Development Of Lymphedema Research Articles

Association of the breast reconstruction modality with the development of postmastectomy lymphedema: A long-term follow-up study

BackgroundWhether the breast reconstruction modality could influence the long-term development of post-mastectomy lymphedema has been little investigated. The present study aimed to evaluate the potential association of the breast reconstruction method with the incidence of lymphedema over an extended follow-up period. MethodsPatients with breast cancer who underwent immediate reconstruction from 2008 to 2014 were reviewed. They were categorized into three groups according to the reconstruction method: tissue expander/implant, abdominal flaps, and latissimus dorsi (LD) muscle flaps. Differences in the cumulative incidence of lymphedema by the reconstruction method were analyzed, as well as their independent influence on the outcome. Further analyses were conducted with propensity-score matching for baseline characteristics. ResultsIn total, 664 cases were analyzed with a median follow-up of 83 months (402 prostheses, 180 abdominal flaps, and 82 LD flaps). The rate of axillary lymph node dissection was significantly higher in the LD flap group than in the other two groups. The 5-year cumulative incidences of lymphedema in the LD flap, abdominal flap, and prosthesis groups were 3.7%, 10.6%, and 10.9%, respectively. In multivariable analyses, compared to the use of the LD flap, that of tissue expander/implant and that of abdominal flaps were associated with increased risks of lymphedema. A similar association was observed in the propensity-score matching analysis. The use of abdominal flaps or prostheses was not associated with the outcomes. ConclusionsOur results suggest that the method of immediate breast reconstruction might be associated with the development of postmastectomy lymphedema.

Variable Anatomy of the Lateral Upper Arm Lymphatic Channel: An Anatomical Risk Factor for Breast Cancer-Related Lymphedema.

The lateral upper arm channel is an accessory lymphatic pathway that drains the upper extremity by means of the deltopectoral groove and supraclavicular nodes, thereby bypassing the axilla. Its variable connectivity to the forearm has not been studied in vivo. Indocyanine green (ICG) lymphography was performed preoperatively to map the superficial and functional arm lymphatics in breast cancer patients without clinical or objective evidence of lymphedema. A retrospective review was performed to extract demographic, ICG imaging, and surgical data. Sixty patients underwent ICG lymphography before axillary lymph node dissection between June of 2019 and October of 2020. In 59%, the lateral upper arm lymphatic channel was contiguous with the forearm (long bundle). In 38%, the lateral upper arm lymphatic channel was present but not contiguous with the forearm (short bundle). In 3%, the lateral upper arm pathway was entirely absent. Seven patients developed at least one sign of lymphedema during postoperative surveillance, of which 71% demonstrated the short bundle variant. Although the lateral upper arm pathway is most often present, its connections to the forearm are frequently absent (short bundle), which, in this pilot report, appears to represent a potential risk factor for the development of lymphedema. Risk, V.

The Utility of Lymphatic Massage in Cosmetic Procedures.

Abstract Lymphedema is a severe debilitating disease characterized by the accumulation of excessive protein-rich fluid in the interstitial space. Given the severe morbidity associated with this disease process, various surgical and nonsurgical treatment modalities have been developed to attempt to reduce the incidence and symptoms associated with lymphedema. Manual lymphatic drainage (MLD) is a component of complete decongestive therapy on-surgical treatment which has demonstrated benefit in reducing the development of lymphedema following surgery. Here we provide a review of literature on MLD and its potential mechanism of action. This paper aims to educate patients, physicians, and surgeons about MLD regarding its efficacy and utility in the treatment paradigm for lymphedema and to translate concepts from the treatment of lymphedema to cosmetic procedures. Level of Evidence: 5

Risk factors of unilateral breast cancer-related lymphedema: an updated systematic review and meta-analysis of 84 cohort studies.

