Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma.

BACKGROUND: Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. METHODS: We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. RESULTS: A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. CONCLUSIONS: Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.

Outcomes of patients with resected stage III/IV acral or mucosal melanoma, treated with adjuvant anti-PD-1 based therapy.

IMPORTANCE: Acral (AM) and mucosal melanomas (MM) are rare subtypes with a poor prognosis. In those with advanced disease, anti-PD-1 (PD1) therapy has reduced activity compared to that seen in non-acral cutaneous melanoma. OBJECTIVE: To determine the efficacy of adjuvant PD1 in resected AM or MM. DESIGN: An international, retrospective cohort study SETTING: Data up to November 2021 collected from 20 centres across 10 countries. PARTICIPANTS: One hundred and ninety four patients with resected stage III or IV1 AM or MM who received adjuvant PD1 were included and compared to matched patients from the Melanoma Institute Australia (MIA) database using a propensity score matching analysis. MAIN OUTCOMES AND MEASURES: Recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) were investigated. RESULTS: Forty five of 139 (32%) AM and 9 of 55 (16%) MM patients completed adjuvant therapy. The main reason for early treatment cessation in both groups was disease recurrence: 51 (37%) and 30 (55%) in the AM and MM groups, respectively. In the AM group adjuvant PD1 was associated with a longer RFS [HR-0.69 (0.52-0.92, p = 0.0127)], DMFS [HR0.58 (0.38-0.89, p = 0.0134)] and OS [HR of 0.59 (0.38-0.92, p-value 0.0196)] when compared to the historical cohort. In the MM group there was no statistical difference in RFS [HR1.36 (0.69-2.68,p-value 0.3799], DMFS or OS. CONCLUSION AND RELEVANCE: After adjuvant PD1, both AM and MM have a high risk of recurrence. Our data suggests a benefit to using adjuvant PD1 therapy in resected AM but not in resected MM. Additional studies to investigate the efficacy of adjuvant PD1 for MM are needed.

Phase space analysis of nonlinear wave propagation in a bistable mechanical metamaterial with a defect.

We study the dynamics of solitary waves traveling in a one-dimensional chain of bistable elements in the presence of a local inhomogeneity ("defect"). Numerical simulations reveal that depending upon its initial speed, an incoming solitary wave can get transmitted, captured, or reflected upon interaction with the defect. The dynamics are dominated by energy exchange between the wave and a breather mode localized at the defect. We derive a reduced-order two degree of freedom Hamiltonian model for wave-breather interaction and analyze it using dynamical systems techniques. Lobe dynamics analysis reveals the fine structure of phase space that leads to the complicated dynamics in this system. This work is a step toward developing a rational approach to defect engineering for manipulating nonlinear waves in mechanical metamaterials.

Exact Coherent Structures and Phase Space Geometry of Preturbulent 2D Active Nematic Channel Flow.

Confined active nematics exhibit rich dynamical behavior, including spontaneous flows, periodic defect dynamics, and chaotic "active turbulence." Here, we study these phenomena using the framework of exact coherent structures, which has been successful in characterizing the routes to high Reynolds number turbulence of passive fluids. Exact coherent structures are stationary, periodic, quasiperiodic, or traveling wave solutions of the hydrodynamic equations that, together with their invariant manifolds, serve as an organizing template of the dynamics. We compute the dominant exact coherent structures and connecting orbits in a preturbulent active nematic channel flow, which enables a fully nonlinear but highly reduced-order description in terms of a directed graph. Using this reduced representation, we compute instantaneous perturbations that switch the system between disparate spatiotemporal states occupying distant regions of the infinite-dimensional phase space. Our results lay the groundwork for a systematic means of understanding and controlling active nematic flows in the moderate- to high-activity regime.

Clinicopathological characteristics and clinical morbidity in high-risk head and neck cutaneous squamous cell carcinoma patients in Western Australia.

