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4072 Optimizing ex-vivo perfusion in Vascularized Composite Allotransplantation using Hyperosmolar solution and Electric Stimulation: Preliminary Results – ERRATUM
- Michael Jonczyk, Philipp Tratnig-Frankl, Korkut Uygun, Curtis L. Cetrulo
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue 1 / 2023
- Published online by Cambridge University Press:
- 28 February 2023, e52
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4072 Optimizing ex-vivo perfusion in Vascularized Composite Allotransplantation using Hyperosmolar solution and Electric Stimulation: Preliminary Results
- Michael Jonczyk, Philipp Tratnig-Frankl
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- Journal:
- Journal of Clinical and Translational Science / Volume 4 / Issue s1 / June 2020
- Published online by Cambridge University Press:
- 29 July 2020, p. 14
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OBJECTIVES/GOALS: Vascularized composite allotransplantation (VCA) restores devastating soft tissue injuries. However, graft viability may be compromised during ischemia time, thus preservation techniques continue to evolve. Here we summarize our preliminary findings from preservation techniques utilizing hyperosmolar extracellular solution (HES) and electric stimulation in a 6 hour ex-vivo perfusion model. METHODS/STUDY POPULATION: A published, MGH rodent hindlimb ex-vivo perfusion model was utilized for this project. Three baseline control elements were taken to compare our results including: a baseline muscle biopsy, harvested hindlimb preserved on ice(4°C) in static cold storage (SCS), and 6 hour perfusion (SNMP) were used to compare results of our four aims. The four aims are shown in Table 1. HES was composed of muscle media and the addition of mannitol until 3 concentrations were made: 300, 500, and 800 mOsm concentrations. In aim 4, the perfusate composition was changed to test a hyper-oncotic purfusate. After 6 hours a muscle biopsy was taken to analyze energy cofactors via liquid chromatography-mass spectrometry, referred to as energy charge. Weight gain (edema), lactate levels, oxygen consumption and energy charge (EC) were used as markers for muscle tissue viability. RESULTS/ANTICIPATED RESULTS: In Aim 1, the higher osmolarity of HES indirectly reduced weight gain but consequentially reduced the EC below 5% when compared to SCS control group. We next incorporate HES into the perfusion model, Aim 2, and noticed a diminution in weight gain. The 500 mOsm group had substantial improvement in EC, lactate production and improved oxygen exchange when compared to a controls: fresh muscle biopsy and SNMP. In Aim 3, after a 6 hour perfusion with the addition of electric stimulation, graft edema improved by 10%, EC improved by 23% and O2 dissociation was highest of all 4 aims. Consequentially, due to muscular contraction the lactate levels were highest. In Aim 4, using a hyper-oncotic perfusate, edema reduced the most during the 6 hour perfusion but revealed lower EC and similar lactate/O2 results. However when left on for 24 hours, edema was significantly higher with lactate build up, EC improved with time as well as O2 dissociation. DISCUSSION/SIGNIFICANCE OF IMPACT: Here we have shown our preliminary results comparing our known ex-vivo perfusion model to multiple hypothesis to improve VCA graft viability. These preservation techniques demonstrate promising results but further studies are ongoing to confirm this encouraging outcome.
3281 Management of Acute Rejection in Penile Allotransplantation
- Michael Jonczyk, Ilse M. Schol, Philipp Tratnig-Frankl, Alexandre G. Lellouch, Dicken S.C. Ko, Curtis L. Cetrulo, Jr.
