Regional Node Basin Recurrence in Melanoma Patients: More Common After Node Dissection for Macroscopic Rather than Clinically Occult Nodal Disease.

BACKGROUND: Recommended treatment for patients with sentinel lymph node (SLN)-positive melanoma has recently changed. Randomized trials demonstrated equivalent survival with close observation versus completion lymph node dissection (CLND), but increased regional node recurrence. We evaluated factors related to in-basin nodal recurrence after lymphadenectomy (LND) for SLN-positive or macroscopic nodal metastases. METHODS: An institutional database and the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were analyzed independently. Exclusions were multiple primaries, multi-basin involvement, or in-transit metastases. Patient demographics, primary tumor thickness and ulceration, lymph nodes retrieved, and use of adjuvant radiotherapy were analyzed. Multivariate analyses were performed to determine factors predicting in-basin nodal recurrence (significance p ≤ 0.05). RESULTS: The retrospective cohort (577 patients) showed an in-basin failure rate of 6.6% after CLND for a positive SLN and 13.1% after LND for palpable disease (p = 0.001). This recurrence risk persisted after adjustment for patient, tumor, and LND factors [hazard ratio (HR) 2.32; p = 0.004]. In the MSLT-I cohort (326 patients), the failure rate after CLND following SLNB was 6.2%, but 10.1% after LND for palpable recurrence in observation patients. After adjustment for other factors, macroscopic disease was associated with an increased risk of recurrence after LND (HR 2.24; p = 0.05). CONCLUSION: After LND for melanoma, in-basin recurrence is infrequent, but a clinically significant fraction will fail. Failure is less likely if dissection is performed for clinically occult disease. Further research is warranted to evaluate the long-term regional control and quality of life associated with nodal basin observation, which has now become standard practice.

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.

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.

Updated evidence-based clinical practice guidelines for the diagnosis and management of melanoma: definitive excision margins for primary cutaneous melanoma.

INTRODUCTION: Definitive management of primary cutaneous melanoma consists of surgical excision of the melanoma with the aim of curing the patient. The melanoma is widely excised together with a safety margin of surrounding skin and subcutaneous tissue, after the diagnosis and Breslow thickness have been established by histological assessment of the initial excision biopsy specimen. Sentinel lymph node biopsy should be discussed for melanomas ≥ 1 mm thickness (≥ 0.8 mm if other high risk features) in which case lymphoscintigraphy must be performed before wider excision of the primary melanoma site. The 2008 evidence-based clinical practice guidelines for the management of melanoma (http://www.cancer.org.au/content/pdf/HealthProfessionals/ClinicalGuidelines/ClinicalPracticeGuidelines-ManagementofMelanoma.pdf) are currently being revised and updated in a staged process by a multidisciplinary working party established by Cancer Council Australia. The guidelines for definitive excision margins for primary melanomas have been revised as part of this process. Main recommendations: The recommendations for definitive wide local excision of primary cutaneous melanoma are: melanoma in situ: 5-10 mm margins invasive melanoma (pT1) ≤ 1.0 mm thick: 1 cm margins invasive melanoma (pT2) 1.01-2.00 mm thick: 1-2 cm margins invasive melanoma (pT3) 2.01-4.00 mm thick: 1-2 cm margins invasive melanoma (pT4) > 4.0 mm thick: 2 cm margins Changes in management as a result of the guideline: Based on currently available evidence, excision margins for invasive melanoma have been left unchanged compared with the 2008 guidelines. However, melanoma in situ should be excised with 5-10 mm margins, with the aim of achieving complete histological clearance. Minimum clearances from all margins should be assessed and stated. Consideration should be given to further excision if necessary; positive or close histological margins are unacceptable.

Final trial report of sentinel-node biopsy versus nodal observation in melanoma.

BACKGROUND: Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial. METHODS: We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted. CONCLUSIONS: Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

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.

The Impact of Smoking on Sentinel Node Metastasis of Primary Cutaneous Melanoma.

BACKGROUND: Although a well-established causative relationship exists between smoking and several epithelial cancers, the association of smoking with metastatic progression in melanoma is not well studied. We hypothesized that smokers would be at increased risk for melanoma metastasis as assessed by sentinel lymph node (SLN) biopsy. METHODS: Data from the first international Multicenter Selective Lymphadenectomy Trial (MSLT-I) and the screening-phase of the second trial (MSLT-II) were analyzed to determine the association of smoking with clinicopathologic variables and SLN metastasis. RESULTS: Current smoking was strongly associated with SLN metastasis (p = 0.004), even after adjusting for other predictors of metastasis. Among 4231 patients (1025 in MSLT-I and 3206 in MSLT-II), current or former smoking was also independently associated with ulceration (p < 0.001 and p < 0.001, respectively). Compared with current smoking, never smoking was independently associated with decreased Breslow thickness in multivariate analysis (p = 0.002) and with a 0.25 mm predicted decrease in thickness. CONCLUSION: The direct correlation between current smoking and SLN metastasis of primary cutaneous melanoma was independent of its correlation with tumor thickness and ulceration. Smoking cessation should be strongly encouraged among patients with or at risk for melanoma.

