Clinical Longevity of Preoperative Injection of Superparamagnetic Iron Oxide Nanoparticles for Delayed Sentinel Lymph Node Biopsy.

Diagnosis of ductal carcinoma in situ (DCIS) represents about 25% of newly diagnosed breast cancers. There is debate about the benefit of sentinel lymph node biopsy (SLNB) for further staging and guidance of therapy in patients with DCIS. Current guidelines recommend SLNB for patients undergoing breast-conserving therapy (BCT) for DCIS. Utilizing superparamagnetic iron oxide (SPIO) nanoparticles as a tracer may allow for a delayed SLNB (d-SLNB), typically within a month of injection. We present our experience with a patient who due to complications from surgery could not complete her d-SLNB for 165 days. The SPIO tracer remained active in the lymph node and remained clinically useful for this five and a half month gap from time of injection. Further study is needed to determine the clinical longevity of SPIO in a lymph node.

Concordant care in sentinel lymph node omission following Choosing Wisely® recommendations at a comprehensive cancer center.

BACKGROUND: In 2016, the SSO and ABIM released a Choosing Wisely® guideline stating SLNB can be safely omitted in women ≥70 with HR â€‹+ â€‹HER-invasive breast cancer. No study evaluating concordance of care with this guideline has been performed within a comprehensive cancer center. METHODS: From 2005 to 2020, there were 382 patients with cT1-2N0 invasive carcinoma ER+/PR+ and HER2-identified as having undergone SLNB. These patients were then separated into two groups; those in the pre-guideline concordance cohort (2005-2015) and those in the post-guideline concordance (2016-2020) cohort. Axillary management concordance was trended over time. RESULTS: 382 patients from 2005 to 2020 with HR â€‹+ â€‹HER- IBC were identified. No difference was seen in SLNB pre-versus post-guidelines (p â€‹= â€‹0.35). Increased concordance was noted as age increased (p â€‹= â€‹0.0068) and adjuvant radiation therapy exclusion (p â€‹< â€‹0.0001) post-guideline release. Concordance improved over the years post-guideline release (R2 â€‹= â€‹0.45). CONCLUSIONS: Surgical guideline adoption occurs over time but may also be affected by outside decisions and factors. Further study into patterns of guideline adoption may facilitate improving adherence to guidelines.

Luminal A Versus B After Choosing Wisely: Does Lymph Node Surgery Affect Oncologic Outcomes?

BACKGROUND: In 2016, the Choosing Wisely campaign recommended against routine sentinel lymph node biopsy (SLNB) in women ≥ 70 years old diagnosed with early-stage hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer. No distinction is made between luminal A and luminal B phenotypes, despite luminal B being considered more aggressive. This study evaluates the effect of SLNB on oncologic outcomes in HER2- luminal B versus luminal A breast cancer. PATIENTS AND METHODS: We performed an IRB-approved, single institution, retrospective cohort study from 2010 to 2020 of women aged ≥ 70 years with clinically node negative, HR+ breast cancer undergoing definitive surgical treatment. Luminal status was defined by gene expression panel testing, Ki67%, and/or pathologic grading. Primary endpoints included locoregional recurrence (LRR), disease free survival (DFS), and overall survival (OS). RESULTS: SLNB did not correlate with significant differences in LRR in luminal A (p = 0.92) or luminal B (p = 0.96) disease. SLNB correlated with improved DFS (p < 0.01) and OS (p < 0.001) in luminal A disease, but not in luminal B disease (DFS p = 0.73; OS p = 0.36). On multivariate analysis, age (HR = 1.17; p < 0.01) and tumor size (HR = 1.03; p < 0.05) were associated with DFS, while SLNB was not (p = 0.71). Luminal status (HR = 0.52, p < 0.05), age (HR = 1.15, p < 0.01), and comorbidities (HR = 1.35, p < 0.05) were associated with OS, but not SLNB (p = 0.71). CONCLUSIONS: Our results suggest that SLNB may be safely omitted in patients aged ≥ 70 years with luminal B disease given similar LRR in luminal A disease. Our findings suggest that DFS and OS are driven by tumor biology, patient age, and comorbidities rather than receipt of SLNB.

