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Nipple discharge is the third most common breast-related complaint but is rarely the presenting symptom of breast cancer. Distinguishing patients with physiologic versus pathologic nipple discharge, and treating the later according to the underlying pathologic condition is of utmost importance. Nipple discharge is categorized as lactational, physiologic, or pathologic. Physiologic nipple discharge (galactorrhea) is typically caused by hyperprolactinemia due to medications (ie, antipsychotics), pituitary tumors, and endocrine disorders. When a suspicious radiologic lesion is identified, pathologic assessment of the lesion is indicated. Patients with pathologic nipple discharge should be referred to a breast surgeon for definitive treatment and follow-up.

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To determine the feasibility and acceptability of using a decision aid (DA) in a breast surgery clinic.42 patients with minimally suspicious mammograms and two physicians participated in this study at an outpatient breast specialty clinic in Virginia.A quasiexperimental single group pilot study was conducted to determine the feasibility of DecisionKEYS, a theory-based, interactive DA intervention. Patients with minimally suspicious mammogram results chose between breast biopsy or close imaging follow-up. The Decisional Conflict Scale was used to measure decisional conflict. The Decision-Making Quality Scale was used to evaluate the overall decision process. Postintervention physician and patient feedback evaluated feasibility and acceptability.Participants and physicians rated the DA as helpful. Decisional Conflict Scale scores were low before and after the intervention. Physicians reported the DA was feasible for workflow, and the majority reported using the DA in making final recommendations. Management recommendation (breast biopsy, close imaging follow-up) changed in 26 of 42 cases from pre- to postintervention. The majority of participants underwent breast biopsy.The feasibility and acceptability of the DA were beneficial to patients and clinic workflow.

Lymphatic drainage from subcostal nodes, along the costal groove, have not previously been characterized as sites for melanoma drainage and metastasis. This study reports a series of patients with subcostal nodes draining primary melanomas, with characterization of the sites of primary melanomas that drain to these nodes.Patients who presented to our institution between 2005 and 2020 with documented cutaneous melanoma and sentinel lymph node biopsy of a subcostal node (sentinel = S), or metastases to subcostal nodes later in clinical management (recurrent = R) were included. Patient demographics, melanoma pathology, nodal features, imaging information, surgical approaches, and outcomes data were collected.Six patients had subcostal sentinel nodes (SNs). Primary sites included the posterior trunk and lateral chest wall. Subcostal nodes were found under ribs 10-12. Subcostal SNs had at least one dimension measuring 3 mm or less. There were no surgical complications related to removing the subcostal SN.Melanoma can metastasize to subcostal lymph nodes and be found at the time of SN biopsy or identified at recurrence. These small nodes are fed by lymphatic channels that run in the neurovascular bundle under the ribs. When lymphatic mapping identifies a subcostal SN, it should be excised.

Inguinal complete lymph node dissection (CLND) for metastatic melanoma exposes the femoral vein and artery. To protect femoral vessels while preserving the sartorius muscle, we developed a novel sartorius and adductor fascial flap (SAFF) technique for coverage.The SAFF technique includes dissection of fascia off sartorius and/or adductor muscles, rotation over femoral vasculature, and suturing into place. Patients who underwent inguinal CLND with SAFF for melanoma at our institution were identified retrospectively from a prospectively-collected database. Patient characteristics and post-operative outcomes were obtained. Multivariate logistic regression assessed associations of palpable and non-palpable disease with wound complications.From 2008 to 2019, 51 patients underwent CLND with SAFF. Median age was 62 years, and 59% were female. Thirty-one (61%) patients were presented with palpable disease and 20 (39%) had non-palpable disease. Fifty-five percent (95% confidence interval CI: 40%-69%) experienced at least one wound complication: wound infection was most common (45%; 95% CI: 31%-60%), while bleeding was the least (2%; 95% CI: 0.05%-11%). Complications were similar, with and without palpable disease.The SAFF procedure covers femoral vessels, minimizes bleeding, preserves the sartorius muscle, and uses standard surgical techniques easily adoptable by surgeons who perform inguinal CLND.

