In Vivo Dynamic and Static Analysis of Lymphatic Dysfunction in Lymphedema Using Near-Infrared Fluorescence Indocyanine Green Lymphangiography.

BACKGROUND: Near-infrared fluorescence indocyanine green lymphangiography, a primary modality for detecting lymphedema, which is a disease due to lymphatic obstruction, enables real-time observations of lymphatics and reveals not only the spatial distribution of drainage (static analysis) but also information on the lymphatic contraction (dynamic analysis). METHODS: We have produced total lymphatic obstruction in the upper limbs of 18 Sprague-Dawley rats through the dissection of proximal (brachial and axillary) lymph nodes and 20-Gy radiation (dissection limbs). After the model formation for 1 week, 9 animal models were observed for 6 weeks using near-infrared fluorescence indocyanine green lymphangiography by injecting 6-µL ICG-BSA (indocyanine green-bovine serum albumin) solution of 20-µg/mL concentration. The drainage pattern and leakage of lymph fluid were evaluated and time-domain signals of lymphatic contraction were observed in the distal lymphatic vessels. The obtained signals were converted to frequency-domain spectrums using signal processing. RESULTS: The results of both static and dynamic analyses proved to be effective in accurately identifying the extent of lymphatic disruption in the dissection limbs. The static analysis showed abnormal drainage patterns and increased leakage of lymph fluid to the periphery of the vessels compared with the control (normal) limbs. Meanwhile, the waveforms were changed and the contractile signal frequency increased by 58% in the dynamic analysis. Specifically, our findings revealed that regular lymphatic contractions, observed at a frequency range of 0.08 to 0.13 Hz in the control limbs, were absent in the dissection limbs. The contractile regularity was not fully restored for the follow-up period, indicating a persistent lymphatic obstruction. CONCLUSIONS: The dynamic analysis could detect the abnormalities of lymphatic circulation by observing the characteristics of signals, and it provided additional evaluation indicators that cannot be provided by the static analysis. Our findings may be useful for the early detection of the circulation problem as a functional evaluation indicator of the lymphatic system.

Clinical Utility of Bioelectrical Impedance Analysis Parameters for Evaluating Patients with Lower Limb Lymphedema after Lymphovenous Anastomosis.

BACKGROUND: In lymphedema, lymphatic fluid accumulates in the interstitial space, and localized swelling appears. Lymphovenous anastomosis (LVA) is the most widely used surgery to rebuild a damaged lymphatic system; however, assessing outcome of LVA involves performing volume measurements, which provides limited information on body composition changes. Therefore, we analyzed the bioelectrical impedance analysis (BIA) parameters that can reflect the status of lymphedema patients who underwent LVA. METHODS: We retrospectively reviewed records of 42 patients with unilateral lower extremity lymphedema who had LVA. We measured the perioperative BIA parameters such as extracellular water (ECW) ratio and volume as defined by the percentage of excess volume (PEV). We evaluated the relationship between the amount of change in PEV and in BIA parameters before and after surgery. We confirmed the correlation between ΔPEV and BIA parameters using Spearman's correlation. RESULTS: Most patients included had secondary lymphedema due to cancer. Average age was 51.76 years and average body mass index was 23.27. PEV and all BIA parameters after surgery showed a significant difference (p < 0.01) compared with preoperative measurements. The ECW ratio aff/unaff showed the strongest correlation with PEV with a correlation coefficient of 0.473 (p < 0.01). CONCLUSION: Our findings suggest that BIA parameters, especially ECW ratio aff/unaff could reflect the status of patients with lower limb lymphedema after LVA. Appropriate use of BIA parameters may be useful in the postoperative surveillance of patients.

Rehabilitation in Advanced Cancer Patients with Bone Metastases and Neural Compromise: Current Status and Future Directions.