Prospective Evaluation of Radar-Localized Reflector-Directed Targeted Axillary Dissection in Node-Positive Breast Cancer Patients after Neoadjuvant Systemic Therapy.

BACKGROUND: This is a prospective, single-institution study to evaluate feasibility and accuracy of radar-localized reflector (RLR)-targeted axillary dissection (TAD) in node-positive breast cancer patients after neoadjuvant systemic therapy (NST). METHODS: Patients with biopsy-proven T1-2, N1-3 disease were eligible. Before NST, a marker clip and/or RLR was placed into the positive node. After NST, RLR was inserted if not placed previously. All patients underwent RLR TAD followed by axillary lymph node dissection (ALND). Primary end points of the trial were feasibility of RLR TAD and false negative rate (FNR). RESULTS: Between 2017 and 2021, 101 patients with N1-3 disease underwent NST. Five patients withdrew from the study, 1 was ineligible, and there were 9 technical failures, thus our final study cohort comprised 86 patients. RLR TAD was performed with probe guidance and confirmed with intraoperative specimen radiograph. After RLR TAD, ALND was performed. Median number of RLR TAD nodes removed was 2 (range 1-10), and the RLR TAD nodes remained positive in 56 patients. Median number of ALND nodes removed was 18 (range 4-46). Accounting for 9 technical failures, feasibility was 90%. All technical failures occurred with attempted placement of RLR after NST. Feasibility rate was 100% when RLR placement occurred at diagnosis. Of the evaluable 86 patients, RLR TAD accurately predicted axillary status in 83 patients, with FNR of 5.1%. CONCLUSION: We demonstrate high accuracy of RLR TAD, especially when RLR is placed before NST. For patients who present with N1-3 disease, this is another step towards axillary surgery de-escalation strategies.

Talimogene Laherparepvec (T-VEC) for the Treatment of Advanced Locoregional Melanoma After Failure of Immunotherapy: An International Multi-Institutional Experience.

BACKGROUND: Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma. METHODS: An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed. RESULTS: Of 112 patients, median age at T-VEC initiation was 69 years (range 21-93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (n = 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (n = 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (p = 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE). CONCLUSIONS: T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.

Ultrasound-guided Intralesional Injection of Talimogene laherparepvec (Imlygic) for Advanced Melanoma: Technical Note on a Preliminary Experience.

PURPOSE: To evaluate the safety and feasibility of ultrasound-guided intralesional injection of Talimogene laherparepvec (Imlygic, T-VEC) in patients with advanced non-palpable melanoma. MATERIALS AND METHODS: Fourteen consecutive patients (mean age, 67.9 years ± 13.0; range, 40-88; 12 males) with unresectable, locally advanced melanoma underwent ultrasound-guided intralesional injections of T-VEC (July 2016-March 2020) into subcutaneous lesions. Tumor response to the injection was evaluated at the last follow-up. Technical success and complication rates were recorded. RESULTS: The T-VEC injection was technically successful in all patients with all lesions successfully punctured (100%). The mean number of lesions, injection cycles, and injection volumes were 4.1 ± 2.6 (1-9), 6.5 ± 3.0 (3-12), and 2.6 mL ± 1.4 (1-4 mL), respectively. During the follow-up period (mean, 21.0 months ± 13.4; range 1-43.6 months), complete remission, partial remission, persistent disease, and disease progression were observed in 6 (42.9%), 3 (21.4%), 1 (7.1%), and 4 (28.6%) patients, respectively. Post-treatment symptoms observed in 9 patients (64.3%), including fever (n = 2), fatigue (n = 1), headache (n = 1), pain (n = 1), mouth sores (n = 1), and flu-like symptoms (n = 3). No injection-related complications occurred in all procedures. CONCLUSION: Intralesional injection of T-VEC for non-palpable metastases under ultrasound guidance is safe and feasible in patients with advanced melanoma.

Does Timing Matter? Surgical Outcomes in High-Grade Sarcomas after Neoadjuvant Radiation Therapy.

