OBJECTIVE: To perform temporal validation of a risk prediction model for breast cancer-related lymphoedema in the European population.
METHODS: Temporal validation of a previously developed prediction model using a new retrospective cohort of women who had undergone axillary lymph node dissection between June 2018 and June 2020.
METHODS: We reviewed clinical records to identify women who did and did not develop lymphoedema within 2 years of surgery and to gather data regarding the variables included in the prediction model. The model was calibrated by calculating Spearman\'s correlation between observed and expected cases. Its accuracy in discriminating between patients who did versus did not develop lymphoedema was assessed by calculating the area under the receiver operating characteristic curve (AUC).
RESULTS: The validation cohort comprised 154 women, 41 of whom developed lymphoedema within 2 years of surgery. The value of Spearman\'s coefficient indicated a strong correlation between observed and expected cases. Sensitivity of the model was higher than in the derivation cohort, as was the value of the AUC.
CONCLUSIONS: The model shows a good capacity to discriminate women at risk of lymphoedema and may therefore help in developing improved care pathways for individual patients.
UNASSIGNED: Identifying risk factors for lymphoedema secondary to breast cancer treatment is vital given its impact on women\'s physical and emotional well-being.
CONCLUSIONS: What problem did the study address? Risk of BCRL. What were the main findings? The prediction model has a good capacity to discriminate women at risk of lymphoedema. Where and on whom will the research have an impact? In clinical practice with women at risk of BCRL.
UNASSIGNED: STROBE checklist. WHAT DOES THIS PAPER CONTRIBUTE TO THE WIDER GLOBAL CLINICAL COMMUNITY?: It presents a validated risk prediction model for BCRL.
UNASSIGNED: There was no patient or public contribution in the conduct of this study.

Secondary lymphoedema is one of the common complications after lymph node dissection for gynecologic malignancies and breast cancer. In this study, the relationship between PLA2 and postoperative lymphoedema in cancer at the molecular level has been explored through transcriptomics and metabolomic assays. Transcriptome sequencing technology, as well as metabolomic assays, were utilized to explore the expression of PLA2 in lymphoedema patients, and search for potential pathways in the pathogenesis and exacerbation mechanism of lymphoedema. The effect of sPLA2 on human lymphatic endothelial cells was investigated by culturing human lymphatic endothelial cells. Secretory phospholipases A2 (sPLA2) showed high expression levels in lymphoedema tissues, however, cytoplasmic phospholipases A2 (cPLA2), showed low expression in lymphoedema, as demonstrated by RT-qPCR. By culturing human lymphatic vascular endothelial cells, the study found that sPLA2 causes HLEC vacuolization and has an inhibitory effect on HLEC proliferation and migration. By detecting sPLA2 in the serum of lymphoedema patients and analyzing clinical data, it was found that sPLA2 was positively correlated with the severity of lymphoedema. Secretory Phospholipase A2 (sPLA2) is highly expressed in lymphoedema tissue, damages lymphatic vessel endothelial cells, is strongly associated with disease severity, and can be used as a potential predictor of disease severity.Abbreviations: PLA2: Phospholipase A2; DEGs: differentially expressed genes; DMP: differential metabolic production.

Coumarin is an effective treatment for primary lymphoedema, as well as lymphoedema related to breast cancer radiotherapy or surgery. However, its clinical use is limited in several countries due to the possible occurrence of hepatotoxicity, mainly in the form of mild to moderate transaminase elevation. It is worth noting that only a few cases of severe hepatotoxicity have been described in the literature, with no reported cases of liver failure. Data available on coumarin absorption, distribution, metabolism, and excretion have been reviewed, focusing on hepatotoxicity studies carried out in vitro and in vivo. Finally, safety and tolerability data from clinical trials have been thoroughly discussed. Based on these data, coumarin-induced hepatotoxicity is restricted to a small subset of patients, probably due to the activation in these individuals of alternative metabolic pathways involving specific CYP450s isoforms. The aim of this work is to stimulate research to clearly identify patients at risk of developing hepatotoxicity following coumarin treatment. Early identification of this subset of patients could open the possibility of more safely exploiting the therapeutical properties of coumarin, allowing patients suffering from lymphoedema to benefit from the anti-oedematous activity of the treatment.

