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Beasley, Georgia Marie

Positions:

Assistant Professor of Surgery

Surgery, Advanced Oncologic and Gastrointestinal Surgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.A. 2001

B.A. — Duke University

M.D. 2008

M.D. — Duke University School of Medicine

M.H.S. 2012

M.H.S. — Duke University

General Surgery Resident, Surgery

Duke University

Surgical Oncology Fellow, Surgery

Ohio State University

Publications:

Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study.

Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma.Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population.The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5-50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75-2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7-10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06).SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

Authors
Beasley, GM; Hu, Y; Youngwirth, L; Scheri, RP; Salama, AK; Rossfeld, K; Gardezi, S; Agnese, DM; Howard, JH; Tyler, DS; Slingluff, CL; Terando, AM
MLA Citation
Beasley, GM, Hu, Y, Youngwirth, L, Scheri, RP, Salama, AK, Rossfeld, K, Gardezi, S, Agnese, DM, Howard, JH, Tyler, DS, Slingluff, CL, and Terando, AM. "Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study." Annals of surgical oncology 24.9 (September 2017): 2728-2733.
PMID
28508145
Source
epmc
Published In
Annals of Surgical Oncology
Volume
24
Issue
9
Publish Date
2017
Start Page
2728
End Page
2733
DOI
10.1245/s10434-017-5883-6

Surveillance strategies in the follow-up of melanoma patients: too much or not enough?

After appropriate initial therapy for patients with stage II-III melanoma, there is no consensus regarding surveillance. Thus, follow-up is highly variable among institutions and individual providers. The National Comprehensive Cancer Network recommends routine clinical examination and consideration of imaging for stage IIB-IIIC every 3-12 mo with no distinction between stages. Detection of recurrence is important as novel systemic therapies and surgical resection of recurrence may provide survival benefits.We retrospectively reviewed 369 patients with stage II and III melanoma treated at Ohio State University from 2009-2015, who underwent surgery as primary therapy. Two hundred forty-seven patients who were followed for a minimum of 6 mo after surgical resection to achieve no evidence of disease status (NED) were included in this analysis. One hundred twenty-two were lost to follow-up after surgery and were excluded.The rate of recurrence for stage IIA/IIB patients was 11% (14/125). Eleven of the 14 (79%) recurrences were detected by clinical symptoms or physical examination. Thirty-nine percent (49/125) of stage IIA or IIB patients were followed by clinical examination only, whereas 61% (76/125) were followed with at least two serial chest x-rays. The median time to first chest x-ray after NED status was 4.7 mo (n = 76), median time to second chest x-ray after NED status was 12.7 mo (n = 76), and 66% (50/76) continued to have additional serial chest x-rays. At median follow-up of 35 mo for the 125 patients with stage IIA/IIB, there was no difference in survival between those followed clinically (95% [95% CI: 0.88-0.99]) versus those followed with at least two serial x-rays (96% [95% CI: 0.89-0.98]). For stage IIC/IIIA-C patients, recurrence was detected in 23% (28/122) at median follow-up 31.2 mo. Fifty percent of recurrences were detected by imaging in asymptomatic patients, whereas 50% (14/28) had recurrence detected on imaging associated clinical findings. Eighty-seven percent (106/122) of stage IIC/IIIA-C patients were followed with at least two serial whole body positron emission tomography/computed tomography (CT) scans or whole body CT scans plus brain magnetic resonance imaging; median time between NED status and second scan was 10.3 mo. Of stage IIC/IIIA-C patients with recurrence, 57% (16/28) went on to surgical resection of the recurrence, whereas 11 (39%) patients received B-RAF inhibitor therapy, immune blockade therapy, or combination therapy.For stage IIA and IIB melanoma, surveillance chest x-rays did not improve survival compared to physical examination alone. However, for stage IIC and IIIA-C melanoma, where the recurrence rates are higher, routine whole body imaging detected 50% of recurrences leading to additional surgery and/or treatment with novel systemic therapies for the majority of patients. Detection of melanoma recurrence is important and specific substage should be used to stratify risk and define appropriate follow-up.

Authors
Kurtz, J; Beasley, GM; Agnese, D; Kendra, K; Olencki, TE; Terando, A; Howard, JH
MLA Citation
Kurtz, J, Beasley, GM, Agnese, D, Kendra, K, Olencki, TE, Terando, A, and Howard, JH. "Surveillance strategies in the follow-up of melanoma patients: too much or not enough?." The Journal of surgical research 214 (June 2017): 32-37.
PMID
28624057
Source
epmc
Published In
Journal of Surgical Research
Volume
214
Publish Date
2017
Start Page
32
End Page
37
DOI
10.1016/j.jss.2017.02.070

Can binimetinib, encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?

Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations. Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT. Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.

Authors
Turner, MC; Rossfeld, K; Salama, AKS; Tyler, D; Beasley, G
MLA Citation
Turner, MC, Rossfeld, K, Salama, AKS, Tyler, D, and Beasley, G. "Can binimetinib, encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?." Expert opinion on pharmacotherapy 18.5 (April 2017): 487-495. (Review)
PMID
28277830
Source
epmc
Published In
Expert Opinion on Pharmacotherapy
Volume
18
Issue
5
Publish Date
2017
Start Page
487
End Page
495
DOI
10.1080/14656566.2017.1299710

Computed Tomography-Based Limb Volume Measurements for Isolated Limb Infusion in Melanoma.

Despite advances in cross-sectional imaging, chemotherapeutic dosing for isolated limb infusion (ILI) in melanoma is currently calculated through cumbersome and potentially imprecise manual measurements. The primary objective of this study was to examine the feasibility of using computed tomography (CT) to calculate limb volume, its concordance with manual measurement, and its ability to predict clinical response and toxicity in patients undergoing ILI.A retrospective analysis of all patients undergoing lower extremity ILI at Duke University Medical Center between 2003 and 2014 was performed. Data pertaining to manually measured limb volume, chemotherapeutic dosing, and patient outcome was obtained. CT-based measurements of limb volume were performed in all patients for whom imaging was available and subsequently compared with manually measured values.CT data were sufficient for measurement in 73 patients. The mean measurement time was 4.61 ± 2.13 min. Although average CT-based measurements were 1.20 L higher in the case of lower limbs, they correlated well with those obtained manually (r (2) = 0.90). Unlike manual measurement, patients with complete responses to chemotherapy had smaller limb volumes than those with disease progression as measured by CT (9.3 vs. 10.7 L; p = .038). Patients suffering grade 3 and 4 toxicities also had statistically lower limb volumes as measured by CT than those who did not (p < .05).CT-based limb volume measurement is feasible for chemotherapy dosing in patients undergoing ILI for melanoma and has predictive value with respect to clinical response and toxicity.

Authors
Brys, AK; Bhatti, L; Bashir, MR; Jaffe, TA; Beasley, GM; Nath, NS; Salama, AKS; Tyler, DS; Mosca, PJ
MLA Citation
Brys, AK, Bhatti, L, Bashir, MR, Jaffe, TA, Beasley, GM, Nath, NS, Salama, AKS, Tyler, DS, and Mosca, PJ. "Computed Tomography-Based Limb Volume Measurements for Isolated Limb Infusion in Melanoma." Annals of surgical oncology 23.4 (April 2016): 1090-1095.
PMID
26572755
Source
epmc
Published In
Annals of Surgical Oncology
Volume
23
Issue
4
Publish Date
2016
Start Page
1090
End Page
1095
DOI
10.1245/s10434-015-4972-7

Immune Checkpoint Inhibitor Therapy as a Novel and Effective Therapy for Aggressive Cutaneous Squamous-cell Carcinoma

Authors
Beasley, GM; Kurtz, J; Vandeusen, J; Howard, JH; Terando, A; Agnese, D; Liebner, D; Jeter, J; Olencki, T
MLA Citation
Beasley, GM, Kurtz, J, Vandeusen, J, Howard, JH, Terando, A, Agnese, D, Liebner, D, Jeter, J, and Olencki, T. "Immune Checkpoint Inhibitor Therapy as a Novel and Effective Therapy for Aggressive Cutaneous Squamous-cell Carcinoma." Clinical Skin Cancer 1.2 (April 2016): 75-81.
Source
crossref
Volume
1
Issue
2
Publish Date
2016
Start Page
75
End Page
81
DOI
10.1016/j.clsc.2017.04.001

Procedure Delegation by Attending Surgeons Performing Concurrent Operations in Academic Medical Centers: Balancing Safety and Efficiency.

Authors
Beasley, GM; Pappas, TN; Kirk, AD
MLA Citation
Beasley, GM, Pappas, TN, and Kirk, AD. "Procedure Delegation by Attending Surgeons Performing Concurrent Operations in Academic Medical Centers: Balancing Safety and Efficiency." Annals of surgery 261.6 (June 2015): 1044-1045.
PMID
25775075
Source
epmc
Published In
Annals of Surgery
Volume
261
Issue
6
Publish Date
2015
Start Page
1044
End Page
1045
DOI
10.1097/sla.0000000000001208

Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma.

We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma.N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects.Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis.Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ.ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

Authors
Turley, RS; Tokuhisa, Y; Toshimitsu, H; Lidsky, ME; Padussis, JC; Fontanella, A; Deng, W; Augustine, CK; Beasley, GM; Davies, MA; Dewhirst, MW; Tyler, DS
MLA Citation
Turley, RS, Tokuhisa, Y, Toshimitsu, H, Lidsky, ME, Padussis, JC, Fontanella, A, Deng, W, Augustine, CK, Beasley, GM, Davies, MA, Dewhirst, MW, and Tyler, DS. "Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma." Annals of surgery 261.2 (February 2015): 368-377.
PMID
24646553
Source
epmc
Published In
Annals of Surgery
Volume
261
Issue
2
Publish Date
2015
Start Page
368
End Page
377
DOI
10.1097/sla.0000000000000635

In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy.

Authors
Beasley, G; Tyler, D
MLA Citation
Beasley, G, and Tyler, D. "In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy." Annals of surgical oncology 22.2 (February 2015): 358-360.
PMID
25266867
Source
epmc
Published In
Annals of Surgical Oncology
Volume
22
Issue
2
Publish Date
2015
Start Page
358
End Page
360
DOI
10.1245/s10434-014-4110-y

Burden of disease predicts response to isolated limb infusion with melphalan and actinomycin D in melanoma.