PURPOSE OF REVIEW: This review aimed to increase the understanding of oncologists and physiatrists about the necessity, efficacy, and safety of rehabilitation in advanced cancer patients with bone metastases and neural compromise. RECENT FINDINGS: Recently, there are growing evidence supporting the safety and efficacy of rehabilitation in patients with bone metastases and neural compromise. Despite the potential benefits of rehabilitation, however, rehabilitative services are considerably underutilized in clinical practice. Many oncologists are not familiar with functional issues and have limited understanding of the available rehabilitative services. Moreover, medical professionals, even physiatrists, have uncertainties and concerns about skeletal complications and often regard rehabilitation as a contraindication in this patient group. This review aimed to raise awareness on the role of rehabilitation in the continuum of cancer treatment, to improve its use in clinical practice. A multidisciplinary team approach involving physiatrist may facilitate integration of relevant clinicians.

Effects of Multimodal Inpatient Rehabilitation vs Conventional Pulmonary Rehabilitation on Physical Recovery After Esophageal Cancer Surgery.

OBJECTIVE: To determine the effects of multimodal rehabilitation initiated immediately after esophageal cancer surgery on physical recovery compared with conventional pulmonary rehabilitation. DESIGN: Retrospective study. SETTING: Private quaternary care hospital. PARTICIPANTS: Fifty-nine inpatients (N=59) who participated in either conventional pulmonary rehabilitation (n=30) or in multimodal rehabilitation (n=29) after esophageal cancer surgery were included. INTERVENTIONS: Both groups performed pulmonary exercises, including deep breathing, chest expansion, inspiratory muscle training, coughing, and manual vibration. In the conventional pulmonary rehabilitation group, light-intensity mat exercise, stretching, and walking were performed. The multimodal rehabilitation group performed resistance exercises and moderate- to high-intensity aerobic interval exercises using a bicycle. MAIN OUTCOME MEASURES: The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30), pain, 6-minute walk test (6MWT), 30-second chair stand test, and grip strengths were assessed before and after the rehabilitation programs. RESULTS: Symptom scales of pain, dyspnea, and insomnia in the EORTC QLQ-C30 as well as 6MWT improved significantly after each program (P<.05). 6MWT (73.1±52.6 vs 28.4±14.3, P<.001, d=1.15), 30-second chair stand test (3.5±3.9 vs 0.35±2.0, P<.001, d=1.06), and left grip strength (1.2±1.3 vs 0.0±1.5, P=.002, d=0.42) improved significantly in the multimodal rehabilitation group compared with the pulmonary rehabilitation group. While right grip strength also showed more improvement for those undergoing the multimodal program, the mean strength difference was not clinically meaningful. CONCLUSIONS: A multimodal inpatient rehabilitation program instituted early after esophageal cancer surgery improved endurance for walking more than conventional pulmonary rehabilitation as measured by the 6MWT and the 30-second chair stand test.

Characteristics of metastatic brachial plexopathy in patients with breast cancer.

PURPOSE: Brachial plexopathy in cancer patients is a rare but significant complication that causes pain and disability of the upper extremities. Clinical features of breast cancer patients with metastatic brachial plexopathy (MBP) have not been studied. We aimed to investigate the characteristics of MBP in breast cancer patients. METHODS: We retrospectively reviewed medical records of patients with breast cancer with MBP who visited Asan Medical Center from 2000 to 2016; we enrolled 44 patients. We comprehensively reviewed the characteristics, range of metastatic lymph nodes, initial symptoms, location, and severity of brachial plexus injury by electrodiagnostic study, radiologic findings, and associated complications. RESULTS: The mean age of patients with MBP was 51.9 ± 9.3 years; 25% were diagnosed with stage IV breast cancer at initial diagnosis. Weakness was the most common initial symptom of MBP (52.3%). Most patients showed limitation of shoulder range of motion and pain; 66% of patients exhibited malignant lymphedema. Forty-one patients were evaluated by electromyography; upper nerve trunk involvement (22.0%) was more frequent than lower nerve trunk involvement (9.8%). Nineteen patients underwent brachial plexus MRI, and supraclavicular area (SCA) metastasis was most frequent (57.9%). Sixteen patients were examined by both brachial plexus MRI and electromyography; patients with SCA metastasis exhibited significantly more frequent malignant lymphedema (p = 0.019) and upper nerve trunk involvement (p = 0.035), compared with patients with non-SCA metastasis. CONCLUSIONS: Our study revealed clinical features of MBP in breast cancer patients. Additional diagnostic evaluation focused on metastasis or aggravated metastatic tumor is needed when breast cancer patients are diagnosed with brachial plexopathy.

