Singhal lab
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Prevention of Lymphedema
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Roldan-Vasquez E, Bharani T, Mitri S, Flores R, Capasso K, Ross J, Singhal D, James TA
Abstract
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Background: Recent advances in breast cancer have progressed toward less aggressive axillary surgery. However, axillary lymph node dissection (ALND) remains necessary in specific cases and can increase the risk of lymphedema. Performing ALND with immediate lymphatic reconstruction (ILR) can help lower this risk. This report outlines the implementation of an Axillary Surgery Referral Program (ASRP) to broaden access to ILR, providing insights for institutions considering similar initiatives.
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Methods: A retrospective study analyzed patients referred to the ASRP at Beth Israel Deaconess Medical Center (BIDMC) between 6 January 2017 and 10 December 2022. Patients were identified from a prospective registry, with data subsequently extracted from electronic medical records. This analysis specifically centered on patients referred from external institutions to undergo ALND with ILR.
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Results: The program received referrals for 131 patients from institutions across five different states. Annual referrals steadily increased over time. The primary indication for referral was residual axillary disease after neoadjuvant chemotherapy (41.2%). Among the referrals, 20 patients (15.3%) no longer required ALND due to axillary pathologic complete response to neoadjuvant therapy. Care coordination played a crucial role in streamlining the patient care process for both efficiency and effectiveness.
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Conclusion: The ASRP expands access to ILR for patients with breast cancer, the majority referred for surgical management of residual disease after chemotherapy. The program provides a model for health care institutions aiming to establish similar specialized referral services. Continued program evaluation will be instrumental in refining axillary surgery referral practices and ensuring optimal patient care.
Granoff MD, Fleishman A, Shillue K, Johnson AR, Ross J, Lee BT, Teller P, James TA, Singhal D.
Abstract
Background: Up to one in three patients may go on to develop breast cancer-related lymphedema (BCRL) after treatment. Immediate lymphatic reconstruction (ILR) has been shown in early studies to reduce the risk of BCRL, but long-term outcomes are limited because of its recent introduction and institutions' differing eligibility requirements. This study evaluated the incidence of BCRL in a cohort that underwent ILR over the long term.
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Methods: A retrospective review of all patients referred for ILR at the authors' institution from September of 2016 through September of 2020 was performed. Patients with preoperative measurements, a minimum of 6 months of follow-up data, and at least one completed lymphovenous bypass were identified. Medical records were reviewed for demographics, cancer treatment data, intraoperative management, and lymphedema incidence.
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Results: A total of 186 patients with unilateral node-positive breast cancer underwent axillary nodal surgery and an attempt at ILR over the study period. Ninety patients underwent successful ILR and met all eligibility criteria, with a mean patient age of 54 ± 12.1 years and median body mass index of 26.6 kg/m 2 [interquartile range (IQR), 24.0 to 30.7 kg/m 2 ]. The median number of lymph nodes removed was 14 (IQR, eight to 19). Median follow-up was 17 months (range, 6 to 49 months). Eighty-seven percent of patients underwent adjuvant radiotherapy, and among them, 97% received regional lymph node irradiation. The overall rate of lymphedema was 9% at the end of the study period.
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Conclusions: With the use of strict follow-up guidelines over the long term, the authors' findings support that ILR at the time of axillary lymph node dissection is an effective procedure that reduces the risk of BCRL in a high-risk patient population.
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Clinical question/level of evidence: Therapeutic, IV.
Spiegel DY, Willcox J, Friedman R, Kinney J, Singhal D, Recht A.
A Prospective Study of Radiation Therapy After Immediate Lymphatic Reconstruction: Analysis of the Dosimetric Implications
Abstract
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Purpose: Axillary lymph node dissection (ALND) and regional nodal irradiation (RNI) are the primary causes of breast cancer-related lymphedema (BCRL). Immediate lymphatic reconstruction (ILR) is a novel surgical procedure that reduces the incidence of BCRL after ALND. The ILR anastomosis is placed in a location thought to be outside the standard radiation therapy fields to prevent radiation-induced fibrosis of the reconstructed vessels; however, there is excess risk of BCRL from RNI even after ILR. The purpose of this study was to understand the radiation dose distribution in relation to the ILR anastomosis.
