Publications by authors named "Ricardo J Gonzalez"

74 Publications

Genomic identification of sarcoma radiosensitivity and the clinical implications for radiation dose personalization.

Transl Oncol 2021 Jul 7;14(10):101165. Epub 2021 Jul 7.

H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, United States. Electronic address:

Background: Soft-tissue sarcomas (STS) are heterogeneous with variable response to radiation therapy (RT). Utilizing the radiosensitivity index (RSI) we estimated the radiobiologic ratio of lethal to sublethal damage (α/β), genomic-adjusted radiation dose(GARD), and in-turn a biological effective radiation dose (BED).

Methods: Two independent cohorts of patients with soft-tissue sarcoma were identified. The first cohort included 217 genomically-profiled samples from our institutional prospective tissue collection protocol; RSI was calculated for these samples, which were then used to dichotomize the population as either highly radioresistant (HRR) or conventionally radioresistant (CRR). In addition, RSI was used to calculate α/β ratio and GARD, providing ideal dosing based on sarcoma genomic radiosensitivity. A second cohort comprising 399 non-metastatic-STS patients treated with neoadjuvant RT and surgery was used to validate our findings.

Results: Based on the RSI of the sample cohort, 84% would historically be considered radioresistant. We identified a HRR subset that had a significant difference in the RSI, and clinically a lower tumor response to radiation (2.4% vs. 19.4%), 5-year locoregional-control (76.5% vs. 90.8%), and lower estimated α/β (3.29 vs. 5.98), when compared to CRR sarcoma. Using GARD, the dose required to optimize outcome in the HRR subset is a BED of 97 Gy.

Conclusions: We demonstrate that on a genomic scale, that although STS is radioresistant overall, they are heterogeneous in terms of radiosensitivity. We validated this clinically and estimated an α/β ratio and dosing that would optimize outcome, personalizing dose.
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http://dx.doi.org/10.1016/j.tranon.2021.101165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274330PMC
July 2021

Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma.

Blood 2021 May;137(19):2621-2633

Department of Blood and Marrow Transplant and Cellular Immunotherapy.

Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory large B-cell lymphoma (LBCL). This study evaluated whether immune dysregulation, present before CAR T-cell therapy, was associated with treatment failure. Tumor expression of interferon (IFN) signaling, high blood levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and high blood interleukin-6 and ferritin levels were each associated with a lack of durable response. Similar to other cancers, we found that in LBCL tumors, IFN signaling is associated with the expression of multiple checkpoint ligands, including programmed cell death-ligand 1, and these were higher in patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, patients with high tumor burden had higher immune dysregulation with increased serum inflammatory markers and tumor IFN signaling. These data support that immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic programs: insufficient axi-cel expansion associated with both circulating M-MDSC and tumor IFN signaling, which also gives rise to expression of immune checkpoint ligands.
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http://dx.doi.org/10.1182/blood.2020007445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120145PMC
May 2021

Expanded Tumor-infiltrating Lymphocytes From Soft Tissue Sarcoma Have Tumor-specific Function.

J Immunother 2021 Feb-Mar 01;44(2):63-70

Immunology.

Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) can generate durable clinical responses in patients with metastatic melanoma and ongoing trials are evaluating efficacy in other advanced solid tumors. The aim of this study was to develop methods for the expansion of tumor-reactive TIL from resected soft tissue sarcoma to a degree required for the ACT. From 2015 to 2018, 70 patients were consented to an institutional review board-approved protocol, and fresh surgical specimens were taken directly from the operating room to the laboratory. Fragments of the tumor (1 mm3) or fresh tumor digest were placed in culture for a period of 4 weeks. Successfully propagated TIL from these cultures were collected and analyzed by flow cytometry. TIL were cocultured with autologous tumor and function was assessed by measurement of interferon-γ in the supernatant by enzyme-linked immunosorbent assay. Initial TIL cultures were further expanded using a rapid expansion protocol. Nearly all specimens generated an initial TIL culture (91% fragment method, 100% digest method). The phenotype of the TIL indicated a predominant CD3+ population after culture (43% fragment, 52% digest) and TIL were responsive to the autologous tumor (56% fragment, 40% digest). The cultured TIL expanded to a degree required for clinical use following rapid expansion protocol (median: 490-fold fragment, 403-fold digest). The data demonstrate the feasibility of TIL culture from fresh soft tissue sarcoma. The derived TIL have tumor-specific reactivity and can be expanded to clinically relevant numbers. An active ACT clinical trial using the methods described in this report is now approved for patients with metastatic soft tissue sarcoma.
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http://dx.doi.org/10.1097/CJI.0000000000000355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111686PMC
August 2019

NCCN Guidelines Insights: Soft Tissue Sarcoma, Version 1.2021.

J Natl Compr Canc Netw 2020 12 2;18(12):1604-1612. Epub 2020 Dec 2.

28UCSF Helen Diller Family Comprehensive Cancer Center; and.

