A multidisciplinary approach to managing lymphorroea in primary lymphoedema: a case study.

This case study describes the successful management of a patient with primary lymphoedema, who was experiencing lymphorrhoea and epidermolysis, using a multidisciplinary approach. The patient had Klippel-Trenaunay syndrome. The multidisciplinary team, in an outpatient clinic in Japan, included a certified lymphoedema therapist, plastic surgeons, and a wound, ostomy and continence nurse. The team performed complex physical therapy and lymphaticovenular anastomosis, which promoted the resolution of the lymphorrhoea. This resulted in improvements in skin condition, the prevention of recurrent cellulitis, and no increase in limb circumferences during the 1-year follow-up period. This report highlights the importance of a multidisciplinary approach to lymphoedema management, including lymphorrhoea control that fitted in with the patient's daily life. It is hoped that this article will contribute to the improvement of the quality of life of patients with lymphoedema.

Lymphatic-venous anastomosis for the treatment of refractory lymphatic ascites following radiation therapy: A case report.

Radical treatments for intra-abdominal malignancies disturb physiological lymphatic drainage and predispose the patients to lymphatic complications such as lymphatic ascites. Despite its infrequent occurrence, lymphatic ascites is a morbid complication, and a definitive treatment protocol for refractory cases has not been established. Surgical treatments are opted depending on the etiology, symptoms, and facility equipment. Lymphatic-venous anastomosis (LVA) bypasses the proximal lymphatic blockages and provides an alternative route for lymphatic fluid recirculation into the venous system, thereby improving the lymphatic congestion. Herein, we report the utility of LVA surgery in the treatment of refractory serous lymphatic ascites that developed after radiation therapy for cervical cancer in a 77-year-old woman. The patient had massive ascites and suffered from abdominal distention and anorexia for 1 year. The ascites was unresponsive to conservative treatment. Under local anesthesia, eight incisions were made in the lower extremities just above the lymphatic channels that were identified by indocyanine green lymphography, and a total of 14 LVAs were created. The postoperative course was uneventful, and the ascites improved significantly. The patient remained free from the recurrence of ascites during 3.5 years of postoperative follow-up. LVA surgery was effective for the improvement and long-term control of lymphatic ascites. This procedure may be a viable option for the management of lymphatic ascites.

Real-time image-sharing to educate a patient with lymphoedema on self-care: a case study.

INTRODUCTION: Compression therapy is important in oedema control in lymphoedema. However, some patients have difficulties starting compression therapy because standard self-care education does not enable them to fully understand lymphoedema and recognise it as their problem. To overcome this, real-time image-sharing education, using a combination of indocyanine green lymphography (ICG) and ultrasonography, may be used to educate patients. In this case study, real-time image-sharing education promoted decision-making and behaviour change in a patient with lower extremity lymphoedema so she would wear elastic stockings. CASE: A 51-year-old woman with a BMI of 31.7 kg/m2 and secondary lower extremity lymphoedema following cervical cancer surgery did not adhere to self-care instructions regarding wearing elastic stockings for 5 years. The oedema worsened, her limb circumference increased and she had two episodes of cellulitis within a year. Because the patient had a negative attitude towards elastic stockings, real-time image-sharing education was used to promote recognition of illness using ICG and an understanding of the condition of lymphoedema using ultrasonography. After the images were shared and explained, the patient discussed her recognition and understanding of lymphoedema, then decided to use compression stockings. She continued to wear them for 4 months, and her limb circumference decreased. CONCLUSION: Real-time image-sharing education using ICG and ultrasonography as self-care support for a lymphoedema patient who would not start compression therapy could result in behavioural changes and the patient starting and continuing to wear elastic stockings.

Establishing a Lymphatic Venous Anastomotic Training Model in Pig Trotters.

