Assessing the Potential for Patient-led Surveillance After Treatment of Localized Melanoma (MEL-SELF): A Pilot Randomized Clinical Trial.

IMPORTANCE: Patient-led surveillance is a promising new model of follow-up care following excision of localized melanoma. OBJECTIVE: To determine whether patient-led surveillance in patients with prior localized primary cutaneous melanoma is as safe, feasible, and acceptable as clinician-led surveillance. DESIGN, SETTING, AND PARTICIPANTS: This was a pilot for a randomized clinical trial at 2 specialist-led clinics in metropolitan Sydney, Australia, and a primary care skin cancer clinic managed by general practitioners in metropolitan Newcastle, Australia. The participants were 100 patients who had been treated for localized melanoma, owned a smartphone, had a partner to assist with skin self-examination (SSE), and had been routinely attending scheduled follow-up visits. The study was conducted from November 1, 2018, to January 17, 2020, with analysis performed from September 1, 2020, to November 15, 2020. INTERVENTION: Participants were randomized (1:1) to 6 months of patient-led surveillance (the intervention comprised usual care plus reminders to perform SSE, patient-performed dermoscopy, teledermatologist assessment, and fast-tracked unscheduled clinic visits) or clinician-led surveillance (the control was usual care). MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of eligible and contacted patients who were randomized. Secondary outcomes included patient-reported outcomes (eg, SSE knowledge, attitudes, and practices, psychological outcomes, other health care use) and clinical outcomes (eg, clinic visits, skin surgeries, subsequent new primary or recurrent melanoma). RESULTS: Of 326 patients who were eligible and contacted, 100 (31%) patients (mean [SD] age, 58.7 [12.0] years; 53 [53%] men) were randomized to patient-led (n = 49) or clinician-led (n = 51) surveillance. Data were available on patient-reported outcomes for 66 participants and on clinical outcomes for 100 participants. Compared with clinician-led surveillance, patient-led surveillance was associated with increased SSE frequency (odds ratio [OR], 3.5; 95% CI, 0.9 to 14.0) and thoroughness (OR, 2.2; 95% CI, 0.8 to 5.7), had no detectable adverse effect on psychological outcomes (fear of cancer recurrence subscale score; mean difference, -1.3; 95% CI, -3.1 to 0.5), and increased clinic visits (risk ratio [RR], 1.5; 95% CI, 1.1 to 2.1), skin lesion excisions (RR, 1.1; 95% CI, 0.6 to 2.0), and subsequent melanoma diagnoses and subsequent melanoma diagnoses (risk difference, 10%; 95% CI, -2% to 23%). New primary melanomas and 1 local recurrence were diagnosed in 8 (16%) of the participants in the intervention group, including 5 (10%) ahead of routinely scheduled visits; and in 3 (6%) of the participants in the control group, with none (0%) ahead of routinely scheduled visits (risk difference, 10%; 95% CI, 2% to 19%). CONCLUSIONS AND RELEVANCE: This pilot of a randomized clinical trial found that patient-led surveillance after treatment of localized melanoma appears to be safe, feasible, and acceptable. Experiences from this pilot study have prompted improvements to the trial processes for the larger trial of the same intervention. TRIAL REGISTRATION: http://anzctr.org.au Identifier: ACTRN12616001716459.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.

PURPOSE: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity. PATIENTS AND METHODS: Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496). RESULTS: The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model (P < .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%). CONCLUSION: A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au.

Normal Growth and Essential Fatty Acid Status in Children With Intestinal Failure on Lipid Limitation.

