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1.
Cancers (Basel) ; 15(21)2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37958303

RESUMO

INTRODUCTION: Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) commonly presents as a peri-implant effusion (seroma). CD30 (TNFRSF8) is a consistent marker of tumor cells but also can be expressed by activated lymphocytes in benign seromas. Diagnosis of BIA-ALCL currently includes cytology and detection of CD30 by immunohistochemistry or flow cytometry, but these studies require specialized equipment and pathologists' interpretation. We hypothesized that a CD30 lateral flow assay (LFA) could provide a less costly rapid test for soluble CD30 that eventually could be used by non-specialized personnel for point-of-care diagnosis of BIA-ALCL. METHODS: We performed LFA for CD30 and enzyme-linked immunosorbent assay (ELISA) for 15 patients with pathologically confirmed BIA-ALCL and 10 patients with benign seromas. To determine the dynamic range of CD30 detection by LFA, we added recombinant CD30 protein to universal buffer at seven different concentrations ranging from 125 pg/mL to 10,000 pg/mL. We then performed LFA for CD30 on cryopreserved seromas of 10 patients with pathologically confirmed BIA-ALCL and 10 patients with benign seromas. RESULTS: Recombinant CD30 protein added to universal buffer produced a distinct test line at concentrations higher than 1000 pg/mL and faint test lines at 250-500 pg/mL. LFA produced a positive test line for all BIA-ALCL seromas undiluted and for 8 of 10 malignant seromas at 1:10 dilution, whereas 3 of 10 benign seromas were positive undiluted but all were negative at 1:10 dilution. Undiluted CD30 LFA had a sensitivity of 100.00%, specificity of 70.00%, positive predictive value of 76.92%, and negative predictive value of 100.00% for BIA-ALCL. When specimens were diluted 1:10, sensitivity was reduced to 80.00% but specificity and positive predictive values increased to 100.00%, while negative predictive value was reduced to 88.33%. When measured by ELISA, CD30 was below 1200 pg/mL in each of six benign seromas, whereas seven BIA-ALCL seromas contained CD30 levels > 2300 pg/mL, in all but one case calculated from dilutions of 1:10 or 1:50. CONCLUSIONS: BIA-ALCL seromas can be distinguished from benign seromas by CD30 ELISA and LFA, but LFA requires less time (<20 min) and can be performed without special equipment by non-specialized personnel, suggesting future point-of-care testing for BIA-ALCL may be feasible.

2.
JCI Insight ; 6(21)2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34747367

RESUMO

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.


Assuntos
Envelhecimento , COVID-19/metabolismo , Proteína 1 Semelhante à Quitinase-3/metabolismo , Envelhecimento/efeitos dos fármacos , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Enzima de Conversão de Angiotensina 2/metabolismo , Linhagem Celular Tumoral , Proteína 1 Semelhante à Quitinase-3/antagonistas & inibidores , Células HEK293 , Humanos , SARS-CoV-2/fisiologia , Tratamento Farmacológico da COVID-19
3.
J Am Heart Assoc ; 10(4): e017437, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33559477

RESUMO

Background Mesenchymal stem cell-derived extracellular vesicles (EVs) promote angiogenesis in the ischemic myocardium. This study examines the difference in vascular density, myocardial perfusion, molecular signaling, and gene expression between normal diet (ND) and high fat diet (HFD) groups at baseline and following intramyocardial injection of EVs. Methods and Results Intact male Yorkshire swine fed either an ND (n=17) or HFD (n=14) underwent placement of an ameroid constrictor on the left circumflex coronary artery. Subsequently, animals received either intramyocardial injection of vehicle-saline as controls; (ND-controls n=7, HFD-controls, n=6) or EVs; (ND-EVs n=10, HFD-EVs n=8) into the ischemic territory. Five weeks later, myocardial function, perfusion, vascular density, cell signaling, and gene expression were examined. EVs improved indices of myocardial contractile function, myocardial perfusion, and arteriogenesis in both dietary cohorts. Interestingly, quantification of alpha smooth muscle actin demonstrated higher basal arteriolar density in HFD swine compared with their ND counterparts; whereas EVs were associated with increased CD31-labeled endothelial cell density only in the ND tissue, which approached significance. Levels of total endothelial nitric oxide synthase, FOXO1 (forkhead box protein O1) , transforming growth factor-ß, phosphorylated VEGFR2 (vascular endothelial growth factor receptor 2), and phosphorylated MAPK ERK1/ERK2 (mitogen-activated protein kinase) were higher in ischemic myocardial lysates from ND-controls compared with HFD-controls. Conversely, HFD-control tissue showed increased expression of phosphorylated endothelial nitric oxide synthase, phosphorylated FOXO1, VEGFR2, and MAPK ERK1/ERK2 with respect to ND-controls. Preliminary gene expression studies indicate differential modulation of transcriptional activity by EVs between the 2 dietary cohorts. Conclusions HFD produces a profound metabolic disorder that dysregulates the molecular mechanisms of collateral vessel formation in the ischemic myocardium, which may hinder the therapeutic angiogenic effects of EVs.