To review and update the incidence and risk factors for breast cancer-related lymphedema based on cohort studies. The study was guided by the Joanna Briggs Institute methodology and the Cochrane handbook for systematic reviews. PubMed, EMBASE, CINAHL, Scopus, Web of Science, The Cochrane Library, CNKI, SinoMed, and Wan Fang Database were searched from inception to November 15, 2021. Cohort studies reported adjusted risk factors were selected. PRISMA guideline was followed. Study quality were evaluated using the Newcastle-Ottawa scale. Random-effects models were adopted. The robustness of pooled estimates was validated by meta-regression and subgroup analysis. Lymphedema incidence and adjusted risk factors in the multivariable analyses with hazard / odds ratios and 95% CIs were recorded. Eighty-four cohort studies involving 58,358 breast cancer patients were included. The pooled incidence of lymphedema was 21.9% (95% CI, 19.8-24.0%). Fourteen factors were identified including ethnicity (black vs. white), higher body mass index, higher weight increase, hypertension, higher cancer stage (III vs. I-II), larger tumor size, mastectomy (vs. breast conservation surgery), axillary lymph nodes dissection, more lymph nodes dissected, higher level of lymph nodes dissection, chemotherapy, radiotherapy, surgery complications, and higher relative volume increase postoperatively. Additionally, breast reconstruction surgery, and adequate finance were found to play a protective role. However, other variables such as age, number of positive lymph nodes, and exercise were not correlated with risk of lymphedema. Treatment-related factors still leading the development of breast cancer-related lymphedema. Other factors such as postoperative weight increase and finance status also play a part. Our findings suggest the need to shift the focus from treatment-related factors to modifiable psycho-social-behavioral factors.

Association between Immediate Breast Reconstruction and the Development of Breast Cancer-Related Lymphedema.

With the increasing number of patients undergoing immediate breast reconstruction after mastectomy, the impact of immediate breast reconstruction on the risk of breast cancer-related lymphedema has become an emerging area of interest. This study aimed to identify the association between immediate breast reconstruction and postoperative lymphedema. A retrospective cohort study was conducted from 2006 to 2016 with 5900 consecutive patients who underwent mastectomy for primary breast cancer with or without immediate breast reconstruction. After excluding patients with synchronous contralateral breast cancer, lymphedema before mastectomy, history of procedures performed in the axillary region, and follow-up data of less than 1 year, the cumulative incidence of lymphedema after immediate breast reconstruction and after no reconstruction was calculated and compared using multivariate Cox regression analysis. Overall, 5497 patients (mean age, 51.7 years) were included, and 630 developed lymphedema. The 5-year cumulative incidence rate of lymphedema was significantly reduced in patients who underwent immediate breast reconstruction versus control patients (9.6% versus 12.2%; P = 0.02). In the multivariate analysis, immediate breast reconstruction status (hazard ratio, 0.75; 95% confidence interval, 0.56 to 0.99; P = 0.042) was an independent predictor for lymphedema. Similar significant associations were observed in the subgroup analyses of patients with a body mass index less than 30 kg/m2 (P = 0.024), in those with fewer than 10 dissected lymph nodes (P = 0.042), or in those with adjuvant radiotherapy (P = 0.048). Immediate breast reconstruction was associated with a reduced risk of lymphedema. These results may be used for predicting the development of lymphedema following breast reconstruction. Risk, II.

Lymphedema of the limb: levels of bypass surgery

The paper provides information on the possible levels of performing shunting operations for limb lymphedema. The aim of the study was to study the anatomy of the lymphatic system of the skin and subcutaneous tissue in the clinic and in the experiment, comparing the data obtained with morphological changes occurring during the development of lymphedema. The substantiation of the levels of shunting operations is presented, taking into account the anatomy of the lymphatic system and pathophysiological changes in tissues during the development of chronic edema.

Acquired lymphedema: Molecular contributors and future directions for developing intervention strategies.

