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OBJECTIVE: Crouzon syndrome with acanthosis nigricans (CAN) is caused by the specific mutation c.1172C>A (p.Ala391Glu) in the fibroblast growth factor receptor 3 gene, and has an estimated prevalence of 1:1,000,000 births. Most cases occur de novo; however, autosomal dominant inheritance may occur. The clinical presentation typically includes craniosynostosis, midface and maxillary hypoplasia, choanal atresia/stenosis, hydrocephalus, and intracranial hypertension. Patients develop acanthosis nigricans, a hyperkeratotic skin disorder. The authors present the first known study to investigate the speech, language, hearing, and feeding of patients with CAN. METHODS: A retrospective case-note review of patients with a genetically confirmed diagnosis of CAN attending the Oxford Craniofacial Unit during a 36-year period (1987-2023) was undertaken. RESULTS: Participants were 6 patients with genetically-confirmed CAN (5 females, 1 male), all cases arose de novo. All patients had craniosynostosis (n = 5/6 multisuture synostosis, n = 1/6 left unicoronal synostosis). Hydrocephalus was managed through ventriculoperitoneal shunt in 67% (n = 4/6) of patients, and 67% (n = 4/6) had a Chiari 1 malformation. Patients had a complex, multifactorial feeding history complicated by choanal atresia/stenosis (100%; n = 6/6), and significant midface hypoplasia. All patients required airway management through tracheostomy (83%; n = 5/6); and/or continuous positive airway pressure (67%; n = 4/6). All patients underwent adenotonsillectomy (100%; n = 6/6). Initial failure to thrive, low weight, and/or height were seen in 100% (n = 6/6) patients; 80% (n = 4/5) had reflux; 100% (n = 6/6) had nasogastric, or percutaneous endoscopic gastrostomy based feeding during their treatment journey. All patients had hearing loss (100%; n = 6/6). Early communication difficulties were common: receptive language disorder (50%; n = 3/6); expressive language disorder (50%; n = 3/6); and speech sound disorder in 50% (n = 3/6)-necessitating the use of Makaton in 80% of patients (n = 3/5). CONCLUSIONS: Patients with CAN experience significant respiratory, neurological, and structural obstacles to hearing, speech, language, and feeding. The authors present a recommended pathway for management to support patients in these domains.
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Background: Urinary tract infections (UTIs) are among the most common bacterial infections worldwide and have become more difficult to treat over the years. Inappropriate antibiotic use has led to increased antibiotic resistance. Materials and methods: We examined 1921 urine culture samples from a single hospital and analyzed them for bacterial spectrum and antibiotic susceptibility. We further analyzed changes in the rates of detected bacteria and of the sensitivity of these uropathogens to antibiotics over the years. Results: In our hospital-based analysis, cystitis was the most frequently diagnosed UTI in women (76%) and men (79%). Escherichia coli (48%) was the most commonly identified uropathogen. Samples demonstrated an increase in the proportion of E. coli (pâ<â0.001) and a decrease in Enterococcus faecalis (pâ<â0.001) over the study time period. Antimicrobial susceptibility analysis showed an increase over time in the number of isolates with resistance to ampicillin/sulbactam (pâ<â0.001) and to third-generation cephalosporins cefotaxime (pâ=â0.043) and ceftazidime (pâ<â0.001). Conclusions: Ampicillin/sulbactam and third-generation cephalosporins are antibiotics frequently used in the treatment of UTIs. When selecting an optimal antimicrobial treatment regimen for patients with UTIs, it is imperative to understand regional and timedependent differences in the prevalence of various uropathogens and antimicrobial resistance patterns. Therefore, continuous surveillance of local pathogen and antimicrobial susceptibility patterns for frequently used antibiotics should be prioritized.
