Publications by authors named "Nicole Kounalakis"

27 Publications

  • Page 1 of 1

Adjuvant Therapy for Stage III Melanoma Without Immediate Completion Lymph Node Dissection.

Ann Surg Oncol 2021 Sep 19. Epub 2021 Sep 19.

Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Introduction: For patients with stage III melanoma with occult lymph node metastasis, the use of adjuvant therapy is increasing, and completion lymph node dissection (CLND) is decreasing. We sought to evaluate the use of modern adjuvant therapy and outcomes for patients with stage III melanoma who did not undergo CLND.

Methods: Patients with a positive SLNB from 2015 to 2020 who did not undergo CLND were evaluated retrospectively. Nodal recurrence, recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival were evaluated.

Results: Among 90 patients, 56 (62%) received adjuvant therapy and 34 (38%) underwent observation alone. Patients who received adjuvant therapy were younger (mean age: 53 vs. 65, p < 0.001) and had higher overall stage (Stage IIIb/c 75% vs. 54%, p = 0.041). Disease recurred in 12 of 34 patients (35%) in the observation group and 11 of 56 patients (20%) in the adjuvant therapy group. The most common first site of recurrence was distant recurrence alone (5/34 patients) in the observation group and nodal recurrence alone (8/90 patients) in the adjuvant therapy group. Despite more adverse nodal features in the adjuvant therapy group, 24-month nodal recurrence rate and RFS were not significantly different between the adjuvant and observation cohorts (nodal recurrence rate: 26% vs. 20%, p = 0.68; RFS: 75% vs. 61%, p = 0.39). Among patients with stage IIIb/c disease, adjuvant therapy was associated with a significantly improved 24-month DMFS (86% vs. 59%, p = 0.04).

Conclusions: In this early report, modern adjuvant therapy in patients who forego CLND is associated with longer DMFS among patients with stage IIIb/c disease.
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http://dx.doi.org/10.1245/s10434-021-10775-8DOI Listing
September 2021

Utility of Quantitative SPECT/CT Lymphoscintigraphy in Guiding Sentinel Lymph Node Biopsy in Head and Neck Melanoma.

Ann Surg Oncol 2020 May 26;27(5):1432-1438. Epub 2019 Nov 26.

Melanoma and Sarcoma Specialists of Georgia, Northside Hospital, Atlanta, GA, USA.

Purpose: To investigate the use of advanced SPECT/CT quantification in guiding surgical selection of positive sentinel lymph nodes (SLNs) in head and neck melanoma.

Methods: We retrospectively reviewed data from patients with cutaneous head and neck melanoma who underwent lymphoscintigraphy with SPECT/CT prior to SLN biopsy (SLNB). Quantification of radiotracer uptake from SPECT/CT data was performed using in-house segmentation software. SLNs identified using SPECT/CT were compared to SLNs identified surgically using an intraoperative γ-probe. A radioactivity count threshold using SPECT/CT for detecting a positive SLN was calculated.

Results: One hundred and five patients were included. Median number of SLNs detected was 3/patient with SPECT/CT and 2/patient with intraoperative γ-probe. The hottest node identified by SPECT/CT and intraoperative γ-probe were identical in 85% of patients. All 20 histologically positive SLNs were identified by SPECT/CT and γ-probe. On follow-up, all nodal recurrences occurred at lymph node levels with the hottest node identified by SPECT/CT and either the hottest or second hottest node identified by γ-probe during SLNB. Using our data, a SPECT/CT radioactivity count threshold of 20% would eliminate the unnecessary removal of 11% of SPECT/CT identified nodes and 12% of intraoperatively detected nodes.

Conclusion: Utilizing SPECT/CT quantification, we propose that a radioactivity count threshold can be developed to help guide the selective removal of lymph nodes in head and neck SLNB. Furthermore, the nodal level containing the hottest node identified by SPECT/CT quantification must be thoroughly investigated for SLNs and undergo careful follow-up and surveillance for recurrence.
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http://dx.doi.org/10.1245/s10434-019-08078-0DOI Listing
May 2020

Frequency and implications of occipital and posterior auricular sentinel lymph nodes in scalp melanoma.

J Surg Oncol 2019 Dec 15;120(8):1470-1475. Epub 2019 Oct 15.

Melanoma and Sarcoma Specialists of Georgia, Northside Hospital, Atlanta, Georgia.

Background: Patients with scalp melanoma have poor oncologic outcomes compared with those with other cutaneous sites. Sentinel lymph node (SLN) biopsy provides prognostic information but is challenging in the head and neck. We explore the anatomic distribution of scalp melanoma and describe the most common sites of SLN drainage and of SLN metastatic disease.

