Impact of chronic lymphocytic leukaemia on melanoma outcomes: A retrospective case-control study.

With new, effective treatments for chronic lymphocytic leukaemia (CLL) the impact of second malignancies is increasingly important. We performed a retrospective case-controlled study examining the effect of CLL and its treatment on melanoma-specific survival and recurrence. A total of 56 patients with melanoma with CLL were matched 1:1 to patients without CLL for age, date of diagnosis, gender and melanoma tumour, node, metastasis (TNM) stage. Multivariate analysis found CLL was associated with significantly worse melanoma-specific mortality (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.27-4.74, p = 0.007) and recurrence (HR 3.44, 95% CI 1.79-6.63, p < 0.001). Patients with CLL had poor immunotherapy tolerance and prior CLL treatment was not associated with melanoma outcomes.

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.

A survey of surgical management of the sentinel node positive melanoma patient in the post-MSLT2 era.

BACKGROUND: The evidence-based management of melanoma patients with a positive sentinel lymph node biopsy (SLNB) has undergone a dramatic shift following publication of practice-changing surgical trials demonstrating no melanoma-specific survival advantage for completion lymph node dissection (CLND) in this scenario. We aimed to survey how surgeons' clinical practice had shifted in response to new evidence from these trials, and at a time when there was starting to become available systemic adjuvant treatments for AJCC Stage III melanoma patients. METHODS: A web-based survey consisting of practice-based questions and hypothetical clinical scenarios about current melanoma practice with regard to positive sentinel node biopsy was developed and sent to the surgical members of a Melanoma and Skin Cancer (MASC) Trials group in December 2018. Responses were analysed using descriptive statistics. RESULTS: There were 212 invitations sent and 65 respondents (31%). Respondents were from 17 countries, 94% of whom practice in specialist melanoma centres or at referral centres. Of these 97% were familiar with the MSLT2 and DeCOG-SLT clinical trials. At survey, 5% of respondents reported routinely recommending CLND and 55% recommend CLND in selected cases. Respondents were most likely to recommend CLND when multiple SLNs were positive. Important factors for surgical decision-making mentioned included size of SLN deposit, number of positive SLNs and likely compliance with the recommended surveillance regimen. CONCLUSION: In line with rapid adoption of published evidence, surgical management of Stage III melanoma has altered significantly, with few surgeons within the cohort now performing routine CLNDs after positive SLNB.

Oncologic Outcomes After Isolated Limb Infusion for Advanced Melanoma: An International Comparison of the Procedure and Outcomes Between the United States and Australia.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose chemotherapy to extremities affected by locally advanced or in-transit melanoma. This study compared the outcomes of melanoma patients treated with ILI in the United States of America (USA) and Australia (AUS). METHODS: Patients with locally recurrent in-transit melanoma treated with ILI at USA or AUS centers between 1992 and 2018 were identified. Demographic and clinicopathologic characteristics were collected. Primary outcomes of treatment response, in-field progression-free survival (IPFS), distant progression-free survival (DPFS), and overall survival (OS) were evaluated by the Kaplan-Meier method. Multivariable analysis evaluated whether availability of new systemic therapies affected outcomes. RESULTS: More ILIs were performed in AUS (n = 411, 60 %) than in the USA (n = 276, 40 %). In AUS, more ILIs were performed for stage 3B disease than in the USA (62 % vs 46 %; p < 0.001). The reported complete response rates were similar (AUS 30 % vs USA 29 %). Among the stage 3B patients, AUS patients had better IPFS (p = 0.001), whereas DPFS and OS were similar between the two countries. Among the stage 3C patients, the USA patients had better OS (p < 0.001), whereas IPFS and DPFS were similar. Availability of new systemic therapies did not affect IPFS or DPFS in either country. However, the USA patients who received ILI after ipilimumab approval in 2011 had significantly improved OS (hazard ratio, 0.62; p = 0.013). CONCLUSIONS: AUS patients were treated at an earlier disease stage than the USA patients with better IPFS for stage 3B disease. The USA patients treated after the availability of new systemic therapies had a better OS.

Radiation-associated breast cancers in a late-effects cohort: Long-term surveillance is essential.