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INTRODUCTION: The aim of the study is to compare length of hospital stay, transfusion rates, and re-intervention rates during hospitalization for transurethral resection of the prostate (TUR-P), open prostatectomy (OP), and laser therapy (LT) for surgical treatment of benign prostatic obstruction (BPO). METHODS: URO-Cert is an organization, in which clinical data of prostatic diseases from 2 university, 19 public, and 3 private hospitals and 270 office-based urologists are collected in order to document treatment quality. Data on diagnostics, therapy, and course of disease are recorded web based. The analysis includes datasets from 2005 to 2017. RESULTS: Of 10,420 patients, 8,389 were treated with TUR-P, 1,334 with OP, and 697 with LT. Median length of hospital stay was 6 days (IQR: 4-7) for TUR-P, 9 days (IQR: 7-11) for OP, and 5 days (IQR: 4-6) for LT (p < 0.001). Risk for a hospital stay ≥7 days was higher for OP versus TUR-P (OR: 7.25; 95% CI = 6.27-8.36; p < 0.001) and LT (OR: 17.89; 95% CI = 14.12-22.65; p < 0.001) and higher for TUR-P versus LT (OR: 2.47; 95% CI = 2.03-3.01; p < 0.001). OP had a significantly higher risk for transfusions than TUR-P (OR: 2.44; 95% CI = 1.74-3.41; p < 0.001) and LT (OR: 3.32; 95% CI = 1.56-7.01; p < 0.001). Transfusion rates were not significantly different between TUR-P and LT (OR: 1.36; 95% CI = 0.66-2.79; p = 0.51). Risk of re-intervention was not different between all 3 approaches. CONCLUSION: OP was associated with higher transfusion rates and longer hospital stay than TUR-P and LT. Risk of transfusion was not different between TUR-P and LT, but TUR-P was inferior to LT concerning length of hospital stay. Re-intervention rates during hospitalization did not differ between the groups.
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Terapia a Laser , Sintomas do Trato Urinário Inferior/cirurgia , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata , Idoso , Transfusão de Sangue , Bases de Dados Factuais , Alemanha , Humanos , Terapia a Laser/efeitos adversos , Tempo de Internação , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/fisiopatologia , Masculino , Complicações Pós-Operatórias/terapia , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/fisiopatologia , Recuperação de Função Fisiológica , Retratamento , Fatores de Tempo , Ressecção Transuretral da Próstata/efeitos adversos , Resultado do Tratamento , UrodinâmicaRESUMO
OBJECTIVES: Although testicular cancer (TC) is the most common tumor in young men in Western countries, there is no official cancer detection/screening program for young men in Germany. The most important TC detection tool is self-examination of the testis. Hypothetically medical students may have a diagnosis lead time and detection superiority. This study was designed to analyze whether medical students have a possible knowledge advantage over students of other faculties concerning TC and to compare male and female cancer screening demeanor and mentality. METHODS: Male and female students of various faculties at the Goethe University Frankfurt/Main, Germany were invited to participate in this internet-based anonymous questionnaire with questions about TC awareness/knowledge, testicular (self) examination, and cancer screening behavior. RESULTS: In total 1,049 students (329 medical and 716 non-medical students) completed the questionnaire. In general, medical students had a significantly higher TC knowledge, especially in the more advanced stages of their medical studies (year 3-6). About 50% of medical students had knowledge of TC whereas only 21.3% of non-medical students knew about the disease (p < 0.01). In addition, medical students conducted scrotal examinations more frequently (34.7%) than non-medical students (18.8%). CONCLUSION: The knowledge about TC is low among students. In general, medical students are more aware of TC and perform more frequent testicular examinations compared to non-medical students. Female TC knowledge rises in the clinical part of studies to the same level as their male counterparts, with the result of more testicular partner examinations.
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Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for patients with CD19 B-cell malignancies. Combination strategies that improve CAR T-cell potency, limit tumor environment-mediated immune dysfunction, and directly reduce tumor burden may increase the potential for durable clinical benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product therapy candidate being tested in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of liso-cel in combination with ibrutinib or acalabrutinib. In prolonged stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR T-cell effector function. RNA-Seq analysis and surface marker profiling of these CAR T cells treated with ibrutinib but not acalabrutinib revealed gene expression changes consistent with skewing toward a memory-like, type 1 T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in combination with CAR T cells. A combination of the defined cell product therapy candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach that may potentiate the promising clinical responses already achieved in CD19 B-cell malignancies with each of these single agents.
