IMPORTANCE Methadone access may be uniquely vulnerable to disruption during COVID-19, and even short delays in access are associated with decreased medication initiation and increased illicit opioid use and overdose death. Relative to Canada, US methadone provision is more restricted and limited to specialized opioid treatment programs. OBJECTIVE To compare timely access to methadone initiation in the US and Canada during COVID-19. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was conducted from May to June 2020. Participating clinics provided methadone for opioid use disorder in 14 US states and territories and 3 Canadian provinces with the highest opioid overdose death rates. Statistical analysis was performed from July 2020 to January 2021. EXPOSURES Nation and type of health insurance (US Medicaid and US self-pay vs Canadian provincial). MAIN OUTCOMES AND MEASURES Proportion of clinics accepting new patients and days to first appointment. RESULTS Among 268 of 298 US clinics contacted as a patient with Medicaid (90%), 271 of 301 US clinics contacted as a self-pay patient (90%), and 237 of 288 Canadian clinics contacted as a patient with provincial insurance (82%), new patients were accepted for methadone at 231 clinics (86%) during US Medicaid contacts, 230 clinics (85%) during US self-pay contacts, and at 210 clinics (89%)during Canadian contacts. Among clinics not accepting new patients, at least 44% of 27 clinics reported that the COVID-19 pandemic was the reason. The mean wait for first appointment was greater among US Medicaid contacts (3.5 days [95% CI, 2.9-4.2 days]) and US self-pay contacts (4.1 days [95% CI, 3.4-4.8 days]) than Canadian contacts (1.9 days [95% CI, 1.7-2.1 days]) (P < .001).Open-access model (walk-in hours for new patients without an appointment) utilization was reported by 57 Medicaid (30%), 57 self-pay (30%), and 115 Canadian (59%) contacts offering an appointment. CONCLUSIONS AND RELEVANCEIn this cross-sectional study of 2 nations, more than 1 in 10 methadone clinics were not accepting new patients. Canadian clinics offered more timely methadone access than US opioid treatment programs. These results suggest that the methadone access shortage was exacerbated by COVID-19 and that changes to the US opioid treatment program model are needed to improve the timeliness of access. Increased open-access model adoption may increase timely access.

BackgroundCheckpoint inhibitors (CPIs) are thought to be effective against cutaneous melanoma in part because of the large burden of somatic mutations (neoantigens) generated from exposure to ultraviolet radiation. However, rare melanoma subtypes arising from acral skin, mucosal surfaces, and the uveal tract are largely sun-shielded. Genomic studies show these sun-shielded melanomas have a paucity of neoantigens and unique biology; they are thought to be largely resistant to immunotherapy. It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma.MethodsWe reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma. Primary tumor histology was categorized as cutaneous, unknown, acral, mucosal, or uveal. We studied demographic data, treatment characteristics, and overall survival (OS) after CPI.ResultsWe treated 428 patients with metastatic melanoma from 2007 to 2019. Primary tumors were cutaneous in 283 (66%), unknown in 55 (13%), acral in 22 (5%), mucosal in 38 (9%), and uveal in 30 (7%). Patients with metastatic disease from cutaneous primary tumors had median OS after CPI of 45 months compared with 17 months for acral (p=0.047), 18 months for mucosal (p=0.003), and 12 months for uveal (p<0.001). For all patients with sun-shielded melanoma (n=90), first treatment with anti-PD-1 or anti-PD-L1 was followed by a median OS of 9 months compared with 18 months after anti-CTLA-4 (p=0.010) and 20 months after combination therapy (p=0.003). There were 21 patients who achieved actual 3-year survival; 20 received both anti-CTLA-4 and anti-PD-1, either sequentially or in combination. Over 80% of 3-year survivors with progressive disease were treated with local therapy after CPI.ConclusionsLong survival in patients with metastatic melanoma from acral, mucosal, and uveal primary tumors was associated with receipt of both anti-CTLA-4 and anti-PD-1 antibodies. Complete responses were rare, and local therapy was frequently employed to control disease progression. While sun-shielded melanomas exhibit worse outcomes after CPI than cutaneous melanomas, with an aggressive multidisciplinary approach, 5-year survival is still possible for 25%–32% of these patients.

Background Checkpoint inhibitors (CPI) have revolutionized the treatment of metastatic melanoma, but most patients treated with CPI eventually develop progressive disease. Local therapy including surgery, ablation or stereotactic body radiotherapy (SBRT) may be useful to manage limited progression, but criteria for patient selection have not been established. Previous work has suggested progression-free survival (PFS) after local therapy is associated with patterns of immunotherapy failure, but this has not been studied in patients treated with CPI. Methods We analyzed clinical data from patients with metastatic melanoma who were treated with antibodies against CTLA-4, PD-1 or PD-L1, either as single-agent or combination therapy, and identified those who had disease progression in 1 to 3 sites managed with local therapy. Patterns of CPI failure were designated by independent radiological review as growth of established metastases or appearance of new metastases. Local therapy for diagnosis, palliation or CNS metastases was excluded. Results Four hundred twenty-eight patients with metastatic melanoma received treatment with CPI from 2007 to 2018. Seventy-seven have ongoing complete responses while 69 died within 6 months of starting CPI; of the remaining 282 patients, 52 (18%) were treated with local therapy meeting our inclusion criteria. Local therapy to achieve no evidence of disease (NED) was associated with three-year progression-free survival (PFS) of 31% and five-year disease-specific survival (DSS) of 60%. Stratified by patterns of failure, patients with progression in established tumors had three-year PFS of 70%, while those with new metastases had three-year PFS of 6% ( P = 0.001). Five-year DSS after local therapy was 93% versus 31%, respectively ( P = 0.046). Conclusions Local therapy for oligoprogression after CPI can result in durable PFS in selected patients. We observed that patterns of failure seen during or after CPI treatment are strongly associated with PFS after local therapy, and may represent a useful criterion for patient selection. This experience suggests there may be an increased role for local therapy in patients being treated with immunotherapy.

Diffuse intrinsic pontine glioma (DIPG) is a devastating disease with an extremely poor prognosis. Recent studies have shown that platelet-derived growth factor receptor (PDGFR) and its downstream effector pathway, PI3K/AKT/mTOR, are frequently amplified in DIPG, and potential therapies targeting this pathway have emerged. However, the addition of targeted single agents has not been found to improve clinical outcomes in DIPG, and targeting this pathway alone has produced insufficient clinical responses in multiple malignancies investigated, including lung, endometrial, and bladder cancers. Acquired resistance also seems inevitable. Activation of the Ras/Raf/MEK/ERK pathway, which shares many nodes of cross talk with the PI3K/AKT pathway, has been implicated in the development of resistance. In the present study, perifosine, a PI3K/AKT pathway inhibitor, and trametinib, a MEK inhibitor, were combined, and their therapeutic efficacy on DIPG cells was assessed. Growth delay assays were performed with each drug individually or in combination. Here, we show that dual inhibition of PI3K/AKT and MEK/ERK pathways synergistically reduced cell viability. We also reveal that trametinib induced AKT phosphorylation in DIPG cells that could not be effectively attenuated by the addition of perifosine, likely due to the activation of other compensatory mechanisms. The synergistic reduction in cell viability was through the pronounced induction of apoptosis, with some effect from cell cycle arrest. We conclude that the concurrent inhibition of the PI3K/AKT and MEK/ERK pathways may be a potential therapeutic strategy for DIPG.