Evaluation of a panel of furochromenones as the activator and inhibitor of tyrosinase.

Tyrosinase is a copper-containing enzyme involved in the biosynthesis of melanin pigment. While the excess production of melanin causes hyperpigmentation of human skin, hypopigmentation results in medical conditions like vitiligo. Tyrosinase inhibitors could be used as efficient skin whitening agents and tyrosinase agonists could be used for enhanced melanin synthesis and skin protection from UV exposure. Among a wide range of tyrosinase-regulating compounds, natural and synthetic derivatives of furochromenones, such as 8-methoxypsoralen (8-MOP), are known to both activate and inhibit tyrosinase. We recently reported a synthetic approach to generate a variety of dihydrofuro[3,2-c]chromenones and furo[3,2-c]chromenones in a metal-free condition. In the present study, we investigated these compounds for their potential as antagonists or agonists of tyrosinase. Using fungal tyrosinase-based in vitro biochemical assay, we obtained one compound (3k) which could inhibit tyrosinase activity, and the other compound (4f) that stimulated tyrosinase activity. The kinetic studies revealed that compound 3k caused 'mixed' type tyrosinase inhibition and 4f stimulated the catalytic efficiency. Studying the mechanisms of these compounds may provide a basis for the development of new effective tyrosinase inhibitors or activators.

The risk of clinically-relevant pancreatic fistula after pancreaticoduodenectomy is better predicted by a postoperative trend in drain fluid amylase compared to day 1 values in isolation.

BACKGROUND: Recent studies support early drain removal after pancreaticoduodenectomy in patients with a drain fluid amylase on postoperative day 1 (DFA1) level of ≤5,000. The use of DFA1 to guide drain management is increasingly common among pancreatic surgeons; however, the benefit of checking additional drain fluid amylases beyond DFA1 is less known. We sought to determine whether a change in drain fluid amylase (ΔDFA) is a more reliable predictor of clinically relevant postoperative fistula than DFA1 alone. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Plan, pancreaticoduodenectomy patients with intraoperative drain placement, known DFA1, highest recorded drain fluid amylase value on postoperative day 2 to 5 (DFA2nd), day of drain removal, and clinically relevant postoperative fistula status were reviewed. Logistic models compared the predictive performance of DFA1 alone versus DFA1 + ΔDFA. RESULTS: A total of 2,417 patients with an overall clinically relevant postoperative fistula rate of 12.6% were analyzed. On multivariable regression, clinical predictors for clinically relevant postoperative fistula included body mass index, steroid use, operative time, and gland texture. These variables were used to develop model 1 (DFA1 alone) and model 2 (DFA1 + ΔDFA). Model 2 outperformed model 1 in predicting the risk of clinically relevant postoperative fistula. According to model 2 predictions, the risk of clinically relevant postoperative fistula increased with any rise in drain fluid amylase, regardless of whether the DFA1 was above or below 5,000 U/L. The risk of clinically relevant postoperative fistula significantly decreased with any drop in drain fluid amylase, with an odds reduction of approximately 50% corresponding with a 70% decrease in drain fluid amylase (P < .001). A risk calculator was developed using DFA1 and a secondary DFA value in conjunction with other clinical predictors for clinically relevant postoperative fistula. CONCLUSION: Clinically relevant postoperative fistula after pancreaticoduodenectomy is more accurately predicted by DFA1 and ΔDFA versus DFA1 in isolation. We developed a novel risk calculator to provide an individualized approach to drain management after pancreaticoduodenectomy.

The Impact of Same-Day Discharge and Enhanced Recovery on Patient Quality of Life After Mastectomy with Implant Reconstruction.

BACKGROUND: This study aimed to evaluate how enhanced recovery (ER) protocols and same-day discharge (SDD) influences patients' postoperative quality of life (QOL). METHODS: Patients who underwent mastectomy with implant-based breast reconstruction from 2008 to 2020 were identified in a prospective database. The study assessed QOL with BREAST-Q and Was It Worth It? (WIWI) questionnaires. Responses were compared between the ER and pre-ER groups and between the SDD and hospital stay (HS) groups using one-way analysis of variance (ANOVA) and chi-square tests. RESULTS: The inclusion criteria were met by 568 patients, with a 43% response rate, and 217 patients were included for analysis. Chest physical well-being was lower for the ER cohort, but postoperative breast satisfaction was higher. Psychosocial status, sexual well-being, and satisfaction with information given did not differ significantly between the ER group and the pre-ER or SDD group. In the compared groups, QOL did not differ significantly. CONCLUSIONS: Enhanced recovery with SDD after mastectomy using implant-based reconstruction did not have an adverse impact on patient postoperative QOL.

