Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema.

Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of secondary lymphedema after cancer treatments, current management is supportive and there are no approved therapeutic agents that can thwart disease progression. We have previously demonstrated that 9-cis-retinoic acid (9-cisRA) has the potential to be repurposed for lymphedema as it mitigates disease by promoting lymphangiogenesis at the site of lymphatic injury. Although the efficacy of 9-cisRA has been demonstrated in previous studies, the mechanism of action is not completely understood. In this study, we demonstrate that when RXRα is specifically deleted in lymphatic endothelial cells, 9-cisRA fails to induce lymphangiogenesis in vitro and prevent pathologic progression of postsurgical lymphedema in vivo. These findings demonstrate that downstream nuclear receptor RXRα plays a critical role in the therapeutic efficacy of 9-cisRA in postsurgical lymphedema.

Oncoplastic Augmentation Mastopexy in Breast Conservation Therapy: Retrospective Study and Postoperative Complications.

BACKGROUND: Oncoplastic techniques, in conjunction with lumpectomy and adjuvant radiotherapy, have been demonstrated to achieve good aesthetic results and cancer outcomes in the treatment of patients with macromastia or significant ptosis. This study evaluated a series of patients undergoing breast conservation with concomitant oncoplastic-augmentation-mastopexy and a contralateral augmentation-mastopexy. METHODS: Patients undergoing lumpectomy for breast conservation were identified via a retrospective chart review. Inclusion criteria included patients with ptosis and preexisting breast implants or insufficient breast volume undergoing oncoplastic implant placement/exchange and mastopexy. Demographic characteristics, operative details, and complications were assessed. RESULTS: Thirty-four consecutive patients (64 breasts, 4 unilateral procedures) were included in the study. Average age was 51.4 years, average body mass index was 27, and 38.2% were smokers/former smokers. The average operative time was 2.5 hours. Furthermore, 38.2% of patients received chemotherapy, and 82.4% of patients received breast adjuvant radiotherapy. The average length of follow-up was 11.7 months. In the sample that received radiation, the capsular contracture rate was 25%, with a 7.1% contracture revision rate. For the entire group, a total of 8 patients (23.5%) underwent revisions for either positive margins (8.8%), capsular contracture (8.8%), implant loss (2.9%), or cosmetic concerns (2.9%). One patient developed a pulmonary embolism. CONCLUSIONS: Oncoplastic-augmentation-mastopexy is a safe technique with acceptable complication rates. This technique is best used for breast cancer patients with breast ptosis and a paucity of breast volume or preexisting implants who wish to pursue breast-conserving therapy. The revision rates are acceptable compared with single-stage cosmetic augmentation procedures as well as other oncoplastic techniques described in the literature, but patients must be clearly counseled on contracture risk.

Safely Shaping the Breast After Implant Removal and Total Intact Capsulectomy Using the Mammary Imbrication Lift and Fixation Technique.

Background: Implant-based breast augmentation is one of the most popular plastic surgery procedures performed worldwide. As the number of patients who have breast implants continues to rise, so does the number of those who request breast implant removal without replacement. There is little in the current scientific literature describing total intact capsulectomy and simultaneous mastopexy procedures. Objectives: Here, the authors present their current method using the mammary imbrication lift and fixation technique after explant and total capsulectomy. Methods: Between 2016 and 2021, a total of 64 patients (mean age: 42.95 years; range, 27-78 years) underwent the described mammary imbrication lift and fixation technique with bilateral breast implant removal and total capsulectomy. Results: Mean follow-up was 6.5 months (range, 1-36 months). Postoperative complications included minor cellulitis in 1 patient (1.6%), late onset hematoma with infection in 1 patient (1.6%), fat necrosis and pulmonary embolism in 1 patient with prior history of thromboembolic events (1.6%), and breast scar irregularity in 4 patients (6.2%) who required subsequent minor scar revision or steroid injections. Two patients (1.6%) underwent revision surgery with bilateral breast fat grafting to improve shape and add volume. Conclusions: The mammary imbrication lift and fixation technique described here can safely and simultaneously be performed with a total intact capsulectomy and explant procedure. This technique avoids wide undermining, intentionally opening the capsule, performing subtotal capsulectomy, and preserving blood supply to the breast tissue and nipple with low complication rates.

