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Background: A major cause of mortality in patients receiving hematopoietic stem cell transplantation (HCT) is acute graft-versus-host disease (GVHD), a multiorgan disorder that includes the skin, liver and gastrointestinal tract. We have previously identified elafin, a protease inhibitor overexpressed in inflamed epidermis, as a diagnostic biomarker of GVHD in the skin, the most commonly involved GVHD organ. However, our initial study was limited to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT patients is GI GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have since been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker of acute GVHD in the general population of previously unstudied acute GVHD patients, and to compare it to ST2 and REG3α. Study Design: 526 patients who received systemic corticosteroid treatment for skin GVHD were analyzed from the Mount Sinai Acute GVHD International Consortium (MAGIC), which includes patients from 25 HCT centers. We used ELISA to measure serum concentrations of elafin, ST2 and REG3α. Patients were divided randomly into equal training and validation sets; and we developed a competing risk regression model for 6-month NRM using elafin concentration in the training set. We developed additional models for 6-month NRM using concentrations of ST2 and REG3α, or the combination of all three biomarkers as predictors. We then constructed ROC curves to evaluate the predictive accuracy of each model and to analyze the ability of each model to stratify patients into high- and low-risk groups. We analyzed the cumulative incidence of 6-month NRM and overall survival in each model and compared the accuracy of each model in the validation set. Results: The area under the receiver operating curve (AUROC) for elafin alone was 0.55 whereas it was 0.75 and statistically superior (P = 0.02) for the combination of ST2 and REG3α. The combination of 3 biomarkers produced an AUROC of 0.76 that was not significantly better than the two biomarker model (P = 0.10). Elafin concentrations, either alone or in combination with ST2 and REG3α, did not produce higher hazard ratios of NRM (data not shown). Patients in the low-risk elafin group paradoxically demonstrated a higher incidence of 6-month NRM, although this difference was not statistically significant (17% vs. 11%, P=0.19), and both overall survival at 6 months (68% vs. 68%, P>0.99) and four-week response (78% vs. 78%, P=0.98) were similar in the low- and high-risk elafin groups (Figure 1). As demonstrated in previous data sets, the combination of ST2 and REG3α divided patients into two groups with a nearly five-fold difference in NRM (6.7% vs. 31%, P Conclusion: We demonstrated that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD in a multicenter population of patients treated systemically for acute GVHD do not predict 6-month NRM, overall survival, or treatment response. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD. Figure 1. Cumulative incidence of nonrelapse mortality and overall survival in high and low risk groups Six-month cumulative incidences of nonrelapse mortality (NRM) in high (solid line) and low (dotted line) risk groups defined by optimized biomarker thresholds (upper panels) and six-month overall survival estimated using the Kaplan-Meier method (lower panels). (A) Cumulative incidence of NRM (14%) and overall survival (75%) in the total validation set (N=263). (B) Cumulative incidence of NRM in the low (N=150) and high (N=113) elafin group (17% vs. 11%, P=0.19). Overall survival in the low and high elafin group (68% vs. 68%, P > 0.99). (C) Cumulative incidence of NRM in the low (N=175) and high (N=88) ST2 + REG3a group (6.7 vs. 31%, P < 0.001). Overall survival in the low and high ST2 + REG3a group (77% vs. 51%, P < 0.001). (D) Cumulative incidence of NRM in the low (N=180) and high (N=83) elafin + ST2 + REG3a group (7.0 vs. 30%, P < 0.001). Overall survival in the low and high elafin + ST2 + REG3a group (79% vs. 64%, P < 0.001). Figure 1 Figure 1. Disclosures Ozbek: Viracor: Patents & Royalties: GVHD biomarker patent with royalties from Viracor. DeFilipp: Omeros, Corp.: Consultancy; Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Syndax Pharmaceuticals, Inc: Consultancy. Grupp: Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding; Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tmunity Therapeutics: Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Kitko: Co-investigator on two NIH grants as part of the cGVHD consortium: Research Funding; Vanderbilt University Medical Center: Current Employment; PER: Other: PER - CME educational talks about GVHD; Horizon: Membership on an entity's Board of Directors or advisory committees. Qayed: Novartis: Honoraria; Mesoblast: Honoraria; Medexus: Honoraria. Reshef: ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Bayer: Consultancy; Gilead and Novartis: Honoraria; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy. Levine: Incyte: Consultancy, Research Funding; Viracor: Patents & Royalties: GVHD biomarker patent with royalties from Viracor; Mesoblast: Consultancy, Research Funding; Equillium Bio: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Talaris Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; Symbio: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Kamada: Research Funding. Ferrara: Eurofins Viracor: Consultancy, Other: Royalties. Chen: Incyte: Consultancy; Gamida: Consultancy.