BACKGROUND: There is no registry data on morbidity and mortality of high-risk cutaneous squamous cell carcinoma (cSCC) in Australia. AIM: To examine the clinicopathological features, mortality and morbidity in high-risk cSCC patients in Western Australia (WA). METHODS: A retrospective cohort study was conducted through hospital record review on cSCC patients discussed at multidisciplinary meetings at the two largest WA hospitals between March 2015 and December 2016. RESULTS: Of 141 patients, 129 were evaluable, with median follow up of 43.9 (range 3.0-53.2) months. Patients were predominantly older males (84%) with significant comorbidities (Charlson Comorbidity Index (CCI) ≥5; 76%) and history of previous nonmelanoma skin cancer (57%) with advanced disease (57% stage IV without distant metastasis; American Joint Committee on Cancer, 7th edition). Pathological high-risk features were common including nodal extracapsular extension (47%) and cranial nerve involvement (16%). Clinical morbidity was significant with a median of 2 (range 0-13) excisions and 2 (range 0-21) cSCC-related hospitalisations for any cSCC event following the index case discussion. Recurrences of the primary index lesion occurred in 60% of patients and 20% had ≥2 recurrences. Median overall survival for patients with nonmetastatic disease was 39.8 (range 25.9-53.7) months and 16.1 (range 0.2-32.0) months for metastatic disease. CCI ≥5, advanced nodal stage and ≥2 recurrences were significantly associated with mortality on multivariable analyses (P < 0.05). Nodal extracapsular extension and any recurrences were identified as significant risk factors for disease-specific mortality on multivariable analyses (P < 0.05). CONCLUSION: High-risk cSCC patients have significant health needs represented by high-baseline comorbidities, multiplicity of cSCC events and the number of healthcare-associated interventions. There is an unmet need for robust cancer data collection.

Long-term hematologic toxicity of 177Lu-octreotate-capecitabine-temozolomide therapy of GEPNET.

Thirty-seven patients with advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs) were treated on a prospective phase II single-center study with four cycles of 7.8 GBq 177Lu-octreotate combined with capecitabine and temozolomide chemotherapy (CAPTEM). Each 8-week cycle combined radiopeptide therapy with 14 days of capecitabine (1500 mg/m2) and 5 days of temozolomide (200 mg/m2). The incidence of grade ≥ 3 hematologic toxicity was analyzed. At a median follow-up of 7-years (range 1-10), six (16%) patients developed persistent hematologic toxicity (PHT) (defined as sustained grade ≥ 3 hematologic toxicity beyond 36-months follow-up) and three (8%) developed MDS/AL with a median time-to-event of 46 and 34 months, respectively. The estimated cumulative incidence of MDS/AL was 11% (95% CI: 3.45-24.01). Development of PHT was the only significant risk factor for secondary MDS/AL (RR, 16; 95% CI: 2.53 to 99.55; P < 0.001). The median PFS was 48 months (95% CI: 40.80-55.20), and the median OS was 86 months (95% CI: 56.90-115.13). Twenty-one deaths were recorded, including 13 (62%) due to progressive disease and all 3 (14%) patients with MDS/AL. 177Lu-octreotate CAPTEM therapy for GEPNETs is associated with a risk of long-term hematologic toxicity. The rising cumulative incidence of MDS/AL > 10% mandates the long-term monitoring of treated patients. However, time to onset is unpredictable, and incidence does not correlate with conventional baseline risk factors. Novel methods are required for the stratification of prospective patients based on genetic risk.

Optimal Control of Active Nematics.

