Targeting IL-6 to prevent cardiac allograft rejection.

Outcomes following heart transplantation remain suboptimal with acute and chronic rejection being major contributors to poor long-term survival. IL-6 is increasingly recognized as a critical pro-inflammatory cytokine involved in allograft injury and has been shown to play a key role in regulating the inflammatory and alloimmune responses following heart transplantation. Therapies that inhibit IL-6 signaling have emerged as promising strategies to prevent allograft rejection. Here, we review experimental and pre-clinical evidence that supports the potential use of IL-6 signaling blockade to improve outcomes in heart transplant recipients.

Use of computed tomography (CT) for preoperative planning in patients undergoing coronary artery bypass grafting (CABG).

Surgical planning for coronary artery bypass grafting (CABG) can be enhanced with the use of computed tomographic (CT) imaging to better understand the surgical field for optimal conduct of the case as well as risk assessment for outcomes. CABG via primary sternotomy, redo sternotomy, and minimally-invasive thoracotomy each pose unique surgical considerations and risks that can be better characterized with a preoperative CT scan. CT and CT angiographic (CTA) techniques with or without intravenous (IV) contrast can provide a noninvasive assessment of the vascular and bony structures and direct surgical planning techniques. Herein we discuss the role of CT/CTA imaging of the chest in preoperative planning of different strategies of CABG.

Immediate Implant Reconstruction Is Associated With a Reduced Risk of Lymphedema Compared to Mastectomy Alone: A Prospective Cohort Study.

OBJECTIVE: We sought to determine the risk of lymphedema associated with immediate breast reconstruction compared to mastectomy alone. BACKGROUND: Immediate breast reconstruction is increasingly performed at the time of mastectomy. Few studies have examined whether breast reconstruction impacts development of lymphedema. METHODS: A total of 616 patients with breast cancer who underwent 891 mastectomies between 2005 and 2013 were prospectively screened for lymphedema at our institution, with 22.2 months' median follow-up. Mastectomies were categorized as immediate implant, immediate autologous, or no reconstruction. Arm measurements were performed preoperatively and during postoperative follow-up using a Perometer. Lymphedema was defined as 10% or more arm volume increase compared to preoperative. Kaplan-Meier and Cox regression analyses were performed to determine lymphedema rates and risk factors. RESULTS: Of 891 mastectomies, 65% (580/891) had immediate implant, 11% (101/891) immediate autologous, and 24% (210/891) no reconstruction. The two-year cumulative incidence of lymphedema was as follows: 4.08% [95% confidence interval (CI): 2.59-6.41%] implant, 9.89% (95% CI: 4.98-19.1%) autologous, and 26.7% (95% CI: 20.4-34.4%) no reconstruction. By multivariate analysis, immediate implant [hazards ratio (HR): 0.352, P < 0.0001] but not autologous (HR: 0.706, P = 0.2151) reconstruction was associated with a significantly reduced risk of lymphedema compared to no reconstruction. Axillary lymph node dissection (P < 0.0001), higher body mass index (P < 0.0001), and greater number of nodes dissected (P = 0.0324) were associated with increased lymphedema risk. CONCLUSIONS: This prospective study suggests that in patients for whom implant-based reconstruction is available, immediate implant reconstruction does not increase the risk of lymphedema compared to mastectomy alone.

Comparison of intra-operative specimen mammography to standard specimen mammography for excision of non-palpable breast lesions: a randomized trial.