Lymphedema is a debilitating chronic disease that mostly develops as an adverse reaction to cancer treatment modalities such as chemotherapy, surgery, and radiotherapy. Lymphedema also appears to be a deteriorating consequence of roundworm infections, as best represented by filariasis. According to its origin, lymphedema is classified as primary lymphedema and acquired lymphedema. The latter is an acquired condition that, hitherto, received a considerably low attention owing to the less number of fatal cases been reported. Notably, despite the low mortality rate in lymphedema, it has been widely reported to reduce the disease-free survival and thus the quality of life of affected patients. Hence, in this review, we focused on acquired lymphedema and orchestration of molecular interplays associated with either stimulation or inhibition of lymphedema development that were, in vast majority, clearly depicted in animal models with their specific and distinct technical approaches. We also discussed some recent progress made in phytochemical-based anti-lymphedema intervention strategies and the specific mechanisms underlying their anti-lymphedema properties. This review is crucial to understand not only the comprehensive aspects of the disease but also the future directions of the intervention strategies that can address the quality of life of affected patients rather than alleviating apparent symptoms only.

T Cell Repertoire Diversity in Lymphedema: Investigating the Antigens Driving the T Cell Response

BACKGROUND: Lymphedema (LE) is a progressive condition that is estimated to affect as many as 1 in 1000 Americans. The disease is a major cause of decreased quality of life and is characterized by swelling, fibrosis, and recurrent infections. Activation of T-helper (Th) inflammatory responses plays a key role in lymphedema development and has been correlated with disease severity. This activation requires interaction with antigen-presenting cells (APCs), suggesting that the T-cell responses occur in response to antigens that are present in tissues after lymphatic injury. Clonal analysis of these T cell responses is significant due to its potential to uncover a common clonal architecture between patients with the disease. Identification of antigen-responsive T cell clones that are selectively expanded has important implications for developing therapies aimed at a common antigen driving the disease process. METHODS: High throughput sequencing (HTS) of clinical lymphedema and normal tissue DNA was utilized to identify unique T cell clones in lymphedematous tissue. Briefly, genomic DNA (gDNA) was isolated from lymphedematous, and control matched upper limb biopsies of six patients. Deep sequencing of the TCR repertoire was conducted by using a two-step biased controlled multiplex PCR to amplify genes of abundant T cell populations. These clones were quantified and characterized by CDR3 sequence length and TCRB Variable (V) gene usage. Predictive analysis of T cell antigen specificity was performed using the Basic Local Alignment Search Tool (BLAST) of the TCR epitope sequences and the activation of antigen-responsive clones was assessed by Flow cytometry. RESULTS: Our analysis demonstrated that the T cell responses in lymphedema are oligoclonal. TCR sequencing of the top five abundant clones in lymphedematous and normal tissue biopsies revealed six conserved amino acid sequences at the CDR3 region unique to the lymphedema group, however, no overlap of T cell repertoires was seen between patients with the disease. BLAST analysis of the corresponding TCRB epitope sequence revealed a list of probable antigens corresponding to each unique clonotype. Of the epitope sequences, unique to LE, staphylococcal enterotoxin represented the highest affinity bacterial antigen, pro-insulin corresponded to the representative self-antigen, and gluten peptide corresponded to plant antigen. CONCLUSION: Our results show that the T cell response in lymphedema is oligoclonal in nature, similar to what is seen in other inflammatory skin diseases such as atopic dermatitis and cutaneous psoriasis. In addition, clonality infers common antigen specificity of a population of T cells. Here we present representative antigens using BLAST analysis of the unique TCRB sequences of clones detected in lymphedematous tissue. Identification of these T cell populations that are selectively expanded in LE may provide a targeted approach for identifying antigenic stimuli or similarly eliminating pathogenic T cell clones as a means of treating the disease.

Axillary-Lateral Thoracic Vessel Juncture Radiotherapy Dose Constraints for Predicting Long-Term Lymphedema Risk in Patients with Breast Cancer

