Squamous Cell Carcinoma with Regional Metastasis to Axilla or Groin Lymph Nodes: a Multicenter Outcome Analysis.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) of the trunk/extremities with nodal metastasis represents a rare but significant clinical challenge. Treatment patterns and outcomes are poorly described. PATIENTS AND METHODS: Patients with cSCC who developed axilla/groin lymph node metastasis and underwent curative-intent surgery between 2005 and 2015 were identified at four Canadian academic centers. Demographics, tumor characteristics, treatment patterns, recurrence rates, and mortality were described. Overall survival (OS) and disease-free survival (DFS) were calculated using Kaplan-Meier analysis. Predictors of survival and any recurrence were explored using Cox regression and logistic regression models, respectively. RESULTS: Of 43 patients, 70% were male (median age 74 years). Median follow-up was 38 months. Median time to nodal metastasis was 11.3 months. Thirty-one and 12 patients had nodal metastasis to the axilla and groin, respectively. A total of 72% and 7% received adjuvant and neoadjuvant radiation, respectively, while 5% received adjuvant chemotherapy. Following surgery, 26% patients developed nodal and/or distant disease recurrence. Crude mortality rate was 39.5%. Mean OS was 5.3 years [95% confidence interval (CI) 3.9-6.8 years], and 5-year OS was 55.1%. Mean DFS was 4.8 years (95% CI 3.3-6.2 years), and five-year DFS was 49.3%. Any recurrence was the only independent predictor of death [p = 0.036, odds ratio (OR) = 29.5], and extracapsular extension (p = 0.028, OR = 189) and age (p = 0.017, OR = 0.823) were independent predictors of recurrence. CONCLUSIONS: This represents the largest contemporary series to date of outcomes for patients with axilla/groin nodal metastases from cSCC. Despite aggressive treatment, outcomes remain modest, indicating the need for a continued multidisciplinary approach and integration of new systemic agents.

The effect of plasma osmolality and baroreceptor loading status on postexercise heat loss responses.

We examined the separate and combined effects of plasma osmolality and baroreceptor loading status on postexercise heat loss responses. Nine young males completed a 45-min treadmill exercise protocol at 58 ± 2% V̇o2 peak, followed by a 60-min recovery. On separate days, participants received 0.9% NaCl (ISO), 3.0% NaCl (HYP), or no infusion (natural recovery) throughout exercise. In two additional sessions (no infusion), lower-body negative (LBNP) or positive (LBPP) pressure was applied throughout the final 45 min of recovery. Local sweat rate (LSR; ventilated capsule: chest, forearm, upper back, forehead) and skin blood flow (SkBF; laser-Doppler flowmetry: forearm, upper back) were continuously measured. During HYP, upper back LSR was attenuated from end-exercise to 10 min of recovery by ∼0.35 ± 0.10 mg·min(-1)·cm(-2) and during the last 20 min of recovery by ∼0.13 ± 0.03 mg·min(-1)·cm(-2), while chest LSR was lower by 0.18 ± 0.06 mg·min(-1)·cm(-2) at 50 min of recovery compared with natural recovery (all P < 0.05). Forearm and forehead LSRs were not affected by plasma hyperosmolality during HYP (all P > 0.28), which suggests regional differences in the osmotic modulation of postexercise LSR. Furthermore, LBPP application attenuated LSR by ∼0.07-0.28 mg·min(-1)·cm(-2) during the last 30 min of recovery at all sites except the forehead compared with natural recovery (all P < 0.05). Relative to natural recovery, forearm and upper back SkBF were elevated during LBPP, ISO, and HYP by ∼6-10% by the end of recovery (all P < 0.05). We conclude that 1) hyperosmolality attenuates postexercise sweating heterogeneously among skin regions, and 2) baroreceptor loading modulates postexercise SkBF independently of changes in plasma osmolality without regional differences.

Muscle metaboreceptors modulate postexercise sweating, but not cutaneous blood flow, independent of baroreceptor loading status.

