Image-Guided Radar Reflector Localization for Small Soft-Tissue Lesions in the Musculoskeletal System.

Preoperative localization of nonpalpable breast lesions using a radar reflector surgical guidance system has become commonplace, but the clinical utility of this emerging technology in the musculoskeletal system has not yet been well established. The system components include a console, a handpiece, an implanted radiofrequency reflector that works as a lesion marker, and an infrared light-emitting probe to guide the surgeon. The reflector can be deployed to localize small nonpalpable nodules within the subcutaneous fat as well as lesions within the deeper soft tissues. It can also be used for lymph nodes and foreign bodies. Localization can be performed both before and after treatment. The objective of this article is to describe the potential applications and our technique and initial experience for radar reflector localization within the musculoskeletal system.

Preoperative Ultrasound Assessment of Regional Lymph Nodes in Melanoma Patients Does not Provide Reliable Nodal Staging: Results From a Large Multicenter Trial.

OBJECTIVE: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging. BACKGROUND: It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low. METHODS: Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen. RESULTS: SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% (95% confidence interval: 4.6-8.7) and the specificity 98.0% (95% CI: 97.5-98.5). Median cross-sectional area of all SN metastases was 0.13 mm2; in US true-positive nodes, it was 6.8 mm2. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for ≤1 mm thickness, 11.9% for >4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy. CONCLUSION: In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy.

Acral Lentiginous Melanoma: A United States Multi-Center Substage Survival Analysis.

BACKGROUND: Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care. OBJECTIVES: To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients. METHODS: Retrospective review of the United States Melanoma Consortium database, a multi-center prospectively collected database of acral lentiginous melanoma patients treated between January 2000 and December 2017. RESULTS: Of the 433 primary acral lentiginous melanoma patients identified (median [range] age: 66 [8-97] years; 53% female, 83% white), 66% presented with stage 0-2 disease and the median time of follow-up for the 392 patients included in the survival analysis was 32.5 months (range: 0-259). The 5-year melanoma-specific survivals by stage were 0 = 100%, I = 93.8%, II = 76.2%, III = 63.4%, IIIA = 80.8%, and IV = 0%. Thicker Breslow depth ((HR) = 1.13; 95% CI = 1.05-1.21; P < .001)) and positive nodal status ((HR) = 1.79; 95% CI = 1.00-3.22; P = .050)) were independent prognostic factors for melanoma-specific survival. Breslow depth ((HR = 1.13; 95% CI = 1.07-1.20; P < .001), and positive nodal status (HR = 2.12; 95% CI = 1.38-3.80; P = .001) were also prognostic factors for recurrence-free survival. CONCLUSION: In this cohort of patients, acral lentiginous melanoma was associated with poor outcomes even in early stage disease, consistent with prior reports. Stage IIB and IIC disease were associated with particularly low melanoma-specific and recurrence-free survival. This suggests that studies investigating adjuvant therapies in stage II patients may be especially valuable in acral lentiginous melanoma patients.

Cultivating the physician workforce: Recruiting, training, and retaining physicians to meet the needs of the population.

In the 10 years since the Lancet Commission on Education of Health Professionals for the 21st Century suggested the changes necessary to transform medical education, the United States remains plagued by shortages of physicians and maldistribution of the physician workforce. Minoritized and rural communities usually suffer the most, with widely documented health disparities across the United States by race, ethnicity, gender identity, education, and zip code. Medical schools can respond by recruiting students more likely to practice in these settings and training them to address the community needs. In 2013, the American Medical Association launched an initiative to trigger transformation in medical education and formed a consortium of schools representing a diversity of U.S. institutions. Consortium member schools highlighted in this article share lessons learned in their efforts to strengthen social accountability and develop needed sectors of the physician workforce. Development of the physician workforce involves recruiting and widening pathways of entry for diverse groups, providing training settings and competencies aligned with community needs, and explicit programming in retention, inclusion and well-being to mitigate against workforce losses.

The Devil's in the Details: Discrepancy Between Biopsy Thickness and Final Pathology in Acral Melanoma.

