Comparison of a Short Versus Long Stokes Shift Near-Infrared Dye During Intraoperative Molecular Imaging.

PURPOSE: Intraoperative molecular imaging (IMI) utilizes optical dyes that accumulate within tumors to assist with detection during a cancer operation. IMI can detect disease not visualized preoperatively, as well as positive margins. However, these dyes are limited by autofluorescence, signal reflection, and photon-scatter. We hypothesize that a novel dye with a wide separation between excitation and emission spectra, SS180, would help overcome these obstacles. PROCEDURES: Two targeted molecular contrast agents, OTL38 and SS180, were selected for this study. Both dyes had the same targeting ligand to folate receptor alpha (FRα). OTL38, a well-annotated IMI agent in human trials, has a Stokes shift of 22 nm, whereas SS180, the new dye, has a Stokes shift of 129 nm. Cell lines were tested for FRα expression and incubated with dyes to demonstrate receptor-dependent binding. Cells were incubated in various concentrations of the dyes to compare dose- and time-dependent binding. Finally, cells tagged with the dyes were injected subcutaneously in a murine model to estimate tumor burden necessary to generate fluorescent signal. RESULTS: Cellular studies demonstrated that SS180 binds cells in a dose-, receptor-, and time-dependent manner and exhibits higher mean fluorescence intensities by flow cytometry when compared with OTL38 for each time point and concentration. In an in vivo flank tumor model, SS180 had a higher tumor-to-background ratio (TBR) than OTL38, though not statistically significant (p = 0.08). Ex vivo, OTL38 had a higher TBR than SS180 (p = 0.02). The subcutaneous model revealed that SS180 had a higher TBR at 5 × 106 cells than OTL38 (p = 0.05). No toxicity was observed in the animals. CONCLUSIONS: SS180 exhibits greater TBRs in vivo, but not ex vivo. These findings suggest that SS180 may have weaker fluorescence, but superior contrast. Studies in large animal models and clinical trials may better elucidate the clinical value of a long Stokes shift.

Intraoperative Near-infrared Imaging Can Identify Neoplasms and Aid in Real-time Margin Assessment During Pancreatic Resection.

OBJECTIVE: To determine if intraoperative near-infrared (NIR) imaging carries benefit in resection of pancreatic neoplasms. BACKGROUND: Resection of pancreatic malignancies is hindered by high rates of local and distant recurrence from positive margins and unrecognized metastases. Improved tumor visualization could improve outcomes. We hypothesized that intraoperative NIR imaging with a clinically approved optical contrast agent could serve as a useful adjunct in assessing margins and extent of disease during pancreatic resections. METHODS: Twenty patients were enrolled in an open-label clinical trial from July 2016 to May 2018. Subjects received second window indocyanine green (ICG) (2.5-5 mg/kg) 24 hours prior to pancreatic resection. NIR imaging was performed during staging laparoscopy and after pancreas mobilization in situ and following resection ex vivo. Tumor fluorescence was quantified using tumor-to-background ratio (TBR). Fluorescence at the specimen margin was compared to pathology evaluation. RESULTS: Procedures included 9 pancreaticoduodenectomies, 10 distal pancreatectomies, and 1 total pancreatectomy; 21 total specimens were obtained. Three out of 8 noninvasive tumors were fluorescent (mean TBR 2.59 ±â€Š2.57). Twelve out of 13 invasive malignancies (n = 12 pancreatic adenocarcinoma, n = 1 cholangiocarcinoma) were fluorescent (mean TBR 4.42 ±â€Š2.91). Fluorescence at the transection margin correlated with final pathologic assessment in 12 of 13 patients. Following neoadjuvant therapy, 4 of 5 tumors were fluorescent; these 4 tumors showed no treatment response on pathology assessment. One tumor had a significant treatment response and showed no fluorescence. CONCLUSIONS: Second window ICG reliably accumulates in invasive pancreatic malignancies and provides real-time feedback during pancreatectomy. NIR imaging may help to assess the response to neoadjuvant therapy.

National trends and disparities of minimally invasive surgery for localized renal cancer, 2010 to 2015.