BACKGROUND: There is growing evidence supporting inherited predisposition to multiple myeloma (MM). Epidemiologic studies have shown that 1st-degree relatives of MM patients (pts) have a 2-4 fold increase in risk of developing MGUS or MM. Genome-wide association studies (GWAS) have identified common SNPs as well as rare high-penetrance variants that collectively explain ~16% of the estimated heritability of multiple myeloma (PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer patients (~8%, PMID 29625052), but prevalence in MM is not known. The aim of our study is to investigate the occurrence of PGV in newly-diagnosed MM (NDMM), and to describe clinical characteristics & outcomes of carriers. METHODS: We analyzed MMRF CoMMpass data (version IA16) and identified 895 NDMM pts for whom whole-exome sequencing of germline DNA was available. We used the clinical annotation pipeline from Sema4, a CLIA/CAP certified genetic testing laboratory, to identify pts with PGV according to ACMG variant classification guidelines. We compared clinical characteristics & disease phenotypes of PGV carriers vs non-carriers. We used Chi-Square and Fisher's Exact tests to assess statistical significance, which we defined as a two-sided p value < 0.05. Logistic regression models were used for multivariate analyses. Kaplan-Meier method and Cox proportional-hazards models were used for uni- and multivariate survival analysis, respectively. Bonferroni method was used to account for multiple testing. RESULTS: We identified 83 PGV in 31 distinct HCG in 79 (8.8%) of 895 NDMM pts (83% European ancestry) [Figure 1A]. Most PGV involved DNA damage repair (DDR) genes (78%), and homologous recombination (HR) genes were the most commonly mutated (34%). PGV in CHEK2 were the most common (n=10, 1.1% of all MM pts). 2 pts carried PGV in TP53 and reported extensive family history of Li-Fraumeni-associated cancers (breast, sarcoma, gastric & melanoma). 6 pts had germline mismatch repair (MMR) gene defects (1:149, considerably higher than the estimated prevalence of Lynch syndrome in Western populations). 4 pts carried PGV in BRCA2 (previously identified in a family study as a potential MM predisposition gene, PMID 11904319). MM pts with a family history of hematologic malignancy (leukemia, lymphoma or MM) in a 1st or 2nd-degree relative were significantly more likely to carry PGV (22 vs 7.6%, OR=3.3, p CONCLUSIONS: PGV in HCG were common (8.8%) in this large cohort of NDMM pts of predominantly European ancestry, especially in those with a family history of hematologic malignancy (1:4, with high prevalence of CHEK2 variants & particularly protein-truncating founder variant c.1100delC), and in those diagnosed before age 40 (1:4). Routine screening in high-prevalence subgroups might be warranted, as carriers may benefit from counseling and enrollment in early cancer detection programs. We observed a clinically and statistically significant PFS1 advantage in carriers of PGV in DDR genes, possibly due to increased sensitivity to MM therapies, a well-described phenomenon in other cancer types (PMID 33158305). Prospective validation of these findings is needed to better understand prognostic & therapeutic implications of PGV in MM. Figure 1 Figure 1. Disclosures Chari: Karyopharm: Consultancy; Takeda Pharmaceutical Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Richter: Sanofi: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

