Effects of protein-enriched nutritional support on skeletal muscle mass and rehabilitative outcomes in brain tumor patients: a randomized controlled trial.

Patients with brain tumors require extensive and prolonged rehabilitation efforts as they suffer from lesion-induced motor weakness as well as treatment-related side effects, often leading to a significant decline in function. Protein supplements have shown positive effects on promoting muscle strength and physical performance in various tumor etiologies. However, reports on their effects specifically in brain tumor patients remain scarce. This study aims to investigate the feasibility and efficacy of protein supplements in enhancing rehabilitative outcomes via muscle strengthening and functional gain in brain tumor patients with neurological demise. Sixty brain tumor patients were randomly assigned to either a protein supplement or a control group, receiving either protein supplements or a placebo for 6 weeks, in conjunction with conventional rehabilitation therapy. Assessments before and after the intervention included laboratory tests, anthropometric measures using bioimpedance analysis, and functional assessments, which included the MMSE, the modified Barthel Index, the Beck Depression Inventory, the Brief Fatigue Inventory, the Timed Up and Go test, the 6-min walk test, the isokinetic quadriceps muscle strength test, and the handgrip power. After the intervention, the levels of serum hemoglobin, protein, albumin, and C-reactive protein were improved in both groups, however, the change was significant only in the protein group. The muscle strength was enhanced in both groups, however, the significant increase in pinch grasp power was only noted in the protein group (P < 0.05). The distance on 6MWT was also significantly extended at follow-up in the protein group (P < 0.01). In the subgroup analysis according to nutritional status, the moderate malnutrition group showed greater augmentation of muscle mass than those with adequate nutrition (P < 0.05). Interestingly, the amelioration of malnutrition was observed only the in protein group. This study using protein supplements to promote the rehabilitative potential of brain tumor patients revealed a significant effect on improving hemodynamic nutritional indices, muscle power reimbursement, and functional improvement, especially in malnourished patients. The safety and feasibility of protein supplements in brain tumor patients were affirmative in this study. Further studies with more patients may help confirm the secondary functional gain resulting from increased muscle power.Trial registration: This study was retrospectively registered in the Clinical Research Information Service, CRIS no. KCT0009113 on Jan 12, 2024.

Contrast-enhanced ultrasonography as an adjunctive method to ICG lymphography for functional lymphaticovenous anastomosis.

BACKGROUND AND OBJECTIVES: Indocyanine green (ICG) lymphography is the reference standard for evaluating lymphedema stage and identifying lymphatic vessels. However, the penetration depth was limited to 1-2 cm from the skin surface. This prospective study compares clinical outcomes following lymphaticovenous anastomoses (LVA) in patients with upper and lower limb lymphedema using contrast-enhanced ultrasonography (CEUS) with ICG as a preoperative imaging modality. METHODS: Under general anesthesia, Sonazoid® was injected subcutaneously to visualize functional lymphatic channels via CEUS. We analyzed the changes in limb circumference and inter-limb ratio (ILR) using bioimpedance to measure electrical resistance between the CEUS plus ICG group and the ICG-only group to see the effect of CEUS-assisted LVA. RESULTS: No significant demographic differences existed between the two groups (CEUS plus ICG group vs. ICG-only group). The ILR decrease of the Z1 value measured using bioimpedance was statistically significant (p = 0.042 for the upper limb, p = 0.002 for the lower limb)- CONCLUSIONS: CEUS allowed us to identify deep-lying, functional, and large lymphatic channels. In conclusion, the combination of CEUS and ICG for identifying lymphatic channels has the potential to lead to a more functional lymphovenous anastomosis.

Development and Validation of a Normal Tissue Complication Probability Model for Lymphedema After Radiation Therapy in Breast Cancer.