Cancer embryonic antigen (CEA) levels in patients with appendiceal adenocarcinoma predict response to neo-adjuvant chemotherapy and overall survival.

BACKGROUND AND OBJECTIVES: Serum tumor markers are widely used for diagnosis, prognosis, treatment response, and surveillance. Our study evaluated cancer embryonic antigen (CEA) in patients with appendiceal adenocarcinoma. METHODS: The National Cancer Database was reviewed (2004-2011) for patients with surgical treatment for appendiceal adenocarcinoma. Patients were stratified into two groups: normal and elevated CEA. Multivariable adjusted Cox proportional hazards regression analyses were used to determine the independent effect of CEA on survival. RESULTS: Our study consisted of 2867 patients, 54.0% having elevated CEA. Patients with elevated CEA were more likely to have Stage IV disease, be female, and African American; all p < 0.001. Three-year overall survival (OS) was significantly higher with normal CEA (75.5% vs. 62.8%, p < 0.001). On multivariable analysis, elevated CEA was associated with worse survival (hazard ratio 1.49, 95% confidence interval 1.23-1.80). Patients with elevated CEA had improved 3-year OS with neo-adjuvant compared to adjuvant chemotherapy (p = 0.004), while those with normal CEA showed no difference. CONCLUSIONS: In patients with surgically treated appendiceal adenocarcinoma, preoperative elevation in CEA independently predicts decreased 3-year survival and correlates with improved OS with neo-adjuvant therapy. CEA levels should be considered in clinical decision-making regarding neo-adjuvant therapy in patients with appendiceal adenocarcinoma.

The impact of mastectomy and reconstruction technique on patient perceived quality of Life.

BACKGROUND: We sought to evaluate the impact of mastectomy type, post-mastectomy reconstruction choice, and procedure bilaterality, on patient perceived postoperative quality of life (QoL). METHODS: Patients who underwent post-mastectomy reconstruction between 2008 and 2020 were identified in a prospective database. QoL was assessed with the BREAST-Q and the Was It Worth It (WIWI) questionnaires. The results were compared between reconstruction type, reconstruction laterality, and type of mastectomy. Responses were compared using one-way analysis of variance (ANOVA) and chi-square tests. RESULTS: 568 patients met inclusion criteria, and 244 patients responded (43%). QoL did not significantly vary between different reconstructions selected, procedure laterality, or mastectomy type. Patients who underwent DIEP flap were significantly more satisfied with their reconstructed breasts than implant-based reconstruction. Overall, over 85% of patients experienced improved or unchanged QoL no matter what reconstruction choices were made. CONCLUSION: Most domains of QOL are not impacted by mastectomy type, post-mastectomy reconstruction, or laterality.

Postoperative Hematomas in the Era of Outpatient Mastectomy: Is Ketorolac Really to Blame?

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols following mastectomy with or without implant-based breast reconstruction (IBBR) include ketorolac for multimodal perioperative analgesia. There are concerns that ketorolac could be associated with increased risk of postoperative hematoma formation. METHODS: Retrospective review of patients undergoing mastectomy with or without IBBR between January 2013 and December 2019 at a single institution. Patients received 15 mg, 30 mg, or no ketorolac depending on ERAS protocol adherence, patient characteristics, and surgeon preference. Clinically significant hematoma was defined as requiring surgical intervention on day of surgery or postoperative day 1. Patients were compared by demographics, surgical characteristics, ketorolac dose, and hematoma prevalence. Univariable and multivariable logistic regression evaluated hematoma formation odds. RESULTS: Eight hundred patients met inclusion criteria: 477 received ketorolac. Those who received ketorolac were younger, had lower ASA scores, were more likely to have bilateral procedures and undergo concomitant IBBR, had longer operative times, were less likely to take antiplatelet or anticoagulation medications, had higher PACU pain scores, and had higher incidence of hematomas requiring surgical intervention. Of the cohort, 4.4% had clinically significant hematomas. The 15 mg and 30 mg ketorolac groups had similar prevalence (6.0% vs 5.8%, p = 0.95). On univariable regression, there were increased odds of hematoma formation in patients who were younger, had bilateral procedures, had longer OR times, and who received ketorolac. On multivariable regression, none of the prior variables remained significant. CONCLUSION: After accounting for associations with longer operative times, concomitant IBBR, and bilateral procedures, ketorolac administration did not remain an independent risk factor for hematoma formation.

Accuracy of Posttreatment Imaging for Evaluation of Residual in Breast Disease After Neoadjuvant Endocrine Therapy.

