Deciphering the Functional Roles of Individual Cancer Alleles Across Comprehensive Cancer Genomic Studies.

Cancer genome data has been growing in both size and complexity, primarily driven by advances in next-generation sequencing technologies, such as Pan-cancer data from TCGA, ICGC, and single-cell sequencing. Yet, discerning the functional role of individual genomic lesions remains a substantial challenge due to the complexity and scale of the data. Previously, we introduced REVEALER, which identifies groups of genomic alterations that significantly associate with target functional profiles or phenotypes, such as pathway activation, gene dependency, or drug response. In this paper, we present a new mathematical formulation of the algorithm. This version (REVEALER 2.0) is considerably more powerful than the original, allowing for rapid processing and analysis of much larger datasets and facilitating higher-resolution discoveries at the level of individual alleles. REVEALER 2.0 employs the Conditional Information Coefficient (CIC) to pinpoint features that are either complementary or mutually exclusive but still correlate with the target functional profile. The aggregation of these features provides a better explanation for the target functional profile than any single alteration on its own. This is indicative of scenarios where several activating genomic lesions can initiate or stimulate a key pathway or process. We replaced the initial three-dimensional kernel estimation with multiple precomputed one-dimensional kernel estimations, resulting in an approximate 150x increase in speed and efficiency. This improvement, combined with its efficient execution, makes REVEALER 2.0 suitable for much larger datasets and a more extensive range of genomic challenges.

Immunotherapy in combination with chemotherapy vs. immunotherapy alone for advanced non-small cell lung cancer and programmed death ligand 1 score <50.

INTRODUCTION: Little is known about the effectiveness of immunotherapy alone or with chemotherapy for patients with non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1) expression <50 %. We examined the outcomes of PD-L1 therapy vs. PD-L1 therapy in combination with chemotherapy as first-line treatment among NSCLC patients with PD-L1 score <50 %. METHODS: We used administrative claims and prior authorization data of a national insurer from November 2015 to July 2021. We selected patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %. Each patient was required to have ≥1 claim of a PD-L1 or PD-1 inhibitor. Treatment groups were propensity-score matched 1:1 on baseline characteristics. We measured PD-L1 therapy duration, incident immune-related adverse events (irAEs), healthcare utilization, costs, and overall survival (OS). RESULTS: In the matched sample totaling 176 patients, mean duration of PD-L1 therapy was similar (4.1 [SD 3.3] months combination vs. 4.0 [SD 4.9] months monotherapy, p = 0.800). IrAEs were similar, both for FDA-recognized irAEs (48.9 % combination, 48.9 % monotherapy, p = 0.710) and other types (34.1 % combination, 39.8 % monotherapy, p = 0.473). The combination group had more all-cause inpatient stays, ER visits, and outpatient visits (all p < 0.001). Total adjusted all-cause medical cost was $112,833 (95 % CI $5,548-$251,973) higher for combination therapy. We saw no difference in OS (adjusted hazard ratio 1.09 [95 % CI 0.72-1.65]). CONCLUSION: This study found no difference in adverse drug effects or survival between PD-L1 monotherapy compared to combination therapy for patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %, though the combination therapy cohort had higher healthcare utilization and costs. MICROABSTRACT: Use of immunotherapy alone or combined with chemotherapy for patients with non-small cell lung cancer and programmed death ligand 1 expression <50 % is understudied. Our observational study using claims and authorization data from a matched sample of 176 patients found no difference in survival or the rate of adverse drug effects between groups, although the chemo-immunotherapy cohort generated higher overall healthcare costs.

Syk Inhibition Reprograms Tumor-Associated Macrophages and Overcomes Gemcitabine-Induced Immunosuppression in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low 5-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAM), which promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In orthotopic PDAC mouse models, genetic deletion of myeloid Syk reprogrammed macrophages into immunostimulatory phenotype, increased the infiltration, proliferation, and cytotoxicity of CD8+ T cells, and repressed PDAC growth and metastasis. Furthermore, gemcitabine (Gem) treatment induced an immunosuppressive microenvironment in PDAC by promoting protumorigenic polarization of macrophages. In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, "re-educated" protumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T-cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the antitumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC. SIGNIFICANCE: Syk blockade induces macrophage polarization to an immunostimulatory phenotype, which enhances CD8+ T-cell responses and improves gemcitabine efficacy in pancreatic ductal adenocarcinoma, a clinically challenging malignancy.