Methods: Retrospective review of scalp melanoma patients who underwent SLN biopsy. Melanoma location was classified as frontal, coronal apex, coronal temporal, or posterior scalp. SLN location was classified by lymph node level and region.

Results: We identified 128 patients with scalp melanoma. The most common primary tumor location was the posterior scalp (43%) and the most frequent SLN drainage site was the level 2 lymph node basin (48%). Total 31 patients (24%) had metastatic disease in an SLN. Scalp SLNs, classified as being in the posterior auricular or occipital region, were localized in 26% of patients. For patients in which a scalp SLN was identified, 30% had a positive scalp SLN (n = 10).

Conclusions: Scalp SLNs are frequent drainage sites for scalp melanoma and, when found, have a 30% chance of harboring metastatic disease. Surgeons, radiologists, and pathologists should be vigilant in identifying, removing, and analyzing scalp SLNs.
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http://dx.doi.org/10.1002/jso.25715DOI Listing
December 2019

A nomogram to predict node positivity in patients with thin melanomas helps inform shared patient decision making.

J Surg Oncol 2019 Dec 10;120(7):1276-1283. Epub 2019 Oct 10.

Department of Surgery, University of Colorado, Aurora, Colorado.

Objective: To develop a nomogram to estimate the probability of positive sentinel lymph node (+SLN) for patients with thin melanoma and to characterize its potential impact on sentinel lymph node biopsy (SLNB) rates.

Methods: Patients diagnosed with thin (0.5-1.0 mm) melanoma were identified from the National Cancer Database 2012 to 2015. A multivariable logistic regression model was used to examine factors associated with +SLN, and a nomogram to predict +SLN was constructed. Nomogram performance was evaluated and diagnostic test statistics were calculated.

Results: Of the 21 971 patients included 10 108 (46.0%) underwent SLNB, with a 4.0% +SLN rate. On multivariable analysis, age, Breslow thickness, lymphovascular invasion, ulceration, and Clark level were significantly associated with SLN status. The area under the receiver operating curve was 0.67 (95% confidence interval, 0.65-0.70). While 15 249 (69.4%) patients had either T1b tumors or T1a tumors with at least one adverse feature, only 2846 (13.0%) had a nomogram predicted probability of a +SLN ≥5%. Using this cut-off, the indication for a SLNB in these patients would be reduced by 81.3% as compared to the American Joint Committee on Cancer 8th edition staging criteria.

Conclusions: The risk predictions obtained from the nomogram allow for more accurate selection of patients who could benefit from SLNB.
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http://dx.doi.org/10.1002/jso.25720DOI Listing
December 2019

Increasing omission of radiation therapy and sentinel node biopsy in elderly patients with early stage, hormone-positive breast cancer.

Breast J 2020 02 25;26(2):133-138. Epub 2019 Aug 25.

Department of Surgery, University of Colorado, Aurora, Colorado.

Prospective evidence demonstrates that there is limited benefit of axillary staging with sentinel lymph node biopsy (SLNB) or radiation therapy (RT) in patients over age 70 with clinical stage I, hormone-positive breast cancer. The clinical impact of this literature is unknown. Our hypothesis is that omission of SLNB and RT has increased over time in these patients, and patient and tumor characteristics can predict when omission strategies are used. A single-center tumor registry was queried for all patients over age 70 with ER+, Her2/neu-negative, clinical T1N0 invasive breast cancer from 2009 to 2017, who underwent breast conservation (n = 141). Date of treatment, age, tumor characteristics, use of SLNB, and use of RT were evaluated. The trend of treatment strategy over time was evaluated. Multivariable analysis was performed on the subgroup of patients after publication of the long-term follow-up CALGB 9343 data . Patients undergoing treatment with omission of RT and SLNB increased over the study period (P = .0006). Patients who did not receive RT were older (78.76 years ± 5.48 vs 73.37 ± 3.63, P < .01). There was no difference between tumor grade and size between uses of RT. Of patients who received SLNB (n = 84), only 3 (3.5%) had a positive LN. On multivariable analysis of patients who were treated after publication of the CALGB 9343 data (2014-2017), only age was predictive of being treated with RT (OR, 0.77; 95% CI, 0.67-0.88). Omission of both RT and SLNB are increasing in clinical practice in appropriately selected patients. The likelihood that patients are offered omission of these interventions increases with age. Low nodal positivity rates suggest that this strategy may be underutilized. Tumor grade and size were not predictive of omission of RT in this group of low-risk patients. Long-term data are needed as these approaches are increasingly adopted.
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http://dx.doi.org/10.1111/tbj.13483DOI Listing
February 2020

Postbiopsy Pigmentation is Prognostic in Head and Neck Melanoma.