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.

Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial.

BACKGROUND: Adjuvant radiotherapy is recommended for patients with melanoma after lymphadenectomy. We previously showed this treatment reduced risk of repeat lymph-node field cancer in patients with a high risk of recurrence but had no effect on overall survival. Here, we aim to update the relapse and survival data from that trial and assess quality of life and toxic effects. METHODS: In the ANZMTG 01.02/TROG 02.01 randomised controlled trial, we enrolled patients who had undergone lymphadenectomy for a palpable lymph-node field relapse and were at high risk of recurrence at 16 hospitals (11 in Australia, three in New Zealand, one in Netherlands, and one in Brazil). We randomly assigned patients (1:1) to adjuvant radiotherapy (48 Gy in 20 fractions, given over a maximum of 30 days) or observation, stratified by institution, areas of lymph-node field (parotid and cervical, axilla, or groin), number of involved nodes (≤3 vs >3), maximum involved node diameter (≤4 cm vs >4 cm), and extent of extracapsular extension (none, limited, or extensive). Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation, but participants were unaware of each other's treatment allocation. In this follow-up, we assessed outcomes every 3 months from randomisation for the first 2 years, then every 6 months up to 5 years, then annually. The primary endpoint was lymph-node field relapse as a first relapse, assessed in patients without major eligibility infringements (determined by an independent data monitoring committee). We assessed late adverse effects (occurring >90 days after surgery or start of radiotherapy) with standard criteria in the as-treated population. This study is registered with ClinicalTrials.gov, number NCT00287196. FINDINGS: Between March 21, 2003, and Nov 15, 2007, we randomly assigned 123 patients to adjuvant radiotherapy (109 eligible for efficacy assessments) and 127 to observation (108 eligible). The final follow-up date was Nov 15, 2011. Median follow-up was 73 months (IQR 61-91). 23 (21%) relapses occurred in the adjuvant radiotherapy group compared with 39 (36%) in the observation group (adjusted hazard ratio [HR] 0·52 [95% CI 0·31-0·88], p=0·023). Overall survival (HR 1·27 [95% CI 0·89-1·79], p=0·21) and relapse-free survival (0·89 [0·65-1·22], p=0·51) did not differ between groups. Minor, long-term toxic effects from radiotherapy (predominantly pain, and fibrosis of the skin or subcutaneous tissue) were common, and 20 (22%) of 90 patients receiving adjuvant radiotherapy developed grade 3-4 toxic effects. 18 (20%) of 90 patients had grade 3 toxic effects, mainly affecting skin (nine [10%] patients) and subcutaneous tissue (six [7%] patients). Over 5 years, a significant increase in lower limb volumes was noted after adjuvant radiotherapy (mean volume ratio 15·0%) compared with observation (7·7%; difference 7·3% [95% CI 1·5-13·1], p=0·014). No significant differences in upper limb volume were noted between groups. INTERPRETATION: Long-term follow-up supports our previous findings. Adjuvant radiotherapy could be useful for patients for whom lymph-node field control is a major issue, but entry to an adjuvant systemic therapy trial might be a preferable first option. Alternatively, observation, reserving surgery and radiotherapy for a further recurrence, might be an acceptable strategy. FUNDING: National Health and Medical Research Council of Australia, Cancer Council Australia, Melanoma Institute Australia, and the Cancer Council South Australia.

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.

Bradycardia as an early warning sign for cardiac arrest during routine laparoscopic surgery.