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.
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http://dx.doi.org/10.6004/jnccn.2020.0058DOI Listing
December 2020

Intraoperative Localization Using an Implanted Radar Reflector Facilitates Resection of Non-Palpable Trunk and Extremity Sarcoma.

Ann Surg Oncol 2021 Jun 18;28(6):3366-3374. Epub 2020 Oct 18.

Sarcoma Department, H. Lee Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.

Background: Resecting non-palpable soft tissue tumors presents a unique challenge, particularly with recurrent disease in which surrounding tissue has been surgically manipulated and often irradiated. SAVI SCOUT is a radar-based localization device that was developed for breast tumor localization and was recently FDA-approved for localization of soft tissue tumors. Application of this technology to soft tissue sarcoma has not been previously reported.

Methods: We assembled a single-institution retrospective case series of patients with trunk and extremity sarcomas resected by five sarcoma surgeons using SAVI SCOUT from December 2018 to May 2020. Reflectors were placed preoperatively using image-guidance, and the radar detector was used intraoperatively to localize the target lesion. Clinical variables were abstracted from the electronic medical record including treatment history, pathology, and early oncologic outcomes. Using a focused review, we compared margin status and recurrence rates with previously published cohorts.

Results: Ten SAVI SCOUT-localized sarcoma resections were performed. Eight were for locally recurrent disease, of which seven (83%) had prior radiation. The remaining lesions became non-palpable after neoadjuvant chemotherapy. SAVI SCOUT facilitated resection in all cases with a margin-negative resection rate (77%) comparable to prior cohorts. In this high-risk population with a median follow-up of 14 months, only one patient recurred locally 7.5 months after SAVI SCOUT-localized resection, requiring re-resection.

Conclusion: SAVI SCOUT technology facilitated resection of non-palpable recurrent sarcoma of the trunk and extremities in all ten cases attempted. In a high-risk patient population, the pattern of recurrence has been primarily distant with one instance of local tumor recurrence.
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http://dx.doi.org/10.1245/s10434-020-09229-4DOI Listing
June 2021

Patterns of recurrence and survival probability after second recurrence of retroperitoneal sarcoma: A study from TARPSWG.

Cancer 2020 11 14;126(22):4917-4925. Epub 2020 Aug 14.

Division of General Surgery, Mount Sinai Hospital, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: In this series from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the authors examined longitudinal outcomes of patients with a second recurrence of retroperitoneal sarcoma (RPS) after complete resection of a first local recurrence (LR).

Methods: Data from patients undergoing resection of a first LR from January 2002 to December 2011were collected from 22 sarcoma centers. The primary outcome was overall survival (OS) after second recurrence.

Results: Second recurrences occurred in 400 of 567 patients (70.5%) after an R0/R1 resection of a first locally recurrent RPS. Patterns of disease recurrence were LR in 323 patients (80.75%), distant metastases (DM) in 55 patients (13.75%), and both LR and DM in 22 patients (5.5%). The main subtype among the LR group was liposarcoma (77%), whereas DM mainly were leiomyosarcomas (43.6%). In patients with a second LR only, a total of 200 patients underwent re-resection (61.9%). The 5-year OS rate varied significantly based on the pattern of failure (P < .001): 45.6% for the LR group, 25.5% for the DM group, and 0% for the group with LR and DM. The only factors found to be associated with improved OS on multivariable analysis were both time between second surgery and the development of the second recurrence (32 months vs 8 months: hazard ratio, 0.44 [P < .001]) and surgery for second recurrence (yes vs no: hazard ratio, 3.25 [P < .001]). The 5-year OS rate for patients undergoing surgery for a second LR was 59% versus 18% in the patients not deemed suitable for surgical resection.

Conclusions: Survival rates after second recurrence of RPS varied based on patterns of disease recurrence and treatment. Durable disease-free survivors were identified after surgery for second LR in patients selected for this intervention.
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http://dx.doi.org/10.1002/cncr.33139DOI Listing
November 2020

Chemotherapy improves distant control in localized high-grade soft tissue sarcoma of the extremity/trunk.

Clin Sarcoma Res 2020 9;10:11. Epub 2020 Jul 9.

Department of Sarcoma, Moffitt Cancer Center and Research Institute, Tampa, FL USA.

Background: Soft tissue sarcomas (STS) are rare and heterogeneous tumors making chemotherapy use controversial. Our goal was to identify a subset of patients with primary STS that benefit with the addition of chemotherapy.

Methods: A retrospective chart review included intermediate to high-grade localized primary STS of the extremity/trunk, and tumor size > 5 cm. The effect of chemotherapy was evaluated for local control (LC), distant control (DC), progression free survival (PFS), and overall survival (OS).

