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Author(s): Diamond, Shawn; Lundy, Jonathan B; Weber, Erin L; Lalezari, Shadi; Rafijah, Gregory; Leis, Amber; Gray, Benjamin L; Lin, Ines C; Gupta, Ranjan | Abstract: PurposeLimited data exist regarding volumetric trends and management of upper-extremity emergencies during periods of social restriction and duress, such as the coronavirus disease 2019 pandemic. We sought to study the effect of shelter-in-place orders on emergent operative upper-extremity surgery.MethodsAll patients undergoing emergent and time-sensitive operations to the finger(s), hand, wrist, and forearm were tracked over an equal number of days before and after shelter-in-place orders at 2 geographically distinct Level I trauma centers. Surgical volume and resources, patient demographics, and injury patterns were compared before and after official shelter-in-place orders.ResultsA total of 58 patients underwent time-sensitive or emergent operations. Mean patient age was 42 years; mean injury severity score was 9 and median American Society of Anesthesiologist score was 2. There was a 40% increase in volume after shelter-in-place orders, averaging 1.4 cases/d. Indications for surgery included high-energy closed fracture (60%), traumatic nerve injury (19%), severe soft tissue infection (15%), and revascularization of the arm, hand, or digit(s) (15%). High-risk behavior, defined as lawlessness, assault, and high-speed auto accidents, was associated with a significantly greater proportion of operations after shelter-in-place orders (40% vs 12.5%; P l .05). Each institution dedicated an average of 3 inpatient beds and one intensive care unit-capable bed to upper-extremity care daily. Resources used included an average of 115 minutes of daily operating room time and 8 operating room staff or personnel per case.ConclusionsHand and upper-extremity operative volume increased after shelter-in-place orders at 2 major Level I trauma centers across the country, demanding considerable hospital resources. The rise in volume was associated with an increase in high-risk behavior.Type of study/level of evidenceTherapeutic IV.

Rhinoplasty is a popular aesthetic and reconstructive surgical procedure. It is one of the top five surgical cosmetic procedures performed worldwide. To evaluate global trends in rhinoplasty research spanning 20 years between 1994 and 2013. The top 15 plastic surgery and otolaryngology journals containing rhinoplasty research were determined using impact factors (IF). A database of rhinoplasty articles from 1994 to 2013 was created to include the following classifications: IF, authors’ geographic location, study design, level of evidence (LOE), and pertinence to aesthetic or reconstructive rhinoplasty. Productivity index and productivity share were calculated for each region. A total of 1244 rhinoplasty articles were included in the database. The mean IF among the 15 journals increased from 0.75 in 1994 to 1.90 in 2013 (p

Regional lymph node status is an important prognostic factor for patients with breast cancer and melanoma. Sentinel lymph node dissection (SLND) is used to determine lymph node status in the surgical staging of the clinically negative axilla in patients with clinical stage I, stage IIA, stage IIB, or stage IIIA T3, N1, M0 breast cancer. SLND is also indicated in patients with melanoma with Breslow depth > 1 mm. For breast cancer and melanoma patients in need of surgical staging of regional lymph nodes, SLND has significantly lowered the rates of surgical complications and morbidity compared to the more invasive complete lymph node dissection.

Since its introduction 20 years ago for the treatment of chronic wounds, negative pressure wound therapy use has expanded to a variety of other wound types. Various mechanisms of action for its efficacy in wound healing have been postulated, but no unifying theory exists. Proposed mechanisms include induction of perfusion changes, microdeformation, macrodeformation, exudate control and decreasing the bacterial load in the wound. We surmise that these different mechanisms have varying levels of dominance in each wound type. Specifically, negative pressure wound therapy is beneficial to acute open wounds because it induces perfusion changes and formation of granulation tissue. Post-surgical incisional wounds are positively affected by perfusion changes and exudate control. In the context of chronic wounds, negative pressure wound therapy removes harmful and corrosive substances within the wounds to affect healing. When skin grafts and dermal substitutes are used to close a wound, negative pressure wound therapy is effective in promoting granulation tissue formation, controlling exudate and decreasing the bacterial load in the wound. In this review, we elucidate some of the mechanisms behind the positive wound healing effects of negative pressure wound therapy, providing possible explanations for these effects in different wound types.