Isolated limb infusion (ILI) with melphalan is a minimally invasive, effective treatment for in transit melanoma. We hypothesized that burden of disease (BOD) would correlate to treatment response.We retrospectively analyzed a prospectively collected database from two academic centers. BOD was stratified as high or low (low ≤ 10 lesions, none >2 cm). Response rates were measured 3 months post-ILI. Multivariable analysis (MV) was used to evaluate the association between the response and BOD. Kaplan-Meier methods with log-rank tests and MV Cox proportional hazard models were used to analyze overall survival (OS) and progression free survival (PFS).Sixty (38 %) patients had low and 100 (62 %) high BOD. Patients with low BOD had an overall response rate (ORR) of 73 % with 50 % CR, compared with an ORR of 47 % with 24 % CR in patients with high BOD (p = 0.002). MV analysis of preoperative, intraoperative, and postoperative parameters showed no significant impact on 3-month response. Patients with a CR at 3 months demonstrated improved PFS over the remainder of the cohort, but OS was similar. Low BOD patients had an increased median PFS of 6.9 versus 3.8 months (p = 0.047) and a increased median OS of 38.4 versus 30.9 months (p = 0.146).Lower BOD is associated with an increased ORR and CR rate with statistically significantly improved PFS in patients undergoing ILI for in transit extremity melanoma. BOD provides useful prognostic information for patient counseling and serves as a marker to stratify patient risk groups.

Authors
Muilenburg, DJ; Beasley, GM; Thompson, ZJ; Lee, J-H; Tyler, DS; Zager, JS
MLA Citation
Muilenburg, DJ, Beasley, GM, Thompson, ZJ, Lee, J-H, Tyler, DS, and Zager, JS. "Burden of disease predicts response to isolated limb infusion with melphalan and actinomycin D in melanoma." Annals of surgical oncology 22.2 (February 2015): 482-488.
PMID
25192683
Source
epmc
Published In
Annals of Surgical Oncology
Volume
22
Issue
2
Publish Date
2015
Start Page
482
End Page
488
DOI
10.1245/s10434-014-4072-0

A Multicenter Phase I Dose Escalation Trial to Evaluate Safety and Tolerability of Intra-arterial Temozolomide for Patients with Advanced Extremity Melanoma Using Normothermic Isolated Limb Infusion

© 2014, Society of Surgical Oncology. Background: l-phenylalanine mustard (LPAM) has been the standard for use in regional chemotherapy (RC) for unresectable in-transit melanoma. Preclinical data demonstrated that regional temozolomide (TMZ) may be more effective. Methods: Patients with AJCC Stage IIIB or IIIC extremity melanoma who failed previous LPAM-based RC were treated with TMZ via isolated limb infusion (ILI) according to a modified accelerated titration design. Drug pharmacokinetic (PK) analysis, tumor gene expression, methylation status of the O 6 -methylguanine methyltransferase (MGMT) promoter, and MGMT expression were evaluated. Primary objectives were to (1) determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TMZ via ILI and (2) explore biomarker correlates of response. Results: 28 patients completed treatment over 2.5 years at 3 institutions. 19 patients were treated at the MTD defined as 3,200 mg/m 2 [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m 2 level while only grade 1 (n=15) and grade 2 (n=4) clinical toxicities occurred at the MTD. At 3-month post-ILI, 10.5% (2/19) had CR, 5.3% (1/19) had PR, 15.8% (3/19) had SD, and 68.4% (13/19) had PD. Neither PK parameters of TMZ nor MGMT levels were associated with response or toxicity. Conclusion: In this first ever use of intra-arterial TMZ in ILI for melanoma, the MTD was determined. While we could not define a marker for TMZ response, the minimal toxicity of TMZ ILI may allow for repeated treatments to increase the response rate as well as clarify the role of MGMT expression.

Authors
Beasley, GM; Speicher, P; Augustine, CK; Dolber, PC; Peterson, BL; Sharma, K; Mosca, PJ; Royal, R; Ross, M; Zager, JS; Tyler, DS
MLA Citation
Beasley, GM, Speicher, P, Augustine, CK, Dolber, PC, Peterson, BL, Sharma, K, Mosca, PJ, Royal, R, Ross, M, Zager, JS, and Tyler, DS. "A Multicenter Phase I Dose Escalation Trial to Evaluate Safety and Tolerability of Intra-arterial Temozolomide for Patients with Advanced Extremity Melanoma Using Normothermic Isolated Limb Infusion." Annals of Surgical Oncology 22.1 (January 1, 2015): 287-294.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
22
Issue
1
Publish Date
2015
Start Page
287
End Page
294
DOI
10.1245/s10434-014-3887-z

Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma.

Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established.A prospective, single-institution database of 243 patients with in-transit melanoma (1995-2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to determine if there was a difference in number of complete responders after immunotherapy.With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021).Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment.

Authors
Jiang, BS; Beasley, GM; Speicher, PJ; Mosca, PJ; Morse, MA; Hanks, B; Salama, A; Tyler, DS
MLA Citation
Jiang, BS, Beasley, GM, Speicher, PJ, Mosca, PJ, Morse, MA, Hanks, B, Salama, A, and Tyler, DS. "Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma." Annals of surgical oncology 21.8 (August 2014): 2525-2531.
PMID
24700302
Source
epmc
Published In
Annals of Surgical Oncology
Volume
21
Issue
8
Publish Date
2014
Start Page
2525
End Page
2531
DOI
10.1245/s10434-014-3671-0

Age and gender differences in substance screening may underestimate injury severity: a study of 9793 patients at level 1 trauma center from 2006 to 2010.

BACKGROUND: Although the relationship between psychoactive substance use and injury is known, evidence remains conflicting on the impact of substance use on clinical outcomes after injury. We hypothesized that preinjury substance use would negatively impact clinical outcomes. METHODS: National Trauma Registry American College of Surgeons identified patients (n = 9793) presenting to Duke Hospital from 2006 to 2010. Logistic regression models assessed potential predictors of receiving substance screening, mortality, length of stay, ventilator requirement, intensive care admission, or emergency department disposition. RESULTS: Forty-seven percent (4607/9793) of patients received blood alcohol screen (BAS) and 31% (3017/9793) received urine drug screen (UDS). Men were more likely to receive both BASs (P < 0.001) and UDSs (P = 0.001) than women after controlling for potential confounders. There was no significant difference between men and women over the legal limit for alcohol (OLLA; 27.2%, 95% confidence interval [CI]: 25.7%-28.8% versus 24.8%, 95% CI: 22.3%-27.5%). Similarly, younger patients more likely received both BASs (P < 0.001) and UDSs (P < 0.001) compared with older patients. The proportion of patients aged ≤45 y OLLA (26.5 %, 95% CI: 24.9%-28.2%) was similar to those aged >45 y OLLA (26.8%, 95% CI: 24.5%-29.3%). After controlling for potential confounders neither alcohol, nor tetrahydrocannabinol, nor cocaine was predictive of mortality, ventilator requirement, length of stay, or emergency department disposition, but a higher alcohol level (P = 0.0174) predicted intensive care admission. CONCLUSIONS: Females and those aged >45 y are less likely to receive BASs and UDSs. Differential screening that is biased may place patients at risk for receiving inadequate care.

Authors
Beasley, GM; Ostbye, T; Muhlbaier, LH; Foley, C; Scarborough, J; Turley, RS; Shapiro, ML
MLA Citation
Beasley, GM, Ostbye, T, Muhlbaier, LH, Foley, C, Scarborough, J, Turley, RS, and Shapiro, ML. "Age and gender differences in substance screening may underestimate injury severity: a study of 9793 patients at level 1 trauma center from 2006 to 2010." J Surg Res 188.1 (May 1, 2014): 190-197.
PMID
24370454
Source
pubmed
Published In
Journal of Surgical Research
Volume
188
Issue
1
Publish Date
2014
Start Page
190
End Page
197
DOI
10.1016/j.jss.2013.11.1103

Age and gender differences in substance screening may underestimate injury severity: A study of 9793 patients at level 1 trauma center from 2006 to 2010

Background Although the relationship between psychoactive substance use and injury is known, evidence remains conflicting on the impact of substance use on clinical outcomes after injury. We hypothesized that preinjury substance use would negatively impact clinical outcomes. Methods National Trauma Registry American College of Surgeons identified patients (n = 9793) presenting to Duke Hospital from 2006 to 2010. Logistic regression models assessed potential predictors of receiving substance screening, mortality, length of stay, ventilator requirement, intensive care admission, or emergency department disposition. Results Forty-seven percent (4607/9793) of patients received blood alcohol screen (BAS) and 31% (3017/9793) received urine drug screen (UDS). Men were more likely to receive both BASs (P < 0.001) and UDSs (P = 0.001) than women after controlling for potential confounders. There was no significant difference between men and women over the legal limit for alcohol (OLLA; 27.2%, 95% confidence interval [CI]: 25.7%-28.8% versus 24.8%, 95% CI: 22.3%-27.5%). Similarly, younger patients more likely received both BASs (P < 0.001) and UDSs (P < 0.001) compared with older patients. The proportion of patients aged < 45 y OLLA (26.5 %, 95% CI: 24.9%-28.2%) was similar to those aged > 45 y OLLA (26.8%, 95% CI: 24.5%-29.3%). After controlling for potential confounders neither alcohol, nor tetrahydrocannabinol, nor cocaine was predictive of mortality, ventilator requirement, length of stay, or emergency department disposition, but a higher alcohol level (P = 0.0174) predicted intensive care admission. Conclusions Females and those aged > 45 y are less likely to receive BASs and UDSs. Differential screening that is biased may place patients at risk for receiving inadequate care. © 2014 Elsevier Inc. All rights reserved.

