Yellow Nail Syndrome: Analysis of 23 Consecutive Patients and Effect of Combined Fluconazole-Vitamin-E Treatment.

INTRODUCTION: Yellow nail syndrome (YNS), a very rare disorder of unknown etiology, is characterized by a triad associating yellow nails, respiratory manifestations, and lymphedema. YNS treatment remains non-codified. METHOD: This retrospective study was conducted from January 2008 to December 2022 in a single tertiary department exclusively dedicated to lymphatic diseases. All consecutive patients with YNS were included. RESULTS: Thirteen men and 10 women were included. Three patients had yellow nails at birth or during childhood. For the other 20 patients, median (Q1-Q3) age at first sign was 50.8 (43-61) years, with first-YNS-sign-to-diagnosis interval of 17 (10-56) months. For 4 patients, YNS was associated with primary intestinal lymphangiectasia. The first YNS sign was chronic cough (45.5%), followed by yellow nails (27.3%), chronic sinusitis (18.2%), and lymphedema (9.1%). At first consultation for all patients, 69.6% had the complete triad, all had yellow nails and cough, 82.6% had chronic sinusitis, and 69.6% had lymphedema. Twelve patients' lymphedema involved only the lower limb(s), 2 the lower and upper limbs, and 2 the lower and upper limbs and face. Nineteen (82.6%) patients were prescribed fluconazole (100 mg/day [n = 8] or 300 mg/week [n = 11]) combined with vitamin E (1,000 mg/day) for a median of 13 months. Responses were complete for 4 (21.1%) patients, partial for 8 (42.1%), and therapeutic failures for 7 (36.8%). CONCLUSIONS: YNS is a rare disease that almost always starts with a chronic cough. Despite inconstant efficacy, fluconazole-vitamin E in combination can be prescribed to treat yellow nails.

The VASCERN PPL working group patient pathway for primary and paediatric lymphoedema.

Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed.

Clinical and Scintigraphic Predictors of Primary Lower Limb Lymphedema-Volume Reduction During Complete Decongestive Physical Therapy.

BACKGROUND: Primary lower limb lymphedema is a chronic debilitating disorder without curative treatment. The initial treatment phase is dedicated to reducing lymphedema volume, whereas the second aims to stabilize that volume. OBJECTIVE: The objective of this study was to analyze clinical and lymphoscintigraphic characteristics during complete decongestive physical therapy as predictors of primary unilateral lower limb lymphedema-volume reduction. DESIGN: This observational, retrospective study included 222 consecutive patients (January 2009-January 2017; median age: 45.8 years) with lymphedema affecting the entire lower limb, who received complete decongestive physical therapy for the first time in a specialized lymphedema management center. METHODS: Complete decongestive physical therapy consisted of low-stretch bandaging, manual lymph drainage, exercises, and skin care for all patients. Lymphoscintigraphy preceded treatment. RESULTS: Median lymphedema evolution was 73 months, and median excess volume was 34%. Median (interquartile range) lymphedema volumes were 2845 (1038-3487) mL before and 1276 (601-2195) mL after a median of 11 days of complete decongestive physical therapy, with 34% median reduction. Multivariate analyses retained age, body mass index >40 kg/m2, and previous cellulitis, as independently associated with lymphedema volume reduction. For each additional year of age, volume reduction increased 0.16%. Unexpectedly, log-transformed initial lymphedema volumes indicated a negative impact, that is, 4.95%, for each log-unit gain. Patients with previous cellulitis episode(s) obtained 6.9% and those with BMI >40 kg/m2 17.1% higher lymphedema volume reductions. Lower limb lymphoscintigraphy was available for 150 (67.6%) patients. Having dermal back flow was associated with greater lymphedema volume reduction than not (respectively, 39% vs 31%). LIMITATIONS: This study was retrospective, and only 67.6% of patients underwent lymphoscintigraphy. CONCLUSION: Our analysis identified clinical and scintigraphic predictors of primary lymphedema volume reduction for patients with unilateral disease. Lymphoscintigraphy helps confirm lymphedema and predict volume reduction. Further study is required to confirm these observations.

The close relationship between heparanase and epithelial mesenchymal transition in gastric signet-ring cell adenocarcinoma.

Heparanase (HPSE), a heparan sulfate-specific endo-ß-D-glucuronidase, plays an important role in tumor cell metastasis through the degradation of extracellular matrix heparan sulfate proteoglycans. Suramin, a polysulfonated naphthylurea, is an inhibitor of HPSE with suramin analogues. Our objective was to analyze the HPSE involvement in gastric signet ring cell adenocarcinoma (SRCA) invasion. High expression of HPSE mRNA and protein was found in the tumor and in ascites of SRCA as well as in KATO-III cell line. Beside of collagen-I, growth factors (TGF-ß1 and VEGF-A, except FGF-2) and epithelial mesenchymal transition (EMT) markers (Snail, Slug, Vimentin, α-SMA and Fibronectin, except E-cadherin) were found higher in main nodules of SRCA as compared to peritumoral sites. Among MDR proteins, MDR-1 and LRP (lung resistance protein) were highly expressed in tumor cells. The formation of 3D cell spheroids was found to be correlated with their origin (adherent or non-adherent KATO-III). After treatment of KATO-III cells with a HPSE inhibitor (suramin), cell proliferation and EMT-related markers, besides collagen-1 expression, were down regulated. In conclusion, in SRCA, HPSE via an autocrine secretion is involved in acquisition of mesenchymal phenotype and tumor cell malignancy. Therefore, HPSE could be an interesting pharmacological target for the treatment of SRCA.

Thrombopoietin Secretion by Human Ovarian Cancer Cells.

The thrombopoietin (TPO) gene expression in human ovary and cancer cells from patients with ovarian carcinomatosis, as well as several cancer cell lines including MDA-MB231 (breast cancer), K562 and HL60 (Leukemic cells), OVCAR-3NIH and SKOV-3 (ovarian cancer), was performed using RT PCR, real-time PCR, and gene sequencing. Human liver tissues are used as controls. The presence of TPO in the cells and its regulation by activated protein C were explored by flow cytometry. TPO content of cell extract as well as plasma of a patient with ovarian cancer was evaluated by ELISA. The functionality of TPO was performed in coculture on the basis of the viability of a TPO-dependent cell line (Ba/F3), MTT assay, and Annexin-V labeling. As in liver, ovarian tissues and all cancer cells lines except the MDA-MB231 express the three TPO-1 (full length TPO), TPO-2 (12 bp deletion), and TPO-3 (116 pb deletion) variants. Primary ovarian cancer cells as well as cancer cell lines produce TPO. The thrombopoietin production by OVCAR-3 increased when cells are stimulated by aPC. OVCAR-3 cell's supernatant can replace exogenous TPO and inhibited TPO-dependent cell line (Ba/F3) apoptosis. The thrombopoietin produced by tumor may have a direct effect on thrombocytosis/thrombosis occurrence in patients with ovarian cancer.