BackgroundA vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade.Participants and methodsParticipants with advanced melanoma received 6MHP vaccines in an incomplete Freund’s adjuvant (6 vaccines over 12 weeks). Pembrolizumab was administered intravenously every 3 weeks. Tumor biopsies at baseline and day 22 were analyzed by multiplex immunohistochemistry. Primary end points were safety (Common Terminology Criteria for Adverse Events V.4.03) and immunogenicity (ex vivo interferon-γ ELISpot assay). Additional end points included changes in the tumor microenvironment (TME) and clinical outcomes.ResultsTwenty-two eligible participants were treated: 6 naïve to PD-1 antibody (Ab) and 16 PD-1 Ab-experienced. Median follow-up was 24.4 months. Most common treatment-related adverse events (any grade) included injection site reactions, fatigue, anemia, lymphopenia, fever, elevated aspartate aminotransferase, pruritus, and rash. Treatment-related dose-limiting toxicities were observed in 3 (14%) participants, which did not cross the study safety bound. A high durable T cell response (Rsp) to 6MHP was detected in only one participant, but twofold T cell Rsps to 6MHP were detected in 7/22 (32%; 90% CI (16% to 52%)) by week 13. Objective clinical responses were observed in 23% (1 complete response, 4 partial responses), including 4/6 PD-1 Ab-naïve (67%) and 1/16 PD-1 Ab-experienced (6%). Overall survival (OS) was longer for PD-1 Ab-naïve than Ab-experienced participants (HR 6.3 (90% CI (2.1 to 28.7)). In landmark analyses at 13 weeks, OS was also longer for those with T cell Rsps (HR 6.5 (90% CI (2.1 to 29.2)) and for those with objective clinical responses. TME evaluation revealed increased densities of CD8+T cells, CD20+B cells, and Tbet+cells by day 22.ConclusionsTreatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral lymphocytes, and induced T cell Rsps associated with prolonged OS. The low T cell Rsp rate in PD-1 Ab-experienced participants corroborates prior murine studies that caution against delaying cancer vaccines until after PD-1 blockade. The promising objective response rate and OS in PD-1 Ab-naïve participants support consideration of a larger study in that setting.

BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.Participants and methodsAn adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.ResultsForty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.Conclusions6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.

BACKGROUND: Identifying factors that impact progression of surgery trainees into academic versus non-academic practices may permit tailoring residency experiences to promote academic careers in institutions charged with the training of future surgeon scientists. The aim of this study was to identify factors associated with progression of surgery trainees into academic versus non-academic practice. METHODS: A survey was distributed to 135 surgeons graduating from the University of Virginia residency program from 1964–2016, a single academic institution. Questions addressed practice type, research productivity, work/life balance, mentorship, and overall sentiment toward research and academic surgery. A 5-point Likert scale measured career satisfaction and influence of factors in practice setting choice. RESULTS: Of the 135 surveys that were electronically distributed, 69 participants responded (response rate: 51%). Of the 54 with known current practice types, 34 (63%) were academic and 20 (37%) non-academic. Academic surgeons reported more publications by the conclusion of surgery training (56% vs 25% with >10 publications, P = .02). More academic surgeons reported > $100,000 in student debt at graduation (44% vs 25%, P < .05). Factors encouraging an academic career were similar for both types of surgeons, including involvement in education of trainees and access to mentorship. Both groups were discouraged from an academic practice by requirements of grant-writing and funding responsibilities. Surgeons in academic practice were more likely to recommend surgery as a career to a current medical student (100% vs 70%, P = .001). CONCLUSION: This knowledge may help to tailor training experiences to promote academic careers. By supporting funding mechanisms and grant-writing programs, while encouraging mentorship and productive research experiences, current surgical trainees may be more enthusiastic about a career in academic practice.

