Impact of Angiotensin Converting Enzyme Inhibitors on Pathologic Complete Response With Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer.

INTRODUCTION: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. RESULTS: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS. CONCLUSION: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC.

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors.

Cancer cells convert nutrients into energy differently compared to healthy cells. This difference in metabolism allows them to grow and divide more quickly and sometimes to migrate to different areas of the body. The environment around cancer cells ­ known as the tumor microenvironment ­ contains a variety of different cells and blood vessels, which are bathed in interstitial fluid. This microenvironment provides nutrients for the cancer cells to metabolize, and therefore influences how well a tumor grows and how it might respond to treatment. Recent advances with techniques such as mass spectrometry, which can measure the chemical composition of a substance, have allowed scientists to measure nutrient levels in the tumor microenvironments of mice. However, it has been more difficult to conduct such studies in humans, as well as to compare the tumor microenvironment to the healthy tissue the tumors arose from. Abbott, Ali, Reinfeld et al. aimed to fill this gap in knowledge by using mass spectrometry to measure the nutrient levels in the tumor microenvironment of 55 patients undergoing surgery to remove kidney tumors. Comparing the type and levels of nutrients in the tumor interstitial fluid, the neighboring healthy kidney and the blood showed that nutrients in the tumor and healthy kidney were more similar to each other than those in the blood. For example, both the tumor and healthy kidney interstitial fluids contained less glucose than the blood. However, the difference between nutrient composition in the tumor and healthy kidney interstitial fluids was insignificant, suggesting that the healthy kidney and its tumor share a similar environment. Taken together, the findings indicate that kidney cancer cells must adapt to the nutrients available in the kidney, rather than changing what nutrients are available in the tissue. Future studies will be required to investigate whether this finding also applies to other types of cancer. A better understanding of how cancer cells adapt to their environments may aid the development of drugs that aim to disrupt the metabolism of tumors.

Dynamic heterogeneity in COVID-19: Insights from a mathematical model.

Critical illness, such as severe COVID-19, is heterogenous in presentation and treatment response. However, it remains possible that clinical course may be influenced by dynamic and/or random events such that similar patients subject to similar injuries may yet follow different trajectories. We deployed a mechanistic mathematical model of COVID-19 to determine the range of possible clinical courses after SARS-CoV-2 infection, which may follow from specific changes in viral properties, immune properties, treatment modality and random external factors such as initial viral load. We find that treatment efficacy and baseline patient or viral features are not the sole determinant of outcome. We found patients with enhanced innate or adaptive immune responses can experience poor viral control, resolution of infection or non-infectious inflammatory injury depending on treatment efficacy and initial viral load. Hypoxemia may result from poor viral control or ongoing inflammation despite effective viral control. Adaptive immune responses may be inhibited by very early effective therapy, resulting in viral load rebound after cessation of therapy. Our model suggests individual disease course may be influenced by the interaction between external and patient-intrinsic factors. These data have implications for the reproducibility of clinical trial cohorts and timing of optimal treatment.

Exercise intensity governs tumor control in mice with breast cancer.

Introduction: Exercise is recommended as an adjunct therapy in cancer, but its effectiveness varies. Our hypothesis is that the benefit depends on the exercise intensity. Methods: We subjected mice to low intensity (Li), moderate intensity (Mi) or high intensity (Hi) exercise, or untrained control (Co) groups based on their individual maximal running capacity. Results: We found that exercise intensity played a critical role in tumor control. Only Mi exercise delayed tumor growth and reduced tumor burden, whereas Li or Hi exercise failed to exert similar antitumor effects. While both Li and Mi exercise normalized the tumor vasculature, only Mi exercise increased tumor infiltrated CD8+ T cells, that also displayed enhanced effector function (higher proliferation and expression of CD69, INFγ, GzmB). Moreover, exercise induced an intensity-dependent mobilization of CD8+ T cells into the bloodstream. Conclusion: These findings shed light on the intricate relationship between exercise intensity and cancer, with implications for personalized and optimal exercise prescriptions for tumor control.

