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Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.
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Vacunas contra la Influenza , Adulto , Humanos , Inmunidad Humoral , Estaciones del Año , Linfocitos T Colaboradores-Inductores , VacunaciónRESUMEN
CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.
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Interleucina-15 , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Terapia Combinada , Antígenos CD40 , Fragmentos Fc de InmunoglobulinasRESUMEN
Historically, total body irradiation (TBI) has been delivered using static, parallel opposed photon beams (2D-TBI). Recently, centers have increasingly used intensity-modulated radiation therapy (IMRT) techniques for TBI. Relative to 2D-TBI, IMRT can reduce doses to critical organs (i.e., lungs and kidneys) while delivering myeloablative doses to the rest of the body, so it may decrease the risk of toxicity while maintaining oncologic outcomes. Despite these potential benefits, delivering TBI using IMRT introduces new challenges in treatment planning and delivery. We describe the extensive experience with IMRT-based TBI at Stanford University and City of Hope Cancer Center. These groups, and others, have reported favorable clinical outcomes and have developed methods to optimize treatment planning and delivery. A critical next step is to evaluate the broader adoption of this approach. Therefore, IMRT-based TBI will be incorporated into a prospective, multi-institutional Children's Oncology Group study with careful procedures and safeguards in place.
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BACKGROUND: Men who have sex with men (MSM) face many challenges and biases in healthcare. Within urology there is a need to better understand how prostate cancer impacts MSM given the unique ways in which side effects that accompany treatment may affect this population. The goal of this study is to explore the experience of MSM with prostate cancer to advance the existing literature in this area and inform implementation and delivery of clinical practice and policy guidelines. METHODS: Four focus groups were conducted with a semi-structured interview guide. Using a phenomenological qualitative approach consistent with grounded theory [1] and naturalistic inquiry principles we sought to better understand the direct experiences of MSM with prostate cancer. Audio transcriptions were thematically analyzed to identify themes that impact MSM throughout their prostate cancer journey. An iterative, team-wide classification process was used to identify, organize, and group common codes into higher-order categories and themes. RESULTS: Patient's choice of provider and their interactions with the healthcare system were strongly impacted by their sexual identities. Participants commented on navigating the heteronormative healthcare environment and the impact of assumptions they encountered. MSM experienced the sexual side effects of prostate cancer treatment in unique ways. Issues with erectile dysfunction and ejaculatory dysfunction had significant impacts on patient's sexual experience, with some describing being forced to explore new modes of sexual expression. Anejaculation was a theme that was distressing for many participants. The emotional impact of a prostate cancer diagnosis was significant in the men interviewed. Common themes included loss of identity and fear for future relationships. CONCLUSIONS: MSM have unique concerns after prostate cancer treatment that differ from men who don't identify as MSM. It is critical that providers familiarize themselves with the concerns of this patient population regarding prostate cancer treatment. An important step toward reducing heteronormative bias in prostate cancer care is to better understand the goals, identity, and sexual practices of MSM and to provide informed anticipatory guidance.
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Disfunción Eyaculatoria , Neoplasias de la Próstata , Minorías Sexuales y de Género , Masculino , Humanos , Grupos Focales , Homosexualidad Masculina , Neoplasias de la Próstata/terapia , SesgoRESUMEN
BACKGROUND: It is known that COVID-19 disproportionally adversely affects the immunocompromised, including kidney transplant recipients (KTR), as compared to the general population. Risk factors for adverse outcomes and vaccine seroconversion patterns are not fully understood. Australia was uniquely positioned to reduce initial case numbers during the 2021-2022 pandemic period due to its relative isolation and several significant public health interventions. South-Western Sydney Local Heath District was one of the predominant regions affected. METHODS: A single centre, prospective cohort study of prevalent renal transplant recipients was conducted between 25th July 2021 and 1st May 2022. Baseline characteristics, COVID-19 vaccination status, COVID-19 diagnosis and outcomes were determined from the electronic medical record, Australian vaccination register and Australian and New Zealand Dialysis and Transplant Registry. Assessment of vaccine-induced seroconversion was assessed with ELISA in a subpopulation. Analysis was performed using SPSS v.28. RESULTS: We identified 444 prevalent transplant recipients (60% male, 50% diabetic, median age 58 years (Interquartile