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 15-16
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OBJECTIVES/SPECIFIC AIMS: Objective: To summarize the diagnosis and management of two acute rejection (AR) episodes in the first penis transplant patient in the U.S. Background: Vascularized composite allotransplantation (VCA) has been utilized for state-of-the-art reconstruction of devastating craniofacial defects, limb loss, and recently, severe genitourinary defects. To date, more than 200 VCA’s have been performed, of which four successful penis transplants have been achieved worldwide (Two in the U.S.). However, despite the technical success of VCAs in general, acute rejection episodes remain a significant postoperative management problem, with 80-85% experiencing at least one episode in the first-year post-transplantation. The incorporation of skin in VCAs, which is highly immunogenic, allows early visible recognition of rejection but requires prompt management to prevent allograft failure as well as the progression of chronic rejection, which has been associated with the frequency of acute rejection episodes in preclinical models. We present the first report of acute rejection in a penile allograft. AR episodes in VCA typically manifest with erythema of the allograft skin and/or maculopapular lesions that can be either patchy, focal or diffuse. Histopathologic assessment is essential for diagnosis and management. The Banff classification of histopathologic criteria for degree of AR is most commonly utilized to direct clinical management. METHODS/STUDY POPULATION: We reviewed the clinical course of the first American patient who underwent penis transplantation at Massachusetts General Hospital in 2016. Postoperatively, routine clinical and chemical assessment (immunosuppression levels, routine blood work) was performed, with increased frequency during AR episodes. Skin punch biopsies were obtained during (suspected) AR episodes, analyzed and graded according to the Banff 2007 classification of rejection of skin-containing composite allografts. Histopathologic tissue assessment included CD3, C4d, CD4/8, CD20 FOXP3 and cellular infiltration (hyper keratinization, lymphocytic infiltrate, dermal erosion, macrophage, eosinophilia, T-cell infiltration) and epidermal or perivascular fibrosis. RESULTS/ANTICIPATED RESULTS: The patient is a 65-year-old male with history of penile carcinoma requiring subtotal penectomy in 2012. He is currently 30-months post penile transplantation (as of 11/15/2018). First Rejection Episode: At 28 days post-transplantation, the patient noted induration, swelling and erythema of the allograft, which was diagnosed as AR clinically (Image 1A). Biopsy showed a Banff Grade III AR, with focal keratinocyte apoptosis with lymphocytic infiltration in epidermis and arteriolar endothelialitis with perivascular inflammation. Initially this episode was treated for 2 days with 2 pulse doses of methylprednisolone (500mg/d IV) with clinical improvement. However, recurrent allograft erythema was observed on postoperative day 32 and an acute rejection grade III according the Banff classification was confirmed by a second biopsy that demonstrated epidermal perivascular lymphocytic infiltrates, spongiosis and dyskeratosis, deep dermis focal lymphocytic infiltrates and focal infiltrates in arterioles as well as endothelialitis in venules. Donor specific antibodies and C4d were negative. CD3+ T cells were present in the epidermis and perivascular space. This was treated with anti-thymocyte globulin (thymoglobulin) course for 4 days (1.5mg/kg/day IV) and 3 more pulse doses of methylprednisolone (500mg/d IV.), followed by a prednisone (250mg/d) taper to baseline. This resulted in complete resolution of AR. Second Rejection Episode: At 10.8 months post VCA the patient presented with penile erythema and scrotal swelling suggestive of AR and received three doses of methylprednisolone (day 1: 500mg/d IV, day 2: 1000mg/d IV and day 3: 500mg/d IV respectively) followed by increased baseline prednisone (10mg PO daily; increased dose compared to previous AR episode). A skin biopsy confirmed Banff Grade III AR. Compared to the previous biopsy, this biopsy demonstrated an increased density of lymphocytic inflammation of the dermis with endarteritis. Prominent involvement of epidermis and adnexal structures corresponding to acute T-cell mediated rejection was also observed (Figure 1). Donor specific antibodies and C4d were again negative. Three doses of ATG (1.5mg/kg/day IV) were administered. In addition, tacrolimus was increased and local tacrolimus (1% ointment) treatment was begun. Clinical signs of rejection improved and repeat biopsy showed dramatic histopathological improvement. Current maintenance immunosuppressive regimen consists of tacrolimus, sirolimus, prednisone, mycophenolic mofetil acid (MMF), rapamycin, and tacrolimus ointment, with no new clinical or histopathological signs of rejection (Image 1B). DISCUSSION/SIGNIFICANCE OF IMPACT: We report the first described case of acute T-cell mediated rejection in penile transplantation. These rejection episodes demonstrated that, even on stringent immunosuppressive regimens, severe acute rejection episodes in VCA may still occur. Edema and acute induration preceded the development of erythema in our cases, representing a harbinger for the more severe grade of rejection that eventually developed. Our experience was consistent with other VCAs in that donor specific antibodies did not develop, despite a severe Banff Grade. Consistent use of topical calcineurin inhibitor based immunosuppression on the allograft skin may be helpful in warding off future episodes, as our patient has been rejection free now for 18 months. To date, no histologic signs of chronic rejection were present on 2-year protocol surveillance biopsy. We have added rapamycin to the current drug regimen, with concurrent reduction of tacrolimus dosing for renal protection, which has been demonstrated in cardiac transplantation to deter the intimal hyperplasia/vasculopathy associated with chronic rejection.