Unraveling a hidden player in lymphovascular invasion in bladder cancer.

Tumor invasion into the lymphatic vasculature represents a critical step during malignant progression of epithelial cancers. In this issue of Cancer Cell, Zheng et al. unravel how cancer-associated fibroblasts interact with lymphatic endothelial cells and the extracellular matrix to promote lymphatic tumor invasion and suggest that these processes could be treatment targets.

In silico clinical studies for optimal COVID-19 vaccination schedules in patients with cancer.

This study introduces a tailored COVID-19 model for patients with cancer, incorporating viral variants and immune-response dynamics. The model aims to optimize vaccination strategies, contributing to personalized healthcare for vulnerable groups.

Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients.

The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.

Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas.

Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge in the granuloma microenvironment (GME) as a direct result of limited oxygen availability. Building on our initial model of avascular oxygen diffusion, here we explore additional aspects of oxygen transport, including the roles of granuloma vasculature, transcapillary transport, plasma dilution, and interstitial convection, followed by cellular metabolism. Approximate analytical solutions are provided for oxygen and glucose concentration, interstitial fluid velocity, interstitial fluid pressure, and the thickness of the convective zone. These predictions are in agreement with prior experimental results from rabbit TB granulomas and from rat carcinoma models, which share similar transport limitations. Additional drug delivery predictions for anti-TB-agents (rifampicin and clofazimine) strikingly match recent spatially-resolved experimental results from a mouse model of TB. Finally, an approach to improve molecular transport in granulomas by modulating interstitial hydraulic conductivity is tested in silico.

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

Efficacy of cariprazine in patients with bipolar depression and higher or lower levels of baseline anxiety: a pooled post hoc analysis.

Post hoc analyses evaluated cariprazine, a dopamine D 3 -preferring D 3 /D 2 receptor partial agonist, in patients with bipolar I depression and high baseline anxiety. Data were pooled from two phase 3, randomized, double-blind, placebo-controlled studies in adults with bipolar I disorder and a major depressive episode (NCT02670538, NCT02670551). Cariprazine 1.5 and 3 mg/d were evaluated in patient subgroups with higher and lower baseline anxiety. In patients with higher baseline anxiety, significant differences for cariprazine 1.5 mg/d versus placebo were observed on change in Montgomery-Åsberg Rating Scale (MADRS) total score, Hamilton Anxiety Rating Scale (HAM-A) total score and subscale scores, and rates of MADRS remission ( P < 0.05 all); nonsignificant numerical improvements were observed for cariprazine 3 mg/d versus placebo. In patients with lower anxiety, differences versus placebo were significant for HAM-A (cariprazine 3 mg/d) and MADRS (cariprazine 1.5 and 3 mg/d) total score changes ( P < 0.05 all). Rates of treatment-emergent mania were low and similar for cariprazine and placebo. Cariprazine 1.5 mg/d had consistent effects on anxiety and depression symptoms in patients with bipolar I depression and higher baseline anxiety; tolerability was favorable. Given few proven treatments for this common comorbidity, these preliminary results are promising.

Tofacitinib Efficacy in Patients with Rheumatoid Arthritis and Probable Depression/Anxiety: Post Hoc Analysis of Phase 3 and 3b/4 Randomized Controlled Trials.