AIMS: Survivors of childhood, adolescent, and young adulthood malignancies have an increased risk of subsequent primary malignancies, particularly after exposure to therapeutic radiation. This study aims to evaluate the mode of surveillance and surveillance compliance, incidence and mode of detection of breast cancer, breast cancer phenotype, and outcomes after radiation-associated breast cancer (RBC) in a late-effects cohort. METHODS: Women exposed to therapeutic radiation attending the late effects service from 1st January 2000 to 20th February 2013. All invasive and in-situ cancers, benign tumors, and deaths were evaluated. The incidence of breast cancer was compared to the Australian general population. Compliance with breast surveillance recommendations, clinicopathological features, and management of breast cancers were examined. RESULTS: The prevalence of RBC was 17.1%. Twenty-eight cases of RBC occurred in 24 women, out of 140 women exposed to chest radiation. Patients whose first attendance was ≥15 years after radiation exposure experienced the highest incidence of RBC at 23%. The incidence of breast cancer was 11.2 times the general population (P < .001). Compliance with surveillance mammography was observed in 18.4%. Breast cancers diagnosed after the first attendance to the service were more likely screen-detected (P = .002). Most were hormone receptor positive (84.0%), invasive ductal carcinomas (82.1%), and managed with mastectomy (89.3%). CONCLUSIONS: Patients attending a dedicated late effects service have a high burden of subsequent malignancies generally occurring after long latency. Judicious management with adherence to long-term surveillance guidelines is advocated.

Factors predicting toxicity and response following isolated limb infusion for melanoma: An international multi-centre study.

INTRODUCTION: Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response. METHODS: Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres. RESULTS: After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response. CONCLUSION: ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low.

Surgical management of recurrent cutaneous squamous cell carcinoma of the head and neck after definitive surgery and radiotherapy.

BACKGROUND: Surgery is the primary treatment for patients with recurrent head and neck cutaneous squamous cell carcinoma (cSCC) who have previously been treated by definitive surgery and radiotherapy. There are limited published data to direct management and the role of immunotherapy is currently under evaluation. METHODS: This was a retrospective study of patients with at least stage III recurrent head and neck cSCC previously managed by definitive surgery and radiotherapy. RESULTS: A total of 30 patients met the inclusion criteria. Eighty-seven percent were male and the median age at the time of surgery was 79 years. After salvage surgery, 7% developed local recurrence and 43% regional or distant failure. The 2-year overall survival and disease-free survival were 45% (95% confidence interval 24-64) and 11% (95% confidence interval 1-34), respectively. Advanced age was associated with a higher risk of overall mortality (P < 0.05). CONCLUSION: Patients with recurrent head and neck cSCC in the setting of previous radiotherapy have high recurrence rates with poor survival justifying consideration for treatment with anti-PD-1 immunotherapy strategies.

Cutaneous leiomyosarcoma: dermal and subcutaneous.

BACKGROUND AND OBJECTIVES: Leiomyosarcoma of skin (LMS) can be sub-classified on pathology appearances as Dermal or Subcutaneous. The aim of this study was to provide treatment recommendations for these uncommon tumours. METHODS: A retrospective review of all patients with dermal and subcutaneous leiomyosarcoma managed at the Peter MacCallum Cancer Centre, Australia from January 2003 to December 2018 was performed. Eighty-three patients were identified (64 dermal leiomyosarcoma, 19 subcutaneous leiomyosarcoma). RESULTS: Subcutaneous leiomyosarcoma were larger (median size 14 mm dermal, 49 mm subcutaneous, P = 0.01). No patient with a dermal leiomyosarcoma developed metastatic disease compared to 4 of the 19 subcutaneous leiomyosarcoma (5-year overall survivals, 98% and 88%, respectively, P = 0.03). The most common site of metastasis was to the lung. No difference in risk of local recurrence was apparent (5-year recurrence-free survivals were 85% and 78%, respectively, P = 0.17). Adjuvant radiotherapy was used in 16 (25%) dermal leiomyosarcoma patients and 13 (68%) subcutaneous leiomyosarcoma patients (P < 0.001). Local recurrence was uncommon in both tumour subtypes when patients received definitive surgical excision (minimum histological margins of 10 mm as per institutional protocol) regardless of whether radiotherapy was used. The 5-year local recurrence-free survival for dermal leiomyosarcoma treated with radiotherapy was 93% versus 83% without radiotherapy (P = 0.7) and for subcutaneous leiomyosarcoma was 69% and 100%, respectively (P = 0.9). CONCLUSIONS: Dermal leiomyosarcoma have an excellent prognosis, particularly after definitive surgical excision with margins of at least 10 mm. Subcutaneous leiomyosarcoma has poorer outcomes and should be managed by wider excision and considered for adjuvant radiotherapy.