PURPOSE: To develop and test a multivariable normal tissue complication probability (NTCP) model predicting lymphedema in patients with breast cancer receiving radiation therapy. METHODS AND MATERIALS: We retrospectively reviewed 1345 patients with breast cancer who received radiation therapy from 2 independent institutions. The patients were divided into a training cohort (institution A, n = 368, all treated with 3-dimensional conformal external beam radiation therapy [RT] with 2 Gy/fraction) and an external validation cohort (institution B, n = 977, treated either with 3-dimensional conformal external beam RT or with volumetric modulated RT and either with 1.8-2.0 Gy/fraction or with 2.67 Gy/fraction). Axillary-lateral thoracic vessel juncture (ALTJ) was delineated. The multivariable model was generated using dosimetric and clinical parameters. The performance of the model was comprehensively validated internally and externally. RESULTS: During a median follow-up of 78.7 months for the entire cohort, 97 patients (7.2%) developed lymphedema. The multivariable model that took into account the number of lymph nodes dissected, as well as the volume of the ALTJ receiving a dose ≥35 Gy equivalent doses in 2-Gy fractions (ALTJ V35), showed good agreement between predicted and observed results for both internal and external validation (Hosmer-Lemeshow P value > .05). The area under the receiver operating characteristic curve (AUC) and negative log-likelihood values for the multivariable NTCP model were 0.89 and 0.19 in internal validation and 0.83 and 0.19 in external validation. In addition, the multivariable model performance was acceptable for hypofractionated regimens (AUC 0.70) and volumetric modulated arc therapy (AUC 0.69). The number of lymph nodes dissected and ALTJ V35 were found to be the most important factors influencing lymphedema after radiation therapy. CONCLUSIONS: We first developed and validated the multivariable NTCP model for the lymphedema incidence in patients with breast cancer after radiation therapy. The multivariable NTCP model showed excellent performance and robustness in predicting lymphedema in both internal and completely independent external validations. The multivariable model for lymphedema prediction was robust and reliable for different treatment modalities and fractionation regimens.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Risk factors for lower extremity lymphedema after surgery in cervical and endometrial cancer.

OBJECTIVE: Lower extremity lymphedema (LEL) is a well-known adverse effect related to cervical and endometrial cancer (CEC); however, very few studies have elucidated the clinicopathologic risk factors related to LEL. We investigated the incidence and risk factors in patients who received primary surgery and/or adjuvant radiotherapy (RT) or chemotherapy for CEC. METHODS: We retrospectively reviewed 2,565 patients who underwent primary surgery following CEC diagnosis between January 2007 and December 2020. LEL diagnosis was based on objective and subjective assessments by experts. We identified important predictors of LEL to construct a nomogram predicting individual risks of LEL. For internal validation of the nomogram, the original data were separated using the split-sample method in a 7:3 ratio of training data and test data. RESULTS: Overall, 858 patients (33.5%) received RT, 586 received external beam RT (EBRT), and 630 received intracavitary RT. During follow-up period, LEL developed in 331 patients, with an overall cumulative 5-year incidence of 13.3%. In multivariate analysis, age at primary treatment, use of docetaxel-based chemotherapy, type of hysterectomy, type of surgical pelvic lymph node (LN) assessment, number of dissected pelvic and para-aortic LNs, and EBRT field were the independent predictors of LEL. We subsequently developed the nomogram showing excellent predictive power for LEL. CONCLUSION: LEL is associated with various treatment modalities, and their interactions may increase the possibility of occurrences. De-escalation strategies for treatment modalities should be considered to reduce LEL in patients with CEC.

Impact of Rehabilitation Nutrition and Healthy Weight Maintenance in Motor-Complete Tetraplegia Patients.

Cachexia and low muscle mass in motor-complete tetraplegia are associated with poor outcomes. This study aimed to document anthropometric, body composition, and nutritional indices in patients and to assess the effect of a comprehensive rehabilitation nutrition program in cachexia and low muscle mass. For 34 motor-complete tetraplegia in the subacute phase, a comprehensive rehabilitation nutrition program was provided for 8 to 9 weeks. Risk of malnutrition, anthropometric and body composition indices, as well as laboratory tests were assessed upon admission and at discharge. A body mass index of less than 20.2 kg/m2 was used as the cut-off value for obesity. Upon admission, 73.5% of patients were classified as obese, half were at risk of malnutrition, and 29.4% were compatible with cachexia. Compared to the premorbid state, the non-obese group showed greater weight reduction (p < 0.01) and higher prevalence of low muscle mass (p = 0.004) than the obese group. Disease duration was different between groups (p < 0.01). After rehabilitation, malnutrition risk, protein levels, and hemodynamic results improved in both groups (p < 0.05). A significant time × group interaction was observed for muscle mass, skeletal muscle mass, and appendicular lean mass index (p < 0.05). Muscle mass was maintained while fat components increased in both groups. Functional improvement was negatively correlated with an increase in fat components (p < 0.05). A personalized rehabilitation nutrition intervention improved the nutritional status, body composition, and functional outcomes in motor-complete tetraplegia. The increase in muscle mass was associated with functional gain; healthy weight gain or maintenance may improve the level of independence. Further studies to endorse this beneficial evidence of rehabilitation nutrition in the maintenance of muscle component are needed.

Low-frequency repetitive magnetic stimulation suppresses neuroblastoma progression by downregulating the Wnt/ß-catenin signaling pathway.