Authors
Beasley, GM; Ostbye, T; Muhlbaier, LH; Foley, C; Scarborough, J; Turley, RS; Shapiro, ML
MLA Citation
Beasley, GM, Ostbye, T, Muhlbaier, LH, Foley, C, Scarborough, J, Turley, RS, and Shapiro, ML. "Age and gender differences in substance screening may underestimate injury severity: A study of 9793 patients at level 1 trauma center from 2006 to 2010." Journal of Surgical Research 188.1 (May 1, 2014): 190-197.
Source
scopus
Published In
Journal of Surgical Research
Volume
188
Issue
1
Publish Date
2014
Start Page
190
End Page
197
DOI
10.1016/j.jss.2013.11.1103

Hypoxia in melanoma: using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma.

BACKGROUND: There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation. METHODS: Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI. RESULTS: A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased. CONCLUSIONS: To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment.

Authors
Speicher, PJ; Beasley, GM; Jiang, B; Lidsky, ME; Palmer, GM; Scarbrough, PM; Mosca, PJ; Dewhirst, MW; Tyler, DS
MLA Citation
Speicher, PJ, Beasley, GM, Jiang, B, Lidsky, ME, Palmer, GM, Scarbrough, PM, Mosca, PJ, Dewhirst, MW, and Tyler, DS. "Hypoxia in melanoma: using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma." Ann Surg Oncol 21.5 (May 2014): 1435-1440.
PMID
23982250
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1435
End Page
1440
DOI
10.1245/s10434-013-3222-0

Efficacy of repeat sentinel lymph node biopsy in patients who develop recurrent melanoma.

Even after negative sentinel lymph node biopsy (SLNB) for primary melanoma, patients who develop in-transit (IT) melanoma or local recurrences (LR) can have subclinical regional lymph node involvement.A prospective database identified 33 patients with IT melanoma/LR who underwent technetium 99m sulfur colloid lymphoscintigraphy alone (n = 15) or in conjunction with lymphazurin dye (n = 18) administered only if the IT melanoma/LR was concurrently excised.Seventy-nine percent (26 of 33) of patients undergoing SLNB in this study had earlier removal of lymph nodes in the same lymph node basin as the expected drainage of the IT melanoma or LR at the time of diagnosis of their primary melanoma. Lymphoscintography at time of presentation with IT melanoma/LR was successful in 94% (31 of 33) cases, and at least 1 sentinel lymph node was found intraoperatively in 97% (30 of 31) cases. The SLNB was positive in 33% (10 of 30) of these cases. Completion lymph node dissection was performed in 90% (9 of 10) of patients. Nine patients with negative SLNB and IT melanoma underwent regional chemotherapy. Patients in this study with a positive sentinel lymph node at the time the IT/LR was mapped had a considerably shorter time to development of distant metastatic disease compared with those with negative sentinel lymph nodes.In this study, we demonstrate the technical feasibility and clinical use of repeat SLNB for recurrent melanoma. Performing SLNB cannot only optimize local, regional, and systemic treatment strategies for patients with LR or IT melanoma, but also appears to provide important prognostic information.

Authors
Beasley, GM; Speicher, P; Sharma, K; Seigler, H; Salama, A; Mosca, P; Tyler, DS
MLA Citation
Beasley, GM, Speicher, P, Sharma, K, Seigler, H, Salama, A, Mosca, P, and Tyler, DS. "Efficacy of repeat sentinel lymph node biopsy in patients who develop recurrent melanoma." Journal of the American College of Surgeons 218.4 (April 2014): 686-692.
PMID
24529806
Source
epmc
Published In
Journal of The American College of Surgeons
Volume
218
Issue
4
Publish Date
2014
Start Page
686
End Page
692
DOI
10.1016/j.jamcollsurg.2013.12.025

Discussion

MLA Citation
"Discussion." Journal of the American College of Surgeons 218.4 (April 2014): 692-694.
Source
crossref
Published In
Journal of The American College of Surgeons
Volume
218
Issue
4
Publish Date
2014
Start Page
692
End Page
694
DOI
10.1016/j.jamcollsurg.2014.01.020

Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma

Background: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as mono therapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. Methods: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130 CAS ), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. Results: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). Conclusions: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial. © 2013 Society of Surgical Oncology.

Authors
Tokuhisa, Y; Lidsky, ME; Toshimitsu, H; Turley, RS; Beasley, GM; Ueno, T; Sharma, K; Augustine, CK; Tyler, DS
MLA Citation
Tokuhisa, Y, Lidsky, ME, Toshimitsu, H, Turley, RS, Beasley, GM, Ueno, T, Sharma, K, Augustine, CK, and Tyler, DS. "Src family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma." Annals of Surgical Oncology 21.3 (March 1, 2014): 1024-1030.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
21
Issue
3
Publish Date
2014
Start Page
1024
End Page
1030
DOI
10.1245/s10434-013-3387-6

SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma.

BACKGROUND: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. METHODS: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130(CAS)), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. RESULTS: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). CONCLUSIONS: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

Authors
Tokuhisa, Y; Lidsky, ME; Toshimitsu, H; Turley, RS; Beasley, GM; Ueno, T; Sharma, K; Augustine, CK; Tyler, DS
MLA Citation
Tokuhisa, Y, Lidsky, ME, Toshimitsu, H, Turley, RS, Beasley, GM, Ueno, T, Sharma, K, Augustine, CK, and Tyler, DS. "SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma." Ann Surg Oncol 21.3 (March 2014): 1024-1030.
PMID
24281418
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
21
Issue
3
Publish Date
2014
Start Page
1024
End Page
1030
DOI
10.1245/s10434-013-3387-6

Resection of residual disease after isolated limb infusion (ILI) is equivalent to a complete response after ili-alone in advanced extremity melanoma

Background: Isolated limb infusion (ILI) is a limb-preserving treatment for in-transit extremity melanoma. The benefit of resecting residual disease after ILI is unclear. Methods: A multi-institutional experience was analyzed comparing patients who underwent ILI plus resection of residual disease (ILI + RES) versus ILI-alone. Results: A total of 176 patients were included, 154 with ILI-alone and 22 with ILI + RES. There were no differences between the groups with respect to gender, age, extremity affected, or time from diagnosis to ILI. All surgical resections were performed as an outpatient procedure, separate from the ILI. Within the ILI + RES group, 15 (68 %) had a partial response (PR), 2 (9 %) stable disease (SD), and 5 (23 %) progressive disease (PD). The ILI-alone group had 52 (34 %) CR, 30 (19 %) PR, 15 (10 %) SD, and 46 (30 %) PD. Eleven (7 %) ILI-alone patients did not have 3-month response available for review. Evaluating overall survival (OS) from date of ILI, the ILI-alone group had a median OS of 30.9 months, whereas the ILI + RES group had not reached median OS, p = 0.304. Although the ILI + RES group had a slightly longer disease-free survival (DFS) compared to those with a CR after ILI-alone (12.4 vs. 9.6), this was not statistically significant, p = 0.978. Within the ILI + RES group, those with an initial PR after ILI had improved DFS versus those with SD or PD after ILI, p < 0.0001. Conclusions: Resection of residual disease after ILI offers a DFS and OS similar to those who have a CR after ILI-alone. It may offer a treatment strategy that benefits patients undergoing ILI. © 2013 Society of Surgical Oncology.

Authors
Wong, J; Ann Chen, Y; Fisher, KJ; Beasley, GM; Tyler, DS; Zager, JS
MLA Citation
Wong, J, Ann Chen, Y, Fisher, KJ, Beasley, GM, Tyler, DS, and Zager, JS. "Resection of residual disease after isolated limb infusion (ILI) is equivalent to a complete response after ili-alone in advanced extremity melanoma." Annals of Surgical Oncology 21.2 (February 1, 2014): 650-655.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
21
Issue
2
Publish Date
2014
Start Page
650
End Page
655
DOI
10.1245/s10434-013-3336-4

Efficacy of repeat sentinel lymph node biopsy in patients who develop recurrent melanoma

Background Even after negative sentinel lymph node biopsy (SLNB) for primary melanoma, patients who develop in-transit (IT) melanoma or local recurrences (LR) can have subclinical regional lymph node involvement. Study Design A prospective database identified 33 patients with IT melanoma/LR who underwent technetium 99m sulfur colloid lymphoscintigraphy alone (n = 15) or in conjunction with lymphazurin dye (n = 18) administered only if the IT melanoma/LR was concurrently excised. Results Seventy-nine percent (26 of 33) of patients undergoing SLNB in this study had earlier removal of lymph nodes in the same lymph node basin as the expected drainage of the IT melanoma or LR at the time of diagnosis of their primary melanoma. Lymphoscintography at time of presentation with IT melanoma/LR was successful in 94% (31 of 33) cases, and at least 1 sentinel lymph node was found intraoperatively in 97% (30 of 31) cases. The SLNB was positive in 33% (10 of 30) of these cases. Completion lymph node dissection was performed in 90% (9 of 10) of patients. Nine patients with negative SLNB and IT melanoma underwent regional chemotherapy. Patients in this study with a positive sentinel lymph node at the time the IT/LR was mapped had a considerably shorter time to development of distant metastatic disease compared with those with negative sentinel lymph nodes. Conclusions In this study, we demonstrate the technical feasibility and clinical use of repeat SLNB for recurrent melanoma. Performing SLNB cannot only optimize local, regional, and systemic treatment strategies for patients with LR or IT melanoma, but also appears to provide important prognostic information. © 2014 by the American College of Surgeons.

Authors
Beasley, GM; Speicher, P; Sharma, K; Seigler, H; Salama, A; Mosca, P; Tyler, DS
MLA Citation
Beasley, GM, Speicher, P, Sharma, K, Seigler, H, Salama, A, Mosca, P, and Tyler, DS. "Efficacy of repeat sentinel lymph node biopsy in patients who develop recurrent melanoma." Journal of the American College of Surgeons 218.4 (January 1, 2014): 686-692.
Source
scopus
Published In
Journal of The American College of Surgeons
Volume
218
Issue
4
Publish Date
2014
Start Page
686
End Page
692
DOI
10.1016/j.jamcollsurg.2013.12.025

Hypoxia in melanoma: Using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma

Background: There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation. Methods: Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI. Results: A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased. Conclusions: To our knowled ge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment. © 2013 Society of Surgical Oncology.