OBJECTIVES: Lipid limitation, that is, ≤1 g · kg⁻¹ · day⁻¹ of soy oil lipid emulsion (SOLE), has been suggested as a method to reduce the risk of intestinal failure (IF)-associated liver disease (IFALD). There are limited data as to the effects of this strategy on growth and essential fatty acid (EFA) status. The aim of the study was to assess growth, prevalence of cholestasis, and EFA deficiency in patients with IF who were provided daily SOLE at a dose ≤1 g · kg⁻¹ · day⁻¹. METHODS: Medical records were retrospectively reviewed from 9 patients age 16 months to 8 years who had IF requiring parenteral nutrition support for >12 months. Parenteral nutrition supplied a mean of 53% of total energy (range 24%-86%). RESULTS: Mean SOLE dose was 0.61 g · kg⁻¹ · day⁻¹ (range 0.4-0.81 g · kg⁻¹ · day⁻¹). After 1 month of lipid limitation between 2011 and 2014, no patient developed IFALD as defined by a direct bilirubin >2 mg/dL. The median direct bilirubin was 0.1 mg/dL (range 0.075-0.85 mg/dL). No patient developed EFA deficiency as defined by a triene-to-tetraene ratio >0.2 (median 0.026, range 0.017-0.076). Height z scores increased from mean of -2.568 (range -10.8 to 0.878) to -0.484 (range -3.546 to 0.822). Weight z scores increased from mean of -1.412 (range -5.871 to 0.906) to -0.595 (range -2.178 to 0.926). CONCLUSIONS: In this case series, lipid limitation allowed normal growth while preventing the development of cholestasis and EFA deficiency.

The Prognostic and Predictive Value of Melanoma-related MicroRNAs Using Tissue and Serum: A MicroRNA Expression Analysis.

The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are < 15%. Hence, melanoma detection in earlier stages (stages I-III) maximises the chances of patient survival. We measured the expression of a panel of 17 microRNAs (miRNAs) (MELmiR-17) in melanoma tissues (stage III; n = 76 and IV; n = 10) and serum samples (collected from controls with no melanoma, n = 130; and patients with melanoma (stages I/II, n = 86; III, n = 50; and IV, n = 119)) obtained from biobanks in Australia and Germany. In melanoma tissues, members of the 'MELmiR-17' panel were found to be predictors of stage, recurrence, and survival. Additionally, in a minimally-invasive blood test, a seven-miRNA panel (MELmiR-7) detected the presence of melanoma (relative to controls) with high sensitivity (93%) and specificity (≥ 82%) when ≥ 4 miRNAs were expressed. Moreover, the 'MELmiR-7' panel characterised overall survival of melanoma patients better than both serum LDH and S100B (delta log likelihood = 11, p < 0.001). This panel was found to be superior to currently used serological markers for melanoma progression, recurrence, and survival; and would be ideally suited to monitor tumour progression in patients diagnosed with early metastatic disease (stages IIIa-c/IV M1a-b) to detect relapse following surgical or adjuvant treatment.

Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma.

PURPOSE: This international, multicenter, single-arm trial assessed efficacy and safety of intralesional rose bengal (PV-10) in 80 patients with refractory cutaneous or subcutaneous metastatic melanoma. METHODS: Sixty-two stage III and 18 stage IV melanoma patients with disease refractory to a median of six prior interventions received intralesional PV-10 into up to 20 cutaneous and subcutaneous lesions up to four times over a 16-week period and were followed for 52 weeks. Objectives were to determine best overall response rate in injected target lesions and uninjected bystander lesions, assess durability of response, and characterize adverse events. RESULTS: For target lesions, the best overall response rate was 51 %, and the complete response rate was 26 %. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8 % of patients having no evidence of disease after 52 weeks. Response was dependent on untreated disease burden, with complete response achieved in 50 % of patients receiving PV-10 to all of their disease. Response of target lesions correlated with bystander lesion regression and the occurrence of locoregional blistering. Adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events. CONCLUSIONS: Intralesional PV-10 yielded durable local control with high rates of complete response. Toxicity was confined predominantly to the injection site. Cutaneous bystander tumor regression is consistent with an immunologic response secondary to ablation. This intralesional approach for local disease control could be complementary to current and investigational treatments for melanoma.

Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial (ANZMTG 02.09 Mel-D).

BACKGROUND: Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, >4 mm in thickness and those with nodal micrometastases at diagnosis, have few options for adjuvant treatment. Recent studies have suggested a role for vitamin D to delay melanoma recurrence and improve overall prognosis. METHODS/DESIGN: This is a pilot placebo-controlled randomised phase II trial to assess the feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients who have been treated for cutaneous melanoma by wide excision of the primary. Patients aged 18-79 years who have completed primary surgical treatment and have Stage IIb, IIc, IIIa (N1a, N2a) or IIIb (N1a, N2a) disease are eligible for randomisation 2:1 to active treatment or placebo. The primary endpoints are sufficiency of dose, adherence to study medication and safety of the drug. The secondary endpoints are participation and progression free survival. The study has been approved by the Ethics Review Committee (RPAH Zone) of the Sydney Local Health District, protocol number X09-0138. DISCUSSION: Effective, non-toxic adjuvant therapy for high risk primary melanoma is not currently available. Favorable outcomes of this phase II study will form the basis for a multi-centre phase III study to assess whether the addition of oral high-dose vitamin D therapy in patients who have completed primary treatment for melanoma and are at high risk of recurrence will: 1. prolong time to recurrence within 5 years 2. improve overall survival at 5 years and 3. be both safe and tolerable. 62 patients have been randomised since the study commenced in December 2010. Target accrual for the study has been met with 75 patients randomised between December 2010 and August 2014.The Mel-D trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG 02.09) TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000351213.