Racial Disparities in Survival Outcomes of Patients With Serous Epithelial Ovarian Cancer: A Retrospective Cohort Analysis.

OBJECTIVE: To identify racial disparities in five-year survival rates in women affected by serous epithelial ovarian carcinoma in the United States (US). METHODS: This retrospective cohort study analyzed data from the 2010 to 2016 Surveillance, Epidemiology, and End Results (SEER) program database. Women with a primary malignancy of serous epithelial ovarian carcinoma, using International Classification of Diseases for Oncology (ICD-O) Topography Coding and ICD-O-3 Histology Coding, were included in this study. Race and ethnicity were combined into the following groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic Other (NHO), and Hispanics. Cancer-specific survival was measured at five years post-diagnosis. A comparison of baseline characteristics was assessed using Chi-squared tests. Unadjusted and adjusted Cox regression models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (CI). RESULTS: From 2010 to 2016, there were 9,630 women with a primary diagnosis of serous ovarian carcinoma identified in the SEER database. A higher proportion of Asian/PI women (90.7%) were diagnosed with high-grade malignancy (poorly differentiated/undifferentiated) compared to NHW women (85.4%). NHB women (9.7%) were less likely to undergo surgery when compared to NHW women (6.7%). Hispanic women had the highest proportion of uninsured women (5.9%), while NHW and NHAPI had the lowest (2.2% each). A higher proportion of NHB (74.2%) and Asian/PI (71.3%) women presented with the distant disease compared to NHW women (70.2%). After adjustment for age, insurance, marital status, stage, metastases, and surgical resection, NHB women had the highest hazard of death within five years compared to NHW women (adjusted (adj) HR 1.22, 95% CI 1.09-1.36, p<0.001). Hispanic women also had lower five-year survival probabilities compared to NHW women (adj HR 1.21, 95% CI 1.12-1.30, p<0.001). Patients undergoing surgery had significantly increased survival probability compared to those who did not (p<0.001). As expected, women with Grade III and Grade IV disease both had significantly lower five-year survival probabilities compared to Grade I (p<0.001). CONCLUSION: This study reveals that there is an association between race and overall survival in patients with serous ovarian carcinoma, with NHB and Hispanic women having the highest hazards of death compared to NHW women. This adds to the existing body of literature as survival outcomes in Hispanic patients relative to NHW patients are not well documented. Because of the potential interplay between overall survival and several factors including race, future studies should aim to investigate other socioeconomic factors that may be impacting survival.

Racial Disparities in Survival Outcomes of Colorectal Cancer Patients After Surgical Resection.

INTRODUCTION: Colorectal cancer is one of the most common cancers in the United States. Significant disparities exist among racial and ethnic minorities diagnosed with colorectal cancer compared to non-Hispanic Whites. However, understanding of survival outcomes following curative surgical resection in this population is limited. OBJECTIVE: To evaluate the association between race and colorectal cancer-specific mortality in patients who were treated with major surgical resection of the colon.  Materials and Methods: This study was a retrospective cohort analysis using the Surveillance, Epidemiology, and End Results (SEER) Program database from 2010 to 2016. The patient population consisted of adult patients (≥18 years old) diagnosed with a primary malignancy of colorectal cancer treated with major surgical resection of the colon. The main outcome measures were survival time at one and five years following diagnosis and cancer-specific death. RESULTS: A total of 120,598 patients with primary colorectal malignancy treated with surgical resection of the colon were identified. Across all racial groups, most patients presented with moderately differentiated colorectal cancer. Non-Hispanic Blacks had the highest proportion of diffuse metastases (p<0.001). After adjusting for covariates, Hispanic respondents had the lowest one-year survival (adjusted HR: 1.26, 95%CI (1.21-1.31) and five-year survival when compared to Whites (adjusted HR: 1.13, 95%CI: 1.10-1.15). Factors associated with a shorter survival include age ≥ 70 years old, unmarried status, metastatic disease, and high-grade tumors (p<0.001).  Conclusions: Racial disparities exist in the overall survival of patients with colorectal cancer who are treated with surgical resection of the colon. Hispanic patients had the highest hazard of death, followed by Non-Hispanic Asian-Pacific Islanders and Non-Hispanic Blacks, compared to Whites. While surgical resection can be curative, the quality and accessibility of post-operative care may differentiate survival outcomes among racial groups.