Scarring following burn injury and its accompanying aesthetic and functional sequelae still pose major challenges. Hypertrophic scarring (HTS) can greatly impact patients' quality of life related to appearance, pain, pruritus and even loss of function of the injured body region. The identification of molecular events occurring in the evolution of the burn scar has increased our knowledge; however, this information has not yet translated into effective treatment modalities. Although many of the pathophysiologic pathways that bring about exaggerated scarring have been identified, certain nuances in burn scar formation are starting to be recognized. These include the effects of neurogenic inflammation, mechanotransduction, and the unique interactions of burn wound fluid with fat tissue in the deeper dermal layers, all of which may influence scarring outcome. Tension on the healing scar, pruritus, and pain all induce signaling pathways that ultimately result in increased collagen formation and myofibroblast phenotypic changes. Exposure of the fat domes in the deep dermis is associated with increased HTS, possibly on the basis of altered interaction of adipose-derived stem cells and the deep burn exudate. These pathophysiologic patterns related to stem cell-cytokine interactions, mechanotransduction, and neurogenic inflammation can provide new avenues of exploration for possible therapeutic interventions.

BACKGROUND Poly-trauma patients often sustain complex head/neck injuries requiring prolonged hospitalizations and multiple operations. Few studies have evaluated the associated injury patterns and risk factors for poor clinical outcomes. METHODS Consecutive poly-trauma patients with operative maxillofacial fractures treated at a level 1 trauma medical center between 1995 and 2013 were evaluated. Concomitant head/neck injuries to identify potential injury patterns were numerated. Lastly, a multivariate analysis was performed to determine independent risk factors for complications during the acute hospitalization period. RESULTS Totally, 232 poly-trauma patients presented with operative maxillofacial fractures, while 38.8% of patients had a secondary maxillofacial fracture, 16.4% had intracranial hemorrhage, 23.7% had skull fractures, and 12.1% had spinal fractures. The rate of complication during admission was 28.3%. Multivariate analysis revealed advanced patient age and increased number of operations to predict the rate of complication. Patients requiring more than one operation had a 1.8-fold increase in complication rate (p

The development of autologous fat grafting to augment or reconstruct tissue defects has become an increasingly popular modality among plastic surgeons. Despite its popularity, a standardized fat grafting protocol has yet to be developed. Great variations exist with regard to almost all the technical features, yielding a reported fat graft survivability that ranges from 40% to 80%. Recent bench approaches have been proposed to improve the long-term viability of fat grafts: although promising results have been shown, empirical evidence has yet to prove the superiority of one particular method. Nevertheless, currently available literature still provides some evidence for optimal results in differing clinical scenarios, in the wait of validating and ultimate studies.The issues of enriched fat grafting techniques and variations in harvesting and delivery in the background of US regulatory constraints demand alterations and variations in techniques. These only complicate the process of validation of any single technique. However, recent studies have brought us closer to making informed decisions on technical choices in lipotransfer. These are elaborated on in this review.

Peripheral nerve injury requiring nerve gap reconstruction remains a major problem. In the quest to find an alternative to autogenous nerve graft procedures, attempts have been made to differentiate mesenchymal stem cells into neuronal lineages in vitro and utilize these cellular constructs for nerve regeneration. Unfortunately, this has produced mixed results, with no definitive procedure matching or surpassing traditional nerve grafting procedures. This review presents a different approach to nerve regeneration. The literature was reviewed to evaluate current methods of using adipose-derived stem cells (ADSCs) for peripheral nerve regeneration in in vivo models of animal peripheral nerve injury. The authors present cited evidence for directing nerve regeneration through paracrine effects of ADSCs rather than through in vitro nerve regeneration. The paracrine effects rely mainly, but not solely, on the elaboration of nerve growth factors and neurotrophic mediators that influence surrounding host cells to orchestrate in vivo nerve regeneration. Although this paradigm has been indirectly referred to in a host of publications, few major efforts for this type of neuromodulatory nerve regeneration have been forthcoming. The ADSCs are initially "primed" in vitro using specialized controlled medium (not for neuronal differentiation but for sustainability) and then incorporated into a hydrogel base matrix designed for this purpose. This core matrix is then introduced into a natural collagen-based nerve conduit. The prototype design concepts, evidence for paracrine influences, and regulatory hurdles that are avoided using this approach are discussed.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Current standard treatment for GBM includes cyto-reductive surgery followed by radiation (RT) and chemotherapy with temozolomide (TMZ).1 CpG methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter has emerged as the most robust predictor of TMZ treatment outcome for newly diagnosed GBM with prognostic implications.2–6 MGMT encodes for a DNA repair enzyme that provides resistance to alkylating chemotherapies, such as TMZ. Because MGMT transcription can be silenced by promoter methylation in tumor cells,7 it is widely assumed that MGMT promoter methylation in patient tumors causes decreased MGMT protein expression, thereby abrogating DNA repair activity necessary for TMZ resistance. However, the relationship between MGMT protein expression and promoter methylation in patient tumor samples has remained controversial.8–13 Furthermore, studies examining MGMT immunohistochemistry (IHC) and survival have not shown consistent correlation with outcome.4,5,9,10,13–19 The lack of definitive evidence has been attributed primarily to difficulty with MGMT IHC scoring; however, other possible reasons include small cohort size,4,5,10,13,18 nonuniform treatments,20,21 and various IHC scoring categories and cutoffs.4,9,10,21 Because of the importance of MGMT status for predicting treatment outcome, stratifying clinical trial patients, and guiding treatment decisions, the aims of the current single-arm retrospective study were to evaluate MGMT protein expression as a prognostic marker for patients with newly diagnosed GBM who were receiving standard of care RT/TMZ, to investigate the relationship between MGMT promoter methylation and protein expression, and to optimize the assessment of MGMT status. On the basis of a large cohort of 418 patients with newly diagnosed primary GBM, 410 of whom received chemoradiation with TMZ, we show that, although MGMT IHC is prognostic of patient survival, the combination of IHC and methylation testing provides optimized assessment of MGMT status.