range (IQR)21.0) and eGFR 56 ml/min/1.73m2 (IQR 21.9). COVID-19 was identified in 32% (n = 142) of patients, of which 38% (n = 54) required hospitalisation and 7% (n = 10) died. At least one COVID-19 vaccination was received by 95% (n = 423) with 17 (4%) patients remaining unvaccinated throughout the study period. Seroconversion after 2 and 3 doses of vaccine was 22% and 48% respectively. Increased COVID-19 related deaths were associated with older age (aOR 1.1, 95% CI 1.004-1.192, p = 0.040), smoking exposure (aOR 8.2, 05% CI 1.020-65.649, p = 0.048) and respiratory disease (aOR 14.2, 95%CI:1.825-110.930, p = 0.011) on multi-variable regression analysis. Receipt of three doses of vaccination was protective against acquiring COVID-19 (aOR 0.48, 95% CI 0.287-0.796, p = 0.005) and death (aOR 0.6, 95% CI: 0.007-0.523, p = 0.011), but not against hospitalisation (p = 0.32). Seroconversion was protective for acquiring COVID-19 on multi-variable regression independent of vaccination dose (aOR 0.1, 95%CI: 0.0025-0.523, p = 0.011). CONCLUSIONS: COVID-19 was associated with a high mortality rate. Older age, respiratory disease and prior smoking exposure may be risk factors for increased mortality. Vaccination of 3 doses is protective against acquiring COVID-19 and death, however not hospitalisation. Antibody response is protective for acquiring COVID-19, however seroconversion rates are low.
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COVID-19 , Vacunas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Estudios Prospectivos , Australia/epidemiología , Prueba de COVID-19 , Vacunas contra la COVID-19 , Pandemias , Seroconversión , COVID-19/epidemiología , COVID-19/prevención & control , Diálisis RenalRESUMEN
PURPOSE: Radiotherapy delivered at ultra-high-dose-rates (≥40 Gy/s), that is, FLASH, has the potential to effectively widen the therapeutic window and considerably improve the care of cancer patients. The underlying mechanism of the FLASH effect is not well understood, and commercial systems capable of delivering such dose rates are scarce. The purpose of this study was to perform the initial acceptance and commissioning tests of an electron FLASH research product for preclinical studies. METHODS: A linear accelerator (Clinac 23EX) was modified to include a non-clinical FLASH research extension (the Clinac-FLEX system) by Varian, a Siemens Healthineers company (Palo Alto, CA) capable of delivering a 16 MeV electron beam with FLASH and conventional dose rates. The acceptance, commissioning, and dosimetric characterization of the FLEX system was performed using radiochromic film, optically stimulated luminescent dosimeters, and a plane-parallel ionization chamber. A radiation survey was conducted for which the shielding of the pre-existing vault was deemed sufficient. RESULTS: The Clinac-FLEX system is capable of delivering a 16 MeV electron FLASH beam of approximately 1 Gy/pulse at isocenter and reached a maximum dose rate >3.8 Gy/pulse near the upper accessory mount on the linac gantry. The percent depth dose curves of the 16 MeV FLASH and conventional modes for the 10 × 10 cm2 applicator agreed within 0.5 mm at a range of 50% of the maximum dose. Their respective profiles agreed well in terms of flatness but deviated for field sizes >10 × 10 cm2 . The output stability of the FLASH system exhibited a dose deviation of <1%. Preliminary cell studies showed that the FLASH dose rate (180 Gy/s) had much less impact on the cell morphology of 76N breast normal cells compared to the non-FLASH dose rate (18 Gy/s), which induced large-size cells. CONCLUSION: Our studies characterized the non-clinical Clinac-FLEX system as a viable solution to conduct FLASH research that could substantially increase access to ultra-high-dose-rate capabilities for scientists.
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Electrones , Radiometría , Humanos , Dosificación Radioterapéutica , Aceleradores de Partículas , Dosímetros de RadiaciónRESUMEN
OBJECTIVE: Bedtime procrastination is a relatively new topic of research and has been found to compromise sleep. Researchers have studied the predictors, but only a few studies have focused on the ways to reduce bedtime procrastination. Mindfulness, a novel variable in this research area, may shed some light on how to decrease bedtime procrastination. This study examined a serial mediation model and hypothesized that the relationship between mindfulness and better sleep quality would be serially mediated by lower levels of boredom and bedtime procrastination. METHODS: This study employed a correlational approach and recruited a sample of 220 participants aged between 17 and 30 (M = 20.34 years, SD = 2.86). In the Qualtrics online survey, participants completed a series of questionnaires measuring mindfulness, boredom, bedtime procrastination, and sleep quality. RESULTS: The analyses provided support for our serial mediation model. Mindfulness predicted a lower level of boredom, which in turn predicted a lower level of bedtime procrastination and subsequently better sleep quality. CONCLUSION: Our findings highlighted the role of mindfulness in curbing bedtime procrastination, setting a foundation for future research on the interventions for sleep issues associated with bedtime procrastination. We discussed the theoretical and practical implications of the findings.