<h3>Purpose/Objective(s)</h3> To study the relationship between the axillary-lateral thoracic vessel juncture (ALTJ) dose and lymphedema risk in women with breast cancer in the context of other known risk factors. <h3>Materials/Methods</h3> A total of 1,488 women with breast cancer, from two institutions, treated with multimodal therapies were analyzed. ALTJ was delineated, and dose-volume histogram (DVH) parameters (maximum dose [D_max], D_mean, D_min, volume receiving 5 Gy [V_5Gy], V_10Gy, V_15Gy, V_20Gy, V_25Gy, V_30Gy, V_35Gy, V_40Gy, V_45Gy, and V_50Gy) were assessed. Doses were converted to the equivalent dose of 2 Gy using a linear-quadratic model (<i>α</i>/<i>β</i> = 3). <h3>Results</h3> The cumulative incidence of lymphedema development was 6.8% at 5-years. Lymphedema risk increased for each 10-Gy increment in the ALTJ D_mean (adjusted hazard ratio 1.2, 95% confidence interval (CI) 1.1–1.4). The random survival forest model better predicted lymphedema risk when ALTJ DVH parameters were integrated into the model with a c-index of 0.91 (<i>p</i> < 0.001). Surgical extent followed by ALTJ D_mean were the most significant indicators of lymphedema risk. In the decision tree model developed with a hierarchical classification and regression tree, the 5-year lymphedema risk was significantly elevated in patients with an ALTJ D_mean >35 Gy (12.8% vs. 1.0%, <i>p</i> < 0.001) among patients who had ≤6 sampled lymph nodes. <h3>Conclusion</h3> A mean dose ≤35 Gy to the ALTJ is a suggested dose constraint for preventing lymphedema in patients who undergo less extensive axillary surgery. Although further validation is required, our dose constraints can be incorporated into future prospective protocols to investigate the impact of axillary treatment.

Breast Cancer-Related Lymphedema Prediction after Postoperative Radiotherapy through Multivariable Logistic Regression Analysis

<h3>Purpose/Objective(s)</h3> We identified novel clinical and dosimetric prognostic factors affecting breast cancer-related lymphedema after postoperative radiotherapy (RT) and developed a multivariable logistic regression model to predict lymphedema in these patients. <h3>Materials/Methods</h3> A total of 580 patients with unilateral breast cancer were retrospectively reviewed. All patients underwent breast surgery and postoperative RT with or without systemic treatment in 2015. With available RT plan data, 532 patients were randomly divided into the train (N=372) and test (N=160) cohort with a 7:3 ratio to generate and validate lymphedema prediction models, respectively. An area under the curve (AUC) value was estimated to compare models. <h3>Results</h3> The median follow-up duration was 5.4 years. One-hundred-four (17.9%) patients experienced lymphedema and cumulative incidence of it as follows: 1-year, 10.5%; 3-year, 16.4%; and 5-year, 17.6%, respectively. Multivariate analysis showed that body mass index ≥25 kg/m² (hazard ratio [HR] 1.845), dissected lymph nodes ≥7 (HR 1.041), and taxane-based chemotherapy (HR 4.200) were significantly associated with increased lymphedema risk. Meanwhile, receiving RT at least 1 month after surgery decreased lymphedema development (HR 0.638). The multivariable logistic regression model using the above factors as well as the minimum dose of axillary level I and supraclavicular lymph node was made with an AUC of 0.761 and 0.794 in the train and test cohort, respectively. <h3>Conclusion</h3> Our study demonstrated that the shorter interval from surgery to RT and other established clinical factors increased lymphedema risk. Combining them with two dosimetric parameters, we suggest the multivariable logistic regression model for breast cancer-related lymphedema prediction after RT.

SHORT DURATION OF UPPER EXTREMITY LYMPHEDEMA CORRELATES WITH A FAVORABLE CYTOKINE RESPONSE AFTER LYMPH NODE TRANSFER SURGERY