Authors
Speicher, PJ; Beasley, GM; Jiang, B; Lidsky, ME; Palmer, GM; Scarbrough, PM; Mosca, PJ; Dewhirst, MW; Tyler, DS
MLA Citation
Speicher, PJ, Beasley, GM, Jiang, B, Lidsky, ME, Palmer, GM, Scarbrough, PM, Mosca, PJ, Dewhirst, MW, and Tyler, DS. "Hypoxia in melanoma: Using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma." Annals of Surgical Oncology 21.5 (January 1, 2014): 1435-1440.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1435
End Page
1440
DOI
10.1245/s10434-013-3222-0

Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma

Purpose. Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established. Methods. A prospective, single-institution database of 243 patients with in-transit melanoma (1995-2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to determine if there was a difference in number of complete responders after immunotherapy. Results. With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021). Conclusions. Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment. © 2014 Society of Surgical Oncology.

Authors
Jiang, BS; Beasley, GM; Speicher, PJ; Mosca, PJ; Morse, MA; Hanks, B; Salama, A; Tyler, DS
MLA Citation
Jiang, BS, Beasley, GM, Speicher, PJ, Mosca, PJ, Morse, MA, Hanks, B, Salama, A, and Tyler, DS. "Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma." Annals of Surgical Oncology 21.8 (January 1, 2014): 2525-2531.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
21
Issue
8
Publish Date
2014
Start Page
2525
End Page
2531
DOI
10.1245/s10434-014-3671-0

Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.

Authors
Hanks, BA; Holtzhausen, A; Evans, KS; Jamieson, R; Gimpel, P; Campbell, OM; Hector-Greene, M; Sun, L; Tewari, A; George, A; Starr, M; Nixon, A; Augustine, C; Beasley, G; Tyler, DS; Osada, T; Morse, MA; Ling, L; Lyerly, HK; Blobe, GC
MLA Citation
Hanks, BA, Holtzhausen, A, Evans, KS, Jamieson, R, Gimpel, P, Campbell, OM, Hector-Greene, M, Sun, L, Tewari, A, George, A, Starr, M, Nixon, A, Augustine, C, Beasley, G, Tyler, DS, Osada, T, Morse, MA, Ling, L, Lyerly, HK, and Blobe, GC. "Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment." J Clin Invest 123.9 (September 2013): 3925-3940.
Website
http://hdl.handle.net/10161/13297
PMID
23925295
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
9
Publish Date
2013
Start Page
3925
End Page
3940
DOI
10.1172/JCI65745

Melanoma

Authors
Augustine, CK; Freedman, JA; Beasley, GM; Tyler, DS
MLA Citation
Augustine, CK, Freedman, JA, Beasley, GM, and Tyler, DS. "Melanoma." 2 (August 29, 2013): 765-775. (Chapter)
Source
scopus
Volume
2
Publish Date
2013
Start Page
765
End Page
775
DOI
10.1016/B978-0-12-382227-7.00066-5

Plasma cytokine analysis in patients with advanced extremity melanoma undergoing isolated limb infusion.

BACKGROUND: Preprocedure clinical and pathologic factors have failed to consistently differentiate complete response (CR) from progressive disease (PD) in patients after isolated limb infusion (ILI) with melphalan for unresectable in-transit extremity melanoma. METHODS: Multiplex immunobead assay technology (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, Millipore Corp., Billerica, MA; and Magpix analytical test instrument, Luminex Corp., Austin, TX) was performed on pre-ILI plasma to determine concentrations of selected cytokines (MIP-1α, IL-1Rα, IP-10, IL-1β, IL-1α, MCP-1, IL-6, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β) on a subset of patients (n = 180) who experienced CR (n = 23) or PD (n = 24) after ILI. Plasma from normal donors (n = 12) was also evaluated. RESULTS: Of 180 ILIs performed, 28 % (95 % confidence interval 22-35, n = 50) experienced a CR, 14 % (n = 25) experienced a partial response, 11 % (n = 21) had stable disease, 34 % (n = 61) had PD, and 13 % (n = 23) were not evaluable for response. Tumor characteristics and pharmacokinetics appeared similar between CR (n = 23) and PD (n = 24) patients who underwent cytokine analysis. Although there were no differences in cytokine levels between CR and PD patients, there were differences between the melanoma patients and controls. MIP-1α, IL-1Rα, IL-1β, IL-1α, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β were significantly higher in normal controls compared to melanoma patients, while IP-10 was lower (p < 0.001) in controls compared to melanoma patients. CONCLUSIONS: Patients with unresectable in-transit melanoma appear to have markedly decreased levels of immune activating cytokines compared to normal healthy controls. This further supports a potential role for immune-targeted therapies and immune monitoring in patients with regionally advanced melanoma.

Authors
Shetty, G; Beasley, GM; Sparks, S; Barfield, M; Masoud, M; Mosca, PJ; Pruitt, SK; Salama, AKS; Chan, C; Tyler, DS; Weinhold, KJ
MLA Citation
Shetty, G, Beasley, GM, Sparks, S, Barfield, M, Masoud, M, Mosca, PJ, Pruitt, SK, Salama, AKS, Chan, C, Tyler, DS, and Weinhold, KJ. "Plasma cytokine analysis in patients with advanced extremity melanoma undergoing isolated limb infusion." Ann Surg Oncol 20.4 (April 2013): 1128-1135.
PMID
23456379
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
20
Issue
4
Publish Date
2013
Start Page
1128
End Page
1135
DOI
10.1245/s10434-012-2785-5

Simultaneous diaphragm and liver resection: a propensity-matched analysis of postoperative morbidity.

BACKGROUND: Although a concomitant diaphragm resection might be required at the time of hepatectomy to achieve tumor-free surgical margins, studies addressing its effect on postoperative morbidity and mortality have been inconclusive. The objective of this study was to determine whether the need for diaphragm resection at the time of hepatectomy truly increases 30-day morbidity or mortality using data from the American College of Surgeons National Surgical Quality Improvement Program. STUDY DESIGN: Data were obtained from the 2005-2010 American College of Surgeons National Surgical Quality Improvement Program Participant User Files based on CPT coding. All patients undergoing a simultaneous liver and diaphragm resection were propensity-matched to a subset of liver resection patients not undergoing a diaphragm resection. The main outcomes measures were 30-day mortality and morbidity. RESULTS: One hundred and ninety-two patients who underwent combined liver and diaphragm resection were matched to 192 patients treated with liver resection alone. The need for concomitant diaphragm resection was associated with a higher overall complication rate (38.54% vs 28.65%; p = 0.048), major complication rate (33.33% vs 23.44%; p = 0.030), and respiratory complication rate (14.06% vs 7.81%; p = 0.058). Postoperative mortality was similar between groups. Combined diaphragm and liver resection was also associated with longer operative times (median 311 minutes vs 247.5 minutes; p < 0.001), higher rates of intraoperative packed RBC transfusion (33.33% vs 23.44%; p = 0.037), and a longer length of hospitalization (median 7 vs 6 days; p = 0.002). CONCLUSIONS: The results of this study, when taken into account with those reported previously, suggest that the need for diaphragm resection at time of hepatectomy increases postoperative morbidity but not mortality.

Authors
Li, GZ; Sloane, JL; Lidsky, ME; Beasley, GM; Reddy, SK; Scarborough, JE; Tyler, DS; Turley, RS; Clary, BM
MLA Citation
Li, GZ, Sloane, JL, Lidsky, ME, Beasley, GM, Reddy, SK, Scarborough, JE, Tyler, DS, Turley, RS, and Clary, BM. "Simultaneous diaphragm and liver resection: a propensity-matched analysis of postoperative morbidity." J Am Coll Surg 216.3 (March 2013): 402-411.
PMID
23266422
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
216
Issue
3
Publish Date
2013
Start Page
402
End Page
411
DOI
10.1016/j.jamcollsurg.2012.11.001

Hepatic abscess

Authors
Beasley, G; Blazer, DG
MLA Citation
Beasley, G, and Blazer, DG. "Hepatic abscess." Contemporary Surgical Management of Liver, Biliary Tract, and Pancreatic Disease. January 1, 2013. 35-46.
Source
scopus
Publish Date
2013
Start Page
35
End Page
46
DOI
10.1142/9789814293068_0003

Predicting disease progression after regional therapy for in-transit melanoma

Importance: Although approximately 30% to 50% of patients experience a complete response after regional chemotherapy for in-transit melanoma, a subset of patients will develop rapidly progressive disease. In the current era of an expanding armamentarium, including both regional and systemic options for treating advanced melanoma, identifying perioperative factors that predict disease progression may obviate unnecessary morbidity associated with regional therapy and avoid delays in systemic therapy. Objective: To identify patient-related clinical and pathological variables, as well as procedural factors, that correlate with disease progression. Design: Using a prospectively maintained database, we identified patients who either underwent first-time melphalan- based isolated limb infusion (ILI) or first-time hyperthermic isolated limb perfusion (HILP) for in-transit melanoma. Response was defined using modified Response Evaluation Criteria in Solid Tumors for cutaneous disease at 3 months after treatment. Survival analyses were performed using the Kaplan-Meier method, with the differences in survival curves compared using a log-rank test. Potential preoperative and procedural predictors of infield progressive disease were analyzed using logistic regression. Participants: Of the 258 patients included in the database, 215 were identified as having undergone firsttime regional therapy. Of these 215 patients, 134 underwent ILI, and 81 underwent HILP. Exposure: Regional therapy (ILI or HILP). Main Outcomes and Measures: Complete response or progressive disease. Results: Of 134 patients who underwent ILI, 43 (32.1%) experienced in-field progressive disease. Of 81 patients who underwent HILP, 9 (11.1%) experienced in-field progressive disease. The median survival for patients with in-field progressive disease was 20.3 months for the ILI cohort and 15.0 months for the HILP cohort. In general, patients with progressive disease were younger, with advanced- stage melanoma and increased tumor burden. Compared with patients who experienced a complete response, patients with in-field progressive disease after ILI were younger (odds ratio, 1.06 [95% CI, 0.90-0.98]; P=.002). For patients who underwent HILP, no clinically relevant preoperative predictors of in-field progressive disease were identified. Procedural variables, including chemotherapeutic dosing, degree of acidosis or base deficit achieved, and peak temperature attained, were not predictors of in-field progressive disease after ILI or HILP. Conclusions and Relevance: Patient, clinical, and procedural factors are unreliable predictors of in-field progressive disease after regional therapy in patients with intransit melanoma. Defining the potential utility of molecular markers in predicting response or failure of regional therapy should be the focus of future research efforts. © 2013 American Medical Association. All rights reserved.