Repetitive magnetic stimulation (rMS) has been suggested as a non-invasive treatment for various neurological or psychiatric diseases. Contrary to the application previously used, the purpose of the present study was to elucidate whether low-frequency rMS could suppress tumor progression in in vitro and in vivo neuroblastoma models, and to explore the underlying mechanisms. The results demonstrated that low-frequency rMS treatment significantly suppressed cell proliferation and tumor progression in the models. Moreover, low-frequency rMS treatment downregulated the Wnt/ß-catenin signaling pathway and induced apoptosis. The Wnt/ß-catenin signaling pathway activator, Wnt agonist, was found to counteract the effect of low-frequency rMS treatment, while the Wnt/ß-catenin signaling pathway inhibitor, Wnt antagonist, exhibited a tumor suppression effect, similar to the effect of low-frequency rMS treatment. Taken together, our data demonstrated that low-frequency rMS treatment suppressed neuroblastoma progression by downregulating the Wnt/ß-catenin signaling pathway, suggesting that low-frequency rMS treatment may be a potential therapeutic strategy for the tumor suppression.

Comparison of Clinical Symptoms and Neurophysiological Findings in Patients With Chemotherapy Induced Peripheral Neuropathy.

Introduction: Taxanes are associated with a distal sensory neuropathy, significantly affecting cancer survivor quality of life. However, chemotherapy-induced peripheral neuropathy (CIPN) assessments are primarily based on clinical symptoms rather than objective neurophysiologic findings. Therefore, we investigated neurophysiologic changes in symptomatic subjects, comparing them with symptom severity. Materials and Methods: Medical charts of 111 subjects who were referred for CIPN diagnosis after chemotherapy for breast or ovarian cancer between May 1, 2016, and December 31, 2019, were retrospectively reviewed. Demographics, anthropometric parameters, and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale data were collected. The nerve conduction study (NCS) results, including sensory nerve action potentials recorded from sural nerves, were analyzed relative to clinical symptoms. To optimize follow-up (FU) NCS diagnostic sensitivity, relative references of FU sural amplitude reductions to >30% and an absolute reference <10 µV were used. Results: Eighty-eight female patients met the criteria, and 20 underwent FU NCS. Baseline and FU sural amplitudes showed significant positive correlation with respective LANSS scores (p < 0.01). FU sural amplitude was significantly lower than the initial result (p < 0.05). The FU LANSS score was not different from the initial score. Initial NCS sensitivity and specificity for clinically suspected CIPN diagnoses with LANSS were 69.7 and 47.3%, respectively. All 20 subjects with FU evaluation were clinically compatible with CIPN (LANSS >12) at initial and FU assessments. Among them, only six (30.0%) had abnormal sural amplitudes (<10µV for ≤50 s, <3 µV for 60 s, <1 µV for 70 s) in the initial NCS. In the FU NCS, sural amplitude became abnormal in five additional subjects. Between the initial and FU NCS, sural amplitude was reduced by > 30% in eight subjects (40.0%). NCS sensitivity increased to 65.0% when including either abnormal sural amplitudes or a > 30% reduction in sural amplitude in FU studies. Conclusions: Although clinical symptoms and NCS results were positively correlated, a single NCS point had limited value for suspected CIPN electrophysiological diagnoses. Serial NCS during chemotherapy might help assess the degree of chemotherapy-induced nerve damage, attain evidence of CIPN prior to symptom aggravation, and monitor the progression of CIPN. Further study is needed to find specific relative references for variable patient factors to increase the sensitivity of electrophysiological studies of clinically suspected CIPN.

The Association Between the Number of Retrieved Pelvic Lymph Nodes and Ipsilateral Lower Limb Lymphedema in Patients With Gynecologic Cancer.

PURPOSE: While the risk of lower limb lymphedema (LLE) after radical surgery for gynecologic malignancies is multifactorial, the limited assessment of lymph nodes (LNs), such as sentinel LN biopsy, has been incorporated into a standard procedure. We assessed the relationship between the number of LNs retrieved from the hemipelvis and the incidence of ipsilateral LLE (iLLE). METHODS: This retrospective study included 103 women with gynecologic cancer who had LNs removed with minimally invasive surgery between January 2014 and December 2018. For early detection of LLE, the patients were followed up by a lymphedema specialist who complied with the International Society of Lymphedema criteria. Potential risk factors for LLE were collected, and the risk factors were further investigated according to the number of LNs removed in a side-specific manner. RESULTS: LLE was diagnosed in 32 (31.1%) patients, and most of them were diagnosed with unilateral (n = 22) LLE rather than bilateral (n = 10). The number of pelvic LNs removed (p = 0.018), no lymphatic mapping (p = 0.034), and radiation (p = 0.020) were associated with the development of one or both LLEs. A side-specific analysis revealed that the incidence of iLLE increased significantly when four or more LNs were removed from the hemipelvis compared with three or fewer LNs (22.9% vs. 8.3%, p = 0.048). CONCLUSIONS: The number of pelvic LNs retrieved was associated with the incidence of LLE in patients with early gynecologic cancer. We identified the cutoff number per hemipelvis through side-specific analysis that could minimize the risk of iLLE. Further studies are needed to validate our results.

