The features and management of acquired resistance to PD1-based therapy in metastatic melanoma.

BACKGROUND: Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown. METHODS: Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated. RESULTS: 299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001). CONCLUSIONS: Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.

Photobiomodulation therapy combined with static magnetic field is better than placebo in patients with fibromyalgia: a randomized placebo-controlled trial.

BACKGROUND: Fibromyalgia is a syndrome characterized by generalized chronic pain and tenderness in specific areas. Photobiomodulation therapy (PBMT) using low-level laser therapy and/or light emitting diode therapy is an electrophysical agent that can be used alone or together with a static magnetic field (PBMT-sMF) to promote analgesia in several health conditions. Little evidence exists regarding the effects of using PBMT and PBMT-sMF in patients with fibromyalgia; this evidence is conflicting. AIM: We aimed to investigate the effects of using PBMT-sMF versus a placebo on reduction of the degree-of-pain rating, impact of fibromyalgia, pain intensity, and satisfaction with treatment in patients with fibromyalgia. DESIGN: A prospectively registered, monocentric, randomized placebo-controlled trial, with blinding of patients, therapists, and assessors, was performed. SETTING: The study was conducted at the Laboratory of Phototherapy and Innovative Technologies in Health (LaPIT) in Brazil, between March and October 2020. POPULATION: Ninety female patients with fibromyalgia were randomized to undergo either PBMT-sMF (N.=45) or placebo (N.=45) treatment. METHODS: Patients from both groups received nine treatment sessions, three times a week, for 3 weeks. Clinical outcomes were collected at baseline, the end of treatment, and at the follow-up appointment 4 weeks post-treatment. The primary outcome was the degree-of-pain rating, measured by the reduction of the tender point count. RESULTS: A decrease in the degree-of-pain rating was observed in patients allocated to the PBMT-sMF group, decreasing the number of tender points when compared to placebo group at the end of treatment (P<0.0001) and at the follow-up assessment (P<0.0001). Patients did not report any adverse events. CONCLUSIONS: PBMT-sMF is superior to placebo, supporting its use in patients with fibromyalgia. CLINICAL REHABILITATION IMPACT: PBMT-sMF might be considered an important adjuvant to the treatment regimens of patients with fibromyalgia.

Photobiomodulation therapy combined with static magnetic field in tibial fracture healing of a dog: A case report.

A 10-week-old male, Xoloitzcuintle (Mexican hairless dog), weighing 8.9 kg was presented after its owner accidentally stepped on its paw. The dog presented with acute pain, inflammation and grade IV lameness in the right hind paw. A complete transverse fracture in the right proximal tibia was diagnosed from radiography. The dog underwent a minimally invasive plate osteosynthesis (MIPO) procedure. After surgery, photobiomodulation therapy combined with static magnetic field (PBMT-sMF) was applied twice daily for 21 days. A multi-wavelength PBMT-sMF device was applied at three sites using different frequencies: proximal and distal of the fracture zone (3000 Hz, 40.35 J per site, and 300 s per site) and in the fracture zone (250 Hz, 39.11 J and 300 s per site). Follow up radiographies were performed after surgery and treatment with PBMT-sMF. Eighteen days post-surgery the healing process of bone was advanced. Fifty-five days post-surgery the callus was enlarged. In addition, radiographic union and clinical union was evidenced by closure of the fracture gap. This case report has reported the use of PBMT-sMF in order to accelerate and improve bone healing following a MIPO procedure on a complete transverse fracture in the proximal tibia of a puppy.

Photobiomodulation Therapy Combined with Static Magnetic Field Reduces Pain in Patients with Chronic Nonspecific Neck and/or Shoulder Pain: A Randomized, Triple-Blinded, Placebo-Controlled Trial.

Photobiomodulation therapy (PBMT) has been used to treat patients with chronic neck and/or shoulder pain. However, it is unknown whether the concurrent use of PBMT and static magnetic field (PBMT-sMF) also has positive effects in these patients. The aim of this study was to investigate the effects of PBMT-sMF versus placebo on pain intensity, range of motion (ROM) and treatment satisfaction in patients with chronic nonspecific neck and/or shoulder pain. A randomized controlled trial, with blinded assessors, therapists and patients was carried out. Seventy-two patients with chronic nonspecific neck and/or shoulder pain were randomized to either active PBMT-sMF (n = 36) or placebo PBMT-sMF (n = 36). Patients were treated twice weekly, over 3 weeks. Primary outcome was pain intensity, measured 15 min after the last treatment session and at 24-, 48-, 72-h, and 7-days after the last treatment. Secondary outcomes were ROM, patient' treatment satisfaction, and adverse effects. PBMT-sMF was able to reduce pain intensity in all time points tested compared to placebo (p < 0.05). There was no difference between groups in the secondary outcomes (p > 0.05). Our results suggest that PBMT-sMF is better than placebo to reduce pain in patients with chronic nonspecific neck and/or shoulder pain at short-term.