BACKGROUND: Lymphatic venous anastomosis (LVA) is a widely accepted surgical procedure for lymphedema. To obtain the best outcomes, surgeons should be well trained. A recent study introduced an LVA training model using pig trotters for their utility and structural similarity to human tissues. However, details regarding the utilization of anastomosis models, such as feasible points for training based on vessel anatomy, have not been clarified. Therefore, we assessed the anatomical details of lymphatic vessels and veins of trotters to establish a practical training model of LVA. METHODS: Ten frozen trotters were used. After thawing at room temperature, indocyanine green fluorescent lymphography was used to visualize the lymphatic course. To dissect the lymphatic vessels and veins from the distal to the proximal end, whole skins were detached thoroughly from the plantar side. Data from the lymphatic vessels and veins were collected based on their courses, diameters, and layouts to clarify adjacent points feasible for LVA training. RESULTS: Both lymphatic vessels and veins were classified into four major courses: dorsal, medial, lateral, and plantar. The majority were dorsal vessels, both lymphatic vessels and veins. The adjacent points were always found in the distal dorsum center and were especially concentrated between the metacarpophalangeal (MP) joint and central interphalangeal crease, followed by the medial and lateral sides. CONCLUSION: The most relevant point for LVA surgical training in the trotter was the dorsal center distal to the MP joint, where parallel vessels of similar sizes were found in all cases. This practical LVA surgical model would improve surgeon skills in not only anastomosis but also preoperative fluorescent lymphography.

Prediction of patients with a tumor proportion score > 50% who do not respond to first-line monotherapy with pembrolizumab.

BACKGROUND: Pembrolizumab is effective as first-line therapy against advanced non-small cell lung cancer (NSCLC) in patients with programmed death ligand-1 (PD-L1) expression levels ≥50% [1]. However, it is not effective in all patients, and the factors predicting responses among this population remain unknown. METHODS: We retrospectively analyzed patients with NSCLC and a PD-L1 tumor proportion score (TPS) > 50%, who received first-line monotherapy with pembrolizumab from February 1, 2017 to April 30, 2018. The study included 11 hospitals, which participated in the Hanshin Oncology clinical Problem Evaluation group (HOPE). We analyzed the differences between responders and non-responders in terms of age, sex, performance status score, degree of progression, histological type, smoking history, expression of PD-L1, use of steroids prior to treatment, metastasis site, and laboratory data. RESULTS: A total of 205 patients were included in this study. Of those, 108 patients exhibiting complete or partial response were defined as responders. Those exhibiting progressive disease (N = 52) were defined as non-responders. In the univariate analysis, Eastern Cooperative Oncology Group performance status score ≥ 2 (p = 0.0832), stage IV disease or recurrence (p = 0.0487), PD-L1 TPS 50-89% (p = 0.0657), use of steroids prior to the administration of pembrolizumab (p = 0.0243), malignant pleural effusion (p = 0.0032), and baseline C-reactive protein (CRP) levels > 1.0 mg/dL (p = 0.0390) were significantly associated with non-response to treatment. In the multivariate analysis, use of steroids prior to the administration of pembrolizumab (odds ratio [OR]: 5.86; 95% confidence interval [CI]: 1.32-31.8; p = 0.0200), malignant pleural effusion (OR: 2.68; 95% CI: 1.15-6.35; p = 0.0228), and baseline CRP > 1.0 mg/dL (OR: 2.17; 95% CI: 1.03-4.68; p = 0.0402) were significantly associated with non-response to treatment. CONCLUSION: In real-world patients with NSCLC and a PD-L1 TPS ≥50%, use of steroids prior to treatment, malignant pleural effusion, and baseline CRP levels > 1.0 mg/dL reduced the response of first-line monotherapy with pembrolizumab.

Microscope-Induced Thermal Burns During Lymphaticovenular Anastomosis.