Ann Surg Oncol 2019 Apr 31;26(4):1046-1054. Epub 2019 Jan 31.

Department of Surgery, Gastrointestinal Tumor and Endocrine Surgery, University of Colorado School of Medicine, Aurora, CO, USA.

Purpose: To assess postbiopsy pigmentation (PBP) as a prognostic feature in patients with cutaneous head and neck (H&N) melanoma.

Methods: Retrospective review of patients undergoing sentinel lymph node biopsy (SLNB) for H&N melanoma (1998-2018). PBP was defined as visible remaining pigment at the scar or biopsy site that was documented on physical exam by both a medical oncologist and a surgeon at initial consultation. Variables associated with disease-free survival (DFS) and overall survival (OS) were analyzed using multivariable Cox proportional hazards models.

Results: Among 300 patients, 34.3% (n = 103) had PBP and 44.7% (n = 134) had microscopic residual disease on final pathology after wide local excision. Prognostic factors associated with DFS included advanced age, tumor depth, ulceration, PBP, and positive SLNB (p < 0.05). Patients with PBP fared worse than their counterparts without PBP in 5-year DFS [44.1% (31.1-56.3%) vs. 73.0% (64.1-80.0%); p < 0.001] and 5-year OS [65.0% (50.0-76.6%) vs. 83.6% (75.7-89.2%); p = 0.005]. After multivariable adjustment, PBP remained associated with shorter DFS [hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.01-2.93; p = 0.047], but was not prognostic of OS.

Conclusions: In patients with H&N melanoma, PBP is associated with significantly shorter DFS. Patients with PBP may warrant greater consideration for SLNB and closer postoperative surveillance.
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http://dx.doi.org/10.1245/s10434-019-07185-2DOI Listing
April 2019

ASO Author Reflections: Impact of SPECT/CT on Sentinel Lymph Node Biopsy in Head and Neck Melanoma.

Ann Surg Oncol 2019 Dec 11;26(Suppl 3):561-562. Epub 2019 Jan 11.

Department of Surgery, Gastrointestinal Tumor and Endocrine Surgery, University of Colorado School of Medicine, Aurora, CO, USA.

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http://dx.doi.org/10.1245/s10434-018-6955-yDOI Listing
December 2019

SPECT/CT Adds Distinct Lymph Node Basins and Influences Radiologic Findings and Surgical Approach for Sentinel Lymph Node Biopsy in Head and Neck Melanoma.

Ann Surg Oncol 2018 Jun 12;25(6):1716-1722. Epub 2018 Jan 12.

Department of Surgery, Gastrointestinal Tumor and Endocrine Surgery, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Planar lymphoscintigraphy (PL) has a lower detection rate of sentinel lymph nodes (SLNs) in head and neck melanoma compared with other sites. We assessed situations when single-photon emission computed tomography/computed tomography (SPECT/CT) identified nodes not seen by PL. We also evaluated the impact of SPECT/CT on surgical approach and oncologic outcomes.

Methods: Patients who underwent SLN biopsy (SLNB) for head and neck melanoma with PL and SPECT/CT between November 2011 and December 2016 were included. Surgeons and radiologists completed a real-time survey inquiring about the utility of SPECT/CT. Patients were divided into two groups: patients with nodal basins identified by both PL and SPECT/CT ('PL + SPECT/CT'), and patients in whom SPECT/CT identified additional nodal basins not seen on PL ('SPECT/CT only'). Patient demographics and long-term outcomes including follow-up duration, recurrence, and survival are described.

Results: In the PL + SPECT/CT group, 73 (61.9%) patients were included and 45 (38.1%) patients were included in the SPECT/CT-only group. SPECT/CT added 51 basins to those seen on PL, primarily in the supraclavicular region (43.1%). Eighteen patients had positive node(s) in the PL + SPECT/CT group compared with two patients in the SPECT/CT-only group. Surgeons reported that 81% of the time, SPECT/CT influenced the location of incision for SLNB.

Conclusions: SPECT/CT influences the location of incision and contributes most to identification of nodes in the supraclavicular region. It also detects additional SLN basins when compared with PL. Further studies are necessary to determine when these additional basins require sampling.
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http://dx.doi.org/10.1245/s10434-017-6298-0DOI Listing
June 2018

Re-excision rates after breast conserving surgery following the 2014 SSO-ASTRO guidelines.

Am J Surg 2017 Dec 20;214(6):1104-1109. Epub 2017 Sep 20.