Fluoroscopic Balloon Dilation Using a Flexible Guide Wire to Treat Obstructive Eustachian Tube Dysfunction.

PURPOSE: To prospectively evaluate the midterm outcomes of fluoroscopic eustachian tube (E-tube) balloon dilation by using a flexible guide wire in patients with obstructive E-tube dysfunction. MATERIALS AND METHODS: From October 2016 to September 2017, adult outpatients with persistent otitis media who were unable to perform the Valsalva maneuver were prospectively enrolled. The analysis included 32 E-tubes from 31 patients (18 women, 13 men; mean age, 47 years old, range 25-72 years). Participants underwent fluoroscopic E-tube balloon dilation with a 0.035-inch flexible guide wire and a 6- × 20-mm balloon catheter. Clinical examinations to check for the ability to perform the Valsalva maneuver and otomicroscopy were conducted at 1 week and then at 1, 3, 12, and 18 months after the procedure. RESULTS: Balloon dilation was technically successful in all E-tubes. The mean time required for the procedure was 6.9 minutes (range, 5.8-10.3 minutes). The Valsalva maneuver was successful in opening 25 of 32 E-tubes (78.1%) at 3 months after balloon dilation. During the median follow-up of 15.9 months, failure of the Valsalva maneuver occurred in 4 of 25 improved E-tubes (16%), yielding a 2-year patency rate of 84%. CONCLUSIONS: The fluoroscopic balloon dilation results were encouraging, and using a flexible guide wire for E-tube balloon dilation did not cause a false passage.

Cumulative Experience in Lymphovenous Anastomosis for Lymphedema Treatment: The Learning Curve Effect on the Overall Outcome.

BACKGROUND: The lymphovenous anastomosis (LVA) has become one of the treatment options for lymphedema. However, it is regarded as a difficult surgery that many young microsurgeons are reluctant to try. This report investigates the learning curve in regard to symptom improvement. METHODS: This is a retrospective analysis performed in 33 consecutive lymphedema patients (38 extremities) who underwent only LVAs from August 2010 to February 2016. Surgical outcomes in regard to surgeon's experience were evaluated. The surgeons experience was divided into three groups: early group with less than 2 years, moderate with 2 to 4 years, and mature group with more than 4 years of experience. RESULTS: A total of 31 limbs (8/8 in upper extremity and 23/30 in lower extremity) showed improvement. When we compare volume change and recurrence of cellulitis with regard to surgeon's experience, there were no statistically significant differences. However, the mean time per LVA was significantly decreased as the experience increased over time (p = 0.017). CONCLUSION: LVA is an effective treatment option to reduce the volume in the affected limb and to improve symptoms involved. Regardless of the number and experience of the surgeons, cellulitis improves significantly after LVA. The experience of the surgeon does not significantly impact the positive outcome while proficiency increases with experience.

Effects of a complex rehabilitation program on edema status, physical function, and quality of life in lower-limb lymphedema after gynecological cancer surgery.

