Predictors of Blood Transfusion in Patients Undergoing Cytoreductive Surgeries for Ovarian Malignancy.

OBJECTIVES: The aims of this study were to describe the baseline estimated blood loss (EBL) in surgery and transfusion rate in patients undergoing cytoreductive surgeries for ovarian malignancy, and identify perioperative variables associated with blood loss and transfusion. METHODS: A retrospective cohort study at a single institution was performed that included patients with known or suspected ovarian malignancy undergoing cytoreductive surgery between 2016 and 2021. t tests, χ2 tests, and multiple logistic regression analyses were used. RESULTS: Among 44 patients meeting inclusion criteria, 61% received perioperative blood transfusion. There were significant differences in EBL and preoperative hemoglobin levels between patients who did and did not receive transfusion (EBL 442.6 vs 236.8 mL, P = 0.0008; preoperative hemoglobin 10.2 vs 11.2 g/dL, P = 0.049). After adjusting for preoperative hemoglobin, the risk of transfusion increased for each additional 200 mL of EBL (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.5-9.5). Stratified by race, the association between EBL and transfusion risk remained statistically significant only for non-Latinx White patients (OR 6.1, 95% CI 1.7-21.9), who made up 77% of the study population, but not for patients of other races and ethnicities (OR 1.0, 95% CI 0.16-6.42). CONCLUSIONS: Perioperative blood transfusion is common in patients undergoing cytoreductive surgery. In this study, EBL and preoperative hemoglobin levels were significantly associated with transfusion receipt. Clinicians should optimize hemoglobin levels and intraoperative blood conservation strategies to reduce the need for transfusion. The results also highlight the importance of considering racial and ethnic differences when developing strategies to reduce transfusion risk.

Differences in single gene expression patterns and signaling pathways between Black and White patients in high grade endometrioid endometrial cancer independent of BMI.

Objective: Endometrial cancer (EC) incidence and mortality are increasing with striking racial disparities. Race and obesity are known risk factors for EC, however, their relationship and impact on tumor biology in higher grade endometrioid EC are unclear. The objective of this pilot study was to identify gene- and pathway-level changes in tumors from Black patients compared to White, both in general and in the context of dichotomized BMI. Methods: A single institution retrospective convenience sample was obtained for grade 2 or 3 endometrioid EC, equally distributed amongst Black and White patients. Tumor samples were analyzed with the Tempus Laboratories xT NGS-based genome profiling test. DESeq2 was applied to identify differentially expressed genes, and then subjected to ingenuity pathway analysis (IPA). Continuous variables were analyzed using unpaired t-tests, and categorical using Chi-squared and Fisher exact tests. Results: 39 representative cases were identified and analyzed from 2006 to 2021. Baseline clinicopathologic characteristics were similar. 157 genes were differentially expressed in tumors from Black patients compared to White regardless of BMI. IPA identified 81 significantly different pathways between Black and White patients with a BMI < 40 kg/m2, and 117 with a BMI ≥ 40 kg/m2. Of these, eleven pathways were consistently and significantly activated or deactivated regardless of BMI. Conclusion: Differences in gene expression and pathway activation in EC exist between race and BMI, which highlights the need for further research to better understand the implications of these differences on endometrioid EC progression, outcomes, and treatment in this historically underserved patient population.

Metastatic Uterine Leiomyosarcoma presenting as small bowel intussusception at two independent visits.

•Metastatic disease to the small bowel may present with intussusception.•Clinical decision making for malignant bowel obstruction is difficult and individual specific.•Malignant bowel obstruction due to metastatic year has an average life expectancy of less than 200 days.

Reduction of Environmental Pollutants and Travel Burden Through an Academic Medical Center-based Electronic Consultation Program.

