Hyperlactataemia is a marker of reduced exercise capacity in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non-cardiac dyspnoea (NCD), and healthy volunteers. METHODS AND RESULTS: Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom-limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P = 0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P < 0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P < 0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52 W (interquartile range 31-73), 150 W (125-175), P < 0.001], but not NCD [53 W (33, 75), P = 0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08 mmol/L/W (0.05-0.11), 0.06 mmol/L/W (0.05-0.08; P = 0.016) in NCD, and 0.04 mmol/L/W (0.03-0.05; P < 0.001) in volunteers. Exercise cardiac index was 4.5 L/min/m2 (3.7-5.5) in HFpEF, 5.2 L/min/m2 (4.3-6.2; P < 0.001) in NCD, and 9.1 L/min/m2 (8.0-9.9; P < 0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553 mL/min (1175-1986) vs. 1758 mL/min (1361-2282; P = 0.024) in NCD and 3117 mL/min (2667-3502; P < 0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P < 0.001). CONCLUSIONS: HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies.

Efficacy of immune checkpoint inhibitors for in-transit melanoma.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM. METHODS: A retrospective review of patients with ITM commenced on an ICI between March 2013 and February 2018 at three tertiary centers in Australia. Patients were excluded if they had previous or synchronous distant metastases. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were based on a composite of radiological and clinical assessments. RESULTS: Fifty-four patients were included: 27 (50%) female; median age 75 (range 26-94); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10 (19%) BRAF mutant. Forty (74%) received single-agent anti-PD-1 (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PD-L1 (atezolizumab) and MEK inhibitor (cobimetinib). The median follow-up was 15 months (2-46).ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single-agent anti-PD-1, 38% for single-agent anti-CTLA4 and 40% for anti-PD-1/anti-CTLA-4. The median PFS was 11.7 months (6.6-not reached). 1-year and 2-year PFS were 48% and 39%, respectively,. Fourteen progressed locoregionally and 11 progressed distantly. The median OS was not reached. 1-year and 2-year OS were 85% and 63%, respectively. No clinicopathological features were associated with ORR. CONCLUSIONS AND RELEVANCE: ICI produce objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence.

Systemic therapies for unresectable locoregional melanoma: a significant area of need.

Immune checkpoint inhibitors and BRAF-MEK inhibitors have revolutionized the management and prognosis of patients with metastatic melanoma. However, there is minimal evidence to guide their incorporation into current treatment paradigms for unresectable stage III disease. The era of effective systemic therapies has prompted a discussion about what constitutes unresectable disease. Patients with unresectable stage III disease can experience significant morbidity from their disease and locoregional therapies, and may progress with distant metastases. Despite increasing use of systemic therapies in unresectable stage III disease, further evidence is needed to establish their degree of benefit in this population.

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.

Management of in-transit melanoma metastases: a review.

In-transit metastases (ITM) of cutaneous melanoma are locoregional recurrences confined to the superficial lymphatics that occur in 3.4-6.2% of patients diagnosed with melanoma. ITM are a heterogeneous disease that poses a therapeutic dilemma. Patients may have a prolonged disease trajectory involving multiple or repeat treatment modalities for frequent recurrences. The management of ITM has evolved without the development of a standardized protocol. Owing to the variability of the disease course there are few dedicated clinical trials, with a number of key trials in stage III melanoma excluding ITM patients. Thus, there is a paucity of quality data on the efficacy of the treatment modalities available for ITM and even fewer studies directly comparing modalities. At present the mainstay of ITM treatment is surgical resection, with intralesional therapies, isolated limb infusion and radiotherapy utilized as second-line measures. The developing role of targeted therapies and immunotherapy has yet to be explored completely in these patients. This review addresses the evidence base of the efficacy of the various treatment modalities available and those factors that have impacted their clinical uptake.