Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

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.     

Free Bipedicled Radial Forearm and Posterior Interosseous Artery Perforator Flap Phalloplasty

IntroductionThe free radial forearm (FRFA) flap is universally still considered as the gold standard technique in penile reconstruction. Typically, a considerably large flap is required, often involving almost the entire circumference of the forearm. Partial necrosis may occur at the distal-most (dorsoradial) part of the flap as a result of insufficient perfusion.AimTo describe a new technique using the posterior interosseous artery (PIOA) to supercharge FRFA phalloplasty.MethodsIn a 12-month period, all patients having FRFA flap phalloplasty were enrolled. Perioperative, after complete flap dissection, an indocyanine green perfusion scan was performed. In case of insufficient perfusion at the distalmost part of the flap, a supramicrosurgical anastomosis was performed between the FRFA pedicle and the PIOA (artery only).Main Outcome MeasuresStudied outcomes included the rate of marginal necrosis, surgical time, postoperative posterior interosseous nerve damage and urethral complications (fistula, stenosis or necrosis).ResultsA total of 27 FRFA flap phalloplasties was performed. Anastomosis of the PIOA was needed in 15 cases. No marginal necrosis was observed in these cases. There were no cases of postoperative posterior interosseous nerve damage. There were no significant differences in urethral complications (fistula, stenosis or necrosis) between the 2 groups.Clinical ImplicationsIn selected cases where insufficient perfusion of the dorsoradial part of the flap is present, patients may benefit from arterial supercharging to prevent postoperative marginal necrosis.Strength & LimitationsStrengths include a single surgeon, thus lending continuity of skill and technique, a consecutive series, and 100% short-term follow-up. Limitations include single institution series and a limited number of patients.ConclusionArterial supercharging is effective in improving perfusion of large FRFA flaps used in phalloplasty when dorsoradial hypoperfusion is detected on an indocyanine green perfusion scan. It is a technically challenging addition to the standard technique because of the small size of the vessels, the close relationship between the PIOA and the posterior interosseous nerve, and the vulnerability of the newly constructed intra-flap anastomosis.De Wolf E, Claes K, Sommeling CE, et al. Free Bipedicled Radial Forearm and Posterior Interosseous Artery Perforator Flap Phalloplasty. J Sex Med 2019;16:1111–1117.     

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 2: Alcohol-Associated Osteonecrosis

Background

Although alcohol is a leading risk factor for osteonecrosis of the femoral head (ONFH) and its prevalence reportedly ranges from 20% to 45%, there are no unified classification criteria for this subpopulation. In 2015, Association Research Circulation Osseous decided to develop classification criteria for alcohol-associated ONFH.

Bending Strength of Wood Treated with Propolis Extract and Silicon Compounds

The modification of wood and its treatment with various preservatives may affect its mechanical properties, hence the knowledge of the character changes in wood caused by impregnation is of great importance. Therefore, the aim of the research was to determine the effect of impregnation, with the propolis-silane preparation (EEP-MPTMOS/TEOS) consisting of the propolis extract (EEP) and silicon compounds: 3-(trimethoxysilyl)propyl methacrylate (MPTMOS) and tetraethoxysilane (TEOS), on the bending strength of treated wood. Moreover, in the study wood treated with components of the propolis-silane formulation was used, namely 70% ethanol, the propolis extract, and silanes (MPTMOS/TEOS). In order to determine whether the impregnation of wood affects its long-term bending, creep tests were performed depending on the humidity. The impregnation of wood with the propolis extract and the propolis-silane preparation (EEP-MPTMOS/TEOS) contributed to the increase in modulus of rapture and work to maximum load values compared to the untreated wood. In dry wood condition, the wood treated with EEP and EEP-MPTMOS/TEOS was characterized by lower modulus of elasticity values than the control samples. In turn, in wet wood condition, wood treated with the propolis-silane preparation showed an increase in the MOE value. Moreover, the impregnation of wood had an influence on the wood creep process under bending loads. The treated wood was characterized by higher relative creep compliance than the untreated wood. The exception was the wood impregnated with EEP-MPTMOS/TEOS, which showed comparable relative creep compliance to the control samples. The presented results indicate that wood treated with a bio-friendly preparation based on propolis and silicon compounds can be used in various application and also in variable humidity conditions.     

Does Tweeting Improve Citations? One-Year Results From the TSSMN Prospective Randomized Trial

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