BackgroundA multipeptide vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe and immunogenic and has clinical activity. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus PD1 blockade.MethodsParticipants with measurable advanced melanoma, age ≥ 18 years, and ECOG performance status 0–1 were administered 6MHP vaccine intradermally and subcutaneously in an incomplete Freund’s adjuvant on days (D) 1, 8, 15, 43, 64, and 85. Pembrolizumab 200 mg was administered intravenously every 3 weeks for up to two years. Biopsies of accessible tumors at baseline and D22 were analyzed by multiparameter immunofluorescence histology. Primary endpoints were safety (CTCAE 4.03) and immunogenicity (ex vivo IFNγ ELIspot assay). Secondary and exploratory endpoints included changes in the tumor microenvironment (TME), and clinical outcomes.ResultsTwenty-two eligible participants were enrolled and treated, including 6 naïve to PD-1 Ab and 16 anti-PD-1 Ab-experienced. Median follow-up was 20 months. Treatment-related adverse events (any grade) experienced by >20% were injection site reactions, fatigue, anemia, nausea, fever, bruising, and rash. Treatment-related dose limiting toxicities (grade 3 elevated AST, skin ulcer, or uveitis) were observed in 3 (14%), which did not cross the study safety bound. Objective clinical responses were observed in 23% (1 CR, 4 PR), including 4/6 anti-PD-1 Ab-naive (67%) and one 1/16 anti-PD1 Ab-experienced (6%). Four participants (18%) had SD as best radiographic response (18%), all in the Ab-experienced cohort. T cell responses to 6MHP were detected in seven participants (32%) by week 13 and were associated with clinical response (CR/PR 80% vs. SD/PD 18%; p = 0.01). Overall survival was prolonged for anti-PD-1 Ab naïve vs experienced (p = 0.0048), for those with T cell response (p = 0.045, landmark analysis after week 13), and for those with objective response (p = 0.0148). TME evaluation in 12 participants revealed significant increases by D22 in the densities (per mm2) of CD8+ T cells (p = 0.0186), CD20+ B cells (P = 0.002), and Tbet+ cells (p = 0.034).ConclusionsIn patients with advanced melanoma, combined treatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral T and B cells, as well as Th1 (Tbet+) cells, and induced T cell responses that were associated with objective response and with overall survival. The promising objective response rate and overall survival in patients naive to PD1 blockade supports consideration of a larger study to assess definitive benefit in that clinical setting.AcknowledgementsWe acknowledge the support of Merck for providing pembrolizumab at no charge, and the University of Virginia Cancer Center Support grant P30 CA044579 for support of shared resource facilities.Trial RegistrationThe clinical trial Mel64 (PATHVACS) is registered with Clinicaltrials.gov (NCT02515227).Ethics ApprovalThe clinical trial Mel64 (PATHVACS) was performed with IRB (#18174) and FDA approval (IND #10825) and is registered with Clinicaltrials.gov (NCT02515227). Written informed consent was obtained from each participant prior to participation in the study.

Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression.Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures.The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.

Background Total body photography may aid in melanoma screening but is not widely applied due to time and cost. We hypothesized that a near-simultaneous automated skin photo-acquisition system would be acceptable to patients and could rapidly obtain total body images that enable visualization of pigmented skin lesions. Methods From February to May 2009, a study of 20 volunteers was performed at the University of Virginia to test a prototype 16-camera imaging booth built by the research team and to guide development of special purpose software. For each participant, images were obtained before and after marking 10 lesions (five “easy” and five “difficult”), and images were evaluated to estimate visualization rates. Imaging logistical challenges were scored by the operator, and participant opinion was assessed by questionnaire. Results Average time for image capture was three minutes (range 2–5). All 55 “easy” lesions were visualized (sensitivity 100%, 90% CI 95–100%), and 54/55 “difficult” lesions were visualized (sensitivity 98%, 90% CI 92–100%). Operators and patients graded the imaging process favorably, with challenges identified regarding lighting and positioning. Conclusions Rapid-acquisition automated skin photography is feasible with a low-cost system, with excellent lesion visualization and participant acceptance. These data provide a basis for employing this method in clinical melanoma screening.

Differentiating melanoma metastasis from benign cutaneous lesions currently requires biopsy or costly imaging, such as positron emission tomography scans. Melanoma metastases have been observed to be subjectively warmer than similarly appearing benign lesions. We hypothesized that infrared (IR) thermography would be sensitive and specific in differentiating palpable melanoma metastases from benign lesions.Seventy-four patients (36 females and 38 males) had 251 palpable lesions imaged for this pilot study. Diagnosis was determined using pathologic confirmation or clinical diagnosis. Lesions were divided into size strata for analysis: 0-5,5-15,15-30, and30 mm. Images were scored on a scale from -1 (colder than the surrounding tissue) to +3 (significantly hotter than the surrounding tissue). Sensitivity and specificity were calculated for each stratum. Logistical challenges were scored.IR imaging was able to determine the malignancy of small (0-5 mm) lesions with a sensitivity of 39% and specificity of 100%. For lesions5-15 mm, sensitivity was 58% and specificity 98%. For lesions15-30 mm, sensitivity was 95% and specificity 100%, and for lesions30 mm, sensitivity was 78% and specificity 89%. The positive predictive value was 88%-100% across all strata, and the negative predictive value was 95% for15-30 mm lesions and 80% for30 mm lesions.Malignant lesions15 mm were differentiated from benign lesions with excellent sensitivity and specificity. IR imaging was well tolerated and feasible in a clinic setting. This pilot study shows promise in the use of thermography for the diagnosis of malignant melanoma with further potential as a noninvasive tool to follow tumor responses to systemic therapies.