Racial and Ethnic Inequality in Survival Outcomes of Women With Triple Negative Breast Cancer.

Purpose Triple-negative breast cancer (TNBC) is the most lethal group of breast cancers. Socioeconomic factors may contribute to differences in survival rates. This study aims to identify racial/ethnic disparities in five-year survival rates among women affected by TNBC in the United States. Methods This retrospective study analyzed data from the 2010-2016 Surveillance, Epidemiology, and End Results Program database. Patients with a primary malignancy of triple-negative breast cancer were included in this study. Cancer-specific survival was measured at five years post-diagnosis. Cox regression models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Results From 2010-2016, there were 26,963 women with a primary diagnosis of TNBC. After adjustment for age, insurance, marital status, stage, and surgery type, Hispanic women had the highest hazard of death when compared to White women (adjusted (adj) HR, 1.14, p<0.001). Further, non-Hispanic Black women also had a lower survival probability when compared to White women (adj HR, 1.06, p=0.002). Conclusion This study reveals that Hispanic women had the highest hazard of death when compared to White women. As TNBC is the most fatal breast cancer, future studies should investigate socioeconomic factors that may worsen prognosis of this disease.

Prolymphangiogenic Effects of 9-cis Retinoic Acid Are Enhanced at Sites of Lymphatic Injury and Dependent on Treatment Duration in Experimental Postsurgical Lymphedema.

Background: Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged lymphatic vessels fail to adequately regenerate and lymphatic obstruction leads to fluid and protein accumulation in the interstitial space and chronic lymphedema develops as a result. There are currently no effective pharmacological agents that reduce the risk of developing lymphedema or treat pre-existing lymphedema, and management is largely palliative. The present study investigated the efficacy of various 9-cis retinoic acid (9-cis RA) dosing strategies in reducing postsurgical lymphedema by utilizing a well-established mouse tail lymphedema model. Methods and Results: Short-duration treatment with 9-cis RA did not demonstrate a significant reduction in postoperative tail volume, nor an improvement in lymphatic clearance. However, long-term treatment with 9-cis RA resulted in decreased overall tail volume, dermal thickness, and epidermal thickness, with an associated increase in functional lymphatic clearance and lymphatic vessel density, assessed by LYVE-1 immunostaining, compared with control. These effects were seen at the site of lymphatic injury, with no significant changes observed in uninjured sites such as ear skin and the diaphragm. Conclusions: Given the reported results indicating that 9-cis RA is a potent promoter of lymphangiogenesis and improved lymphatic clearance at sites of lymphatic injury, investigation of postoperative 9-cis RA administration to patients at high risk of developing lymphedema may demonstrate positive efficacy and reduced rates of postsurgical lymphedema.

Closed Ring Avulsion Injury With Isolated Arterial Insufficiency.

Ring avulsion injuries are an uncommon, often catastrophic, pattern of digit injuries that result from sudden traction onto a ring-bearing digit. The reconstructive treatment of these injuries can be complex because of the characteristic involvement of nerves, muscles, vasculature, and bone. There is paucity of literature describing isolated arterial injuries in the absence of overlying soft tissue and underlying bone involvement. We present an unusual case of a closed ring avulsion injury, wherein a patient initially presented to his local urgent care center with a cool and pale digit without wounds or fractures, and abnormal pulse oximetry readings prompted his transfer to a tertiary care center for further evaluation. Surgical exploration demonstrated isolated disruption of both digital arteries and the preservation of both digital nerves. The digit was successfully revascularized with venous autografting and stripping of arterial thrombi.

Smoking as a Risk Factor for Surgical Site Complications in Implant-Based Breast Surgery.