Association Between Oncology Clinical Pathway Utilization and Toxicity and Cost Outcomes in Patients With Metastatic Solid Tumors.

PURPOSE: This retrospective observational study compared cancer care toxicity and cost outcomes for patients with metastatic cancer with nine different cancer types prescribed on- versus off-pathway regimens. METHODS: This study used claims and authorization data from a national insurer between January 1, 2018, and October 31, 2021. Participants included adults with metastatic breast, lung, colorectal, pancreatic, melanoma, kidney, bladder, gastric, or uterine cancer, who were prescribed first-line anticancer regimens. Multivariable regressions were used to assess outcomes including counts of emergency room visits or hospitalizations, use of supportive care medications, immune-related adverse events (IRAEs), and health care costs. RESULTS: Of the 8,357 patients in the study, 5,453 (65.3%) were prescribed on-pathway regimens. The on-pathway proportion trended downward, from 74.3% in 2018 to 59.8% in 2021. The on- and off-pathway groups had a similar proportion of patients with treatment-related hospitalization (adjusted odds ratio [aOR], 1.080; P = .201) and IRAEs (aOR, 0.961; P = .497). More all-cause hospitalizations (aOR, 1.679; P = .013) were observed among patients with melanoma treated on-pathway. The on-pathway group had higher use of supportive care drugs in bladder cancer (aOR, 4.602; P < .001) and colorectal cancer (aOR, 4.465; P < .001), and lower use in breast (aOR, 0.668; P = .001) and lung cancer (aOR, 0.550; P < .001). On average, on-pathway patients incurred $17,589 less total health care cost (P < .001), and $22,543 lower chemotherapy cost (P < .001) than those from the off-pathway group. CONCLUSION: Our findings suggest that use of on-pathway regimens was associated with significant cost savings. Toxicity outcomes were variable by disease, but overall, there were similar numbers of treatment-related hospitalizations and IRAEs compared to off-pathway regimens. This cross-institutional study provides evidence to support the use of clinical pathway regimens for patients with metastatic cancer.

Targeting macrophage Syk enhances responses to immune checkpoint blockade and radiotherapy in high-risk neuroblastoma.

Background: Neuroblastoma (NB) is considered an immunologically cold tumor and is usually less responsive to immune checkpoint blockade (ICB). Tumor-associated macrophages (TAMs) are highly infiltrated in NB tumors and promote immune escape and resistance to ICB. Hence therapeutic strategies targeting immunosuppressive TAMs can improve responses to ICB in NB. We recently discovered that spleen tyrosine kinase (Syk) reprograms TAMs toward an immunostimulatory phenotype and enhances T-cell responses in the lung adenocarcinoma model. Here we investigated if Syk is an immune-oncology target in NB and tested whether a novel immunotherapeutic approach utilizing Syk inhibitor together with radiation and ICB could provide a durable anti-tumor immune response in an MYCN amplified murine model of NB. Methods: Myeloid Syk KO mice and syngeneic MYCN-amplified cell lines were used to elucidate the effect of myeloid Syk on the NB tumor microenvironment (TME). In addition, the effect of Syk inhibitor, R788, on anti-tumor immunity alone or in combination with anti-PDL1 mAb and radiation was also determined in murine NB models. The underlying mechanism of action of this novel therapeutic combination was also investigated. Results: Herein, we report that Syk is a marker of NB-associated macrophages and plays a crucial role in promoting immunosuppression in the NB TME. We found that the blockade of Syk in NB-bearing mice markedly impairs tumor growth. This effect is facilitated by macrophages that become immunogenic in the absence of Syk, skewing the suppressive TME towards immunostimulation and activating anti-tumor immune responses. Moreover, combining FDA-approved Syk inhibitor, R788 (fostamatinib) along with anti-PDL1 mAb provides a synergistic effect leading to complete tumor regression and durable anti-tumor immunity in mice bearing small tumors (50 mm3) but not larger tumors (250 mm3). However, combining radiation to R788 and anti-PDL1 mAb prolongs the survival of mice bearing large NB9464 tumors. Conclusion: Collectively, our findings demonstrate the central role of macrophage Syk in NB progression and demonstrate that Syk blockade can "reeducate" TAMs towards immunostimulatory phenotype, leading to enhanced T cell responses. These findings further support the clinical evaluation of fostamatinib alone or with radiation and ICB, as a novel therapeutic intervention in neuroblastoma.