Vascularized lymph node transfer surgery (VLNT) can provide benefit to lymphedema patients. Cytokines may play a role in the development of lymphedema and in the regeneration of lymphatic vessels after VLNT. Our primary aim was to investigate whether the VLNT patients have a specific cytokine profile. Our secondary aim was to see whether the preoperative lymphedema or severity affects the postoperative cytokine response. Wound exudate was gathered from 18 patients undergoing VLNT on the first and sixth postoperative day (POD). The concentrations of IL-10, TNF-α, TGF-β1 and VEGF-C were analyzed using enzymelinked immune-sorbent assays. A general score was generated to assess the benefit of the surgery. The changes in cytokine concentrations (1st POD-6th POD) were correlated with the pre- and postoperative lymphedema related factors. A shorter duration of lymphedema preoperatively correlated with an increase in the concentration of IL-10 and TNF-β during the first six PODs (IL-10: r=0.495, p=0.051; TNF-α: r=0.737, p=0.006) and a decrease in the concentration of TGF-ß1 (r= -0.613, p=0.020). The increase of the concentration of TNF-α during the first six PODs also correlated with a greater total general score (r=0.775, p=0.005) and hence indicated a better response to the surgery. The patients with a shorter duration of lymphedema preoperatively had a more favorable cytokine response during the first six PODs after VLNT.

Reduction of Arm Lymphedema Using Manual Lymphatic Therapy (Godoy Method).

Background: The manual lymphatic drainage (MLD) technique used during the early stages following surgical treatment of breast cancer can help prevent the progression of clinical lymphedema.Objective: The objective of this study was to evaluate the effectiveness of manual lymphatic therapy (MLT) (Godoy method) in reducing the development of lymphedema immediately after breast cancer treatment.Method: A randomized, blind, crossover, clinical trial was conducted involving 66 women with breast cancer-related lymphedema (BCRL), who underwent one hour of manual physical therapy and one hour of the control procedure. To evaluate the volume before and after the application of the MLT technique, volumetry, a water displacement technique was used. For statistical analysis, the paired t-test with 5% alpha error by Stats Direct 3(StatsDirect Ltd, Wirral, UK) was used.Results: A significant reduction in the volume of the limb was found in all patients (p-value = 0.0001, paired t-test).Conclusion: MLT is effective in reducing lymphedema after breast cancer treatment.

Superficial and Functional Lymphatic Anatomy of the Upper Extremity.

Knowledge of detailed lymphatic anatomy in humans is limited, as the small size of lymphatic channels makes it difficult to image. Most current knowledge of the superficial lymphatic system has been obtained from cadaveric dissections. Indocyanine green lymphography was performed preoperatively to map the functional arm lymphatics in breast cancer patients without clinical or objective evidence of lymphedema. A retrospective review was performed to extract demographic, indocyanine green imaging, and surgical data. Three main functional forearm channels with variable connections to two upper arm pathways were identified. The median forearm channel predominantly courses in the volar forearm (99 percent). The ulnar forearm channel courses in the volar forearm in the majority of patients (66 percent). The radial forearm channel courses in the dorsal forearm in the majority of patients (92 percent). Median (100 percent), radial (91 percent), and ulnar (96 percent) channels almost universally connect to the medial upper arm channel. In contrast, connections to the lateral upper arm channel occur less frequently from the radial (40 percent) and ulnar (31 percent) channels. This study details the anatomy of three forearm lymphatic channels and their connections to the upper arm in living adults without lymphatic disease. Knowledge of these pathways and variations is relevant to any individual performing procedures on the upper extremities, as injury to the superficial lymphatic system can predispose patients to the development of lymphedema.

The impact of rehabilitation sport on breast cancer-related lymphoedema and quality of life

PurposeSurgery and radiotherapy as part of breast cancer treatment can lead to lymphoedema of the upper extremities (breast cancer-related lymphoedema = BCRL) and reduce the quality of life (health-related quality of life = HRQoL). The aim of the present study was to investigate the influence of paddling in a dragon boat (PP) on HRQoL and BCRL in breast cancer survivors (BCS).MethodsBetween April and October 2017, a prospective case–control study evaluated the effects of PP compared to a control group. In the paddle group (n = 28), weekly arm circumference measurements were taken at four defined anatomic areas of the arm before and after training; in the control group (n = 70), the measurements were taken once a month. At the beginning and end of the study, questionnaires from both groups (SF 36, EORTC QLQ C30) were evaluated to understand the differences in HRQoL.ResultsThe paddle group started with a higher HRQoL compared to the control group. Most interesting, whether the affected or unaffected arm, whether before or after training—the arm circumference decreased over time in the paddling group. A pre-existing lymphoedema was not negatively influenced by paddling. In the paddle group, the physical health was constant over the season, while the physical health of the control group decreased significantly over time.ConclusionPP in a dragon boat does not lead to the development or worsening of pre-existing lymphoedema due to breast cancer therapy, and seems to have a positive effect on the quality of life.

Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema.

Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

ROCC/GOG-3043: A randomized non-inferiority trial of robotic versus open radical hysterectomy for early-stage cervical cancer.

TPS5605 Background: Minimally invasive surgery (MIS) is associated with improved perioperative safety outcomes, but, in 2018, the Laparoscopic Approach to Cervical Cancer (LACC) trial, a non-inferiority study comparing laparoscopic versus open radical hysterectomy for early stage cervical cancer, reported significantly worse disease-specific (DSS) and overall survival (OS) in the MIS group. Criticisms of the LACC trial include lack of proper preoperative imaging and assessment, use of transcervical uterine manipulators, and lack of proper tumor containment leading to peritoneal contamination. Subsequent retrospective studies have reported conflicting results. Given the potential benefit of MIS, the ROCC trial seeks to address the limitations of the LACC trial. Methods: ROCC is a multi-center, prospective, randomized, non-inferiority trial. The primary objective is to determine whether robotic-assisted (RBT) radical hysterectomy is not inferior to abdominal (OPEN) approach with respect to 3-year disease-free survival (DFS). Secondary objectives include DSS, OS, patterns of recurrence, peri- and postoperative complications, long-term morbidity, impact on patient-reported outcome (PRO) measures and development of lower extremity lymphedema (LEL). Key inclusion criteria include patients with histologically confirmed adenocarcinoma, squamous cell, and adenosquamous cell carcinoma of FIGO 2018 stage IA2-IB2. All patients must have a preoperative pelvic MRI confirming that the cervical tumor is &lt; 4 cm in size, no obvious evidence of extracervical extension and no nodal or other regional metastasis. Intraoperatively, the use of transcervical uterine manipulators is not allowed and specific detailed surgical techniques for proper tumor containment is required. Photographic evidence of specimen with tumor contained is mandated. We estimate the 3-year DFS to be 92% in the control (OPEN) arm. If the DFS does not differ by more than 7% and the one-sided 95% CI does not cross the non-inferiority boundary, then the RBT arm will be deemed non-inferior. 840 patients will be enrolled (420 per arm, 89 events total), which provides 90% power to exclude an absolute decrease in DFS by 7% (HR &lt; = 1.375) with a log-rank test for non-inferiority with a one-sided alpha of 0.05. The primary analysis will be conducted in all randomized patients (ITT). Given the LACC findings of worse oncologic outcomes with MIS, a formal DSMC will conduct periodic reviews of safety including two planned formal interim analyses for futility (harm) after accrual of 370 and 640 patients using an aggressive Lan-DeMets beta-spending function similar to a Pocock boundary. Results of this trial may be practice changing and will either support or refute the findings of the LACC trial. The study is currently activating sites for enrollment. Clinical trial information: NCT04831580.

Risk factors for lower extremity lymphedema after cervical cancer treatment: a systematic review and meta-analysis.