Background GWAS have identified common SNPs & rare high-penetrance variants that explain ~16% of the estimated heritability of multiple myeloma (MM)(PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer pts (~8%), but prevalence in MM is not known. The aim of our study is to investigate the occurrence of PGV in newly-diagnosed MM (NDMM) and describe clinical characteristics & outcomes of carriers. Methods We analyzed MMRF CoMMpass data & identified 895 NDMM pts with whole-exome sequencing of germline DNA. We used the clinical annotation pipeline from Sema4, a CLIA/CAP certified genetic testing laboratory, to identify pts with PGV according to ACMG variant classification guidelines. We compared clinical characteristics & disease phenotypes of PGV carriers vs non-carriers. We used Chi-Square and Fisher’s Exact tests to assess statistical significance. Results We identified 83 PGV in 31 distinct HCG in 79 (8.8%) of 895 NDMM pts (83% European ancestry). Most PGV involved DNA damage repair (DDR) genes (78%), & homologous recombination (HR) genes were the most commonly mutated (34%). PGV in CHEK2 were most common (n=10,1.1% of all MM pts). 2 pts carried PGV in TP53, & 6 pts had mismatch repair (MMR) gene defects (1:149). MM pts with family history (FH) of hematologic malignancy (HM) in a 1st or 2nd-degree relative were more likely to carry PGV (22 vs 7.6%,OR=3.3,p Conclusions PGV in HCG were common (8.8%) in this large cohort of NDMM pts of predominantly European ancestry, especially in those with FH of HM (1:4, with high prevalence of CHEK2 variants), and in those

Background: Epidemiologic studies have shown familial aggregations of multiple myeloma (MM) and other hematologic malignancies, but little is known about heritable genetic susceptibilities in these patients. The purpose of this study is to investigate the prevalence of known germline cancer-predisposing mutations (CPM) in patients with multiple myeloma (MM). Methods: We analyzed a set of 895 newly diagnosed MM patients from the Multiple Myeloma Research Foundation (MMRF) CoMMpass registry for whom whole-exome sequencing of germline DNA data was available. We used the clinical annotation pipeline from Sema4, a CLIA- and CAP-certified genetic testing laboratory, in a research context, to identify patients with pathogenic or likely pathogenic CPM according to ACMG variant classification guidelines, and compared their characteristics against those without CPM. Statistical significance was assessed using the Chi-Square and Fisher's Exact tests and defined as a two-sided p value Results: We identified 83 germline CPM in 31 distinct genes in 79 (8.8%) of 895 patients. Homologous recombination (HR) pathway gene mutations were the most common (n = 38, 46%), with CHEK2 being the most frequently mutated gene (n = 10, 12%). Notably, the number of mismatch repair (MMR) gene defects was considerably higher (n = 6, 1:149) than the estimated prevalence in the general population. CPM carriers were significantly more likely to be diagnosed with MM before age 40 (6.3% vs 1.8%, p = 0.025) and to have a family history (FH) of MM or leukemia (16.4% vs 6.3%, p = 0.01) than those without a CPM. Likelihood of having a FH of any malignancy was also significantly higher in the CPM group (70.9% vs 54.5%, p = 0.028). Interestingly, common CHEK2 founder mutations were observed at a much higher rate in patients with a FH of MM or leukemia (8.7% vs 0.68%, p = 0.0013). Conclusions: Our results suggest that a significant proportion of patients with MM carry germline cancer-predisposing mutations, especially those diagnosed at a very young age ( Citation Format: Santiago Thibaud, Aaron Etra, Ryan Subaran, Zachry Soens, Scott Newman, Rong Chen, Ajai Chari, Hearn J. Cho, Sundar Jagannath, Deepu Madduri, David T. Melnekoff, Shambavi Richard, Joshua Richter, Larysa Sanchez, Alessandro Lagana, Samir Parekh, Kenan Onel. Heritable cancer mutations in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 868.

Background Several studies in solid organ transplantation have shown a correlation between donor and recipient sex mismatch and risk of graft loss. In this study, we aimed to analyze the impact of donor and recipient sex matching on patient and pancreas graft survival in a large single‐center cohort. Methods We retrospectively analyzed all first simultaneous pancreas‐kidney transplants performed between 1979 and 2017 at the Medical University of Innsbruck. Results Of 452 patients, 54.6% (247) received a sex‐matched transplant. Patient survival (P = .86), death‐censored pancreas graft survival (dcPGS, P = .26), and death‐censored kidney graft survival (dcKGS, P = .24) were similar between the sex‐matched and sex‐mismatched groups. Patient survival and dcPGS at 1, 5, and 15 years were 95.9%, 90.0%, and 62.1% and 86.1%, 77.1%, and 56.7% in the sex‐matched group and 93.6%, 86.2%, and 62.4% and 83.1%, 73.3%, and 54.3% in the sex‐mismatched group. Sex matching led to a lower odds of severe postoperative complications (41.2% vs 49.0%; OR 0.57, 95%CI 0.33‐0.97; P = .038); however, no increased odds of other adverse postoperative outcomes was detected. Conclusion Our study demonstrates that sex matching reduced the odds of postoperative complications but did not impact other early and late outcome parameters in our cohort.