OBJECTIVE: The purpose of this study was to investigate the effects of a complex rehabilitation (CR) program and complex decongestive therapy (CDT) on edema status, physical function, and quality of life in patients with unilateral lower-limb lymphedema after gynecologic cancer surgery. METHODS: In this randomized pilot study, 40 patients with secondary unilateral lymphedema, after gynecologic surgery for cervical, endometrial, or ovarian cancer, that had been diagnosed based on clinical assessment and 10% volume differences between the legs were randomly assigned to the CDT (n=20) and CDT combined with CR (CRCDT; n=20) groups. CR comprised stretching, strengthening, and aerobic exercises performed for 40min, five times a week for 4weeks. Intensive CDT was administered by a physical therapist during weeks 0-2 and by the patients themselves during weeks 2-4. Limb volume, bioimpedance, muscular strength, EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30) score, 30-s chair stand test, muscular strength, and GCLQ-K (Korean version of the Gynecological Cancer Lymphedema Questionnaire) score were assessed at baseline and after 4weeks of treatment. RESULTS: The edema status, fatigue, pain, and GCLQ-K scores were significantly improved in both groups after the 4-week intervention (P<0.05). Physical function and fatigue in EORTC QLQ-C30 and the 30-s chair stand test and quadriceps muscle strength were significantly improved in the CRCDT group compared with the CDT group (P<0.05). CONCLUSIONS: CR improves physical function, fatigue, and muscular strength without increasing edema status in patients with unilateral lower-limb lymphedema after gynecologic cancer surgery.

Prevalence and risk factors of adhesive capsulitis of the shoulder after breast cancer treatment.

PURPOSE: The present study investigated the prevalence and risk factors of adhesive capsulitis of the shoulder in breast cancer patients between 13 and 18 months after surgery. METHODS: This study included 271 women who underwent surgery for breast cancer with a postoperative period of 13-18 months. Current adhesive capsulitis was defined as restriction of external rotation and one or more additional directional restrictions with history of shoulder pain. Cumulative adhesive capsulitis was defined as current adhesive capsulitis or a previous history of adhesive capsulitis after breast cancer surgery. Multivariate logistic regression analysis was performed to examine associations between current or cumulative adhesive capsulitis and potential risk factors. RESULTS: Among the 271 study patients, 28 (10.3%) and 21 (7.7%) had cumulative or current adhesive capsulitis, respectively. The incidences of cumulative and current adhesive capsulitis were higher in those aged 50-59 years (odds ratio [OR], 9.912; 95% confidence interval [CI], 1.790-54.880; and OR, 12.395; 95% CI, 1.187-129.444, respectively) and those who underwent mastectomy (OR, 6.805; 95% CI, 1.800-25.733; and OR, 9.645; 95% CI, 2.075-44.829, respectively) or mastectomy with reconstruction (OR, 13.122; 95% CI, 2.488-69.218; and OR, 20.075; 95% CI, 2.873-140.261, respectively). CONCLUSIONS: Adhesive capsulitis of the shoulder is a common problem after breast cancer treatment. An age of 50-59 years and mastectomy are major risk factors for adhesive capsulitis, and breast reconstruction additionally increases the risk. Patients with these risk factors require greater attention for early diagnosis and proper treatment.

Effects of a physical therapy program combined with manual lymphatic drainage on shoulder function, quality of life, lymphedema incidence, and pain in breast cancer patients with axillary web syndrome following axillary dissection.

PURPOSE: The aim of this study was to evaluate the effects of physical therapy (PT) combined with manual lymphatic drainage (MLD) on shoulder function, pain, lymphedema, visible cords, and quality of life (QOL) in breast cancer patients with axillary web syndrome (AWS). METHODS: In this prospective, randomized trial, 41 breast cancer patients with visible and palpable cords on the arm and axilla and a numeric rating scale (NRS) pain score of >3 were randomly assigned to PT (3 times/week for 4 weeks; n = 20) and PT combined with MLD (5 times/week for 4 weeks; PTMLD; n = 21) groups. MLD was performed by a physical therapist and the patients themselves during week 1 and weeks 2-4, respectively. Arm volume, shoulder function (muscular strength; active range of motion; and disabilities of the arm, shoulder, and hand [DASH]); QOL (European Organization for Research and Treatment of Cancer Core and Breast Cancer-Specific QOL questionnaires), and pain (NRS) were assessed at baseline and after 4 weeks of treatment. RESULTS: QOL including functional and symptom aspects, shoulder flexor strength, DASH, and NRS scores were significantly improved in both groups after the 4-week intervention (P < 0.05). NRS score and arm volume were significantly lower in the PTMLD group than in the PT group (P < 0.05). Lymphedema was observed in the PT (n = 6), but not PTMLD, group (P < 0.05). CONCLUSIONS: PT improves shoulder function, pain, and QOL in breast cancer patients with AWS and combined with MLD decreases arm lymphedema.

