Immediate lymphatic reconstruction: Lessons learned over eight years.

Immediate lymphatic reconstruction (ILR) is recognized as a surgical approach used to reduce the risk of developing secondary lymphedema, and evidence demonstrating the efficacy of ILR is favorable. Our Lymphatic Center has become a centralized location offering ILR for the risk-reduction in breast cancer-related lymphedema (BCRL) in New England. Over the course of our experience, we made several modifications and adapted our approach to enhance the operative success of this procedure. These include advancements in our use of indocyanine green (ICG) imaging to identify baseline lymphatic anatomical variation, utilization of fluorescein isothiocyanate for lymphatic vessel visualization, application of the lymphosome concept to guide arm injection sites, verification of anastomotic patency (using ICG), localization of reconstruction to guide radiation therapy, incorporation of intraoperative tools to facilitate better anatomic visualization of the axilla, and addition of a lower extremity vein graft to mitigate venous-related complications. Collecting information from each surgery in a standardized manner, including intraoperative lymphatic channel measurements, and deploying clips for possible future radiation exposure, enables future studies on ILR patient outcomes. In this contribution, we aimed to share our institutional modifications with the surgical community to facilitate further adoption, conversation, and advancement of ILR for the risk-reduction in BCRL.

Discordant Breast and Axillary Pathologic Response to Neoadjuvant Chemotherapy.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) for breast cancer has the advantage of determining in vivo response to treatment, enabling more conservative surgery, and facilitating the understanding of tumor biology. Pathologic complete response (pCR) after NAC is a predictor of improved overall survival. However, some patients demonstrate a discordant response to NAC between the breast and axillary nodes. This study was designed to identify factors that correlate to achieving a breast pCR without an axillary node pCR following NAC and explore the potential clinical implications. METHODS: The National Cancer Database was used to identify patients diagnosed with clinical T1-4, N1-3 breast cancer between 2004 and 2017. Patients underwent NAC followed surgical resection of the breast cancer and axillary node surgery. Multivariable analyses were used to identify clinical and pathologic factors associated with discordant pathologic response. RESULTS: In total, 13,934 patients met the inclusion criteria. Of these, 4292 (30.8%) patients demonstrated a breast pCR without a corresponding axillary pCR on final pathology. After adjusting for covariates, factors associated with higher discordance between axillary response in our cohort of breast pCR patients included older age (≥ 54), treatment at a community facility, T1 tumors, HR-positive, HER2 negative, low-grade tumors, and cN2/3 disease. CONCLUSIONS: Discordance between breast and axillary pCR is not infrequent and may be related to a number of patient-related factors and tumor characteristics impacting nodal response to NAC. Further investigation into differing responses to NAC is warranted to better understand the mechanism of this phenomenon and to determine how these findings may influence treatment.

Tracking Symptoms of Patients With Lymphedema Before and After Power-Assisted Liposuction Surgery.

PURPOSE: Lymphedema negatively impacts patients from a psychosocial standpoint and consequently affects patient's quality of life. Debulking procedures using power-assisted liposuction (PAL) are currently deemed an effective treatment for fat-dominant lymphedema and improves anthropometric measurements as well as quality of life. However, there have been no studies specifically evaluating changes in symptoms related to lymphedema after PAL. An understanding of how symptoms change after this procedure would be valuable for preoperative counseling and to guide patient expectations. METHODS: A cross-sectional study was performed in patients with extremity lymphedema who underwent PAL from January 2018 to December 2020 at a tertiary care facility. A retrospective chart review and follow-up phone survey were conducted to compare signs and symptoms related to lymphedema before and after PAL. RESULTS: Forty-five patients were included in this study. Of these, 27 patients (60%) underwent upper extremity PAL and 18 patients (40%) underwent lower extremity PAL. The mean follow-up time was 15.5±7.9 months. After PAL, patients with upper extremity lymphedema reported having resolved heaviness (44%), as well as improved achiness (79%) and swelling (78%). In patients with lower extremity lymphedema, they reported having improved all signs and symptoms, particularly swelling (78%), tightness (72%), and achiness (71%). CONCLUSIONS: In patients with fat-dominant lymphedema, PAL positively impacts patient-reported outcomes in a sustained fashion over time. Continuous surveillance of postoperative studies is required to elucidate factors independently associated with the outcomes found in our study. Moreover, further studies using a mixed method approach will help us better understand patient's expectations to achieve informed decision and adequate treatment goals.