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Atención Plena , Procrastinación , Humanos , Adulto Joven , Adolescente , Adulto , Calidad del Sueño , Tedio , SueñoRESUMEN
BACKGROUND: Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer. METHODS: In this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting. FINDINGS: Between May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths. INTERPRETATION: 24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term. FUNDING: Insightec and the National Cancer Institute.
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Antígeno Prostático Específico , Neoplasias de la Próstata , Anciano , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapiaRESUMEN
Despite recent advances, non-Hodgkin's B cell lymphoma patients often relapse or remain refractory to therapy. Therapeutic resistance is often associated with survival signaling via nuclear factor κB (NF-κB) transcription factor, an attractive but undruggable molecular target. In this study, we describe a bipartite inhibitor comprising a NF-κB-specific decoy DNA tethered to a CpG oligodeoxynucleotide (ODN) targeting Toll-like receptor-9-expressing B cell lymphoma cells. The Bc-NFκBdODN showed efficient uptake by human diffuse large B cell (U2932, OCI-Ly3), Burkitt (RaJi), and mantle cell (Jeko1) lymphomas, respectively. We confirmed that Bc-NFκBdODN inhibited NF-κB nuclear translocation and DNA binding, resulting in CCND2 and MYC downregulation. Bc-NFκBdODN enhanced radiosensitivity of lymphoma cells in vitro. In xenotransplanted human lymphoma, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors. When combined with a local 3-Gy dose of radiation, Bc-NFκBdODN effectively arrested OCI-Ly3 lymphoma progression. In immunocompetent mice, intratumoral injections of Bc-NFκBdODN suppressed growth of directly treated and distant A20 lymphomas, as a result of systemic CD8 T cell-dependent immune responses. Finally, systemic administration of Bc-NFκBdODN to mice bearing disseminated A20 lymphoma induced complete regression and extended survival of most of the treated mice. Our results underscore clinical relevance of this strategy as monotherapy and in support of radiation therapy to benefit patients with resistant or relapsed B cell lymphoma.
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Linfoma de Células B/terapia , FN-kappa B/antagonistas & inhibidores , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/antagonistas & inhibidores , Tolerancia a Radiación/efectos de los fármacos , Receptor Toll-Like 9/antagonistas & inhibidores , Animales , Apoptosis , Proliferación Celular , Humanos , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Oligodesoxirribonucleótidos/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pathway Commons (https://www.pathwaycommons.org) is an integrated resource of publicly available information about biological pathways including biochemical reactions, assembly of biomolecular complexes, transport and catalysis events and physical interactions involving proteins, DNA, RNA, and small molecules (e.g. metabolites and drug compounds). Data is collected from multiple providers in standard formats, including the Biological Pathway Exchange (BioPAX) language and the Proteomics Standards Initiative Molecular Interactions format, and then integrated. Pathway Commons provides biologists with (i) tools to search this comprehensive resource, (ii) a download site offering integrated bulk sets of pathway data (e.g. tables of interactions and gene sets), (iii) reusable software libraries for working with pathway information in several programming languages (Java, R, Python and Javascript) and (iv) a web service for programmatically querying the entire dataset. Visualization of pathways is supported using the Systems Biological Graphical Notation (SBGN). Pathway Commons currently contains data from 22 databases with 4794 detailed human biochemical processes (i.e. pathways) and â¼2.3 million interactions. To enhance the usability of this large resource for end-users, we develop and maintain interactive web applications and training materials that enable pathway exploration and advanced analysis.