Treatment and prognostic significance of positive interval sentinel nodes in patients with primary cutaneous melanoma.

BACKGROUND: Interval sentinel nodes (SNs) are lymph nodes receiving direct lymphatic drainage from a primary site and lying between the tumor and a recognized node field. It is not clear what further nodal surgery should be performed when interval nodes are found to contain micrometastatic disease. In this study, the incidence, location, and treatment of interval SNs in melanoma patients were analyzed to develop recommendations regarding the treatment of patients with interval SNs. METHODS: A retrospective review was undertaken of all patients with primary cutaneous melanoma who underwent lymphoscintigraphy at a single institution between 1992 and 2007. Data concerning the primary melanoma, location of SNs, treatment and survival were analyzed. RESULTS: Of 4895 patients who had a lymphoscintigram during the study period, 442 (9.0%) had an interval SN identified on lymphoscintigraphy. Interval SNs occurred significantly more often in patients with melanomas on the posterior trunk than in those with melanomas at other sites (P<0.001). A total of 197 patients (44.6%) with an identified interval SN underwent excision biopsy of the node. Of the 16 patients found to have metastatic melanoma in their interval SN, four also had negative SNs in a recognized lymph node field, and no other positive nodes were found on completion lymphadenectomy. CONCLUSIONS: Interval SNs are present in approximately 1 in 10 melanoma patients but are about half as likely to contain metastases as SNs in recognized node fields. If a positive interval SN is found, completion lymphadenectomy of the recognized lymph node field is only recommended if a SN in this field is also positive.

Treatment of melanoma metastases in a limb by isolated limb perfusion and isolated limb infusion.

In-transit melanoma metastases are often confined to a limb. In this circumstance, treatment by isolated limb perfusion or isolated limb infusion can be a remarkably effective regional treatment option.

Isolated limb infusion with melphalan and actinomycin D in melanoma patients: factors predictive of acute regional toxicity.

IMPORTANCE OF THE FIELD: Isolated limb infusion (ILI) is a simple, minimally invasive technique of delivering high concentrations of cytotoxic drugs to a diseased limb for achieving disease control in that limb. Recent studies have suggested that mild hyperthermic (38 degrees C) ILI might be the best initial treatment for extensively recurrent limb melanoma given its simplicity, low morbidity and a complete response rate of 30 - 40%. AREAS COVERED IN THIS REVIEW: Since 1994 when ILI was first described by Thompson et al., the procedure has been adopted by several centres around the world; research and improvements in the technique have resulted in reduction in limb toxicity without reducing its clinical efficacy. The pharmacokinetics of melphalan and the clinical efficacy and adverse effects of ILI from various centres are summarised. Minor but possibly important differences in the ILI techniques used in different institutions may be important in improving its efficacy and reducing the toxic effects. WHAT THE READER WILL GAIN: An understanding of the efficacy and toxicity associated with ILI with cytotoxic drugs in melanoma patients and of methods to optimise regional therapy for malignant disease in a limb. TAKE HOME MESSAGE: ILI with mild hyperthermia (38 degrees C) is well tolerated with tumour remission rates in melanoma patients similar to those achieved by isolated limb perfusion. Mild (grade I - II) and moderate/severe (grade > or = III) limb toxicities occur in 58 - 68% and 32 - 41% of patients, respectively, but long-term morbidity is rare. A high peak and high final melphalan concentration in the infusate, the AUC of melphalan concentration in the infusate and an increased postoperative serum creatine phosphokinase concentration are factors predictive of acute regional toxicity. Drug dose adjusted for ideal body weight and gender may reduce acute toxicity following ILI. It has been suggested that the use of papaverine prior to the infusion of melphalan might increase its efficacy, but it may also increase toxicity. Large prospective studies are needed to more accurately define the perioperative factors that influence acute regional toxicity after ILI and to establish strategies to optimise clinical outcome.