Standard specimen mammography (SSM) is performed in the radiology department after wire-localized excision of non-palpable breast lesions to confirm the presence of the target and evaluate margins. Alternatively, intra-operative specimen mammography (ISM) allows surgeons to view images in the operating room (OR). We conducted a randomized study comparing ISM and SSM. Women undergoing wire-localized excision for breast malignancy or imaging abnormality were randomized to SSM or ISM. For SSM, the specimen was transported to the radiology department for imaging and interpretation. For ISM, the specimen was imaged in the OR for interpretation by the surgeon and sent for SSM. Interpretation time was from specimen leaving OR until radiologist interpretation for SSM and from placement in ISM device until surgeon interpretation for ISM. Procedure and interpretation times were compared. Concordance between ISM and SSM for target and margins was evaluated. 72 patients were randomized, 36 ISM and 36 SSM. Median procedure times were similar, 48.5 (17-138) min for ISM, and 54 (17-40) min for SSM (p = 0.72), likely since specimens in both groups traveled to radiology for SSM. Median interpretation time was significantly shorter with ISM, 1 (0.5-2.0) and 9 (4-16) min for ISM and SSM, respectively (p < 0.0001). Among specimens with ISM and SSM, concordance was 100 % (35/35) for target and 93 % (14/15) for margins. In this randomized trial, use of ISM compared with SSM significantly reduced interpretation times, while accurately identifying the target. This could result in decreased operative costs from shorter OR times with use of ISM.

The need for preoperative baseline arm measurement to accurately quantify breast cancer-related lymphedema.

Breast cancer-related lymphedema (BCRL) is a feared outcome of breast cancer treatment, yet the push for early screening is hampered by a lack of standardized quantification. We sought to determine the necessity of preoperative baseline in accounting for temporal changes of upper extremity volume. 1028 women with unilateral breast cancer were prospectively screened for lymphedema by perometry. Thresholds were defined: relative volume change (RVC) ≥10 % for clinically significant lymphedema and ≥5 % including subclinical lymphedema. The first postoperative measurement (pseudo-baseline) simulated the case of no baseline. McNemar's test and binomial logistic regression models were used to analyze BCRL misdiagnoses. Preoperatively, 28.3 and 2.9 % of patients had arm asymmetry of ≥5 and 10 %, respectively. Without baseline, 41.6 % of patients were underdiagnosed and 40.1 % overdiagnosed at RVC ≥ 5 %, increasing to 50.0 and 54.8 % at RVC ≥ 10 %. Increased pseudo-baseline asymmetry, increased weight change between baselines, hormonal therapy, dominant use of contralateral arm, and not receiving axillary lymph node dissection (ALND) were associated with increased risk of underdiagnosis at RVC ≥ 5 %; not receiving regional lymph node radiation was significant at RVC ≥ 10 %. Increased pseudo-baseline asymmetry, not receiving ALND, and dominant use of ipsilateral arm were associated with overdiagnosis at RVC ≥ 5 %; increased pseudo-baseline asymmetry and not receiving ALND were significant at RVC ≥ 10 %. The use of a postoperative proxy even early after treatment results in poor sensitivity for identifying BCRL. Providers with access to patients before surgery should consider the consequent need for proper baseline, with specific strategy tailored by institution.

The impact of breast cancer-related lymphedema on the ability to perform upper extremity activities of daily living.

We sought to assess the association of breast cancer-related lymphedema (BCRL) with the ability to perform upper extremity activities of daily living (ADL) in our patient population. 324 breast cancer patients who had received treatment for unilateral breast cancer at our institution between 2005 and 2014 were prospectively screened for lymphedema. Bilateral arm measurements were performed pre-operatively and during post-operative follow-up using a Perometer. Patients completed an extensive quality of life (QOL) questionnaire at the time of each study assessment. Lymphedema was defined as a relative volume change (RVC) of ≥10% from the patient's pre-operative baseline measurement. Linear regression models were used to evaluate the relationship between post-operative arm function score (as a continuous variable) and RVC, demographic, clinical, and QOL factors. By multivariate analysis, greater fear of lymphedema (p < 0.0001), more pain (p < 0.0001), body mass index >25 (p = 0.0015), mastectomy (p = 0.0001), and having an axillary node dissection (p = 0.0045) were all associated with lower functional scores. Higher emotional well-being score (p < 0.0001) and adjuvant chemotherapy (p = 0.0005) were associated with higher post-operative functional score. Neither low-level volume changes (5-10 % RVC) nor BCRL (RVC ≥10 %) were associated with ability to perform upper extremity ADL as measured by self-report (p = 0.99, p = 0.79). This prospective study demonstrates that low-level changes in arm volume (RVC 5-10 %) as well as clinically significant BCRL (RVC ≥10 %) did not impact the self-reported ability to use the affected extremity for ADL. These findings may help to inform clinicians and patients on the importance of prospective screening for lymphedema and QOL which enables early detection and intervention.

Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort.

Taxane-based chemotherapy for the treatment of breast cancer is associated with fluid retention in the extremities; however, its association with development of breast cancer-related lymphedema is unclear. We sought to determine if adjuvant taxane-based chemotherapy increased risk of lymphedema or mild swelling of the upper extremity. 1121 patients with unilateral breast cancer were prospectively screened for lymphedema with perometer measurements. Lymphedema was defined as a relative volume change (RVC) of ≥10 % from preoperative baseline. Mild swelling was defined as RVC 5- <10 %. Clinicopathologic characteristics were obtained via medical record review. Kaplan-Meier and Cox proportional hazard analyses were performed to determine lymphedema rates and risk factors. 29 % (324/1121) of patients were treated with adjuvant taxane-based chemotherapy. The 2-year cumulative incidence of lymphedema in the overall cohort was 5.27 %. By multivariate analysis, axillary lymph node dissection (ALND) (p < 0.0001), higher body mass index (p = 0.0007), and older age at surgery (p = 0.04) were significantly associated with increased risk of lymphedema; however, taxane chemotherapy was not significant when compared to no chemotherapy and non-taxane chemotherapy (HR 1.14, p = 0.62; HR 1.56, p = 0.40, respectively). Chemotherapy with docetaxel was significantly associated with mild swelling on multivariate analysis in comparison to both no chemotherapy and non-taxane chemotherapy groups (HR 1.63, p = 0.0098; HR 2.15, p = 0.02, respectively). Patients who receive taxane-based chemotherapy are not at an increased risk of lymphedema compared to patients receiving no chemotherapy or non-taxane adjuvant chemotherapy. Those treated with docetaxel may experience mild swelling, but this does not translate into subsequent lymphedema.

Surgical excision of radial scars diagnosed by core biopsy may help predict future risk of breast cancer.

Radial scars (RS's) are benign breast lesions known to be associated with carcinomas and other high-risk lesions (HRL's). The upgrade rate to carcinoma after core biopsy revealing RS is 0-40 %. We sought to determine the outcomes of RS with and without HRL diagnosed by core biopsy. Patients who underwent core biopsy revealing RS without carcinoma at our institution between 1/1996 and 11/2012 were identified from a surgical pathology database. Retrospective chart review was utilized to classify patients as RS-no HRL or RS-HRL. HRL was defined as ADH, LCIS, and/or ALH. We determined upgrade rate to carcinoma at surgical excision, and upgrade to HRL for RS-no HRL patients. Univariate analysis was performed to identify risk factors for upgrade in RS-no HRL patients. 156 patients underwent core biopsy revealing RS, 131 RS-no HRL (84 %), and 25 RS-HRL (16 %). The overall rate of upgrade to invasive carcinoma was 0.8 % (1/124). 1.0 % (1/102) of RS-no HRL and 13.6 % (3/22) of RS-HRL patients were upgraded to DCIS (P = 0.0023). The upgrade of RS-no HRL to HRL at excision was 21.6 % (22/102). By univariate analysis, RS-no HRL with radiologic appearance of a mass/architectural distortion had a significantly higher rate of upgrade to HRL or carcinoma compared with calcifications (P = 0.03). Excision of RS to rule out associated invasive carcinoma is not warranted, given a <1 % rate of upgrade at excision. However, excision to evaluate for non-invasive cancer or HRL may be considered to help guide clinical decision-making about use of chemoprevention.