Radiation-Associated Thyroid Cancer Surveillance and Management in a Cohort of Late Effects Patients.

BACKGROUND AND AIMS: Compared to the general population, the incidence of thyroid cancer in childhood and adolescent and young adult malignancy survivors is increased 14.0-18.0 times (CI 11.7-23.8). The cumulative incidence is variably reported as 0.5% by age 45 with 30-year incidence of 1.3% in women and 0.6% in men. This study aims to evaluate the incidence of radiation-associated thyroid cancer amongst patients treated with prior radiation to the thyroid followed up in a late effects service. A secondary aim was to assess screening compliance in this cohort. METHODS: The medical records of all patients attending the late effects service from 1 January 2000 to 20 February 2013 were interrogated to identify patients exposed to thyroid irradiation. The screening compliance and incidence of thyroid cancer were assessed for the duration whilst under the guidance of the late effect service. Mode of diagnosis, all imaging and cytology were retrieved from the institutional electronic record. Cytology was categorized according to Bethesda. RESULTS: Four hundred and sixty-five patients were exposed to direct or scatter neck irradiation. Compliance with thyroid surveillance was observed in 76.9%. Ultrasound features of microcalcification and increased internal vascularity had a low sensitivity (62.5%) for predicting a malignant nodule, which improved when used in conjunction with a Bethesda IV-VI result (91.7%). However, cytological assessment was not performed in 45.6% of operative cases. Thirty-three patients had thyroid carcinoma of which 45.4% (n = 15) were incidental. The majority were papillary thyroid cancers (88.9%); of which 12.5% were node positive and 34.4% were multifocal. The incidence of thyroid cancer was elevated 57.6 times compared to the Australian general population (p < 0.001). CONCLUSION: Due to the high incidence of thyroid cancer, this study supports screening in this cohort. However, due to the risk of overtreatment, we endorse further investigation of thyroid nodules with ultrasound-guided fine-needle aspiration cytology based on sonographic criteria as for the general population and American Thyroid Association guidelines.

International Multicenter Experience of Isolated Limb Infusion for In-Transit Melanoma Metastases in Octogenarian and Nonagenarian Patients.

BACKGROUND: Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON). PATIENTS AND METHODS: ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (< 80 years). A cytotoxic drug combination of melphalan and actinomycin-D was used. RESULTS: Of the 687 patients undergoing a first ILI, 160 were ON patients (median age 84 years; range 80-100 years). Compared with the younger cohort (n = 527; median age 67 years; range 29-79 years), ON patients were more frequently female (70.0% vs. 56.9%; p = 0.003), had more stage IIIB disease (63.8 vs. 53.3%; p = 0.02), and underwent more upper limb ILIs (16.9% vs. 9.5%; p = 0.009). ON patients experienced similar Wieberdink limb toxicity grades III/IV (25.0% vs. 29.2%; p = 0.45). No toxicity-related limb amputations were performed. Overall response for ON patients was 67.3%, versus 64.6% for younger patients (p = 0.53). Median in-field progression-free survival was 9 months for both groups (p = 0.88). Median distant progression-free survival was 36 versus 23 months (p = 0.16), overall survival was 29 versus 40 months (p < 0.0001), and melanoma-specific survival was 46 versus 78 months (p = 0.0007) for ON patients compared with younger patients, respectively. CONCLUSIONS: ILI in ON patients is safe and effective with similar response and regional control rates compared with younger patients. However, overall and melanoma-specific survival are shorter.

Preoperative ß-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial.