Association of Patient, Physician, and Practice-Level Factors with Uptake of Payer-Led Oncology Clinical Pathways.

Importance: Payers use oncology clinical pathways programs to increase evidence-based drug prescribing and control drug spending. However, compliance with these programs has been low, which may decrease their efficacy, and factors associated with pathway compliance are unknown. Objective: To determine extent of pathway compliance and identify factors associated with pathway compliance using characteristics of patients, practices, and the companies that develop cancer treatment pathways. Design, Setting, and Participants: This cohort study comprised patients with claims and administrative data from a national insurer and a pathways health care professional between July 1, 2018, and October 31, 2021. Adult patients with metastatic breast, lung, colorectal, pancreatic, melanoma, kidney, bladder, gastric, and uterine cancer being treated in the first line were included. Six months of continuous insurance coverage prior to the date of treatment initiation was required for determination of baseline characteristics. Stepwise logistic regression was used to identify factors associated with pathway compliance. Main Outcomes and Measures: Use of a pathway program-endorsed treatment regimen in the first-line setting for metastatic cancer. Results: Among 17 293 patients (mean [SD] age, 60.7 [11.2] years; 9183 [53.1%] women; mean [SD] Black patients per census block, 0.10 [0.20]), 11 071 patients (64.0%) were on-pathway, and 6222 (36.0%) were off-pathway. Factors associated with increased pathway compliance were higher health care utilization during the 6-month baseline period (measured in inpatient visits and emergency department visits) (5220 on-pathway inpatient visits [47.2%] vs 2797 off-pathway [45.0%]; emergency department visits, 3304 [27.1%] vs 1503 [24.2%]; adjusted odds ratio [aOR] for inpatient visits, 1.32; 95% CI, 1.22-1.43; P < .001), volume of patients with this insurance provider per physician (mean [SD] visits: on-pathway, 128.0 [258.3] vs off-pathway, 121.8 [161.4]; aOR, 1.12; 95% CI, 1.04-1.20; P = .002), and practice participation in the Oncology Care Model (on-pathway participation, 2601 [23.5%] vs 1305 [21.0%]; aOR, 1.13; 95% CI, 1.04-1.23; P = .004). Higher total medical cost during the 6-month baseline period were associated with decreased pathway compliance (mean [SD] costs: on-pathway, $55 990 [$69 706] vs $65 955 [$74 678]; aOR, 0.86; 95% CI, 0.83-0.88; P < .001). There was heterogeneity in odds of pathway compliance between different malignancies. Pathway compliance rates trended down from the reference year of 2018. Conclusions and Relevance: In this cohort study, despite generous financial incentives, compliance with payer-led pathways remained at historically reported low rates. Factors such as increasing exposure to the program due to the number of patients impacted and participation in other value-based payment programs, such as the Oncology Care Model, were positively associated with compliance; factors such as the type of cancer and patient complexity may have played a role, but the directionality of potential effects was unclear.

Cost Per Relapse Avoided for Ozanimod Versus Other Selected Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis in the United States.

