3D-SARC: A Pilot Study Testing the Use of a 3D Augmented-Reality Model with Conventional Imaging as a Preoperative Assessment Tool for Surgical Resection of Retroperitoneal Sarcoma.

BACKGROUND: Retroperitoneal sarcomas (RPSs) present a surgical challenge, with complex anatomic relationships to organs and vascular structures. This pilot study investigated the role of three-dimensional (3D) augmented reality (3DAR) compared with standard imaging in preoperative planning and resection strategies. METHODS: For the study, 13 patients who underwent surgical resection of their RPS were selected based on the location of their tumor (right, left, pelvis). From the patients' preoperative computed tomography (CT) scans, 3DAR models were created using a D2P program and projected by an augmented-reality (AR) glass (Hololens). The 3DAR models were evaluated by three experienced sarcoma surgeons and compared with the baseline two-dimensional (2D) contrast-enhanced CT scans. RESULTS: Three members of the surgical team evaluated 13 models of retroperitoneal sarcomas, resulting in a total of 26 responses. When the surgical team was asked to evaluate whether the 3DAR better prepared the surgeon for planned surgical resection, 10 responses favored the 3DAR, 5 favored the 2D CT scans and 11 showed no difference (p = 0.074). According to 15 (57.6 %) of the 26 responses, the 3DAR offered additional value over standard imaging in the preoperative planning (median score of 4; range, 1-5). The median stated likelihood that the surgeons would consult the 3DAR was 5 (range, 2-5) for the preoperative setting and 3 (range, 1-5) for the intraoperative setting. CONCLUSIONS: This pilot study suggests that the use of 3DAR may provide additional value over current standard imaging in the preoperative planning for surgical resection of RPS, and the technology merits further study.

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.

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.

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.

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.

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.

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.

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.

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.

High mammographic density in women is associated with protumor inflammation.

BACKGROUND: Epidemiological studies have consistently shown that increased mammographic density (MD) is a strong risk factor for breast cancer. We previously observed an elevated number of vimentin+/CD45+ leukocytes in high MD (HMD) epithelium. In the present study, we aimed to investigate the subtypes of immune cell infiltrates in HMD and low MD (LMD) breast tissue. METHODS: Fifty-four women undergoing prophylactic mastectomy at Peter MacCallum Cancer Centre or St. Vincent's Hospital were enrolled. Upon completion of mastectomy, HMD and LMD areas were resected under radiological guidance in collaboration with BreastScreen Victoria and were subsequently fixed, processed, and sectioned. Fifteen paired HMD and LMD specimens were further selected according to their fibroglandular characteristics (reasonable amount [> 20%] of tissue per block on H&E stains) for subsequent IHC analysis of immune cell infiltration. RESULTS: Overall, immune cell infiltrates were predominantly present in breast ducts and lobules rather than in the stroma, with CD68+ macrophages and CD20+ B lymphocytes also surrounding the vasculature. Macrophages, dendritic cells (DCs), B lymphocytes, and programmed cell death protein 1 (PD-1) expression were significantly increased in HMD epithelium compared with LMD. Moreover, significantly higher levels of DCs, CD4+ T cells, and PD-1 were also observed in HMD stroma than in LMD stroma. The increased expression of interleukin (IL)-6 and IL-4, with unaltered interferon-γ, indicate a proinflammatory microenvironment. CONCLUSIONS: Our work indicates that the immune system may be activated very early in breast cancer development and may in part underpin the breast cancer risk associated with HMD.

1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

BACKGROUND: There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma > 1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma > 1 mm in BT. METHODS: This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma > 1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients' QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation. RESULTS: Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p < 0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p = 0.036). After 12 months' follow-up, no differences were noted in QoL between groups. DISCUSSION: This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.

Correction to: 1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

In the original article John F. Thompson was inadvertently omitted as an author. The author list is updated as shown in this correction.

Safety and Efficacy of Isolated Limb Infusion Chemotherapy for Advanced Locoregional Melanoma in Elderly Patients: An Australian Multicenter Study.

BACKGROUND: Isolated limb infusion (ILI) offers a minimally invasive treatment option for locally advanced extremity melanoma. OBJECTIVE: The aim of the current study was to evaluate the safety and efficacy of ILI in elderly patients in an Australian multicenter setting. METHODS: The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were identified and analyzed, with the main focus on elderly patients (≥75 years of age). All institutions used the same protocol: melphalan was circulated in the isolated limb for 20-30 min (±actinomycin D), and toxicity, responses, and survival were recorded. RESULTS: Characteristics of patients aged ≥75 years (n = 148) were similar to those aged <75 years (n = 168), except that older patients had more melanoma deposits (median 4 vs. 5; p = 0.035) and lower limb volumes (5.4 vs. 6.5 L; p = 0.001). Median drug circulation times were lower in the older group (21 vs. 24 min; p = 0.04), and older patients experienced less limb toxicity (grade III/IV in 22 and 37% of patients, respectively; p = 0.003). A complete response (CR) was seen in 27% of patients aged ≥75 years and in 38% of patients aged <75 years (p = 0.06), while overall response rates were 72 and 77%, respectively (p = 0.30). No difference in survival was seen (p = 0.69). CONCLUSIONS: The ILI technique proved safe and effective in elderly patients. When present, toxicity was localized, and lower compared with younger patients, possibly due to shorter drug circulation times. CR rates were higher in younger patients, although not significantly, while overall response and survival were equal. Optimization of perioperative factors in elderly patients may allow response rates to be raised further, while maintaining low toxicity.