Background: We evaluated the impact of electronic consultation (eConsult) in reducing the environmental pollutants associated with health care delivery. Methods: A retrospective analysis of the eConsult data between July 2018 and December 2022 was extracted from the electronic health record (Epic). Travel time and mileage from the patient home to the academic medical center (AMC) were calculated along with fuel expenditure and greenhouses gas savings. Projected savings through the end of the decade were forecast using a random walk model. Results: A total of 15,499 eConsults were submitted to AMC specialist providers from community primary care providers. Completed eConsults (n = 11,590) eliminated the need for a face-to-face visit with a specialist provider, eliminating mileage, fuel, time, and pollutants associated with face to face visits. In-state travel distance saved was 310,858 miles, travel time saved was 5,491 h, with an associated fuel reduction of 13,575 gallons and $56,893 savings. This reduced greenhouse gas emissions by 128 metric tons of carbon dioxide, 0.022 tons of nitrogen oxide, 0.005 tons of methane, and 0.001 tons of nitrous oxide. Out of state travel distance saved was 188,346 miles with 2,842 h reduced travel time, and associated fuel reduction of 8,225 gallons and of $34,118. Reduced greenhouse gas emissions were equivalent to 77 metric tons of carbon dioxide, 0.0132 tons of nitrogen oxide, 0.0033 tons of methane, and 0.0007 tons of nitrous oxide. Conclusion: This study indicates that medical care provided through telehealth modalities reduces the environmental impact of pollutants associated with face to face visits.

Rosacea and Its Association With Malignancy: Systematic Review.

BACKGROUND: Rosacea is a chronic inflammatory skin condition that predominantly manifests as facial flushing, irritation, and acne. Rosacea and cancer are thought to be linked by the commonality of inflammatory and immune response dysfunction. Studies that have looked into this possible association have reported mixed results. OBJECTIVE: Given the conflicting literature on this topic, our study sought to evaluate the overall association between rosacea and several cancers commonly investigated in the literature. METHODS: A systematic review was conducted using the Cochrane, PubMed, Embase, and Ovid databases. Studies were screened independently for inclusion of rosacea and glioma and breast, thyroid, hepatic, or skin cancers. Using information from the articles, rosacea and each cancer were categorized as having a positive, negative, or unclear association. RESULTS: Our systematic review included 39 full-text studies that investigated the association between rosacea and various malignancies. Among the malignancies of concern, 41% (16/39) of the studies reported an association with basal cell carcinoma, with 2 cohorts revealing an adjusted risk ratio (RR) of 1.50 (95% CI 1.35-1.67) and 0.72 (95% CI 0.56-0.93). In total, 33% (13/39) of the studies reported an association with squamous cell carcinoma, with 2 cohorts revealing an adjusted RR of 1.4 (95% CI 1.02-1.93) and 1.30 (95% CI 0.90-1.88). A total of 8% (3/39) of the studies reported an association between breast cancer and melanoma, with breast cancer cohorts revealing an adjusted RR of 8.453 (95% CI 1.638-43.606), 1.03 (95% CI 0.89-1.20), and 1.36 (95% CI 1.18-1.58) and melanoma cohorts revealing an adjusted RR of 1.10 (95% CI 0.95-1.27), 0.63 (95% CI 0.47-0.85), and 0.96 (95% CI 0.57-1.62). A total of 5% (2/39) of the studies reported an association among nonmelanoma skin cancers, hepatic cancer, and thyroid carcinomas, with nonmelanoma skin cancer cohorts revealing an adjusted RR of 1.36 (95% CI 1.26-1.47) and 2.66 (95% CI 1.53-4.61), hepatic cancer cohorts revealing an adjusted RR of 1.42 (95% CI 1.06-1.90) and 1.32 (95% CI 0.89-1.95), and thyroid carcinoma cohorts revealing an adjusted RR of 1.06 (95% CI 0.68-1.65) and 1.59 (95% CI 1.07-2.36). Only 1 cohort reported an association with glioma, revealing an adjusted RR of 1.36 (95% CI 1.18-1.58). According to our review, patients with rosacea were statistically more likely to have nonmelanoma skin cancers, breast cancer, and glioma. Rosacea was not found to be substantially associated with melanoma. The associations between rosacea and hepatic and thyroid cancers were unclear because of conflicting results. CONCLUSIONS: The current literature shows that rosacea is significantly associated with increased odds of nonmelanoma skin cancers, glioma, and breast cancer. Rosacea does not appear to be associated with melanoma. Further studies should be conducted to clarify the association between thyroid and hepatic cancers and rosacea.