BACKGROUND: Neoadjuvant endocrine therapy (NET) can help downstage certain breast cancers prior to surgical resection. This study measured the accuracy of conventional mammography (MMG), ultrasound (US), magnetic resonance imaging (MRI), and contrast-enhanced mammography (CEM) for assessing breast tumor size in response to NET. PATIENTS AND METHODS: Patients who underwent surgery after NET from 2013 to 2021 were identified. The maximal dimension of residual tumor on imaging was compared with the maximal dimension on final pathology. Lin's concordance correlation coefficient (rc) and Spearman's rank correlation coefficient (r) were used to assess agreement. RESULTS: In total, 119 patients with invasive breast cancer underwent NET, posttreatment imaging, and surgery. Tumor size reported on posttreatment CEM correlated with size on final pathology to within 1 cm in n = 42 (58%) of patients, equivalent to the accuracy of MRI (n = 35, 58%). Size was accurately predicted by US in 54% and in 48% of MMG. Posttreatment imaging tumor size was moderately correlated with final tumor size on pathology CEM (r = 0.49; rc = 0.38), MRI (r = 0.52; rc = 0.45), and US (r = 0.41; rc = 0.28). MMG was weakly correlated (r = 0.21; rc = 0.16). Similar findings were shown in subgroup analysis; in those who received all four post-NET imaging, CEM and MRI again performed comparably, with r = 0.36 and 0.41, respectively, US (r = 0.43) and MMG (r = 0.28). CONCLUSIONS: Compared with mammography and US, CEM and MRI had higher accuracy in estimating final tumor size for breast cancers treated with NET. Contrast-enhanced imaging is a helpful adjunct when response to preoperative therapy will impact clinical management.

dV-Trainer vs. da Vinci Simulator: Comparison of Virtual Reality Platforms for Robotic Surgery.

BACKGROUND: A virtual reality (VR) curriculum performed on the da Vinci Simulation System (DVSS) was previously shown to be effective in training fellows. The dV-Trainer is a separate platform with similar features to the da Vinci console, but its efficacy and utility versus the DVSS simulator are not well known. MATERIALS AND METHODS: A mastery-based VR curriculum was completed by surgical fellows on the DVSS (2014-2016) and on the dV-Trainer (2016-2018) at a large academic center. Pre-test/post-test scores were used to evaluate performance between the two groups. Data was collected prospectively. RESULTS: Forty-six fellows enrolled in the curriculum: surgical oncology (n=31), hepatobiliary (n=5), head/neck (n=4), endocrine (n=2), cardiothoracic (n=2), gynecology (n=1) and transplant surgery (n=1). Twenty-four used the DVSS and twenty-two used the dV-Trainer. Compared to the DVSS, the dV-Trainer was associated with lower scores on 2 of 3 VR modules in the pre-test (P=0.027, P<0.001, respectively) and post-test (P=0.021, P<0.001, respectively). Fellows in the dV-Trainer era scored lower on inanimate drills as well. Average VR curriculum score was lower on the dV-Trainer (71.3% vs 83.34%, P<0.001). dV-Trainer users spent more time completing the pre-test and post-test; however, overall simulator time to complete the curriculum was not significantly different (297 vs 231 minutes, P=0.142). Both groups showed improvement in scores after completion of the VR curriculum. CONCLUSIONS: The dV-Trainer simulator allows for more usability outside the operating room to complete VR modules; however, the DVSS simulator group outperformed the dV-Trainer group on the post-test.

Alkyl Enol Ethers: Development in Intermolecular Organic Transformation.

Alkyl enol ethers (AEE) are versatile synthetic intermediates with a unique reactivity pattern. This review article summarizes the synthesis of AEE as well as its reactivity and how enol ether undergoes intermolecular reactions for various bond formation, leading to the construction of several useful organic molecules. The synthetic applications of alkyl enol ethers towards intermolecular bond-forming reactions include metal-catalyzed reactions, cycloaddition and heterocycle formation as well as rwactions in the field of natural products synthesis. The achievement of these impressive transformations prove the countless synthetic potential of AEE. The main objective of this review is to bring attentiveness among synthetic chemists to show how AEE extensively can be used to react with both electrophiles as well as nucleophiles, thereby behaving as an ambiphilic reactant. We trust that the unique reactivity pattern of alkyl enol ethers and the fundamental mechanistic idea can attract chemists in AEE chemistry. Exclusively, intermolecular reactions of AEE with other functionalized moieties have not been reviewed to the best of our knowledge.

Will It Play in Peoria? A Pilot Study of a Robotic Skills Curriculum for Surgical Oncology Fellows.