PURPOSE: The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by ß-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative ß-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer. PATIENTS AND METHODS: In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (n = 30; 80-160 mg daily) or placebo (n = 30) for 7 days prior to surgery. The primary endpoint investigated the effect of propranolol on prometastatic and proinflammatory gene expression within the primary tumor. RESULTS: Propranolol downregulated primary tumor expression of mesenchymal genes (P = 0.002) without affecting epithelial gene expression (P = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (P = 0.03), NF-κB/Rel (P < 0.01), and AP-1 (P < 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all P < 0.01). Patients with clinical evidence of drug response (lowered heart rate and blood pressure) demonstrated elevated tumor infiltration of CD68+ macrophages and CD8+ T cells. CONCLUSIONS: One week of ß-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that ß-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of ß-blockade on cancer recurrence and survival.See related commentary by Blaes et al., p. 1781.

Topical and intralesional therapies for in-transitmelanoma.

This report surveys the role of topical and intralesional agents in the management of in-transit melanoma. The extent and progression of in-transit disease is highly variable and many patients can have a protracted period of locoregional control. These agents are useful in the management of patients who have progressed beyond local surgical excision in whom more aggressive therapies, such as isolated limb infusion or use of talimogene laherparepvec, are not appropriate or have failed. In general, these agents are modestly effective and associated with frequent but only minor toxicity. As the mechanism of action of many of these agents includes initiation of a local immune response, combinations with immune checkpoint inhibitors are currently being explored.

The Prognosis and Natural History of In-Transit Melanoma Metastases at a High-Volume Centre.

BACKGROUND: Patients with in-transit melanoma metastases (ITM) experience a diverse spectrum of clinical presentations and a highly variable disease course. There is no standardized treatment protocol for these patients due to the limited data comparing treatment modalities for ITM. This is the first study to describe the disease trajectory and natural history of a large cohort of patients with ITM. METHODS: A retrospective study of patients treated for ITM between 2004 and 2018 at the Peter MacCallum Cancer Centre was performed. Clinical and pathological characteristics for primary and in-transit episodes were analyzed for predictors of relapse-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival. RESULTS: A total of 109 patients with 303 episodes of ITM were identified: 52 (48%) females, median age 70.1 years (range 35-92). The median RFS for all episodes was 5 months (95% confidence interval [CI] 4.2-5.7). Eighty-seven percent of episodes involving isolated in-transit lesions underwent surgical excision, compared with 17% involving more than five in-transit lesions. A trend was seen between a greater number of lesions and shorter RFS (p = 0.055). The median DMFS was 34.8 months (95% CI 22.8-51.6). Factors associated with shorter DMFS included primary tumor thickness (hazard ratio [HR] 1.08, 95% CI 1.01-1.15; p = 0.026), site of primary tumor (p = 0.008), and BRAF mutation (HR 2.12, 95% CI 1.14-3.94; p = 0.018). CONCLUSIONS: Locoregional relapse is common in patients with ITM regardless of treatment modality. Characteristics of the ITM may predict for RFS, while primary tumor characteristics remain important predictors of DMFS.

Inguinal and Ilio-inguinal Lymphadenectomy in Management of Palpable Melanoma Lymph Node Metastasis: A Long-Term Prospective Evaluation of Morbidity and Quality of Life.

PURPOSE: Prospective data are lacking on long-term morbidity of inguinal lymphadenectomy including the influence of extent of surgery, use of radiotherapy, and patient factors. The aim of this study is to evaluate the effects of these factors on patient outcome, quality of life (QOL), regional symptoms, and limb volumes after inguinal or ilio-inguinal lymphadenectomy for melanoma. METHODS: Analysis of the subgroup of patients with inguinal lymph node field relapse of melanoma, treated by inguinal or ilio-inguinal lymphadenectomy in the ANZMTG/TROG randomized trial of adjuvant radiotherapy versus observation. RESULTS: Sixty-nine patients, 46 having undergone inguinal and 23 ilio-inguinal lymphadenectomy, with median follow-up of 73 months were analyzed. Mean limb volume increased rapidly after surgery (7% by 3 months) and continued to increase for at least another 18 months. Patients with body mass index (BMI) ≥ 25 kg/m2 had greater limb volume increase than normal-weight patients (13.3% versus 6.9%, P = 0.030). QOL improved over the first 18 months, but despite initial improvement, regional symptoms persisted long term. Type of surgery (inguinal or ilio-inguinal lymphadenectomy) had no demonstrably significant effect on limb volume (9.9% versus 13.4%, P = 0.35), QOL (P = 0.68), or regional symptoms (P = 0.65). There was no difference in overall survival between inguinal and ilio-inguinal lymphadenectomy [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.40-1.40, P = 0.43]. CONCLUSIONS: Inguinal lymphadenectomy for melanoma is a potentially morbid procedure with significant increases in limb volume. Patients report reasonable QOL but may have ongoing regional symptoms. Overweight/obesity is associated with poorer QOL, increased limb volume, and regional symptoms.