University of Colorado School of Medicine, Department of Surgery, Aurora, CO, USA. Electronic address:

Background: In 2014, SSO-ASTRO published guidelines which recommended "no ink on tumor" as adequate margins for patients undergoing breast conservation for invasive breast cancer. In 2016, new SSO-ASTRO-ASCO guidelines recommended 2 mm margins for DCIS. We evaluated whether these guidelines affected re-excision rates at our institution.

Methods: Patients treated with breast conservation surgery from January 1, 2010-March 1, 2016 were identified. Re-excision rates, tumor characteristics, and presence of residual disease were recorded. The 2016 guidelines were retrospectively applied to the same cohort and expected re-excision rates calculated.

Results: Re-excision rates did not significantly decline before and after 2014 guideline adoption (11.9% before, 10.9% after; p = 0.65) or when the 2016 guidelines were retrospectively applied (8.4%; p = 0.10).

Conclusions: The 2014 and 2016 guidelines had minimal impact on our re-excision rates, as most re-excisions were done for DCIS and 2016 guidelines supported our prior institutional practices of 2 mm margins for these patients.
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http://dx.doi.org/10.1016/j.amjsurg.2017.08.023DOI Listing
December 2017

Patterns of Fractionation and Boost Usage in Adjuvant External Beam Radiotherapy for Ductal Carcinoma in Situ in the United States.

Clin Breast Cancer 2018 06 29;18(3):220-228. Epub 2017 Jun 29.

Department of Radiation Oncology, University of Colorado Denver School of Medicine, Aurora, CO. Electronic address:

Background: While the roles of hypofractionated (HFxn) radiotherapy and lumpectomy boost in the adjuvant management of invasive breast cancer are supported by the results of clinical trials, randomized data supporting their use for ductal carcinoma in situ (DCIS) are forthcoming. We sought to evaluate current national trends and identify factors associated with HFxn and boost usage using the National Cancer Database.

Patients And Methods: We queried the National Cancer Database for women diagnosed with DCIS from 2004 to 2014 undergoing external beam radiotherapy after breast conservation surgery. Patients were categorized as receiving either conventional fractionation (CFxn) or HFxn and as either receiving or not receiving a boost. Multiple logistic regression was performed to identify demographic, clinical, and treatment factor associations.

Results: A total of 101,615 women were identified, with 87,641 (86.2%) receiving CFxn, 13,974 (13.8%) receiving HFxn, and most patients in each group (84.9% and 57.7%, respectively) receiving a boost. Implementation of HFxn increased from 4.3% in 2004 to 33.0% in 2014, and the use of a boost declined from 83.3% to 74.6%. HFxn receipt was independently associated with later year of diagnosis, older age, higher income, greater distance from treatment facility, greater facility volume, academic facility type, Western residence, smaller lesions, and nonreceipt of a boost. Factors associated with boost receipt included earlier year of diagnosis, younger age, higher income, community facility type, adverse pathologic features, and nonreceipt of HFxn.

Conclusion: Although CFxn with a boost remains the most common external beam radiotherapy strategy for DCIS, implementation of HFxn without a boost appears to be increasing. Practice patterns at present seem to be driven by guidelines for invasive breast cancer and nonclinical factors.
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http://dx.doi.org/10.1016/j.clbc.2017.06.009DOI Listing
June 2018

Implications of Sentinel Lymph Node Drainage to Multiple Basins in Head and Neck Melanoma.

Ann Surg Oncol 2017 May 5;24(5):1386-1391. Epub 2017 Jan 5.

Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Sentinel lymph node biopsy (SLNB) for head and neck melanoma is challenging due to unpredictable drainage. We sought to determine the frequency of drainage to multiple lymphatic basins and asked if this was associated with prognosis in a large, single-center cohort.

Methods: We queried patients diagnosed with head and neck melanomas who had a SLNB performed from January 1998 to April 2016. Demographic and clinical characteristics were compared using Student's t test, Pearson chi-square analysis, log-rank test, Wilcoxon-Mann-Whitney test, and Kaplan-Meier curves.

Results: We identified 269 patients with head and neck melanoma that had SLNBs performed in the following locations: 223 neck, 92 parotid/preauricular, 29 occipital/posterior auricular, 1 axilla. There were 68 (25%) patients who had drainage to multiple basins. These patients were similar to those with single basin drainage in age, gender distribution, Breslow depth, and percent with a positive SLNB (all p > 0.05). Fewer patients with drainage to multiple basins had a completion lymph node dissection (CLND, p = 0.03). A trend toward increased 3-year locoregional recurrence was seen for patients with drainage to multiple basins in univariate analysis (27% vs. 18%, p = 0.10) but was lost in multivariate analysis (p = 0.49), possibly because of higher recurrence rates in patients with positive nodes but no CLND (p = 0.02). No difference was detected for distant recurrence or overall survival based on SLN drainage.