Low-intensity LASER and LED (photobiomodulation therapy) for pain control of the most common musculoskeletal conditions.

Pain is the most common reason for physician consultations and the number one reason for missed work or school days is musculoskeletal pain. Pain management is utilized for easing the suffering and improving the Quality of Life of those living with chronic pain. Over the past several decades, physicians have become increasingly willing to prescribe opioids to manage pain. However, the opioid use can cause side effects as poor coordination, sedation, mood swings, depression, and anxiety combined with a dependence on the drugs. In the rehabilitation setting, patients benefit most when their health providers utilize a multimodal approach combining different types of therapies and when patients take on a significant role in optimal management of their own pain. The use of light as a therapeutic alternative form of medicine to manage pain and inflammation has been proposed to fill this void. Photobiomodulation therapy applied in the form of low-intensity Light Amplification by Stimulated Emission of Radiation (LASER) and light-emitting diode (LED) has been shown to reduce inflammation and swelling, promote healing, and reduce pain for an array of musculoskeletal conditions. There is evidence that photobiomodulation therapy reduces pain intensity in non-specific knee pain, osteoarthritis, pain post-total hip arthroplasty, fibromyalgia, temporomandibular diseases, neck pain, and low back pain. Therefore, the purpose of this paper was to present the up-to-dated evidence about the effects of low-intensity LASER and LED (photobiomodulation therapy) on pain control of the most common musculoskeletal conditions. We observed that the photobiomodulation therapy offers a non-invasive, safe, drug-free, and side-effect-free method for pain relief of both acute and chronic musculoskeletal conditions as well as fibromyalgia.

Immediate effects of photobiomodulation therapy combined with a static magnetic field on the subsequent performance: a preliminary randomized crossover triple-blinded placebo-controlled trial.

There is evidence about the effects of photobiomodulation therapy (PBMT) alone and combined with a static magnetic field (PBMT-sMF) on skeletal muscle fatigue, physical performance and post-exercise recovery in different types of exercise protocols and sports activity. However, the effects of PBMT-sMF to improve the subsequent performance after a first set of exercises are unknown. Therefore, the aim of this study was to investigate the effects of PBMT-sMF, applied between two sets of exercises, on the subsequent physical performance. A randomized, crossover, triple-blinded (assessors, therapist, and volunteers), placebo-controlled trial was carried out. Healthy non-athlete male volunteers were randomized and treated with a single application of PBMT-sMF and placebo between two sets of an exercise protocol performed on isokinetic dynamometer. The order of interventions was randomized. The primary outcome was fatigue index and the secondary outcomes were total work, peak work, and blood lactate levels. Twelve volunteers were randomized and analyzed to each sequence. PBMT-sMF decreased the fatigue index compared to the placebo PBMT-sMF at second set of the exercise protocol (MD = -6.08, 95% CI -10.49 to -1.68). In addition, PBMT-sMF decreased the blood lactate levels post-intervention, and after the second set of the exercise protocol compared to placebo (p<0.05). There was no difference between PBMT-sMF and placebo in the remaining outcomes tested. Volunteers did not report adverse events. Our results suggest that PBMT-sMF is able to decrease skeletal muscle fatigue, accelerating post-exercise recovery and, consequently, increasing subsequent physical performance when applied between two sets of exercises.

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

PURPOSE: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. METHODS: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. RESULTS: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred. CONCLUSIONS: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

Cancer immunotherapy-related adverse events: causes and challenges.

Despite the success and ongoing promise of monoclonal antibody-targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint-targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

Photobiomodulation therapy as a tool to prevent hamstring strain injuries by reducing soccer-induced fatigue on hamstring muscles.

