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BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.
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Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Antígeno Ki-1 , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Idoso , Adolescente , Doença de Hodgkin/terapia , Doença de Hodgkin/imunologia , Adulto Jovem , Criança , Receptores de Antígenos Quiméricos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melfalan/uso terapêutico , Melfalan/administração & dosagem , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/imunologia , Carmustina/uso terapêutico , Carmustina/administração & dosagem , Etoposídeo/uso terapêutico , Etoposídeo/administração & dosagem , Pré-Escolar , Citarabina/uso terapêutico , Citarabina/administração & dosagemRESUMO
BACKGROUND: Alcohol use disorder (AUD) affects 283 million people worldwide and its prevalence is increasing. Despite the role of the cerebellum in executive control and its sensitivity to alcohol, few studies have assessed its involvement in AUD-relevant functional networks. The goal of this study is to compare resting-state functional connectivity (FC) patterns in abstinent adults with a history of AUD and controls (CTL). We hypothesized that group differences in cerebro-cerebellar FC would be present, particularly within the frontoparietal/executive control network (FPN). METHODS: Twenty-eight participants completed a resting-state functional magnetic resonance imaging (rsfMRI) study. CTL participants had no history of AUD, comorbid psychological conditions, or recent heavy drinking and/or drug use. AUD participants had a history of AUD, with sobriety for at least 30 days prior to data collection. Multivariate pattern analysis, an agnostic, whole-brain approach, was used to identify regions with significant differences in FC between groups. Seed-based analyses were then conducted to determine the directionality and extent of these FC differences. Associations between FC strength and executive function were assessed using correlations with Wisconsin Card Sorting Test (WCST) performance. RESULTS: There were significant group differences in FC in nodes of the FPN, ventral attention network, and default mode network. Post hoc analyses predominantly identified FC differences within the cerebro-cerebellar FPN, with AUD showing significantly less FC within the FPN. In AUD, FC strength between FPN clusters identified in the multivariate pattern analysis (MVPA) analysis (Left Crus II, Right Frontal Cortex) was positively associated with performance on the WCST. CONCLUSIONS: Our results show less engagement of the FPN in individuals with AUD than in CTL. FC strength within this network was positively associated with performance on the WCST. These findings suggest that long-term heavy drinking alters cerebro-cerebellar FC, particularly within networks that are involved in executive function.
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Investigations of saturated spirocycles toward selective C-H functionalization reactions are scarce, despite their potential applications. In this work, we uncovered fundamental reactivity and selectivity differences between saturated heterocycles and their spirocyclic analogues using a model radical C-H xanthylation coupled with computational analysis. Ultimately, this study sheds light on the fundamental, understudied radical reactivity of spirocycles, thereby allowing for a pronounced chemical tunability that will prove to be advantageous in the expansion of their chemical space and applications in medicinal chemistry.
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The heterohexameric ATPases associated with diverse cellular activities (AAA)-ATPase Pex1/Pex6 is essential for the formation and maintenance of peroxisomes. Pex1/Pex6, similar to other AAA-ATPases, uses the energy from ATP hydrolysis to mechanically thread substrate proteins through its central pore, thereby unfolding them. In related AAA-ATPase motors, substrates are recruited through binding to the motor's N-terminal domains or N terminally bound cofactors. Here, we use structural and biochemical techniques to characterize the function of the N1 domain in Pex6 from budding yeast, Saccharomyces cerevisiae. We found that although Pex1/ΔN1-Pex6 is an active ATPase in vitro, it does not support Pex1/Pex6 function at the peroxisome in vivo. An X-ray crystal structure of the isolated Pex6 N1 domain shows that the Pex6 N1 domain shares the same fold as the N-terminal domains of PEX1, CDC48, and NSF, despite poor sequence conservation. Integrating this structure with a cryo-EM reconstruction of Pex1/Pex6, AlphaFold2 predictions, and biochemical assays shows that Pex6 N1 mediates binding to both the peroxisomal membrane tether Pex15 and an extended loop from the D2 ATPase domain of Pex1 that influences Pex1/Pex6 heterohexamer stability. Given the direct interactions with both Pex15 and the D2 ATPase domains, the Pex6 N1 domain is poised to coordinate binding of cofactors and substrates with Pex1/Pex6 ATPase activity.