OBJECTIVES: The aim of this study was to identify clinical patterns of occurrence, management and outcomes surrounding cardiac arrest during laparoscopic surgery using the Australian Incident Monitoring Study (AIMS) database to guide possible prevention and treatment. SETTING: The AIMS database includes incident reports from participating clinicians from secondary and tertiary healthcare centres across Australia and New Zealand. PARTICIPANTS: The AIMS database holds over 11 000 peri- and intraoperative incidents. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was to characterize the pattern of events surrounding cardiac arrest. The secondary outcome was to identify successful management strategies in the possible prevention and treatment of cardiac arrest during laparoscopic surgery. RESULTS: Fourteen cases of cardiac arrest during laparoscopic surgery were identified. The majority of cases occurred in 'fit and healthy' patients during elective gynaecological and general surgical procedures. Twelve cases of cardiac arrest were directly associated with pneumoperitoneum with bradycardia preceding cardiac arrest in 75% of these. Management included deflation of pneumoperitoneum, atropine administration and cardiopulmonary resuscitation with circulatory restoration in all cases. The results imply vagal mechanisms associated with peritoneal distension as the predominant contributor to bradycardia and subsequent cardiac arrest during laparoscopy. CONCLUSIONS: Bradycardia during gas insufflation is not necessarily a benign event and appears to be a critical early warning sign for possible impending and unexpected cardiac arrest. Immediate deflation of pneumoperitoneum and atropine administration are effective measures that may alleviate bradycardia and possibly avert progression to cardiac arrest.

Australian multi-center experience outside of the Sydney Melanoma Unit of isolated limb infusion chemotherapy for melanoma.

INTRODUCTION: Isolated limb infusion (ILI) is a minimally invasive alternative to isolated limb perfusion (ILP) for delivering high-dose regional chemotherapy to treat locally advanced limb melanoma. The current study aimed to evaluate the applicability of ILI in four Australian tertiary referral centers outside of its originating institution, the Sydney Melanoma Unit (SMU; currently known as the Melanoma Institute Australia). METHODS: Data of 131 patients, treated between 1992 and 2008 were collectively analyzed. The ILI procedures were based on the Sydney Melanoma Unit protocol using melphalan. Response was determined using the WHO criteria and toxicity was assessed using the Wieberdink scale. RESULTS: The median patient age was 74 years (range 28-100). Fifty-six percent were female. Overall response (OR) rate to ILI was 63% (CR 27%; PR 36%). Wieberdink toxicity grade III or higher was seen in 13%. No toxicity-related amputations occurred. Median follow-up was 24 months; median survival was 58 months. In patients with a complete response (CR), median survival was 101 months; in patients with a partial response (PR) this was 41 months (P = 0.026). On univariate analysis a younger age, lower-limb procedures and a lower Breslow thickness of the primary melanoma were associated with a favorable response. On multivariate analysis Breslow thickness and lower-limb ILI remained significant predictors for response. CONCLUSION: In this, to date, largest multi-center study of ILI for melanoma the results are comparable to other reports and demonstrate that ILI can be widely implemented and safely applied across tertiary referral centers.

Therapeutic options for chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is a rare acquired immune-mediated progressive or relapsing disorder causing peripheral neuropathic disease of duration more than two months. Many individuals with chronic inflammatory demyelinating polyradiculoneuropathy fail to make a long-term recovery with current treatment regimes. The aim of this study was to prospectively review the literature to determine the effectiveness of therapies for chronic inflammatory demyelinating polyradiculoneuropathy. METHODS: Articles published from January 1990 to December 2012 were searched for studies to treat adults with chronic inflammatory demyelinating polyradiculoneuropathy. Peer-reviewed full-text articles published in English were included. RESULTS: Nine placebo-controlled double-blinded randomised trials were reviewed to treat subjects with chronic inflammatory demyelinating polyradiculoneuropathy exhibiting various degrees of effectiveness. The most effect treatments were; three randomised controlled trials using intravenous immunoglobulin, a study comparing pulsed dexamethasone and short term prednisolone and rituximab all showed promising results and were well tolerated. CONCLUSION: IVIg and corticosteroids remain first line treatments for CIDP. Therapies using monoclonal antibodies, such as Rituximab and Natalizumab offer the most promise for treatment of Chronic inflammatory demyelinating polyradiculoneuropathy however they also need further research, as does the use of stem cell therapy for treating Chronic inflammatory demyelinating polyradiculoneuropathy. Large randomised controlled trials and better patient selection are required to address responsiveness of CIDP patients to conventional treatments to elucidate mechanisms of action and future directions for therapeutic improvement.

Diamide linked γ-cyclodextrin dimers as molecular-scale delivery systems for the medicinal pigment curcumin to prostate cancer cells.

