Tumor and Ablation Margin Visibility during Cryoablation of Musculoskeletal Tumors: Comparing Intraprocedural PET/CT Images with CT-Only Images.

PURPOSE: To compare tumor and ice-ball margin visibility on intraprocedural positron emission tomography (PET)/computed tomography (CT) and CT-only images and report technical success, local tumor progression, and adverse event rates for PET/CT-guided cryoablation procedures for musculoskeletal tumors. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant and institutional review board-approved retrospective study evaluated 20 PET/CT-guided cryoablation procedures performed with palliative and/or curative intent to treat 15 musculoskeletal tumors in 15 patients from 2012 to 2021. Cryoablation was performed using general anesthesia and PET/CT guidance. Procedural images were reviewed to determine the following: (a) whether the tumor borders could be fully assessed on PET/CT or CT-only images; and (b) whether tumor ice-ball margins could be fully assessed on PET/CT or CT-only images. The ability to visualize tumor borders and ice-ball margins on PET/CT images was compared with that on CT-only images. RESULTS: Tumor borders were fully assessable for 100% (20 of 20; 95% CI, 0.83-1) of procedures on PET/CT versus 20% (4 of 20; 95 CI, 0.057-0.44) of procedures on CT only (P < .001). The tumor ice-ball margin was fully assessable in 80% (16 of 20; 95% CI, 0.56-0.94) of procedures using PET/CT versus 5% (1 of 20; 95% CI, 0.0013-0.25) of procedures using CT only (P < .001). Primary technical success was achieved in 75% (15 of 20; 95% CI, 0.51-0.91) of procedures. There was local tumor progression in 23% (3/13; 95% CI, 0.050-0.54) of the treated tumors with at least 6 months of follow-up. There were 3 adverse events (1 Grade 3, 1 Grade 2, and 1 Grade 1). CONCLUSIONS: PET/CT-guided cryoablation of musculoskeletal tumors can provide superior intraprocedural visualization of the tumor and ice-ball margins compared with that provided by CT alone. Further studies are warranted to confirm the long-term efficacy and safety of this approach.

Intubation Success in Critical Care Transport: A Multicenter Study.

INTRODUCTION: Tracheal intubation (TI) is a lifesaving critical care skill. Failed TI attempts, however, can harm patients. Critical care transport (CCT) teams function as the first point of critical care contact for patients being transported to tertiary medical centers for specialized surgical, medical, and trauma care. The Ground and Air Medical qUality in Transport (GAMUT) Quality Improvement Collaborative uses a quality metric database to track CCT quality metric performance, including TI. We sought to describe TI among GAMUT participants with the hypothesis that CCT would perform better than other prehospital TI reports and similarly to hospital TI success. METHODS: The GAMUT Database is a global, voluntary database for tracking consensus quality metric performance among CCT programs performing neonatal, pediatric, and adult transports. The TI-specific quality metrics are "first attempt TI success" and "definitive airway sans hypoxia/hypotension on first attempt (DASH-1A)." The 2015 GAMUT Database was queried and analysis included patient age, program type, and intubation success rate. Analysis included simple statistics and Pearson chi-square with Bonferroni-adjusted post hoc z tests (significance = p < 0.05 via two-sided testing). RESULTS: Overall, 85,704 patient contacts (neonatal n [%] = 12,664 [14.8%], pediatric n [%] = 28,992 [33.8%], adult n [%] = 44,048 [51.4%]) were included, with 4,036 (4.7%) TI attempts. First attempt TI success was lowest in neonates (59.3%, 617 attempts), better in pediatrics (81.7%, 519 attempts), and best in adults (87%, 2900 attempts), p < 0.001. Adult-focused CCT teams had higher overall first attempt TI success versus pediatric- and neonatal-focused teams (86.9% vs. 63.5%, p < 0.001) and also in pediatric first attempt TI success (86.5% vs. 75.3%, p < 0.001). DASH-1A rates were lower across all patient types (neonatal = 51.9%, pediatric = 74.3%, adult = 79.8%). CONCLUSIONS: CCT TI is not uncommon, and rates of TI and DASH-1A success are higher in adult patients and adult-focused CCT teams. TI success rates are higher in CCT than other prehospital settings, but lower than in-hospital success TI rates. Identifying factors influencing TI success among high performers should influence best practice strategies for TI.

Benchmarking Pain Assessment Rate in Critical Care Transport.

The purpose of this study is to determine the rate of pain assessment in pediatric neonatal critical care transport (PNCCT). The GAMUT database was interrogated for an 18-month period and excluded programs with less than 10% pediatric or neonatal patient contacts and less than 3 months of any metric data reporting during the study period. We hypothesized pain assessment during PNCCT is superior to prehospital pain assessment rates, although inferior to in-hospital rates. Sixty-two programs representing 104,445 patient contacts were analyzed. A total of 21,693 (20.8%) patients were reported to have a documented pain assessment. Subanalysis identified 17 of the 62 programs consistently reporting pain assessments. This group accounted for 24,599 patients and included 7,273 (29.6%) neonatal, 12,655 (51.5%) pediatric, and 4,664 (19.0%) adult patients. Among these programs, the benchmark rate of pain assessment was 90.0%. Our analysis shows a rate below emergency medical services and consistent with published hospital rates of pain assessment. Poor rates of tracking of this metric among participating programs was noted, suggesting an opportunity to investigate the barriers to documentation and reporting of pain assessments in PNCCT and a potential quality improvement initiative.

Evidence for pericyte origin of TSC-associated renal angiomyolipomas and implications for angiotensin receptor inhibition therapy.