Bright illumination sources using xenon lamps have improved microsurgical visualization under an operating microscope; however, surgeons must recognize the potential for accidental thermal damage to soft tissues.In this article, we present 2 reports of microscopic thermal burn in lymphaticovenular anastomosis (LVA).A 23-year-old woman and a 57-year-old woman with bilateral lymphedema of the legs had LVAs on both legs under local anesthesia. The burn wound in a 23-year-old woman was full thickness, and the one in a 57-year-old woman was deep dermal burn. Both of them healed without skin grafting.Working distance and high illumination intensity are important risk factor. The use of epinephrine as part the local anesthetic mixture that decreases blood flow is also a major risk factor for thermal burns. Lymphaticovenular anastomosis particularly requires high magnification, which leads to increasing the intensity and decreasing the working distance. The surgical conditions around LVA are inherently prone to microscope-induced thermal burns.

Simultaneous Determination of Size and Position of Silver and Gold Nanoparticles in Onion Cells using Laser Ablation-ICP-MS.

Size distribution and mapping analyses of Ag and Au nanoparticles (NPs) have been made using an ICP-MS combined with laser ablation sampling technique (LA-ICP-MS). With the femtosecond laser (Ti:S laser) ablation system, the measured size distribution was modified to be smaller, whereas this disintegration could be reduced when the nanosecond laser (ArF Excimer laser) ablation was employed. This suggests that both the size and position of the NPs can be defined by the nanosecond LA-ICP-MS technique. More importantly, based on the peak-height analyses (PHA) of the measured signal intensity profiles, the present form of the analytes, whether particulate or ionic form, could be defined. This is very important to investigate the transport of the NPs within biological samples. To demonstrate the unique feature of the technique, imaging analyses of Ag and Au NPs, together with distribution analysis of the ionic form, were conducted on onion cells, prepared through dosing experiments of the Ag and Au NPs. There were clear differences in both the increasing rates of the numbers of NPs and the concentration range of the ionic form between the Ag and Au. The data obtained here demonstrate clearly that the LA-ICP-MS technique can become a major analytical tool to obtain both the size distribution and position of NPs from tissue samples.

Mechanical Dilation With a Nylon Monofilament for 0.1-mm Anastomoses.

Despite advances in supermicrosurgical techniques, the ability to anastomose vessels with a diameter of less than 0.2 mm remains limited. One of the reasons for this limitation is that the dilation methods currently available, such as inserting the tip of a microforceps into the lumen or topical application of a vasodilator such as papaverine hydrochloride or xylocaine spray, are not effective in very small vessels. To overcome this problem, we have developed a method whereby nylon monofilaments are placed inside the vessel lumen to act as a dilator. Using this method, a smaller nylon monofilament is inserted into the vessel as a guide before inserting a larger nylon monofilament as a dilator. After the smaller guide monofilament has been inserted, it is then much easier to insert another monofilament for dilation, even if it is a larger one. Using this method, even a vessel with a diameter of less than 0.1 mm could be dilated to greater than 0.2 mm. The dilator monofilament can also be used as an intravascular stent in the anastomosis. We have found that anastomosis of vessels with a diameter of less than 0.1 mm is possible using this method. In our experience, the immediate patency rate has been 100%. We believe mechanical dilation with a nylon monofilament is helpful for supermicrosurgery and even ultramicrosurgery.

Mechanical Dilation Using Nylon Monofilament Aids Multisite Lymphaticovenous Anastomosis Through Improving the Quality of Anastomosis.

Lymphaticovenous anastomosis (LVA) is now a common treatment for lymphedema. It is important to create as many bypasses as possible to maximize the efficacy of LVA. We have developed a method whereby nylon monofilaments are placed inside the vessel lumen to act as dilators. We refer to this technique as mechanical dilation (MD) to distinguish it from intravascular stenting. In this study, we investigated the efficacy of the conventional supermicrosurgery technique performed with and without MD as a treatment for lower limb lymphedema. The LVA was performed using conventional supermicrosurgery alone in 10 patients (group without MD) and in combination with MD in another 10 patients (group with MD). The mean number of successful LVAs performed per hour was significantly higher in the group with MD than in the group without MD (1.42 ± 0.16 vs 1.14 ± 0.15; P < 0.05). The mean amount of improvement in the lower extremity lymphedema index was significantly greater in the group with MD than in the group without MD (7.34 ± 1.57 vs 4.41 ± 1.53; P = 0.003 < 0.05). A statistically significant correlation was found between the number of successful LVAs and amount of improvement in lymphedema (r = 0.449, P = 0.047 < 0.05). Our findings suggest that use of MD does not shorten the operating time or increase the number of LVAs that can be performed but may make it possible to increase the number of successful LVAs that can be performed between vessels with a diameter of less than 0.3 mm. Use of MD could increase the improvement rate of lymphedema to a greater extent than that achieved by conventional microsurgery alone.

Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung.

BACKGROUND: Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. METHODS: We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 -/- mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 -/- mice. RESULTS: In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 -/- and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 -/- mice. Aldh2 -/- tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 -/- mice than in WT mice. CONCLUSIONS: ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a "premature lung aging" effect.

Unified Synthesis of Right Halves of Halichondrins A-C.

The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with the C1-C19 building blocks 10a-c, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C-C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A-C in excellent overall yields. The right halves of halichondrins A-C (1a-c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.

Visualization of Accessory Lymphatic Pathways in Secondary Upper Extremity Lymphedema Using Indocyanine Green Lymphography.

INTRODUCTION: The anatomical variations in accessory lymphatic pathways around the axillary region may work as a drainage route for excess lymphatic fluid accumulation in secondary upper extremity lymphedema. In this report, accessory lymphatic pathways extending to the shoulder, neck, and breast regions in secondary upper extremity lymphedema patients are shown using indocyanine green (ICG) lymphography. PATIENTS AND METHODS: Between January 2012 and May 2015, 30 limbs of 29 patients with upper extremity lymphedema after malignant tumor resection were evaluated. ICG lymphography was performed after chronic lymphedema formation. RESULTS: Of the 30 limbs, accessory lymphatic pathways were identified across the axillary region in 3 patients using ICG lymphography. In 2 of these 3 patients, accessory drainage lymphatics were connected to the cervical lymph nodes. In regard to the distribution of dermal backflow patterns, dermal backflow appeared in 26 patients-in the forearm in 26 patients and in the upper arm in 20 patients. CONCLUSIONS: Accessory lymphatic pathways are thought to be the drainage routes in the affected arm, which may prevent edema progression to the terminal stage. Variations in the lymphatic system are easily visualized using ICG lymphography. Understanding of accessory lymphatic routes in lymphedema patients may provide new insight for further understanding the pathophysiology of lymphedema.

Indocyanine Green Lymphographic Signs of Lymphatic Collateral Formation in Lower Extremity Lymphedema After Cancer Resection.

Indocyanine green lymphography has recently been used to assess lymphatic vessel function in lymphedema patients. Postoperative collateral lymphatic vessels toward ipsilateral axillary lymph nodes are rarely seen above the umbilical level in lower lymphedema patients. Between January 2012 and December 2014, we performed indocyanine green lymphography of 192 limbs in 96 lower extremity lymphedema cases. As a result, dermal back flow appeared in 95 cases, with 38 in the lower abdominal area and 31 in the genital area. We confirmed 3 cases of superficial lymphatic collateral ways extending above the umbilical level to the axillary lymph nodes. All 3 cases had similarity in lower abdominal edema, so excessive lymphatic fluid in the lower abdomen was assumed to be the cause. Lymphatic collateral ways from abdomen to axillary lymph nodes in this study was likely to be designed to prevent the progress of lymphedema.

Practical route to the left wing of CTX1B and total syntheses of CTX1B and 54-deoxyCTX1B.

Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant-sensitive bisallylic ether moiety, by a 6-exo radical cyclization/ring-closing metathesis strategy. This new route enabled us to achieve the second-generation total synthesis of CTX1B and the first synthesis of 54-deoxyCTX1B.

Synthetic ciguatoxin CTX 3C induces a rapid imbalance in neuronal excitability.