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Antígenos CD19/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Adenina/administração & dosagem , Adenina/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Biomarcadores , Terapia Combinada , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Camundongos , Neoplasias/etiologia , Neoplasias/metabolismo , Piperidinas/administração & dosagem , Pirazinas/administração & dosagem , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.
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ADP-Ribosil Ciclase 1 , Astato/uso terapêutico , Imunoconjugados/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , ADP-Ribosil Ciclase 1/análise , Astato/administração & dosagem , Astato/farmacocinética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacocinética , Masculino , Mieloma Múltiplo/patologia , Neoplasia Residual/patologiaRESUMO
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in vivo in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic.
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Inibidores da Angiogênese/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos Quiméricos/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Lenalidomida/farmacologia , Camundongos , Mieloma Múltiplo/patologiaRESUMO
Chimeric antigen receptor (CAR) T cell therapy for hematologic malignancies is fraught with several unknowns, including number of functional T cells that engage target tumor, durability and subsequent expansion and contraction of that engagement, and whether toxicity can be managed. Non-invasive, serial imaging of CAR T cell therapy using a reporter transgene can address those issues quantitatively. We have transduced anti-CD19 CAR T cells with the prostate-specific membrane antigen (PSMA) because it is a human protein with restricted normal tissue expression and has an expanding array of positron emission tomography (PET) and therapeutic radioligands. We demonstrate that CD19-tPSMA(N9del) CAR T cells can be tracked with [18F]DCFPyL PET in a Nalm6 model of acute lymphoblastic leukemia. Divergence between the number of CD19-tPSMA(N9del) CAR T cells in peripheral blood and bone marrow and those in tumor was evident. These findings underscore the need for non-invasive repeatable monitoring of CAR T cell disposition clinically.
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Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Imunoterapia Adotiva , Tomografia por Emissão de Pósitrons/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Animais , Antígenos CD19/metabolismo , Antígenos de Superfície/genética , Glutamato Carboxipeptidase II/genética , Humanos , Leucemia Experimental/diagnóstico por imagem , Leucemia Experimental/patologia , Lisina/análogos & derivados , Camundongos Endogâmicos NOD , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/fisiologia , Ureia/análogos & derivadosRESUMO
Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein-coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell-derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.
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Imunoterapia Adotiva/métodos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/imunologia , Animais , Especificidade de Anticorpos , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Antígeno de Maturação de Linfócitos B/imunologia , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/genética , Anticorpos de Cadeia Única/uso terapêutico , Pesquisa Translacional Biomédica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: The study aimed to compare the incidence of cardiovascular events (CVEs) after donor nephrectomy (DN) and radical tumor nephrectomy (RN), according to an estimated glomerular filtration rate (eGFR), were evaluated over time. MATERIALS AND METHODS: Follow-up was collected for DN who underwent surgery from 1998 to 2007 for CVE and renal function. All DN were matched for age to patients treated by RN or adenoma enucleation (control group), who were eligible for DN. eGFR was estimated using the Cockgroft-Gould formula. Patients with preoperative comorbidities were excluded. RESULTS: Thirty DN (median age 48.9 years) were included with a median follow-up of 138.5 months (interquartile range 119-159). No significant differences in patients' characteristics were found preoperatively (p > 0.5). Four out of 30 DN developed a CVE (3 myocardial infarctions (MI), 1 stroke), 2 of 30 patients in the control group (both MI) and 8 of 30 RN patients (6 MI, 2 strokes, p > 0.05). Arterial hypertension developed in 14 DN (46.7%), in 12 (40%) after RN and in 15 controls. The CVE occurred after a median time of 68 months (5-231) and were related to a drop of â¼30% in the eGFR irrespective of the group. CONCLUSION: Decline of renal function after nephrectomy is the main risk factor for CVE. Close monitoring of renal function and new onset hypertension is warranted.