Conclusions: Head and neck melanoma SLNB drainage to multiple basins is common. Drainage to multiple basins does not seem to be associated with increased sentinel lymph node positivity, locoregional recurrence, distant recurrence, or survival.
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http://dx.doi.org/10.1245/s10434-016-5744-8DOI Listing
May 2017

Breast Cancer Following Radiation for Hodgkin Lymphoma: Clinical Scenarios and Risk-Reducing Strategies.

Oncology (Williston Park) 2016 12;30(12):1063-70

Since most patients with Hodgkin lymphoma survive their disease, long-term issues such as development of second primary malignancies arise, especially in patients treated with multimodal therapy including radiation therapy plus chemotherapy. The risk of breast cancer is significantly elevated in women exposed to high-dose ionizing radiation to the chest before age 40. The case of a 48-year-old patient with a lump in her right breast is presented as a clinical scenario in this article. We review available strategies for screening and risk reduction through chemoprevention or risk-reducing surgery, as well as challenges for management of breast cancer in patients with prior exposure to radiation for Hodgkin lymphoma. The Children's Oncology Group clinical practice guidelines for long-term follow-up care of pediatric cancer survivors provide recommendations that have been endorsed by American and European oncologists.
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December 2016

SPECT/CT Improves Detection of Metastatic Sentinel Lymph Nodes in Patients with Head and Neck Melanoma.

Ann Surg Oncol 2016 08 16;23(8):2652-7. Epub 2016 Mar 16.

Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA.

Background: A positive sentinel lymph node (SLN) is the most important prognostic factor for predicting survival in cutaneous melanoma. This study aimed to evaluate how the addition of single-photon emission computed tomography (SPECT) and computed tomography (CT) to planar lymphoscintigraphy (PL) alters SLN identification, yield, and localization of metastatic nodes in head and neck melanoma.

Methods: This retrospective review examined patients undergoing SLN biopsy for cutaneous melanoma of the head and neck between July 2003 and December 2015. Patient demographics and pathologic outcomes were compared for patients undergoing SPECT-CT versus PL. A multivariable logistic regression analysis was used to identify factors associated with the identification of a positive SLN.

Results: Among 176 patients undergoing SLN biopsy, 91 underwent PL and 85 underwent SPECT-CT and PL. The patients in the SPECT-CT group were older than the PL patients (p = 0.050) but the groups did not differ in gender (p = 0.447), Breslow thickness (p = 0.744), or total number of SLNs identified (p = 0.633). As shown by the multivariate regression analysis, only Breslow thickness [odds ratio (OR) 1.47; 95 % confidence interval (CI) 1.17-1.84] and SPECT-CT (OR 3.58; 95 % CI 1.24-10.4) were associated with a positive SLN.

Conclusion: The use of SPECT-CT for patients with head and neck cutaneous melanoma significantly increases the likelihood of retrieving a positive SLN. Long-term follow-up evaluation is needed for further definition of the impact that SPECT-CT has on recurrence and survival.
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http://dx.doi.org/10.1245/s10434-016-5175-6DOI Listing
August 2016

Association of sentinel lymph node diameter with melanoma metastasis.

Am J Surg 2016 Aug 6;212(2):315-20. Epub 2016 Jan 6.

Department of Surgery, School of Medicine, University of Colorado, Anschutz Medical Campus, Room 5401, 12631 E. 17th Ave., C302, Aurora, CO 80045, USA. Electronic address:

Background: Lymph nodes are an important part of the immune system and the size of the lymph node reflects local immunologic activity. The purpose of this study was to examine the association between sentinel lymph node (SLN) size and the presence of nodal metastasis in patients with melanoma.

Methods: Retrospective review of a prospectively maintained database of patients undergoing SLN biopsy for cutaneous melanoma between February 1995 and January 2013. The maximum pathologic diameter and the volume of the largest node was used. A nodal diameter of 1.5 cm, included in 2 interquartile ranges of both positive and negative SLNs, was used as the cutoff for multivariate regression.

Results: Of 1,017 SLN biopsies, 826 (81%) had complete size measurements and were included in the analysis. Patients with a positive SLN were younger (median 50 vs 53 years, P = .032), had deeper primary lesions (2 vs 1.4 mm, P < .001), and had larger SLN volume (.8 vs .6 cc, P = .009) or maximum diameter (1.9 vs. 1.6 cm, P = .03). Sex, pathologic ulceration, mitosis, and the type or location of the primary was not statistically different. On multivariate analysis; age, depth of primary, and both SLN volume and maximum diameter remained significant. An SLN greater than 1.5 cm in maximum diameter has a 60% increased odds ratio of being positive after adjusting for age, sex, and depth of primary lesion (P = .046).