INTRODUCTION: To implement a mastery-based robotic surgery curriculum using virtual reality (VR) and inanimate reality (IR) drills at multiple Complex General Surgical Oncology (CGSO) fellowships. PATIENTS AND METHODS: A prospective study of curriculum feasibility and efficacy was conducted at four CGSO fellowship sites. All sites had simulators, and kits were provided to perform 19 biotissue drills. Fellows from three non-UPMC sites (n = 15) in 2016-2018 were compared with fellows from University of Pittsburgh (UPMC; n = 15) where the curriculum was validated in 2014-2018. RESULTS: All fellows completed the pre- and post-test. There was no difference in pre-test scores between UPMC and non-UPMC sites. Only 7 of 15 non-UPMC fellows completed the VR curriculum (47% compliance) compared with all 15 UPMC fellows completing the VR curriculum (100% compliance). UPMC had higher curriculum times (217 versus 93 mins) and % mastery (86% versus 55%). Time spent on curriculum was associated with % mastery (p = 0.01). Both groups showed improvement between pre- and post-test. Post-test VR scores trended higher for UPMC (221 versus 180). Between the non-UPMC sites, there was a difference in compliance (p = 0.03) and % mastery (p = 0.03). Zero non-UPMC fellows performed the biotissue drills, while five contemporary UPMC fellows completed 253 biotissue drills. Approximately 140 UPMC faculty and 300 staff hours were spent on the pilot. CONCLUSIONS: A proficiency curriculum can result in improved robotic console skills. However, multiple barriers to implementation potentially exist, including availability of simulators, availability of a training robot, on-site support staff, and universal buy-in from fellows, faculty, and leadership.

Radical resection of a giant rib osteosarcoma with complex chest wall reconstruction.

INTRODUCTION: Primary rib osteosarcoma is a rare chest wall tumor with variable presentation. Large tumors greater than 10 cm are even rarer and present a challenge for surgical management. PRESENTATION OF CASE: A 61-year-old male with a giant osteosarcoma of the left 2nd rib underwent multidisciplinary management including induction therapy with doxorubicin and cisplatin, followed by en bloc resection with left ribs 1-5, spinous processes of ribs 2-5, small volume lung resection, and chest wall reconstruction with polypropylene mesh and poly methyl methacrylate (PMMA or bone cement). There were no perioperative complications. At 6 months follow-up, the patient remains disease-free. Functional and cosmetic outcome are excellent. DISCUSSION: This 20 cm mass and resection of ribs 1-5 with resulting 25 cm chest wall defect is the largest primary rib osteosarcoma reported in literature. An R0 resection and chest wall reconstruction using polypropylene mesh and bone cement was feasible and safe. CONCLUSION: Giant chest wall defects involving multi-rib resection can be effectively reconstructed with commonly available and inexpensive polypropylene mesh and PMMA to achieve good cosmetic and functional outcomes.

Extracorporeal membrane oxygenation after traumatic injury.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) for acute respiratory failure after injury is controversial and poorly described. METHODS: We reviewed our single-center experience with use of ECMO from January 2006 to November 2015 at a Level 1 primary adult resource center for trauma to determine the association of in-hospital mortality with patient demographics and clinical variables. RESULTS: Forty-six patients were treated with ECMO. Patients requiring venoarterial ECMO (n = 7) were excluded. Thirty-nine (85%) were cannulated for venovenous ECMO. Of these, 44% patients survived to discharge. Median age was 28 years. Survivors had a lower BMI and PaCO2 at time of cannulation. Nonsurvivors were more severely injured (median Injury Severity Score, 41 vs. 25; p = 0.03), had a lower arterial pH on arrival, and a shorter length of stay (11 vs. 41 days; p = 0.006). Neither mechanism of injury nor indication for ECMO was associated with mortality. Forty-one percent developed at least one ECMO-related complication, but this was not associated with mortality. Ninety-four percent of the survivors were anticoagulated with heparin versus 55% of nonsurvivors (p = 0.01). Median Injury Severity Score and presence of TBI were not significantly different between survivors and nonsurvivors who were anticoagulated. CONCLUSION: The use of venovenous ECMO for acute lung injury after trauma should be considered in special patient populations. Ability to tolerate systemic anticoagulation was associated with improved survival. LEVEL OF EVIDENCE: Therapeutic study, level V.

Current status of the microbiome in renal transplantation.