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Methods and Materials: This prospective study included 13 patients treated with ALND/ILR from October 2020 to June 2022. A twirl clip deployed during surgery was used to identify the ILR anastomosis site during radiation treatment planning. All cases were planned using a 3D-conformal technique with opposed tangents and an obliqued supraclavicular (SCV) field.
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Results: RNI deliberately targeted axillary Levels 1 to 3 and the SCV nodal region in 4 patients and was limited to Level 3 and SCV nodes in 9 patients. The ILR clip was located in Level 1 in 12 patients and Level 2 in 1 patient. In patients with radiation directed at only Level 3 and SCV, the ILR clip was still within the radiation field in 5 of these patients and received a median dose of 3939 cGy (range, 2025-4961 cGy). The median dose to the ILR clip was 3939 cGy (range, 139-4961 cGy) for the entire cohort. The median dose was 4275 cGy (range, 2025-4961 cGy) when the ILR clip was within any radiation field and 233 cGy (range, 139-280 cGy) when the clip was outside all fields.
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Conclusion: The ILR anastomosis was often directly irradiated with 3D-conformal techniques and received substantial radiation dose, even when the site was not deliberately targeted. Long-term analysis will help determine whether minimizing radiation dose to the anastomosis will decrease BCRL rates.
Friedman R, Spiegel DY, Kinney J, Willcox J, Recht A, Singhal D.
Abstract
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Purpose: Immediate lymphatic reconstruction (ILR) is a procedure known to reduce the risk of lymphedema in patients undergoing axillary lymph node dissection (ALND). However, patients who receive adjuvant radiotherapy are at increased risk of lymphedema. The aim of this study was to quantify the extent of radiation at the site of surgical prevention.
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Methods: We recently began deploying clips at the site of ILR to identify the site during radiation planning. A retrospective review was performed to identify breast cancer patients who underwent ILR with clip deployment and adjuvant radiation therapy from October 2020 to April 2022. Patients were excluded if they had not completed radiotherapy. The exposure and dose of radiation received by the site was determined and recorded.
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Results: In a cohort of 11 patients, the site fell within the radiation field in 7 patients (64%) and received a median dose of 4280 cGy. Among these 7 patients, 3 had sites located within tissue considered at risk of oncologic recurrence and the remaining 4 sites received radiation from a tangential field treating the breast or chest wall. The median dose to the ILR site for the 4 patients whose sites were outside the radiation fields was 233 cGy.
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Conclusion: Our findings suggest that even when the site of surgical prevention was not within the targeted radiation field during treatment planning, it remains susceptible to radiation. Strategies for limiting radiation at this site are needed.
Abstract
No abstract available.
Anna Rose Johnson, Aaron Fleishman, Melisa D Granoff, Kathy Shillue, Mary Jane Houlihan, Ranjna Sharma, Kari J Kansal, Paige Teller, Ted A James, Bernard T Lee, Dhruv Singhal.
Abstract
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Background: Breast cancer–related lymphedema affects one in five patients. Its risk is increased by axillary lymph node dissection and regional lymph node radiotherapy. The purpose of this study was to evaluate the impact of immediate lymphatic reconstruction or the lymphatic microsurgical preventative healing approach on postoperative lymphedema incidence.
Methods: The authors performed a retrospective review of all patients referred for immediate lymphatic reconstruction at the authors’ institution from September of 2016 through February of 2019. Patients with preoperative measurements and a minimum of 6 months’ follow-up data were identified. Medical records were reviewed for demographics, cancer treatment data, intraoperative management, and lymphedema incidence.