BACKGROUND: The impact of time to surgical resection after neoadjuvant external beam radiation therapy (EBRT) in the high-grade soft tissue and retroperitoneal sarcomas has not been well established. We aimed to evaluate how surgical timing from EBRT affects oncologic and perioperative outcomes. METHODS: We performed a single institution retrospective cohort study of patients with biopsy-proven, high-grade sarcoma who completed neoadjuvant EBRT and resection from January 1, 1999 to September 1, 2018. We collected demographic and clinicopathologic variables, stratifying patients by time interval between EBRT and surgery: <6, 6-8, 8-10, and >10 wk. Primary outcomes collected were as follows: disease-free survival, overall survival, and perioperative complications. RESULTS: Of the 269 patients identified, 146 met inclusion criteria. The median follow-up was 24 mo. Overall and local recurrence were 37% (n = 54) and 14.4% (n = 21), respectively. Time to surgery did not affect recurrence (P = 0.82) or survival (P = 0.88). Positive margins (odds ratio 2.7, confidence interval 1.14, 6.51, P < 0.05) were predictive of recurrence. Primary tumor location, surgical timing, histology, and intraoperative radiation therapy were not associated with differences in recurrence. The overall complication rate was 28%, with 63% from wound infections. Fewer postoperative complications occurred in the < 6-wk cohort versus > 6-wk cohort (15% versus 38%, P < 0.05). CONCLUSIONS: We found no difference in oncologic outcomes associated with the timing of surgical resection after EBRT. Patients undergoing resection >6 wk were at higher risk for all complications without impacting wound complication rates. Future studies may include preoperative optimization of patients requiring delays in surgical planning to decrease perioperative complication rates.

Trends in Surgical Axillary Management in Early Stage Breast Cancer in Elderly Women: Continued Over-Treatment.

INTRODUCTION: In the past two decades, three prospective randomized trials demonstrated that elderly women with early stage hormone positive breast cancer had equivalent disease-specific mortality regardless of axillary surgery. In 2016, the Choosing Wisely campaign encouraged patients and providers to reconsider the role of axillary surgery in this population. We sought to identify factors that contribute to adopting non-operative management of the axilla in these patients. MATERIALS AND METHODS: We performed a retrospective analysis of women ≥ 70 years old with cT1/T2, hormone positive invasive ductal carcinoma who underwent partial or total mastectomy, with/without axillary surgery, and did not receive adjuvant chemotherapy from the National Cancer Database from 2004 to 2015. We used multivariable log-binomial regression to model the risk of undergoing axillary surgery across region, care setting, and Charlson-Deyo scores, and analyzed temporal trends using Poisson regression. From 2004 to 2015, 87,342 of 99,940 women who met inclusion criteria (83%) had axillary surgery. Over time, axillary surgery increased from 78% to 88% (p < 0.001). This rise was consistent across region (p = 0.81) and care setting (p = 0.09), but flattened as age increased (p < 0.001). Omitting axillary surgery was more likely in patients treated in New England (RR 0.88, 95% CI 0.86, 0.89) and patients ≥ 85 (RR 0.66, 95% CI 0.65, 0.67). CONCLUSIONS: Axillary surgery continues to be the preferred option of axillary management in elderly women with early stage, clinically node negative, hormone-positive, invasive breast cancer despite no survival benefit. Identifying factors to improve patient selection and dissemination of current recommendations can improve adoption of current evidence on axillary surgery in the elderly.

Nodal positivity decreases with age in women with early-stage, hormone receptor-positive breast cancer.

BACKGROUND: Despite data demonstrating the safety of omitting axillary surgery in older women with early-stage breast cancer, the incidence of axillary surgery remains high. It was hypothesized that the prevalence of nodal positivity would decrease with advancing age. METHODS: The National Cancer Data Base was used to construct a cohort of adult women with early-stage, clinically node-negative, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative breast cancer treated between 2013 and 2015. Multivariable logistic regression was used to assess the relationship between age and nodal positivity, and this was stratified by the axillary surgery category. Modified Poisson regression was used to estimate the proportion of women receiving adjuvant therapy according to age and nodal status. RESULTS: The incidence of axillary surgery among women aged 70 and older (n = 51,917) remained high nationwide (86%). There was a significant decrease in nodal positivity with advancing age in women with early-stage, ER+, clinically node-negative breast cancer from the youngest cohort up to patients aged 70 to 89 years, and this was independent of histologic subtype (ductal vs lobular), race, comorbidities, and socioeconomic factors. Overall, less than 10% of women aged 70 or older who underwent surgery had node-positive disease, regardless of axillary surgery type, and almost 95% of node-positive patients aged 70 or older were at pathological stage N1mi or N1. CONCLUSIONS: Axillary surgery may be safely omitted for many older women with ER+, clinically node-negative, early-stage breast cancer. Nodal positivity declines with advancing age, and this suggests varied biology in older patients versus younger patients.