Evaluation in a porcine wound model and long-term clinical assessment of an autologous heterogeneous skin construct used to close full-thickness wounds.

Acute and chronic wounds involving deeper layers of the skin are often not adequately healed by dressings alone and require therapies such as skin grafting, skin substitutes, or growth factors. Here we report the development of an autologous heterogeneous skin construct (AHSC) that aids wound closure. AHSC is manufactured from a piece of healthy full-thickness skin. The manufacturing process creates multicellular segments, which contain endogenous skin cell populations present within hair follicles. These segments are physically optimized for engraftment within the wound bed. The ability of AHSC to facilitate closure of full thickness wounds of the skin was evaluated in a swine model and clinically in 4 patients with wounds of different etiologies. Transcriptional analysis demonstrated high concordance of gene expression between AHSC and native tissues for extracellular matrix and stem cell gene expression panels. Swine wounds demonstrated complete wound epithelialization and mature stable skin by 4 months, with hair follicle development in AHSC-treated wounds evident by 15 weeks. Biomechanical, histomorphological, and compositional analysis of the resultant swine and human skin wound biopsies demonstrated the presence of epidermal and dermal architecture with follicular and glandular structures that are similar to native skin. These data suggest that treatment with AHSC can facilitate wound closure.

Introducing the Harm Reduction Collaboration Framework for Policy, Systems, and Environmental Change.

This article is temporarily under embargo.

Expanding Our Impact in Cervical Cancer Treatment: Novel Immunotherapies, Radiation Innovations, and Consideration of Rare Histologies.

Cervical cancer is a socially and scientifically distinguishable disease. Its pathogenesis, sexual transmission of high-risk HPV to a metaplastic portion of the uterine cervix, makes cervical cancer preventable by safe and effective HPV vaccines commercially available since 2006. Despite this, cervical cancer remains the deadliest gynecologic cancer in the world. Regrettably, global incidence and mortality rates disproportionately affect populations where women are marginalized, where HIV infection is endemic, and where access to preventive vaccination and screening for preinvasive disease are limited. In the United States, cervical cancer incidence has gradually declined over the last 25 years, but mortality rates remain both constant and disparately higher among communities of color because of the adverse roles that racism and poverty play in outcome. Until these conditions improve and widespread prevention is possible, treatment innovations are warranted. The last standard-of-care treatment changes occurred in 1999 for locally advanced disease and in 2014 for metastatic and recurrent disease. The viral and immunologic nature of HPV-induced cervical cancer creates opportunities for both radiation and immunotherapy to improve outcomes. With the advent of T cell-directed therapy, immune checkpoint inhibition, and techniques to increase the therapeutic window of radiation treatment, an overdue wave of innovation is currently emerging in cervical cancer treatment. The purpose of this review is to describe the contemporary developmental therapeutic landscape for cervical cancer that applies to most tumors and to discuss notable rare histologic subtypes that will not be adequately addressed with these treatment innovations.

Opioid prescription by gynecologic oncologists: An analysis of Medicare Part D claims.