Background Smoking is a cause of many postoperative complications, including delayed wound healing, tissue necrosis, and reconstructive flap loss. However, there is a paucity of evidence-based guidelines for smoking cessation in patients undergoing implant-based breast surgery. Objective The objective of this study was to determine if smoking is associated with wound dehiscence or superficial/deep surgical site infection (SSI) in women undergoing implant-based breast surgery. Methods Using theAmerican College of Surgeons National Surgical Quality Improvement Program, data was obtained of U.S. adult females (n=10,077) between the ages of 18 and 70 who underwent insertion of a breast prosthesis from 2014 to 2016. The patient's preoperative smoking status, demographics, and comorbidities were analyzed to determine association with wound dehiscence, superficial SSI, and deep SSI. Unadjusted and adjusted logistic regression analyses were used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Results Patients who smoked had a statistically significant higher proportion of wound complications (2.4%) compared to non-smokers (1.3%; p<0.01). Adjusted analysis demonstrated a significantly higher odds of wound complications in smoking patients compared to those who did not smoke (OR 2.0; 95% CI 1.3-3.2). Conclusions Our study suggests that smoking is an independent risk factor for postoperative complications in patients undergoing implant-based breast surgery. These results have significant clinical implications, as increased precautions can be taken in smokers undergoing breast surgery to minimize postoperative wound complications. Future studies may determine the optimal amount of time that patients should abstain from smoking prior to implant-based breast surgery.

Ischemia and reperfusion injury in superficial inferior epigastric artery-based vascularized lymph node flaps.

Vascularized lymph node transfer (VLNT) is a promising treatment modality for lymphedema; however, how lymphatic tissue responds to ischemia has not been well defined. This study investigates the cellular changes that occur in lymph nodes in response to ischemia and reperfusion. Lymph node containing superficial epigastric artery-based groin flaps were isolated in Prox-1 EGFP rats which permits real time identification of lymphatic tissue by green fluorescence during flap dissection. Flaps were subjected to ischemia for either 1, 2, 4, or 8 hours, by temporarily occluding the vascular pedicle. Flaps were harvested after 0 hours, 24 hours, or 5 days of reperfusion. Using EGFP signal guidance, lymph nodes were isolated from the flaps and tissue morphology, cell apoptosis, and inflammatory cytokines were quantified and analyzed via histology, immunostaining, and rtPCR. There was a significant increase in collagen deposition and tissue fibrosis in lymph nodes after 4 and 8 hours of ischemia compared to 1 and 2 hours, as assessed by picrosirius red staining. Cell apoptosis significantly increased after 4 hours of ischemia in all harvest times. In tissue subject to 4 hours of ischemia, longer reperfusion periods were associated with increased rates of CD3+ and CD45+ cell apoptosis. rtPCR analysis demonstrated significantly increased expression of CXCL1/GRO-α with 2 hours of ischemia and increased PECAM-1 and TNF-α expression with 1 hour of ischemia. Significant cell death and changes in tissue morphology do not occur until after 4 hours of ischemia; however, analysis of inflammatory biomarkers suggests that ischemia reperfusion injury can occur with as little as 2 hours of ischemia.

Small Peptide Modulation of Fibroblast Growth Factor Receptor 3-Dependent Postnatal Lymphangiogenesis.

BACKGROUND: The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes as well as a wide range of human diseases. In particular, FGFR3 has been implicated in the mechanism by which 9-cis retinoic acid (9-cisRA) induces lymphangiogenesis and improves lymphedema. The purpose of this study was to validate the efficacy of a novel small peptide FGFR3 inhibitor, peptide P3 (VSPPLTLGQLLS), and to elucidate the role of FGFR3 in 9-cisRA-induced lymphangiogenesis using this peptide. METHODS AND RESULTS: Peptide P3 effectively inhibited FGFR3 phosphorylation. In vitro, peptide P3-mediated FGFR3 inhibition did not decrease lymphatic endothelial cell (LEC) proliferation, migration, or tubule formation. However, peptide P3-mediated FGFR3 inhibition did block 9-cisRA-stimulated LEC proliferation, migration, and tubule formation. In vivo, peptide P3-mediated FGFR3 inhibition was sufficient to inhibit 9-cisRA-induced tracheal lymphangiogenesis. CONCLUSION: FGFR3 does not appear to be essential to nonpromoted LEC proliferation, migration, and tubule formation. However, FGFR3 may play a key role in LEC proliferation, migration, tubule formation, and postnatal in vivo lymphangiogenesis when pharmacologically induced by 9-cisRA. P3 may have the potential to be used as a precise regulatory control element for 9-cisRA-mediated lymphangiogenesis.