Immune cells infiltrating the microenvironment of melanoma metastases may either limit or promote tumor progression, but the characteristics that distinguish these effects are obscure. In this study, we systematically evaluated the composition and organization of immune cells that infiltrated melanoma metastases in human patients. Three histologic patterns of immune cell infiltration were identified, designated immunotypes A, B, and C. Immunotype A was characterized by no immune cell infiltrate. Immunotype B was characterized by infiltration of immune cells limited only to regions proximal to intratumoral blood vessels. Immunotype C was characterized by a diffuse immune cell infiltrate throughout a metastatic tumor. These immunotypes represented 29%, 63%, and 8% of metastases with estimated median survival periods of 15, 23, and 130 months, respectively. Notably, from immunotypes A to C, there were increasing proportions of B cells and decreasing proportions of macrophages. Overall, the predominant immune cells were T cells (53%), B cell lineage cells (33%), and macrophages (13%), with natural killer and mature dendritic cells only rarely present. Whereas higher densities of CD8+ T cells correlated best with survival, a higher density of CD45+ leukocytes, T cells, and B cells also correlated with increased survival. Together, our findings reveal striking differences in the immune infiltrate in melanoma metastases in patients, suggesting microenvironmental differences in immune homing receptors and ligands that affect immune cell recruitment. These findings are important, not only by revealing how the immune microenvironment can affect outcomes but also because they reveal characteristics that may help improve individualized therapy for patients with metastatic melanoma. Cancer Res; 72(5); 1070–80. ©2012 AACR.

Large centers have described triangular intermuscular space (TIS) sentinel nodes (SNs) for some melanomas of the back. However, their management remains controversial and poorly characterized, especially as related to the ipsilateral axillary node basin. The aim of this study was to summarize our experience with TIS SN, which may contribute to defining their appropriate surgical management.We performed a retrospective review on surgical patients from January 1993 to April 2009. Among 293 patients with upper back melanoma, data were collected on those with TIS SN.Fourteen patients (5%) with melanoma of the upper back had a TIS SN, 6 of whom (43%) were incorrectly identified at lymphoscintigraphy as axillary, and 11 of whom (79%) had a concurrent axillary SN. Micrometastatic disease was identified in TIS SN in two patients (14%) and in an axillary SN in one (9%). We found direct lymphatic drainage independently to the TIS and to the axilla, as well as a more typical pattern of drainage first to the TIS node and then to axillary nodes.We defined three patterns of lymphatic drainage to TIS and axillary nodes. The TIS and axilla are anatomically linked; patients with SN in both locations should undergo biopsies of both for optimal nodal staging. We recommend directed evaluation for TIS SN in patients with upper back melanomas and recommend clearing the TIS at the time of TIS SN biopsy. Melanoma can metastasize to TIS SN, and we discuss considerations for management of the axilla in patients with positive TIS nodes.

e21080 Background: A 31-GEP test is predictive of metastasis in cutaneous melanoma. We hypothesized that GEP testing would “upgrade” surveillance to routine imaging in at least 16% of stage IB/IIA patients, similar to the upgrade rate from sentinel node biopsy. Methods: A GEP score was obtained for consecutive patients with Stage IB/IIA melanoma treated between 6/2014-6/2016. A retrospective review of a prospectively collected database was performed. Results: 67 patients with Stage IB/IIA melanoma met inclusion criteria. In four cases, a GEP result was not available. Of the 63 tested cases, 68% were Stage IB (N = 43), and 32% were Stage IIA (N = 20). A high-risk result was seen in 12% of stage IB (5/43) and 42% of stage IIA (8/19) patients. Insurance denied coverage of scans in 1/13 patients with a high-risk GEP result. The remaining 12 Stage IB/IIA patients with high-risk scores were “upgraded” to high-intensity surveillance. With a median follow-up of 14 months, 1/13 patients with a high-risk GEP result developed distant metastases 21 months after diagnosis of a Stage IIA melanoma. Conclusions: Results from this retrospective single institution study show that GEP testing altered patient management in 19% of Stage IB/IIA patients. Early detection in 1/13 patients with high-risk scores in this series supports further investigation into stratifying traditionally low-risk patients by GEP testing.