Nearly all patients with tuberous sclerosis complex (TSC) develop renal angiomyolipomas, although the tumor cell of origin is unknown. We observed decreased renal angiomyolipoma development in patients with TSC2- polycystic kidney disease 1 deletion syndrome and hypertension that were treated from an early age with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers compared with patients who did not receive this therapy. TSC-associated renal angiomyolipomas expressed ANG II type 1 receptors, platelet-derived growth factor receptor-ß, desmin, α-smooth muscle actin, and VEGF receptor 2 but did not express the adipocyte marker S100 or the endothelial marker CD31. Sera of TSC patients exhibited increased vascular mural cell-secreted peptides, such as VEGF-A, VEGF-D, soluble VEGF receptor 2, and collagen type IV. These findings suggest that angiomyolipomas may arise from renal pericytes. ANG II treatment of angiomyolipoma cells in vitro resulted in an exaggerated intracellular Ca(2+) response and increased proliferation, which were blocked by the ANG II type 2 receptor antagonist valsartan. Blockade of ANG II signaling may have preventative therapeutic potential for angiomyolipomas.

Collecting duct cells that lack normal cilia have mislocalized vasopressin-2 receptors.

Polycystic kidney disease (PKD) is a ciliopathy characterized by renal cysts and hypertension. These changes are presumably due to altered fluid and electrolyte transport in the collecting duct (CD). This is the site where vasopressin (AVP) stimulates vasopressin-2 receptor (V2R)-mediated aquaporin-2 (AQP2) insertion into the apical membrane. Since cysts frequently occur in the CD, we studied V2R and AQP2 trafficking and function in CD cell lines with stunted and normal cilia [cilia (-), cilia (+)] derived from the orpk mouse (hypomorph of the Tg737/Ift88 gene). Interestingly, only cilia (-) cells grown on culture dishes formed domes after apical AVP treatment. This observation led to our hypothesis that V2R mislocalizes to the apical membrane in the absence of a full-length cilium. Immunofluorescence indicated that AQP2 localizes to cilia and in a subapical compartment in cilia (+) cells, but AQP2 levels were elevated in both apical and basolateral membranes in cilia (-) cells after apical AVP treatment. Western blot analysis revealed V2R and glycosylated AQP2 in biotinylated apical membranes of cilia (-) but not in cilia (+) cells. In addition, apical V2R was functional upon apical desmopressin (DDAVP) treatment by demonstrating increased cAMP, water transport, and benzamil-sensitive equivalent short-circuit current (I(sc)) in cilia (-) cells but not in cilia (+) cells. Moreover, pretreatment with a PKA inhibitor abolished DDAVP stimulation of I(sc) in cilia (-) cells. Thus we propose that structural or functional loss of cilia leads to abnormal trafficking of AQP2/V2R leading to enhanced salt and water absorption. Whether such apical localization contributes to enhanced fluid retention and hypertension in PKD remains to be determined.

Loss of primary cilia upregulates renal hypertrophic signaling and promotes cystogenesis.

Primary cilia dysfunction alters renal tubular cell proliferation and differentiation and associates with accelerated cyst formation in polycystic kidney disease. However, the mechanism leading from primary ciliary dysfunction to renal cyst formation is unknown. We hypothesize that primary cilia prevent renal cyst formation by suppressing pathologic tubular cell hypertrophy and proliferation. Unilateral nephrectomy initiates tubular cell hypertrophy and proliferation in the contralateral kidney and provides a tool to examine primary cilia regulation of renal hypertrophy. Conditional knockout of the primary cilia ift88 gene leads to delayed, adult-onset renal cystic disease, which provides a window of opportunity to conduct unilateral nephrectomy and examine downstream kinetics of renal hypertrophy and cyst formation. In wild-type animals, unilateral nephrectomy activated the mTOR pathway and produced appropriate structural and functional hypertrophy without renal cyst formation. However, in ift88 conditional knockout animals, unilateral nephrectomy triggered increased renal hypertrophy and accelerated renal cyst formation, leading to renal dysfunction. mTOR signaling also increased compared with wild-type animals, suggesting a mechanistic cascade starting with primary ciliary dysfunction, leading to excessive mTOR signaling and renal hypertrophic signaling and culminating in cyst formation. These data suggest that events initiating hypertrophic signaling, such as structural or functional loss of renal mass, may accelerate progression of adult polycystic kidney disease toward end-stage renal disease.

The exocyst protein Sec10 interacts with Polycystin-2 and knockdown causes PKD-phenotypes.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by formation of renal cysts that destroy the kidney. Mutations in PKD1 and PKD2, encoding polycystins-1 and -2, cause ADPKD. Polycystins are thought to function in primary cilia, but it is not well understood how these and other proteins are targeted to cilia. Here, we provide the first genetic and biochemical link between polycystins and the exocyst, a highly-conserved eight-protein membrane trafficking complex. We show that knockdown of exocyst component Sec10 yields cellular phenotypes associated with ADPKD, including loss of flow-generated calcium increases, hyperproliferation, and abnormal activation of MAPK. Sec10 knockdown in zebrafish phenocopies many aspects of polycystin-2 knockdown-including curly tail up, left-right patterning defects, glomerular expansion, and MAPK activation-suggesting that the exocyst is required for pkd2 function in vivo. We observe a synergistic genetic interaction between zebrafish sec10 and pkd2 for many of these cilia-related phenotypes. Importantly, we demonstrate a biochemical interaction between Sec10 and the ciliary proteins polycystin-2, IFT88, and IFT20 and co-localization of the exocyst and polycystin-2 at the primary cilium. Our work supports a model in which the exocyst is required for the ciliary localization of polycystin-2, thus allowing for polycystin-2 function in cellular processes.