Real-World Outcomes of Talimogene Laherparepvec Therapy: A Multi-Institutional Experience.

BACKGROUND: Talimogene laherparepvec (TVEC) is an FDA-approved oncolytic herpes virus used to treat unresectable stage IIIB to IV metastatic melanoma via intralesional injection. This study aims to characterize the efficacy TVEC in patients with unresectable stage IIIB to IV melanoma. METHODS: We performed a multi-institutional, IRB-approved review of all patients who received TVEC at 3 centers from October 2015 to October 2018. Clinicopathologic characteristics, TVEC treatment data, and outcomes were assessed. RESULTS: One hundred and twenty-one patients received TVEC, of which 80 patients had available treatment response data with at least 3-month follow-up. Anatomic sites treated were 19 (24%) head and neck, 9 (11%) upper extremity, 12 (15%) torso, and 40 (50%) lower extremity. Thirty-four (42.5%) patients did not receive therapy before TVEC. Side effects were mild and self-limited, most commonly flu-like symptoms seen in 22 (28%) patients. Median follow-up was 9 months (range 3 to 28 months), with complete local response in 31 (39%) and partial response in 14 (18%) patients. Of complete responders, 29 (37%) had no evidence of disease at last follow-up and received a median of 6 (range 2 to 12) cycles of therapy. CONCLUSIONS: Talimogene laherparepvec is a well-tolerated, durable treatment option for patients with unresectable locoregional melanoma, particularly in stage IIIB/C disease. Additionally, we found that TVEC can be administered safely across anatomic sites that are otherwise not amenable to other local therapies.

Does Surgical Margin Impact Recurrence in Noninvasive Intraductal Papillary Mucinous Neoplasms?: A Multi-institutional Study.

OBJECTIVE: The relevance of margin positivity on recurrence after resection of intraductal papillary mucinous neoplasms (IPMNs) is poorly defined and represents one reason controversy remains regarding optimal surveillance recommendations. METHODS: Patients undergoing surgery for noninvasive IPMN at 8 academic medical centers from the Central Pancreas Consortium were analyzed. A positive margin was defined as presence of IPMN or pancreatic intraepithelial neoplasia. RESULTS: Five hundred two patients underwent surgery for IPMN; 330 (66%) did not have invasive cancer on final pathology and form the study cohort. Of these, 20% harbored high grade dysplasia. A positive margin was found in 20% of cases and was associated with multifocal disease (P = 0.02). The majority of positive margins were associated with low grade dysplasia. At a median follow-up of 36 months, 34 (10.3%) patients recurred, with 6.7% developing recurrent cystic disease and 3.6% developing invasive cancer. On multivariate analysis, margin positivity was not associated with recurrence of either IPMN or invasive cancer (P > 0.05). No association between margin status and development of recurrence at the margin was found. Only 6% of recurrences developed at the resection margin and median time to recurrence was 22 months. Of note, 18% of recurrences occurred > 5 years following surgery. CONCLUSION: Margin positivity after resection for noninvasive IPMNs is primarily due to low grade dysplasia and is not associated with developing recurrence in the remnant pancreas or at the resection margin. Long-term surveillance is required for all patients, as a significant number of recurrences developed over 5 years after the index operation.

Complete blood counts, liver function tests, and chest x-rays as routine screening in early-stage breast cancer: value added or just cost?