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ATPases Associadas a Diversas Atividades Celulares , Proteínas de Membrana , Fosfoproteínas , Proteínas de Saccharomyces cerevisiae , Adenosina Trifosfatases/metabolismo , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Membranas Intracelulares/metabolismo , Proteínas de Membrana/metabolismo , Peroxissomos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Fosfoproteínas/metabolismoRESUMO
Ti-catalyzed oxidative alkyne carboamination with alkenes and azo compounds can yield either α,ß-unsaturated imines or cyclopropyl imines through a common azatitanacyclohexene intermediate. Herein, we report the synthesis of a model azatitanacyclohexene complex (3) through the ring-opening of a cyclopropyl imine with Cp2Ti(BTMSA) (BTMSA = bis(trimethylsilyl)acetylene). 3 readily undergoes thermal or reductant-catalyzed ring contraction to an azatitanacyclopentene (4), analogous to the proposed mechanism for forming α,ß-unsaturated imines in the catalytic reaction. A cyclopropyl imine or an α,ß-unsaturated imine could be liberated via the oxidation of 3 or 4 with azobenzene, respectively, further implicating the role of these metallacycles in the Ti-catalyzed carboamination reaction.
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Considering light transport in disordered media, the medium is often treated as an effective medium requiring accurate evaluation of an effective refractive index. Because of its simplicity, the Maxwell-Garnett (MG) mixing rule is widely used, although its restriction to particles much smaller than the wavelength is rarely satisfied. Using 3D finite-difference time-domain simulations, we show that the MG theory indeed fails for large particles. Systematic investigation of size effects reveals that the effective refractive index can be instead approximated by a quadratic polynomial whose coefficients are given by an empirical formula. Hence, a simple mixing rule is derived which clearly outperforms established mixing rules for composite media containing large particles, a common condition in natural disordered media.
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Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1 +/CD274+ (PD-L1) + dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.
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The heterohexameric AAA-ATPase Pex1/Pex6 is essential for the formation and maintenance of peroxisomes. Pex1/Pex6, similar to other AAA-ATPases, uses the energy from ATP hydrolysis to mechanically thread substrate proteins through its central pore, thereby unfolding them. In related AAA-ATPase motors, substrates are recruited through binding to the motor's N-terminal domains or N-terminally bound co-factors. Here we use structural and biochemical techniques to characterize the function of the N1 domain in Pex6 from budding yeast, S. cerevisiae. We found that although Pex1/ΔN1-Pex6 is an active ATPase in vitro, it does not support Pex1/Pex6 function at the peroxisome in vivo. An X-ray crystal structure of the isolated Pex6 N1 domain shows that the Pex6 N1 domain shares the same fold as the N terminal domains of PEX1, CDC48, or NSF, despite poor sequence conservation. Integrating this structure with a cryo-EM reconstruction of Pex1/Pex6, AlphaFold2 predictions, and biochemical assays shows that Pex6 N1 mediates binding to both the peroxisomal membrane tether Pex15 and an extended loop from the D2 ATPase domain of Pex1 that influences Pex1/Pex6 heterohexamer stability. Given the direct interactions with both Pex15 and the D2 ATPase domains, the Pex6 N1 domain is poised to coordinate binding of co-factors and substrates with Pex1/Pex6 ATPase activity.
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Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS-associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One-year overall survival was 61%, and progression-free survival was 58%. The 48-week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well-controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease.