INTRODUCTION: This study assessed the cost-effectiveness of ozanimod compared with commonly used disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). METHODS: Annualized relapse rate (ARR) and safety data were obtained from a network meta-analysis (NMA) of clinical trials of RRMS treatments including ozanimod, fingolimod, dimethyl fumarate, teriflunomide, interferon beta-1a, interferon beta-1b, and glatiramer acetate. ARR-related number needed to treat (NNT) relative to placebo and annual total MS-related healthcare costs was used to estimate the incremental annual cost per relapse avoided with ozanimod vs each DMT. ARR and adverse event (AE) data were combined with drug costs and healthcare costs to manage relapses and AEs in order to estimate annual cost savings with ozanimod vs other DMTs, assuming a 1 million USD fixed treatment budget. RESULTS: Treatment with ozanimod was associated with lower incremental annual healthcare costs to avoid a relapse, ranging from $843,684 vs interferon beta-1a (30 µg; 95% confidence interval [CI] - $1,431,619, - $255,749) to $72,847 (95% CI - $153,444, $7750) vs fingolimod. Compared with all other DMTs, ozanimod was associated with overall healthcare cost savings ranging from $8257 vs interferon beta-1a (30 µg) to $2178 vs fingolimod. Compared with oral DMTs, ozanimod was associated with annual cost savings of $6199 with teriflunomide 7 mg, $4737 with teriflunomide 14 mg, $2178 with fingolimod, and $2793 with dimethyl fumarate. CONCLUSION: Treatment with ozanimod was associated with substantial reductions in annual drug costs and total MS-related healthcare costs to avoid relapses compared with other DMTs. In the fixed-budget analysis, ozanimod demonstrated a favorable cost-effective profile relative to other DMTs.

Comparative efficacy and safety of ozanimod and ponesimod for relapsing multiple sclerosis: A matching-adjusted indirect comparison.

BACKGROUND: Ozanimod and ponesimod are sphingosine 1-phosphate receptor modulators approved by the U.S. Food and Drug Administration for treatment of relapsing forms of multiple sclerosis (MS). Given that no head-to-head trials have assessed these two treatments, we performed a matching-adjusted indirect comparison (MAIC) to compare efficacy and safety outcomes between ozanimod and ponesimod for MS. METHODS: A MAIC compared efficacy and safety of ozanimod and ponesimod at 2 years. Outcomes included annualized relapse rate (ARR) and percentage change from baseline in brain volume loss (BVL) as well as rates of any treatment-emergent adverse events (TEAEs), serious adverse events (AEs), AEs leading to discontinuation, and other safety outcomes. Individual patient-level data were obtained for ozanimod from the RADIANCE-B trial, while aggregate-level patient data were obtained for ponesimod from the OPTIMUM trial. The MAIC was not anchored owing to lack of a common comparator across the two trials. The following characteristics were matched between the trials' populations: age, sex, time since MS symptom onset, relapses in prior year, Expanded Disability Status Scale score, disease-modifying therapies received in the prior 2 years, absence of gadolinium-enhancing T1 lesions, and percentage of patients from Eastern Europe. RESULTS: After matching, key baseline characteristics were balanced between patients receiving ozanimod and ponesimod. Compared with ponesimod, ozanimod had a numerically lower ARR (rate ratio: 0.80 [95% CI: 0.57, 1.10]) and was associated with a significant reduction in BVL (% change difference: 0.20 [95% CI: 0.05, 0.36]). Additionally, ozanimod was associated with a significantly lower risk of TEAEs (risk difference: -11.9% [95% CI: -16.8%, -7.0%]), AEs leading to discontinuation (-6.1% [95% CI: -8.9%, -3.4%]), and lymphocyte count <0.2 K/µL (-2.3% [95% CI: -4.2%, -0.5%]). There were no statistically significant differences in the other safety outcomes. CONCLUSION: The MAIC results suggest that, compared with ponesimod, ozanimod is more effective in preserving brain volume, is comparable in terms of reducing relapse rates, and has a favorable safety profile.

A flexible adhesive surface electrode array capable of cervical electroneurography during a sequential autonomic stress challenge.