INTRODUCTION: The aim of our work is to assess the prevalence of probable major depressive disorder and/or probable generalized anxiety disorder (pMDD/pGAD) in patients with moderate to severe rheumatoid arthritis (RA), and to evaluate the efficacy of tofacitinib on RA symptoms stratified by baseline pMDD/pGAD status. METHODS: Data were pooled from five phase 3 randomized controlled trials (RCTs) and one phase 3b/4 RCT, assessing tofacitinib 5 or 10 mg twice daily (BID), adalimumab (two RCTs), or placebo. pMDD/pGAD was defined as Short Form-36 Health Survey (SF-36) Mental Component Summary (MCS) score ≤ 38. Efficacy outcomes over 12 months included least squares mean change from baseline in SF-36 MCS score and Health Assessment Questionnaire-Disability Index, proportions of patients with pMDD/pGAD in those with baseline pMDD/pGAD, and American College of Rheumatology 20/50/70 response, and Disease Activity Score in 28 joints, erythrocyte sedimentation rate remission (< 2.6) rates. RESULTS: A total of 4404 patients with non-missing baseline values were included. Baseline pMDD/pGAD was reported by 44.5%, 39.8%, 45.4%, and 39.1% of patients receiving tofacitinib 5 mg BID, tofacitinib 10 mg BID, adalimumab, and placebo, respectively. SF-36 MCS improvements were greater for tofacitinib versus adalimumab/placebo through month 6, with numerical improvements for tofacitinib versus adalimumab sustained through month 12, when the proportions of patients with baseline pMDD/pGAD who continued to have pMDD/pGAD were reduced. RA efficacy outcomes were generally similar in patients with/without baseline pMDD/pGAD. CONCLUSIONS: The percentage of patients with pMDD/pGAD reduced from baseline over 1 year of treatment with tofacitinib or adalimumab. Effective treatment of underlying RA may lead to improvements in depression and anxiety, based on the SF-36 MCS. Specially designed studies using gold-standard diagnostic tools would be warranted to investigate this further. Video Abstract available for this article. TRIAL REGISTRATION: NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT02187055. Video Abstract (MP4 204475 KB).

Tofacitinib is a medicine used to treat rheumatoid arthritis (swollen and painful joints). A total of 4400 patients with moderate or severe rheumatoid arthritis who were taking part in tofacitinib clinical trials completed a survey about their general health and well-being at that time. We used their answers to determine whether they were likely to have depression or anxiety. We then looked at how common depression or anxiety was in patients with rheumatoid arthritis, and whether having depression or anxiety affected how patients responded to tofacitinib treatment. It is important to note that tofacitinib is not approved for the treatment of depression or anxiety, and these clinical trials were not designed to assess whether tofacitinib improved depression or anxiety symptoms. About 40% of patients likely had depression or anxiety when they started a clinical trial. This percentage decreased among patients who received tofacitinib treatment over a year. Patients treated with tofacitinib showed more improvement in their depression or anxiety than those treated with placebo. Over a year of treatment, tofacitinib improved signs and symptoms of rheumatoid arthritis, for example, the number of swollen or painful joints and fatigue. Having depression or anxiety did not change the way that patients responded to tofacitinib. This research shows how treating rheumatoid arthritis symptoms may also improve depression and anxiety symptoms. However, specially designed studies are needed to confirm this.

Evidence for the natural infection of cucurbit chlorotic yellows virus (CCYV) in lettuce plants from India.

In the years 2021 and 2022, lettuce plants showing blistering, chlorosis, mosaic, rosetting/ excess proliferation, and stunting symptoms were subjected to leaf-dip transmission electron microscopy, RT-PCR followed by sequence analysis and bio-assay to unfold the identity of associated virus(es). The association of long filamentous virions (~ 850 nm in length) as seen through leaf-dip transmission electron microscopy suggested the possible infection by a potyvirus or crinivirus, either singly or in combination. RT-PCR assays using generic primers targeting the RdRp region of criniviruses and the NIb region of potyviruses revealed the association of both a crinivirus as well as a potyvirus. The gel-purified RT-PCR products derived from the RdRp region of criniviruses upon cloning, sequencing, and NCBI BLAST analysis indicated the associated crinivirus as cucurbit chlorotic yellows virus (CCYV). Further, RT-PCR assays using specific primers targeting CP and CP minor genes of CCYV followed by cloning and sequencing confirmed its association with the diseased lettuce plants. Besides, the bioassay based on whitefly-mediated virus transmission followed by RT-PCR confirmed the infectivity of CCYV from diseased to healthy lettuce plants. The results of this study confirmed the natural infection of CCYV in lettuce host for the first time in the world indicating its distribution across the crop families.