Safety and efficacy of isolated limb infusion with cytotoxic drugs in elderly patients with advanced locoregional melanoma.

INTRODUCTION: The treatment of elderly patients with advanced metastatic melanoma confined to a limb remains controversial. Isolated limb infusion (ILI) is an effective minimally invasive alternative to isolated limb perfusion (ILP) and is therefore a potentially valuable therapeutic option for this group. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin-D was used. RESULTS: Eighty-six patients (46%) were >or=75 years of age (range: 75-93). The patient characteristics in both groups were comparable except that the older group comprised more women (71% vs. 54%; P = 0.02) and had a lower body mass index (median: 24.4 vs. 26.4; P = 0.008). Complete response rates were 34% for those >or=75 years and 41% in the younger group (P = 0.28). There was no difference in limb recurrence free interval after a complete response (median: 24 months for both groups; P = 0.51) or in survival (median: 36 months for <75, 39 months for >or=75; P = 0.36) between both groups. Older patients experienced less limb toxicity after the procedure (Wieberdink grade III/IV toxicity in 36%) compared with younger patients (51%; P = 0.009) while systemic toxicity, complications, and long-term morbidity were similar. CONCLUSIONS: Elderly patients with advanced metastatic melanoma of the limb experience the same or lower toxicity after ILI compared with younger patients while response rates, limb recurrence free interval, survival, and morbidity are similar. ILI is an attractive alternative to the more laborious ILP, especially for older patients.

Isolated limb infusion as palliative treatment for advanced limb disease in patients with AJCC stage IV melanoma.

INTRODUCTION: In the treatment of patients with advanced limb melanoma a major treatment dilemma can arise when distant metastases are present also. Isolated limb infusion (ILI) has proved to be a useful limb-saving treatment and could potentially be of palliative value in patients with American Joint Committee on Cancer (AJCC) stage IV melanoma. METHODS: We identified 37 patients with advanced symptomatic limb disease as well as documented distant metastases at the time of their ILI. In all patients a drug combination of melphalan and actinomycin D was used. RESULTS: Fifty one percent had visceral distant metastases and 49% had cutaneous distant metastases only. The overall response rate in the treated limb was 76% [complete response (CR) rate 22%, partial response (PR) rate 54%]. Median response duration was 11 months (28 months for patients with CR; p = 0.08). Median survival after CR was 22 months, 17 months after PR, and only 4 months for those with stable or progressive disease (p = 0.002). Patients with visceral distant metastases had a significantly decreased survival compared with those with cutaneous distant metastases only (8 and 21 months, respectively; p = 0.03). Limb salvage was achieved in 86% of the patients. The procedure was well tolerated, with only one patient developing Wieberdink grade IV toxicity (threatened/actual compartment syndrome) and none requiring amputation as a result of the procedure (grade V toxicity). CONCLUSIONS: Minimally invasive ILI can effectively be used as palliative treatment to provide local tumor control and limb salvage in stage IV melanoma patients with advanced, symptomatic limb disease.

Factors predictive of acute regional toxicity after isolated limb infusion with melphalan and actinomycin D in melanoma patients.

INTRODUCTION: Isolated limb infusion (ILI) with cytotoxic drugs is a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation to treat metastatic melanoma confined to a limb. Response rates and duration of response following ILI are similar to those after ILP. Previously we have shown that more significant limb toxicity is not associated with a higher response rate or improved patient outcome. In this study we sought to determine factors predicting toxicity following ILI. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin D was used. Drug circulation time was 20-30 min under mild hyperthermic conditions (38-39 degrees C). Limb toxicity was assessed using the Wieberdink scale. RESULTS: The average patient age was 74 years (range 29-93 years) and 62% were female. Most patients (134/185) had MD Anderson stage III disease (satellites and in-transit metastases). Toxicity grade I (no reaction) occurred in 3 patients, grade II (slight erythema and edema) in 105 patients, grade III (considerable erythema and edema +/- blistering) in 72 patients, and grade IV (threatened or actual compartment syndrome) in 5 patients. No patient developed grade V toxicity (requiring amputation). On univariate analysis high peak and high final melphalan concentrations were found to be predictive factors for grade III/IV limb toxicity as well as the area under the curve of the melphalan concentration. Surprisingly, a greater rise in the CO(2) level during the procedure was associated with lower toxicity in the univariate analysis. Increased serum creatine phosphokinase (CK) postoperatively was related to higher toxicity score. In the multivariate analysis high final melphalan concentration and shorter tourniquet time were independent predictive risk factors for developing grade III/IV limb toxicity. CONCLUSIONS: ILI is a safe alternative to the more invasive and laborious ILP technique to treat melanoma confined to a limb. Regional acute toxicity following ILI is mild to moderate in most patients. Based on the predictive factors found in this series, altering melphalan dose and tourniquet time may allow further reductions in post-ILI toxicity without compromising effectiveness.