Conclusions: Larger SLN maximum diameter is associated with nodal positivity independent of age, sex, depth of primary lesion, and location of SLN biopsy. The etiology and significance of larger SLNs warrant further analysis.
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http://dx.doi.org/10.1016/j.amjsurg.2015.09.022DOI Listing
August 2016

Analysis of melanoma recurrence following a negative sentinel lymph node biopsy.

Melanoma Manag 2015 Aug 10;2(3):285-294. Epub 2015 Aug 10.

Department of Surgery, University of Colorado School of Medicine, 13001 E 17th Pl, Aurora, CO 80045, USA.

Little attention has been paid to the characteristics and outcomes of patients who experience distant, local or regional recurrence of melanoma following a negative sentinel lymph node biopsy. This article aims to review the published literature on the topic and presents some general summaries regarding this patient population. Patients who experience a disease recurrence following a negative sentinel lymph node biopsy have a worse overall survival compared with patients with a positive sentinel lymph node biopsy. The implications and possible explanations for these findings are discussed in order to both underscore the need for in-depth investigation of local, regional or distant melanoma recurrence among patients following a true negative sentinel lymph node biopsy, as well as increased efforts to minimize the rate of false negative sentinel lymph node biopsies.
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http://dx.doi.org/10.2217/mmt.15.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094687PMC
August 2015

Breast Cancer Risk Reduction, Version 2.2015.

J Natl Compr Canc Netw 2015 Jul;13(7):880-915

Breast cancer is the most frequently diagnosed malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. To assist women who are at increased risk of developing breast cancer and their physicians in the application of individualized strategies to reduce breast cancer risk, NCCN has developed these guidelines for breast cancer risk reduction.
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http://dx.doi.org/10.6004/jnccn.2015.0105DOI Listing
July 2015

Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer.

PLoS One 2014 3;9(1):e81126. Epub 2014 Jan 3.

Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America ; Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America ; Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.

TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR) or amplified human epidermal growth factor receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC progression, using the isogenic MCF10 progression series, which models breast carcinogenesis from nontransformed epithelium to malignant basal-like breast cancer. We observed that mGluR1 is expressed in human breast cancer and that in MCF10A cells, which model nontransformed mammary epithelium, but not in MCF10AT1 cells, which model atypical ductal hyperplasia, mGluR1 overexpression results in increased proliferation, anchorage-independent growth, and invasiveness. In contrast, mGluR1 knockdown results in a decrease in these activities in malignant MCF10CA1d cells. Similarly, pharmacologic inhibition of glutamatergic signaling in MCF10CA1d cells results in a decrease in proliferation and anchorage-independent growth. Finally, transduction of MCF10AT1 cells, which express c-Ha-ras, using a lentiviral construct expressing GRM1 results in transformation to carcinoma in 90% of resultant xenografts. We conclude that mGluR1 cooperates with other factors in hyperplastic mammary epithelium to contribute to TNBC progression and therefore propose that glutamatergic signaling represents a promising new molecular target for TNBC therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081126PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880256PMC
September 2014

Long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel lymph node biopsy result.

JAMA Surg 2013 May;148(5):456-61

Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.

Objective: To analyze the predictors and patterns of recurrence of melanoma in patients with a negative sentinel lymph node biopsy result.

Design: Retrospective chart review of a prospectively created database of patients with cutaneous melanoma. SETTING Tertiary university hospital.

Patients: A total of 515 patients with melanoma underwent a sentinel lymph node biopsy without evidence of metastatic disease between 1996 and 2008.

Main Outcome Measures: Time to recurrence and overall survival.

Results: Of 515 patients, 83 (16%) had a recurrence of melanoma at a median of 23 months during a median follow-up of 61 months (range, 1-154 months). Of these 83 patients, 21 had melanoma that metastasized in the studied nodal basin for an in-basin false-negative rate of 4.0%. Patients with recurrence had deeper primary lesions (mean thickness, 2.7 vs 1.8 mm; P < .01) that were more likely to be ulcerated (32.5% vs 13.5%; P < .001) than those without recurrence. The primary melanoma of patients with recurrence was more likely to be located in the head and neck region compared with all other locations combined (31.8% vs 11.7%; P < .001). Median survival following a recurrence was 21 months (range, 1-106 months). Favorable characteristics associated with lower risk of recurrence included younger age at diagnosis (mean, 49 vs 57 years) and female sex (9% vs 21% for males; P < .001).