Light Makes a Surface Banana-Bond Split: Photodesorption of Molecular Hydrogen from RuO2(110).

The coordination of H2 to a metal center via polarization of its σ bond electron density, known as a Kubas complex, is the means by which H2 chemisorbs at Ru(4+) sites on the rutile RuO2(110) surface. This distortion of electron density off an interatomic axis is often described as a 'banana-bond.' We show that the Ru-H2 banana-bond can be destabilized and split using visible light. Photodesorption of H2 (or D2) is evident by mass spectrometry and scanning tunneling microscopy. From time-dependent density functional theory, the key optical excitation splitting the Ru-H2 complex involves an interband transition in RuO2 which effectively diminishes its Lewis acidity, thereby weakening the Kubas complex. Such excitations are not expected to affect adsorbates on RuO2 given its metallic properties. Therefore, this common thermal cocatalyst employed in photocatalysis is, itself, photoactive.

Sentinel Lymph Node Biopsy in T4 Melanoma: An Important Risk-Stratification Tool.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a sensitive test for detecting subclinical nodal metastatic disease in patients with melanoma without evidence of lymph node involvement. The prognostic significance of SLN positivity in patients with melanoma >4 mm thick (T4) is unclear. The survival curves in the current AJCC staging system suggest that the status of the SLN is not predictive of outcome for patients with T4 melanoma. METHODS: Patients with primary T4 melanoma without clinical nodal involvement who underwent SLNB between 2002 and 2012 at Peter MacCallum Cancer Centre were included in the analysis with chart review performed to collect clinical, pathological, and outcome data. A meta-analysis was performed including similar studies of SLNB in T4 melanoma, which reported overall survival (OS) data. RESULTS: Of 217 patients who underwent SLNB, 78 patients had a positive SLN (36 %). The 5-year OS for SLNB negative and positive patients was 68 and 45 %, respectively [hazard ratio (HR) 2.82; 95 % CI 1.76-4.51; P = .001]. On multivariate analysis, the only predictors of OS were the status of the SLN (HR 2.88; 95 % CI 1.75­4.73) and the presence of satellitosis (HR 2.59; 95 % CI 1.30-5.76). The meta-analysis identified 10 studies that met the inclusion criteria. All reported similar findings, demonstrating a significant difference in OS according to sentinel lymph node status; the pooled analysis of 2104 patients demonstrated an overall HR for OS according to SLNB status of 2.3 (95 % CI 1.95-2.71). CONCLUSIONS: SLNB provides important prognostic information for patients with T4 melanoma. This information is important when stratifying patients for clinical trials.

Australian Multicenter Study of Isolated Limb Infusion for Melanoma.

PURPOSE: Isolated limb infusion (ILI) offers a less invasive alternative to isolated limb perfusion (ILP) for the treatment of locally advanced extremity melanoma. In Australia, ILI has essentially completely replaced ILP. The aim of this study was to collect and evaluate the results of ILI in an Australian multicenter setting. PATIENTS AND METHODS: The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were collectively analyzed, with all five institutions using the same protocol. Melphalan was circulated in the isolated limb for 20-30 min (±actinomycin D). Response was determined using the World Health Organization criteria, and limb toxicity was assessed using the Wieberdink scale. RESULTS: The median patient age was 74 years (range 28-100) and 59 % of patients were female. Overall response rate was 75 % (complete response [CR] 33 %; partial response 42 %). Stable disease was seen in 18 % of patients and progressive disease in 7 %. Wieberdink grade III or higher was seen in 30 % of the cases. No toxicity-related amputations occurred, and median survival was 44 months. In patients with a CR, median survival was 80 months (p = 0.014). On multivariate analysis, Breslow thickness, lower-limb ILI, and a procedure performed at the Melanoma Institute Australia remained significant predictors for response, although not for survival. CONCLUSIONS: This Australian multicenter study of ILI is the largest reported to date. ILI is a useful technique that can be safely and effectively performed across tertiary referral centers for the successful management of advanced extremity melanoma. Increased optimization of perioperative factors might allow response rates to be raised further, while maintaining acceptable toxicity.