Risk of lymphedema after mastectomy: potential benefit of applying ACOSOG Z0011 protocol to mastectomy patients.

Axillary lymph node dissection (ALND) and radiation therapy (RT) are commonly recommended for mastectomy patients with positive sentinel lymph node biopsy (SLNB). Effective alternatives to ALND that reduce lymphedema risk are needed. We evaluated rates of lymphedema in mastectomy patients who received SLNB with RT, compared to ALND with or without RT. 627 breast cancer patients who underwent 664 mastectomies between 2005 and 2013 were prospectively screened for lymphedema, median 22.8 months follow-up (range 3.0-86.9). Each mastectomy was categorized as SLNB-no RT, SLNB + RT, ALND-no RT, or ALND + RT. RT included chest wall ± nodal radiation. Perometer arm volume measurements were obtained pre- and post-operatively. Lymphedema was defined as ≥10 % arm volume increase. Kaplan-Meier and Cox regression analyses were performed to determine lymphedema rates and risk factors. Of 664 mastectomies, 52 % (343/664) were SLNB-no RT, 5 % (34/664) SLNB + RT, 9 % (58/664) ALND-no RT, and 34 % (229/664) ALND + RT. The 2 year cumulative lymphedema incidence was 10.0 % (95 % CI 2.6-34.4 %) for SLNB + RT compared with 19.3 % (95 % CI 10.8-33.1 %) for ALND-no RT, and 30.1 % (95 % CI 23.7-37.8 %) for ALND + RT. The lowest cumulative incidence was 2.19 % (95 % CI 0.88-5.40 %) for SLNB-no RT. By multivariate analysis, factors significantly associated with increased lymphedema risk included RT (p = 0.0017), ALND (p = 0.0001), greater number of lymph nodes removed (p = 0.0006), no reconstruction (p = 0.0418), higher BMI (p < 0.0001) and older age (p = 0.0021). In conclusion, avoiding completion ALND and instead receiving SLNB with RT may decrease lymphedema risk in patients requiring mastectomy. Future trials should investigate the safety of applying the ACOSOG Z0011 protocol to mastectomy patients.

Impact of body mass index and weight fluctuation on lymphedema risk in patients treated for breast cancer.

Identifying risk factors for lymphedema in patients treated for breast cancer has become increasingly important, given the current lack of standardization surrounding diagnosis and treatment. Reports on the association of body mass index (BMI) and weight change with lymphedema risk are conflicting. We sought to examine the impact of pre-operative BMI and post-treatment weight change on the incidence of lymphedema. From 2005 to 2011, 787 newly diagnosed breast cancer patients underwent prospective arm volume measurements with a Perometer pre- and post-operatively. BMI was calculated from same-day weight and height measurements. Lymphedema was defined as a relative volume change (RVC) of ≥ 10 %. Univariate and multivariate Cox proportional hazards models were used to evaluate the association between lymphedema risk and pre-operative BMI, weight change, and other demographic and treatment factors. By multivariate analysis, a pre-operative BMI ≥ 30 was significantly associated with an increased risk of lymphedema compared to a pre-operative BMI <25 and 25- <30 (p = 0.001 and p = 0.012, respectively). Patients with a pre-operative BMI 25- <30 were not at an increased risk of lymphedema compared to patients with a pre-operative BMI <25 (p = 0.409). Furthermore, a cumulative absolute weight fluctuation of 10 pounds gained/lost per month post-operatively significantly increased risk of lymphedema (HR: 1.97, p = < 0.0001). In conclusion, pre-operative BMI of ≥ 30 is an independent risk factor for lymphedema, whereas a BMI of 25- <30 is not. Large post-operative weight fluctuations also increase risk of lymphedema. Patients with a pre-operative BMI ≥ 30 and those who experience large weight fluctuations during and after treatment for breast cancer should be considered at higher-risk for lymphedema. Close monitoring or early intervention to ensure optimal treatment of the condition may be appropriate for these patients.