Authors
Lidsky, ME; Turley, RS; Beasley, GM; Sharma, K; Tyler, DS
MLA Citation
Lidsky, ME, Turley, RS, Beasley, GM, Sharma, K, and Tyler, DS. "Predicting disease progression after regional therapy for in-transit melanoma." JAMA Surgery 148.6 (2013): 493-498.
PMID
23558401
Source
scival
Published In
JAMA Surgery
Volume
148
Issue
6
Publish Date
2013
Start Page
493
End Page
498
DOI
10.1001/jamasurg.2013.695

Resection of Residual Disease after Isolated Limb Infusion (ILI) Is Equivalent to a Complete Response after ILI-Alone in Advanced Extremity Melanoma

Authors
Wong, J; Ann Chen, Y; Fisher, KJ; Beasley, GM; Tyler, DS; Zager, JS
MLA Citation
Wong, J, Ann Chen, Y, Fisher, KJ, Beasley, GM, Tyler, DS, and Zager, JS. "Resection of Residual Disease after Isolated Limb Infusion (ILI) Is Equivalent to a Complete Response after ILI-Alone in Advanced Extremity Melanoma." Annals of Surgical Oncology (2013): 1-6.
PMID
24162840
Source
scopus
Published In
Annals of Surgical Oncology
Publish Date
2013
Start Page
1
End Page
6

A multi-institution experience comparing the clinical and physiologic differences between upper extremity and lower extremity melphalan-based isolated limb infusion.

BACKGROUND: Although studies of melphalan-based isolated limb infusion (ILI) combine data from upper extremity (UE) treatments with those from lower extremity (LE) treatments, differences between the 2 may be clinically important. METHODS: Candidates for UE ILI (n = 51) and LE ILI (n = 192) were identified from prospective databases at 2 institutions. The Response Evaluation Criteria in Solid Tumors and Wieberdink toxicity scale were used as appropriate. RESULTS: The following patients had indications for UE ILI: melanoma, 36 of 47 patients (77%); sarcoma, 5 of 47 patients (11%); Merkel cell sarcoma, 3 of 47 patients (6%), and squamous cell carcinoma, 3 of 47 patients (6%). The patients who underwent UE ILI, as expected, had lower limb volumes (mean, 2.5 L vs 8.6 L; P < .001) and lower mean melphalan doses (20.7 mg vs 49.5 mg; P < .001). On perfusate blood gas analysis, the mean base excess at 30 minutes (-13.9 vs -9.1; P < .001) and the mean pH at 30 minutes (7.06 vs 7.15; P < .001) were lower for UE procedures than for LE procedures, although the mean ischemic time was longer in LE procedures (67.2 minutes) than in UE procedures (61.6 minutes; P = .03). The rate of regional toxicity grade ≥3 for UE ILI was 7% compared with 24% (P = .005) for LE ILI. There was no difference in the complete response rate for melanoma UE procedures (28%; 95% confidence interval, 16%-44%) compared with LE ILI procedures (32%; 95% confidence interval, 25%-39%). CONCLUSIONS: ILI for UE disease was associated with similar complete response rates but lower toxicity than ILI for LE disease and with different physiologic sequelae despite comparable methods. The UE appears relatively resistant to toxic effects of melphalan-based ILI as currently performed, which suggests a potential for further optimization of drug dosing for UE ILI.

Authors
Beasley, GM; Sharma, K; Wong, J; Miller, M; Turley, RS; Lidsky, M; Masoud, M; Dewhirst, MW; Mosca, PJ; Zager, JS; Tyler, DS
MLA Citation
Beasley, GM, Sharma, K, Wong, J, Miller, M, Turley, RS, Lidsky, M, Masoud, M, Dewhirst, MW, Mosca, PJ, Zager, JS, and Tyler, DS. "A multi-institution experience comparing the clinical and physiologic differences between upper extremity and lower extremity melphalan-based isolated limb infusion." Cancer 118.24 (December 15, 2012): 6136-6143.
PMID
22674423
Source
pubmed
Published In
Cancer
Volume
118
Issue
24
Publish Date
2012
Start Page
6136
End Page
6143
DOI
10.1002/cncr.27676

A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity.

BACKGROUND: Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. METHODS: A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. RESULTS: A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. CONCLUSION: This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

Authors
Beasley, GM; Coleman, AP; Raymond, A; Sanders, G; Selim, MA; Peterson, BL; Brady, MS; Davies, MA; Augustine, C; Tyler, DS
MLA Citation
Beasley, GM, Coleman, AP, Raymond, A, Sanders, G, Selim, MA, Peterson, BL, Brady, MS, Davies, MA, Augustine, C, and Tyler, DS. "A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity." Ann Surg Oncol 19.12 (November 2012): 3896-3905.
PMID
22549288
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
19
Issue
12
Publish Date
2012
Start Page
3896
End Page
3905
DOI
10.1245/s10434-012-2373-8

A multicenter prospective evaluation of the clinical utility of F-18 FDG-PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma.

OBJECTIVE/BACKGROUND: There is a high risk of relapse in stage IIIB/IIIC melanoma. The utility of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose positron emission tomography integrated with computed tomography (FDG-PET/CT) in these patients to evaluate response to treatment or for surveillance after treatment is currently not well defined. METHODS: Prospective data from 2 centers identified 97 patients with stage IIIB/IIIC extremity melanoma undergoing isolated limb infusion (ILI) who had whole body FDG-PET/CT scans before and every 3 months after treatment. Clinical response was determined at 3 months by Response Evaluation Criteria In Solid Tumors. RESULTS: Complete response (CR) after ILI occurred in 33% (32/97) of patients. FDG-PET/CT accurately identified 59% of patients who were CRs (19/32), whereas 41% (13/32) had residual metabolic activity in the extremity that was histologically negative for melanoma. The 3-year disease-free rate was 62.2% (95% CI: 40.1%-96.4%) for those patients who were CRs by both clinical/pathologic examination and FDG-PET/CT (n = 19) compared to only 29.4% (95% CI: 9.9%-87.2%) of those CRs who still had residual FDG-PET/CT activity (n = 13). FDG-PET/CT was utilized for surveillance of disease recurrence outside the regional field of treatment. Fifty-two percent (51/97) of patients developed disease outside the extremity at a median time of 212 days from pre-ILI FDG-PET/CT. In 47% (29/62) of these cases, the recurrence was resected. CONCLUSIONS: Although FDG-PET/CT does not appear to accurately identify patients who appear to be CRs to ILI, it does appear to identify a subgroup of patients whose regional progression-free survival is markedly worse. However, FDG-PET/CT appears to be an excellent method for surveillance in stage IIIB/IIIC patients after ILI with ability to identify surgically resectable recurrent disease in these high-risk patients.

Authors
Beasley, GM; Parsons, C; Broadwater, G; Selim, MA; Marzban, S; Abernethy, AP; Salama, AKS; Eikman, EA; Wong, T; Zager, JS; Tyler, DS
MLA Citation
Beasley, GM, Parsons, C, Broadwater, G, Selim, MA, Marzban, S, Abernethy, AP, Salama, AKS, Eikman, EA, Wong, T, Zager, JS, and Tyler, DS. "A multicenter prospective evaluation of the clinical utility of F-18 FDG-PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma." Ann Surg 256.2 (August 2012): 350-356.
PMID
22691370
Source
pubmed
Published In
Annals of Surgery
Volume
256
Issue
2
Publish Date
2012
Start Page
350
End Page
356
DOI
10.1097/SLA.0b013e318256d1f5

Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma.

PURPOSE: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). EXPERIMENTAL DESIGN: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. RESULTS: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. CONCLUSIONS: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.

Authors
Turley, RS; Fontanella, AN; Padussis, JC; Toshimitsu, H; Tokuhisa, Y; Cho, EH; Hanna, G; Beasley, GM; Augustine, CK; Dewhirst, MW; Tyler, DS
MLA Citation
Turley, RS, Fontanella, AN, Padussis, JC, Toshimitsu, H, Tokuhisa, Y, Cho, EH, Hanna, G, Beasley, GM, Augustine, CK, Dewhirst, MW, and Tyler, DS. "Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma." Clin Cancer Res 18.12 (June 15, 2012): 3328-3339.
PMID
22496203
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
12
Publish Date
2012
Start Page
3328
End Page
3339
DOI
10.1158/1078-0432.CCR-11-3000

Correction

MLA Citation
"Correction." Journal of the American College of Surgeons 214.2 (February 2012): 245-245.
Source
crossref
Published In
Journal of The American College of Surgeons
Volume
214
Issue
2
Publish Date
2012
Start Page
245
End Page
245
DOI
10.1016/j.jamcollsurg.2011.10.013

Patterns of recurrence following complete response to regional chemotherapy for in-transit melanoma

Background: Even after complete response (CR) to regional chemotherapy for in-transit melanoma, many patients develop recurrence. Understanding the probability, location, and timing of recurrences can optimize management strategies for this patient population. Methods: A prospective database identified patients who underwent 81 first-time hyperthermic isolated limb perfusions (HILPs) and 133 first-time isolated limb infusions (ILIs). Response was defined using the response evaluation criteria in solid tumors; recurrence was defined as development of new disease after in-field CR. Results: HILP exhibited a significantly higher CR rate than ILI (44 vs. 28 %, p = .01). Among 36 HILP-CRs and 37 ILI-CRs, the 3-year recurrence rate was 65 % (95 % confidence interval [95 % CI]: 43-79 %) and 85 % (95 % CI: 63-94%), respectively. Median time to first recurrence was longer for HILP-CR than ILI-CR (23 vs. 8 months, p = .02). There was no statistically significant difference in median time to in-field recurrence between HILP-CR and ILI-CR (46 vs. 25 months, p = .15), but HILP-CR showed a longer median time to out-of-field recurrence (42 vs. 14 months, p = .02). Finally, the overall survival (OS) difference between HILP-CR and ILI-CR (3-year survival: 77 vs. 54 %) did not achieve statistical significance (p = .10). Conclusions: In the largest series comparing patterns of recurrence, we demonstrate that out-of-field recurrence after CR to HILP occurs later than after CR to ILI, though control of in-field disease remains similar. There remains no statistically significant difference in overall survival after CR to the 2 procedures. © 2012 Society of Surgical Oncology.