Results: A total of 97 women with unilateral node-positive breast cancer underwent axillary nodal surgery and attempt at immediate lymphatic reconstruction over the study period. Thirty-two patients underwent successful immediate lymphatic reconstruction with a mean patient age of 54 years and body mass index of 28 ± 6 kg/m2. The median number of lymph nodes removed was 14 and the median follow-up time was 11.4 months (range, 6.2 to 26.9 months). Eighty-eight percent of patients underwent adjuvant radiotherapy of which 93 percent received regional lymph node radiotherapy. Mean L-Dex change was 2.9 units and mean change in volumetry by circumferential measurements and perometry was −1.7 percent and 1.3 percent, respectively. At the end of the study period, we found an overall 3.1 percent rate of lymphedema.
Conclusion: Using multiple measurement modalities and strict follow-up guidelines, the authors’ findings support that immediate lymphatic reconstruction at the time of axillary surgery is a promising, safe approach for lymphedema prevention in a high-risk patient population.
Abstract
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No abstract available.
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Johnson AR, Kimball S, Epstein S, Recht A, Lin SJ, Lee BT, James TA, Singhal D
Abstract
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Background: Axillary surgery and radiotherapy are important aspects of breast cancer treatment associated with development of lymphedema. Studies demonstrate that Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) may greatly reduce the incidence of lymphedema in high-risk groups. The objective of this study is to summarize the evidence relating lymphedema incidence to axillary lymph node dissection (ALND), regional lymph node radiation (RLNR) therapy, and LYMPHA.
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Methods: We performed a literature search to identify studies involving breast cancer patients undergoing ALND with or without RLNR. Our primary outcome was the development of lymphedema. We analyzed the effect of LYMPHA on lymphedema incidence. We chose the DerSimonian and Laird random-effects meta-analytic model owing to the clinical, methodological, and statistical heterogeneity of studies.
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Results: Our search strategy yielded 1476 articles. After screening, 19 studies were included. Data were extracted from 3035 patients, 711 of whom had lymphedema. The lymphedema rate was significantly higher when RLNR was administered with ALND compared with ALND alone (P < 0.001). The pooled cumulative incidence of lymphedema was 14.1% in patients undergoing ALND versus 2.1% in those undergoing LYMPHA and ALND (P = 0.029). The pooled cumulative incidence of lymphedema was 33.4% in those undergoing ALND and RLNR versus 10.3% in those undergoing ALND, RLNR, and LYMPHA (P = 0.004).
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Conclusion: Axillary lymph node dissection and RLNR are important interventions to obtain regional control for many patients but were found to constitute an increased risk of development of lymphedema. Our findings support that LYMPHA, a preventive surgical technique, may reduce the risk of breast cancer-related lymphedema in high-risk patients.
Hahamoff M, Gupta N, Munoz D, Lee BT, Clevenger P, Shaw C, Spiguel L, Singhal D.
Abstract
Background: Breast cancer-related lymphedema (BCRL) is one of the most significant survivorship issues in breast cancer management. Presently, there is no cure for BCRL. The single greatest risk factor for developing BCRL is an axillary lymph node dissection (ALND). Lymphatic Microsurgical Preventative Healing Approach (LYMPHA) is a surgical procedure to reduce the risk of lymphedema in patients undergoing an ALND. We present our single institution results after offering LYMPHA in the context of an established lymphedema surveillance program.
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Materials and methods: A retrospective review of our lymphedema surveillance program at the University of Florida was performed over a 2-year period (March 2014-March 2016). LYMPHA was offered to patients undergoing ALND beginning in March 2015. Patients who developed lymphedema were compared with those who did not. Demographics and potential risk factors for development of lymphedema such as age, body mass index, clinical stage, radiotherapy, and chemotherapy were reviewed.
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Results: Eighty-seven patients participated in the surveillance program over the study period with an average age of 60 y (range 32-83) and body mass index of 30 kg/m2 (range 17-46). The single most significant risk factor for the development for lymphedema was an ALND (P < 0.001). One of 67 patients undergoing a sentinel lymph node biopsy developed lymphedema (1.5%). Four of 10 patients who underwent an ALND alone developed lymphedema (40%). One of 8 patients in the ALND + LYMPHA group developed transient lymphedema (12.5%).
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Conclusions: Offering LYMPHA with ALND decreased our institutional rate of lymphedema from 40% to 12.5%. Long-term follow-up and randomized control trials are necessary to further elucidate the promise of this surgical technique to reduce the incidence of BCRL.