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Bases de Datos Factuales , Redes y Vías Metabólicas , Programas Informáticos , Genoma Humano , Genómica/métodos , Humanos , Metabolómica/métodosRESUMEN
Objectives: Asian Americans have poor HIV-related outcomes, yet culturally salient barriers to care remain unclear, limiting development of targeted interventions for this group. We applied the 'what matters most' theory of stigma to identify structural and cultural factors that shape the nature of stigma before and after immigration from China to the US.Design: Semi-structured interviews were conducted with 16 immigrants to New York from China, recruited from an HIV clinic and community centers. Deductive followed by focal inductive qualitative analyses examined how Chinese cultural values (lian, guanxi, renqing) and structural factors influenced stigma before and after immigration.Results: In China, HIV stigma was felt through the loss of lian (moral status) and limited guanxi (social network) opportunities. A social structure characterized by limited HIV knowledge, discriminatory treatment from healthcare systems, and human rights violations impinged on the ability of people living with HIV to fulfill culturally valued goals. Upon moving to the US, positions of structural vulnerability shifted to enable maintenance of lian and formation of new guanxi, thus ameliorating aspects of stigma.Conclusions: HIV prevention and stigma reduction interventions among Chinese immigrants may be most effective by both addressing structural constraints and facilitating achievement of cultural values through clinical, peer, and group interventions.
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Síndrome de Inmunodeficiencia Adquirida , Emigrantes e Inmigrantes , Infecciones por VIH , China , Emigración e Inmigración , Humanos , Estigma SocialRESUMEN
PURPOSE/OBJECTIVES: The aim of this study is to compare intrafractional motion using two commercial non-invasive immobilization systems for linac-based intracranial stereotactic radiosurgery (SRS) under guidance with a surface-guided radiotherapy (SGRT) system. MATERIALS/METHODS: Twenty-one patients who received intracranial SRS were retrospectively selected. Ten patients were immobilized with a vacuum fixation biteplate system, while 11 patients were immobilized with an open-face mask system. A setup margin of 1 mm was used in treatment planning. Real-time surface motion data in 37 treatment fractions using the vacuum fixation system and 44 fractions using the open-face mask were recorded by an SGRT system. Variances of intrafractional motion along three translational directions and three rotational directions were compared between the two immobilization techniques with Levene's tests. Intrafractional motion variation over time during treatments was also evaluated. RESULTS: Using the vacuum fixation system, the average and standard deviations of the shifts were 0.01 ± 0.18 mm, -0.06 ± 0.30 mm, and 0.02 ± 0.26 mm in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) directions, and -0.02 ± 0.19°, -0.01 ± 0.13°, and 0.01 ± 0.13° for rotations in yaw, roll, and pitch, respectively; using the open-face mask system, the average and standard deviations of the shifts were -0.06 ± 0.20 mm, -0.02 ± 0.35 mm, and 0.01 ± 0.40 mm in the AP, SI, and LR directions, and were 0.05 ± 0.23°, 0.02 ± 0.21°, and 0.00 ± 0.16° for rotations in yaw, roll, and pitch, respectively. There was a significant increase in intrafractional motion variance over time during treatments. CONCLUSION: Patients with the vacuum fixation system had significantly smaller intrafractional motion variation compared to those with the open-face mask system. Using intrafractional motion techniques such as surface imaging system is recommended to minimize dose deviation due to intrafractional motion. The increase in intrafractional motion over time indicates clinical benefits with shorter treatment time.