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Infecções por HIV , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV , Estudos Prospectivos , Herpesvirus Humano 8/fisiologiaRESUMO
Pacific salmon transfer large quantities of material to tributaries during their spawning migrations, including carcass tissue and labile nutrients but also persistent organic pollutants (POPs) and heavy metals. We conducted a Before-After-Control-Intervention experiment by adding salmon carcasses and eggs to a Michigan (USA) stream that had never received inputs from non-native salmon to understand the bioaccumulation and persistence of biotransported contaminants. Our experimental outcomes were compared to previous studies using meta-analysis. Coincident with the introduction of salmon, the PCB and DDE burden of resident trout significantly increased. However, we did not observe changes in total mercury (Hg). Two years after the salmon addition experiment concluded, resident trout POP concentrations had returned to pre-addition levels, with no difference between the treatment and control reaches. Analysis of effect sizes suggested that the contaminant response observed in our experiment is consistent with field survey observations. Our study suggested that the consumption of salmon eggs drove the increase in POP burden of resident trout while Hg bioaccumulation was influenced by watershed sources. Critically, our study suggests that ecosystems are capable of quickly recovering from POP inputs from species migrations if contaminant sources are removed.
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Mercúrio , Oncorhynchus , Bifenilos Policlorados , Poluentes Químicos da Água , Animais , Rios , Ecossistema , Poluentes Químicos da Água/análise , Salmão , Truta , Mercúrio/análise , Bifenilos Policlorados/análiseRESUMO
Classical metalation reactions such as the metal-halogen exchange have had a transformative impact on organic synthesis owing to their broad applicability in building carbon-carbon bonds from carbon-halogen bonds. Extending the metal-halogen exchange logic to a metal-carbon exchange would enable the direct modification of carbon frameworks with new implications in retrosynthetic analysis. However, such a transformation requires the selective cleavage of highly inert chemical bonds and formation of stable intermediates amenable to further synthetic elaborations, hence its development has remained considerably challenging. Here we introduce a skeletal metalation strategy that allows lactams, a prevalent motif in bioactive molecules, to be readily converted into well-defined, synthetically useful organonickel reagents. The reaction features a selective activation of unstrained amide C-N bonds mediated by an easily prepared Ni(0) reagent, followed by CO deinsertion and dissociation under mild room temperature conditions in a formal carbonyl-to-nickel-exchange process. The underlying principles of this unique reactivity are rationalized by organometallic and computational studies. The skeletal metalation is further applied to a direct CO excision reaction and a carbon isotope exchange reaction of lactams, underscoring the broad potential of metal-carbon exchange logic in organic synthesis.
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Endothelial phospholipase Cγ (PLCγ) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLCγ was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLCγ expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLCγ was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLCγ (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo- and immunotherapy. Mechanistically, pY1173/PLCγ signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLCγ/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLCγ and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLCγ pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.
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Permeabilidade Capilar , Carcinoma de Células Renais , Neoplasias Renais , Animais , Humanos , Camundongos , Permeabilidade Capilar/genética , Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Fosforilação , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína Tirosina Quinase CSK/metabolismoRESUMO
CONTEXT: In Cushing disease, the association between the rate of serum cortisol decline and recurrent disease after corticotroph adenoma removal has not been adequately characterized. OBJECTIVE: To analyze postoperative serum cortisol and recurrence rates in Cushing disease. METHODS: Patients with Cushing disease and pathology-confirmed corticotroph adenoma were retrospectively studied. Cortisol halving time was estimated using exponential decay modeling. Halving time, first postoperative cortisol, and nadir cortisol values were collected using immediate postoperative inpatient laboratory data. Recurrence and time-to-recurrence were estimated and compared among cortisol variables. RESULTS: A total of 320 patients met inclusion/exclusion criteria for final analysis, and 26 of those patients developed recurrent disease. Median follow-up time was 25 months (95% CI, 19-28 months), and 62 patients had ≥ 5 years follow-up time. Higher first postoperative cortisol and higher nadir were associated with increased risk of recurrence. Patients who had a first postoperative cortisol ≥ 50 µg/dL were 4.1 times more likely to recur than those with a first postoperative cortisol < 50 µg/dL (HR 4.1, 1.8-9.2; P = .0003). Halving time was not associated with recurrence (HR 1.7, 0.8-3.8, P = .18). Patients with a nadir cortisol ≥2 µg/dL were 6.6 times more likely to recur than those with a nadir cortisol of < 2 µg/dL (HR 6.6, 2.6-16.6, P < .0001). CONCLUSION: Postoperative nadir serum cortisol is the most important cortisol variable associated with recurrence and time-to-recurrence. Compared to first postoperative cortisol and cortisol halving time, a nadir < 2 µg/dL showed the strongest association with long-term remission and typically occurs within the first 24 to 48 hours after surgery.