This study introduces a flexible, adhesive-integrated electrode array that was developed to enable non-invasive monitoring of cervical nerve activity. The device uses silver-silver chloride as the electrode material of choice and combines it with an electrode array consisting of a customized biopotential data acquisition unit and integrated graphical user interface (GUI) for visualization of real-time monitoring. Preliminary testing demonstrated this electrode design can achieve a high signal to noise ratio during cervical neural recordings. To demonstrate the capability of the surface electrodes to detect changes in cervical neuronal activity, the cold-pressor test (CPT) and a timed respiratory challenge were employed as stressors to the autonomic nervous system. This sensor system recording, a new technique, was termed Cervical Electroneurography (CEN). By applying a custom spike sorting algorithm to the electrode measurements, neural activity was classified in two ways: (1) pre-to-post CPT, and (2) during a timed respiratory challenge. Unique to this work: (1) rostral to caudal channel position-specific (cephalad to caudal) firing patterns and (2) cross challenge biotype-specific change in average CEN firing, were observed with both CPT and the timed respiratory challenge. Future work is planned to develop an ambulatory CEN recording device that could provide immediate notification of autonomic nervous system activity changes that might indicate autonomic dysregulation in healthy subjects and clinical disease states.

Identification of cognitive impairment, depression, and fatigue among multiple sclerosis patients in a large comprehensive care center: A mixed-methods, qualitative study.

BACKGROUND: Despite studies suggesting a high prevalence of cognitive impairment, depression, and fatigue (CDF) among patients with multiple sclerosis (MS), standardized CDF tools are used infrequently in clinical practice, potentially resulting in underdiagnosis. We documented the use of standardized tools to identify CDF in MS and sought to understand provider attitudes toward the tools and their use. METHODS: This mixed-methods study analyzed electronic health records (EHRs) from a large US urban MS center to determine the frequency and types of CDF screenings and numbers of MS treatment encounters (January 2018-December 2019). Participants included neurologists and nurse practitioners with ≥30 eligible patients and a convenience sample of adult MS patients (≥18 years) with at least outpatient encounters during the study period. Semistructured provider interviews (n = 6; the principal investigator and 1 provider were excluded) were conducted, transcribed, coded, and analyzed to characterize screening patterns. Assessments included proportions of encounters and patients who had standardized CDF screenings, positive screening results, and documentation of a treatment recommendation, as well as provider attitudes toward tools and reported barriers and facilitators for use. Bivariate analysis was used to evaluate the relationship between screening rates and patient and provider covariates for groups with sufficient sample size (n = 30). RESULTS: The final population included 260 unique patients, 489 outpatient encounters, and 8 providers. Of 260 patients (75% female, 83% aged <65 years), 24% (n = 63) were screened with a depression tool. Only 2% (n = 4) were screened with a tool measuring cognitive impairment, and none were screened with a tool measuring fatigue. Screening rates varied little by provider type. Higher depression screening rates were associated with white race (difference: 13.2%; 95% CI: 2.8-23.5%; P = .01), ≤2 visits during the study period (difference: 7.6%; 95% CI: 0.6-14.5%; P = .03), and provider experience >10 years (difference: 14.6%; 95% CI: 3.5-25.8%; P = .01). Lack of support staff and perception of limited treatment options were commonly cited barriers to standardized screening in provider interviews. The higher rate of depression screening is likely driven by institutional culture and priorities. CONCLUSION: Providers recognize the importance of CDF to patients, despite infrequent use of standardized screening. Integrating screening into institutional practices may enable ongoing tracking of assessment scores and provide a more comprehensive and longitudinal picture of symptom progression.

Effectiveness, safety and treatment adherence of biosimilar follow-on insulin in diabetes management.

AIM: To assess the change in HbA1c after initiation of biosimilar follow-on insulin (Basaglar) or reference insulin (Lantus) among patients with type 2 diabetes. We also compared treatment adherence, safety events and costs at 1 year after initiation of insulin. MATERIALS AND METHODS: Using claims data from a large US health plan during 2016-2020, we identified adults with type 2 diabetes who initiated either Basaglar or Lantus. Generalized linear regression modelling assessed the differences in outcomes between the two groups. A 0.4% margin was used to determine non-inferiority for HbA1c. RESULTS: The study included 1136 Basaglar users and 6304 Lantus users. Both Lantus and Basaglar groups showed more than 1% reduction in HbA1c over 6 months and over 12 months. Reduction in HbA1c with Basaglar was similar (non-inferior) to that with Lantus, with an adjusted difference of Basaglar to Lantus of 0.14% (95% CI -0.02 to 0.30) over 6 months and 0.17% (95% CI 0.02 to 0.32) over 12 months. Rates of adverse events were similar for both hypoglycaemia and vascular events. The Basaglar group showed higher adherence in terms of proportion of days covered (adjusted difference 0.06, 95% CI 0.04 to 0.08). Medical costs were similar, but the cost of Basaglar was lower (adjusted mean cost difference -$462, 95% CI -$556 to -$363) after adjustment. CONCLUSIONS: In patients with type 2 diabetes, Basaglar provided similar glycaemic control compared with Lantus, had a similar safety profile and lower drug costs, and showed more favourable adherence.

