Inflammatory Manifestations of Experimental Lymphatic Insufficiency

BACKGROUND: Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic. METHODS AND FINDINGS: We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response. CONCLUSIONS: We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency

qRT-PCR Confirmation of the Results of Microarray Hybridization

<p>The graph represents fold-changes of expression in lymphedema, relative to normal controls, for each of eight representative genes, by microarray hybridization and qRT-PCR. For <i>MYD88</i> by microarray and <i>HADH2</i> by qRT-PCR, the log (gene expression) equaled zero. <i>HADH2, hydroxysteroid (17-beta) dehydrogenase; 2MMP, matrix metalloproteinase; MYD88, myeloid differentiation primary response gene 88.</i></p

Dynamic Imaging of Immune Traffic in Experimental Lymphedema

<div><p>(A) In vivo bioluminescence imaging of immune traffic. Bioluminescence imaging was performed at defined time points following the introduction of <i>luc⁺</i> cells. This figure contains a representative series of imaging experiments for paired normal control (A) and lymphedema (B) mice. Photon densities range from red (high) to blue (low). In general, clearance of bioluminescent immunocytes from the lymphedematous tails was delayed, but remained unimpaired in the surgical sham controls. The left panel shows a perceptible increase in photon densities in lymphedema on day 3 post-injection (post-operative day 10). Within several days, the disparity in cellular clearance is even more evident (middle panel); as late as day 17 post-injection, there is still visible bioluminescence in the lymphedematous tail, while all activity has cleared from the normal tail (right panel). The original surgical site is depicted by the white arrows. The black marks on the tail denote 8-mm vertical distances; splenocyte injection was performed 24 mm below the surgical site. </p> <p>(B) Quantitative assessment of in vivo bioluminescence imaging of immune traffic. Relative photon density, expressed as a percent of the observed value on day 1, was significantly greater in lymphedema than in normal controls, both at day 3 and at day 7 post-injection (*, <i>p <</i> 0.05; §, <i>p <</i> 0.02). </p></div

LYVE-1 Immunohistochemical Staining

<p>Immunohistochemical staining for LYVE-1 is depicted in surgical sham controls (A) and in lymphedema (B) (black arrows). The lymphedema response is characterized by the presence of numerous dilated microlymphatic structures in the dermis and subdermis. Lymphedema produces a statistically significant increase in average cross-sectional vessel area.</p

Tail Volume Changes at Post-Surgical Day 7 and at Day 14

<p>Tail Volume Changes at Post-Surgical Day 7 and at Day 14</p

Delayed colorectal cancer care during covid-19 pandemic (decor-19). Global perspective from an international survey

Background The widespread nature of coronavirus disease 2019 (COVID-19) has been unprecedented. We sought to analyze its global impact with a survey on colorectal cancer (CRC) care during the pandemic. Methods The impact of COVID-19 on preoperative assessment, elective surgery, and postoperative management of CRC patients was explored by a 35-item survey, which was distributed worldwide to members of surgical societies with an interest in CRC care. Respondents were divided into two comparator groups: 1) ‘delay’ group: CRC care affected by the pandemic; 2) ‘no delay’ group: unaltered CRC practice. Results A total of 1,051 respondents from 84 countries completed the survey. No substantial differences in demographics were found between the ‘delay’ (745, 70.9%) and ‘no delay’ (306, 29.1%) groups. Suspension of multidisciplinary team meetings, staff members quarantined or relocated to COVID-19 units, units fully dedicated to COVID-19 care, personal protective equipment not readily available were factors significantly associated to delays in endoscopy, radiology, surgery, histopathology and prolonged chemoradiation therapy-to-surgery intervals. In the ‘delay’ group, 48.9% of respondents reported a change in the initial surgical plan and 26.3% reported a shift from elective to urgent operations. Recovery of CRC care was associated with the status of the outbreak. Practicing in COVID-free units, no change in operative slots and staff members not relocated to COVID-19 units were statistically associated with unaltered CRC care in the ‘no delay’ group, while the geographical distribution was not. Conclusions Global changes in diagnostic and therapeutic CRC practices were evident. Changes were associated with differences in health-care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical factors. Strategic planning is required to optimize CRC care