Results: In this cohort (n = 273), patients were treated with surgery (98%), radiation (81%), and chemotherapy (24.5%). With a median follow-up of 51 months, the entire cohort's 5-year LC, DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, respectively. The addition of chemotherapy did not provide a DC benefit (p = 0.238) for the entire cohort. High-grade disease (n = 210) experienced a 5-year benefit in DC (68% vs. 54.4%, p = 0.04), which was more pronounced with MAI (Mesna, Adriamycin, Ifosfamide) based regimens (74.2%, p = 0.016), and a 5-year PFS (50.8% vs 45%, p = 0.025) and OS benefit (76.2% vs 70%, p = 0.067) vs. no chemotherapy. On multivariate analysis of the high-grade subset, chemotherapy independently predicted for a DC benefit (HR 0.48 95% CI 0.26-89, p = 0.019). The benefit of chemotherapy was more pronounced with MAI, showing a significant benefit in DC (HR 0.333 95% CI 0.145-0.767, p = 0.01) and PFS (HR 0.52 95% CI 0.28-0.99, p = 0.047).

Conclusion: In patients with localized STS > 5 cm, the high-grade subset had a distant control benefit with the addition of chemotherapy, leading to improved progression free survival. This is more pronounced with the use of MAI and should be considered in patients eligible for this regimen.
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http://dx.doi.org/10.1186/s13569-020-00132-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350709PMC
July 2020

Re-biopsy of partially sampled thin melanoma impacts sentinel lymph node sampling as well as surgical margins.

Melanoma Manag 2019 Jun 26;6(2):MMT17. Epub 2019 Apr 26.

Moffitt Cancer Center, Department of Cutaneous Oncology, 12902 Magnolia Drive, Tampa, FL 33602, USA.

Aim: To assess the impact of re-biopsy on partially sampled melanoma (MIS), atypical melanocytic proliferation (AMP) and thin invasive melanoma.

Materials & Methods: We retrospectively identified cases of re-biopsied partially sampled neoplasms initially diagnosed as melanoma , AMP or thin melanoma (Breslow depth ≤0.75 mm).

Results & Conclusion: Re-biopsy led to sentinel lymph node biopsy (SLNB) in 18.3% of cases. No patients upstaged from AMP or MIS had a positive SLNB. One out of nine (11.1%) initially diagnosed as a thin melanoma ≤0.75 mm, upstaged with a re-biopsy, had a positive SLNB. After re-biopsy 8.5% underwent an increased surgical margin. Selective re-biopsy of partially sampled melanoma with gross residual disease can increase the accuracy of microstaging and optimize treatment regarding surgical margins and SLNB.
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http://dx.doi.org/10.2217/mmt-2018-0011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688556PMC
June 2019

Management of intussusception in patients with melanoma.

J Surg Oncol 2019 Jun 7;119(7):897-902. Epub 2019 Feb 7.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.

Background: Increased cross-sectional imaging for surveillance of metastatic melanoma has led to more diagnoses of asymptomatic intussusception.

Methods: We performed a multi-institutional retrospective review of patient records with a history of metastatic melanoma and a diagnosis of intussusception. Patients were divided into three groups: 1) asymptomatic patients without current evidence of melanoma (no evidence of disease [NED]); 2) asymptomatic intussusception and known active metastatic melanoma; 3) symptomatic intussusception and known active metastatic melanoma; the number of patients requiring surgery and intraoperative findings were recorded.

Results: We reviewed 73 patients diagnosed with intussusception from 2004 to 2017. Among asymptomatic patients with NED (n = 16), 14 spontaneously resolved and 2 underwent pre-emptive surgery without abnormal intraoperative findings. Of asymptomatic patients with active metastatic disease (n = 32), 25 were initially observed and 7 underwent pre-emptive surgery and 9 of the 25 initially observed patients required surgery for development of symptoms. In this group, all 16 patients undergoing surgery (50% of the group) had intraoperative findings of intussusception and/or metastatic intestinal melanoma.. All symptomatic patients with metastatic melanoma (n = 25) underwent surgery; all had intraoperative findings of intussusception and/or metastatic melanoma except 1 (Meckel's diverticulum).

Conclusion: Asymptomatic patients with NED do not require surgery and intussusception will likely resolve spontaneously. Asymptomatic patients with known metastatic melanoma may be initially observed, but a low threshold for surgery should be maintained. Symptomatic patients with known metastases should undergo surgery.
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http://dx.doi.org/10.1002/jso.25393DOI Listing
June 2019

Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both?

Ann Surg Oncol 2019 Feb 11;26(2):379-385. Epub 2018 Oct 11.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Background: Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB.

Methods: All patients treated at a single institution for SLNB-positive MCC (1998-2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity.

Results: The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients).

Conclusions: Regional failure was infrequent (≤ 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity.
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http://dx.doi.org/10.1245/s10434-018-6810-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771265PMC
February 2019

Resection Margins in Merkel Cell Carcinoma: Is a 1-cm Margin Wide Enough?

Ann Surg Oncol 2018 Oct 2;25(11):3334-3340. Epub 2018 Aug 2.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Background: Guidelines regarding specific resection margins for primary Merkel cell carcinoma (MCC) are not well established. The current National Comprehensive Cancer Network (NCCN) guidelines recommend 1- to 2-cm resection margins. This study aimed to determine the impact of margin width on local recurrence (LR), disease-specific survival (DSS), overall survival (OS), and type of wound closure.