OBJECTIVE: To identify the risk factors for lymphoedema following axillary lymph node dissection (ALND) in a European sample and to propose a lymphoedema prediction model for this population.
METHODS: Predictive retrospective cohort study comparing women who developed lymphoedema in 2 years of undergoing ALND with those who did not developed lymphoedema.
METHODS: We reviewed the clinical records of 504 women who, between January 2008 and May 2018, underwent surgery for breast cancer that involved ALND. Logistic regression was used to identify significant risk factors for lymphoedema. The prediction accuracy of the model was assessed by calculating the area under the receiver operating characteristic curve.
RESULTS: Of the 504 women whose records were analysed, 156 developed lymphoedema. Significant predictors identified in the regression model were level of lymph node dissection, lymph node status, post-operative complications, body mass index (BMI) and number of lymph nodes extracted. The prediction model showed good sensitivity (80%) in the study population.
CONCLUSIONS: The factor contributing most to the risk of lymphoedema was the level of lymph node dissection, and the only patient-related factor in the prediction model was BMI. The model offers good predictive capacity in this population and it is a simple tool that breast care units could use to assess the risk of lymphoedema following ALND. Nurses with specialist knowledge of lymphoedema have a key role to play in ensuring that women receive holistic and individualized care.
CONCLUSIONS: What problem did the study address? Secondary lymphoedema is one of the main complications in the treatment of breast cancer. What were the main findings? The prediction model included five factors associated with the risk of lymphoedema following ALND. The strongest predictor was the level of lymph node dissection, and the only patient-related factor was BMI. Where and on whom will the research have an impact? The prediction model offers breast care units a tool for assessing the risk of lymphoedema in women undergoing surgery involving ALND. The results highlight the importance of weight reduction as a preventive measure and support a more conservative surgical approach.

UNASSIGNED: Secondary lymphoedema of the extremities is an important quality-of-life issue for patients who were treated for their malignancies. Indocyanine green (ICG) fluorescent lymphography may be helpful for assessing lymphoedema and for planning lymphaticovenular anastomosis (LVA). The objective of the present clinical trial is to confirm whether or not ICG fluorescent lymphography using the near-infrared monitoring camera is useful for assessing the indication for LVA, for the identification of the lymphatic vessels before the conduct of LVA, and for the confirmation of the patency of the anastomosis site during surgery.
UNASSIGNED: This trial is a phase III, multicentre, single-arm, open-label clinical trial to assess the efficacy and safety of ICG fluorescent lymphography when assessing and treating lymphoedema of patients with secondary lymphoedema who are under consideration for LVA. The primary endpoint is the identification rate of the lymphatic vessels at the incision site based on ICG fluorescent lymphograms obtained before surgery. The secondary endpoints are 1) the sensitivity and specificity of dermal back flow determined by ICG fluorescent lymphography as compared with 99mTc lymphoscintigraphy-one of the standard diagnostic methods and 2) the usefulness of ICG fluorescent lymphography when confirming the patency of the anastomosis site after LVA.
UNASSIGNED: The protocol for the study was approved by the Institutional Review Board of each institution. The trial was filed for and registered at the Pharmaceuticals and Medical Devices Agency in Japan. The trial is currently on-going and is scheduled to end in June 2020.
UNASSIGNED: jRCT2031190064; Pre-results.

Background: The International Lymphedema Framework developed an international study, Lymphedema Impact and Prevalence International (LIMPRINT), to estimate the prevalence and impact of chronic edema (CO) in heterogeneous populations. Methods and Results: A validation study using the LIMPRINT methodology was undertaken in Denmark. Participants with CO were identified from inpatient services and compared with those identified within a specialist lymphedema service and three primary care settings. Of 452 inpatients available for screening, CO was present in 177 (39%) and absent in 275 (61%). In addition, 723 participants were found from specialist and primary care services (LPCSs). Inpatients were significantly older and more likely to be underweight or normal weight. They were more likely to suffer from heart failure/ischaemic heart disease (44.6% vs. 23.4%, p < 0.001) and have neurological problems (18.1% vs. 10.9% p = 0.009). Patients in the inpatient group were nearly all suffering from secondary lymphedema and were less likely to have a cancer or venous diagnosis, but more likely to have immobility as the cause of CO (44.0% vs. 17.7%, p < 0.001). No inpatients had midline CO compared with 30 within LPCSs. Fewer in the inpatient group had standard CO treatment (17.1% vs. 73.5%, p < 0.001) and subjective control of swelling was worse (19.9% vs. 66.7%, p < 0.001). While the inpatient group experienced fewer acute infections, when they did so, they were more likely to be admitted to hospital for this (78.6% vs. 51.0%, p = 0.049). Conclusion: The prevalence of CO in inpatient facilities is high and those with CO have multiple comorbidities that vary according to setting. The feasibility study showed that the methodology could be adapted for use in different health systems.

BACKGROUND: Lymphoedema may cause complex problems that can strongly influence patients\' health-related quality of life (HRQoL). The main purpose of this study was to investigate the impact of lymphoedema on HRQoL in patients with varying forms of lymphoedema.
METHODS: The Lymphoedema Quality of Life Inventory (LyQLI), measuring three domains, physical, psychosocial and practical, and the Short Form 36 Health Survey Questionnaire (SF-36), measuring eight health domains, were sent to 200 lymphoedema patients. Out of those who answered both questionnaires, 88 patients had lymphoedema secondary to cancer treatment and they additionally received the Functional Assessment of Cancer Therapy Scale-General (FACT-G). The relation between continuous variables and the three domains were analysed by Spearman\'s correlation coefficients, and Kruskal-Wallis test was used to analyse categorical variables.
RESULTS: Altogether 129 patients completed the LyQLI and SF-36 and 79 of them also completed FACT-G. Twenty per cent had a high mean score (≥2.0) in at least one domain of the LyQLI, thus having a low HRQoL. Lower HRQoL was found in the practical domain of LyQLI in patients with lower limb lymphoedema compared to patient with lymphoedema in upper limb or head/neck (p = 0.002) and in patients working part-time compared to patients working full-time (p = 0.005). The impact on HRQoL tended to decrease with age, with a significant correlation in the psychosocial domain (rs = 0.194, p = 0.028). Compared with the general Swedish population, patients with lymphoedema scored significantly lower in general health (p = 0.006), vitality (p = 0.002) and social functioning (p = 0.025) assessed by the SF-36. From a cancer-specific view, HRQoL was similar to other Swedish studies using the FACT-G.
CONCLUSIONS: This study indicates that about 20% of the patients with lymphoedema had major impact on their HRQoL. More effort and research is needed to identify, understand and support groups of patients with severe lymphoedema-related problems.