Anti-inflammatory and lymphangiogenetic effects of low-level laser therapy on lymphedema in an experimental mouse tail model.

The aim of the present study was to investigate the therapeutic mechanism of low-level laser therapy (LLLT) in the mouse tail lymphedema model. Six-week-old female mice were classified into the laser treatment group, sham treatment group, and surgical control group (10 mice per group). LLLT was administered daily for 10 min from the surgical day to 11 days (12 times). Macrophage activation and lymphatic vessel regeneration were evaluated through immunohistochemical staining with anti-F4/80 and anti-LYVE-1 antibodies, respectively, at 12 days post-procedure. Quantitative real-time polymerase chain reaction (qPCR) was performed to measure messenger RNA (mRNA) expression of vascular endothelial growth factor A, B, C, R1, R2, and R3 (VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, and VEGFR3) at 12 days post-procedure. Student's t and one-way ANOVA tests were performed for statistical analyses. Significance was defined as p < 0.05. The thickness of the tail rapidly increased until 6 days in the laser and sham groups. The mice in the laser group showed a significantly decreased thickness compared with the sham group at 10 and 12 days. Immunohistochemistry assay revealed that LLLT reduced inflammation and induced new lymphatic vessel growth. qPCR showed that expressions of VEGFR3 were (p = 0.002) increased in the laser group. These results suggest that LLLT has anti-inflammatory and lymphangiogenetic effects for the management of lymphedema.

Pilot study of effective methods for measuring and stretching for pectoral muscle tightness in breast cancer patients.

[Purpose] To evaluate differences in pectoral muscle tightness according to arm abduction angle and to determine the best arm abduction angle for stretching of pectoral muscle tightness in breast cancer patients. [Subjects and Methods] Horizontal abduction differences of shoulders were measured bilaterally by arm abduction to 45°, 90°, and 135° to determine the best arm abduction angle for measuring pectoral muscle tightness. Thirty-two patients were divided into three pectoral muscle stretching groups (A: 45°, B: 90°, and C: 135°). We measured the shoulder range of motion, scores of the Disabilities of the Arm, Shoulder, and Hand, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the Breast Module, and pain levels (using a visual analog scale) before and after therapy. [Results] The differences in degree of horizontal abduction between shoulders were significantly larger for arm abduction to 90° and 135° than that to 45°. Groups B and C showed greater improvements in horizontal abduction limitations than group A. [Conclusion] Horizontal abduction differences between shoulders are prominent when arms are abducted to 90° and 135°. The appropriate arm abduction angle for measuring horizontal abduction and effective stretching of pectoral muscle tightness may be >90°.

Ultrasonographic features of the skin and subcutis: correlations with the severity of breast cancer-related lymphedema.