Superficial and Functional Lymphatic Anatomy of the Upper Extremity.

BACKGROUND: Knowledge of detailed lymphatic anatomy in humans is limited, as the small size of lymphatic channels makes it difficult to image. Most current knowledge of the superficial lymphatic system has been obtained from cadaveric dissections. METHODS: Indocyanine green lymphography was performed preoperatively to map the functional arm lymphatics in breast cancer patients without clinical or objective evidence of lymphedema. A retrospective review was performed to extract demographic, indocyanine green imaging, and surgical data. RESULTS: Three main functional forearm channels with variable connections to two upper arm pathways were identified. The median forearm channel predominantly courses in the volar forearm (99 percent). The ulnar forearm channel courses in the volar forearm in the majority of patients (66 percent). The radial forearm channel courses in the dorsal forearm in the majority of patients (92 percent). Median (100 percent), radial (91 percent), and ulnar (96 percent) channels almost universally connect to the medial upper arm channel. In contrast, connections to the lateral upper arm channel occur less frequently from the radial (40 percent) and ulnar (31 percent) channels. CONCLUSIONS: This study details the anatomy of three forearm lymphatic channels and their connections to the upper arm in living adults without lymphatic disease. Knowledge of these pathways and variations is relevant to any individual performing procedures on the upper extremities, as injury to the superficial lymphatic system can predispose patients to the development of lymphedema.

Evaluation of online Spanish and English health materials for preventive mastectomy. are we providing adequate information?

PURPOSE: Breast cancer remains the leading cause of cancer-related death in US Hispanic women. When present, lower health literacy levels potentially within this patient population require tailored materials to address health disparities. We aim to evaluate and compare Spanish and English online health care informative resources on preventive mastectomy. METHODS: A Google web search using "preventive mastectomy" and "mastectomía preventiva" was conducted. The first ten institutional/organizational websites in each language were selected. Assessment of mean reading grade level, cultural sensitivity, understandability, and actionability was carried out utilizing validated tools. RESULTS: The mean reading grade level for English materials was 14.69 compared with 11.3 for Spanish, both exceeding the recommended grade level established by the AMA and NIH. The mean cultural sensitivity score for English information was 2.20 compared with 1.88 for Spanish information, both below the acceptability benchmark of 2.5. English webpages scored 65% and 35% for understandability and actionability, respectively, while Spanish webpages scored 47% and 18%. CONCLUSIONS: Online English and Spanish preventive mastectomy materials were written at an elevated reading level and lacked cultural sensitivity. Spanish language information demonstrated inferior understandability, actionability, and cultural sensitivity. Addressing these issues provides an opportunity to help resolve health literature disparities regarding preventive mastectomy for US Hispanic women.

The Role of Oncotype DX® Recurrence Score in Predicting Axillary Response After Neoadjuvant Chemotherapy in Breast Cancer.

INTRODUCTION: Oncotype DX® recurrence score (RS) is well-recognized for guiding decision making in adjuvant chemotherapy; however, the predictive capability of this genomic assay in determining axillary response to neoadjuvant chemotherapy (NCT) has not been established. METHODS: Using the National Cancer Data Base (NCDB), we identified patients diagnosed with T1-T2, clinically N1/N2, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER +/HER2 -) invasive ductal carcinoma of the breast between 2010 and 2015. Patients with an Oncotype DX® RS who received NCT were included. RS was defined as low (< 18), intermediate (18-30), or high (> 30). Unadjusted and adjusted analyses were performed to determine the association between axillary pathologic complete response (pCR) and RS. RESULTS: This study included a total of 158 women. RS was low in 56 (35.4%) patients, intermediate in 62 (39.2%) patients, and high in 40 (25.3%) patients. The majority of patients presented with clinical N1 disease (89.2%). Axillary pCR was achieved in 23 (14.6%) patients. When stratifying patients with axillary pCR by RS, 11 (47.8%) patients had a high RS, 6 (26.1%) patients had an intermediate RS, and 6 (26.1%) patients had a low RS. Comparing cohorts by RS, 27.5% of patients with high RS tumors had an axillary pCR, compared with only 9.7% in the intermediate RS group, and 10.7% in the low RS group (p = 0.0268). CONCLUSION: Our findings demonstrate that Oncotype DX® RS is an independent predictor of axillary pCR in patients with ER +/HER2 - breast cancers receiving NCT. A greater proportion of patients with a high RS achieved axillary pCR. These results support Oncotype DX® as a tool to improve clinical decision making in axillary management.