Background Metastatic melanoma to abdominal and retroperitoneal viscera carries a poor prognosis possibly resulting in reluctance to offer surgical management. There is value in defining the morbidity of such surgery. Methods Review of a prospectively maintained database identified patients with metastatic melanoma to abdominal or retroperitoneal viscera who underwent surgery from 9/99 to 8/06. Results Nineteen patients underwent surgery for metastasis to abdominal or retroperitoneal viscera detected by clinical symptoms (80%), or imaging (20%). The median length of stay was 7 days. There was no perioperative mortality. Surgical complications occurred in four patients. At initial follow-up, 13 patients (68%) had returned to baseline function, 7 of which reported improvement. Four patients (21%) had minimal symptoms, and only two patients (11%) had significantly limited function. Median follow-up was 35 months, at which time 9 of the 19 patients (47%) were still alive, with 3- and 5-year Kaplan–Meier survival estimates of 53% (SE 12) and 45% (SE 12), respectively, and 2 of the 19 patients are alive at over 8 years since surgery. Conclusion In selected cases, surgery may have both palliative benefit and curative potential for patients with visceral metastases of melanoma. Surgical management of such patients should be encouraged in appropriate clinical settings. J. Surg. Oncol. 2009;100:481–483. © 2009 Wiley-Liss, Inc.

The objective is to evaluate the sensitivity and clinical utility of intraoperative mobile gamma camera (MGC) imaging in sentinel lymph node biopsy (SLNB) in melanoma. The false-negative rate for SLNB for melanoma is approximately 17%, for which failure to identify the sentinel lymph node (SLN) is a major cause. Intraoperative imaging may aid in detection of SLN near the primary site, in ambiguous locations, and after excision of each SLN. The present pilot study reports outcomes with a prototype MGC designed for rapid intraoperative image acquisition. We hypothesized that intraoperative use of the MGC would be feasible and that sensitivity would be at least 90%. From April to September 2008, 20 patients underwent Tc99 sulfur colloid lymphoscintigraphy, and SLNB was performed with use of a conventional fixed gamma camera (FGC), and gamma probe followed by intraoperative MGC imaging. Sensitivity was calculated for each detection method. Intraoperative logistical challenges were scored. Cases in which MGC provided clinical benefit were recorded. Sensitivity for detecting SLN basins was 97% for the FGC and 90% for the MGC. A total of 46 SLN were identified: 32 (70%) were identified as distinct hot spots by preoperative FGC imaging, 31 (67%) by preoperative MGC imaging, andmore » 43 (93%) by MGC imaging pre- or intraoperatively. The gamma probe identified 44 (96%) independent of MGC imaging. The MGC provided defined clinical benefit as an addition to standard practice in 5 (25%) of 20 patients. Mean score for MGC logistic feasibility was 2 on a scale of 1-9 (1 = best). Intraoperative MGC imaging provides additional information when standard techniques fail or are ambiguous. Sensitivity is 90% and can be increased. This pilot study has identified ways to improve the usefulness of an MGC for intraoperative imaging, which holds promise for reducing false negatives of SLNB for melanoma.« less

Immune-mediated cancer regression requires tumor infiltration by antigen-specific effector T cells, but lymphocytes are commonly sparse in melanoma metastases. Activated T cells express CXCR3, whose cognate chemokines are CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC. Little is known about expression of these chemokines in lymph node (LN) metastases of melanoma. We evaluated whether metastatic melanoma induces these CXCR3-cognate chemokines in human LN-derived tissues. In addition, as these chemokines can be induced by interferon (IFN), we evaluated whether type I or II IFNs (IFN-α or IFN-γ, respectively) can modulate chemokine expression in an in vitro model of the human tumor microenvironment. Production of CXCL9-11 by melanoma-infiltrated nodes (MIN) was no different than tumor-free nodes; both produced less chemokine than activated LN (sentinel immunized nodes, SIN). These data suggest that melanoma infiltration into LN neither induces nor reduces CXCL9-11. Stimulation with IFN-α or IFN-γ increased production of CXCL10-11 from MIN, but not tumor-free node or SIN. IFN-γ also increased production of CXCL9 in MIN. In IFN-treated SIN, CD14+ cells were the primary source of CXCL9-11, whereas melanoma cells were the source of chemokine in MIN. Melanoma cells in MIN express IFN receptors. Consistent with these observations, multiple human melanoma lines expressed IFN receptors and produced CXCL9-11 in response to IFN treatment. Thus, melanoma infiltration of LN is insufficient to induce the production of CXCL9-11, but melanoma may be a significant source of IFN-induced chemokines. Collectively, these data suggest that IFN-α or IFN-γ may act in the tumor microenvironment to increase the chemotactic gradient for CXCR3+ T cells.