Dissecting the Impact of the Gut Microbiome on Cancer Immunotherapy.

The gut microbiome has emerged as a key regulator of response to cancer immunotherapy. However, there is a gap in our understanding of the underlying mechanisms by which the microbiome influences immunotherapy. To this end, we developed a mathematical model based on i) gut microbiome data derived from preclinical studies on melanomas after fecal microbiota transplant, ii) mechanistic modeling of antitumor immune response, and iii) robust association analysis of murine and human microbiome profiles with model-predicted immune profiles. Using our model, we could distill the complexity of these murine and human studies on microbiome modulation in terms of just two model parameters: the activation and killing rate constants of immune cells. We further investigated associations between specific bacterial taxonomies and antitumor immunity and immunotherapy efficacy. This model can guide the design of studies to refine and validate mechanistic links between the microbiome and immune system.

Mathematical modeling of intratumoral immunotherapy yields strategies to improve the treatment outcomes.

Intratumoral injection of immunotherapy aims to maximize its activity within the tumor. However, cytokines are cleared via tumor vessels and escape from the tumor periphery into the host-tissue, reducing efficacy and causing toxicity. Thus, understanding the determinants of the tumor and immune response to intratumoral immunotherapy should lead to better treatment outcomes. In this study, we developed a mechanistic mathematical model to determine the efficacy of intratumorally-injected conjugated-cytokines, accounting for properties of the tumor microenvironment and the conjugated-cytokines. The model explicitly incorporates i) the tumor vascular density and permeability and the tumor hydraulic conductivity, ii) conjugated-cytokines size and binding affinity as well as their clearance via the blood vessels and the surrounding tissue, and iii) immune cells-cancer cells interactions. Model simulations show how the properties of the tumor and of the conjugated-cytokines determine treatment outcomes and how selection of proper parameters can optimize therapy. A high tumor tissue hydraulic permeability allows for the uniform distribution of the cytokines into the tumor, whereas uniform tumor perfusion is required for sufficient access and activation of immune cells. The permeability of the tumor vessels affects the blood clearance of the cytokines and optimal values depend on the size of the conjugates. A size >5 nm in radius was found to be optimal, whereas the binding of conjugates should be high enough to prevent clearance from the tumor into the surrounding tissue. In conclusion, development of strategies to improve vessel perfusion and tissue hydraulic conductivity by reprogramming the microenvironment along with optimal design of conjugated-cytokines can enhance intratumoral immunotherapy.

Impact of tardive dyskinesia on patients and caregivers: a survey of caregivers in the United States.

BACKGROUND: Tardive dyskinesia (TD) has a multidimensional impact on patients with TD and, as importantly, their caregivers. An online survey was developed and administered to assess patient and caregiver burden of TD. Survey participants were unpaid caregivers for patients with diagnoses of TD and schizophrenia, bipolar disorder, and/or major depressive disorder. Overall, 162 caregivers rated the 7-day impact of TD on the physical, psychological, and social functioning of patients and the impact of TD on these domains in their own lives and in their professional lives. RESULTS: Across physical, psychological, and social domains, most caregivers (82.7%) reported that TD had severe impact on the cared-for patients, and 23.5% reported severe impact of TD in their own lives. Caregivers experienced 46.4% activity impairment, and caregivers who were employed (n = 136) experienced 49.5% overall work impairment because of TD-related caregiving. CONCLUSIONS: These results suggest that TD imposes substantial burden for both caregivers and patients.

Desmoplasia in cervical cancer is associated with a more aggressive tumor phenotype.