Conclusion: Overall, recurrence of melanoma (16%) after a negative sentinel lymph node biopsy result was similar to that in previously reported studies with an in-basin false-negative rate of 4.0%. Lesions of the head and neck, the presence of ulceration, increasing Breslow thickness, older age, and male sex are associated with increased risk of recurrence, despite a negative sentinel lymph node biopsy result.
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http://dx.doi.org/10.1001/jamasurg.2013.1335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856253PMC
May 2013

A neoadjuvant biochemotherapy approach to stage III melanoma: analysis of surgical outcomes.

Immunotherapy 2012 Jul;4(7):679-86

Division of GI, Tumor & Endocrine Surgery, University of Colorado Medical Center, Aurora, CO, USA.

Aims: Completion lymph node dissection (CLND) and adjuvant therapy are recommended for node-positive melanoma patients. We sought to analyze our institution's experience with neoadjuvant biochemotherapy in stage III patients.

Methods: Clinical information was extracted from a retrospective database on stage III melanoma patients. Eligible patients received two cycles of biochemotherapy prior to their CLND.

Results: There were 153 patients available for analysis. The average tumor depth was 2.5 mm. More than half of all patients presented with sentinel lymph node-positive disease. Surgical complications occurred in 23% of patients. Patients who experienced an adverse event during their neoadjuvant therapy had a worse overall survival when compared with those who did not (p = 0.005).

Conclusion: Our data suggest that aggressive neoadjuvant treatment prior to CLND does not impact surgical complications. Our surgical outcomes are similar to the current literature when adjuvant therapy is used in stage III melanoma. The inability to tolerate neoadjuvant therapy in stage III melanoma is a negative prognostic indicator.
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http://dx.doi.org/10.2217/imt.12.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883760PMC
July 2012

The RET G691S polymorphism is a germline variant in desmoplastic malignant melanoma.

Melanoma Res 2012 Feb;22(1):92-5

Department of Internal Medicine, Exempla Saint Joseph Hospital, Denver, Colorado, USA.

The RET protooncogene was originally identified in 1985. It encodes for a receptor tyrosine kinase. The RET receptor is activated by its ligand glial cell-derived neurotrophic factor. A polymorphism, RETp (G691S), in the intracellular juxtamembrane domain of RET, which enhances signaling by glial cell-derived neurotrophic factor has been described and studied previously in pancreatic cancer, medullary thyroid cancer, the multiple endocrine neoplasia 2 syndromes, and recently in cutaneous malignant melanoma. In particular, it has been shown that desmoplastic melanomas, which have neurotrophic features, have a high frequency of this polymorphism. In previous studies, however, it was not clear whether this was a germline or somatic change. Previous studies on pancreatic cancer indicated that both mechanisms may occur. To clarify this further we examined peripheral blood cell DNA from 30 patients with desmoplastic melanomas and 30 patients with nondesmoplastic melanoma for the RETp. In this study, a germline polymorphism was found in 30% of the patients with desmoplastic melanomas and 21% of the patients with nondesmoplastic melanoma. These findings indicate that the RETp may be a genetic risk factor for the development of desmoplastic melanoma.
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http://dx.doi.org/10.1097/CMR.0b013e32834defd6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708080PMC
February 2012

Partial breast irradiation in a patient with bilateral breast cancers and CREST syndrome.

Brachytherapy 2011 Nov-Dec;10(6):486-90. Epub 2011 Feb 24.

Department of Surgery, University of Colorado Medical Center, Aurora, CO 80045, USA.

Purpose: To describe the first documented use of partial breast irradiation (PBI) in a patient with calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias (CREST) syndrome.

Methods And Materials: A 50-year-old woman with well-controlled CREST syndrome for 6 years was diagnosed with bilateral early-staged breast cancers. She underwent bilateral lumpectomies, sentinel lymph node biopsies, and PBI delivered via bilateral MammoSite catheters (Cytyc Corp., Marlborough, MA) followed by chemotherapy. She was monitored perioperatively, at 6 months and at 1 year for worsening of her CREST-related symptoms and complications associated with surgery and radiation therapy. Both surgeon and patient's opinion of her cosmetic outcome were also recorded at 1-year followup.

Results: The patient experienced mild acute cellulitic changes in the perioperative period, which resolved with antibiotics. At 6 months, she exhibited a Grade 1 late toxicity, which has remained stable at 1-year followup. The patient and surgeon are very pleased with her cosmetic outcome.