The underlying problem in lymphatic filariasis is irreversible swelling of the limbs (lymphoedema), which is a unique feature of lymphatic insufficiency. It is still unclear whether the natural ability of lymphatics to form functional lymphatic vasculature is achieved or attenuated in the lymphoedemal pathology. Clinical studies have clearly shown that circulating lymphatic progenitors (CLPs), a subset of bone marrow-derived mononuclear cells (PBMCs), contribute to post-natal lymph vasculogenesis. CLP-based revascularisation could be a promising strategy to bypass the endothelial disruption and damage incurred by the filarial parasites. Thus our aim was to compare and characterise the functional prowess of PBMCs in physiological and lymphoedemal pathology.
PBMCs were isolated from venous blood sample from drug-naive endemic normals (EN) and drug-deprived filarial lymphoedema (FL) individuals using density gradient centrifugation. Adhesion, transwell migration and in vitro matrigel assays were employed to characterise the lymphvasculogenic potential of PBMCs. CLPs were phenotypically characterised using flow cytometry; expression levels of lymphatic markers and inflammatory cytokines were quantified using qRT-PCR and ELISA, respectively.
PBMCs from FL group display poor adherence to fibronectin (P = 0.040), reduced migration towards SDF-1α (P = 0.035), impaired tubular network (P = 0.004) and branching point (P = 0.048) formation. The PBMC mRNA expression of VEGFR3 (P = 0.039) and podoplanin (P = 0.050) was elevated, whereas integrin α9 (P = 0.046) was inhibited in FL individuals; additionally, the surface expression of CD34 (P = 0.048) was significantly reduced in the FL group compared to the EN group.
PBMCs from filarial lymphoedema show defective and dysregulated lymphvasculogenic function compared to endemic normals.

OBJECTIVE: To define the clinical characteristics, investigations, management and outcomes of lymphoedema in a paediatric cohort.
METHODS: A retrospective chart review of children with lymphoedema seen at two tertiary paediatric hospitals since 1998. Telephone interviews with parents were performed when information was missing. Information recorded included demographic data, features of diagnosis and clinical presentation, symptoms, complications and treatment.
RESULTS: A total of 86 patients with lymphoedema were identified. Eighty cases (93%) were primary and six cases (7%) were secondary. Most were female (60%). Location of swelling was most commonly the lower limbs (94%). There were 13 cases (15%) of genital involvement. Swelling presented in the first 12 months of life in 60% of primary lymphoedema patients. Complications of lymphoedema occurred in 73% of patients. Lymphoscintigraphy was the most common investigation used (65%), followed by ultrasound (57%) and magnetic resonance imaging (MRI) (35%). Eight of the 48 (17%) lymphoscintigraphs produced a false negative result or were inconclusive with a correct diagnosis subsequently made clinically and using MRI. Average time to diagnosis was 9 months. Lymphoedema was managed with compression garments (99%), manual lymph drainage (97%) and multilayered bandaging (68%). Eight patients had an operative procedure as a part of management.
CONCLUSIONS: Primary lymphoedema is more common than secondary lymphoedema in children. Onset tends to be during infancy for both males and females, and the lower limb is typically involved. Causes of secondary lymphoedema are diverse and rare. Diagnosis in children is often delayed but is possible based on history and physical examination alone and when further investigation is necessary MRI is effective.

OBJECTIVE: Lymphoedema is estimated to affect up to 300,000 Canadians but remains underrecognised and undertreated. A retrospective chart review was conducted to determine the clinical characteristics and treatment practices of lymphoedema in a Canadian wound care clinic.
METHODS: Data were collected retrospectively from dictated clinic notes of 326 lymphoedema patients at a wound clinic in a regional rehabilitation hospital.
RESULTS: The mean age (±SD) of diagnosis was 66.8 (±15.5). Patients had 7.3 (±3.3) comorbidities and took 8.4 (±4.6) concomitant medications. The most common comorbidities were venous disease (73%), hypertension (60%), and obesity (46%). Clinic patients were less likely to be women, have arm lymphoedema, or have cancer-related aetiology compared with previous studies, reflecting a two-tiered model of care delivery in the area. Treatments prescribed by the clinic were consistent best practice recommendations for conservative treatment.
CONCLUSIONS: A significant proportion of the wound clinic\'s patients had lymphoedema. Lack of resources, lack of awareness among primary care providers, and patient adherence are barriers to lymphoedema care.