PURPOSE OF REVIEW: An imbalance between pathogenic and protective microbiota characterizes dysbiosis. Presence of dysbiosis may affect immunity, tolerance, or disease depending on a variety of conditions. In the transplant patient population, the need for immunosuppression and widespread use of prophylactic and therapeutic antimicrobial agents create new posttransplant microbiota communities that remain to be fully defined. RECENT FINDINGS: Studies in mice have demonstrated significant bidirectional interactions between microbiota-derived products and host immune cells. The stimulation of regulatory T cell and T helper cell type 17 cells by specific products leads to maintenance of immune homeostasis versus activation of inflammation, respectively. Dysbiosis may lead to development of antigen cross-reactivity, which may affect alloreactivity. Certain immunologic sequelae of microbiota are pronounced in chronic kidney disease, because of uremia and renal metabolism of microbiota metabolites. Dietary modifications, probiotics, and fecal microbiota transplant have been investigated for alteration of microbiota in humans. SUMMARY: Researchers have begun to identify dysbioses associated with clinical conditions, including chronic kidney disease, posttransplant infection, and rejection. This information will allow clinicians not only to select at-risk patients for early intervention, but also to develop therapies that restore the microbiota to a state of homeostasis or tolerance.

Sequential kidney-liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency.

BACKGROUND: Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end-stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency. METHODS: A 29-year-old male with ESRD secondary to LCAT deficiency underwent a sequential kidney-liver transplantation from the same living donor (LD). One year following the kidney transplant, auxiliary partial orthotopic liver transplant (APOLT) of a left lateral segment from the same donor was performed. RESULTS: At 5 years follow-up, there have been no major complications, readmissions, or rejection episodes. Serum lipid abnormalities recurred within the first year, but liver and kidney allograft function remains intact. CONCLUSION: Few cases of sequential transplantation from the same LD have been performed in adults. This is the first APOLT and multi-organ transplant performed for LCAT deficiency. Sequential organ transplant from the same LD for ESRD secondary to a metabolic disorder of the liver is feasible in adults and should be further investigated.

Recreational marijuana use is not associated with worse outcomes after renal transplantation.

As marijuana (MJ) legalization is increasing, kidney transplant programs must develop listing criteria for marijuana users. However, no data exist on the effect of MJ on kidney allograft outcomes, and there is no consensus on whether MJ use should be a contraindication to transplantation. We retrospectively reviewed 1225 kidney recipients from 2008 to 2013. Marijuana use was defined by positive urine toxicology screen and/or self-reported recent use. The primary outcome was death at 1 year or graft failure (defined as GFR<20 mL/min/1.73 m2 ). The secondary outcome was graft function at 1 year. Using logistic regression analyses, we compared these outcomes between MJ users and non-users. Marijuana use was not associated with worse primary outcomes by unadjusted (odds ratio 1.07, 95% CI 0.45-2.57, P=.87) or adjusted (odds ratio 0.79, 95% CI 0.28-2.28, P=.67) analysis. Ninety-two percent of grafts functioned at 1 year. Among these, the mean creatinine (1.52, 95% CI 1.39-1.69 vs 1.46, 95% CI 1.42-1.49; P=.38) and MDRD GFR (50.7, 95% CI 45.6-56.5 vs 49.5, 95% CI 48.3-50.7; P=.65) were similar between groups. Isolated recreational MJ use is not associated with poorer patient or kidney allograft outcomes at 1 year. Therefore, recreational MJ use should not necessarily be considered a contraindication to kidney transplantation.

Using a Bedside Video-assisted Test Tube Test to Assess Stoma Viability: A Report of 4 Cases.

Mucosal discoloration of an intestinal stoma may indicate self-limited venous congestion or necrosis necessitating operative revision. A common bedside technique to assess stoma viability is the "test tube test". A clear tube is inserted into the stoma and a hand-held light is used to assess the color of the stoma. A technique (video-assisted test tube test [VATTT]) developed by the authors utilizes a standard video bronchoscope inserted into a clear plastic blood collection tube to visually inspect and assess the mucosa. This technique was evaluated in 4 patients (age range 49-72 years, all critically ill) with a discolored stoma after emergency surgery. In each case, physical exam revealed ischemic mucosa at the surface either immediately after surgery or after worsening hypotension weeks later. Serial test tube test assessments were ambiguous when trying to assess deeper mucosa. The VATTT assessment showed viable pink mucosa beneath the surface and until the fascia was revealed in 3 patients. One (1) patient had mucosal ischemia down to the fascia, which prompted operative revision of the stoma. The new stoma was assessed with a VATTT and was viable for the entire length of the stoma. VATTT provided an enhanced, magnified, and clearer way to visually assess stoma viability in the postoperative period that can be performed at the bedside with no adverse events. It may prevent unnecessary relaparotomy or enable earlier diagnosis of deep ostomy necrosis. Validity and reliability studies are warranted.