PURPOSE: Assessing the severity of breast cancer-related lymphedema (BCRL) requires various clinical tools, yet no standardized methodology is available. Ultrasonography shows promise for diagnosing lymphedema and evaluating its severity. This study explored the clinical utility of ultrasonography in patients with BCRL. METHODS: In this retrospective cross-sectional study, patients with unilateral BCRL were examined. The analyzed data included demographics, lymphedema location, International Society of Lymphology (ISL) stage, surgical history, treatment regimens, and arm circumference. Skin, subcutis, and muscle thicknesses were assessed ultrasonographically at predetermined sites, and the percentage of excess thickness was calculated. Multivariate logistic regression analysis was employed to identify associations between ultrasonographic measurements and advanced lymphedema (ISL 2 or 3). The Lymphedema Quality of Life arm questionnaire was used to evaluate patient-reported outcomes regarding lymphedema and their correlations with ultrasonographic findings. RESULTS: Among 118 patients, 71 were classified as ISL 0-1 and 47 as ISL 2-3. Patients with advanced lymphedema were older, had higher nodal stages, underwent more axillary lymph node dissections, and had higher rates of dominant-arm lymphedema. Multivariate logistic regression revealed significant associations of greater skin thickness (adjusted odds ratio [OR], 4.634; 95% confidence interval [CI], 1.233 to 17.419), subcutis thickness (adjusted OR, 7.741; 95% CI, 1.649 to 36.347), and subcutis echogenicity (adjusted OR, 4.860; 95% CI, 1.517 to 15.566) with advanced lymphedema. Furthermore, greater skin thickness (P=0.016) and subcutis echogenicity (P=0.023) were correlated with appearance-related discomfort. CONCLUSION: Ultrasonographic measurements were significantly associated with advanced lymphedema in BCRL. Ultrasonography represents a valuable diagnostic and severity assessment tool for lymphedema.

Lymphatic remapping by long-term lymphoscintigraphy follow-up in secondary lymphedema after breast cancer surgery.

The purpose of the study is to investigate long-term changes on lymphoscintigraphy and their association with clinical factors in breast cancer-related lymphedema (BCRL) patients. This single-center cohort study included BCRL patients who underwent baseline and follow-up lymphoscintigraphy. The percentage of excessive circumference (PEC) of the affected upper limb compared with the unaffected side was used as an indicator of the clinical severity of BCRL. Each 99mTc-phytate lymphoscintigraphy image was categorized according to the Taiwan lymphoscintigraphy staging system. Clinical parameters and the lymphoscintigraphy stage at baseline and follow-up were compared and analyzed. Eighty-seven patients were included. Baseline and follow-up lymphoscintigraphies were performed at median 7 (interquartile range [IQR]: 2‒14) and 78 (IQR: 49‒116) months after surgery, respectively. Both lymphoscintigraphy stage and PEC showed variable change with overall increases in their severity. Stepwise multivariable analysis revealed follow-up lymphoscintigraphy stage (P = 0.001) to be independent variables for PEC at follow-up, however, baseline lymphoscintigraphy stage was not. The clinical courses of BCRL and patients' lymphoscintigraphy patterns showed diverse changes over long-term follow-up. In addition to initial lymphoscintigraphy for diagnosis, lymphatic remapping by follow-up lymphoscintigraphy can be useful to visualize functional changes in the lymphatic system that may guide the optimal management in BCRL.

Does Lymphovenous Anastomosis Effect Mammalian Target of Rapamycin Inhibitor-associated Lymphedema Patients?

The mammalian target of rapamycin (mTOR) inhibitors are used to prevent organ transplant rejection and are preferred over other immunosuppressants due to its low nephrotoxicity. However, mTOR inhibitors have been associated with various adverse effects including lymphedema. Although rare in incidence, previously known treatments for mTOR inhibitor-induced lymphedema were limited to discontinuation of related drugs and complex disruptive therapy with variable results. In this article, three patients who developed lymphedema in their lower limbs after using mTOR inhibitors, including two bilateral and one unilateral case, were treated with physiologic surgery methods such as lymphovenous anastomosis (LVA) and lymph node transfer. The efficacy of the treatment was evaluated. In the three cases described, cessation of the drug did not lead to any reduction in edema. The use of LVA and lymph node transfer resulted in early reductions in volume but failed to sustain over time. All patients underwent secondary nonphysiologic surgery such as liposuction resulting in sustained improvement. This series presents the first physiologic approach to mTOR inhibitor-induced lymphedema. Although further study is warranted, the physiologic surgical options may have limited success and nonphysiologic options may offer better sustainable results.

Investigation of optimizing indocyanine green solution for in vivo lymphatic research using near-infrared fluorescence indocyanine green lymphangiography.