Elemental bio-imaging of melanoma in lymph node biopsies.

The spatial distribution of trace elements in human lymph nodes partially infiltrated by melanoma cells was determined by elemental bio-imaging. Imaging of (31)P within the nodal capsule and normal lymph node tissue showed a clear demarcation of the tumour boundary, with a significant decrease in relative (31)P concentration within the tumour. The location of the tumour boundary was confirmed by haematoxylin and eosin staining of serial sections and observation by light microscopy. Further enhancement of the tumour boundary was achieved by imaging the (31)P/(34)S ratio. (31)P/(66)Zn ratio images showed a decreasing ratio beyond the tumour boundary that extended into peritumour normal lymph node tissue.

Chemoablation of metastatic melanoma using intralesional Rose Bengal.

To study the effects of intralesional Rose Bengal for chemoablation of metastatic melanoma. Twenty-six target lesions in 11 patients with locoregionally recurrent disease were injected with the agent PV-10 (10% w/v Rose Bengal in saline) at a dose of 0.5 ml/cc lesion volume. An additional 28 untreated lesions were observed for potential bystander effect. The treatment was well tolerated and an objective response was observed in 12 target lesions, with an additional seven lesions remaining static over at least 12 weeks of observation. In this dose-evaluation study, response rate was dose dependent, increasing to 69% after higher dose injections. Nontarget lesions exhibited a 27% objective response rate that increased to 44% in patients exhibiting a positive response of target lesions. These findings indicate that intralesional Rose Bengal is nontoxic and could benefit patients with metastatic melanoma.

Current status of isolated limb infusion with mild hyperthermia for melanoma.

PURPOSE: Recurrent disease confined to a limb is a frequently encountered clinical problem in patients with melanoma. Regional chemotherapy by isolated limb perfusion (ILP) provides effective treatment but is invasive, complex and costly. Isolated limb infusion (ILI) is a simple yet effective alternative to ILP. MATERIALS AND METHODS: ILI involves drug administration into a limb via percutaneously inserted catheters after vascular isolation of the limb has been achieved with a tourniquet. The infused drug is circulated for 30 minutes via a simple extracorporeal circuit incorporating a heater (to produce mild hyperthermia). RESULTS: Limb tumour remission rates are similar to those achieved by conventional ILP. ILI is well tolerated, and elderly patients and those with major medical co-morbidities and serious peripheral vascular problems can be treated. CONCLUSIONS: ILI with mild hyperthermia is an established alternative to hyperthermic ILP for patients with recurrent limb melanoma. It can also be used for patients with soft tissue sarcomas and a variety of serious, chronic dermatological conditions.

Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology.

PURPOSE: To review the long-term duration of limb tumor complete remission (CR) and patient survival following therapeutic hyperthermic isolated limb perfusion (ILP) with cytotoxic drugs for melanoma. METHODS: A retrospective case series of 124 ILPs performed in 111 patients. RESULTS: There were 120 assessable ILPs. Patient staging (M.D. Anderson system) was stage II 11.7%, stage IIIA 44.2%, stage IIIAB 33.3%, and stage IV 10.8%. CR was initially attained after 83 ILPs (69.2%) and partial remission (PR) after 19 ILPs (15.8%). Limb CR was maintained in 28 (33.7%) of the 83 cases. Disease recurred in the perfused limb after an initial CR in the remaining 55 cases (median time to recurrence, 11 months); in 19 of these cases, the limb was disease-free at last follow-up after further locoregional treatment. A long-term CR was achieved, with or without further treatment, in 47 (56.6%) of the 83 cases in which an initial CR had occurred (mean follow-up, 97 months; median, 65 months). There was no significant difference in long-term local remission for stage IIIA and IIIAB patients. Five-year survival for those who had a partial or no response to ILP was 7%. Ten-year survival for those who had a long-term CR was 49%. CONCLUSIONS: ILP, with or without further locoregional treatment, achieved long-term control of recurrent and metastatic limb disease in 56.6% of cases in which an initial CR was achieved. A complete response to ILP was a positive prognostic indicator for survival, probably reflecting more favorable tumor biology in this subset of patients.