BackgroundThe main risk factors for the development of lower extremity lymphedema after cervical cancer treatment are controversial. Our aim was to evaluate the main risk factors of lower extremity lymphedema after cervical cancer treatment.MethodsWe searched the English database PubMed, Embase, Medline, Central and the Chinese database CNKI to obtain relevant studies. Inclusion criteria: (I) the subjects were cervical cancer patients receiving treatment; (II) cohort studies or case-control studies; (III) exposure factors were not limited; (IV) the outcome was lower extremity lymphedema after treatment; (V) the odds ratio (OR) value and 95% confidence interval of exposure factors can be obtained. The chi-square test was used to test for heterogeneity. The Egger test was used to test for publication bias. OR (95% CI) was calculated using inverse variance.ResultsA total of 12 retrospective studies with a total of 3,401 patients were included in this literature review. The incidence of lower extremity lymphedema after cervical cancer treatment was between 12.6% and 43.1%. Meta-analysis results demonstrated that the main risk factors were: body mass index (BMI) (OR =1.37, 95% CI: 1.10–1.71, P=0.005), age (OR =1.68, 95% CI: 1.07–2.64, P=0.02), International Federation of Gynecology and Obstetrics (FIGO) stage (OR =1.50, 95% CI: 1.24–1.82, P<0.001), radiotherapy (OR =2.87, 95% CI: 1.71–4.82, P<0.001), lymph node (LN) dissection (OR =3.24, 95% CI: 1.44–7.31, P=0.005), and the number of LNs dissected (OR =2.34, 95% CI: 1.80–3.05, P<0.001). Egger’s test showed that there was no publication bias among the literatures (P>0.05).ConclusionsBMI, age, FIGO stage, radiotherapy, LN dissection and the number of LNs removed are the main risk factors for lower extremity lymphedema after cervical cancer treatment. When treating patients with cervical cancer, effective interventions should be sought to reduce the risk of lower extremity edema.

Adipose Tissue in Lymphedema: A Central Feature of Pathology and Target for Pharmacologic Therapy.

Lymphedema is a chronic condition of impaired lymphatic flow that results in limb swelling and debilitation. The pathophysiology of lymphedema is characterized by lymphatic stasis that triggers inflammation, fibrosis, and adipose tissue deposition in the extremities. Most often, this condition occurs in cancer survivors in the years after treatment with combinations of surgery, radiation, or chemotherapy, with the major risk factor being lymph node dissection. Interestingly, obesity and body mass index are independent risk factors for development of lymphedema, suggesting interactions between adipose and lymphatic tissue biology. Currently, treatment of lymphedema involves palliative approaches, including compression garments and physical therapy, and surgical approaches, including liposuction, lymphovenous bypass, and vascularized lymph node transfer. Emerging lymphedema therapies that focus on weight loss or reducing inflammation have been tested in recent clinical trials, yielding mixed results with no effect on limb volumes or changes in bioimpedance measurements. These studies highlight the need for novel therapeutic strategies that target the driving forces of lymphedema. In this light, animal models of lymphedema demonstrate a role of adipose tissue in the progression of lymphedema and suggest these processes may be targeted in the treatment of lymphedema. Herein, we review both conventional and experimental therapies for lymphedema as well as the defining characteristics of its pathophysiology. We place emphasis on the aberrant fibroadipose tissue accumulation in lymphedema and propose a new approach to experimental treatment at the level of adipocyte metabolism.

Prolymphangiogenic Effects of 9-cis Retinoic Acid Are Enhanced at Sites of Lymphatic Injury and Dependent on Treatment Duration in Experimental Postsurgical Lymphedema.

Background: Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged lymphatic vessels fail to adequately regenerate and lymphatic obstruction leads to fluid and protein accumulation in the interstitial space and chronic lymphedema develops as a result. There are currently no effective pharmacological agents that reduce the risk of developing lymphedema or treat pre-existing lymphedema, and management is largely palliative. The present study investigated the efficacy of various 9-cis retinoic acid (9-cis RA) dosing strategies in reducing postsurgical lymphedema by utilizing a well-established mouse tail lymphedema model. Methods and Results: Short-duration treatment with 9-cis RA did not demonstrate a significant reduction in postoperative tail volume, nor an improvement in lymphatic clearance. However, long-term treatment with 9-cis RA resulted in decreased overall tail volume, dermal thickness, and epidermal thickness, with an associated increase in functional lymphatic clearance and lymphatic vessel density, assessed by LYVE-1 immunostaining, compared with control. These effects were seen at the site of lymphatic injury, with no significant changes observed in uninjured sites such as ear skin and the diaphragm. Conclusions: Given the reported results indicating that 9-cis RA is a potent promoter of lymphangiogenesis and improved lymphatic clearance at sites of lymphatic injury, investigation of postoperative 9-cis RA administration to patients at high risk of developing lymphedema may demonstrate positive efficacy and reduced rates of postsurgical lymphedema.