Muscle fatigue is a potential risk factor for hamstring strain injuries in soccer players. The aim of this study was to verify the effect of photobiomodulation therapy (PBMT) on the hamstrings' muscle fatigue of soccer players during a simulated match. Twelve male amateur soccer players (~ 25 years) participated in this randomized, crossover, double-blinded, placebo-controlled trial. The volunteers were evaluated in two sessions, with a minimum 7-day interval. At each session, volunteers received either PBMT (300 J per thigh) or placebo treatment on the hamstrings prior to the simulated soccer match. Muscle strength and functional capacity were evaluated through isokinetic dynamometry and countermovement jump (CMJ) tests, respectively, before and immediately after the simulated soccer match. Players had lower reductions on hamstring eccentric peak torque [4.85% (ES = 0.31) vs. 8.72% (ES = 0.50)], hamstring-to-quadriceps torque ratio [3.60% (ES = 0.24) vs. 7.75% (ES = 0.50)], and CMJ height [1.77% (ES = 0.09) vs. 5.47% (ES = 0.32)] when treated with PBMT compared to placebo. Magnitude-based inference supports that PBMT promoted 75%, 69%, and 53% chances for beneficial effects on hamstring eccentric peak torque, hamstring-to-quadriceps torque ratio, and CMJ height, respectively, compared to placebo treatment. In conclusion, PBMT applied before a simulated soccer match proved to be effective in attenuating the hamstrings' muscle fatigue. These findings support PBMT as a promising tool to prevent hamstring strain injury in soccer players.

Photobiomodulation therapy (PBMT) on acute pain and inflammation in patients who underwent total hip arthroplasty-a randomized, triple-blind, placebo-controlled clinical trial.

When conservative treatments fail, hip osteoarthritis (OA), a chronic degenerative disease characterized by cartilage wear, progressive joint deformity, and loss of function, can result in the need for a total hip arthroplasty (THA). Surgical procedures induced tissue trauma and incite an immune response. Photobiomodulation therapy (PBMt) using low-level laser therapy (LLLT) and/or light-emitting diode therapy (LEDT) has proven effective in tissue repair by modulating the inflammatory process and promoting pain relief. Therefore, the aim of this study was to analyze the immediate effect of PBMt on inflammation and pain of patients undergoing total hip arthroplasty. The study consisted of 18 post-surgical hip arthroplasty patients divided into two groups (n = 9 each) placebo and active PBMt who received one of the treatments in a period from 8 to 12 h following THA surgery. PBMt (active or placebo) was applied using a device consisting of nine diodes (one super-pulsed laser of 905 nm, four infrared LEDs of 875 nm, and four red LEDs 640 nm, 40.3 J per point) applied to 5 points along the incision. Visual analog scale (VAS) and blood samples for analysis of the levels of the cytokines TNF-α, IL-6, and IL-8 were recorded before and after PBMt application. The values for the visual analog scale as well as those in the analysis of TNF-α and IL-8 serum levels decreased in the active PBMt group compared to placebo-control group (p < 0.05). No decrease was observed for IL-6 levels. We conclude that PBMt is effective in decreasing pain intensity and post-surgery inflammation in patients receiving total hip arthroplasty.

Photobiomodulation therapy (PBMT) and/or cryotherapy in skeletal muscle restitution, what is better? A randomized, double-blinded, placebo-controlled clinical trial.

Cryotherapy for post-exercise recovery remains widely used despite the lack of quality evidence. Photobiomodulation therapy (PBMT) studies (with both low-level laser therapy and light-emitting diode therapy) have demonstrated positive scientific evidence to suggest its use. The study aims to evaluate PBMT and cryotherapy as a single or combined treatment on skeletal muscle recovery after eccentric contractions of knee extensors. Fifty healthy male volunteers were recruited and randomized into five groups (PBMT, cryotherapy, cryotherapy + PBMT, PMBT + cryotherapy, or placebo) for a randomized, double-blinded, placebo-controlled trial that evaluated exercise performance (maximum voluntary contraction (MVC)), delayed onset muscle soreness (DOMS), and muscle damage (creatine kinase (CK)). Assessments were performed at baseline; immediately after; and at 1, 24, 48, 72, and 96 h. Comparator treatments was performed 3 min after exercise and repeated at 24, 48, and 72 h. PBMT was applied employing a cordless, portable GameDay™ device (combination of 905 nm super-pulsed laser and 875- and 640-nm light-emitting diodes (LEDs); manufactured by Multi Radiance Medical™, Solon - OH, USA), and cryotherapy by flexible rubber ice packs. PBMT alone was optimal for post-exercise recovery with improved MVC, decreased DOMS, and CK activity (p < 0.05) from 24 to 96 h compared to placebo, cryotherapy, and cryotherapy + PBMT. In the PBMT + cryotherapy group, the effect of PBMT was decreased (p > 0.05) but demonstrated significant improvement in MVC, decreased DOMS, and CK activity (p < 0.05). Cryotherapy as single treatment and cryotherapy + PBMT were similar to placebo (p > 0.05). We conclude that PBMT used as single treatment is the best modality for enhancement of post-exercise restitution, leading to complete recovery to baseline levels from 24 h after high-intensity eccentric contractions.