In this work we present the first systematic framework to sculpt active nematic systems, using optimal control theory and a hydrodynamic model of active nematics. We demonstrate the use of two different control fields, (i) applied vorticity and (ii) activity strength, to shape the dynamics of an extensile active nematic that is confined to a disk. In the absence of control inputs, the system exhibits two attractors, clockwise and counterclockwise circulating states characterized by two co-rotating topological +1/2 defects. We specifically seek spatiotemporal inputs that switch the system from one attractor to the other; we also examine phase-shifting perturbations. We identify control inputs by optimizing a penalty functional with three contributions: total control effort, spatial gradients in the control, and deviations from the desired trajectory. This work demonstrates that optimal control theory can be used to calculate nontrivial inputs capable of restructuring active nematics in a manner that is economical, smooth, and rapid, and therefore will serve as a guide to experimental efforts to control active matter.

A mean-field game model for homogeneous flocking.

Empirically derived continuum models of collective behavior among large populations of dynamic agents are a subject of intense study in several fields, including biology, engineering, and finance. We formulate and study a mean-field game model whose behavior mimics an empirically derived nonlocal homogeneous flocking model for agents with gradient self-propulsion dynamics. The mean-field game framework provides a non-cooperative optimal control description of the behavior of a population of agents in a distributed setting. In this description, each agent's state is driven by optimally controlled dynamics that result in a Nash equilibrium between itself and the population. The optimal control is computed by minimizing a cost that depends only on its own state and a mean-field term. The agent distribution in phase space evolves under the optimal feedback control policy. We exploit the low-rank perturbative nature of the nonlocal term in the forward-backward system of equations governing the state and control distributions and provide a closed-loop linear stability analysis demonstrating that our model exhibits bifurcations similar to those found in the empirical model. The present work is a step towards developing a set of tools for systematic analysis, and eventually design, of collective behavior of non-cooperative dynamic agents via an inverse modeling approach.

Medicines access programs to cancer medicines in Australia and New Zealand: An exploratory study.

Medicines Access Programs (MAP) offer access to publicly unfunded medicines at the discretion of pharmaceutical companies. Limited literature is available on their extent and scope in Australia and New Zealand. This study aims to identify MAPs for cancer medicines that were operational in 2014-15 in Australia and New Zealand and describe their characteristics. A preliminary list of MAPs was sent to hospital pharmacists in Australia and New Zealand to validate and collect further information. Pharmaceutical companies were contacted directly to provide information regarding MAPs offered. Key stakeholders were interviewed to identify issues with MAPs. Fifty-one MAPs were identified covering a range of indications. The majority of MAPs were provided free of charge to the patient for medicines that were registered or in the process of being registered but were not funded. Variability in the number of MAPs across institutions and characteristics was observed. Australia offered more MAPs than New Zealand. Only two of 17 pharmaceutical companies contacted agreed to provide information on their MAPs. Eight stakeholder interviews were conducted. This identified that while MAPs are widely operational there is lack of clinical monitoring, inequity to access, operational issues and lack of transparency. Our results suggest a need for a standardised and mandated policy to mitigate issues with MAPs.

A qualitative evaluation of general practitioners' perceptions regarding access to medicines in New Zealand.

OBJECTIVE: The objective of this study was to evaluate general practitioners' (GPs) perceptions regarding access to medicines in New Zealand. DESIGN: Qualitative. SETTING: Primary care. PARTICIPANTS: GPs. MAIN OUTCOME MEASURES: GPs' views and perceptions. RESULTS: GPs were of the view that the current range of medicines available in New Zealand was reasonable; however, it was acknowledged that there were some drugs that patients were missing out on. When considering the range of subsidised medicines available in New Zealand, some GPs felt that there had been an improvement over recent years. It was highlighted that unexpected funding changes could create financial barriers for some patients and that administrative procedures and other complexities created barriers in receiving a subsidy for restricted medicines. GPs also reported problems with the availability and sole supply of certain medicines and claimed that switching from a branded medicine to its generic counterpart could be disruptive for patients. CONCLUSIONS: The research concluded that although there were some issues with the availability of certain drugs, most GPs were satisfied with the broader access to medicines situation in New Zealand. This view is to contrary to the situation presented by the pharmaceutical industry. The issues around sole supply, the use of generic medicines and the administrative barriers regarding funding of medicines could be improved with better systems. The current work provides a solid account of what GPs see as the advantages and disadvantages of the current system and how they balance these demands in practice.

