Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma.

BACKGROUND: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT. METHODS: We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3 months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort. RESULTS: Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1 years at SFD and 1.2 years at RFD. The 3 year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2 years of therapy, total savings amounted to $1.1 million in drug costs and 384 h saved despite the extended DoT (median 3.4 years), as compared to the calculated cost of 2 years at SFD. CONCLUSIONS: ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials.

Gynecologic tract melanoma in the contemporary therapeutic era: High rates of local and distant disease progression.

BACKGROUND: Gynecologic tract melanoma (GTM) is a rare malignancy with historically poor outcomes. The current study examines patterns of care and oncologic outcomes in a large single-institution cohort from the contemporary therapeutic era. METHODS: Patterns of care and predictors of outcomes were evaluated for all GTM patients without metastatic disease at diagnosis who were treated at our institution between 2009 and 2020 with >6 months of follow-up. RESULTS: Of the 124 patients included, anatomic subsites were vulvar (n = 82, 66%), vaginal (n = 34, 27%), or cervical (n = 8, 6%). Primary tumor was resected for 85% (n = 106) with surgical nodal evaluation for 60% (n = 75). Systemic therapy, most commonly immune checkpoint inhibitors (ICI, 58% systemic therapy), was used to treat all except one unresectable patient (17/18) and 33% (35/106) of resectable patients. Seven patients received neoadjuvant ICI. Fourteen patients received adjuvant radiation therapy to the pelvis (RT, 13% of those undergoing resection). With a median follow-up of 45 months, 100 patients (81%) recurred. Four-year actuarial outcomes were: 46% local control, 53% nodal control, 36% distant metastasis-free survival, 17% disease-free survival, 49% melanoma-specific survival and 48% overall survival. Mitotic rate > 10/mm2, nodal involvement and non-vulvar anatomic subsite were associated with poor outcomes. Patients treated after 2016 did not have significantly better outcomes than those treated earlier. CONCLUSIONS: Patients with GTM continue to have poor outcomes in the contemporary therapeutic era with particularly notable poor local disease control relative to other mucosal melanoma subtypes. More effective oncologic therapy is needed.

Increasing availability of illicit and prescription opioids among people who inject drugs in a Canadian setting, 2010-2014.

BACKGROUND: Nonmedical use of prescription opioid and illicit opioid has been increasing at an alarming rate in North America over the past decade. OBJECTIVE: We sought to examine the temporal trends and correlates of the availability of illicit and prescription opioids among people who inject drugs (PWID) in Vancouver, Canada. METHODS: Data were derived from three prospective cohort studies of PWID in Vancouver between 2010 and 2014. In semiannual interviews, participants reported the availability of five sets of illicit and prescription opioids: (1) heroin; (2) Percocet (oxycodone/acetaminophen), Vicodin (hydrocodone/acetaminophen), or Demerol (meperidine); (3) Dilaudid (hydromorphone); (4) Morphine; (5) oxycontin/OxyNEO (controlled-release oxycodone). We defined perceived availability as immediate (e.g., available within 10 minutes) versus no availability/available after 10 minutes. The trend and correlation of immediate availability were identified by multivariable generalized estimating equations logistic regression. RESULTS: Among 1584 participants, of which 564 (35.6%) were female, the immediate availability of all illicit and prescribed opioids (except for oxycontin/OxyNEO) increased over time, independent of potential confounders. The Adjusted Odds Ratios of immediate availability associated with every calendar year increase were between 1.09 (95% confidence interval 1.05-1.12) (morphine and Dilaudid) and 1.13 (95% confidence interval 1.09-1.17) (Percocet/Vicodin/Demerol) (all p-values <0.05). CONCLUSION: The availability of most prescription opioids had continued to increase in recent years among our sample of PWID in Vancouver. Concurrent increases in the availability of heroin were also observed, raising concerns regarding combination of both illicit and prescription opioid use among PWID that could potentially increase the risk of overdose.