Supplemental Digital Content is available in the text., Background. The Banff Criteria have been accepted as a system for grading histological rejection in graft skin in human vascularized composite allotransplantation (VCA). Preclinical swine hindlimb transplantation models have an important role in translational studies in VCA. However, unified grading criteria for rejection in swine skin have not yet been established. Methods. Two hundred fourteen swine skin biopsy specimens were reviewed, including 88 native skin biopsies and 126 specimens from the skin component of heterotopic swine hindlimb transplants. Thorough review was performed in a blinded fashion by an expert veterinary pathologist with attention paid to the applicability of the Banff criteria as well as specific histologic characteristics and trends. Clinical and histopathologic rejection scores were then directly compared. Results. Two hundred fourteen specimens reviewed showed significant similarities between swine and human skin, as previously published. Notable swine-specific characteristics, including paucicellular infiltration with rare epidermal cell infiltration or necrosis, were accounted for in a proposed grading system that parallels the Banff Criteria. Conclusions. This comprehensive grading system, based on the Banff Classification for skin rejection in VCA, provides a standardized system for more accurate comparison of rejection in preclinical swine VCA models.

Background Upper limb loss is a devastating condition with dramatic physical, psychological, financial, and social consequences. Improvements in the fields of prosthetics and vascularized composite allotransplantation have opened exciting new frontiers for treatment and rehabilitation following upper limb loss. Each modality offers a unique set of advantages and limitations with regard to the restoration of hand function following amputation. Methods Presented in this article is a discussion outlining the complex considerations and decisions encountered when determining patient appropriateness for either prosthetic rehabilitation or vascularized composite allotransplantation following upper limb loss. In this review, the authors examine how psychosocial factors, nature of injury, rehabilitation course, functional outcomes, and risks and benefits may affect overall patient selection for either rehabilitative approach. Results This review summarizes the current state of the literature. Advancements in both prosthetic and biological strategies demonstrate promise with regard to facilitating rehabilitation following upper limb loss. However, there remains a dearth of research directly comparing outcomes in prosthetic rehabilitation to that following upper extremity transplantation. Conclusions Few studies have performed a direct comparison between patients undergoing vascularized composite allotransplantation and those undergoing prosthetic rehabilitation. Upper extremity transplantation and prosthetic reconstruction should not be viewed as competing options, but rather as two treatment modalities with different risk-to-benefit profiles and indications.

Vascularized composite allotransplantation (VCA) is a relatively new field in reconstructive medicine. Likely a result of the unique tissue composition of these allografts-including skin and often a bone marrow component-the immunology and rejection patterns do not always mimic those of the well-studied solid organ transplantations. While the number and type of VCAs performed is rapidly expanding, there is still much to be discovered and understood in the field. With more patients, new findings and patterns emerge and add to our understanding of VCA. Here, we present a case report of an upper extremity transplant recipient with trauma-induced rejection.

The present review discusses current developments in tolerance induction for solid organ transplantation with a particular emphasis on chimerism-based approaches. It explains the basic mechanisms of chimerism-based tolerance and provides an update on ongoing clinical tolerance trials. The concept of "delayed tolerance" is presented, and ongoing preclinical studies in the nonhuman primate setting-including current limitations and hurdles regarding this approach-are illustrated. In addition, a brief overview and update on cell-based tolerogenic clinical trials is provided. In a critical approach, advantages, limitations, and potential implications for the future of these different regimens are discussed.