Methods: All patients who underwent resection of primary MCC at a single institution from 2000 to 2015 were reviewed. Patient demographics, clinicopathologic characteristics, treatments, and outcomes were reviewed.

Results: A total of 240 patients underwent resection of primary MCC with resection margin width identified in the operative report. The median age was 76 years, and 65.8% of the patients were men. Of the 240 patients, 85 (35.4%) had head and neck primaries, 140 (58.3%) had extremity primaries, and 15 (6.3%) had trunk primaries. In terms of margins, 69 patients (28.8%) had a margin of 1 cm, 36 patients (15%) had a margin of 1.1-1.9 cm, and 135 patients (56.2%) had a margin of 2 cm or more. The median follow-up period was 21 months. The LR rate was 2.9% for a margin of 1 cm, 2.8% for a margin of 1.1-1.9 cm, and 5.2% for a margin of 2 cm or more (p = 0.80). The 5-year OS was 63.6% for a margin of 1 cm, 59.7% for a margin of 1.1-1.9, and 70.7% for a margin of 2 cm or more (p = 0.66). The 5-year DSS was 80.3% for a margin of 1 cm, 66.2% for a margin of 1.1-1.9 cm, and 91.8% for a margin of 2 cm or more (p = 0.28). For wound closure, 43.5, 50, and 65.9% of the patients respectively required a flap or graft with a margin of 1, 1.1-1.9, and 2 cm or more (p = 0.006).

Conclusions: A 1-cm resection margins did not increase the risk of LR. Margin width did not make a significant difference in DSS or OS. Larger resection margins increase the need for a graft or flap closure.
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http://dx.doi.org/10.1245/s10434-018-6688-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771268PMC
October 2018

Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 05;16(5):536-563

Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for STS provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumors, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis, staging, and treatment of STS of the extremities, superficial trunk, or head and neck; outlines treatment recommendations by disease stage; and reviews the evidence to support the guidelines recommendations.
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http://dx.doi.org/10.6004/jnccn.2018.0025DOI Listing
May 2018

Pancreaticoduodenectomy in the surgical management of primary retroperitoneal sarcoma.

Eur J Surg Oncol 2018 06 5;44(6):810-815. Epub 2018 Feb 5.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: In retroperitoneal sarcoma (RPS), the optimal extent of resection must balance adequate disease control with potential for morbidity. We sought to study the frequency and outcomes after a Whipple procedure or pancreaticoduodenectomy (PD) in patients undergoing resection for primary RPS.

Methods: Participating referral centers within the Trans-Atlantic Retroperitoneal Sarcoma Working Group provided retrospective data from January 2007 to December 2016 for patients with primary RPS who underwent PD along with the total number of consecutive resections done during the same time period. Data from participating centers were combined for analysis.

Results: In total, 29 patients underwent PD among 2068 resections performed for primary RPS (1.4%). The predominant histologic subtypes were liposarcoma and leiomyosarcoma. All PD patients underwent concomitant resection of additional organs (median: 2, range: 1-5), including 13 patients (45%) who also received vena cava resection. Definitive evidence of microscopic invasion of the duodenum or pancreas was seen in 84% of patients. Postoperatively, 10 patients (34%) had major complications including 8 (28%) that developed a clinically-significant pancreatic leak. One postoperative death (3.4%) occurred. With a median follow-up of 4.8 years, 19 patients (66%) developed disease recurrence. The patterns of recurrence were dependent on histologic subtype.

Conclusion: Although infrequent, when PD is done for primary RPS, resection of additional organs is often required and major complication rates are moderate. The recurrence rate is overall high and the pattern of recurrence is dictated by histologic subtype.
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http://dx.doi.org/10.1016/j.ejso.2018.01.086DOI Listing
June 2018

Current principles of surgery for retroperitoneal sarcomas.

J Surg Oncol 2018 Jan 8;117(1):33-41. Epub 2018 Jan 8.

Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.

Surgery for primary retroperitoneal sarcomas (RPS) often requires a technically challenging, en bloc multivisceral resection to optimize outcomes. Surgery may also be appropriate for patients with localized recurrent RPS. Anatomic considerations and tumor biology driven by histologic subtype may guide the extent of resection in patients with RPS. This review provides an overview of the current surgical principles for primary and recurrent RPS.
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http://dx.doi.org/10.1002/jso.24919DOI Listing
January 2018

Paratesticular Liposarcoma Masquerading as an Inguinal Hernia.

Urology 2018 Mar 1;113:e5-e6. Epub 2017 Dec 1.

Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, Tampa, FL.