Neoadjuvant checkpoint inhibitor immunotherapy for resectable mucosal melanoma.

Background: Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for patients with resectable MM. Method: Under an institutionally approved protocol, we identified adult MM patients with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities. Results: We identified 36 patients. Median age was 62; 58% were female. Seventy-eight percent of patients received anti-PD1 + anti-CTLA4. Node positive disease or satellite lesions was present at the time of treatment initiation in 47% of patients. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of patients did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2 months with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for patients with objective response and for patients with pathologic response. OS was significantly higher for patients with pathologic response. Grade 3 toxicities were reported in 39% of patients. Conclusion: Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these patients.

Increasing diversion of methadone in Vancouver, Canada, 2005-2015.

BACKGROUND AND AIM: Although methadone, an opioid agonist, has been an effective medication used to treat opioid use disorder for over 40years, recent studies have found that methadone was identified in more than a quarter of prescription opioid-related deaths among people who use illicit drugs in Vancouver, Canada. Thus, we sought to longitudinally examine the availability of diverted methadone among people who inject drugs (PWID). DESIGN AND METHODS: Data were collected from three prospective cohorts of PWID in Vancouver, Canada between December 2005 and May 2015. Multivariable generalized estimating equation logistic regression was used to identify temporal trends in the immediate availability of diverted methadone (defined as the ability to acquire illicit methadone in <10min). RESULTS: A total of 2092 participants, including 727 (34.8%) women, were included in the present study. In the multivariable analyses after adjusting for a range of potential confounders, later calendar year (adjusted odds ratio [AOR]=1.21 per year; 95% confidence interval [CI]: 1.19-1.23) was independently and positively associated with reporting immediate availability of diverted methadone. CONCLUSIONS: We observed a significant increase in the reported availability of diverted methadone among PWID over a ten-year follow-up period. Further research is needed to identify strategies to limit methadone diversion and assess the impact of alternative medications that are equally effective but safer, such as buprenorphine/naloxone.

Deregulation of Rab and Rab effector genes in bladder cancer.

Growing evidence indicates that Rab GTPases, key regulators of intracellular transport in eukaryotic cells, play an important role in cancer. We analysed the deregulation at the transcriptional level of the genes encoding Rab proteins and Rab-interacting proteins in bladder cancer pathogenesis, distinguishing between the two main progression pathways so far identified in bladder cancer: the Ta pathway characterized by a high frequency of FGFR3 mutation and the carcinoma in situ pathway where no or infrequent FGFR3 mutations have been identified. A systematic literature search identified 61 genes encoding Rab proteins and 223 genes encoding Rab-interacting proteins. Transcriptomic data were obtained for normal urothelium samples and for two independent bladder cancer data sets corresponding to 152 and 75 tumors. Gene deregulation was analysed with the SAM (significant analysis of microarray) test or the binomial test. Overall, 30 genes were down-regulated, and 13 were up-regulated in the tumor samples. Five of these deregulated genes (LEPRE1, MICAL2, RAB23, STXBP1, SYTL1) were specifically deregulated in FGFR3-non-mutated muscle-invasive tumors. No gene encoding a Rab or Rab-interacting protein was found to be specifically deregulated in FGFR3-mutated tumors. Cluster analysis showed that the RAB27 gene cluster (comprising the genes encoding RAB27 and its interacting partners) was deregulated and that this deregulation was associated with both pathways of bladder cancer pathogenesis. Finally, we found that the expression of KIF20A and ZWINT was associated with that of proliferation markers and that the expression of MLPH, MYO5B, RAB11A, RAB11FIP1, RAB20 and SYTL2 was associated with that of urothelial cell differentiation markers. This systematic analysis of Rab and Rab effector gene deregulation in bladder cancer, taking relevant tumor subgroups into account, provides insight into the possible roles of Rab proteins and their effectors in bladder cancer pathogenesis. This approach is applicable to other group of genes and types of cancer.