Cording following treatment for breast cancer.

Treatment for breast cancer may result in the formation of palpable cords in the axillary region. Our aim was to evaluate cording incidence, risk factors, and association with upper extremity functional impairment and measured arm volume change. We included 308 patients with unilateral breast cancer prospectively screened for upper extremity lymphedema, symptoms and function. Patients were assessed pre- and post-operatively and at 3-8-month intervals with perometer arm measurements and the LEFT-BC questionnaire. Cording was determined by patient self-report. The cumulative incidence of cording and its association with clinicopathologic factors, upper extremity functional impairment, and measured arm volume change were analyzed. 31.5 % (97/308) of patients reported cording, with a cumulative incidence of 36.2 % at 24 months post-operative. Clinicopathologic factors significantly associated with cording by multivariate analysis included axillary lymph node dissection (p < 0.0001) and younger age at diagnosis (p = 0.0005). Cording was associated with increased functional impairment (p = 0.0018) and an arm volume increase of ≥5 % (p = 0.028). Cording following breast cancer treatment is common, and may occur beyond the post-operative period. Our findings emphasize the importance of identifying patients at high risk for cording, and developing strategies to minimize functional impairment and arm volume elevation associated with cording. Future studies should investigate the effectiveness of interventions for cording following breast cancer treatment.

Defining a threshold for intervention in breast cancer-related lymphedema: what level of arm volume increase predicts progression?

The purpose of this study is to evaluate arm volume measurements and clinico-pathologic characteristics of breast cancer patients to define a threshold for intervention in breast cancer-related lymphedema. We prospectively performed arm volume measurements on breast cancer patients using a Perometer. Arm measurements were performed pre- and post-operatively, and change in arm volume was quantified using a relative volume change (RVC) equation. Patient and treatment risk factors were evaluated. Cox proportional hazards models with time-dependent covariates for RVC were used to evaluate whether RVC elevations of ≥3 to <5 % or ≥5 to <10 % occurring ≤3 months or >3 months after surgery were associated with progression to ≥10 % RVC. 1,173 patients met eligibility criteria with a median of 27 months post-operative follow-up. The cumulative incidence of ≥10 % RVC at 24 months was 5.26 % (95 % CI 4.01-6.88 %). By multivariable analysis, a measurement of ≥5 to <10 % RVC occurring >3 months after surgery was significantly associated with an increased risk of progression to ≥10 % RVC (HR 2.97, p < 0.0001), but a measurement of ≥3 to <5 % RVC during the same time period was not statistically significantly associated (HR 1.55, p = 0.10). Other significant risk factors included a measurement ≤3 months after surgery with RVC of ≥3 to <5 % (p = 0.007), ≥5 to <10 % (p < 0.0001), or ≥10 % (p = 0.023), axillary lymph node dissection (ALND) (p < 0.0001), and higher BMI at diagnosis (p = 0.0028). Type of breast surgery, age, number of positive or number of lymph nodes removed, nodal radiation, chemotherapy, and hormonal therapy were not significant (p > 0.05). Breast cancer patients who experience a relative arm volume increase of ≥3 to <5 % occurring >3 months after surgery do not have a statistically significant increase in risk of progression to ≥10 %, a common lymphedema criterion. Our data support utilization of a ≥5 to <10 % threshold for close monitoring or intervention, warranting further assessment. Additional risk factors for progression to ≥10 % include ALND, higher BMI, and post-operative arm volume elevation.

Residual lymph node disease after neoadjuvant chemotherapy predicts an increased risk of lymphedema in node-positive breast cancer patients.