Impact of geographic distribution of accredited breast centers.

The National Accreditation Program for Breast Centers (NAPBCs) is dedicated to improving the quality of care in patients with breast disease. Geographic distribution of health care resources is an important measure of quality, yet little is known regarding breast center allocation patterns concerning population demand and impact on health outcomes. The purpose of this study was to analyze the distribution of NAPBC programs in the United States (USA) and evaluate the impact on breast cancer survival. Using the Centers for Disease Control and Prevention 2014 data base, we identified the incidence and mortality rates for breast cancer by state. We also determined the concentration of NAPBC programs in each state (ie, the number of centers per 1000 cases of breast cancer). Data were analyzed using Spearman's (nonparametric) rank correlation coefficients. Five hundred and seventy NAPBC programs were identified. Across the United States, there was a mean of 2.8 programs/1000 breast cancer diagnoses. A positive correlation (r = .45) between breast cancer incidence and the number of programs was identified (P = .0009). There was no statistically significant correlation between mortality and NAPBC program concentration (r = -0.20, P = .16). NAPBC-accredited program distribution within the United States correlates with breast cancer incidence per state. However, the number of NAPBC programs per state did not alter overall mortality rates. Added measures beyond survival, as well as further insight into referral patterns to NAPBC programs, may be required to demonstrate the value and impact of NAPBC accreditation.

Role of Sentinel Lymph Node Biopsy in Microinvasive Breast Cancer.

BACKGROUND: Microinvasive ductal carcinoma (DCISM), defined as DCIS with a focus of invasive carcinoma ≤ 1 mm, can be managed similarly to pure DCIS; however, management of the axilla in DCISM has been a subject of debate. Reports in the literature differ on the utility and necessity of sentinel lymph node biopsy (SLNB) for DCISM. The aim of the present study was to identify risk factors for nodal disease in patients with DCISM, which can help develop a selective approach to SLNB in this patient population. METHODS: The National Cancer Database was used to select patients with DCISM (pT1mi), diagnosed from 2012 to 2015, who underwent SLNB. Multivariable regression analysis was performed to determine associations between sentinel lymph node metastasis and relevant clinical variables. RESULTS: Our cohort comprised of 2609 patients with pT1mi who underwent SLNB. Of these, 76 (2.9%) were found to have sentinel lymph node metastases on final pathology. Low/intermediate grade tumors were associated with decreased SLN metastasis (OR 0.50, CI 0.28-0.92). Age and receptor status of the tumor did not have a clear association in predicting SLN metastases. CONCLUSIONS: The rate of sentinel node metastases in DCISM is low at only 2.9% in this national study. Tumor grade was identified as influencing the risk of SLN metastases. This information can factor into shared decision-making for SLNB in patients with DCISM.

Evaluating the role of sentinel lymph node biopsy in patients with DCIS treated with breast conserving surgery.

INTRODUCTION: The role of sentinel lymph node biopsy (SLNB) for patients with ductal carcinoma in-situ (DCIS) is limited given the rarity of nodal metastasis in non-invasive disease. Although SLNB is typically a safe procedure, there are potential complications and associated costs. The purpose of this study is to assess national surgical practice patterns and clinical outcomes with respect to the use of SLNB for DCIS in patients undergoing breast conserving surgery (BCS). METHODS: Case-level data from the National Cancer Data Base (NCDB) was assessed to identify adult patients ≥ 18 with DCIS, who underwent BCS and SLNB. Patient demographics and hospital characteristics were grouped for analytic purposes. A multivariate analysis was performed for patient and hospital characteristics. RESULTS: We identified 15,422 patients with DCIS undergoing BCS in 2015, of which 2,698 (18%) underwent SLNB. A multivariate analysis demonstrated a significant association between greater frequency of SLNB in patients age range of 60-69, receipt of care at a community facility, and higher nuclear grade DCIS. Positive sentinel nodes metastasis was identified in 0.9% patients undergoing BCS and SLNB for DCIS. CONCLUSION: The role of SLNB in patients with DCIS undergoing BCS is limited and does not routinely provide meaningful information or benefit to clinical management. Despite this, nearly one in five patients undergoing BCS for DCIS had lymph node sampling performed. Given the potential increased morbidity and financial implications, this finding represents an opportunity for further education and improvement in patient selection for SLNB.