Despite the tireless efforts of many researchers in lymphatic research, indocyanine green (ICG) solution conditions suitable for lymphatic circulation tests have not been perfectly established yet. We aimed to investigate the optimal in vivo conditions of ICG solution to avoid photobleaching and quenching effects, which may affect the accuracy of lymphatic circulation evaluation. After ICG fluorescence intensity (or ICG intensity) was assessed under different in vitro conditions, the image quality of brachial lymph nodes (LNs) and collecting lymphatic vessels (LVs) in eight rats was investigated. The in vitro results showed that ICG intensity depends on concentration and time in various solvents; however, the brightest intensity was observed at a concentration of 8-30 µg/mL in all solvents. ICG concentration in the albumin (bovine serum albumin; BSA) solution and rat's plasma showed more than two times higher fluorescence intensity than in distilled water (DW) in the same range. However, saline reduced the intensity by almost half compared to DW. In the in vivo experiment, we obtained relatively high-quality images of the LNs and LVs using ICG in the BSA solution. Even at low concentrations, the result in the BSA solution was comparable to those obtained from high-concentration solutions commonly used in conventional circulation tests. This study provides valuable information about the conditions for optimal ICG intensity in near infrared fluorescence indocyanine green (NIRF-ICG) lymphangiography, which may be useful not only for the diagnosis of lymphatic circulation diseases such as lymphedema but also for preclinical research for the lymphatic system.

The effects of postoperative treadmill exercise on rats with secondary lymphedema.

Cancer-related lymphedema (LE) is often caused by radiotherapy and surgery such as lymph node dissection (LND). Previous studies have reported that exercise is beneficial to relieve LE, but the changes in the lymphatic system following exercise are still unclear. This study aimed to examine the changes in lymphatic drainage pathways over the exercise period and beneficial effects of exercise in rats with LE. Twelve rats were randomly allocated into exercise and control groups (EG and CG; n = 6 each). To obtain LE, inguinal and popliteal LND followed by 20 Gy irradiation was performed. Treadmill exercise was 30 minutes/day, 5 days/week over the four-week period. Consecutive indocyanine green (ICG) lymphography images were collected and classified into five patterns: i) linear; ii) splash; iii) stardust; iv) diffuse, and v) none. Ankle thickness was measured weekly. Histopathological evaluation was performed to examine the skin thickness, collagen area fraction (%) and lymphatic vessel density in harvested tissue. ICG lymphography exhibited more linear and splash patterns in the EG at week 3. The difference of swelling between both groups was significantly different at week 4 (p = 0.016). Histopathologic data revealed a thinner epidermis (p = 0.041) and dermis (p = 0.002), lower collagen area fraction (%, p = 0.002), and higher lymph vessel density (p = 0.002) in the EG than the CG. In conclusion, we found that postoperative exercise can facilitate improvement in lymphatic fluid retention in the lymphedema rat model, resulting in improvement of pathological conditions in the lymphatic system.

Lymphatic channel sheet of polydimethylsiloxane for preventing secondary lymphedema in the rat upper limb model.

Secondary lymphedema is a severe complication of cancer treatment, but there is no effective curative method yet. Lymph node dissection and radiation therapy for cancer treatment may lead to secondary lymphedema, which is a chronic disease induced by malfunction of lymphatic flow. The lymphatic channel sheet (LCS) is an artificial micro-fluidic structure that was fabricated with polydimethylsiloxane to maintain lymphatic flow and induce lymphangiogenesis. The structure has two-dimensional multichannels that increase the probability of lymphangiogenesis and allow for relatively easy application. We verified the efficacy of the lymphatic channel sheet through macroscopic and microscopic observation in small animal models, which underwent brachial lymph node dissection and irradiation. The lymphatic channel sheet enabled the successful transport of lymphatic fluid from the distal to the proximal area in place of the removed brachial lymph nodes. It prevented swelling and abnormal lymphatic drainage during the follow-up period. Lymphangiogenesis was also identified inside the channel by histological analysis after 8 weeks. According to these experimental results, we attest to the roles of the lymphatic channel sheet as a lymphatic pathway and scaffold in the rat upper limb model of secondary lymphedema. The lymphatic channel sheet maintained lymphatic flow after lymph node dissection and irradiation in an environment where lymph flow is cut off. It also relieved symptoms of secondary lymphedema by providing a lymph-friendly space and inducing lymphangiogenesis.