The use of opioids across all specialties has increased greatly over the last 2 decades and along with it, opioid misuse, overdose and death. The contribution of opioids prescribed for gynecologic cancers to this problem is unknown. Data from other surgical specialties show prescriber factors including gender, geographic location, board certification, experience, and fellowship training influence opioid prescribing. To characterize national-level opioid prescription patterns among gynecologic oncologists treating Medicare beneficiaries. The Centers for Medicare and Medicaid Services database was used to access Medicare Part D opioid claims prescribed by gynecologic oncologists in 2016. Prescription and prescriber characteristics were recorded including medication type, prescription length, number of claims, and total day supply. Region of practice was determined according to the US Census Bureau Regions. Board certification data were obtained from American Board of Obstetrics and Gynecology website. Bivariate statistical analysis and linear regression modeling were performed using Stata version 14.2. In 2016, 494 board-certified US gynecologic oncologists wrote 24,716 opioid prescriptions for a total 267,824 days of treatment (median 8 [interquartile range {IQR} 6, 11] prescribed days per claim). Gynecologic oncologists had a median of 33 opioid claims (IQR 18, 64). Male physicians had significantly more opioid prescription claims than females (P < 0.01) including after adjustment for differences in years of experience. There was no difference in prescribed days per claim between male and female physicians. Physicians in the South had the greatest number of opioid prescription claims and significantly more than physicians in all other regions (P < 0.01). Gynecologic oncologists who were board certified for >15 years had a greater number of median opioid claims (28 IQR 16, 50) than those with <5 years since board certification (22 IQR 15, 38) (P= 0.04). Physicians who were board certified in palliative care (n = 19) had significantly more opioids claims (median 40; IQR 18, 91) than those without (median 32; IQR 18, 64) (P< 0.01). In 2016, there were gender-based, regional, and experience-related variations in opioid prescribing by providers caring for Medicare-insured patients.

Skene's Gland Adenocarcinoma: Borrowing From Prostate Cancer Experience for the Evaluation and Management of a Rare Malignancy.

OBJECTIVE: To determine if adenocarcinoma of the Skene's glands in women, which has a histological and immunohistochemical appearance similar to prostate cancer, can be evaluated and managed with the same tools we use for prostate cancer. METHODS: Serum prostate-specific antigen kinetics, 3D multiparametric (MP) magnetic resonance imaging (MRI), fluciclovine F-18 positron emission tomography (PET), and androgen deprivation therapy (ADT) were employed in a case of Skene's gland adenocarcinoma. RESULTS: The 3D MP MRI clarified the anatomy of the primary lesion and fluciclovine F-18 PET significantly improved our ability to stage the tumor prompting pelvic lymph node dissection that may have otherwise not been performed. ADT resulted in a significant impact on prostate-specific antigen kinetics despite the patient having a testosterone level in the normal range for a postmenopausal woman. CONCLUSION: Despite the rarity of Skene's gland adenocarcinoma, we can employ many of the tools at our disposal for the evaluation and management of prostate cancer to benefit the women found to have this malignancy.

A short course of tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in the presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts.

Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.

Risk factors associated with delayed discharge following robotic assisted surgery for gynecologic malignancy.

BACKGROUND: The risk factors for extended length of stay (LOS) have not been examined in a cohort of patients with complex social and medical barriers who undergo robotic assisted (RA) surgery for gynecologic malignancies. We sought to identify those patients with a LOS > 24 h after robotic surgery and the risk factors associated with delayed discharge. Then we aimed to develop a predictive model for clinical care and identify modifiable pre-operative risk factors. METHODS: After IRB approval, data was abstracted from medical records of all patients with a gynecologic malignancy who underwent a RA laparoscopic surgery from 2010 to 2015. Univariable and multivariable logistic regression was performed to identify independent risk factors associated with delayed discharge defined as LOS > 24 h. A multi-variable logistic regression model was performed using a stepwise backward selection for the final prediction model. All testing was two-sided and a p-value < 0.05 was considered statistically significant. RESULTS: Of the 406 eligible and evaluable patients, 194 (48%) had a LOS > 24 h. Age ≥ 60 years, a higher usage of narcotic medication, a longer surgical time, and a larger estimated blood loss were all associated with LOS > 24 h (p < 0.05). Many of these women had a social work consultation and went home with home care services despite no surgical or post-operative complications. Our prediction model has the potential to correctly classified 75% of the patients discharged within 24 h. CONCLUSIONS: The development of a pre-hospitalization risk stratification and anticipating the possible need for home care services pre-operatively shows promise as a strategy to decrease LOS in patients classified as high-risk. These findings warrant prospective validation through the use of this prediction model in our institution.

Association of obesity with survival in patients with endometrial cancer.