Real-world disease-modifying therapy pathways from administrative claims data in patients with multiple sclerosis.

BACKGROUND: Over a dozen disease-modifying therapies (DMTs) have been approved for treatment of multiple sclerosis (MS). Treatment guidelines focus on when to initiate, change, and discontinue treatment but provide little guidance on how to select or sequence DMTs. This study assessed sequencing patterns of DMTs in patients with newly diagnosed MS. METHODS: Adults newly diagnosed with MS in the United States were identified from January 2007 to October 2017 using IBM MarketScan database. Patients had ≥12 months of continuous enrollment prior to diagnosis and ≥ 2 years of follow-up. Treatment pathways consisting of up to 3 DMT courses were reported, and each treatment course ended with discontinuation, switch, or end of follow-up. RESULTS: In total, 14,627 MS patients were treated with DMTs and had ≥2 years of follow-up. More than 400 DMT treatment pathways were observed. Glatiramer acetate was the most common DMT; 40% of patients initiated this treatment. Among these, 51.3% had 2 DMT courses during follow-up and 26.5% had 3 DMT courses. Approximately 70% of patients switched or discontinued their initial DMT, and rates of switch and discontinuation differed by initial DMT. Injectable DMTs were used most commonly over the study period (87.5% as first course to 66.6% as third course). Oral DMTs were more common as second or third treatment courses (29.9% and 31.8%, respectively). CONCLUSIONS: A wide variety in treatment patterns were observed among patients newly diagnosed with MS. Further examination of DMT prescribing practices is needed to understand the reasons behind treatment discontinuation and treatment cycling.

A qualitative study of smokers' assessments of four smoking cessation interventions delivered in a hospital emergency department.

BACKGROUND: A recent clinical trial of 1056 adults who smoke tested the efficacy of four components of a treatment intervention initiated in a hospital emergency department (ED) and found two of them to be clinically effective. This paper explores study participants' attitudes towards the four components, whether they identified important interactions, and suggestions for further tailoring. METHODS: Telephone interviews were conducted with participants at the end of the three-month study period. Each participant had received at least one intervention component: nicotine replacement therapy, referral to a smokers' telephone quitline, a brief negotiation interview, or the smartphone-enabled SmokefreeTXT program. Interviews were audio-recorded, transcribed, and analyzed using an iterative approach, grounded in the data, using thematic analysis. RESULTS: Between March 2017 and September 2018, 63 interviews were conducted with participants who received at least one intervention component. The sample was diverse with respect to race, ethnicity, gender, and sociodemographic status. Intervention components were generally well-received by participants. Four themes were identified: Intervention Context, Intervention Content, Communications, and Recommendations. Provision of smoking cessation interventions to ED patients led to reduced self-reported smoking for most. Nicotine replacement therapy diminished cravings, while behavioral interventions provided social support that helped motivate and sustain behavior change. CONCLUSIONS: Intervention components were feasible and acceptable. The data suggest that pharmacological and behavioral interventions be offered simultaneously, that communication skills training be provided to those who deliver the interventions, and that interventions should respect participants' autonomy and preferences concerning intervention timing, frequency, and termination.

CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity.

Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a "two cell type" whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.

Seizure exacerbation with anti-seizure medications in adult patients with epilepsy.