The Role of Escin as a Topical Agent for Lymphedema Treatment in a Rat Model.

Escin, a naturally derived material isolated from horse chestnut, is used as an anti-inflammatory and anti-edema agent. This study aimed to evaluate its effects on lymphedema in a rat tail model. We divided the rats into five groups. The treatment groups received topical application of escin gel at concentrations of 20%, 10%, 2%, and 0.5% for 4 weeks. The fifth group served as a control. We performed volumetric (water displacement) tests, H&E staining, and LYVE-1 immunohistochemical staining, followed by statistical evaluation. All treatment groups showed significant volumetric reductions compared with the control group, but no significant differences were observed between the treatment groups. H&E staining showed a significant reduction in dermal thickness in the 20%, 10%, and 2% escin treatment groups compared to the control group. Within the treatment groups, the 2% escin group showed a significant difference compared with the 20% and 10% escin groups (p = 0.021 for both). LYVE-1 immunohistochemical staining revealed a significantly higher mean lymphatic vessel count in the 2% escin group compared with the 20%, 10%, and 0.5% escin-treated groups and the control group (p = 0.019, p = 0.025, p = 0.019, and p = 0.032 respectively). Topical escin applied to a rat tail model of acute lymphedema resulted in a significant reduction in tail volume, reduced dermal thickness, and increased lymphatic structures. The 2% escin concentration may be the optimal dose for improving lymphedema in this model. Further research is warranted to explore the clinical application of escin in patients with lymphedema.

The effects of inspiratory muscle training with pulmonary rehabilitation on NSCLC patients during radiation therapy: A pilot clinical study.

BACKGROUND: The effects of inspiratory muscle training (IMT) with pulmonary rehabilitation (PR) on patients with non-small cell lung cancer (NSCLC) receiving radiotherapy (RT) have not previously been reported. This pilot study aimed to determine the effectiveness of IMT with PR on respiratory muscles and exercise capacity of NSCLC patients receiving RT. METHODS: We retrospectively analyzed 20 patients who underwent RT for NSCLC. The rehabilitation included IMT, stretching, strengthening, and aerobic exercises three times a week for 4 weeks with concurrent RT. IMT training lasted 10 min, consisting of one cycle of 30 breaths using the Powerbreathe KH1 device in the hospital by a physical therapist. Patients underwent two IMT sessions at home daily at an intensity of approximately 30%-50% of the participant's maximum inspiratory muscle pressure (MIP) using the threshold IMT tool. We analyzed the results from the respiratory muscle strength test, pulmonary function test, 6-min walk test (6MWT), cardiopulmonary function test, cycle endurance test (CET), Inbody test, grip measurement, knee extensor/flexor strength measurement, Cancer Core Quality of Life Questionnaire (EORTCQ-C30), and NSCLC 13 (EORTC-LC13). RESULTS: There were no adverse events during evaluation and IMT with PR. MIP (60.1 ± 25.1 vs. 72.5 ± 31.9, p = 0.005), 6MWT (439.2 ± 97.1 vs. 60.7 ± 97.8, p = 0.002), CET (181.39 ± 193.12 vs. 123.6 ± 87.6, p = 0.001), knee extensor (14.4 ± 5.3 vs. 17.4 ± 5, p = 0.012), and knee flexor (14.0 ± 5.2 vs. 16.9 ± 5.5, p = 0.004) significantly improved after IMT with PR. CONCLUSION: IMT with PR appears effective on respiratory muscles and exercise capacity without adverse events in NSCLC patients who underwent RT.