In cancer of the uterine cervix, the role of desmoplasia, i.e., peritumoral stromal remodeling characterized by fibroblast activation and increased extracellular matrix deposition, is not established. We conducted a retrospective cohort study based on data from 438 patients who had undergone surgical treatment for cervical cancer as part of the prospective Leipzig Mesometrial Resection study between 1999 and 2021. Using non-parametric tests, Kaplan-Meier plotting, and Cox regression modeling, we calculated the prognostic impact of desmoplasia and its association with other risk factors. Desmoplasia was present in 80.6% of cases and was associated with a higher frequency of lymphovascular space involvement (76.5 vs. 56.5%, p < 0.001) and venous infiltration (14.4 vs. 2.4%, p < 0.001). Lymph node metastasis (23.0 vs. 11.8%, p < 0.05) and parametrial involvement (47.3 vs. 17.6%, p < 0.0001) were also more common in patients with desmoplasia. The presence of desmoplasia was associated with inferior overall (80.2% vs. 94.5% hazard ratio [HR] 3.8 [95% CI 1.4-10.4], p = 0.002) and recurrence-free survival (75.3% vs. 87.3%, HR 2.3 [95% CI 1.2-4.6], p = 0.008). In addition, desmoplasia was associated with significantly less peritumoral inflammation (rho - 0.43, p < 0.0001). In summary, we link desmoplasia to a more aggressive phenotype of cervical cancer, reduced peritumoral inflammation, and inferior survival.

Treatment patterns, health care resource utilization, and costs associated with use of atypical antipsychotics as first vs subsequent adjunctive treatment in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent mental health condition associated with substantial economic burden. Inadequate response to first-line antidepressant monotherapy is common, with most patients requiring 1 or more changes in their treatment regimen. Adjunctive treatment with atypical antipsychotics (AAs) is a guideline-recommended treatment option in patients with inadequate response. However, patients often cycle through multiple treatments before receiving adjunctive AAs, and the economic impact of this delay is unknown. OBJECTIVE: To describe adjunctive treatment patterns among patients with MDD and compare health care resource utilization (HCRU) and costs between patients whose first adjunctive therapy included an AA and those who received an AA after other adjunctive treatments. METHODS: The Merative MarketScan Commercial Database (January 1, 2014, to June 30, 2019) was used to identify patients with administrative claims meeting the following inclusion criteria: adults with newly diagnosed MDD (first observed MDD diagnosis = index diagnosis date); continuous health insurance for at least 6 months pre-index and at least 3 months post-index; and initiation of MDD treatment within 60 days post-index. Lines of therapy (LOTs), HCRU, and costs were analyzed in patients who received AA adjunctive therapy, including those who initiated AAs as the first adjunctive treatment and those who initiated AAs as subsequent adjunctive treatment. RESULTS: Of 508,830 patients meeting inclusion criteria, 121,060 (24%) received adjunctive treatment and 20,797 (4%) received an AA as adjunctive therapy. Mean time to adjunctive therapy initiation was approximately 7.3 months for AA adjunctive therapy. Patients who initiated an AA as their first adjunctive therapy compared with patients who initiated an AA as their subsequent adjunctive therapy had fewer LOTs on average (0.9 LOTs vs 3.9 LOTs) and shorter time between index diagnosis date and initiation of an AA (5 months vs 12 months). Subsequent AA initiators had significantly greater HCRU than first AA initiators (driven primarily by outpatient visits) and incurred significantly higher total health care costs, with mean all-cause and mental health-related health care cost differences per patient per year of $2,441 and $1,762, respectively (both P < 0.05). CONCLUSIONS: Less than 5% of patients in this study received an adjunctive AA as part of their MDD treatment regimen, suggesting underutilization of this recommended therapeutic approach. Patients who received an AA as their first adjunctive treatment regimen had lower HCRU and health care costs than subsequent AA initiators. Along with published evidence of clinical benefits, this potential impact on economic burden should be considered when making treatment choices for patients with inadequate response to antidepressants.