PURPOSE: We hypothesized that initial biopsy may understage acral lentiginous melanoma (ALM) and lead to undertreatment or incomplete staging. Understanding this possibility can potentially aid surgical planning and improve primary tumor staging. METHODS: A retrospective review of primary ALMs treated from 2000 to 2017 in the US Melanoma Consortium database was performed. We reviewed pathology characteristics of initial biopsy, final excision specimens, surgical margins, and sentinel lymph node biopsy (SLNB). RESULTS: We identified 418 primary ALMs (321 plantar, 34 palmar, 63 subungual) with initial biopsy and final pathology results. Median final thickness was 1.8 mm (range 0.0-19.0). There was a discrepancy between initial biopsy and final pathology thickness in 180 (43%) patients with a median difference of 1.6 mm (range 0.1-16.4). Final T category was increased in 132 patients (32%), including 47% of initially in situ, 32% of T1, 39% of T2, and 28% of T3 lesions. T category was more likely to be increased in subungual (46%) and palmar (38%) melanomas than plantar (28%, p = 0.01). Among patients upstaged to T2 or higher, 71% had ≤ 1-cm margins taken. Among the 27 patients upstaged to T1b or higher, 8 (30%) did not have a SLNB performed, resulting in incomplete initial staging. CONCLUSIONS: In this large series of ALMs, final T category was frequently increased on final pathology. A high index of suspicion is necessary for lesions initially in situ or T1 and consideration should be given to performing additional punch biopsies, wider margin excisions, and/or SLNB.

Correlation Between Surgical and Histologic Margins in Melanoma Wide Excision Specimens.

INTRODUCTION: Wide surgical excision is the standard treatment for localized primary cutaneous melanomas, with a narrow histologic margin associated with an increased risk of local recurrence. The correlation between surgical and histologic margins is poorly documented in the literature. METHODS: An audit was performed to (1) document the shrinkage of formalin-fixed specimens, and (2) use a precisely measured surgical margin in vivo to predict the histologic margin. For patients presenting for wide excision of melanomas and other malignant skin tumors, measured surgical margin, in vivo and ex vivo specimen width, and histologic margins after formalin fixation were recorded. The effects of clinicopathologic characteristics, including age, sex, body mass index (BMI), tumor type, anatomic site, and presence of visible tumor in predicting specimen shrinkage and histologic margin were assessed. RESULTS: In total, 252 specimens were evaluated. When compared with measured width in vivo, the formalin-fixed specimens showed a mean shrinkage of 14% (R2 = 0.98), regardless of patient age, sex, BMI, or site of the lesion. The measured surgical margin was not a strong predictor of the histologic margin, with a high degree of variability (R2 = 0.55) not explained by patient factors, tumor subtype, or presence of visible tumor at the time of excision (p > 0.05). CONCLUSIONS: A consistent 14% shrinkage rate of wide excision specimens was found across all patients and excision sites, and we propose a clinically useful 15% correction factor that will account for fixation and shrinkage of cutaneous excision specimens. Excision margins measured by the surgeon were a poor predictor of the histologic margins.

Exploring the characteristics and context that allow Master Adaptive Learners to thrive.

Because change is ubiquitous in healthcare, clinicians must constantly make adaptations to their practice to provide the highest quality care to patients. In a previous article, Cutrer et al. described a metacognitive approach to learning based on self-regulation, which facilitates the development of the Master Adaptive Learner (MAL). The MAL process helps individuals to cultivate and demonstrate adaptive expertise, allowing them to investigate new concepts (learn) and create new solutions (innovate). An individual's ability to learn in this manner is driven by several internal characteristics and is also impacted by numerous aspects of their context. In this article, the authors examine the important internal and contextual factors that can impede or foster Master Adaptive Learning.

Melanoma expression of matrix metalloproteinase-23 is associated with blunted tumor immunity and poor responses to immunotherapy.