Mutations in isocitrate dehydrogenase 1 (IDH1) and associated CpG island hypermethylation represent early events in the development of low-grade gliomas and secondary glioblastomas. To identify candidate tumor suppressor genes whose promoter methylation may contribute to gliomagenesis, we compared methylation profiles of IDH1 mutant (MUT) and IDH1 wild-type (WT) tumors using massively parallel reduced representation bisulfite sequencing.Reduced representation bisulfite sequencing was performed on ten pathologically matched WT and MUT glioma samples and compared with data from a methylation-sensitive restriction enzyme technique and data from The Cancer Genome Atlas (TCGA). Methylation in the gene retinol-binding protein 1 (RBP1) was identified in IDH1 mutant tumors and further analyzed with primer-based bisulfite sequencing. Correlation between IDH1/IDH2 mutation status and RBP1 methylation was evaluated with Spearman correlation. Survival data were collected retrospectively and analyzed with Kaplan-Meier and Cox proportional hazards analysis. All statistical tests were two-sided.Methylome analysis identified coordinated CpG island hypermethylation in IDH1 MUT gliomas, consistent with previous reports. RBP1, important in retinoic acid metabolism, was found to be hypermethylated in 76 of 79 IDH1 MUT, 3 of 3 IDH2 MUT, and 0 of 116 IDH1/IDH2 WT tumors. IDH1/IDH2 mutation was highly correlated with RBP1 hypermethylation (n = 198; Spearman R = 0.94, 95% confidence interval = 0.92 to 0.95, P.001). The Cancer Genome Atlas showed IDH1 MUT tumors (n = 23) to be RBP1-hypermethylated with decreased RBP1 expression compared with WT tumors (n = 124). Among patients with primary glioblastoma, patients with RBP1-unmethylated tumors (n = 102) had decreased median overall survival compared with patients with RBP1-methylated tumors (n = 22) (20.3 months vs 36.8 months, respectively; hazard ratio of death = 2.48, 95% confidence interval = 1.30 to 4.75, P = .006).RBP1 promoter hypermethylation is found in nearly all IDH1 and IDH2 mutant gliomas and is associated with improved patient survival. Because RBP1 is involved in retinoic acid synthesis, our results suggest that dysregulation of retinoic acid metabolism may contribute to glioma formation along the IDH1/IDH2-mutant pathway.