There are numerous reports of seizure exacerbation related to specific anti-seizure medications (ASMs); however, a quantitative analysis with clearly defined parameters for seizure exacerbation in an outpatient setting is lacking. This retrospective study examines adult patients starting a single ASM and follows patient outcomes over the course of treatment, with quantitative evaluation of the incidence of paradoxical seizure exacerbation. In this study, outpatient encounters with five epileptologists at the Baylor College of Medicine Comprehensive Epilepsy Center were evaluated over a 10-month period. Seizure exacerbation was defined as an increase in seizure frequency at least 2 times greater than the baseline seizure frequency after initiation of an ASM, with return to baseline after ASM discontinuation. Patients were stratified into four categories: (1) probable ASM-induced seizure exacerbation; (2) possible ASM-induced seizure exacerbation; (3) non-ASM induced seizure exacerbation; or (4) no seizure exacerbation. Out of a total of 236 encounters where an ASM was initiated, we found that 5.5% of patients experienced some form of seizure exacerbation. However, only 1.3% of patients had probable ASM-induced seizure exacerbation. Consistent with prior studies, our data indicate seizure exacerbation in adults is rare with the initiation of ASMs. However, further studies with a larger sample size are necessary to better understand what factors may predispose patients to potential medication-induced seizure exacerbation.

Immune checkpoint inhibitors: immune-related adverse events, healthcare utilization, and costs among commercial and Medicare Advantage patients.

BACKGROUND: Immune checkpoint inhibitors (ICI) are increasingly used across multiple cancer types and stages and little is known about real-world outcomes. This study sought to determine healthcare utilization, costs, immune-related adverse events (irAEs), and all-cause mortality of single-agent versus combination ICI in the USA. MATERIALS AND METHODS: This is a retrospective study conducted with 2016-2018 data from the HealthCore Integrated Research Database, consisting of commercial and Medicare-insured adult patients with a cancer diagnosis using ICI in the USA. Outcomes were healthcare utilization, costs, and irAEs (FDA-recognized and others) up to 1-year post-index between patients using ICI monotherapy (mono, PD-1/PD-L1 inhibitor) and combination therapy (combo, PD-1/PD-L1 with CTLA-4 inhibitors). RESULTS: In total, 9084 patients received monotherapy and 904 patients received combo therapy. Mean age 65 years for mono and 58 years for combo. Overall, the combo arm had higher rates of FDA-recognized irAEs (67.4% vs. 45.9%), especially endocrinopathies (27.7% vs 14.7%) and dermatitis (25.9% vs. 12.4%). All-cause mortality over 1-year follow-up was similar, 30.7% in mono vs 30.8% in combo arms. The combo group had higher rates of all-cause inpatient hospitalizations (55.4% mono vs 65.6% combo) and emergency department (ED) visits (33.7% mono vs 41.4% combo). IrAE-related hospitalizations were higher in combo (55.2% vs 42.1%). IrAE-related ED visits were 15.7% mono vs 22.7% combo. This increased toxicity and health care utilization was reflected in significant differences in healthcare costs. Stark differences were seen in all-cause medical costs as well as costs related to inpatient and ED utilization and costs attributed to irAEs. CONCLUSIONS: Higher rates of irAEs, healthcare utilization, and costs occur with combination immunotherapy. As further indications are approved for combination ICI, our study highlights the real-world tradeoffs involved with combination therapy regarding burdens of toxicity and increased healthcare utilization.

Intra-patient stability of tumor mutational burden from tissue biopsies at different time points in advanced cancers.