Authors
Sharma, K; Beasley, G; Turley, R; Raymond, AK; Broadwater, G; Peterson, B; Mosca, P; Tyler, D
MLA Citation
Sharma, K, Beasley, G, Turley, R, Raymond, AK, Broadwater, G, Peterson, B, Mosca, P, and Tyler, D. "Patterns of recurrence following complete response to regional chemotherapy for in-transit melanoma." Annals of Surgical Oncology 19.8 (2012): 2563-2571.
PMID
22476748
Source
scival
Published In
Annals of Surgical Oncology
Volume
19
Issue
8
Publish Date
2012
Start Page
2563
End Page
2571
DOI
10.1245/s10434-012-2315-5

A multi-institutional experience of repeat regional chemotherapy for recurrent melanoma of extremities

Background. Hyperthermic isolated limb perfusion (HILP) or isolated limb infusion (ILI) are well-accepted regional chemotherapy techniques for in-transit melanoma of extremity. The role and efficacy of repeat regional chemotherapy for recurrence and which salvage procedure is better remains debatable. We aimed to compare toxicities and clinical outcomes by procedure types and the sequence. Methods. Data from 44 patients, who underwent repeat HILPs or ILIs from 3 institutions beginning 1997 to 2010, were retrospectively reviewed. Regional toxicity assessed by Wieberdink grade, systemic toxicity assessed by serum creatine phosphokinase level, length of hospital stay (LOS), response rates at 3 months after the procedure, and time to in-field progression (TTP) were analyzed. Results. Of 44 patients, 46% were men and 54% women with a median age of 66 (range 29-85) years at diagnosis. The median follow-up was 21.4 (range 4-153) months. Of 70 ILIs and 28 HILPs, the following groups were identified: group A, ILI → ILI (n = 25); group B, ILI → HILP (n = 10); group C, HILP → ILI (n = 12); and group D, HILP → HILP (n = 3). The comparison of Wieberdink grade, serum creatine phosphokinase level, LOS, and response rate between procedures (HILP vs. ILI), between sequence (initial vs. repeat), and among their interactions showed no statistically significant differences. TTP after initial procedure did not differ between HILP and ILI (P = 0.08), and no survival difference was seen (P = 0.65) when TTP after repeat procedure was compared. Conclusions. Most patients tolerated repeat regional chemotherapy without increased toxicity or LOS. No statistical difference in clinical outcomes was noted when comparing repeat procedures, even though repeat HILPs showed higher complete response compared to repeat ILIs. © Society of Surgical Oncology 2011.

Authors
Chai, CY; Deneve, JL; Beasley, GM; Marzban, SS; Chen, YA; Rawal, B; Grobmyer, SR; Hochwald, SN; Tyler, DS; Zager, JS
MLA Citation
Chai, CY, Deneve, JL, Beasley, GM, Marzban, SS, Chen, YA, Rawal, B, Grobmyer, SR, Hochwald, SN, Tyler, DS, and Zager, JS. "A multi-institutional experience of repeat regional chemotherapy for recurrent melanoma of extremities." Annals of Surgical Oncology 19.5 (2012): 1637-1643.
PMID
22143576
Source
scival
Published In
Annals of Surgical Oncology
Volume
19
Issue
5
Publish Date
2012
Start Page
1637
End Page
1643
DOI
10.1245/s10434-011-2151-z

Treatment of in-transit melanoma: an opportunity to discover critical knowledge.

Authors
Beasley, GM; Tyler, DS
MLA Citation
Beasley, GM, and Tyler, DS. "Treatment of in-transit melanoma: an opportunity to discover critical knowledge." Oncology (Williston Park) 25.14 (December 2011): 1351-1355.
PMID
22329186
Source
pubmed
Published In
Oncology
Volume
25
Issue
14
Publish Date
2011
Start Page
1351
End Page
1355

Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are used to manage advanced extremity melanoma, but no consensus exists as to which treatment is preferable and how to monitor patients post-treatment. STUDY DESIGN: Using a prospectively maintained database, we reviewed our experience with melphalan-based HILP (which included 62 first-time and 10 second-time) and ILI (which included 126 first-time and 18 second-time) procedures performed in 188 patients. PET/CT was obtained 3 months postregional treatment for 1 year and then every 6 months thereafter. RESULTS: Overall response rate (complete response [CR] + partial response) of HILP was 81% (80% CI, 73-87%), and overall response rate from ILI was 43% (80% CI, 37-49%) for first-time procedures only. HILP had a CR rate of 55% with a median duration of 32 months, and ILI had a CR rate of 30% with median duration of 24 months. Patients who experienced a regional recurrence after initial regional treatment were more likely to achieve a CR after repeat HILP (50%, n = 10) compared with repeat ILI (28%, n = 18). Although the spectrum of toxicity was similar for ILI and HILP, the likelihood of rare catastrophic complication of limb loss was greater with HILP (2 of 62) than ILI (0 of 122). PET/CT was effective for surveillance after regional therapy to identify regional nodal and pulmonary disease that was not clinically evident, but often amenable to surgical resection (25 of 49; 51% of cases). In contrast, PET/CT was not effective at predicting complete response to treatment with an accuracy of only 50%. CONCLUSIONS: In the largest single-institution regional therapy series reported to date, we found that although ILI is effective and well-tolerated, HILP is a more definitive way to control advanced disease.

Authors
Raymond, AK; Beasley, GM; Broadwater, G; Augustine, CK; Padussis, JC; Turley, R; Peterson, B; Seigler, H; Pruitt, SK; Tyler, DS
MLA Citation
Raymond, AK, Beasley, GM, Broadwater, G, Augustine, CK, Padussis, JC, Turley, R, Peterson, B, Seigler, H, Pruitt, SK, and Tyler, DS. "Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution." J Am Coll Surg 213.2 (August 2011): 306-316.
PMID
21493111
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
213
Issue
2
Publish Date
2011
Start Page
306
End Page
316
DOI
10.1016/j.jamcollsurg.2011.03.013

Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma.

PURPOSE: Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. PATIENTS AND METHODS: Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). CONCLUSION: To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.

Authors
Beasley, GM; Riboh, JC; Augustine, CK; Zager, JS; Hochwald, SN; Grobmyer, SR; Peterson, B; Royal, R; Ross, MI; Tyler, DS
MLA Citation
Beasley, GM, Riboh, JC, Augustine, CK, Zager, JS, Hochwald, SN, Grobmyer, SR, Peterson, B, Royal, R, Ross, MI, and Tyler, DS. "Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma." J Clin Oncol 29.9 (March 20, 2011): 1210-1215.
PMID
21343562
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
9
Publish Date
2011
Start Page
1210
End Page
1215
DOI
10.1200/JCO.2010.32.1224

Minimally invasive intra-arterial regional therapy for metastatic melanoma: Isolated limb infusion and percutaneous hepatic perfusion

Introduction: In-transit melanoma or melanoma presenting as unresectable liver metastases are clinical situations with limited therapeutic options. Regional intra-arterial therapies provide efficacious treatment alternatives for these patients. Through surgical techniques of vascular isolation, regional therapies deliver high-dose chemotherapy to tumor cells while minimizing systemic exposure. However, percutaneous techniques such as isolated limb infusion (ILI) and percutaneous hepatic perfusion (PHP) have been developed, which provide a minimally invasive means of obtaining vascular isolation of target organs. Areas covered: Areas covered in this review include the techniques of ILI and PHP, the chemotherapeutic agents utilized during these regional therapies and the clinical responses seen after ILI and PHP. The pharmacokinetics of regional chemotherapy utilized during ILI and PHP is also reviewed with an additional focus on novel ways to optimize drug delivery to improve response rates and attempts to define the potential systemic manifestations of regional therapeutics. Expert opinion: Unresectable hepatic and limb in-transit metastases from melanoma are very difficult to treat. Systemic chemotherapy has largely been ineffective. Both the minimally invasive, percutaneous techniques of ILI and PHP are excellent methods used to deliver extremely high-dose chemotherapy regionally to patients harboring metastatic melanoma confined to an extremity or liver, respectively. Studies, from prospectively maintained databases as well as Phase II and III trials, have shown the great efficacy of these techniques. © 2011 Informa UK, Ltd.

Authors
Han, D; Beasley, GM; Tyler, DS; Zager, JS
MLA Citation
Han, D, Beasley, GM, Tyler, DS, and Zager, JS. "Minimally invasive intra-arterial regional therapy for metastatic melanoma: Isolated limb infusion and percutaneous hepatic perfusion." Expert Opinion on Drug Metabolism and Toxicology 7.11 (2011): 1383-1394.
PMID
21978383
Source
scival
Published In
Expert Opinion on Drug Metabolism & Toxicology
Volume
7
Issue
11
Publish Date
2011
Start Page
1383
End Page
1394
DOI
10.1517/17425255.2011.609555

Standardizing regional therapy: Developing a consensus on optimal utilization of regional chemotherapy treatments in Melanoma

Authors
Beasley, GM; Tyler, DS
MLA Citation
Beasley, GM, and Tyler, DS. "Standardizing regional therapy: Developing a consensus on optimal utilization of regional chemotherapy treatments in Melanoma." Annals of Surgical Oncology 18.7 (2011): 1814-1818.
PMID
21416154
Source
scival
Published In
Annals of Surgical Oncology
Volume
18
Issue
7
Publish Date
2011
Start Page
1814
End Page
1818
DOI
10.1245/s10434-011-1656-9

Limb preservation with isolated limb infusion for locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms

Objective: To demonstrate the efficacy of isolated limb infusion (ILI) in limb preservation for patients with locally advanced soft-tissue sarcomas and nonmelanoma cutaneous malignant neoplasms. Background: Locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms, including softtissue sarcomas of the extremities, can pose significant treatment challenges. We report our experience, including responses and limb preservation rates, using ILI in cutaneous and soft-tissue malignant neoplasms. Methods: We identified 22 patients with cutaneous and soft-tissue malignant neoplasms who underwent 26 ILIs with melphalan and dactinomycin from January 1, 2004, through December 31, 2009, from 5 institutions. Outcome measures included limb preservation and in-field response rates. Regional toxic effects were measured using the Wieberdink scale and serum creatinine phosphokinase levels. Results: The median age was 70 years (range, 19-92 years), and 12 patients (55%) were women. Fourteen patients (64%) had sarcomas, 7 (32%) had Merkel cell carcinoma, and 1 (5%) had squamous cell carcinoma. The median length of stay was 5.5 days (interquartile range, 4-8 days). Twenty-five of the 26 ILIs (96%) resulted in Wieberdink grade III or less toxicity, and 1 patient (4%) developed grade IV toxicity. The median serum creatinine phosphokinase level was 127 U/L for upper extremity ILIs and 93 U/L for lower extremity ILIs. Nineteen of 22 patients (86%) underwent successful limb preservation. The 3-month in-field response rate was 79% (21% complete and 58% partial), and the median follow-up was 8.6 months (range, 1-63 months). Five patients underwent resection of disease after an ILI, of whom 80% are disease free at a median of 8.6 months. Conclusions: Isolated limb infusion provides an attractive alternative therapy for regional disease control and limb preservation in patients with limb-threatening cutaneous and soft-tissue malignant neoplasms. Short-term response rates appear encouraging, yet durability of response is unknown. ©2011 American Medical Association. All rights reserved.

Authors
Turaga, KK; Beasley, GM; III, JMK; Delman, KA; Grobmyer, SR; Gonzalez, RJ; Letson, GD; Cheong, D; Tyler, DS; Zager, JS
MLA Citation
Turaga, KK, Beasley, GM, III, JMK, Delman, KA, Grobmyer, SR, Gonzalez, RJ, Letson, GD, Cheong, D, Tyler, DS, and Zager, JS. "Limb preservation with isolated limb infusion for locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms." Archives of Surgery 146.7 (2011): 870-875.
PMID
21768436
Source
scival
Published In
Archives of Surgery
Volume
146
Issue
7
Publish Date
2011
Start Page
870
End Page
875
DOI
10.1001/archsurg.2011.139

Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy.

Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

Authors
Augustine, CK; Toshimitsu, H; Jung, S-H; Zipfel, PA; Yoo, JS; Yoshimoto, Y; Selim, MA; Burchette, J; Beasley, GM; McMahon, N; Padussis, J; Pruitt, SK; Ali-Osman, F; Tyler, DS
MLA Citation
Augustine, CK, Toshimitsu, H, Jung, S-H, Zipfel, PA, Yoo, JS, Yoshimoto, Y, Selim, MA, Burchette, J, Beasley, GM, McMahon, N, Padussis, J, Pruitt, SK, Ali-Osman, F, and Tyler, DS. "Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy." Mol Cancer Ther 9.7 (July 2010): 2090-2101.
PMID
20571072
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
9
Issue
7
Publish Date
2010
Start Page
2090
End Page
2101
DOI
10.1158/1535-7163.MCT-10-0073

What's new in neoadjuvant therapy for breast cancer?

Neoadjuvant treatment of breast cancer is currently being used in patients with advanced disease as well as with increasing application in those that present with initially operable breast cancer. The current clinical benefits of the use of NAC include: NAC increases the possibility of the use of BCS, the safety of NAC is comparable with that of adjuvant chemotherapy, and pCR may be predictive of overall survival. Although there are still unresolved clinical questions regarding the use of neoadjuvant therapy in initially operable breast cancer, there appears to be equivalent survival to the standard of care. Future research should be aimed at tailoring treatment to individual patients using specific tumor characteristics that may predict response to different types of chemotherapy, molecular targeted therapy, and endocrine therapy.

Authors
Beasley, GM; Olson, JA
MLA Citation
Beasley, GM, and Olson, JA. What's new in neoadjuvant therapy for breast cancer?. January 2010.
PMID
20919523
Source
epmc
Volume
44
Publish Date
2010
Start Page
199
End Page
228
DOI
10.1016/j.yasu.2010.05.013

Optimizing regional infusion treatment strategies for melanoma of the extremities.

The incidence of malignant melanoma is increasing faster than any other cancer. In cases of recurrent melanoma confined to the extremities, hyperthermic isolated limb perfusion and isolated limb infusion provide a way to isolate the extremity and deliver a dose of chemotherapy several orders of magnitude higher than would be tolerated systemically. Although complete response rates of up to 80% for hyperthermic isolated limb perfusion and 44% for isolated limb infusion have been observed, there is still room for improvement and standardization in these two procedures in an attempt to optimize response while minimizing toxicity. Currently, new chemotherapy agents and small-molecule inhibitors are being investigated as a means of overcoming chemoresistance and improving response rates. In patients with advanced cutaneous disease confined to the extremities, evaluation of these new therapies can be very informative, as tissue acquisition at multiple treatment time points is easy owing to the superficial and multifocal nature of the disease. Through studying the biomolecular and genetic alterations in tumor tissue in response to these new therapies, genetically customized treatment regimens in which tumor resistance and sensitivity is predicted and treatment strategy is optimized before treatment begins may soon be available. Progress in regional therapy will prove not only beneficial for patients with disease confined to an extremity, but may also provide insight into developing novel treatment strategies for patients with systemic disease for whom current disease management options are poor.

Authors
Coleman, A; Augustine, CK; Beasley, G; Sanders, G; Tyler, D
MLA Citation
Coleman, A, Augustine, CK, Beasley, G, Sanders, G, and Tyler, D. "Optimizing regional infusion treatment strategies for melanoma of the extremities." Expert Rev Anticancer Ther 9.11 (November 2009): 1599-1609. (Review)
PMID
19895244
Source
pubmed
Published In
Expert Review of Anticancer Therapy
Volume
9
Issue
11
Publish Date
2009
Start Page
1599
End Page
1609
DOI
10.1586/era.09.126

A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma.

BACKGROUND: Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed. METHODS: Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. RESULTS: Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n=14) and pain (n=12). Grade 3 toxicities included shortness of breath (n=1), hypertension (n=1), serologic toxicities (n=4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels. CONCLUSIONS: Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.

Authors
Beasley, GM; McMahon, N; Sanders, G; Augustine, CK; Selim, MA; Peterson, B; Norris, R; Peters, WP; Ross, MI; Tyler, DS
MLA Citation
Beasley, GM, McMahon, N, Sanders, G, Augustine, CK, Selim, MA, Peterson, B, Norris, R, Peters, WP, Ross, MI, and Tyler, DS. "A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma." Cancer 115.20 (October 15, 2009): 4766-4774.
PMID
19637344
Source
pubmed
Published In
Cancer
Volume
115
Issue
20
Publish Date
2009
Start Page
4766
End Page
4774
DOI
10.1002/cncr.24509

Predictive factors of regional toxicity and serum creatine phosphokinase levels after isolated limb infusion for melanoma: a multi-institutional analysis.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive technique delivering regional chemotherapy to treat in-transit extremity melanoma. Determining perioperative factors that could predict toxicity is important to optimize strategies to improve clinical outcomes after regional chemotherapy in melanoma. METHODS: Perioperative factors from 171 ILI patients performed at eight centers from 2001 to 2008 were reviewed. The Wieberdink limb toxicity scale and creatine phosphokinase (CK) levels were used to measure toxicity. Logistic regression analysis was used to estimate the association between toxicity and perioperative parameters. RESULTS: Mild (grades I-II) and severe (grades >or=III) limb toxicity developed in 68% and 32% of patients, respectively. Melphalan adjusted for ideal body weight (aIBW) and papaverine were used in 47% and 63% of patients, respectively. Median peak CK for all patients was 563 U/l, and median peak occurred at postoperative day 4. On univariate analysis, papaverine and high CK levels (>563 U/l) were significantly associated with higher toxicity. On the contrary, aIBW was significantly associated with a lower risk of severe toxicity. Perfusate blood gas at 30 min [pH, PaO(2), and base excess (BE) ], limb temperature, and ischemia time were not predictive of limb toxicity. On multivariate analysis, severe toxicity was associated with female sex (P = 0.01), papaverine (P = 0.01), and high peak CK levels (P < 0.01). Independent predictors of high CK levels included younger age, unadjusted melphalan dose, and low PaO(2) at 30 min. CONCLUSIONS: ILI can be performed with an acceptable morbidity. Papaverine use, female gender, and high peak CK were associated with higher limb toxicity. CK levels can be diminished significantly with aIBW.

Authors
Santillan, AA; Delman, KA; Beasley, GM; Mosca, PJ; Hochwald, SN; Grobmyer, SR; Andtbacka, RH; Noyes, RD; Kane, JM; Ross, MI; Tyler, DS; Zager, JS
MLA Citation
Santillan, AA, Delman, KA, Beasley, GM, Mosca, PJ, Hochwald, SN, Grobmyer, SR, Andtbacka, RH, Noyes, RD, Kane, JM, Ross, MI, Tyler, DS, and Zager, JS. "Predictive factors of regional toxicity and serum creatine phosphokinase levels after isolated limb infusion for melanoma: a multi-institutional analysis." Ann Surg Oncol 16.9 (September 2009): 2570-2578.
PMID
19543771
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
16
Issue
9
Publish Date
2009
Start Page
2570
End Page
2578
DOI
10.1245/s10434-009-0563-9

Surgical excision of infected arteriovenous grafts: technique and review.

Infected prosthetic arteriovenous grafts for hemodialysis present a profound risk to patient well being. Here we present five recent cases and describe our technique for total graft excision. We also review the literature and discuss the much debated role of partial, subtotal, and total graft excision.

Authors
Ceppa, EP; Sileshi, B; Beasley, GM; Lawson, JH
MLA Citation
Ceppa, EP, Sileshi, B, Beasley, GM, and Lawson, JH. "Surgical excision of infected arteriovenous grafts: technique and review." The journal of vascular access 10.3 (July 2009): 148-152. (Review)
PMID
19670165
Source
epmc
Published In
The journal of vascular access
Volume
10
Issue
3
Publish Date
2009
Start Page
148
End Page
152

Optimizing regional therapy for melanoma.