A man with left scrotal swelling felt to represent inguinal hernia underwent computed tomography scan for reported bleeding after prostate biopsy. Computed tomography scan revealed a 15-cm extratesticular left scrotal mass containing both fat and soft tissue components, raising concern for dedifferentiated liposarcoma. At surgery and pathology, the mass was separate from the left testis, epididymis, and spermatic cord. Histopathologic findings were consistent with paratesticular dedifferentiated liposarcoma.
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http://dx.doi.org/10.1016/j.urology.2017.11.035DOI Listing
March 2018

Isolated Limb Infusion: A Single-Center Experience with Over 200 Infusions.

Ann Surg Oncol 2017 Dec 10;24(13):3842-3849. Epub 2017 Oct 10.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Background: Isolated limb infusion (ILI) is a minimally invasive technique for delivering regional chemotherapy to an extremity for patients with locally advanced cutaneous malignancies and sarcoma.

Methods: A single-institution, prospectively collected database was analyzed for intention-to-treat with ILI.

Results: From 2007 to 2016, 163 patients underwent 205 procedures (201 were successfully completed), and four malignancies were treated: melanoma (72.1% of all ILIs), sarcoma (23.4%), squamous cell carcinoma (SCC; 2.0%) and Merkel cell carcinoma (MCC; 2.5%). A median grade II regional Wieberdink toxicity score was observed, with 88.1% of patients experiencing grade II or less. Median follow-up was 21.8 months, and overall response rate (ORR) was 59.0% for melanoma, 48.9% for sarcoma, 50.0% for SCC, and 60.0% for MCC. A significant difference (p = 0.04) between upper (76.9%) and lower extremity (55.1%) ORR was observed in patients with melanoma. When comparing responders with nonresponders, patients with melanoma had significantly longer in-field progression-free survival (IPFS; 14.1 vs. 3.2 months, p < 0.001), distant metastatic-free survival (DMFS; not reached vs. 25.8 months, p = 0.006), and overall survival (OS; 56.0 vs. 26.7 months, p = 0.0004). Sarcoma responders had a significantly longer IPFS (13.0 vs. 2.7 months, p < 0.0001), but no significant distant metastatic or OS advantage. Over a median follow-up of 19.3 months, sarcoma patients had an overall limb salvage rate of 68.4%.

Conclusion: ILI is a well-tolerated procedure for patients with locally advanced melanoma, sarcoma, and other cutaneous malignancies. ILI responders had a significantly longer time to IPFS, while melanoma responders also had a DMFS and OS advantage.
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http://dx.doi.org/10.1245/s10434-017-6107-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771340PMC
December 2017

Large Chest and Abdominal Wall Defect Reconstruction With Anterolateral Thigh Free Flap to Right Gastroepiploic Artery Anastomosis.

Eplasty 2017 18;17:ic24. Epub 2017 Sep 18.

Division of Plastic Surgery, Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609249PMC
September 2017

Myoepithelial carcinoma with RB1 mutation: remarkable chemosensitivity to carcinoma of unknown origin therapy.

BMC Cancer 2017 04 8;17(1):250. Epub 2017 Apr 8.

Sarcoma Department, 12901 Bruce B Downs Blvd., Tampa, FL, 33612, USA.

Background: Myoepithelial carcinoma of soft tissue is a rare, malignant neoplasm that is morphologically and immunophenotypically similar to its counterpart in salivary gland. It demonstrates myoepithelial differentiation, possessing both epithelial and myogenic characteristics. Thought to be chemotherapy insensitive, the optimal treatment regimen of this tumor has yet to be established and only a select few cases in the literature discuss treatment efficacy in detail.

Case Presentation: Here we present a case of a young adult with metastatic myoepithelial carcinoma with an initial excellent response to systemic therapy utilizing carboplatin and paclitaxel with continued complete response after 3 years. The patient also underwent complete surgical excision and received adjuvant radiation to the primary site of disease. Exome sequencing revealed an inactivating mutation in RB1 which we believe to be the first such mutation to be reported in this cancer type.

Conclusions: Given increasing evidence suggesting RB1 loss is associated with responsiveness to conventional chemotherapies, particularly platinum-based regimens, we hypothesize that this genetic feature predisposed chemosensitivity in our patient's tumor.
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http://dx.doi.org/10.1186/s12885-017-3249-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385017PMC
April 2017

Staged reconstruction brachytherapy has lower overall cost in recurrent soft-tissue sarcoma.

J Contemp Brachytherapy 2017 Feb 31;9(1):20-29. Epub 2017 Jan 31.

Radiation Oncology.

Purpose: Adjuvant brachytherapy (AB) with immediate (IR) and staged reconstruction (SR) are distinct treatment modalities available for patients with recurrent soft tissue sarcoma (STS). Although SR may offer local control and toxicity benefit, it requires additional upfront procedures, and there is no evidence that it improves overall survival. With the importance of value-based care, our goal is to identify which technique is more cost effective.

Material And Methods: A retrospective review of 22 patients with recurrent extremity STS treated with resection followed by AB alone. Hospital charges were used to compare the cost between SR and IR at the time of initial treatment, at 6-month intervals following surgery, and cumulative cost comparisons at 18 months.