We examined whether sustained changes in baroreceptor loading status during prolonged postexercise recovery can alter the metaboreceptors' influence on heat loss. Thirteen young males performed a 1-min isometric handgrip exercise (IHG) at 60% maximal voluntary contraction followed by 2 min of forearm ischemia (to activate metaboreceptors) before and 15, 30, 45, and 60 min after a 15-min intense treadmill running exercise (>90% maximal heart rate) in the heat (35°C). This was repeated on three separate days with continuous lower body positive (LBPP, +40 mmHg), negative (LBNP, -20 mmHg), or no pressure (Control) from 13- to 65-min postexercise. Sweat rate (ventilated capsule; forearm, chest, upper back) and cutaneous vascular conductance (CVC; forearm, upper back) were measured. Relative to pre-IHG levels, sweating at all sites increased during IHG and remained elevated during ischemia at baseline and similarly at 30, 45, and 60 min postexercise (site average sweat rate increase during ischemia: Control, 0.13 ± 0.02; LBPP, 0.12 ± 0.02; LBNP, 0.15 ± 0.02 mg·min(-1)·cm(-2); all P < 0.01), but not at 15 min (all P > 0.10). LBPP and LBNP did not modulate the pattern of sweating to IHG and ischemia (all P > 0.05). At 15-min postexercise, forearm CVC was reduced from pre-IHG levels during both IHG and ischemia under LBNP only (ischemia: 3.9 ± 0.8% CVCmax; P < 0.02). Therefore, we show metaboreceptors increase postexercise sweating in the middle to late stages of recovery (30-60 min), independent of baroreceptor loading status and similarly between skin sites. In contrast, metaboreflex modulation of forearm but not upper back CVC occurs only in the early stages of recovery (15 min) and is dependent upon baroreceptor unloading.

Local infusion of ascorbate augments NO-dependent cutaneous vasodilatation during intense exercise in the heat.

Recent work demonstrates that nitric oxide (NO) contributes to cutaneous vasodilatation during moderate (400 W of metabolic heat production) but not high (700 W of metabolic heat production) intensity exercise bouts performed in the heat (35°C). The present study evaluated whether the impairment in NO-dependent cutaneous vasodilatation was the result of a greater accumulation of reactive oxygen species during high (700 W of metabolic heat production) relative to moderate (500 W of metabolic heat production) intensity exercise. It was shown that local infusion of ascorbate (an anti-oxidant) improves NO-dependent forearm cutaneous vasodilatation during high intensity exercise in the heat. These findings provide novel insight into the physiological mechanisms governing cutaneous blood flow during exercise-induced heat stress and provide direction for future research exploring whether oxidative stress underlies the impairments in heat dissipation that may occur in older adults, as well as in individuals with pathophysiological conditions such as type 2 diabetes. Nitric oxide (NO)-dependent cutaneous vasodilatation is reportedly diminished during exercise performed at a high (700 W) relative to moderate (400 W) rate of metabolic heat production. The present study evaluated whether this impairment results from increased oxidative stress associated with an accumulation of reactive oxygen species (ROS) during high intensity exercise. On two separate days, 11 young (mean ± SD, 24 ± 4 years) males cycled in the heat (35°C) at a moderate (500 W) or high (700 W) rate of metabolic heat production. Each session included two 30 min exercise bouts followed by 20 and 40 min of recovery, respectively. Cutaneous vascular conductance (CVC) was monitored at four forearm skin sites continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control); (2) 10 mm ascorbate (Ascorbate); (3) 10 mm l-NAME; or (4) 10 mm ascorbate + 10 mm l-NAME (Ascorbate + l-NAME). At the end of each 500 W exercise bout, CVC was attenuated with l-NAME (∼35% CVCmax ) and Ascorbate + l-NAME (∼43% CVCmax ) compared to Control (∼60% CVCmax ; all P < 0.04); however, Ascorbate did not modulate CVC during exercise (∼60% CVCmax ; both P > 0.87). Conversely, CVC was elevated with Ascorbate (∼72% CVCmax ; both P < 0.03) but remained similar to Control (∼59% CVCmax ) with l-NAME (∼50% CVCmax ) and Ascorbate + l-NAME (∼47% CVCmax ; all P > 0.05) at the end of both 700 W exercise bouts. We conclude that oxidative stress associated with an accumulation of ascorbate-sensitive ROS impairs NO-dependent cutaneous vasodilatation during intense exercise.

Do nitric oxide synthase and cyclooxygenase contribute to the heat loss responses in older males exercising in the heat?

This study evaluated the separate and combined roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in forearm sweating and cutaneous vasodilatation in older adults during intermittent exercise in the heat. Twelve healthy older (62 ± 7 years) males performed two 30 min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C, 20% relative humidity). The exercise bouts were followed by 20 and 40 min of recovery, respectively. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) were evaluated at four skin sites that were continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control), (2) 10 mm ketorolac (non-selective COX inhibitor), (3) 10 mm N(G) -nitro-l-arginine methyl ester (l-NAME; non-selective NOS inhibitor) or (4) a combination of 10 mm ketorolac + 10 mm l-NAME. Sweating was not different between the four sites during either exercise bout (main effect P = 0.92) (average of last 5 min of second exercise, Control, 0.80 ± 0.06; ketorolac, 0.77 ± 0.09; l-NAME, 0.74 ± 0.07; ketorolac + l-NAME, 0.77 ± 0.09 mg min(-1) cm(-2) ). During both exercise bouts, relative to CVC evaluated at the Control site (average of last 5 min of second exercise, 69 ± 6%max), CVC was similar at the ketorolac site (P = 0.62; 66 ± 4%max) whereas it was attenuated to a similar extent at both the l-NAME (49 ± 8%max) and ketorolac + l-NAME (54 ± 8%max) sites (both P < 0.05). Thus, we demonstrate that NOS and COX are not functionally involved in forearm sweating whereas only NOS contributes to forearm cutaneous vasodilatation in older adults during intermittent exercise in the heat.

Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 µM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 µM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P < 0.05). However, during both exercise bouts, there were no differences in CVC or sweating between the treatment sites (all P > 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P < 0.05). We show angiotensin II impairs cutaneous perfusion independent of oxidative stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise.

Mechanisms underlying the postexercise baroreceptor-mediated suppression of heat loss.

Reports indicate that postexercise heat loss is modulated by baroreceptor input; however, the mechanisms remain unknown. We examined the time-dependent involvement of adenosine receptors, noradrenergic transmitters, and nitric oxide (NO) in modulating baroreceptor-mediated changes in postexercise heat loss. Eight males performed two 15-min cycling bouts (85% VO2max) each followed by a 45-min recovery in the heat (35°C). Lower body positive (LBPP), negative (LBNP), or no (Control) pressure were applied in three separate sessions during the final 30-min of each recovery. Four microdialysis fibres in the forearm skin were perfused with: (1) lactated Ringer's (Ringer's); (2) 4 mmol·L(-1) Theophylline (inhibits adenosine receptors); (3) 10 mmol·L(-1) Bretylium (inhibits noradrenergic transmitter release); or (4) 10 mmol·L(-1) l-NAME (inhibits NO synthase). We measured cutaneous vascular conductance (CVC; percentage of maximum) calculated as perfusion units divided by mean arterial pressure, and local sweat rate. Compared to Control, LBPP did not influence CVC at l-NAME, Theophylline or Bretylium during either recovery (P > 0.07); however, CVC at Ringer's was increased by ~5-8% throughout 30 min of LBPP during Recovery 1 (all P < 0.02). In fact, CVC at Ringer's was similar to Theophylline and Bretylium during LBPP. Conversely, LBNP reduced CVC at all microdialysis sites by ~7-10% in the last 15 min of Recovery 2 (all P < 0.05). Local sweat rate was similar at all treatment sites as a function of pressure condition (P > 0.10). We show that baroreceptor input modulates postexercise CVC to some extent via adenosine receptors, noradrenergic vasoconstriction, and NO whereas no influence was observed for postexercise sweating.

Cyclooxygenase inhibition does not alter methacholine-induced sweating.

Cholinergic agents (e.g., methacholine) induce cutaneous vasodilation and sweating. Reports indicate that either nitric oxide (NO), cyclooxygenase (COX), or both can contribute to cholinergic cutaneous vasodilation. Also, NO is reportedly involved in cholinergic sweating; however, whether COX contributes to cholinergic sweating is unclear. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) were evaluated in 10 healthy young (24 ± 4 yr) adults (7 men, 3 women) at four skin sites that were continuously perfused via intradermal microdialysis with 1) lactated Ringer (control), 2) 10 mM ketorolac (a nonselective COX inhibitor), 3) 10 mM N(G)-nitro-l-arginine methyl ester (l-NAME, a nonselective NO synthase inhibitor), or 4) a combination of 10 mM ketorolac + 10 mM l-NAME. At the four skin sites, methacholine was simultaneously infused in a dose-dependent manner (1, 10, 100, 1,000, 2,000 mM). Relative to the control site, forearm CVC was not influenced by ketorolac throughout the protocol (all P > 0.05), whereas l-NAME and ketorolac + l-NAME reduced forearm CVC at and above 10 mM methacholine (all P < 0.05). Conversely, there was no main effect of treatment site (P = 0.488) and no interaction of methacholine dose and treatment site (P = 0.711) on forearm sweating. Thus forearm sweating (in mg·min(-1)·cm(-2)) from baseline up to the maximal dose of methacholine was not different between the four sites (at 2,000 mM, control 0.50 ± 0.23, ketorolac 0.44 ± 0.23, l-NAME 0.51 ± 0.22, and ketorolac + l-NAME 0.51 ± 0.23). We show that both NO synthase and COX inhibition do not influence cholinergic sweating induced by 1-2,000 mM methacholine.