Authors
Beasley, GM; Tyler, DS
MLA Citation
Beasley, GM, and Tyler, DS. "Optimizing regional therapy for melanoma." Ann Surg Oncol 16.5 (May 2009): 1095-1097.
PMID
19189189
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
16
Issue
5
Publish Date
2009
Start Page
1095
End Page
1097
DOI
10.1245/s10434-009-0329-4

A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive approach for treating in-transit extremity melanoma, with only two US single-center studies reported. Establishing response and toxicity to ILI as compared with hyperthermic isolated limb perfusion is important for optimizing future regional chemotherapeutic strategies in melanoma. STUDY DESIGN: Patient characteristics and procedural variables were collected retrospectively from 162 ILIs performed at 8 institutions (2001 to 2008) and compared using chi-square and Student's t-test. ILIs were performed for 30 minutes in patients with in-transit melanoma. Melphalan dose was corrected for ideal body weight (IBW) in 42% (n = 68) of procedures. Response was determined at 3 months by Response Evaluation Criteria in Solid Tumors; toxicity was assessed using the Wieberdink Limb Toxicity Scale. RESULTS: In 128 evaluable patients, complete response rate was 31%, partial response rate was 33%, and there was no response in 36% of patients. For all patients (n = 162), 36% had Wieberdink toxicity grade >or=3 with one toxicity-related amputation. On multivariate analysis, smaller limb volumes were associated with better overall response (p = 0.021). Use of papaverine in the circuit to achieve cutaneous vasodilation was associated with better response (p < 0.001) but higher risk of grade >or=3 toxicity (p = 0.001). Correction of melphalan dose for ideal body weight did not alter complete response (p = 0.345), but did lead to marked reduction in toxicity (p < 0.001). CONCLUSIONS: In the first multi-institutional analysis of ILI, a complete response rate of 31% was achieved with acceptable toxicity demonstrating this procedure to be a reasonable alternative to hyperthermic isolated limb perfusion in the management of advanced extremity melanoma.

Authors
Beasley, GM; Caudle, A; Petersen, RP; McMahon, NS; Padussis, J; Mosca, PJ; Zager, JS; Hochwald, SN; Grobmyer, SR; Delman, KA; Andtbacka, RH; Noyes, RD; Kane, JM; Seigler, H; Pruitt, SK; Ross, MI; Tyler, DS
MLA Citation
Beasley, GM, Caudle, A, Petersen, RP, McMahon, NS, Padussis, J, Mosca, PJ, Zager, JS, Hochwald, SN, Grobmyer, SR, Delman, KA, Andtbacka, RH, Noyes, RD, Kane, JM, Seigler, H, Pruitt, SK, Ross, MI, and Tyler, DS. "A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US." J Am Coll Surg 208.5 (May 2009): 706-715.
PMID
19476821
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
208
Issue
5
Publish Date
2009
Start Page
706
End Page
715
DOI
10.1016/j.jamcollsurg.2008.12.019

Optimizing melphalan pharmacokinetics in regional melanoma therapy: does correcting for ideal body weight alter regional response or toxicity?

BACKGROUND: This study aims to determine what effect correcting melphalan dosing for ideal body weight (IBW) has on toxicity and response in isolated limb infusion (ILI) in patients with advanced extremity melanoma. METHODS: This was an open observational study examining whether correcting the melphalan dose for IBW will influence response and toxicity in patients undergoing ILI for advanced extremity melanoma in 41 patients undergoing 42 procedures (13 without correction for IBW; and 29 with correction for IBW). Melphalan pharmacokinetics, limb toxicity, serologic toxicity, and response at 3 months were compared. RESULTS: The corrected group had a lower estimated limb volume (V (esti)) to melphalan volume at steady state (V (ss)) (P < .0001) ratio as well as lower incidence of grade > or =3 regional toxicity, serologic toxicity, and compartment syndrome (P = .0249, P = .027, P = .02). There was a positive correlation of V (esti)/V (ss) to toxicity (P = .0127, r = .382). No significant difference in response (P = .3609) between the groups was found, although there was a trend of association between V (esti)/V (ss) and response (P = .051, r = .3383). CONCLUSIONS: Correcting for IBW in ILI lowers toxicity without significantly altering response rates.

Authors
McMahon, N; Cheng, TY; Beasley, GM; Spasojevic, I; Petros, W; Augustine, CK; Zipfel, P; Padussis, JC; Sanders, G; Tyler, DS
MLA Citation
McMahon, N, Cheng, TY, Beasley, GM, Spasojevic, I, Petros, W, Augustine, CK, Zipfel, P, Padussis, JC, Sanders, G, and Tyler, DS. "Optimizing melphalan pharmacokinetics in regional melanoma therapy: does correcting for ideal body weight alter regional response or toxicity?." Ann Surg Oncol 16.4 (April 2009): 953-961.
PMID
19184236
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
16
Issue
4
Publish Date
2009
Start Page
953
End Page
961
DOI
10.1245/s10434-008-0288-1

Current clinical and research approaches to optimizing regional chemotherapy: novel strategies generated through a better understanding of drug pharmacokinetics, drug resistance, and the development of clinically relevant animal models.

A common treatment modality for in transit melanoma of the extremity has been hyperthermic isolated limb perfusion (HILP) with melphalan and more recently, isolated limb infusion (ILI) with melphalan with or without dactinomycin. Research in the area has primarily focused on maximizing drug delivery through a better understanding of pharmacokinetics while maintaining acceptable levels of toxicity. Although other agents continue to be explored as regional chemotherapy agents, melphalan is currently the drug of choice, although temozolomide has demonstrated promising preclinical results. Resistance mechanisms to melphalan and melphalan pharmacokinetics are studied using animal models of HILP and ILI. The addition of modulators to overcome resistance to the traditional chemotherapy regimen may ultimately improve the clinical response in patients with in-transit melanoma of the extremity.

Authors
Beasley, GM; Kahn, L; Tyler, DS
MLA Citation
Beasley, GM, Kahn, L, and Tyler, DS. "Current clinical and research approaches to optimizing regional chemotherapy: novel strategies generated through a better understanding of drug pharmacokinetics, drug resistance, and the development of clinically relevant animal models." Surg Oncol Clin N Am 17.4 (October 2008): 731-viii. (Review)
PMID
18722915
Source
pubmed
Published In
Surgical Oncology Clinics of North America
Volume
17
Issue
4
Publish Date
2008
Start Page
731
End Page
viii
DOI
10.1016/j.soc.2008.04.002

Isolated limb infusion for in-transit malignant melanoma of the extremity: a well-tolerated but less effective alternative to hyperthermic isolated limb perfusion.

BACKGROUND: Isolated limb infusion (ILI) is a recently described minimally invasive technique developed in Australia for delivering regional chemotherapy. This study examined the efficacy and toxicity of ILI, compared to hyperthermic isolated limb perfusion (HILP), in treating extremity in-transit melanoma. METHODS: Variables from a prospective single institution database of 120 regionally treated melanoma patients (1995-2007) were compared using chi-square analysis. This included 61 consecutive ILI treatments in 58 patients and 59 HILP treatments in 54 patients. Response was defined at 3 months using the response evaluation criteria in solid tumors (RECIST). ILI was performed using melphalan (LPAM) and dactinomycin for 30 min after limb temperature reached 37 degrees C. HILP was performed using LPAM for 60 min after limb temperature reached 38.5 degrees C. RESULTS: For ILI (n = 61), the complete response (CR) rate was 30%, the partial response (PR) rate was 14%, and there was no response (NR) in 56% of patients. The median duration of CR was 12 months and 18% of patients experienced (grade >or=3) toxicity. HILP (n = 59) was associated with a better (P < 0.001) response rate (CR 57%, PR 31%, and NR 12%) however, more patients (32%) experienced grade >or=3 toxicity (P = 0.037). The dose of LPAM was corrected for ideal body weight (IBW) in 40 out of 61 ILI procedures, and 13 of 59 HILP procedures. This dosing modification was associated with decreased toxicity (P = 0.024) without diminishing response. CONCLUSION: ILI was found to be a well-tolerated alternative to HILP. While ILI does not appear to be as effective as HILP, it does seem to be associated with less morbidity.

Authors
Beasley, GM; Petersen, RP; Yoo, J; McMahon, N; Aloia, T; Petros, W; Sanders, G; Cheng, T-Y; Pruitt, SK; Seigler, H; Tyler, DS
MLA Citation
Beasley, GM, Petersen, RP, Yoo, J, McMahon, N, Aloia, T, Petros, W, Sanders, G, Cheng, T-Y, Pruitt, SK, Seigler, H, and Tyler, DS. "Isolated limb infusion for in-transit malignant melanoma of the extremity: a well-tolerated but less effective alternative to hyperthermic isolated limb perfusion." Ann Surg Oncol 15.8 (August 2008): 2195-2205.
PMID
18528730
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
15
Issue
8
Publish Date
2008
Start Page
2195
End Page
2205
DOI
10.1245/s10434-008-9988-9

Future directions in regional treatment strategies for melanoma and sarcoma.

Hyperthermic isolated limb perfusion (HILP) with melphalan and more recently isolated limb infusion (ILI) with melphalan +/- dactinomycin are common treatment modalities for both in-transit melanoma of the extremity and advanced extremity sarcoma. In order to further optimize treatment, future research should focus on selection of appropriate patients, verification of a technique that produces consistent results while maintaining acceptable toxicity, and development of novel strategies and agents. Development of these novel agents and strategies has potential to not only improve the efficacy of regional chemotherapy but may also help guide future strategies for systemic treatment.

Authors
Beasley, GM; Ross, MI; Tyler, DS
MLA Citation
Beasley, GM, Ross, MI, and Tyler, DS. "Future directions in regional treatment strategies for melanoma and sarcoma." Int J Hyperthermia 24.3 (May 2008): 301-309. (Review)
PMID
18393007
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
24
Issue
3
Publish Date
2008
Start Page
301
End Page
309
DOI
10.1080/02656730701827573
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