Results: Median follow-up was 31 months. Staged reconstruction ( = 12) was associated with an 18-month local control benefit (85% vs. 42%, = 0.034), compared to IR ( = 10). Staged reconstruction had a longer hospital stay during initial treatment (10 vs. 3 days, = 0.002), but at 18 months, the total hospital stay was no longer different (11 vs. 11 days). Initially, there was no difference in the cost of SR and IR. With longer follow-up, cost eventually favored SR, which was attributed primarily to the costs associated with local failure (LF). On multivariate analysis, cost of initial treatment was associated with length of hospital stay (~$4.5K per hospital day, < 0.001), and at 18 months, the cumulative cost was ~175K lower with SR ( = 0.005) and $58K higher with LF ( = 0.02).

Conclusions: In recurrent STS, SR has a longer initial hospital stay when compared to IR. At 18 months, SR had lower rates of LF, translating to lower total costs for the patient. SR is the more cost-effective brachytherapy approach in the treatment of STS, and should be considered as healthcare transitions into value-based medicine.
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http://dx.doi.org/10.5114/jcb.2017.65641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346606PMC
February 2017

Isolated Limb Infusion as a Limb Salvage Strategy for Locally Advanced Extremity Sarcoma.

J Am Coll Surg 2017 Apr 15;224(4):635-642. Epub 2017 Feb 15.

Sarcoma Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Background: Treatment-resistant, locally advanced soft tissue sarcomas often require amputation for complete tumor extirpation. Isolated limb infusion (ILI) selectively delivers high-dose chemotherapy to the extremity in an attempt to achieve limb salvage. The aim of this study was to report perioperative and oncologic outcomes after ILI in patients with extremity soft tissue sarcomas.

Study Design: From 1994 to 2016, 77 patients underwent 84 ILIs at a total of 5 institutions. Melphalan and actinomycin D were circulated for 30 minutes after complete tourniquet occlusion of the limb, then actively washed out to prevent systemic exposure.

Results: The procedure was performed in an upper extremity on 19 patients (21 infusions) and in a lower extremity on 58 patients (63 infusions). The 3-month overall response rate (ORR) for the entire cohort was 58%, and there was a statistically significant difference (p = 0.03) between upper (37%) and lower extremity (66%) ORR. With median follow-up of 20.6 months (range 0.6 to 146.1 months), the overall limb salvage rate was 77.9%. For those who underwent amputation due to progression of disease, the median time to amputation was 4.5 months. With a median follow-up of 20.6 months, the median overall survival for the entire cohort was 44.3 months. The distant metastatic-free survival was longer for responders than nonresponders (p = 0.01), though the disease-specific survival was not different for the same groups (p = 0.2).

Conclusions: Isolated limb infusion for extremity soft tissue sarcoma results in an objective response for half of the patients who are otherwise facing amputation, and offers prolonged limb salvage for the vast majority of patients. The procedure is well tolerated without serious complications.
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http://dx.doi.org/10.1016/j.jamcollsurg.2016.12.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771304PMC
April 2017

Resection of Gastrointestinal Metastases in Stage IV Melanoma: Correlation with Outcomes.

Am Surg 2016 Nov;82(11):1109-1116

Department of Cutaneous Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

The prognosis of patients with gastrointestinal (GI) melanoma metastases is poor. Surgery renders select patients disease free and/or palliates symptoms. We reviewed our single-institution experience of resection with GI melanoma metastases. A retrospective review was performed on patients who underwent surgery for GI melanoma metastases from 2007 to 2013. Fifty-four patients were identified and separated based on completeness of resection into curative 13 (24%) and palliative 41 (75.9%) groups. Thiry-six (63.2%) were symptomatic preoperatively with bleeding and/or obstruction/pain with 91.7 per cent achieving objective symptom relief. Thirty-day operative mortality was 0 per cent. The most common complication was wound infection (n = 5); major complications like anastomotic leak (n = 1) were uncommon. With a median follow-up of 9.5 months (range 0.2-75.8), median overall survival was not reached (curative) versus 9.53 months (palliative group). Median recurrence-free and progression-free survival after resection were 18.89 and 1.97 months in the curative versus palliative groups, respectively. On multivariate analysis, resection to no clinical evidence of disease (P = 0.012) and presence of single metastases (P = 0.031) were associated with improved overall survival. Surgery for GI metastases from melanoma provides symptomatic relief without major morbidity. Fewer metastases and curative resection were associated with improved survival.
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November 2016

Practical Issues for Retroperitoneal Sarcoma.

Cancer Control 2016 Jul;23(3):249-64

Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL 33612, USA.

Background: Retroperitoneal sarcoma is rare. Using initial specimens on biopsy, a definitive diagnosis of histological subtypes is ideal but not always achievable.

Methods: A retrospective institutional review was performed for all cases of adult retroperitoneal sarcoma from 1996 to 2015. A review of the literature was also performed related to the distribution of retroperitoneal sarcoma subtypes. A meta-analysis was performed.