There are no validated biomarkers that measure a patient's response to therapy for acute graft-versus-host disease (GVHD), the leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP estimates GVHD-mediated damage to crypts throughout the lower GI tract at single time points (Hartwell et al., JCI Insight, 2017; Major- Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker and would compare favorably to clinical response, the gold standard which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We computed MAPs and clinical responses for each patient. MAPs of patients who experienced 6 month NRM increased significantly compared to MAPs of patients who survived (p=0.0004). In patients whose initial MAPs were low (Ann Arbor 1, MAP 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). We found that patients whose MAPs rose above the previously determined high-risk threshold MAP of 0.290 had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold had a large increase in mortality (Fig 2). When measured at day 28, MAPs predicted NRM more accurately than clinical responses, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first laboratory test validated as a response biomarker for acute GVHD treatment and more accurately predicts survival than clinical response after 28 days of treatment. The MAP may serve as a novel endpoint in future trials of GVHD treatment.

PURPOSE OF REVIEW: In this review, we discuss novel strategies that allow for extended preservation of vascularized composite allografts and their potential future clinical implications for the field of vascularized composite allotransplantation (VCA). RECENT FINDINGS: The current gold standard in tissue preservation – static cold preservation on ice – is insufficient to preserve VCA grafts for more than a few hours. Advancements in the field of VCA regarding matching and allocation, desensitization, and potential tolerance induction are all within reasonable reach to achieve; these are, however, constrained by limited preservation time of VCA grafts. While machine perfusion holds many advantages over static cold preservation, it does not significantly elongate the preservation time. More extreme preservation techniques, such as cryopreservation approaches, are, however, specifically difficult to apply to composite tissues as the susceptibility to ischemia and cryoprotectant agents varies greatly by tissue type. SUMMARY: In the current scope of extended preservation protocols, high subzero approaches of VCA grafts will be particularly critical enabling technologies for the implementation of tolerance protocols clinically. Ultimately, advances in both preservation techniques and tolerance induction have the potential to transform the field of VCA and eventually lead to broad application of reconstructive transplantation.

Background We describe the feasibility and long-term outcomes of using femoral vein (FV) for arteriovenous fistula (AVF) and lower extremity bypass (LEB) creation. Methods All patients undergoing AVF or LEB using autogenous FV by a single surgeon (April 2006 to September 2013) were reviewed. Perioperative (30-d) complications and long-term outcomes are described. Results Forty-four patients underwent vascular reconstruction with FV (AVF = 27 and LEB = 17). Perioperative morbidity was 43.2%, including harvest site infection and or seroma in 15.9%. No patients suffered from compartment syndrome or venous thromboembolic event. At median follow-up of 50.0 mon, overall patency was 70.4% for AVF (primary = 37.0% and secondary = 70.3%) and 76.5% for LEB (primary = 70.6% and secondary = 76.5%). Long-term lower extremity swelling occurred in 18.2% of patients. Conclusions Perioperative morbidity following FV harvest is high, but long-term patency rates are excellent. FV harvest is feasible and should be considered as a valid conduit in patients without useable great saphenous vein or other more commonly used sources of autogenous vein.

Background One in 16 surgical patients prescribed opioids becomes a long-term user. Overprescribing opioids after surgery is common, and the lack of multidisciplinary procedure-specific guidelines contributes to the wide variation in opioid prescribing practices. We hypothesized that a single-institution, multidisciplinary expert panel can establish consensus on ideal opioid prescribing for select common surgical procedures. Study Design We used a 3-step modified Delphi method involving a multidisciplinary expert panel of 6 relevant stakeholder groups (surgeons, pain specialists, outpatient surgical nurse practitioners, surgical residents, patients, and pharmacists) to develop consensus ranges for outpatient opioid prescribing at the time of discharge after 20 common procedures in 8 surgical specialties. Prescribing guidelines were developed for opioid-naive adult patients without chronic pain undergoing uncomplicated procedures. The number of opioid tablets was defined using oxycodone 5 mg oral equivalents. Results For all 20 surgical procedures reviewed, the minimum number of opioid tablets recommended by the panel was 0. Ibuprofen was recommended for all patients unless medically contraindicated. The maximum number of opioid tablets varied by procedure (median 12.5 tablets), with panel recommendations of 0 opioid tablets for 3 of 20 (15%) procedures, 1 to 15 opioid tablets for 11 of 20 (55%) procedures, and 16 to 20 tablets for 6 of 20 (30%) procedures. Overall, patients who had the procedures voted for lower opioid amounts than surgeons who performed them. Conclusions Procedure-specific prescribing recommendations may help provide guidance to clinicians who are currently overprescribing opioids after surgery. Multidisciplinary, patient-centered consensus guidelines for more procedures are feasible and may serve as a tool in combating the opioid crisis.