Risk of Lymphedema Following Contemporary Treatment for Breast Cancer: An Analysis of 7617 Consecutive Patients From a Multidisciplinary Perspective.

OBJECTIVE: The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making. SUMMARY BACKGROUND DATA: Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear. METHODS: We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients. RESULTS: Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I-II vs RNI including axilla I-II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients). CONCLUSIONS: Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.

Feasibility of Bioimpedance Analysis to Assess the Outcome of Complex Decongestive Therapy in Cancer Treatment-Related Lymphedema.

Background: Cancer treatment-related lymphedema (CTRL) affects patients physically, psychologically and emotionally, and remains a significant quality of life issue among patients with cancer. Reliable methods to measure changes in lymphedema are required for early detection, acute intensive treatment, and long-term management. Here, we evaluated the use of bioimpedance analysis (BIA) as a tool to measure lymphedema before and after treatment. Patients and Methods: Patients with CTRL who were admitted to a secondary university hospital between October 2017 and July 2018 for complex decongestive therapy (CDT) were eligible for this prospective cohort study. Circumferential measure (CM) and BIA were used to evaluate lymphedema at admission (initial) and before discharge (follow-up, FU). Volume was calculated from the CM using the truncated cone formula. The inter-limb ratios (ILRs) of the circumference, volume, and impedance were also calculated as the unaffected limb to affected limb. Each parameter before and after treatment and correlations between parameters also were analyzed. Results: A total of 29 patients (12 upper- and 17 lower-extremity CTRL) completed were included in this analysis. Absolute value and the ILRs of circumference, volume or impedance, and extracellular water/total body water (ECW/TBW) were significantly improved at FU (p < 0.01, p < 0.05). The initial and FU absolute values, ILRs, ECW/TBW correlated significantly with each other (p < 0.01, p < 0.05). The cutoff values of ECW/TBW for moderate and severe degree of CTRL were 0.3855 and 0.3955, respectively. The changes of ILRs between initial and FU assessments were significantly different among three groups according to lymphedema severity (p < 0.01, p < 0.05). Conclusions: BIA data correlates significantly with clinical measurement, and therefore can be a practical tool in monitoring outcome measure after lymphedema treatment. In addition, BIA is more sensitive to subtle changes in lymphedema, and therefore can be useful for the long-term maintenance of lymphedema.

Environmental enrichment synergistically improves functional recovery by transplanted adipose stem cells in chronic hypoxic-ischemic brain injury.

We investigated the effects of environmental enrichment (EE) on the function of transplanted adipose stem cells (ASCs) and the combined effect of EE and ASC transplantation on neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in 7-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At 6 weeks of age, the mice were randomly injected with either ASCs or PBS into the striatum and were randomly assigned to either EE or standard cages (SC), comprising ASC-EE (n=18), ASC-SC (n=19), PBS-EE (n=12), PBS-SC (n=17), and untreated controls (n=23). Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. The fate of transplanted cells and the levels of endogenous neurogenesis, astrocyte activation, and paracrine factors were also measured. As a result, EE and ASC transplantation synergistically improved rotarod latency, forelimb-use asymmetry, and grip strength compared to those of the other groups. The number of engrafted ASCs and ßIII-tubulin(+) neurons derived from the transplanted ASCs was significantly higher in mice in EE than those in SC. EE and ASC transplantation also synergistically increased BrdU(+)ßIII-tubulin(+) neurons, GFAP(+) astrocytic density, and fibroblast growth factor 2 (FGF2) level but not the level of CS-56(+) glial scarring in the striatum. In conclusion, EE and ASC transplantation synergistically improved neurobehavioral functions. The underlying mechanisms of this synergism included enhanced repair processes such as higher engraftment of the transplanted ASCs, increased endogenous neurogenesis and astrocytic activation coupled with upregulation of FGF2.