BACKGROUND: Matrix metalloproteinase-23 (MMP-23) can block the voltage-gated potassium channel Kv1.3, whose function is important for sustained Ca(2+) signaling during T cell activation. MMP-23 may also alter T cell activity and phenotype through cleavage of proteins affecting cytokine and chemokine signaling. We therefore tested the hypothesis that MMP-23 can negatively regulate the anti-tumor T cell response in human melanoma. METHODS: We characterized MMP-23 expression in primary melanoma patients who received adjuvant immunotherapy. We examined the association of MMP-23 with the anti-tumor immune response - as assessed by the prevalence of tumor-infiltrating lymphocytes and Foxp3(+) regulatory T cells. Further, we examined the association between MMP-23 expression and response to immunotherapy. Considering also an in trans mechanism, we examined the association of melanoma MMP-23 and melanoma Kv1.3 expression. RESULTS: Our data revealed an inverse association between primary melanoma MMP-23 expression and the anti-tumor T cell response, as demonstrated by decreased tumor-infiltrating lymphocytes (TIL) (P = 0.05), in particular brisk TILs (P = 0.04), and a trend towards an increased proportion of immunosuppressive Foxp3(+) regulatory T cells (P = 0.07). High melanoma MMP-23 expression is also associated with recurrence in patients treated with immune biologics (P = 0.037) but not in those treated with vaccines (P = 0.64). Further, high melanoma MMP-23 expression is associated with shorter periods of progression-free survival for patients receiving immune biologics (P = 0.025). On the other hand, there is no relationship between melanoma MMP-23 and melanoma Kv1.3 expression (P = 0.27). CONCLUSIONS: Our data support a role for MMP-23 as a potential immunosuppressive target in melanoma, as well as a possible biomarker for informing melanoma immunotherapies.

Evaluation of the Generic Drug User Fee Act (GDUFA) Program for Fiscal Years 2013-2022.

The effectiveness of the regulatory initiatives, strategies, and incentives put forth in the first two authorizations of the Generic Drug User Fees Act (GDUFA) were evaluated using factors including the number of Abbreviated New Drug Application (ANDA) withdrawals and first-cycle approvals. GDUFA was originally authorized in 2012 for FY 2013-2017 (GDUFA I) and reauthorized for FY 2018-2022 (GDUFA II). ANDA approvals were analyzed from the Drugs @ FDA database covering 2013-2022. From the applications, the approval time, dosage form and route of administration (ROA), product indication, market status of the product, first generic status, company and company size filing the ANDA were noted. Despite the COVID pandemic, there was more than a 40% increase in ANDA approvals during GDUFA II relative to GDUFA I. Oral and parenteral drugs were the two leading categories of approved generics during both iterations of GDUFA. There was more than a 120% increase in withdrawn applications during GDUFA II, which reflects the partial refund that is now offered to incentivize companies to withdraw inadequate applications prior to review. This also appears to have contributed to an increase in the number of first-cycle approvals, which increased by 100% between GDUFA I and II. Due to the COVID-19 public health emergency, there was a decrease in activity within the generic drug program and market. Therefore, it is important to consider this impact when observing actual trends from this study.

Effect of smoking on melanoma incidence: a systematic review with meta-analysis.

BACKGROUND: There is a strong correlation between cigarette smoking and the development of many cancer types. It is therefore paradoxical that multiple reports have suggested a reduced incidence of melanoma in smokers. This study aimed to analyze all existing studies of melanoma incidence in smokers relative to non-smokers. METHODS: Searches of MEDLINE and Embase were conducted for studies reporting data on melanoma in smokers and never-smokers. No study design limitations or language restrictions were applied. The outcome examined was the association between smoking status and melanoma. Analyses focussed on risk of melanoma in smokers and never-smokers generated from multivariable analyses and these were pooled using a fixed effects model. Risk of bias was assessed using the Newcastle-Ottawa tool. FINDINGS: Forty-nine studies that included 59,429 melanoma patients were identified. Pooled analyses showed that current-smokers had a significantly-reduced risk of melanoma both in males (risk ratio (RR) 0.60, 95%CI_0.56 to0.65, p < .001) and females (RR 0.79- 95%-CI-0.73-to-0.86, p < .001). Male former-smokers had a 16% reduction in melanoma risk compared to never-smokers (RR-0.84,-95%CI-0.77-to-0.93, p < .001), but no risk reduction was observed in female former-smokers (RR-1.0-95%CI-0.92-to-1.08). INTERPRETATION: Current-smokers have a significantly-reduced risk of developing melanoma compared to never-smokers, with a reduction in melanoma risk of 40% in men and 21% in women.