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Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Neoplasias Renais/cirurgia , Nefrectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Adulto , Feminino , Seguimentos , Humanos , Incidência , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Fatores de Tempo , Doadores de TecidosRESUMO
PURPOSE: Alpha-emitting radionuclides exhibit a potential advantage for cancer treatments because they release large amounts of ionizing energy over a few cell diameters (50-80 µm), causing localized, irreparable double-strand DNA breaks that lead to cell death. Radioimmunotherapy (RIT) approaches using monoclonal antibodies labeled with α emitters may thus inactivate targeted cells with minimal radiation damage to surrounding tissues. Tools are needed to visualize and quantify the radioactivity distribution and absorbed doses to targeted and nontargeted cells for accurate dosimetry of all treatment regimens utilizing α particles, including RIT and others (e.g., Ra-223), especially for organs and tumors with heterogeneous radionuclide distributions. The aim of this study was to evaluate and characterize a novel single-particle digital autoradiography imager, the ionizing-radiation quantum imaging detector (iQID) camera, for use in α-RIT experiments. METHODS: The iQID camera is a scintillator-based radiation detection system that images and identifies charged-particle and gamma-ray/x-ray emissions spatially and temporally on an event-by-event basis. It employs CCD-CMOS cameras and high-performance computing hardware for real-time imaging and activity quantification of tissue sections, approaching cellular resolutions. In this work, the authors evaluated its characteristics for α-particle imaging, including measurements of intrinsic detector spatial resolutions and background count rates at various detector configurations and quantification of activity distributions. The technique was assessed for quantitative imaging of astatine-211 ((211)At) activity distributions in cryosections of murine and canine tissue samples. RESULTS: The highest spatial resolution was measured at â¼20 µm full width at half maximum and the α-particle background was measured at a rate as low as (2.6 ± 0.5) × 10(-4) cpm/cm(2) (40 mm diameter detector area). Simultaneous imaging of multiple tissue sections was performed using a large-area iQID configuration (ø 11.5 cm). Estimation of the (211)At activity distribution was demonstrated at mBq/µg-levels. CONCLUSIONS: Single-particle digital autoradiography of α emitters has advantages over traditional film-based autoradiographic techniques that use phosphor screens, in terms of spatial resolution, sensitivity, and activity quantification capability. The system features and characterization results presented in this study show that the iQID is a promising technology for microdosimetry, because it provides necessary information for interpreting alpha-RIT outcomes and for predicting the therapeutic efficacy of cell-targeted approaches using α emitters.
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Autorradiografia/instrumentação , Autorradiografia/métodos , Câmaras gama , Radioimunoterapia/instrumentação , Radioimunoterapia/métodos , Animais , Antígenos CD20/administração & dosagem , Astato , Cães , Desenho de Equipamento , Feminino , Antígenos Comuns de Leucócito/administração & dosagem , Linfonodos/diagnóstico por imagem , Linfonodos/imunologia , Linfonodos/efeitos da radiação , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/radioterapia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Imagens de Fantasmas , Radiografia , SoftwareRESUMO
α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, (211)At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to (211)At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of (211)At-labeled anti-CD20 mAb ([(211)At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with (211)At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [(211)At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail.
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Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Astato/uso terapêutico , Imunoconjugados/uso terapêutico , Linfoma de Células B/radioterapia , Animais , Feminino , Humanos , Células Jurkat , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Radioimunoterapia , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non-small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression. METHODS: We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses. RESULTS: OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts. CONCLUSIONS: These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden.
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Neoplasias Ósseas/prevenção & controle , Carcinoma Pulmonar de Células não Pequenas/prevenção & controle , Enoxaparina/farmacologia , Neoplasias Pulmonares/prevenção & controle , Osteólise/tratamento farmacológico , Osteoprotegerina/metabolismo , Ligante RANK/antagonistas & inibidores , Animais , Anticoagulantes/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Osteoprotegerina/imunologia , Taxa de Sobrevida , Carga Tumoral , Células Tumorais CultivadasRESUMO
The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. (90)Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 µCi of anti-CD38 pretargeted (90)Y-DOTA-biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 µCi of anti-CD38 pretargeted (90)Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared with none (0%) of the control animals.