Metastatic melanoma to abdominal and retroperitoneal viscera carries a poor prognosis possibly resulting in reluctance to offer surgical management. There is value in defining the morbidity of such surgery.Review of a prospectively maintained database identified patients with metastatic melanoma to abdominal or retroperitoneal viscera who underwent surgery from 9/99 to 8/06.Nineteen patients underwent surgery for metastasis to abdominal or retroperitoneal viscera detected by clinical symptoms (80%), or imaging (20%). The median length of stay was 7 days. There was no perioperative mortality. Surgical complications occurred in four patients. At initial follow-up, 13 patients (68%) had returned to baseline function, 7 of which reported improvement. Four patients (21%) had minimal symptoms, and only two patients (11%) had significantly limited function. Median follow-up was 35 months, at which time 9 of the 19 patients (47%) were still alive, with 3- and 5-year Kaplan-Meier survival estimates of 53% (SE 12) and 45% (SE 12), respectively, and 2 of the 19 patients are alive at over 8 years since surgery.In selected cases, surgery may have both palliative benefit and curative potential for patients with visceral metastases of melanoma. Surgical management of such patients should be encouraged in appropriate clinical settings.

Purpose Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy. Current recommendations include offering regional lymph node evaluation by either sentinel lymph node biopsy (SLNB) or complete lymph node dissection (CLND) to all patients with MCC; however, we hypothesized a cohort of low-risk patients may exist for whom regional nodal metastasis would be unlikely. Methods A retrospective review of the Department of Veterans Affairs national health care database was performed. Patients undergoing resection of primary MCC were identified; and demographic, medical, and social history; tumor characteristics; nodal status; and recurrence events were recorded. Results Between 1995 and 2006, 346 patients were diagnosed with MCC. Of these, 213 underwent resection of the primary lesion and evaluation of the draining lymph node basin. Fifty-four patients (25%) had tumors ≤ 1.0 cm in diameter. Average tumor diameter was 0.7 cm, and 63% were located on the head or neck. Only two patients (4%) with tumors ≤ 1.0 cm had regional lymph node metastasis, compared with 51 (24%) of 213 patients with tumors more than 1.0 cm (P < .0001). Both patients had clinically evident nodal disease at presentation and underwent CLND. Both have remained recurrence-free for 40 months. Thirteen (25%) of 51 patients with nodal metastasis and tumors more than 1 cm had occult nodal metastasis. Conclusion In this series, patients with MCC ≤ 1.0 cm were unlikely to have regional lymph node metastasis, suggesting that regional nodal evaluation may reasonably be avoided in these patients. However, these data support SLNB for MCC more than 1 cm in diameter.

Successful management of epithelial skin cancers with imiquimod 5% cream (Aldara®), an immunomodulatory agent, led to speculation that it may promote an immune response against melanoma. Studies, mostly case reports, have assessed the value of imiquimod as a topical treatment for dermal melanoma metastases that prove difficult to manage surgically. The precise value of imiquimod, however, in treatment of dermal and subcutaneous metastases remains unclear. A case at our institution elucidates histopathologically that subcutaneous metastases may progress despite excellent treatment of superficial dermis in the same location. In preparation for a clinical trial using imiquimod to treat patients with dermal melanoma metastases, we have treated several patients off protocol. We present a case report in which the observed changes are documented photographically and histologically. The patient experienced dramatic improvement in the locally treated dermis with concurrent regional treatment failure in the subcutaneous space. Our experience supports growing evidence that imiquimod for some provides an effective option for dermal disease. The unique histological documentation we provide regarding the differential effectiveness of imiquimod in treating various tissue components may help guide future investigations regarding optimal clinical application of imiquimod therapy for melanoma metastases.