Results: Liposarcoma is the most common subtype (45%), followed by leiomyosarcoma (21%), not otherwise specified (8%), and undifferentiated pleomorphic sarcoma (6%) by literature review. Data from Moffitt Cancer Center demonstrate the same general distribution for subtypes of retroperitoneal sarcoma. A pathology-based algorithm for the diagnosis of retroperitoneal sarcoma is illustrated, and common pitfalls in the pathology of retroperitoneal sarcoma are discussed.

Conclusions: An informative diagnosis of retroperitoneal sarcoma via specimens on biopsy is achievable and meaningful to guide effective therapy. A practical and multidisciplinary algorithm focused on the histopathology is helpful for the management of retroperitoneal sarcoma.
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http://dx.doi.org/10.1177/107327481602300308DOI Listing
July 2016

Management of Truncal Sarcoma.

Surg Clin North Am 2016 Oct;96(5):1003-13

Sarcoma Department, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33606, USA. Electronic address:

The management of truncal sarcoma presents unique challenges to the treating physician for reasons specific to this tumor location. First, the reconstruction options after resection of the abdominal or chest wall require a balance between cosmesis and structural integrity due to the multiplanar forces exerted on this region. Second, the histologies that commonly arise in this region are often associated with high local recurrence rates, which often require complex decision making due to prior therapy. Finally, sarcomas of the trunk in the inguinal region involve those organs in the genitourinary system, of which resection can have significant psychosocial implications.
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http://dx.doi.org/10.1016/j.suc.2016.06.005DOI Listing
October 2016

Soft Tissue Sarcoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2016 06;14(6):758-86

Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for Soft Tissue Sarcoma (available at NCCN.org) provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumor, desmoid tumors, and rhabdomyosarcoma. This manuscript discusses guiding principles for the diagnosis and staging of STS and evidence for treatment modalities that include surgery, radiation, chemoradiation, chemotherapy, and targeted therapy.
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http://dx.doi.org/10.6004/jnccn.2016.0078DOI Listing
June 2016

Implications of staged reconstruction and adjuvant brachytherapy in the treatment of recurrent soft tissue sarcoma.

Brachytherapy 2016 Jul-Aug;15(4):495-503. Epub 2016 May 12.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address:

Purpose: Prior studies illustrated a reduction in wound complications with the use of staged reconstruction (SR) and negative pressure wound therapy when treating soft tissue sarcoma (STS) with surgical resection followed by high-dose-rate adjuvant brachytherapy. The purpose of this study is to compare the outcomes of SR and immediate reconstruction (IR) brachytherapy in recurrent STS.

Methods And Materials: A retrospective review of 40 patients with recurrent STS of the local extremity and trunk treated with resection followed by adjuvant brachytherapy alone. Margin status was defined as positive (SM(+)) if there was microscopic involvement (R1) or ≤1 mm margin and negative (SM(-)) if >1 mm margin was obtained. SR and IR were compared regarding toxicity, local control, and limb preservation.

Results: Median followup was 27 months. When comparing the SR (n = 22) and IR (n = 18) cohorts, there was a significantly lower final SM(+) rate in SR (32% vs. 83%, p < 0.01). A 2-year local control benefit seen with SR (80% vs. 34%; p = 0.012) and a final SM(-) (81% vs. 39%; p = 0.023). SR was associated with less toxicity on multivariate analysis, including a 90% decrease in persistent edema, an 80% decrease in wound dehiscence, and a 94% decrease in nonhealing wounds, when compared to IR. Ten of 31 (32%) extremity cases required eventual amputation from either chronic wound complications (n = 4) or local recurrence (n = 6). SR predicted for a benefit in 2-year limb preservation (88% vs. 50%; p = 0.008).

Conclusion: In our series, the treatment with SR brachytherapy resulted in less morbidity and an improved final SM(-) rate. This technique translated to an improvement in both local control and limb preservation of recurrent STS.
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http://dx.doi.org/10.1016/j.brachy.2016.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771533PMC
July 2017

Is a Wider Margin (2 cm vs. 1 cm) for a 1.01-2.0 mm Melanoma Necessary?

Ann Surg Oncol 2016 07 8;23(7):2336-42. Epub 2016 Mar 8.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Background: The current NCCN recommendation for resection margins in patients with melanomas between 1.01 and 2 mm deep is a 1-2 cm radial margin. We sought to determine whether margin width had an impact on local recurrence (LR), disease-specific survival (DSS), and type of wound closure.

Methods: Melanomas measuring 1.01-2.0 mm were evaluated at a single institution between 2008 and 2013. All patients had a 1 or 2 cm margin.