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Radiocirugia , Humanos , Inmovilización/métodos , Posicionamiento del Paciente , Radiocirugia/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Estudios RetrospectivosRESUMEN
Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) who respond to salvage chemotherapy. However, relapse after ASCT remains a frequent cause of treatment failure, with poor subsequent prognosis. Because cHL is uniquely vulnerable to programmed cell death-1 (PD-1) blockade, PD-1 blockade given as consolidation after ASCT could improve ASCT outcomes. We therefore conducted a multicohort phase 2 study of pembrolizumab in patients with RR cHL after ASCT, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary end point) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Thirty patients were treated on this study. The median age was 33 years, and 90% were high-risk by clinical criteria. Seventy-seven percent completed all 8 cycles. Toxicity was manageable, with 30% of patients experiencing at least 1 grade 3 or higher adverse event (AE), and 40% at least 1 grade 2 or higher immune-related AE. Two patients were lost to follow-up in complete remission at 12 months. The PFS at 18 months for the 28 evaluable patients was 82%, meeting the primary end point. The 18-month overall survival was 100%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with RR cHL, and resulted in a promising PFS in a high-risk patient cohort, supporting the testing of this strategy in a randomized trial. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adulto , Anciano , Quimioterapia de Consolidación/métodos , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/cirugía , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunología , Terapia Recuperativa/métodos , Trasplante AutólogoRESUMEN
BACKGROUND: Haemorrhagic and thrombotic complications are common in dialysis patients on warfarin; thus, accurate international normalized ratio (INR) monitoring is critical. For expediency and patient comfort, blood sampling from the haemodialysis access or circuit is commonly performed. Point-of-care (POC) INR machines allow both peripheral vein preservation and rapid results, yet are not validated in the haemodialysis population. METHODS: A prospective cohort study in haemodialysis patients taking warfarin was undertaken. Three paired samples were drawn over a single session: peripheral blood INR, POC INR, and dialysis INR. Agreement using Bland-Altman analysis and correlation coefficients between the peripheral blood INR, haemodialysis INR, and POC INR were calculated. Inappropriate dosing decisions based on haemodialysis or POC INR were quantified. RESULTS: Amongst 34 patients, agreement between the dialysis INR and peripheral blood INR was high, with the haemodialysis INR differing from the peripheral INR by <±0.2, 85.2% of the time. Correlation between the 2 methods was high (r = 0.914; p < 0.001). POC INR differed from peripheral INR values by <±0.2, 67.6% of the time, with less agreement at higher INR values. Dosing decisions were incongruent between the dialysis and peripheral INR in 6%, whilst the POC and peripheral INR disagreed in 26%. CONCLUSIONS: There was good agreement and correlation between the peripheral blood, haemodialysis access/circuit, and POC INR values. POC INR was less reliable at higher values, and dosing decisions differed from the peripheral INR in a quarter of cases.
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Anticoagulantes/uso terapéutico , Recolección de Muestras de Sangre/métodos , Relación Normalizada Internacional , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Diálisis Renal , Warfarina/uso terapéutico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Bone metastases are the most common cause of cancer-related pain. Radiation therapy (RT) is a very common and effective treatment to relieve pain. Conventionally fractionated RT typically consists of the following regimens: 8 Gy in a single treatment, 20 Gy in five fractions, 24 Gy in six fractions, or 30 Gy in ten fractions. All treatment regimens have similar rates of pain relief (range 50-80%), with single-fraction treatment often requiring retreatment. While many painful bony metastases can be managed with RT alone, some may be more complex, often requiring multidisciplinary management, including the need for surgical stabilization or augmentation prior to RT. There are multiple assessment tools including the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which allows clinicians to assess the proper course of treatment for these patients. For patients with good prognosis, oligometastatic disease, or those presenting with more radioresistant tumors, stereotactic body radiotherapy (SBRT) may be another option, which offers ablative doses of radiation delivered over several treatments. This chapter reviews the fundamentals of RT for palliation.
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Neoplasias Óseas , Radiocirugia , Neoplasias Óseas/complicaciones , Neoplasias Óseas/radioterapia , Fraccionamiento de la Dosis de Radiación , Humanos , Dolor , Manejo del Dolor , Cuidados PaliativosRESUMEN
AIMS: Postoperative urinary retention (POUR) is a common complication of urogynecological surgery. Our study aimed to identify demographic and perioperative risk factors to construct a prediction model for POUR in urogynecology. METHODS: Our retrospective cohort study reviewed all patients undergoing pelvic reconstructive surgeries at our tertiary care center (Jan 1, 2013-May 1, 2019). Demographic, pre-, intra- and postoperative variables were collected from medical records. The primary outcome, POUR, was defined as (1) early POUR (E-POUR), failing initial trial of void or; (2) late POUR (L-POUR), requiring an indwelling catheter or intermittent catheterization on discharge. Risk factors were identified through univariate and multivariate logistic regression analyses. A clinical prediction model was constructed with the most significant and clinically relevant risk factors. RESULTS: In 501 women, 182 (36.3%) had E-POUR and 61 of these women (12.2% of the entire cohort) had L-POUR. Multivariate logistic regression revealed preoperative postvoid residual (PVR) over 200 ml (odds ratio [OR]: 3.17; p = 0.026), voiding dysfunction symptoms extracted from validated questionnaires (OR: 3.00; p = 0.030), and number of concomitant procedures (OR: 1.30 per procedure; p = 0.021) as significant predictors of E-POUR; preoperative PVR more than 200 ml (OR: 4.07; p = 0.011) and antiincontinence procedure with (OR: 3.34; p = 0.023) and without (OR: 2.64; p = 0.019) concomitant prolapse repair as significant predictors of L-POUR. A prediction model (area under the curve: 0.70) was developed for E-POUR. CONCLUSIONS: Elevated preoperative PVR is the most significant risk factor for POUR. Alongside other risk factors, our prediction model for POUR can be used for patient counseling and surgical planning in urogynecologic surgery.