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Adenoma Hipofisário Secretor de ACT , Adenoma , Hipersecreção Hipofisária de ACTH , Humanos , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/cirurgia , Hidrocortisona , Estudos Retrospectivos , Adenoma/complicações , Recidiva Local de Neoplasia , RecidivaRESUMO
The utility of obtaining screening urine cultures for febrile neutropenia (FN) during hematopoietic stem cell transplant (HCT) is unknown. In 667 adult HCT patients with FN, only 40 (6%) were found with bacteriuria. Antibiotics were modified in 3 patients (0.4%) based on urine cultures and none developed urinary-associated infectious complications.
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This dataset was collected for the purpose of applying fault detection and diagnosis (FDD) techniques to real data from an industrial facility. The data for an air handling unit (AHU) is extracted from a building management system (BMS) and aligned with the Project Haystack naming convention. This dataset differs from other publicly available datasets in three main ways. Firstly, the dataset does not contain fault detection ground truth. The lack of labelled datasets in the industrial setting is a significant limitation to the application of FDD techniques found in the literature. Secondly, unlike other publicly available datasets that typically record values every 1 min or 5 min, this dataset captures measurements at a lower frequency of every 15 min, which is due to data storage constraints. Thirdly, the dataset contains a myriad of data issues. For example, there are missing features, missing time intervals, and inaccurate data. Therefore, we hope this dataset will encourage the development of robust FDD techniques that are more suitable for real world applications.
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New COVID-19 ventilation guidelines have resulted in higher energy consumption to maintain indoor air quality (IAQ), and energy efficiency has become a secondary concern. Despite the significance of the studies conducted on COVID-19 ventilation requirements, a comprehensive investigation of the associated energy challenges has not been discussed. This study aims to present a critical systematic review of the Coronavirus viral spreading risk mitigation through ventilation systems (VS) and its relation to energy use. COVID-19 heating, ventilation and air conditioning (HVAC)-related countermeasures proposed by industry professionals have been reviewed and their influence on operating VS and energy consumption have also been discussed. A critical review analysis was then conducted on publications from 2020 to 2022. Four research questions (RQs) have been selected for this review concerning i) maturity of the existing literature, ii) building types and occupancy profile, iii) ventilation types and effective control strategies and iv) challenges and related causes. The results reveal that employing HVAC auxiliary equipment is mostly effective and increased fresh air supply is the most significant challenge associated with increased energy consumption due to maintaining IAQ. Future studies should focus on novel approaches toward solving the apparently conflicting objectives of minimizing energy consumption and maximizing IAQ. Also, effective ventilation control strategies should be assessed in various buildings with different occupancy densities. The implications of this study can be useful for future development of this topic not only to enhance the energy efficiency of the VS but also to enable more resiliency and health in buildings.
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Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.