A review of the influence of mammographic density on breast cancer clinical and pathological phenotype.

PURPOSE: It is well established that high mammographic density (MD), when adjusted for age and body mass index, is one of the strongest known risk factors for breast cancer (BC), and also associates with higher incidence of interval cancers in screening due to the masking of early mammographic abnormalities. Increasing research is being undertaken to determine the underlying histological and biochemical determinants of MD and their consequences for BC pathogenesis, anticipating that improved mechanistic insights may lead to novel preventative or treatment interventions. At the same time, technological advances in digital and contrast mammography are such that the validity of well-established relationships needs to be re-examined in this context. METHODS: With attention to old versus new technologies, we conducted a literature review to summarise the relationships between clinicopathologic features of BC and the density of the surrounding breast tissue on mammography, including the associations with BC biological features inclusive of subtype, and implications for the clinical disease course encompassing relapse, progression, treatment response and survival. RESULTS AND CONCLUSIONS: There is reasonable evidence to support positive relationships between high MD (HMD) and tumour size, lymph node positivity and local relapse in the absence of radiotherapy, but not between HMD and LVI, regional relapse or distant metastasis. Conflicting data exist for associations of HMD with tumour location, grade, intrinsic subtype, receptor status, second primary incidence and survival, which need further confirmatory studies. We did not identify any relationships that did not hold up when data involving newer imaging techniques were employed in analysis.

Negative Sentinel Lymph Node Biopsy in Patients with Melanoma: The Patient's Perspective.

BACKGROUND: The majority of patients undergoing sentinel lymph node biopsy (SLNB) for melanoma will have a negative SLN. The long-term sequelae of a negative result are important when discussing this staging investigation with patients. The objective of this study was to assess rates of lymphoedema and quality of life for these patients. METHODS: A prospective, cross-sectional study was performed on patients under routine follow-up with a history of melanoma, who had undergone sentinel lymph node biopsy where no metastasis was found (N0) at a high-volume melanoma centre. Relevant limbs were measured to assess for lymphoedema and patients completed the FACT-M quality of life instrument and a study specific questionnaire. RESULTS: A total of 102 patients were recruited. Wound complications were observed in 25% and lymphoedema in 2% of patients. Physical and functional well-being scores were lowest in patients seen within 3 months of their SLNB. Functional well-being and quality of life improved over the 2 years following the procedure. CONCLUSIONS: SLNB has low complication rates. The procedure is associated with a short-term impact on patient quality of life and well-being. The vast majority of patients are pleased with the outcomes of this procedure and the information that it provides.

Evaluation of the efficacy and toxicity of upper extremity isolated limb infusion chemotherapy for melanoma: An Australian multi-center study.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive treatment for patients with locally advanced extremity melanoma. Most studies combine results of upper-limb ILI (UL-ILI) and lower-limb ILI (LL-ILI), leaving UL-ILIs relatively underreported as LL-ILIs comprise the vast majority in these reports. However, differences between the two procedures may be clinically important. The aim of this study was to evaluate the efficacy and toxicity of UL-ILI in an Australian multi-center setting. PATIENTS AND METHODS: 316 ILI procedures for melanoma performed between 1992 and 2008 in five Australian institutions were analyzed. In all institutions melphalan (±actinomycin D) was circulated in the isolated limb for 20-30 min. RESULTS: Baseline patient characteristics for UL-ILI (n = 27) and LL-ILI (n = 289) were similar, except that more men underwent UL-ILI (66% vs. 38%; p = 0.007) and disease in LL-ILI was mostly located on the distal limb (p = 0.02). Median tourniquet times were shorter for UL-ILI (38 vs. 48 min; p = 0.04) and UL-ILI patients experienced less limb toxicity (Grade III/IV in 24% vs. 31%; p = 0.01). Complete response (CR) rates were similar: 33% after LL-ILI (p = 0.70), 30% after UL-ILI, while overall response (OR) rates were higher after LL-ILI: (76%) than UL-ILI (59%; p = 0.05). No difference in survival was seen. CONCLUSIONS: UL-ILI is safe to perform and effective, resulting in low limb toxicity. CR rates were similar to those for LL-ILI, but OR rates were lower for UL-ILI. It may be possible to improve OR rates achieved by UL-ILI by optimizing perioperative factors, while maintaining low toxicity.