Current National Comprehensive Cancer Network guidelines for breast cancer staging include pre-treatment complete blood count (CBC) and liver function tests (LFT) to screen for occult metastatic disease. To date, the relevance of these tests in detecting metastatic disease in asymptomatic women with early-stage breast cancer (Stage I/II) has not been demonstrated. Although chest x-rays are no longer recommended in the NCCN guidelines, many centers continue to include this imaging as part of their screening process. We aim to determine the clinical and financial impact of these labs and x-rays in the evaluation of early-stage breast cancer patients. A single institution IRB-approved retrospective chart review was conducted of patients with biopsy-proven invasive breast cancer treated from January 1, 2005­December 31, 2009. We collected patient demographics, clinical and pathologic staging, chest x-ray, CBC, and LFT results at the time of referral. Patients were stratified according to radiographic stage at the time of diagnosis. We obtained Medicare reimbursement fees for cost analysis. From 2005 to 2009, 1609 patients with biopsy-proven invasive breast cancer were treated at our institution. Of the 1082 patients with radiographic stage I/II disease, 27.3 % of patients had abnormal CBCs. No additional testing was performed to evaluate these abnormalities. In the early-stage population, 24.7 % of patients had elevated LFTs, resulting in 84 additional imaging studies. No metastatic disease was detected. The cost of CBC, LFTs and chest x-rays was $110.20 per patient, totaling $106,410.99. Additional tests prompted by abnormal results cost $58,143.30 over the five-year period. We found that pre-treatment CBCs, LFTs, and chest x-rays did not improve detection of occult metastatic disease but resulted in additional financial costs. Avoiding routine ordering of these tests would save the US healthcare system $25.7 million annually.

Improving our understanding of the surgical oncology workforce.

OBJECTIVE: This study characterizes the surgical oncology workforce as a baseline for future workforce projections. BACKGROUND: Measuring the capacity of the surgical oncology workforce is difficult due to the wide variety of surgeons who contribute to surgical cancer care. We hypothesize that the bulk of surgical oncology care is provided by general surgeons. METHODS: Using Medicare claims data linked to the North Carolina Central Cancer Registry, all patients 65 years or older who had a diagnosis of incident cancer of the bladder, breast, colon/rectum, esophagus, gallbladder, kidney, liver, lung, skin (melanoma-only), ovary, pancreas, prostate, small bowel, stomach, or uterus in 2005 and who underwent an extirpative procedure for cancer were identified. The proportion of procedures performed by different types of providers was examined. RESULTS: A total of 7759 patients underwent 16,734 extirpative surgical procedures. Excluding procedures for gynecologic/urologic malignancies, the proportion of procedures performed by general surgeons and surgical oncologists was 48% and 12%, respectively. Patients treated by general surgeons were more likely to be older, female, minority, and from areas of high poverty. For each tumor type, travel distances were shorter for patients treated by general surgeons than those treated by specialists. CONCLUSIONS: Workforce projections must account for the significant overlap in the scope of services delivered by providers of different specialties and for the large contribution of general surgeons to cancer care. Efforts to improve the quality of cancer care need to move beyond centralization and focus on educating the surgeons who are providing the bulk of oncology care.

Epigenetic regulation of human alpha1d-adrenergic receptor gene expression: a role for DNA methylation in Sp1-dependent regulation.

A growing body of evidence implicates alpha1-adrenergic receptors (alpha1ARs) as potent regulators of growth pathways. The three alpha1AR subtypes (alpha1aAR, alpha1bAR, alpha1dAR) display highly restricted tissue expression that undergoes subtype switching with many pathological stimuli, the mechanistic basis of which remains unknown. To gain insight into transcriptional pathways governing cell-specific regulation of the human alpha1dAR subtype, we cloned and characterized the alpha1dAR promoter region in two human cellular models that display disparate levels of endogenous alpha1dAR expression (SK-N-MC and DU145). Results reveal that alpha1dAR basal expression is regulated by Sp1-dependent binding of two promoter-proximal GC boxes, the mutation of which attenuates alpha1dAR promoter activity 10-fold. Mechanistically, chromatin immunoprecipitation data demonstrate that Sp1 binding correlates with expression of the endogenous gene in vivo, correlating highly with alpha1dAR promoter methylation-dependent silencing of both episomally expressed reporter constructs and the endogenous gene. Further, analysis of methylation status of proximal GC boxes using sodium bisulfite sequencing reveals differential methylation of proximal GC boxes in the two cell lines examined. Together, the data support a mechanism of methylation-dependent disruption of Sp1 binding in a cell-specific manner resulting in repression of basal alpha1dAR expression.