A Caucasian baby girl presented at birth with a dark, irregular, raised skin lesion measuring approximately 2 cm in diameter on the medial aspect of her right leg (Fig 1). There was no history of melanoma in her family and no evidence of melanoma in her mother. At two weeks of age, she underwent an incisional biopsy of the lesion at a community hospital. Histologic review showed a superficial spreading invasive malignant melanoma with Breslow thickness greater than 2.5 mm, with a positive deep margin. There was angiolymphatic invasion but no definite ulceration. She was referred to our institution, where clinical exam revealed an otherwise healthy newborn girl, a black lesion on the right leg with a central scar measuring 1.5 cm in diameter. There were small palpable inguinal nodes in each groin, possibly more prominent on the right but not clinically suspicious. One week later, a wide local excision was performed with a 1 cm margin (Fig 1) and a full thickness skin graft. Lymphoscintigraphy revealed a sentinel node in the right groin, and a sentinel lymph node biopsy was performed. Her final pathology revealed an atypical malignant melanoma arising in a nevus with congenital features with Breslow thickness of 2.58 mm and Clark’s level V (Fig 2A). Margins were widely clear. The lesion was consistent with a primary melanoma, rather than metastatic disease from maternal origin. The sentinel node was positive for metastatic melanoma, with mitotic figures (Fig 2B) and S100 staining (Fig 2C). She underwent staging studies including CT scans of her head, chest, abdomen and pelvis as well as a bone scan. These were negative for metastatic disease. One month later, completion right inguinal lymph node dissection was performed, yielding five lymph nodes without metastatic disease. Her postoperative course was complicated by a wound abscess in the right groin that was drained operatively and healed well. Her final staging, at the age of 9 weeks, was therefore Stage IIIA (T3aN1aM0). No additional treatment was performed. She has been followed to her current age of 32 months without evidence of recurrence by clinical exam, serial chest radiographs, and annual CT scans of the abdomen and pelvis. She has had an excisional biopsy of a suspicious skin lesion from her lower abdomen at age 22 months that was an atypical nevus. She has normal function of her right lower extremity without lymphedema and is healthy and developmentally appropriate (Fig 3).

Our surgery residency includes an annual Resident Research Day (RRD) for presentation of resident research. We hypothesized that RRD stimulates the development of novel research. We evaluated this among our residents and at other institutions.An electronic survey was distributed to current and alumni residents at our institution. The survey questions addressed residents' perceptions of RRD and were graded on a 5-point Likert scale. Another electronic survey was distributed to Program Directors (PDs) or Associate Program Directors (APDs) for all U.S. general surgery residencies. Questions assessed type of RRD and impact on research productivity. Microsoft Excel (Microsoft Corporation, Redmond, Washington) and MedCalc (MedCalc Software, Inc, Mariakerke, Belgium) software were used for analyses.The response rate was 76% (47/62) among residents and alumni. These 47 respondents submitted 98 projects to RRD, which included retrospective clinical studies (53%), basic science (35%), medical education research (6%), and prospective clinical papers (6%). Twenty projects (20%) were created expressly for RRD, of which 7 were presented at outside scientific meetings and 8 were published in peer-reviewed journals. The response rate was 47% among PD/APD (88/188). Most programs have an RRD or similar forum (78%) without difference between university and community programs (p = 0.78). Higher rates of resident submission were associated with dedicated research time for most residents (p = 0.01). Required submission was associated with novel projects created for RRD (p0.001). Thirty-seven percent of programs reported greater than 25% of submitted projects were created for RRD.RRD and similar forums occur at most general surgery training programs. They stimulate research activity and satisfy most residents' expectations. RRD leads to completion of novel research projects that are presented both internally and in peer-reviewed form.