Topological chaos, braiding and bifurcation of almost-cyclic sets.

In certain two-dimensional time-dependent flows, the braiding of periodic orbits provides a way to analyze chaos in the system through application of the Thurston-Nielsen classification theorem (TNCT). We expand upon earlier work that introduced the application of the TNCT to braiding of almost-cyclic sets, which are individual components of almost-invariant sets [Stremler et al., "Topological chaos and periodic braiding of almost-cyclic sets," Phys. Rev. Lett. 106, 114101 (2011)]. In this context, almost-cyclic sets are periodic regions in the flow with high local residence time that act as stirrers or "ghost rods" around which the surrounding fluid appears to be stretched and folded. In the present work, we discuss the bifurcation of the almost-cyclic sets as a system parameter is varied, which results in a sequence of topologically distinct braids. We show that, for Stokes' flow in a lid-driven cavity, these various braids give good lower bounds on the topological entropy over the respective parameter regimes in which they exist. We make the case that a topological analysis based on spatiotemporal braiding of almost-cyclic sets can be used for analyzing chaos in fluid flows. Hence, we further develop a connection between set-oriented statistical methods and topological methods, which promises to be an important analysis tool in the study of complex systems.

Topological chaos and periodic braiding of almost-cyclic sets.

In certain (2+1)-dimensional dynamical systems, the braiding of periodic orbits provides a framework for analyzing chaos in the system through application of the Thurston-Nielsen classification theorem. Periodic orbits generated by the dynamics can behave as physical obstructions that "stir" the surrounding domain and serve as the basis for this topological analysis. We provide evidence that, even in the absence of periodic orbits, almost-cyclic regions identified using a transfer operator approach can reveal an underlying structure that enables topological analysis of chaos in the domain.

Evaluating pharmacists' views, knowledge, and perception regarding generic medicines in New Zealand.

BACKGROUND: Generic medicines are commonly used in New Zealand; however, Pharmaceutical Management Agency of New Zealand (PHARMAC) has indicated a need for better information to the public. Studies on consumers' perceptions suggest that pharmacists play an important role in consumers' choice; hence, "quality use of generic medicines" can be promoted with a better understanding of pharmacists' views, knowledge, and perception. OBJECTIVES: (1)To evaluate pharmacists' perceptions, views, and knowledge of and willingness to recommend generic medicines. (2) To explore pharmacists perceptions of the safety, quality, and efficacy of generic medicines. (3) To assess pharmacists' views on current policy with respect to substitution of generic medicines. METHODS: A cross-sectional survey using a postal questionnaire was conducted, and questionnaires were sent to 625 randomly selected pharmacists from a list of 1594 pharmacists who had agreed to release their details for research purposes. RESULTS: Three-hundred and sixty pharmacists responded to the questionnaire (a response rate of 58%). Seventy percent of pharmacists stated there is no difference in safety between original brand and generic medicines. However, 65% stated that original brand medicines were of higher quality than their generic counterparts, and half stated that generic medicines and original brand medicines are equally effective. A large number of pharmacists reported concerns regarding brand substitution and offered suggestions, such as the need for advertising campaigns, patient pamphlets, updating prescribers' software, and distinct packaging for generic medicines. It was found that pharmacists' perceptions of generic medicines are primarily driven by PHARMACs policies and their experiences with consumers. CONCLUSIONS: About one-third of pharmacists correctly defined the term "generic medicines," suggesting discrepancies in pharmacists' knowledge and perceptions of generic medicines. Concerns were raised regarding: quality, safety, and effectiveness; however, most of the pharmacists acknowledged the economic benefits to the health care system.

BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression.

The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases). 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS). BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%), poor for BRCAX with an LCS (40-50%), and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%). This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.