BACKGROUND: Tumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Genomic landscape heterogeneity is a well-established cancer feature. Molecular characteristics may differ even within the same tumor specimen and undoubtedly evolve with time. However, the degree to which TMB differs between tumor biopsies within the same patient has not been established. METHODS: We curated data on 202 patients enrolled in the PREDICT study (NCT02478931), seen at the University of California San Diego (UCSD), who had 404 tissue biopsies for TMB (two per patient, mean of 722 days between biopsies) to assess difference in TMB before and after treatment in a pan-cancer cohort. We also performed an orthogonal analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database to examine difference in TMB between first and last biopsies. RESULTS: The mean (95% CI) TMB difference between samples was 0.583 [- 0.900-2.064] (p = 0.15). Pearson correlation showed a flat line for time elapsed between biopsies versus TMB change indicating no correlation (R2 = 0.0001; p = 0.8778). However, in 55 patients who received ICIs, there was an increase in TMB (before versus after mean mutations/megabase [range] 12.50 [range, 0.00-98.31] versus 14.14 [range, 0.00-100.0], p = 0.025). Analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database also indicated largely stable TMB patterns; TMB increases were only observed in specific tumors (e.g., breast, colorectal, glioma) within certain time intervals. CONCLUSIONS: Overall, our results suggest that tissue TMB remains stable with time, though specific therapies such as immunotherapy may correlate with an increase in TMB. TRIAL REGISTRATION: NCT02478931 , registered June 23, 2015.

Human induced pluripotent stem cell-derived macrophages ameliorate liver fibrosis.

With an increasing number of patients with degenerative hepatic diseases, such as liver fibrosis, and a limited supply of donor organs, there is an unmet need for therapies that can repair or regenerate damaged liver tissue. Treatment with macrophages that are capable of phagocytosis and anti-inflammatory activities such as secretion of matrix metalloproteinases (MMPs) provide an attractive cellular therapy approach. Human induced pluripotent stem cells (iPSCs) are capable of efficiently generating a large-scale, homogenous population of human macrophages using fully defined feeder- and serum-free differentiation protocol. Human iPSC-macrophages exhibit classical surface cell markers and phagocytic activity similar to peripheral blood-derived macrophages. Moreover, gene and cytokine expression analysis reveal that these macrophages can be efficiently polarized to pro-inflammatory M1 or anti-inflammatory M2 phenotypes in presence of LPS + IFN-γ and IL-4 + IL-13, respectively. M1 macrophages express high level of CD80, TNF-α, and IL-6 while M2 macrophages show elevated expression of CD206, CCL17, and CCL22. Here, we demonstrate that treatment of liver fibrosis with both human iPSC-derived macrophage populations and especially M2 subtype significantly reduces fibrogenic gene expression and disease associated histological markers including Sirius Red, αSMA and desmin in immunodeficient Rag2-/- γc-/- mice model, making this approach a promising cell-based avenue to ameliorate fibrosis.

Do Acupuncture Services Reduce Subsequent Utilization of Opioids and Surgical Interventions Compared to Noninvasive Therapies among Patients with Pain Conditions?

OBJECTIVE: To compare prescribed opioid use and invasive surgical interventions between patients using acupuncture and those using non-steroidal anti-inflammatory drugs (NSAIDs)/physical therapy (PT). DESIGN: Retrospective observational study of administrative claims. SETTING: Large commercial insurance plan. SUBJECTS: 52 346 each treated with either acupuncture or NSAIDs/PT. METHODS: Users of acupuncture and NSAIDs/PT were identified from January 1, 2014, to December 31, 2017. The first date of each service was defined as the index date. Acupuncture patients were 1:1 propensity score matched to the NSAIDs/PT group on baseline characteristics. Outcomes included opioid use, subsequent invasive surgical procedures, healthcare utilization such as hospitalizations or emergency department (ED) visits, and costs. These were assessed in the 12-month period before index date (baseline) and 12-month period following index date (follow-up) using difference-in-difference (DID) analysis. Results for opioid use were stratified by those with and without baseline opioid use. RESULTS: The acupuncture group had fewer patients initiating opioids post-index both among those with (49.2% vs 56.5%, P < .001) and without (15.9% vs 22.6%, P < .001) baseline opioid use. There was a small increase in invasive surgical procedures with acupuncture (3.1% vs 2.8%, P = .006). A reduction in ED visits was observed with acupuncture (DID -4.6% for all-cause; -3.3% for pain-related, all P < .001). Acupuncture was associated with higher total medical and pharmacy costs (DID +$1331 per patient, P = .006). CONCLUSIONS: Acupuncture showed a modest effect in reducing opioid use and ED visits. More research on acupuncture's place in emergency care, pain relief, and comparison to other types of non-opioid treatment is needed.