Spiguel L, Shaw C, Katz A, Guo L, Chen HC, Lee BT, Singhal D.
Abstract
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The Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) procedure entails performing a lymphovenous bypass (LVB) at the time of axillary lymph node dissection to reduce lymphedema risk. The two most common fluorophores utilized in LVB are blue dye and indocyanine green. We developed a novel application of fluorescein isothiocyanate for intraoperative lymphatic mapping. Our goal is to demonstrate the safety and efficacy of fluorescein isothiocyanate for this application. We reviewed a prospectively collected database on breast cancer patients who underwent LYMPHA from March to September 2015. Fluorescein isothiocyanate was used to identify arm lymphatic channels after axillary lymph node dissection to perform an LVB between disrupted lymphatics and axillary vein tributaries. Data on preoperative and intraoperative variables were analyzed. Thirteen patients underwent LYMPHA with intraoperative fluorescein isothiocyanate lymphatic mapping from March to September 2015. Average patient age was 50 years with a mean body mass index of 28. On average, 3.4 lacerated lymphatic channels were identified at an average distance of 2.72 cm (range, 0.25-5 cm) caudal to the axillary vein. On average, 1.7 channels were bypassed per patient. Eleven anastomoses were performed to the accessory branch of the axillary vein and 1 to a lateral branch. In 1 patient, a bypass was not performed due to poor lymphatic caliber and inadequate length of the harvested vein tributary. No intraoperative adverse events were noted. Fluorescein isothiocyanate is a safe and effective method for intra-operative lymphatic mapping. Fluorescein isothiocyanate imaging allows for simultaneous dissection and lymphatic visualization, making it an ideal agent for lymphatic mapping and dissection in open surgical fields, such as in the LYMPHA procedure.
Johnson AR, Singhal D.
Abstract
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Although surgical and medical treatment options are available for the treatment of chronic lymphedema, there is no cure. Recent advances in microsurgery have provided an opportunity to perform immediate lymphatic reconstruction after lymphadenectomy for disease prevention. In this review, we provide the historical background leading to a paradigm shift in performing this procedure. We will also discuss the current evidence for immediate lymphatic reconstruction, potential oncologic procedures amenable to this approach, and detail ongoing challenges.
Bao Ngoc N Tran, Joseph P Angelo, Jeong Heon Lee, Qing Z Ruan, Rita G Laurence, Hak Soo Choi, Bernard T Lee, Dhruv Singhal.
Abstract
Background: Breast cancer-related lymphedema affects more than 400,000 survivors in the United States. In 2009, lymphatic microsurgical preventive healing approach (LYMPHA) was first described as a surgical technique to prevent lymphedema by bypassing divided arm lymphatics into adjacent veins at the time of an axillary lymph node dissection. We describe the first animal model of LYMPHA.
Methods: In Yorkshire pigs, each distal hind limb lymphatic system was cannulated and injected with a different fluorophore (human serum albumin-conjugated indocyanine green or Evans Blue). Fluorescence-assisted resection and exploration imaging system was used to map the respective lymphangiosomes to the groin. Baseline lymphatic clearance of each hind limb lymphangiosome was obtained by measuring the fluorescence of each dye from centrally obtained blood samples. A lymphadenectomy versus lymphadenectomy with LYMPHA was then performed. The injections were then repeated to obtain clearance rates that were compared against baseline values.
Results: Human serum albumin-conjugated indocyanine green and Evans Blue allowed for precise lymphatic mapping of each respective hind limb using fluorescence-assisted resection and exploration imaging. Lymphatic clearance from the distal hind limb dropped 68% when comparing baseline clearance versus after a groin lymphadenectomy. In comparison, lymphatic clearance dropped only 21% when comparing baseline clearance versus a lymphadenectomy with LYMPHA.
Conclusions: We describe the first animal model for LYMPHA, which will enable future studies to further evaluate the efficacy and potential limitations of this technique. Of equal importance, we demonstrate the power of optical imaging to provide real-time lymphatic clearance rates for each hind limb.