Conclusions: Accelerated PBI was delivered safely to a patient with collagen vascular disease. By decreasing the surface area receiving radiation with accelerated PBI, we believe that the toxicity associated with the treatment was minimized. Future studies will be necessary to clarify the use of PBI in patients with collagen vascular disease.
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http://dx.doi.org/10.1016/j.brachy.2011.01.010DOI Listing
February 2012

Abdominal perineal resection improves survival for nonmetastatic adenocarcinoma of the anal canal.

Ann Surg Oncol 2009 May 25;16(5):1310-5. Epub 2009 Feb 25.

Department of Surgery, General and Oncologic Surgery, City of Hope, Duarte, CA, USA.

Background: There remains a lack of consensus regarding the optimal treatment for patients with curable adenocarcinoma of the anal canal (AAC). We sought to determine the role of definitive surgical resection and radiation in a large cohort of patients with AAC.

Materials And Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) registry to identify all patients with nonmetastatic AAC from 1988 to 2004 and analyzed clinical factors, treatment modalities, and overall survival in this cohort. Kaplan-Meier survival curves were constructed to compare 5-year overall survival based on treatment groups: abdominal perineal resection (APR) only, APR and external beam radiation (APR and EBR), and EBR only. We performed a Cox regression analysis to determine factors predictive of outcome.

Results: A total of 165 patients were identified with nonmetastatic AAC. Of these, 30 patients were treated with an APR only, 42 patients with an APR and EBR, and 93 patients with EBR only. The 5-year survival for APR only, APR and EBR, and EBR only was 58%, 50%, and 30%, respectively. The difference in survival was statistically significant (APR vs. EBR, P = .02; APR and EBR vs. EBR, P = 0.04). Multivariate analysis completed on 86 patients in this cohort confirmed that factors accounting for the survival differences included age (P = 0.004), nodal stage (P = 0.001), and treatment groups (P = 0.03). The hazard ratio between EBR only compared with APR only was 2.78.

Conclusions: Definitive surgical treatment in the form of an APR with or without EBR is associated with improved survival in patients with AAC.
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http://dx.doi.org/10.1245/s10434-009-0392-xDOI Listing
May 2009

Lipopolysaccharide transiently activates THP-1 cell adhesion.

J Surg Res 2006 Sep 20;135(1):137-43. Epub 2006 Feb 20.

Department of Surgery, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.

Lipopolysaccharide stimulation of adherent THP-1 cells induces morphological changes that are associated with the reorganization of the actin cytoskeleton. We hypothesized that LPS would also increase THP-1 cell adhesion and sought to determine the signaling mechanisms regulating this response. We show that LPS significantly increases THP-1 cell attachment after 1 h, supporting the idea that LPS can stimulate integrin function. By 4 h however, the number of adherent cells returned to control levels. Importantly, detached cells were determined to be viable by propidium iodide staining, indicating that the increase in cell adhesion was transient. LPS-induced adhesion to fibrinogen- but not fibronectin-coated wells was also transient, suggesting that adhesion reflected beta2 integrin activation. This idea was supported by the fact that LPS-induced adhesion could be blocked by a function-blocking anti-beta2 integrin antibody. Interestingly, the protein tyrosine phosphatase (PTP) inhibitor, phenylarsine oxide, prevented cell detachment. Taken together, these data suggest that LPS-mediated integrin activation is transient and can be regulated by PTP-mediated signaling events.
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http://dx.doi.org/10.1016/j.jss.2005.12.018DOI Listing
September 2006

Tumor cell and circulating markers in melanoma: diagnosis, prognosis, and management.

Curr Oncol Rep 2005 Sep;7(5):377-82

The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.

The search is on for biomarkers for use in the diagnosis, staging, prognosis, and management of patients with melanoma. As with many types of cancer, the hematogenous spread of melanoma is a bad prognostic sign, and many groups have attempted to detect circulating melanoma cells in patients with different stages of melanoma. Some studies have used direct extraction of intact tumor cells from the peripheral blood and others the detection of surrogate markers of circulating melanoma cells, such as tyrosinase or MART-1. However, a correlation between the detection of intact melanoma cells in the circulation and prognosis is controversial. Many other biomarkers have also been studied, including lactate dehydrogenase, S100, TA90, and C-reactive protein. Much progress has been made, and preliminary studies have shown promise with many of these markers. Finally, the detection of tumor-specific circulating DNA has shown promise as a prognostic and diagnostic marker of disease in melanoma as well. In this review we examine the most promising biomarkers for use in patients with cutaneous melanoma.
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http://dx.doi.org/10.1007/s11912-005-0065-2DOI Listing
September 2005
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