BACKGROUND: Axillary lymph node dissection (ALND) is recommended for patients with clinically node-positive breast cancer and carries a risk of lymphedema>30%. Patients with node-positive breast cancer may consider neoadjuvant chemotherapy, which can reduce node positivity. We sought to determine if neoadjuvant chemotherapy reduced the risk of lymphedema in patients undergoing ALND for node-positive breast cancer. METHODS: The 229 patients who underwent unilateral ALND and chemotherapy were divided into two groups: 30% (68/229) had neoadjuvant and 70% (161/229) had adjuvant chemotherapy. Prospective arm volumes were measured via perometry preoperatively and at 3- to 7-month intervals after surgery. Lymphedema was defined as relative volume change (RVC)≥10%, >3 months from surgery. Kaplan-Meier curves and multivariate regression models were used to identify risk factors for lymphedema. RESULTS: Fifteen percent (10/68) of neoadjuvant patients compared with 23% (37/161) of adjuvant patients developed RVC≥10% (hazard ratio=0.76, p=0.39). For all patients, body mass index was significantly associated with lymphedema (p=0.0003). For neoadjuvant patients, residual lymph node disease after chemotherapy was associated with a ninefold greater risk of lymphedema compared to those without residual disease (p=0.038). CONCLUSIONS: Patients who underwent neoadjuvant chemotherapy did not have a statistically significant reduction in risk of lymphedema. Among patients who receive neoadjuvant chemotherapy, residual lymph node disease predicted a greater risk of lymphedema. These patients should be closely monitored for lymphedema and possible early intervention for the condition.

Minimally invasive surgical coronary artery bypass in women.

Minimally invasive coronary artery bypass grafting (CABG) has emerged as a viable alternative to conventional sternotomy CABG in select patients requiring coronary revascularization. Specific techniques vary, but minimally invasive CABG (i.e., MIDCAB) usually involves revascularization of the left anterior descending (LAD) artery with the left internal mammary artery (LIMA). Minimally invasive CABG can be performed without cardiopulmonary bypass through a small anterior thoracotomy incision with robotic assistance. Use of minimally invasive CABG may offer specific benefits for women requiring revascularization, particularly given that female gender is an independent risk factor for inferior outcomes following CABG. Here we describe how to perform robot-assisted minimally invasive CABG, with a focus on technical modifications aimed at improving outcomes in women.

Comparison of relative versus absolute arm size change as criteria for quantifying breast cancer-related lymphedema: the flaws in current studies and need for universal methodology.

The purpose of this article is to evaluate arm measurements of breast cancer patients to critically assess absolute change in arm size compared to relative arm volume change as criteria for quantifying breast cancer-related lymphedema (BCRL). We used pre-operative measurements of 677 patients screened for BCRL before and following treatment of unilateral breast cancer at Massachusetts General Hospital between 2005 and 2008 to model the effect of an absolute change in arm size of 200 mL or 2 cm compared to relative arm volume change. We also used sequential measurements to analyze temporal variation in unaffected arm volume. Pre-operative arm volumes ranged from 1,270 to 6,873 mL and correlated strongly (Kendall's τ = 0.55) with body mass index (BMI). An absolute arm volume change of 200 mL corresponded to relative arm volume changes ranging from 2.9 to 15.7 %. In a subset of 45 patients, modeling of a 2-cm change in arm circumference predicted relative arm volume changes ranging from 6.0 to 9.8 %. Sequential measurements of 124 patients with >6 measurements demonstrated remarkable temporal variation in unaffected arm volume (median within-patient change 10.5 %). The magnitude of such fluctuations correlated (τ = 0.36, P < 0.0001) with pre-operative arm volume, patient weight, and BMI when quantified as absolute volume change, but was independent of these variables when quantified as relative arm volume change (P > .05). Absolute changes in arm size used as criteria for BCRL are correlated with pre-operative and temporal changes in body size. Therefore, utilization of absolute volume or circumference change in clinical trials is flawed because specificity depends strongly on patient body size. Relative arm volume change is independent of body size and should thus be used as the standard criterion for diagnosis of BCRL.

Sentinel lymph node biopsy at the time of mastectomy does not increase the risk of lymphedema: implications for prophylactic surgery.