Ciguatera is a human global disease caused by the consumption of contaminated fish that have accumulated ciguatoxins (CTXs), sodium channel activator toxins. Symptoms of ciguatera include neurological alterations such as paraesthesiae, dysaesthesiae, depression, and heightened nociperception, among others. An important issue to understand these long-term neurological alterations is to establish the role that changes in activity produced by CTX 3C represent to neurons. Here, the effects of synthetic ciguatoxin CTX 3C on membrane potential, spontaneous spiking, and properties of synaptic transmission in cultured cortical neurons of 11-18 days in vitro (DIV) were evaluated using electrophysiological approaches. CTX 3C induced a large depolarization that decreased neuronal firing and caused a rapid inward tonic current that was primarily GABAergic. Moreover, the toxin enhanced the amplitude of miniature postsynaptic inhibitory currents (mIPSCs), whereas it decreased the amplitude of miniature postsynaptic excitatory currents (mEPSCs). The frequency of mIPSCs increased, whereas the frequency of mEPSCs remained unaltered. We describe, for the first time, that a rapid membrane depolarization caused by CTX 3C in cortical neurons activates mechanisms that tend to suppress electrical activity by shifting the balance between excitatory and inhibitory synaptic transmission toward inhibition. Indeed, these results suggest that the acute effects of CTX on synaptic transmission could underlie some of the neurological symptoms caused by ciguatera in humans.

Chronic ciguatoxin treatment induces synaptic scaling through voltage gated sodium channels in cortical neurons.

Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10-13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin. These findings identify an unanticipated role for ciguatoxin in the regulation of homeostatic plasticity in central neurons involving NaV channels and raise the possibility that some of the neurological symptoms of ciguatera might be explained by these compensatory mechanisms.

Total Synthesis of Limonin.

Limonoids are highly oxygenated C13α-triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (±)-limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13α configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet-oxygen cycloaddition and a Baeyer-Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Suárez reaction to construct the unique AA' ring system.

Differential effects of ciguatoxin and maitotoxin in primary cultures of cortical neurons.

Ciguatoxins (CTXs) and maitotoxins (MTXs) are polyether ladder shaped toxins derived from the dinoflagellate Gambierdiscus toxicus. Despite the fact that MTXs are 3 times larger than CTXs, part of the structure of MTXs resembles that of CTXs. To date, the synthetic ciguatoxin, CTX 3C has been reported to activate voltage-gated sodium channels, whereas the main effect of MTX is inducing calcium influx into the cell leading to cell death. However, there is a lack of information regarding the effects of these toxins in a common cellular model. Here, in order to have an overview of the main effects of these toxins in mice cortical neurons, we examined the effects of MTX and the synthetic ciguatoxin CTX 3C on the main voltage dependent ion channels in neurons, sodium, potassium, and calcium channels as well as on membrane potential, cytosolic calcium concentration ([Ca(2+)]c), intracellular pH (pHi), and neuronal viability. Regarding voltage-gated ion channels, neither CTX 3C nor MTX affected voltage-gated calcium or potassium channels, but while CTX 3C had a large effect on voltage-gated sodium channels (VGSC) by shifting the activation and inactivation curves to more hyperpolarized potentials and decreasing peak sodium channel amplitude, MTX, at 5 nM, had no effect on VGSC activation and inactivation but decreased peak sodium current amplitude. Other major differences between both toxins were the massive calcium influx and intracellular acidification produced by MTX but not by CTX 3C. Indeed, the novel finding that MTX produces acidosis supports a pathway recently described in which MTX produces calcium influx via the sodium-hydrogen exchanger (NHX). For the first time, we found that VGSC blockers partially blocked the MTX-induced calcium influx, intracellular acidification, and protected against the short-term MTX-induced cytotoxicity. The results presented here provide the first report that shows the comparative effects of two prototypical ciguatera toxins, CTX 3C and MTX, in a neuronal model. We hypothesize that the analogies and differences in the bioactivity of these two toxins, produced by the same microorganism, may be strongly linked to their chemical structure.