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Retención Urinaria , Femenino , Humanos , Modelos Estadísticos , Complicaciones Posoperatorias , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Retención Urinaria/epidemiología , Retención Urinaria/etiologíaRESUMEN
PURPOSE: To describe the key clinical, imaging, and arthroscopic characteristics of anchor arthropathy after arthroscopic shoulder stabilization procedures and, secondarily, to define risk factors for the development of anchor-induced arthropathy. METHODS: A total of 23 patients who underwent revision arthroscopic shoulder surgery and were diagnosed with glenohumeral arthropathy were retrospectively identified from prospectively collected data registries between January 2000 and May 2018. Data included initial diagnosis and index procedure performed, presenting arthropathy symptoms including duration, and examination findings before revision surgery. Pre-revision imaging was used to assess presence of glenohumeral osteoarthritis and chondromalacia, anchors/sutures, loose bodies, and labral pathology. The same parameters were recorded intraoperatively during revision surgery. Descriptive statistics were performed for demographic data and means with standard deviations were calculated for continuous data. A McNemar-Bowker test was used to analyze marginal homogeneity between preoperative imaging and intraoperative findings. RESULTS: Mean age at presentation was 33.4 ± 11.7 years (range 16-59, 17 male patients; 6 female patients). More than one half (13/23) developed symptoms within 10 months after index arthroscopic procedure (mean 32.2 ± 59.9 months, range <1 to 165.2 months) with 87% presenting with pain and 100% presenting with loss of motion on examination. Plain radiographs demonstrated humeral osteoarthritis in 57% (13/23) of patients, magnetic resonance imaging (MRI) revealed recurrent labral pathology in 19 of 23 (83%) patients, potential proud implants in 12 of 23 (52%), and loose bodies in 12 of 23 (52%). Intraoperatively, all had evidence of osteoarthritis; 22 of 23 (96%) had prominent implants. Humeral head chondromalacia was present in 21 of 23 patients (91%), the majority of which was linear stripe wear, and 6 of 23 (26%) had severe global glenohumeral osteoarthritis. Statistical analysis revealed a 54.5% (95% confidence interval 0.327-0.749) sensitivity of MRI identification of proud implants with a specificity of 100% (95% confidence interval 0.055-1). The ability of MRI to accurately assess chondromalacia of the humeral head (P = .342) or glenoid (P = .685) was not statistically significant. CONCLUSIONS: Anchor arthropathy is characterized by symptoms of pain and stiffness on examination and in many cases develops early after stabilization surgery (<10 months). Implants were implicated in the majority of cases of humeral head chondromalacia. MRI scans may produce false-negative identification of proud implants and can be a poor predictor of the severity of chondromalacia and intra-articular pathology; thus, a high index of clinical suspicion is necessary in patients with motion loss and pain postoperatively. LEVEL OF EVIDENCE: Level IV, case series.