Diffusion imaging has shown promise as a predictive and prognostic biomarker in glioma. We assessed the ability of graded functional diffusion maps (fDMs) and apparent diffusion coefficient (ADC) characteristics to predict overall survival (OS) in recurrent glioblastoma multiforme (GBM) patients treated with bevacizumab. Seventy-seven patients with recurrent GBMs were retrospectively examined. MRI scans were obtained before and approximately 6 weeks after treatment with bevacizumab. Graded fDMs were created by registering datasets to each patient’s pretreatment scan and then performing voxel-wise subtraction between post- and pretreatment ADC maps. Voxels were categorized according to the degree of change in ADC within pretreatment fluid-attenuated inversion recovery (FLAIR) and contrast-enhancing regions of interest (ROIs). We found that the volume of tissue showing decreased ADC within both FLAIR and contrast-enhancing regions stratified OS (log-rank, P < .05). fDMs applied to contrast-enhancing ROIs more accurately predicted OS compared with fDMs applied to FLAIR ROIs. Graded fDMs (showing voxels with decreased ADC between 0.25 and 0.4 mm 2 /ms) were more predictive of OS than traditional (single threshold) fDMs, and the predictive ability of graded fDMs could be enhanced even further by adding the ADC characteristics from the fDM-classified voxels to the analysis (log-rank, P < .001). These results demonstrate that spatially resolved diffusion-based tumor metrics are a powerful imaging biomarker of survival in patients with recurrent GBM treated with bevacizumab.

The purpose of the current study was to quantify the reduction in T2 signal abnormality accompanying administration of the anti-angiogenic drug bevacizumab in recurrent glioblastoma (GBM) patients using a voxel-wise differential quantitative T2 (DQT2) mapping technique. Twenty-six patients with recurrent GBM treated with bevacizumab were scanned before and 4-6 weeks after treatment on a 1.5T clinical MR scanner. Quantitative T2 maps were created from proton density and T2-weighted images acquired using a standard multi-echo fast-spin echo sequence. T2 maps after treatment were co-registered with T2 maps prior to treatment in the same patient, and then voxel-wise subtraction was performed to create DQT2 maps for each patient. Results suggest DQT2 maps allow visualization and quantification of voxel-wise T2 changes resulting from anti-VEGF therapy. Results demonstrated a significant decrease in T2 within pre-treatment T2 abnormal regions (mean reduction = 49.4 ms at 1.5T) following anti-VEGF treatment (Wilcoxon signed rank test, P < 0.0001). An elevated residual, post-treatment, median T2 was predictive of both progression-free (Log-rank, P = 0.0074) and overall survival (Log-rank, P = 0.0393). © 2011 Springer Science+Business Media, LLC.

We would like to thank D’Alessandris and colleagues for their interest in our study. We agree that following 2 negative phase III trials of upfront bevacizumab, both with significant crossover in the placebo arms, the optimal timing of bevacizumab administration is unclear. 1,2 Our study showed that the deferred use of bevacizumab to later recurrences was not associated with diminished efficacy. Additionally, we suggested that deferring bevacizumab to later recurrences may be beneficial for some, but not all patients. D’Alessandris and colleagues observed that the time between diagnosis and initiation of bevacizumab was progressively longer in each recurrence cohort, and the overall survival (OS) from bevacizumab administration was statistically similar, which would imply that delayed bevacizumab resulted in an increase in OS. While it is true that the OS from time of diagnosis was progressively longer in each of the recurrence cohorts (first, second, and 3+ recurrences), we intentionally avoided making the conclusion that deferred use of bevacizumab led to an improved OS. Since it is likely that patients receiving bevacizumab at later recurrences were subject to selection bias enriching for those with greater OS, we strongly believe that the limitations of a retrospective study prohibit this conclusion, and suggest that a randomized prospective study is needed to answer this question. In a similar study by Hamza and colleagues, deferring bevacizumab to later recurrences did not change progression-free survival and showed a longer OS from date of surgery, but again this must be interpreted with caution. 3 In both studies, the clinician’s judgment to defer bevacizumab to later recurrences presumably selected for less aggressive disease, such as tumors with less edema, mass effect, enhancement, or steroid requirement. Moreover, this highly selected group of patients who deferred bevacizumab to later progressions may be confounded by markers of improved survival such as isocitrate dehydrogenase 1 (IDH1) mutation and methylation of O 6 -DNA methylguanine-methyltransferase (MGMT). Our study did not find a difference in MGMT methylation among the cohorts, but the percentage of IDH1 mutations increased with each recurrence cohort, suggesting a selection bias. Hamza et al also point out that data for prognostic markers were not included in their study and that the question of deferring bevacizumab to later recurrences must be examined prospectively. From our study, we conclude that delaying bevacizumab in recurrent glioblastoma patients is not associated with diminishing effectiveness. Furthermore, we identified patients who were unable to continue therapy at early progressions, and suggest this population might benefit from early bevacizumab. More work is needed to identify both the optimal timing and patient subpopulations to maximize the benefits of bevacizumab therapy.