Long-Term Oncologic Outcomes After Isolated Limb Infusion for Locoregionally Metastatic Melanoma: An International Multicenter Analysis.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose regional chemotherapy to patients with locally advanced or in-transit melanoma located on a limb. The current international multicenter study evaluated the perioperative and long-term oncologic outcomes for patients who underwent ILI for stage 3B or 3C melanoma. METHODS: Patients undergoing a first-time ILI for stage 3B or 3C melanoma (American Joint Committee on Cancer [AJCC] 7th ed) between 1992 and 2018 at five Australian and four United States of America (USA) tertiary referral centers were identified. The primary outcome measures included treatment response, in-field (IPFS) and distant progression-free survival (DPFS), and overall survival (OS). RESULTS: A total of 687 first-time ILIs were performed (stage 3B: n = 383, 56%; stage 3C; n = 304, 44%). Significant limb toxicity (Wieberdink grade 4) developed in 27 patients (3.9%). No amputations (grade 5) were performed. The overall response rate was 64.1% (complete response [CR], 28.9%; partial response [PR], 35.2%). Stable disease (SD) occurred in 14.5% and progressive disease (PD) in 19.8% of the patients. The median follow-up period was 47 months, with a median OS of 38.2 months. When stratified by response, the patients with a CR or PR had a significantly longer median IPFS (21.9 vs 3.0 months; p < 0.0001), DPFS (53.6 vs 12.7 months; p < 0.0001), and OS (46.5 vs 24.4 months; p < 0.0001) than the nonresponders (SD + PD). CONCLUSION: This study is the largest to date reporting long-term outcomes of ILI for locoregionally metastatic melanoma. The findings demonstrate that ILI is effective and safe for patients with stage 3B or 3C melanoma confined to a limb. A favorable response to ILI is associated with significantly longer IFPS, DPFS, and OS.

Accuracy of partial biopsies in the management of cutaneous melanoma.

BACKGROUND: The recommended method for histopathological diagnosis of cutaneous melanoma is excisional biopsy, although partial biopsies (shave and punch) are often used. Following a partial biopsy, treatment guidelines recommend a narrow excisional biopsy to plan definitive management. There is limited evidence on the benefits of direct wide local excision (WLE) following diagnostic partial biopsies. METHODS: Retrospective cohort study of cutaneous melanoma cases, from two tertiary referral centres from January 2013 to December 2015. Demographic and histopathological data, including tumour thickness (T-stage) from initial biopsy and subsequent excisions, were collected. Logistic regression was used to examine histopathological T-staging between biopsy and subsequent excisions (upstaging). RESULTS: 2304 melanomas (2157 patients) were identified; 455 shave, 308 punch, 14 incisional and 1527 excisional biopsies. Out of 1527, 5 (<1%) excisional biopsies were upstaged from original biopsy T-stage to final WLE; compared to 28/455 (6%) for shave, 45/308 (15%) for punch and 2/14 (14%) for incisional biopsies. Histopathology upstaging were increased with punch (OR, 52.1; 95% CI, 20.5-132.4. P < 0.001) and shave biopsy (OR, 20.0; 95% CI, 7.7-52.0. P < 0.001) compared to excisional biopsy. Upstaging rates of 9.4% for desmoplastic (OR, 6.9; 95% CI, 2.4-19.7. P < 0.001) and 21.9% for acral lentiginous (OR, 18.4; 95% CI, 6.9-49.2. P < 0.001) melanomas were elevated compared to 1.4% for superficial spreading melanoma. CONCLUSIONS: In most cases, partial biopsy (particularly shave biopsy) can provide sufficient information to plan for definitive surgical melanoma management. Punch and incisional biopsies have elevated upstaging rates, a consideration in planning therapy. Partial biopsies of desmoplastic or acral lentiginous melanomas have high rates of upstaging and should have a complete excision prior to definitive treatment.