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Inestabilidad de la Articulación , Articulación del Hombro , Adolescente , Artroscopía , Femenino , Humanos , Inestabilidad de la Articulación/etiología , Inestabilidad de la Articulación/cirugía , Masculino , Dolor , Estudios Retrospectivos , Articulación del Hombro/diagnóstico por imagen , Articulación del Hombro/cirugía , Resultado del TratamientoRESUMEN
PURPOSE: To report clinical and patient-reported outcome measures (PROMs) in patients undergoing revision surgery after diagnosis of anchor-induced arthropathy. METHODS: Patients who underwent revision arthroscopic shoulder surgery and were diagnosed with post-instability glenohumeral arthropathy performed from January 2006 to May 2018 were included in the current study. Patients were excluded if they underwent prior open shoulder procedures, if glenoid bone loss was present, or if prerevision imaging and records were incomplete or not available. Data included initial diagnosis and index procedure performed, presenting arthropathy symptoms including duration, exam findings before revision surgery, and surgical intervention. PROMs were prospectively collected before surgery and at minimum 2-year follow-up. RESULTS: Fourteen patients were included with a mean (± standard deviation) age at presentation of 35.2 ± 12.1 years (range 16 to 59). The follow-up rate was 86%, with a mean follow-up of 3.8 years (range 1.1 to 10.6). Mean time to development of arthropathy symptoms was 48.2 months (range <1 month to 13.8 years), all presenting with pain and decreased range of motion on exam. At time of revision surgery, all patients underwent either open or arthroscopic removal of previous implants, including anchors and suture material. Six patients underwent additional revision stabilization procedures, 1 underwent total shoulder arthroplasty, and 7 underwent arthroscopic intraarticular debridement, capsular release, and chondroplasty with or without microfracture. Pain significantly improved in 79% of patients (P = .05). Significant improvements in all PROMs were observed, including 12-item Short Form (43.8 to 54.8, P < .01); Disabilities of the Arm, Shoulder, and Hand, shortened version (31.8 to 8.4, P < .01); Single Assessment Numeric Evaluation (47.0 to 84.5, P < .05); and American Shoulder and Elbow Surgeons (61.6 to 92.1, P < .01). Average external rotation significantly improved, from 31° ± 22° to 52° ± 24° (P = .02). CONCLUSION: Rapid intervention after diagnosis, through either revision arthroscopic or open debridement and stabilization, can lead to significant improvement in range of motion, pain, and overall patient function and satisfaction. LEVEL OF EVIDENCE: IV, retrospective case series.
Asunto(s)
Inestabilidad de la Articulación , Articulación del Hombro , Adolescente , Adulto , Artroscopía , Humanos , Inestabilidad de la Articulación/cirugía , Persona de Mediana Edad , Rango del Movimiento Articular , Reoperación , Estudios Retrospectivos , Articulación del Hombro/cirugía , Resultado del Tratamiento , Adulto JovenRESUMEN
The use of total body irradiation as part of conditioning regimens for acute leukaemia is progressively declining because of concerns of late toxic effects and the introduction of radiation-free regimens. Total marrow irradiation and total marrow and lymphoid irradiation represent more targeted forms of radiotherapy compared with total body irradiation that have the potential to decrease toxicity and escalate the dose to the bone marrow for high-risk patients. We review the technological basis and the clinical development of total marrow irradiation and total marrow and lymphoid irradiation, highlighting both the possible advantages as well as the current roadblocks for widespread implementation among transplantation units. The exact role of total marrow irradiation or total marrow and lymphoid irradiation in new conditioning regimens seems dependent on its technological implementation, aiming to make the whole procedure less time consuming, more streamlined, and easier to integrate into the clinical workflow. We also foresee a role for computer-assisted planning, as a way to improve planning and delivery and to incorporate total marrow irradiation and total marrow and lymphoid irradiation in multi-centric phase 2-3 trials.
Asunto(s)
Trasplante de Médula Ósea , Médula Ósea/efectos de la radiación , Leucemia Mieloide Aguda/terapia , Irradiación Linfática , Acondicionamiento Pretrasplante , Humanos , Irradiación Linfática/efectos adversos , Dosis de Radiación , Planificación de la Radioterapia Asistida por Computador , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/tendencias , Resultado del Tratamiento , Irradiación Corporal Total/efectos adversosRESUMEN
Lipid nanodiscs (LNDs), comprising a phospholipid bilayer encircled by two molecules of a recombinant membrane scaffold protein, can be targeted to tumors with covalently attached antibodies (Abs) or their fragments. Antibody attachment to click chemistry based PEGylated lipids on LNDs including DOTA allowed PET imaging with the positron emitter 64Cu. Carcinoembryonic antigen (CEA) positive tumors in CEA transgenic mice were chosen as a tumor target. Fab' fragments, that otherwise are rapidly cleared by the kidney due to their small size, were retained in circulation when conjugated to LNDs. Untargeted PET imaging of 64Cu-DOTA-LNDs revealed low tumor uptake (4-5% ID/g) in the range expected for the enhanced permeability retention (EPR) effect with high liver uptake (17-21% ID/g) indicating gut clearance. Fab' targeted LNDs showed little improvement over untargeted LNDs, but intact IgG targeted LNDs gave high tumor uptake (40% ID/g) with low liver (8% ID/g), demonstrating that tumor targeting with antibody conjugated LNDs is feasible.