Purpose: To compare "standardization," "Gaussian normalization," and "Z-score normalization" intensity transformation techniques in dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) estimates of cerebral blood volume (CBV) in human gliomas. DSC-MRI is a well-established biomarker for CBV in brain tumors; however, DSC-MRI estimates of CBV are semiquantitative. The use of image intensity transformation algorithms provides a mechanism for obtaining quantitatively similar CBV maps with the same intensity scaling. Materials and Methods: The coefficient of variance (CV) in normal-appearing white matter and relative contrast between tumor regions and normal tissue was compared between the three CBV transformations across five different MR scanners in 96 patients with gliomas. Results: The results suggest all normalization techniques improved variability and relative tumor contrast of CBV measurements compared with nonnormalized CBV maps. The results suggest Gaussian normalization of CBV maps provided slightly lower CV in normal white matter and provided slightly higher tumor contrast for glioblastomas (WHO grade IV) compared with other techniques. Conclusion: The results suggest Gaussian normalization of leakage-corrected CBV maps may be the best choice for image intensity correction for use in large-scale, multicenter clinical trials where MR scanners and protocols vary widely due to ease of implementation, lowest variability, and highest tumor to normal tissue contrast. Copyright © 2012 Wiley Periodicals, Inc.

Functional diffusion mapping (fDM) has shown promise as a sensitive imaging biomarker for predicting survival in initial studies consisting of a small number of patients, mixed tumor grades, and before routine use of anti-angiogenic therapy. The current study tested whether fDM performed before and after radiochemotherapy could predict progression-free and overall survival in 143 patients with newly diagnosed glioblastoma from 2007 through 2010, many treated with anti-angiogenic therapy after recurrence. Diffusion and conventional MRI scans were obtained before and 4 weeks after completion of radiotherapy and concurrent temozolomide treatment. FDM was created by coregistering pre-and posttreatment apparent diffusion coefficient (ADC) maps and then performing voxel-wise subtraction. FDMs were categorized according to the degree of change in ADC in pre-and posttreatment fluid-attenuated inversion recovery (FLAIR) and contrast-enhancing regions. The volume fraction of fDM-classified increasing ADC(), decreasing ADC(-), and change in ADC(/-) were tested to determine whether they were predictive of survival. Both Bonferroni-corrected univariate log-rank analysis and Cox proportional hazards modeling demonstrated that patients with decreasing ADC in a large volume fraction of pretreatment FLAIR or contrast-enhancing regions were statistically more likely to progress earlier and expire sooner than in patients with a lower volume fraction. The current study supports the hypothesis that fDM is a sensitive imaging biomarker for predicting survival in glioblastoma. © 2012 The Author(s).

Promoter methylation of O6-methylguanine DNA methyltransferase (MGMT) is associated with a favorable prognosis in glioblastoma multiforme (GBM) and has been hypothesized to occur early in tumor transformation of glial cells. Thus, a possible link exists between the site of malignant transformation and MGMT promoter methylation status. Using the Analysis of Differential Involvement (ADIFFI) statistical mapping technique in a total of 358 patients with GBM, we demonstrate that human de novo GBMs occur in a high frequency contiguous with the posterior subventricular zone (SVZ); MGMT promoter methylated GBMs are lateralized to the left hemisphere, while MGMT unmethylated GBMs are lateralized to the right hemisphere; and tumors near the left temporal lobe have a significantly longer overall survival compared with tumors occurring elsewhere, independent of treatment or MGMT methylation status. © 2011 Elsevier Inc.

Background: Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that can develop within months to years after transplantation, and imaging often reveals multiple lesions with homogeneous or ring enhancement. The clinical and imaging presentation of PT-PCNSL can often be nonspecific and present a diagnostic challenge. Case Description: A 56-year-old woman presented to a tertiary university emergency room with altered mental status 15 months after undergoing renal transplantation. On brain MRI, she was found to have three rim-enhancing mass lesions, and biopsy revealed PT-PCNSL. Conclusion: There has been a steady increase in the number of patients living following organ transplantation in the United States and an increasing likelihood that PT-PCNSL will increasingly be encountered in neurosurgical practice. We present here a case of PT-PCNSL and a brief review of the relevant clinical characteristics, treatment options, and prognosis of PT-PCNSL.