Participation and experience of third-year medical students in handoffs: time to sign out?

BACKGROUND: Although interns are expected to be competent in handoff communication, it is currently unclear what level of exposure, participation, and comfort medical students have with handoffs prior to graduation. OBJECTIVE: The aim of this study is to characterize passive and active involvement of third-year medical students in the major components of the handoff process. DESIGN: An anonymous voluntary retrospective cross-sectional survey administered in 2010. PARTICIPANTS: Rising fourth-year students at two large urban private medical schools. MAIN MEASURES: Participation and confidence in active and passive behaviors related to written signout and verbal handoffs during participants' third-year clerkships. KEY RESULTS: Seventy percent of students (n = 204) responded. As third-year medical students, they reported frequent participation in handoffs, such as updating a written signout for a previously admitted patient (58 %). Students who reported frequent participation (at least weekly) in handoff tasks were more likely to report being confident in that task (e.g., giving verbal handoff 62 % vs. 19 %, p < 0.001). Students at one site that did not have a handoff policy for medical students reported greater participation, more confidence, and less desire for training. Nearly all students believed they had witnessed an error in written signout (98 %) and almost two-thirds witnessed an error due to verbal handoffs (64 %). CONCLUSIONS: During their third year, many medical students are participating in handoffs, although reported rates differ across training environments. Medical schools should consider the appropriate level of competence for medical student participation in handoffs, and implement corresponding curricula and assessment tools to ensure that medical students are able to effectively conduct handoffs.

Expectations for medical student work hours in inpatient clinical clerkships.

BACKGROUND: No standards regarding what should be learned during medical school exist. PURPOSE: We investigated what medical students and clerkship directors (CDs) believe students are, and should be, doing during clerkships. METHODS: From January to June 2011, Mount Sinai School of Medicine CDs (n = 4) and 3rd-year students (n = 132) estimated how students spend time and should spend time during clerkships. Mann-Whitney U-tests compared students' and CDs' replies. RESULTS: All CDs and 105 of 132 students (79.5%) participated. Medicine CDs believed that students did more rounding and studying, and surgery CDs perceived that students did more note writing and studying and less waiting than students reported. Medicine CDs felt students should round more, whereas surgery CDs felt students should spend more total time in the hospital as well as in educational activities and studying than students did ( p < .05). CONCLUSIONS: Students and CDs disagree about how students allocate (and should allocate) time during clerkships.

Implementing shared decision making for early-stage breast cancer treatment using a coproduction learning collaborative: the SHAIR Collaborative protocol.

BACKGROUND: Shared decision making (SDM) in breast cancer care improves outcomes, but it is not routinely implemented. Results from the What Matters Most trial demonstrated that early-stage breast cancer surgery conversation aids, when used by surgeons after brief training, improved SDM and patient-reported outcomes. Trial surgeons and patients both encouraged using the conversation aids in routine care. We will develop and evaluate an online learning collaborative, called the SHared decision making Adoption Implementation Resource (SHAIR) Collaborative, to promote early-stage breast cancer surgery SDM by implementing the conversation aids into routine preoperative care. Learning collaboratives are known to be effective for quality improvement in clinical care, but no breast cancer learning collaborative currently exists. Our specific aims are to (1) provide the SHAIR Collaborative resources to clinical sites to use with eligible patients, (2) examine the relationship between the use of the SHAIR Collaborative resources and patient reach, and (3) promote the emergence of a sustained learning collaborative in this clinical field, building on a partnership with the American Society of Breast Surgeons (ASBrS). METHODS: We will conduct a two-phased implementation project: phase 1 pilot at five sites and phase 2 scale up at up to an additional 32 clinical sites across North America. The SHAIR Collaborative online platform will offer free access to conversation aids, training videos, electronic health record and patient portal integration guidance, a feedback dashboard, webinars, support center, and forum. We will use RE-AIM for data collection and evaluation. Our primary outcome is patient reach. Secondary data will include (1) patient-reported data from an optional, anonymous online survey, (2) number of active sites and interviews with site champions, (3) Normalization MeAsure Development questionnaire data from phase 1 sites, adaptations data utilizing the Framework for Reporting Adaptations and Modifications-Extended/-Implementation Strategies, and tracking implementation facilitating factors, and (4) progress on sustainability strategy and plans with ASBrS. DISCUSSION: The SHAIR Collaborative will reach early-stage breast cancer patients across North America, evaluate patient-reported outcomes, engage up to 37 active sites, and potentially inform engagement factors affecting implementation success and may be sustained by ASBrS.

Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node.

The sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T cells (Foxp3(+)) and dendritic cells (conventional: CD11c(+), mature: CD86(+)) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunological primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared with those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathological variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared with the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions.

Serum microRNAs as biomarkers for recurrence in melanoma.

BACKGROUND: Identification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection. METHODS: We screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence. RESULTS: A signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden. CONCLUSION: Our data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time.

Melanoma In Situ: A Critical Review and Re-Evaluation of Current Excision Margin Recommendations.

Most international clinical guidelines recommend 5-10 mm clinical margins for excision of melanoma in situ (MIS). While the evidence supporting this is weak, these guidelines are generally consistent. However, as a result of the high incidence of subclinical extension of MIS, especially of the lentigo maligna (LM) subtype, wider margins will often be needed to achieve complete histologic clearance. In this review, we assessed all available contemporary evidence on clearance margins for MIS. No randomized trials were identified and the 31 non-randomized studies were largely retrospective reviews of single-surgeon or single-institution experiences using Mohs micrographic surgery (MMS) for LM or staged excision (SE) for treatment of MIS on the head/neck and/or LM specifically. The available data challenge the adequacy of current international guidelines as they consistently demonstrate the need for clinical margins > 5 mm and often > 10 mm. For LM, any MIS on the head/neck, and/or ≥ 3 cm in diameter, all may require wider clinical margins because of the higher likelihood of subclinical spread. Histologic clearance should be confirmed prior to undertaking complex reconstruction. However, it is not clear whether wider margins are necessary for all MIS subtypes. Indeed, it seems that this is unlikely to be the case. Until optimal surgical margins can be better defined in a randomized trial setting, ideally controlling for MIS subtype and including correlation with histologic excision margins, techniques such as preliminary border mapping of large, ill-defined lesions and, most importantly, sound clinical judgement will be needed when planning surgical clearance margins for the treatment of MIS.

Taking Care of the Puerto Rican Patient: Historical Perspectives, Health Status, and Health Care Access.

Introduction: Hispanics are the largest minority group in the US at 18% of the population, of which Puerto Ricans are the second largest subgroup. Puerto Ricans have poorer health status than other US Hispanic and non-Hispanic populations. Thus, health care providers need to know about and distinguish the health care problems of Puerto Ricans to improve their health. Although there are some published curricula addressing how to provide health care to Hispanic populations, none address the specific needs of Puerto Ricans. Methods: We developed a 60-minute interactive workshop consisting of a PowerPoint presentation and case discussion aimed at increasing health care providers' knowledge and understanding of the historical perspective that led to Puerto Rican identity, health issues and disparities, and the health care access problems of mainland and islander Puerto Ricans. Evaluation consisted of pre- and postworkshop questionnaires. Results: There were a total of 64 participants with diverse ethnoracial identities including medical students, residents, faculty, physicians, researchers, administrators, and students/faculty from nursing, occupational therapy, genetic counseling, biomedical sciences, and social work programs. A comparison of pre- and postworkshop data showed a statistically significant increase in participants' confidence in meeting all learning objectives. Participants positively commented on the interactive nature of the workshop, the case discussion, and the historical perspective provided. Discussion: With the increasing migration of Puerto Ricans to the US mainland this module can uniquely improve the preparation of current and future health care providers to provide competent care to Puerto Rican patients.