Acute GVHD biomarkers predict long-term outcomes after GVHD diagnosis. Our group has validated the MAGIC algorithm which uses the concentrations of 2 GVHD biomarkers, ST2+REG3a, to predict lethal GVHD (defined as death from GVHD without relapse) [Hartwell 2017]. Other published biomarker combinations that predict GVHD outcomes include ST2+ REG3a+TNFR1 [Levine 2015], ST2+TIM3 [Abu Zaid 2017], ST2+TNFR1 [McDonald 2015], TIM3+TNFR1+IL6 [McDonald 2015], as well as AREG alone [Holtan 2018]. It is not clear which biomarker combination best predicts lethal GVHD because these algorithms were developed using different patient cohorts with different endpoints. To answer this question, we compared the predictive accuracy of different biomarker combinations as well as these six specific combinations in the same patient cohort. We studied 522 patients with serum samples at GVHD diagnosis who were transplanted at 19 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 1, 2004 and April 30, 2017. Patients were divided into training (n = 253) and validation (n = 269) sets; validation patients were transplanted after November 1, 2015 and had not previously been used to generate an algorithm. Biomarkers were measured by ELISA and log-transformed values were used to predict 1-year lethal GVHD by competing risk regression. Four of the 6 biomarkers (ST2, REG3a, TNFR1, and TIM3) independently predicted lethal GVHD in the training set. We then developed algorithms that predicted lethal GVHD using all possible combinations of these 4 biomarkers as well as the published combination of TIM3+TNFR1+IL6 and AREG alone. The best algorithms of 1-4 biomarkers for predicting lethal GVHD were REG3a alone, ST2+REG3a, ST2+REG3a+TNFR1, and ST2+REG3a+TNFR1+TIM3. While ST2+REG3a was the most accurate combination based on the lowest Akaike Information Criterion (AIC), the other published biomarker combinations produced similar AICs. Therefore, we used the independent validation set to compare all six published algorithms. We generated area under the receiver operating characteristic curves (AUC) for each algorithm (FIG 1). We next determined the threshold that maximized sensitivity and specificity for each algorithm and calculated the cumulative incidence of lethal GVHD in the resulting high and low risk strata (FIG 2). Highly similar results were obtained when the cumulative incidence of non-relapse mortality was used as the endpoint. In a validation set of previously unanalyzed patients, several biomarker combinations reproducibly stratified patients with GVHD for risk of death. The best 4 algorithms, all of which included ST2, produced comparable outcomes. Adding TNFR1 to ST2+ REG3a did not improve accuracy. The ST2+REG3a algorithm best identifies patients at onset of GVHD for high risk of lethal GVHD and NRM, and thus remains a standard for biomarker-based risk prediction.

Purpose of review For patients with devastating injuries in whom standard reconstruction is not an option, vascularized composite allotransplantation (VCA) has become a viable means of restoring form and function. However, immunological rejection continues to be a problem in VCA and has not yet been fully characterized. As the field is relatively new, much of the data on rejection and immunosuppression have been extrapolated from that of solid organ transplantation. In this review, we cover the basic mechanisms of rejection as they relate specifically to VCA with analysis of recent literature and future directions. Recent findings Recent clinical studies have supported previously postulated T-cell-mediated mechanism of acute rejection and have also made strides in differentiating rejection from inflammation from other skin conditions and with different treatment regimens. Antibody-mediated rejection has been described in recent cases as well as treatment of presensitized patients receiving VCAs. With more long-term grafts, chronic changes, including vasculopathy, are being reported. Summary Clinically observed types of rejection in VCA include mainly cell-mediated, antibody-mediated and chronic rejection. Advances in diagnosis and treatment of rejection have been made, but there is still much to be learned about VCA-specific rejection.