Women diagnosed with or at high risk for breast cancer increasingly choose prophylactic mastectomy. It is unknown if adding sentinel lymph node biopsy (SLNB) to prophylactic mastectomy increases the risk of lymphedema. We sought to determine the risk of lymphedema after mastectomy with and without nodal evaluation. 117 patients who underwent bilateral mastectomy were prospectively screened for lymphedema. Perometer arm measurements were used to calculate weight-adjusted arm volume change at each follow-up. Of 234 mastectomies performed, 15.8 % (37/234) had no axillary surgery, 63.7 % (149/234) had SLNB, and 20.5 % (48/234) had axillary lymph node dissection (ALND). 88.0 % (103/117) of patients completed the LEFT-BC questionnaire evaluating symptoms associated with lymphedema. Multivariate analysis was used to assess clinical characteristics associated with increased weight-adjusted arm volume and patient-reported lymphedema symptoms. SLNB at the time of mastectomy did not result in an increased mean weight-adjusted arm volume compared to mastectomy without axillary surgery (p = 0.76). Mastectomy with ALND was associated with a significantly greater mean weight-adjusted arm volume change compared to mastectomy with SLNB (p < 0.0001) and without axillary surgery (p = 0.0028). Patients who underwent mastectomy with ALND more commonly reported symptoms associated with lymphedema compared to those with SLNB or no axillary surgery (p < 0.0001). Patients who underwent mastectomy with SLNB or no axillary surgery reported similar lymphedema symptoms. Addition of SLNB to mastectomy is not associated with a significant increase in measured or self-reported lymphedema rates. Therefore, SLNB may be performed at the time of prophylactic mastectomy without an increased risk of lymphedema.

Novel approaches for long-term lung transplant survival.

Allograft failure remains a major barrier in the field of lung transplantation and results primarily from acute and chronic rejection. To date, standard-of-care immunosuppressive regimens have proven unsuccessful in achieving acceptable long-term graft and patient survival. Recent insights into the unique immunologic properties of lung allografts provide an opportunity to develop more effective immunosuppressive strategies. Here we describe advances in our understanding of the mechanisms driving lung allograft rejection and highlight recent progress in the development of novel, lung-specific strategies aimed at promoting long-term allograft survival, including tolerance.

IL-6 Directed Therapy in Transplantation.

Purpose of Review: IL-6 is a pleiotropic, pro-inflammatory cytokine that plays an integral role in the development of acute and chronic rejection after solid organ transplantation. This article reviews the experimental evidence and current clinical application of IL-6/IL-6 receptor (IL-6R) signaling inhibition for the prevention and treatment of allograft injury. Recent Findings: There exists a robust body of evidence linking IL-6 to allograft injury mediated by acute inflammation, adaptive cellular/humoral responses, innate immunity, and fibrosis. IL-6 promotes the acute phase reaction, induces B cell maturation/antibody formation, directs cytotoxic T-cell differentiation, and inhibits regulatory T-cell development. Importantly, blockade of the IL-6/IL-6R signaling pathway has been shown to mitigate its harmful effects in experimental studies, particularly in models of kidney and heart transplant rejection. Currently, available agents for IL-6 signaling inhibition include monoclonal antibodies against IL-6 or IL-6R and janus kinase inhibitors. Recent clinical trials have investigated the use of tocilizumab, an anti-IL-6R mAb, for desensitization and treatment of antibody-mediated rejection (AMR) in kidney transplant recipients, with promising initial results. Further studies are underway investigating the use of alternative agents including clazakizumab, an anti-IL-6 mAb, and application of IL-6 signaling blockade to clinical cardiac transplantation. Summary: IL-6/IL-6R signaling inhibition provides a novel therapeutic option for the prevention and treatment of allograft injury. To date, evidence from clinical trials supports the use of IL-6 blockade for desensitization and treatment of AMR in kidney transplant recipients. Ongoing and future clinical trials will further elucidate the role of IL-6 signaling inhibition in other types of solid organ transplantation.