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ADP-Ribosil Ciclase 1/imunologia , Anticorpos Monoclonais/uso terapêutico , Compostos Heterocíclicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias de Plasmócitos/radioterapia , Compostos Organometálicos/uso terapêutico , Radioimunoterapia/métodos , Animais , Células Cultivadas , Feminino , Humanos , Camundongos , Camundongos Nus , Camundongos Transgênicos , Ensaios Antitumorais Modelo de Xenoenxerto , Radioisótopos de Ítrio/uso terapêuticoRESUMO
RANK ligand (RANKL), acting through its cognate receptor RANK, is a key factor for bone remodeling and metastasis by regulating the differentiation, survival and activation of osteoclasts. RANKL is also crucial for the development of mouse mammary glands during pregnancy and has been recently linked to the etiology of breast cancer via its direct activity on RANK-expressing normal or transformed breast epithelial cells, leading to increased mitogenesis, enhanced regenerative potential of mammary stem cells, and increased invasion and migration. We demonstrate that higher RANK expression in MDA-MB-231 breast cancer cells (MDA-231-RANK cells) is sufficient to confer a significantly greater metastatic growth rate in the bone compared with MDA-MB-231 cells which do not express high levels of RANK. Blockade of osteoclastic bone resorption, achieved with treatment by either RANKL inhibition or zoledronic acid, did reduce skeletal tumor progression of MDA-231-RANK cells suggesting that the vicious cycle contributes to metastatic growth. However, RANKL inhibition reduced skeletal growth of MDA-231-RANK tumors to a significantly greater extent than zoledronic acid, indicating that skeletal growth of RANK-positive tumors is also driven by direct RANKL effects. RANKL stimulated the expression of multiple genes associated with cell invasive behavior, including several matrix metalloproteinases and other genes previously defined as part of a bone metastasis gene signature. These data indicate that RANKL provokes breast cancer bone metastases via two distinct, but potentially overlapping mechanisms: stimulation of tumor-associated osteoclastogenesis and stimulation of RANK-expressing tumor cells.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Ligante RANK/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , HumanosRESUMO
OBJECTIVE: To preserve renal function, nephron sparing surgery (NSS) for renal tumors should be performed. Little is known about perioperative morbidity and long-term functional outcome of patients after elective NSS compared with radical nephrectomy (RN) in renal tumors >4 cm. MATERIALS AND METHODS: Eight-hundred twenty-nine patients were treated with either RN (n = 641) or NSS (n = 188) for renal tumors >4 cm. After pairing the cohort for age, grading, TNM, size, gender, and preoperative renal function and excluding patients with imperative indication and metastases, 247 patients remained for functional analysis. Serum creatinine (SCr) values were used to estimate glomerular filtration rate (eGFR) via Modification of Diet in Renal Disease. Chronic kidney disease (CKD) was defined as eGFR <60 mL/min/1.73 m(2) and regression analyses were used to identify clinical risk factors for CKD and perioperative complications stratified by the Clavien-Dindo score. RESULTS: The Charlson comorbidity index was similar between patients undergoing NSS (n = 101) and RN (n = 146) (P = .583). The complication rates did not differ significantly between both groups (P = .091). Age (OR 0.94, P = .009), ASA score 3+4 (OR 3.55, P = .004), RN (OR 10.75, P < .001), and preoperative eGFR (OR 1.06, P < .001) were independent risk factors for developing CKD postoperatively, whereas tumor size had no impact (OR 1.01, P = .245). Overall survival was comparable between the groups (P = .896). CONCLUSION: Although overall survival was similar, patients undergoing RN for renal tumors >4 cm had a significantly higher risk of developing CKD than patients treated with NSS. Complication rate did not differ significantly between both groups, even for tumors >7 cm. Our findings support elective NSS for tumors >4 cm, whenever NSS is technically feasible for maintaining renal function.