Diamide linked γ-cyclodextrin (γ-CD) dimers are proposed as molecular-scale delivery agents for the anticancer agent curcumin. N,N'-Bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)succinamide (66γCD2su) and N,N'-bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)urea (66γCD2ur) markedly suppress the degradation of curcumin by forming a strong 1:1 cooperative binding complexes. The results presented in this study describe the potential efficacy of 66γCD2su and 66γCD2ur for intracellular curcumin delivery to cancer cells. Cellular viability assays demonstrated a dose-dependent antiproliferative effect of curcumin in human prostate cancer (PC-3) cells that was preserved by the curcumin-66γCD2su complex. In contrast, delivery of curcumin by 66γCD2ur significantly delayed the antiproliferative effect. We observed similar patterns of gene regulation in PC-3 cells for curcumin complexed with either 66γCD2su or 66γCD2ur in comparison to curcumin alone, although curcumin delivered by either 66γCD2su or 66γCD2ur induces a slightly higher up-regulation of heme oxygenase-1. Highlighting their nontoxic nature, neither 66γCD2su nor 66γCD2ur carriers alone had any measurable effect on cell proliferation or candidate gene expression in PC-3 cells. Finally, confocal fluorescence imaging and uptake studies were used to demonstrate the intracellular delivery of curcumin by 66γCD2su and 66γCD2ur. Overall, these results demonstrate effective intracellular delivery and action of curcumin when complexed with 66γCD2su and 66γCD2ur, providing further evidence of their potential applications to deliver curcumin effectively in cancer and other treatment settings.

Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.

BACKGROUND: The use of radiotherapy after therapeutic lymphadenectomy for patients with melanoma at high risk of further lymph-node field and distant recurrence is controversial. Decisions for radiotherapy in this setting are made on the basis of retrospective, non-randomised studies. We did this randomised trial to assess the effect of adjuvant radiotherapy on lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes. METHODS: This randomised controlled trial included patients from 16 hospitals in Australia, New Zealand, the Netherlands, and Brazil. To be eligible for this trial, patients had to be at high risk of lymph-node field relapse, judged on the basis of number of nodes involved, extranodal spread, and maximum size of involved nodes. After lymphadenectomy, randomisation was done centrally by computer and patients assigned by telephone in a ratio of 1:1 to receive adjuvant radiotherapy of 48 Gy in 20 fractions or observation, with institution, lymph-node field, number of involved nodes, maximum node diameter, and extent of extranodal spread as minimisation factors. Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation. The primary endpoint was lymph-node field relapse (as a first relapse), analysed for all eligible patients. The study is registered at ClinicalTrials.gov, number NCT00287196. The trial is now closed and follow-up discontinued. FINDINGS: 123 patients were randomly allocated to the adjuvant radiotherapy group and 127 to the observation group between March 20, 2002, and Sept 21, 2007. Two patients withdrew consent and 31 had a major eligibility infringement as decided by the independent data monitoring committee, resulting in 217 eligible for the primary analysis (109 in the adjuvant radiotherapy group and 108 in the observation group). Median follow-up was 40 months (IQR 27-55). Risk of lymph-node field relapse was significantly reduced in the adjuvant radiotherapy group compared with the observation group (20 relapses in the radiotherapy group vs 34 in the observation group, hazard ratio [HR] 0·56, 95% CI 0·32-0·98; p=0·041), but no differences were noted for relapse-free survival (70 vs 73 events, HR 0·91, 95% CI 0·65-1·26; p=0·56) or overall survival (59 vs 47 deaths, HR 1·37, 95% CI 0·94-2·01; p=0·12). The most common grade 3 and 4 adverse events were seroma (nine in the radiotherapy group vs 11 in the observation group), radiation dermatitis (19 in the radiotherapy group), and wound infection (three in the radiotherapy group vs seven in the observation group). INTERPRETATION: Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy. FUNDING: National Health and Medical Research Council of Australia, Cancer Australia, Melanoma Institute Australia, Cancer Council of South Australia.

Increased Early Cancer Diagnosis: Unveiling Immune-Cancer Biology to Explain Clinical "Overdiagnosis".

Even though clinically small 'early' cancers represent many millions of cells biologically, when removed surgically, these often never recur or regrow, nor reduce the individual's lifespan. However, some early cancers remain quiescent and indolent; while others grow and metastasize, threatening life. Distinguishing between these different clinical behaviours using clinical/pathological criteria is currently problematic. It is reported that many suspicious lesions and early cancers are being removed surgically that would not threaten the patient's life. This has been termed 'overdiagnosis', especially in the sphere of cancer screening. Although a controversial and emotive topic, it poses clinical and public health policy challenges. The diagnostic differentiation between 'non-lethal' and 'lethal' tumor forms is generally impossible. One perspective gathering evidential support is that a dynamic balance exists between the immune response and malignant processes governing 'lethality', where many more cancers are produced than become clinically significant due to the immune system preventing their progression. Higher medical screening "diagnosis" rates may reflect lead-time effects, with more 'non-progressing' cancers detected when an early immune-cancer interaction is occurring. We present a model for this immune-cancer interaction and review 'excess' or 'overdiagnosis' claims that accompany increasingly sensitive diagnostic and screening technologies. We consider that immune tools should be incorporated into future research, with potential for immune system modulation for some early cancers.

Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

BACKGROUND: For stage IV melanoma, systemic medical therapy (SMT) is used most frequently; surgery is considered an adjunct in selected patients. We retrospectively compared survival after surgery with or without SMT versus SMT alone for melanoma patients developing distant metastases while enrolled in the first Multicenter Selective Lymphadenectomy Trial. METHODS: Patients were randomized to wide excision and sentinel node biopsy, or wide excision and nodal observation. We evaluated recurrence site, therapy (selected by treating clinician), and survival after stage IV diagnosis. RESULTS: Of 291 patients with complete data for stage IV recurrence, 161 (55 %) underwent surgery with or without SMT. Median survival was 15.8 versus 6.9 months, and 4-year survival was 20.8 versus 7.0 % for patients receiving surgery with or without SMT versus SMT alone (p < 0.0001; hazard ratio 0.406). Surgery with or without SMT conferred a survival advantage for patients with M1a (median > 60 months vs. 12.4 months; 4-year survival 69.3 % vs. 0; p = 0.0106), M1b (median 17.9 vs. 9.1 months; 4-year survival 24.1 vs. 14.3 %; p = 0.1143), and M1c (median 15.0 vs. 6.3 months; 4-year survival 10.5 vs. 4.6 %; p = 0.0001) disease. Patients with multiple metastases treated surgically had a survival advantage, and number of operations did not reduce survival in the 67 patients (42 %) who had multiple surgeries for distant melanoma. CONCLUSIONS: Our findings suggest that over half of stage IV patients are candidates for resection and exhibit improved survival over patients receiving SMT alone, regardless of site and number of metastases. We have begun a multicenter randomized phase III trial comparing surgery versus SMT as initial treatment for resectable distant melanoma.

Cutaneous malignant melanoma incidence is strongly associated with European depigmented skin type regardless of ambient ultraviolet radiation levels: evidence from Worldwide population-based data.

Current public health advice is that high ultraviolet radiation (UVR) exposure is the primary cause of Malignant Melanoma of skin (CMM), however, despite the use of sun-blocking products incidence of melanoma is increasing. To investigate the UVR influence on CMM incidence worldwide WHO, United Nations, World Bank databases and literature provided 182 country-specific melanoma incidence estimates, daily UVR levels, skin colour (EEL), socioeconomic status (GDP PPP), magnitude of reduced natural selection (Ibs), ageing, urbanization, percentage of European descendants (Eu%), and depigmentation (blonde hair colour), for parametric and non-parametric correlations, multivariate regressions and analyses of variance. Worldwide, UVR levels showed negative correlation with melanoma incidence ("rho" = -0.515, p < 0.001), remaining significant and negative in parametric partial correlation (r = -0.513, p < 0.001) with other variables kept constant. After standardising melanoma incidence for Eu%, melanoma correlation with UVR disappeared completely ("rho" = 0.004, p = 0.967, n = 127). The results question classical views that UVR causes melanoma. No correlation between UVR level and melanoma incidence was present when Eu% (depigmented or light skin type) was kept statistically constant, even after adjusting for other known variables. Countries with lower UVR levels and more Eu% (depigmented or light skin people) have higher melanoma incidence. Critically, this means that individual genetic low skin pigmentation factors predict melanoma risk regardless of UVR exposure levels, and even at low-UVR levels.

Chronovaccination: Harnessing circadian rhythms to optimize immunisation strategies.

Vaccination, as a public health measure, offers effective protection of populations against infectious diseases. Optimising vaccination efficacy, particularly for higher-risk individuals, like the elderly whose immunocompromised state can prevent the development of robust vaccine responses, is vital. It is now clear that 24-hour circadian rhythms, which govern virtually all aspects of physiology, can generate oscillations in immunological responses. Consequently, vaccine efficacy may depend critically on the time of day of administration(s), including for Covid-19, current vaccines, and any future diseases or pandemics. Published clinical vaccine trials exploring diurnal immune variations suggest this approach could represent a powerful adjunct strategy for optimising immunisation, but important questions remain to be addressed. This review explores the latest insights into diurnal immune variation and the outcomes of circadian timing of vaccination or 'chronovaccination'.