BACKGROUND: Obesity confers an overall increased risk for development of endometrial cancer. However there are conflicting reports regarding the effect of obesity on patients' overall and disease specific survival. The purpose of this study was to evaluate the effect of obesity on survival in women with endometrial cancer. METHODS: After IRB approval, records of women with diagnosis and treatment of endometrial cancer from 1999 to 2016 were abstracted for histopathological, treatment and demographic data. Death was confirmed by query of the Social Security Death Index. Kaplan Meier survival curves and Cox regression modeling was performed with Stata version 14.0. RESULTS: Of 1732 evaluable patients, there were significant differences in age at diagnosis, histology (endometrioid versus non-endometrioid), stage, race, grade, hypertension, hyperlipidemia, diabetes, and treatment between normal weight, overweight, obese, and morbidly obese patients (p < 0.01). There was a linear association of younger age at diagnosis with increasing obesity (p < 0.01) R2 = 0.04. Younger age, endometrioid histology, lower stage, and statin use were independently associated with decreased hazard of death (p < 0.01). However, in stratified analysis of non-endometrioid histologies, patients with Stage 3 and 4 disease over the age of 65 showed a survival benefit for women associated with obesity (p = 0.02). CONCLUSIONS: Obesity is associated with younger age at diagnosis and earlier stage disease. Obesity is associated with improved disease specific survival for stage 3 and 4 non-endometrioid endometrial cancers.

The Urogenital Epithelium and Corporal Tissues Are the Primary Targets of Rejection in Penile Vascularized Composite Allotransplantation: A New Real-Time Tissue-Based Monitoring System.

BACKGROUND: Although significant surgical advances have been made in the form of microvascular surgery and autologous free tissue transfer, penile reconstruction still poses several difficult challenges. Although interest in penile vascularized composite allotransplantation has grown since the first attempted transplant in 2006, little is known regarding the kinetics of rejection and subsequent function of penile allografts. The penis contains multiple tissue types that are not qualified by the Banff 2007 vascularized composite allotransplantation classification system, including urogenital mucosal epithelium and erectile tissues. In this study, the authors investigate the propagation of rejection and the resultant function following rejection in rat and human penile tissues. METHODS: Rejected human and rat penile tissues were examined using an ex vivo real-time tissue-based derivative of the classic mixed lymphocyte reaction assay to determine the interactions occurring between en bloc penile tissues and peripheral blood mononuclear cells (autologous and allogeneic). Correlative in vivo heterotopic rat penile vascularized composite allotransplantation was used to correlate ex vivo findings. RESULTS: In both human and rat ex vivo systems and in vivo rat vascularized composite allotransplantation, the urethral mucosa was the first to undergo rejection-associated apoptosis. The urethral mucosa was the most immunogenic and led to the highest level of peripheral blood mononuclear cell proliferative generations in all systems, whereas the neural tissues of the penis remained immune privileged. CONCLUSION: These findings are the first to describe the kinetics of rejection in both human and rat penile vascularized composite allotransplantation and that the urethral mucosa is the most antigenic, suffering the highest level of rejection-associated apoptosis and peripheral blood mononuclear cell proliferative aggregation.

Response to trametinib in recurrent low-grade serous ovarian cancer with NRAS mutation: A case report.

Low-grade serous ovarian cancer represents a minority of ovarian cancers and has distinctive features from high grade epithelial ovarian cancer. While less aggressive, in advanced stage they can be poorly chemo-responsive and incur a treatment challenge. Next generation sequencing of tumors has allowed for the potential for targeted therapy in cancer treatment, which can allow for avoidance of traditional cytotoxic chemotherapy. We present a case of a 56 year old female with advanced recurrent low grade serous ovarian cancer found to have NRAS mutation who underwent targeted therapy with trametinib with immediate and sustained disease response. We review the response and toxicity experienced by the patient, as well as treatment for her toxicity.

Knowledge of Pelvic Floor Disorders in Obstetrics.