Photobiomodulation Therapy Improves Performance and Accelerates Recovery of High-Level Rugby Players in Field Test: A Randomized, Crossover, Double-Blind, Placebo-Controlled Clinical Study.

Pinto, HD, Vanin, AA, Miranda, EF, Tomazoni, SS, Johnson, DS, Albuquerque-Pontes, GM, de Oliveira Aleixo Junior, I, Grandinetti, VdS, Casalechi, HL, de Tarso Camillo de Carvalho, P, and Pinto Leal Junior. Photobiomodulation therapy improves performance and accelerates recovery of high-level rugby players in field test: A randomized, crossover, double-blind, placebo-controlled clinical study. J Strength Cond Res 30(12): 3329-3338, 2016-Although growing evidence supports the use of photobiomodulation therapy (PBMT) for performance and recovery enhancement, there have only been laboratory-controlled studies. Therefore, the aim of this study was to analyze the effects of PBMT in performance and recovery of high-level rugby players during an anaerobic field test. Twelve male high-level rugby athletes were recruited in this randomized, crossover, double-blinded, placebo-controlled trial. No interventions were performed before the Bangsbo sprint test (BST) at familiarization phase (week 1); at weeks 2 and 3, pre-exercise PBMT or placebo were randomly applied to each athlete. Photobiomodulation therapy irradiation was performed at 17 sites of each lower limb, employing a cluster with 12 diodes (4 laser diodes of 905 nm, 4 light emitting diodes [LEDs] of 875 nm, and 4 LEDs of 640 nm, 30 J per site, manufactured by Multi Radiance Medical). Average time of sprints, best time of sprints, and fatigue index were obtained from BST. Blood lactate levels were assessed at baseline, and at 3, 10, 30, and 60 minutes after BST. Athletes' perceived fatigue was also assessed through a questionnaire. Photobiomodulation therapy significantly (p ≤ 0.05) improved the average time of sprints and fatigue index in BST. Photobiomodulation therapy significantly decreased percentage of change in blood lactate levels (p ≤ 0.05) and perceived fatigue (p ≤ 0.05). Pre-exercise PBMT with the combination of super-pulsed laser (low-level laser), red LEDs, and infrared LEDs can enhance performance and accelerate recovery of high-level rugby players in field test. This opens a new avenue for wide use of PBMT in real clinical practice in sports settings.

The thermal impact of phototherapy with concurrent super-pulsed lasers and red and infrared LEDs on human skin.

From the very first reports describing the method of action of phototherapy, the effects have been considered to be the result of photochemical and photophysical interactions between the absorbed photons and tissue and not related to secondary changes in tissue or skin temperature. However, thermal effects have been recently reported in dark pigmented skin when irradiated with single wavelengths of 810 and 904 nm of low-level laser therapy (LLLT) devices even with doses that do not exceed those recommended by the World Association of Laser Therapy (WALT). The aim of this study was to evaluate the thermal impact during the concurrent use of pulsed red and infrared LEDs and super-pulsed lasers when applied to light, medium, and dark pigmented human skin with doses typically seen in clinical practice. The study evaluated the skin temperature of 42 healthy volunteers (males and females 18 years or older, who presented different pigmentations, stratified according to Von Luschan's chromatic scale) via the use of a thermographic camera. Active irradiation was performed with using the multi-diode phototherapy cluster containing four 905-nm super-pulsed laser diodes (frequency set to 250 Hz), four 875-nm infrared-emitting diodes, and four 640-nm LEDs (manufactured by Multi Radiance Medical™, Solon, OH, USA). Each of the four doses were tested on each subject: placebo, 0 J (60 s); 10 J (76 s); 30 J (228 s); and 50 J (380 s). Data were collected during the last 5 s of each dose of irradiation and continued for 1 min after the end of each irradiation. No significant skin temperature increases were observed among the different skin color groups (p > 0.05), age groups (p > 0.05), or gender groups (p > 0.05). Our results indicate that the concurrent use of super-pulsed lasers and pulsed red and infrared LEDs can be utilized in patients with all types of skin pigmentation without concern over safety or excessive tissue heating. Additionally, the doses and device utilized in present study have demonstrated positive outcomes in prior clinical trials. Therefore, it can be concluded that the effects seen by the concurrent use of multiple wavelengths and light sources were the result of desirable photobiomodulation effect and not related to thermal influence.