Autologous fat transfer is often used to smooth contour irregularities in the reconstructed breast. A potential concern with this technique is that it results in calcified lesions in the breast that can complicate subsequent cancer surveillance. The purpose of this review was to determine how fat grafting to the reconstructed breast impacts postoperative breast imaging. This is a matched cohort analysis of patients who underwent postmastectomy breast reconstruction with and without fat grafting as a secondary procedure. Nonfat grafted reconstructive patients were matched based on age, year of initial reconstruction, and type of reconstruction. Postoperative imaging at our institution was required for inclusion. The two groups were compared in terms of incidence and distribution of radiographic studies performed in follow-up and the need for biopsies. Fifty-one reconstructed breasts with a history of fat grafting were compared to 51 nonfat grafted, reconstructed breasts. The fat grafted group underwent a total of 204 breast imaging studies over a mean follow-up of 4.2 years, while the nonfat grafted group underwent 167 studies over 4.1 years (p = 0.21). More mammograms, ultrasounds, and magnetic resonance images were performed after fat grafting, but a significant difference was evident only for mammography (34 versus 12, p = 0.05). The incidence of breast biopsy to clarify abnormal imaging was nonsignificantly higher in the fat grafted group (17.6% versus 7.8%, p = 0.14). Fewer than 10 percent of imaging studies in the fat grafted cohort were performed to investigate a clinical or radiographic abnormality occupying the same breast quadrant as prior fat injection. Breast cancer patients treated with fat grafting required more breast imaging and biopsies than their nonfat grafted counterparts, but the areas of suspicion poorly corresponded to the site of prior fat grafting. Multimodal breast reconstruction may drive the additional diagnostic burden and not the fat grafting technique itself.

Background: In comparison with open distal pancreatectomy (ODP), laparoscopic distal pancreatec- tomy (LDP) is associated with fewer complications and shorter hospital stays, but comparative cost data for the two approaches are limited. Methods: Records of all distal pancreatectomies carried out from January 2009 to June 2013 were reviewed and stratified according to operative complexity. Patient factors and outcomes were recorded. Total variable costs (TVCs) were tabulated for each patient, and stratified by category (e.g. 'floor', 'operating room' (OR), 'radiology'). Costs for index admissions and 30-day readmissions were compared between LDP and ODP groups. Results: Of 153 procedures, 115 (70 LDP, 45 ODP) were selected for analysis. The TVC of the index admission was US$3420 less per patient in the LDP group (US$10 480 versus US$13 900; P = 0.06). Although OR costs were significantly greater in the LDP cohort (US$5756 versus US$4900; P = 0.02), the shorter average hospitalization in the LDP group (5.2 days versus 7.7 days; P = 0.01) resulted in a lower overall cost. The total cost of index hospitalization combined with readmission was significantly lower in the LDP cohort (US$11 106 versus US$14 803; P = 0.05). Conclusions: In appropriately selected patients, LDP is more cost-effective than ODP. The increased OR cost associated with LDP is offset by the shorter hospitalization. These data clarify targets for further cost reductions.

Importance Upper lip avulsion after traumatic dog bite is a serious cause of facial disfigurement for which there is no consensus on management in the acute setting. Objective This review was prompted by a case at our institution and is intended to display the available evidence in the management of the patient after dog bite injury to the upper lip. Our main goals are to create a management algorithm using current evidence and to stimulate further clinical investigation to improve outcomes in patients with facial dog bite injuries. Evidence Review A review of English literature was performed using Pubmed/MEDLINE for case reports and case series of lip replantation using microvascular anastomosis. Additional review of hyperbaric oxygen therapy, medicinal leech therapy, lip reconstruction methods, and reapproximation was performed. Reference searches were performed for all retrieved articles. Findings Microvascular replantation is a successful method of acute management in dog bite injuries of the lip. Hyperbaric oxygen therapy and medicinal leech therapy improve outcomes. Immediate cross-lip flaps and immediate reapproximation are alternative techniques that can be performed in the acute setting, but further investigation is required. Conclusions The repair of the upper lip after a dog bite is a priority due to the functional and psychiatric sequelae associated with facial disfigurement. Microvascular replantation should be considered first-line. Immediate reapproximation without microvascular reanastomosis and immediate reconstruction may also be performed. A stepwise clinical algorithm may aid the surgeon in the acute management of dog bite trauma to the lip.