OBJECTIVES: The aim of this study was to investigate knowledge and demographic factors associated with a lack of knowledge proficiency about urinary incontinence (UI) and pelvic organ prolapse (POP) among pregnant and postpartum women. METHODS: This was a cross-sectional survey of women receiving antepartum and postpartum care at 9 Connecticut sites. Knowledge was assessed using the validated Prolapse and Incontinence Knowledge Questionnaire. Lack of knowledge proficiency was defined as less than 80% and less than 50% correct responses on the Prolapse and Incontinence Knowledge Questionnaire UI and POP subscales. Logistic regression was used to evaluate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. RESULTS: Surveys from 399 diverse pregnant and postpartum women were analyzed. Three quarters showed a lack of knowledge proficiency about UI and POP (74.2%, 70.6%). After adjustment, increased odds of lacking UI knowledge proficiency were associated with primiparity versus nulliparity (OR, 4.73; 95% CI, 2.24-9.98), Hispanic versus white race (OR, 2.72; 95% CI, 1.18-6.01), and having a high school diploma/General Education Development/less (OR, 3.17; 95% CI, 1.34-7.48) or some college (OR, 2.55; 95% CI, 1.08-6.01) versus bachelor's degree; greater lack of POP knowledge proficiency was associated with having a high school diploma/General Education Development versus bachelor's degree (OR, 2.11; 95% CI, 1.05-4.26) and never seeing a urologist/urogynecologist versus those who had (OR, 0.30; 95% CI, 0.12-0.77). Women working in a medical field versus those who did not demonstrated decreased odds of lacking UI and POP knowledge proficiency (ORs, 0.26 [95% CI, 0.13-0.52] and 0.38 [95% CI, 0.21-0.70]). CONCLUSIONS: Pregnant and postpartum women lack knowledge about UI and POP. Preconceptional counseling provides an opportunity for educational intervention.

Palliative Care and Symptom Management for Women with Advanced Ovarian Cancer.

The purpose of this article is to review data supporting the benefit of palliative care, specifically for women with advanced ovarian cancer. Authors discuss barriers to implementation of palliative care, including confusion with hospice and challenges of prognostication. Generalist-level palliative techniques for treatment of pain, shortness of breath, bowel obstruction, and ascites are described. A description of physician-assisted suicide in legalized states is provided. Resources for physicians regarding communication and end-of-life decision making support for patients and their families.

Acceptability and feasibility of a Fitbit physical activity monitor for endometrial cancer survivors.

OBJECTIVE: Endometrial cancer survivors are the least physically active of all cancer survivor groups and exhibit up to 70% obesity. While studies suggest lifestyle interventions result in improved health outcomes, recruitment and availability of these programs are limited. The purpose was to evaluate the acceptability and validity of the Fitbit Alta™ physical activity monitor (Fitbit) for socioculturally diverse endometrial cancer survivors. METHODS: Thirty endometrial cancer survivors were given wrist-worn Fitbits to wear for 30 days. Participants then returned the Fitbits, completed the Godin Leisure-Time Exercise Questionnaire (GLTEQ), Technology Acceptance Questionnaire, and answered qualitative prompts. Correlations between daily Fitbit step counts, demographic factors, body mass index (BMI), and GLTEQ Index, were analyzed using Stata 13.0. Concordance Correlation Coefficient using U statistics was used to examine convergent validity. RESULTS: Twenty-five participants completed the study. Mean age was 62 ±â€¯9 years. Mean BMI was 32 ±â€¯9 kg·m-2. Self-identified race/ethnicity was 36% Hispanic, 36% non-Hispanic white, 16% non-Hispanic black and 12% Asian. Participants wore the Fitbits a median of 93% of possible days. Median daily Fitbit step count was 5325 (IQR: 3761-8753). Mean Technology Acceptance score was 2.8 ±â€¯0.5 out of 4.0. Younger (<65 years) and employed participants were more likely to achieve at least 6000 daily steps (p < 0.05). There was no correlation (CCC = 0.00, p = 0.99) between step count and GLTEQ Index. Most free responses reflected positive experiences. CONCLUSIONS: The Fitbits were well accepted in this sample. Self-reported physical activity was not associated with steps recorded. The physical activity data indicate an insufficiently active population.

Desensitization and Prevention of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA. METHODS: Skin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry. RESULTS: Sensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6). CONCLUSIONS: In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.