3156 Breast Cancer Surgical Management: Novel Surgical Trends, Appropriate Axillary intervention, and associated Complications
- Michael Jonczyk, Jolie Jean, Roger Graham, Abhishek Chatterjee
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 120-121
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OBJECTIVES/SPECIFIC AIMS: Treatment of breast cancer surgery can be classified into two overall groups: Breast-Conserving Therapy (BCT) (including partial mastectomy (PM) and oncoplastic surgery (OS)) and MAST (including mastectomy (M) and M with breast reconstruction (M+R)). Breast reconstruction (OS or M+R) offers patients an improved quality of life by aesthetically symmetric breast, higher patient satisfaction and reduced re-excision rates. Furthermore, subgroups of M+R, mastectomy with implant placement (M+I) has doubled to 21%, meanwhile mastectomy with muscular flap reconstruction (M+MF) has declined to only 2% of overall breast cancer intervention. Furthermore, in patients with with ductal carcinoma in situ (DCIS), published national guidelines recommend that sentinel lymph node biopsy (SLNB) should be offered when treated with M and should not be offered when treated with BCS. Overall complication rates for breast cancer surgery vary depending on short-term or long term outcome but are approximately 2-40%. Mortality and overall morbidity are overall low in less than 5% of cases. Known wound or infectious complications have been associated with smoking, radiation, obesity and diabetes. Nevertheless, other patient comorbidities and surgical predictors influencing acute postoperative complications are contentious. Single institutional studies or reviews compared single or two groups of breast cancer interventions for post-operative complication rates. Few studies with large enough patient cohort to analyze all possible variables influencing post-operative acute complications following all breast cancer surgeries. Understanding surgical complications is crucial to patient safety and improving health outcomes. Therefore, this study examines the 30-day postoperative complication rates in breast cancer patients who underwent a PM, M, M+R, or OS. Using the NSQIP database, we aim to elucidate these surgical trends and complications trends, while expanding our understanding of predictive surgical factors. We also examined appropriate axillary management associated with surgical interventions between 2005 and 2016. METHODS/STUDY POPULATION: A retrospective cohort analysis was conducted using the ACS-NSQIP database from 2005 to 2017. All participant user files (PUF) were obtained and approved by ACS NSQIP. The Tufts Medical Center Institutional Review Board deemed this study exempt from institutional review, given ACS NSQIP database is a de-identified data set. Inclusion criteria for this study were women with classified post-operative diagnosis of invasive breast cancer (IBC) or ductal carcinoma in-situ (DCIS) breast cancer who underwent either any BCT or any MAST procedure. Post-operative diagnosis was classified according International Classification of Diseases Ninth/Tenth Revision (ICD-9/10) code for IBC or DCIS. Surgical (M, PM, OS, M+R) and axillary lymph node categorization were done using CPT codes known for each intervention. Exclusion criteria included males, benign breast surgery, surgery for benign breast disease, lobular carcinoma, patients undergoing breast cancer surgery with 2 CPT codes with ambiguous category placement and septic patients at time of surgery. For each intervention, a total of 16 complications were clustered into 8 groups and examined over the 13-year period. ALN management was categorized as follows: no intervention on ALNs, or ALN surgery (SLNB or ALN dissection (ALND)). Chi-square tests were performed for demographic and complication rate analysis. Smoothed linear regression and non-parametric Mann- Kendall test assessed complication trends. Uni-variate and multivariate logistical regression were computed to associate odd’s ratio for comorbidities, surgical predictors and patients demographics. RESULTS/ANTICIPATED RESULTS: A total of 226,899 patients met the inclusion criteria. Annual breast surgery trends changed as follows: PM 45.6% to 45.9 (p=0.21), M 36.8% to 25.5% (p=0.001), M+R 15.7% to 23.6% (p=0.03) and OS 1.8% to 5.0% (p=0.001). Analyzing the patient cohort who underwent breast conservation, categorical analysis showed a decreased use of PM alone (96% to 90%) with an increased use of OS (4% to 10%). For the patient cohort undergoing mastectomy, M alone decreased (69% to 52%); M+R with muscular flap decreased (9% to 2%); and M+R with implant placement increased (20% to 41%) – all 3 trends p<0.0001. The rate of ALN management has changed as follows: SNLB or ALND significantly increased in mastectomy patients from 53.6% to 69.5% (SS 1.5%, R2 0.69, p < 0.01), while it changed little in the BCS population: 22.5% to 26.4% (SS 0.4%, R2 0.18, p = 0.09). Complication rates have steadily increased in all mastectomy groups (p< 0.05) but not in BCT. Cumulative complication rates between surgical categories were significantly different in each complication cluster (all p<0.0001). Overall complication rates were: PM: 2.25%, OS: 3.2%, M: 6.56%, M+MF: 13.04% and M+I: 5.68%. The most common predictive risk factors were mastectomy interventions, increasing operative time, ASA class and BMI, smoking, recent weight loss, history of CHF, COPD and bleeding disorders (all p<0.001). Patients who were non-diabetic, younger (<60) and treated as outpatient all had protective OR for an acute complication (p<0.0001). DISCUSSION/SIGNIFICANCE OF IMPACT: The modern era of breast surgery is identified by the increasing use of reconstruction for patients undergoing breast conservation (in the form of OS) and mastectomy (in the form of M+R). Despite national recommendations for the management of axillary lymph nodes in patients undergoing breast surgery for DCIS, nearly 30% of cases continue to be mismanaged: more than 30% of patients with DCIS undergoing mastectomy fail to receive SLNB, and more than 26% of DCIS patients undergoing BCS are still receiving axillary lymph node surgery. Our study provides data showing significant trends that will impact the future of both breast cancer surgery and breast training programs. We also provide data comparing nationwide acute complication rates following different breast cancer surgeries that can be used to inform patients during surgical decision making.