Analysis of active surveillance as a treatment modality in ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Current clinical trials are exploring active surveillance (AS) of DCIS. The purpose of this study is to characterize current practice trends in the use of AS. The findings may inform clinical trials and provide insight into factors influencing adoption into practice. The National Cancer Database was used to identify women diagnosed with DCIS from 2004 to 2015. Management with AS was defined as any patient not undergoing surgery, chemotherapy, or radiation therapy. Multivariable logistic regression was used to assess patterns of AS. Of 84 281 women with DCIS, 342 (0.4%) underwent AS. Increased age (OR 1.16, CI 1.15-1.17), Hispanic or non-Hispanic black ethnicities (OR 1.91 CI 1.42-2.56; 1.54 CI 1.13-2.10), treatment at an academic facility (OR 1.64 CI 1.31-2.10), and low-volume facilities (OR 1.60 CI 1.06-2.42) were associated with an increased use of AS. Patients with ≥1 comorbidities (OR 0.70 CI 0.49-0.98), high-grade tumors (OR 0.671 CI 0.51-0.89), and private insurance (OR 0.69 CI 0.53-0.89) less frequently underwent AS. Of all patients undergoing AS, 11% received endocrine therapy. Active surveillance is currently an infrequently used treatment modality for patients with DCIS. We observed variations in AS based on age, ethnicity, comorbidities, facility type, facility volume, insurance status, and tumor grade. Most patients managed with AS did not receive hormone therapy. This information may further inform strategies for clinical trials, as well as guide quality of care in the adoption of future management options for DCIS.

Site-directed mutagenesis study of the microenvironment characteristics of Lys213 of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase.

Saccharomyces cerevisiae phosphoenolpyruvate (PEP) carboxykinase catalyzes the reversible formation of oxaloacetate and adenosine triphosphate from PEP, adenosine diphosphate and carbon dioxide, and uses Mn(2+) as the activating metal ion. Comparison with the crystalline structure of homologous Escherichia coli PEP carboxykinase [Tari et al. Nature Struct. Biol. 4 (1997) 990-994] shows that Lys(213) is one of the ligands to Mn(2+) at the enzyme active site. Coordination of Mn(2+) to a lysyl residue is infrequent and suggests a low pK(a) value for the epsilon-NH(2) group of Lys(213). In this work, we evaluate the role of neighboring Phe(416) in contributing to provide a low polarity microenvironment suitable to keep the epsilon-NH(2) of Lys(213) in the unprotonated form. Mutation Phe416Tyr shows that the introduction of a hydroxyl group in the lateral chain of the residue produces a substantial loss in the enzyme affinity for Mn(2+), suggesting an increase of the pK(a) of Lys(213). A study of the effect of pH on K(m) for Mn(2+) indicate that the affinity of recombinant wild type enzyme for the metal ion is dependent on deprotonation of a group with pK(a) of 7.1+/-0.2, compatible with the low pK(a) expected for Lys(213). This pK(a) value increases at least 1.5 pH units upon Phe416Tyr mutation, in agreement with the expected effect of an increase in the polarity of Lys(213) microenvironment. Theoretical calculations of the pK(a) of Lys(213) indicate a value of 6.5+/-0.9, and it increases to 8.2+/-1.6 upon Phe416Tyr mutation. Additionally, mutation Phe416Tyr causes a loss of 1.3 kcal mol(-1) in the affinity of the enzyme for PEP, an effect perhaps related to the close proximity of Phe(416) to Arg(70), a residue previously shown to be important for PEP binding.