Results: We identified 965 patients who had a 1 cm (n = 302, 31.3 %) or 2 cm margin (n = 663, 68.7 %). Median age was 64 years, and 592 (61.3 %) were male; 32.5 and 48.7 % of head and neck and extremity patients had a 1 cm margin versus 18.9 % of trunk patients (p < 0.001). LR was 2.0 and  2.1 % for a 1 and 2 cm margin, respectively (p = not significant). Five-year DSS was 87 % for a 1 cm margin and 85 % for a 2 cm margin (p = not significant). Breslow thickness, melanoma on the head and neck, lymphovascular invasion, and sentinel lymph node biopsy (SLNB) status significantly predicted LR on univariate analysis; however, only location and SLNB status were associated with LR on multivariate analysis. Margin width was not significant for LR or DSS. Wider margins were associated with more frequent graft or flap use only on the head and neck (p = 0.025).

Conclusions: Our data show that selectively using a narrower margin of 1 cm did not increase the risk of LR or decrease DSS. Avoiding a 2 cm margin may decrease the need for graft/flap use on the head and neck.
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http://dx.doi.org/10.1245/s10434-016-5167-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904729PMC
July 2016

Recurrence and survival analysis of resected soft tissue sarcomas of pelvic retroperitoneal structures.

J Surg Oncol 2016 Jan 6;113(1):103-7. Epub 2016 Jan 6.

Department of Sarcoma, Moffitt Cancer Center, Tampa, Florida.

Background: The purpose is to determine the clinicopathologic factors related to survival and recurrence of primary resected pelvic soft tissue sarcomas (STS).

Methods: Demographic/clinical variables were recorded.

Results: Thirty-five pts were identified. Median follow-up was 24.2 months. There were 23 (65.7%) high/intermediate-grade and 12 (34.3%) low-grade tumors included in the final analysis. Eight patients (22.9%) received neoadjuvant therapy. Margins were grossly negative in 27 (77.1%, 17-R0, 10-R1) and grossly positive (R2) in 8 (22.9%). Adjuvant therapy was used in 13 patients (37.1%). The 2- and 3-year RFS was 56.5% and 51.3%, with 14 patients recurring at a median time of 16 months (6-local, 8-distant). All distant recurrences were in high-grade tumors. There were no differences in RFS for margins (R0 vs. R1), neoadjuvant/adjuvant therapy, size (≥10 vs. <10 cm) or gender. High/intermediate-grade tumors had worse RFS (P < 0.008). The 2- and 3-year OS was 80.9%. OS was improved for R0/R1 resection (P < 0.001). Resection to R0/R1 margin was a significant predictor of improved OS (P = 0.001).

Conclusions: High/intermediate-grade lesions were associated with worse OS and RFS. Resection to gross negative margins was the only independent predictor of OS. Adjuvant therapy may be reserved for high-grade lesions due to increased metastatic potential. J
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http://dx.doi.org/10.1002/jso.24090DOI Listing
January 2016

BRAF inhibition for advanced locoregional BRAF V600E mutant melanoma: a potential neoadjuvant strategy.

Melanoma Res 2016 Feb;26(1):83-7

Departments of aCutaneous Oncology bAnatomic Pathology, Moffitt Cancer Center Departments of cOncologic Sciences dSurgery, University of South Florida Morsani College of Medicine eDepartment of Pathology, Veterans Administration, Tampa, Florida fDepartment of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia gGeorgetown-Lombardi Comprehensive Cancer Center and Department of Medicine, Medstar-Georgetown University Hospital, Washington, DC, USA hUniversity of Groningen, Department of Surgical Oncology, University Medical Center Groningen, The Netherlands.

Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival.
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http://dx.doi.org/10.1097/CMR.0000000000000214DOI Listing
February 2016

Dermal melanoma: A report on prognosis, outcomes, and the utility of sentinel lymph node biopsy.

J Surg Oncol 2016 Jan 10;113(1):98-102. Epub 2015 Dec 10.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.

Introduction: Historically dermal melanoma (DM) has been labeled as either stage IIIB (in-transit) or stage IV (M1a) disease. We sought to investigate the natural history of DM and the utility and prognostic significance of sentinel lymph node biopsy (SLNB).

Methods: Patients with DM undergoing SLNB at a single center from 1998 to 2009 were identified.

Results: Eighty-three patients met criteria, 10 (12%) patients had a positive SLNB. Of those, 5 (50%) recurred (all with distant disease). Twenty-one (29%) of the 73 SLNB negative patients recurred and of those, 15 (71%) developed distant metastases, whereas 6 (29%) developed local or regional recurrence, including two false-negative regional nodal recurrences. No in-transit recurrences were recorded. Five-year recurrence-free and disease-specific survival was significantly better for patients with a negative SLNB versus positive SLNB (56.8% vs. 22.2% P = 0.02, 81.1% vs. 61.0%, P = 0.05, respectively).

Conclusion: SLNB has prognostic significance for RFS and DSS, and should be utilized in the management of DM based on a >10% yield and low false-negative rate. Our data demonstrate patients with DM do not recur in an in-transit fashion, which along with the survival outcomes suggest the behavior of DM is consistent with primary cutaneous melanoma of similar thickness rather than an isolated in-transit or distant dermal metastasis from a regressed cutaneous primary.
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http://dx.doi.org/10.1002/jso.24088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904728PMC
January 2016
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