecca A. Betensky Kathryn V. Papp Rebecca E. Amariglio Bernard J. Hanseeuw Rachel Buckley Jasmeer Chhatwal Trey Hedden Gad A. Marshall Yakeel T. Quiroz Nancy J. Donovan Jonathan Jackson Jennifer R. Gatchel Jennifer S. Rabin Heidi Jacobs Hyun‐Sik Yang Michael Properzi Dylan R. Kirn Dorene M. Rentz Keith A. Johnson 《Annals of neurology》2019,85(2):181-193
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Transmetatarsal amputation (TMA) is the procedure of choice in treating forefoot gangrene and infection. Foot and ankle and vascular surgeons work closely together in limb salvage, but little is known about the timing of vascular intervention to achieve a healed amputation site. This study retrospectively looked at 153 patients with peripheral vascular disease who underwent TMA with a minimum of a 3-year follow-up. A total of 102 patients received vascular intervention: 79 endovascular and 23 open bypass. The primary focus of this study was to look at the timing of vascular intervention, incidence of wound healing, and incidence of limb loss. There was an overall 44% rate of limb loss. Patients who underwent open bypass did better than those who underwent endovascular intervention with a lower incidence of limb loss (87% compared with 51%), and quicker time to wound healing. The timing of vascular intervention, performed either before or after TMA, had no association with wound healing or limb loss. Similarly, the time interval between vascular intervention and TMA had no association with wound healing or limb loss. Comorbidities, including end-stage renal disease on hemodialysis, hyperlipidemia, and congestive heart failure, showed a significant association with TMA stump nonhealing and limb loss. Body mass index ≥30, end-stage renal disease on hemodialysis, and hyperlipidemia were all risk factors for limb loss. 相似文献