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Neoplasias da Mama , Neoplasias Mamárias Animais , Humanos , Feminino , Animais , Epitopos/metabolismo , Vinorelbina/metabolismo , Vinorelbina/uso terapêutico , Receptor ErbB-2 , Neoplasias da Mama/metabolismo , Imunoterapia , Peptídeos/metabolismo , Células Dendríticas , Trastuzumab/uso terapêutico , Trastuzumab/metabolismoRESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) has a progressive, unremitting clinical course. Vasoreactivity testing (VdT) during right heart catheterisation (RHC) identifies a subgroup with excellent long-term response to calcium channel blockade (CCB). Reporting on these patients is limited. Established in 2011, the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry offers the opportunity to assess the frequency of VdT during RHC, treatment and follow up of PAH patients. METHODS: Registry data from 3,972 PAH patients with index RHC revealed 1,194 VdT appropriate patients. Data was analysed in three groups: 1) VdT+CCB+: VdT positive, CCB treated; 2) VdT+CCB-: VdT positive, no CCB prescribed, 3) VdT-/noVdT: VdT negative, or VdT not tested. Data was reviewed for adherence to guidelines, clinical response (World Health Organization functional class [WHO FC], 6-minute-walk-distance [6MWD], RHC), and outcomes (survival or lung transplantation). RESULTS: Patients included had idiopathic (IPAH=1,087), heritable (HPAH=67) and drug or toxin-induced PAH (DPAH=40). A VdT was performed in 22% (268/1,194), with incomplete data in 26% (70/268); 28% (55/198) were VdT+. Analysis group allocation was: VdT+CCB+ (33/55), VdT+CCB- (22/55), VdT- (143)/noVdT (996). From patients with 1-year data VdT+CCB+ and VdT-/noVdT patients improved WHO FC, 6MWD and cardiac index (CI); VdT+CCB- data remained similar. Within the VdT+CCB+ group, 30% (10/33) were long-term CCB responders with a 100% 5-year survival; non-responders had a 61% survival at 5.4 years. Long-term responders were younger at diagnosis (40 yrs vs 54 yrs). CONCLUSION: Use of VdT testing and documentation is poor in this contemporary patient cohort. Nonetheless, survival in VdT+CCB+ patients from the PHSANZ registry is excellent, supporting guidelines promoting VdT testing. Strategies to promote the use of VdT are warranted.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão Arterial Pulmonar/terapia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Pulmonar Primária Familiar , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/tratamento farmacológico , Cateterismo CardíacoRESUMO
BACKGROUND: Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. METHODS: We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. RESULTS: Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. CONCLUSION: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).
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Neoplasias Colorretais , Humanos , Cetuximab/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas B-raf , Proteínas de Membrana , GTP Fosfo-HidrolasesRESUMO
Cancer fatalism-the belief that death is inevitable when cancer is present-has been identified as a barrier to cancer screening, detection, and treatment. Our study examined the relationship between self-reported cancer fatalism and adherence to cancer screening guidelines of the breasts, cervix, colon, and prostate among a diverse sample of urban-dwelling adults in Brooklyn, New York. Between May 2019 and August 2020, we conducted a cross-sectional survey of adults 40 + years of age (n = 2,341) residing in Brooklyn neighborhoods with high cancer mortality. Multivariable logistic regression models were used to assess the odds of reporting cancer screening completion across three fatalistic cancer belief categories (low, med, high). Participants' median age was 61 (IQR 51, 71) years, 61% were women, 49% self-identified as non-Hispanic black, 11% Hispanic, 4% Asian, and 6% more than one race. There were no statistically significant differences in the proportion of low, some, or high fatalistic beliefs identified among male respondents compared to women. Among women, we observed that high fatalistic cancer beliefs were associated with higher odds (OR 2.01; 95% CI 1.10-3.65) of completing breast but not cervical (1.04; CI 0.55-1.99) or colon (1.54; CI 0.88-2.69) cancer screening. Men with high fatalistic cancer beliefs had a trend towards lower odds of prostate screening (OR 0.53: 95% CI 0.18-1.57) compared to men with low fatalistic beliefs, but neither was statistically significant. Findings suggest that high fatalistic cancer beliefs may be an important factor in cancer screening utilization among women. Further examination in longitudinal cohorts with a larger sample of men may be needed in order to identify any significant effect.