Wide local excision of primary cutaneous melanoma usually provides clear margins and excellent local control. Nonclassical presentations of cutaneous melanoma, however, can challenge this treatment algorithm. Specifically, persistent melanoma-in-situ (MIS) at the margin not suspected clinically makes planning definitive wide local excision more difficult. We hypothesized that the use of punch biopsies as a mapping tool would allow us to obtain clear margins in these challenging cases.Punch biopsies were performed at sites 1 to 2 cm from prior positive margins. Subsequent wide local excision was planned, including all punch biopsy sites with positive findings: atypical melanocytic hyperplasia, MIS, or invasive melanoma. The management of three patients was documented prospectively. Standard surgical techniques were used independent of an experimental protocol. Medical records were reviewed, and data were summarized under institutional review board protocol HIC 10803.The results of punch biopsies identified invasive melanoma, MIS, or atypical melanocytic hyperplasia in all three patients with MIS at the margins. All three mapping procedures were well tolerated and resulted in resection with negative margins in a single definitive resection.Melanoma mapping with punch biopsy technique allows for definitive excision in cases when disease persists at the margins of the reexcision or in cases with unclear clinical examinations.

e19062 Background: Sentinel lymph node biopsy (SLNB) is the standard method for staging cutaneous melanoma and involves identifying the first node(s) draining a tumor, by detecting an intradermally-injected radioactive colloid tracer. Intra-operatively the sentinel node(s) are identified with a hand-held gamma probe. Pre-operative lymphoscintigraphy is obtained to identify draining lymph node basins, but requires coordinating schedules between nuclear medicine and the operating room. A pilot study utilizing Mobile Gamma Camera (MGC) devices in conjunction with conventional lymphoscintigraphy for intraoperative sentinel node localization provided clinical benefit in 20% of patients. However, utilizing MGC devices to localize lymph node basins at the time of surgery independent of conventional lymphoscintigraphy with a fixed gamma camera (FGC) has not been adequately studied. Here, we present the results of a clinical trial utilizing MGC devices to localize lymph node basins in a manner blinded to the FGC images in order to compare the modalities directly. Methods: In 2011-12 18 patients underwent Tc99 sulfur colloid lymphoscintigraphy, and MGC survey immediately pre-operative by the study surgeon. The study surgeon established an operative plan using the MGC survey, while blinded to lymphoscintigraphy results. SLNB was then performed with use of a gamma probe and intra-operative MGC imaging. Results: 22 lymph node basins were detected in 18 imaged patients by lymphoscintigraphy. All of these basins were identified by the study surgeon using the MGC device in the pre-operative setting prior to un-blinding. In every case the operative plan established based on pre-operative MGC imaging was confirmed by the FGC images. In two cases, additional information from the MGC images aided surgical decision-making. 5 of 22 lymph node basins were positive for metastasis. All of these basins were identified by pre-operative MGC imaging, and all individual positive nodes were identified by intra-operative MGC imaging. Conclusions: Pre-operative MGC imaging in sentinel lymph node biopsy can provide comparable information for operative planning, compared to standard FGC imaging.

Immune-mediated cancer regression requires tumor infiltration by Ag-specific effector T cells, but lymphocytes are commonly sparse in melanoma metastases. Activated T cells express CXCR3, whose cognate chemokines are CXCL9/MIG, CXCL10/IP-10 and CXCL11/I-TAC. Little is known about expression of these chemokines in lymph node (LN) metastases of melanoma. We evaluated whether metastatic melanoma induces these CXCR3-cognate chemokines in human LN-derived tissues. Also, because these chemokines can be induced by interferon (IFN), we evaluated whether type I or II IFNs (IFN-α or IFN-γ, respectively) can modulate chemokine expression in an in vitro model of the human tumor microenvironment. Production of CXCL9-11 by melanoma-infiltrated nodes (MIN) was no different than tumor-free nodes (TFN); both produced less than activated LN (sentinel immunized nodes, SIN). These data suggest melanoma infiltration into LN neither induces nor reduces CXCL9-11. Stimulation with IFN-α or IFN-γ increased production of CXCL10-11 from MIN, but not TFN or SIN. IFN-γ also increased production of CXCL9 in MIN. In IFN-treated MIN, the primary source of CXCL9-11 was melanoma cells themselves, whereas CD14+ cells were the source of these molecules in SIN. Melanoma cell lines expressed IFN receptors and produced CXCL9-11 in response to IFN treatment. Treatment of melanoma cell lines or primary melanomas in vitro with IFN-γ induced the migration of CXCR3+ T cells in transwell assays, whereas T cell did not significantly migrate in response to resting melanoma cells. Thus, melanoma infiltration of LN is insufficient to induce the production of CXCL9-11, but melanoma may be a significant source of IFN-induced chemokines. Collectively, these data suggest that IFN-α or IFN-γ may act in the tumor microenvironment to increase the chemotactic gradient for CXCR3+ T cells, thus enhancing the capacity of therapeutic vaccines to mediate clinical efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3827.