PURPOSE: To investigate national utilization trends of minimally-invasive partial nephrectomy (PN) and minimally-invasive radical nephrectomy (RN), and to identify disparities in the usage of these techniques across different sociodemographic subgroups. MATERIALS AND METHODS: A retrospective cohort study was conducted using the National Cancer Database to identify patients undergoing partial or RN for cT1N0M0 renal cancer diagnosed between 2010 and 2015. Main outcomes of interest were the utilizations of minimally-invasive (robotic and laparoscopic) PN and RN. RESULTS: A total of 46,346 and 37,712 subjects who underwent PN and RN, respectively, were analyzed. During the study interval, increased utilization of robotic surgery paralleled the decreased utilization of open surgery. Robotic PN increased from 35.2% to 63.7% and robotic RN increased from 10.3% to 26.3%. The utilization of laparoscopic surgery was decreasing for PN but stable for RN through the study period. In the PN cohort, multivariable logistic regression showed non-Hispanic black (odds ratio [OR] = 0.90 [95% CI, 0.84-0.96]) and Hispanic (OR = 0.91 [0.84-0.99]) subjects were associated with less utilization of minimally invasive surgery (MIS) (vs. non-Hispanic white). Younger (18-64 years) Medicare (OR = 0.83 [0.77-0.90]), Medicaid (OR = 0.80 [0.74-0.87]), and uninsured (OR = 0.55 [0.49-0.62]) were also associated with less utilization of MIS (vs. private insurance). Compared with low socioeconomic status (SES), upper middle (OR = 1.14 [1.07-1.21]) and high (OR = 1.24 [1.16-1.33]) SES were associated with higher utilization of MIS. Similar demographic, insurance, and SES-related disparities were identified in the RN cohort. CONCLUSIONS: Utilization of MIS for localized renal cancer has increased significantly and was mainly attributed to increased usage of robotic surgery. Racial/ethnic, insurance, and SES related disparities in MIS utilization were identified. Our findings demonstrate a targetable subgroup of patients who do not have the same access to advances in surgical technology.

Obesity and 30-Day Outcomes Following Minimally Invasive Nephrectomy.

OBJECTIVE: To evaluate the association between obesity and postoperative outcomes following minimally invasive partial nephrectomy (MIPN) and minimally invasive radical nephrectomy (MIRN). METHODS: Using the National Surgical Quality Improvement Project database, we identified adult patients who underwent either MIPN or MIRN from 2012 to 2016. Patients were stratified by body mass index (BMI) according the World Health Organization classification of obesity (nonobese [BMI 18.5-29.9 kg/m2], class I obesity [BMI 30-34.9 kg/m2], class II obesity [BMI 35-39.9 kg/m2], and class III obesity [BMI≥40 kg/m2]). Multivariable logistic regressions alternately including obesity class, comorbidity score, and both were used to evaluate the association among these variables with post-operative outcomes. RESULTS: A total of 21,334 patients (MIPN=10,444, MIRN=10,890) were included. When only obesity class or comorbidity score was included in our multivariable logistic regression model, both variables were associated with increased odds of overall 30-day complications. However, when both class or comorbidity were included in the model, comorbidity but not obesity was found to be associated with increased postoperative complications. Obesity was also not found to be associated with unplanned readmission. However, obesity was independently associated with prolonged operative time and discharge to continued care in the full model. CONCLUSION: This NSQIP study suggests that BMI does not independently predict the likelihood of overall complications or readmission within 30 days, and should not be considered a major barrier for MIPN or MIRN. Instead, obesity should be taken into consideration with other comorbidities when risk-stratifying patients prior to minimally invasive nephrectomy.

Structural and Functional Role of Acetyltransferase hMOF K274 Autoacetylation.

Many histone acetyltransferases undergo autoacetylation, either through chemical or enzymatic means, to potentiate enzymatic cognate substrate lysine acetylation, although the mode and molecular role of such autoacetylation is poorly understood. The MYST family of histone acetyltransferases is autoacetylated at an active site lysine residue to facilitate cognate substrate lysine binding and acetylation. Here, we report on a detailed molecular investigation of Lys-274 autoacetylation of the human MYST protein Males Absent on the First (hMOF). A mutational scan of hMOF Lys-274 reveals that all amino acid substitutions of this residue are able to bind cofactor but are significantly destabilized, both in vitro and in cells, and are catalytically inactive for cognate histone H4 peptide lysine acetylation. The x-ray crystal structure of a hMOF K274P mutant suggests that the reduced stability and catalytic activity stems from a disordering of the residue 274-harboring a α2-ß7 loop. We also provide structural evidence that a C316S/E350Q mutant, which is defective for cognate substrate lysine acetylation; and biochemical evidence that a K268M mutant, which is defective for Lys-274 chemical acetylation in the context of a K274-peptide, can still undergo quantitative K274 autoacetylation. Together, these studies point to the critical and specific role of hMOF Lys-274 autoacetylation in hMOF stability and cognate substrate acetylation and argues that binding of Ac-CoA to hMOF likely drives Lys-274 autoacetylation for subsequent cognate substrate acetylation.

The role of antimalarials in the exacerbation of psoriasis: a systematic review.

OBJECTIVE: To critically review the body of literature that refutes or supports the role of antimalarials in the exacerbation of psoriasis. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were reviewed to identify English-language publications from 1966-2005 examining the role of antimalarials in the exacerbation of psoriasis. A total of 374 articles were identified, of which 32 studies met the inclusion criteria. All available clinical trials or reported cases of the use of antimalarials for patients with psoriasis were included. Data from clinical studies were summarized according to the level of evidence and the outcome of the study. Data were entered into a standardized data extraction form by two independent reviewers. RESULTS AND CONCLUSION: No randomized trial evidence was found. Only one cohort study was available for review. A total of 31 case series and case reports were obtained. There is no strong evidence to refute or support the role of antimalarials in the exacerbation of psoriasis. Controlled trials of antimalarial therapy and its effect on psoriasis are warranted.