Assuntos
Neoplasias Renais/cirurgia , Nefrectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Creatinina/sangue , Procedimentos Cirúrgicos Eletivos , Feminino , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Neoplasias Renais/epidemiologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Recuperação de Função Fisiológica/fisiologia , Fatores de Risco , Resultado do TratamentoRESUMO
MOTIVATION: Most current approaches to high-throughput biological data (HTBD) analysis either perform individual gene/protein analysis or, gene/protein set enrichment analysis for a list of biologically relevant molecules. Bayesian Networks (BNs) capture linear and non-linear interactions, handle stochastic events accounting for noise, and focus on local interactions, which can be related to causal inference. Here, we describe for the first time an algorithm that models biological pathways as BNs and identifies pathways that best explain given HTBD by scoring fitness of each network. RESULTS: Proposed method takes into account the connectivity and relatedness between nodes of the pathway through factoring pathway topology in its model. Our simulations using synthetic data demonstrated robustness of our approach. We tested proposed method, Bayesian Pathway Analysis (BPA), on human microarray data regarding renal cell carcinoma (RCC) and compared our results with gene set enrichment analysis. BPA was able to find broader and more specific pathways related to RCC. AVAILABILITY: Accompanying BPA software (BPAS) package is freely available for academic use at http://bumil.boun.edu.tr/bpa.
Assuntos
Algoritmos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Teorema de Bayes , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Modelos Biológicos , SoftwareRESUMO
OBJECTIVE: ⢠To determine the value of systematic intraoperative peripheral frozen sections (FS) with or without extended resection during nerve-sparing radical prostatectomy for prediction of biochemical recurrence (BCR) compared with inked surgical margins. PATIENTS AND METHODS: ⢠Between 1999 and 2003, in a prospective study, multiple peripheral FS (median 14; range 5-20) were taken from the urethral stump, circumferentially from the bladder neck, and from the lateral pedicles in 200 consecutive bilateral nerve-sparing radical prostatectomies for clinically localized prostate cancer by a single surgeon. ⢠Patients with stage pT3b or more and/or positive lymph nodes were excluded. ⢠Of the 188 patients, 178 (94.7%) were followed over a median of 82 months (62-124). ⢠BCR, defined as prostate-specific antigen (PSA) ≥ 0.2 ng/mL, was related to status of both, inked specimen margins and FS. RESULTS: ⢠Of all 188 prostatectomy specimens, 49 (26.1%) had positive surgical margins (PSM); these were found posterolaterally in 15 (30.6%), apically in 13 (26.5%), basally in 10 (20.4%) and at multiple sites in 11 (22.4%) specimens. ⢠Intraoperative peripheral FS were positive in 19 (10.7%) patients, including 6.2% at urethral stump, 3.3% at lateral pedicles and 1.1% at bladder neck. ⢠In organ-confined disease, BCR-free survival was 93.3% (111/119) for patients with negative surgical margins (NSM) and 72% (18/25) for patients with PSM (inked specimen), but negative peripheral FS (P < 0.001). ⢠Five- and 10-year BCR-free survival for NSM was 94.9% and 92.8%, for PSM with negative peripheral FS it was 75.3% and 70.6%, and for PSM with positive peripheral FS it was 62.5% and 62.5%, respectively. CONCLUSIONS: ⢠Frozen section biopsies of peripheral resection margins during nerve-sparing radical prostatectomy are not reliable in predicting PSM. ⢠Intraoperative achievement of a locally disease-free status, as monitored by negative circumferential intraoperative FS of peripheral margins, is not associated with a statistically significant BCR-free survival benefit compared with patients with negative surgical margins on the prostatectomy specimen. ⢠Based on these findings, we do not recommend a routine of systematically taking intraoperative FS biopsies during nerve-sparing radical prostatectomy.
Assuntos
Secções Congeladas , Recidiva Local de Neoplasia/patologia , Próstata/patologia , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Idoso , Métodos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Próstata/inervação , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Traumatismos do Sistema Nervoso/prevenção & controleRESUMO
RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.