Treatment of refractory chromomycosis by isolated limb infusion with melphalan and actinomycin D.

BACKGROUND: Chromomycosis is frequently resistant to systemic and local therapies, and advanced bulky disease can compromise limb function. METHODS: A man developed extensive chromomycosis of the left arm, refractory to multiple systemic and local treatments. Regional chemotherapy with the isolated limb infusion (ILI) technique using melphalan and actinomycin D markedly reduced disease bulk and greatly improved function of the arm over the next 2 months. Repeat ILI was performed 10 months later, again with good improvement in mobility of the elbow and significant debulking of disease. At the present time, there is some persistent but stable disease, which is controlled by heat therapy with disposable pocket warmers. The patient declined any further systemic therapy. CONCLUSION: ILI rapidly reduced disease bulk, restoring the limb to normal function within a few weeks. Although not curative, ILI could be an effective adjunctive treatment for severe chromomycosis in patients resistant to or intolerant of other therapies.

Cholesteryl ester transfer protein variants have differential stability but uniform inhibition by torcetrapib.

Cholesteryl ester transfer protein (CETP) is an important modulator of high density lipoprotein cholesterol in humans and thus considered to be a therapeutic target for preventing cardiovascular disease. The gene encoding CETP has been shown to be highly variable, with multiple single nucleotide polymorphisms responsible for altering both its transcription and sequence. Examining nine missense variants of CETP, we found some had significant associations with CETP mass and high density lipoprotein cholesterol levels. Two variants, Pro-373 and Gln-451, appear to be more stable in vivo, an observation mirrored by partial proteolysis studies performed in vitro. Because these naturally occurring variant proteins are potentially present in clinical populations that will be treated with CETP inhibitors, all commonly occurring haplotypes were tested to determine whether the proteins they encode could be inhibited by torcetrapib, a compound currently in clinical trials in combination with atorvastatin. Torcetrapib behaved similarly with all variants, with no significant differences in inhibition.

Epidermal growth factor reduces ischemia-reperfusion injury in rat small intestine.

OBJECTIVE: To measure the effect of pre-ischemic administration of intraluminal epidermal growth factor on the changes in intestinal permeability induced by 30 mins of superior mesenteric artery occlusion, followed by 2 hrs of reperfusion. DESIGN: Prospective, randomized, placebo-controlled experimental study. SETTING: University basic science research laboratory. SUBJECTS: Healthy, young, adult, male Sprague-Dawley rats. INTERVENTIONS: A 10-cm segment of small intestine was isolated and studied in situ in rats that were anesthetized with fentanyl and mechanically ventilated. Intestinal ischemia-reperfusion injury was induced by temporary occlusion of the superior mesenteric artery for 30 mins, followed by 2 hrs of reperfusion. Three groups were studied: time controls with a sham operation, saline-treated ischemia-reperfusion, and epidermal growth factor-treated ischemia-reperfusion. Epidermal growth factor, 100 ng/min, was infused intraluminally, beginning 30 mins before and continued until 40 mins after ischemia. MEASUREMENTS AND MAIN RESULTS: Intestinal permeability was measured for each 10-min time period by using chromium-labeled EDTA. Histopathologic injury was assessed by light microscopy. After superior mesenteric artery occlusion, intestinal permeability increased approximately ten-fold and was sustained for 2 hrs of reperfusion in saline-treated rats. Pretreatment with epidermal growth factor significantly reduced the permeability changes during reperfusion by >60% compared with saline-treated animals (p <.05). Histopathologic sections revealed apparently more extensive loss of epithelial cells and mucosal disruption in saline-treated intestine compared with epidermal growth factor-treated intestine. CONCLUSION: Pre-ischemic administration of intraluminal epidermal growth factor significantly protects against intestinal ischemia-reperfusion injury.