Assuntos
Indutores da Angiogênese/farmacologia , Circulação Coronária/fisiologia , Vasos Coronários/diagnóstico por imagem , Dieta Hiperlipídica/efeitos adversos , Vesículas Extracelulares/patologia , Isquemia Miocárdica/etiologia , Miocárdio/metabolismo , Animais , Doença Crônica , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Masculino , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/metabolismo , Miocárdio/patologia , Neovascularização Patológica/diagnóstico , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Fosforilação , Suínos
4.
Stem Cell Reports ; 16(2): 324-336, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33482101

RESUMO

Hemorrhagic shock induces an aberrant immune response characterized by simultaneous induction of a proinflammatory state and impaired host defenses. The objective of this study was to evaluate the impact of conditionally immortalized neutrophil progenitors (NPs) on this aberrant immune response. We employed a mouse model of hemorrhagic shock, followed by the adoptive transfer of NPs and subsequent inoculation of Staphylococcus aureus to induce pneumonia. We observed that transplant of NPs decreases the proportion of host neutrophils that express programmed death ligand 1 and intercellular adhesion molecule 1 in the context of prior hemorrhage. Following hemorrhage, NP transplant decreased proinflammatory cytokines in the lungs, increased neutrophil migration into the airspaces, and enhanced bacterial clearance. Further, hemorrhagic shock improved NP engraftment in the bone marrow. These results suggest that NPs hold the potential for use as a cellular therapy in the treatment and prevention of secondary infection following hemorrhagic shock.


Assuntos
Células Progenitoras Mieloides/imunologia , Células Progenitoras Mieloides/metabolismo , Neutrófilos/imunologia , Pneumonia/imunologia , Choque Hemorrágico/imunologia , Choque Hemorrágico/metabolismo , Staphylococcus aureus/imunologia , Animais , Antígeno B7-H1/metabolismo , Medula Óssea/imunologia , Linhagem Celular , Movimento Celular , Terapia Baseada em Transplante de Células e Tecidos , Citocinas/metabolismo , Modelos Animais de Doenças , Imunidade , Molécula 1 de Adesão Intercelular/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/transplante , Pneumonia/microbiologia , Choque Hemorrágico/complicações
5.
J Perinatol ; 41(3): 544-550, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33097819

RESUMO

OBJECTIVE: Severe bronchopulmonary dysplasia (sBPD) can lead to long term morbidity. We created a sBPD multidisciplinary team in 2011 to optimize care and improve outcomes. STUDY DESIGN: Retrospective chart review of three groups between 2008 and 2016: patients with sBPD born before 2011, patients with sBPD born after 2011, and patients with moderate BPD born after 2011. RESULTS: Infants with sBPD after 2011 had a shorter NICU length of stay compared with children born before 2011 (mean 140 days vs 170 days p < 0.007), weighed more at discharge (z-score -0.8 vs -1.35 p = 0.01), had less failure to thrive post discharge (32% vs 51% p = 0.05) and had more well visits in the first six months of life (mean 6.7 vs 5.3 p = 0.04). No difference was observed in the rate of readmissions in the first two years of life. CONCLUSION: Our multidisciplinary team has improved the inpatient management of patients with sBPD.


Assuntos
Displasia Broncopulmonar , Assistência ao Convalescente , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/terapia , Criança , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Pacientes Internados , Equipe de Assistência ao Paciente , Alta do Paciente , Estudos Retrospectivos
6.
Ann Gastroenterol ; 33(1): 73-79, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31892801

RESUMO

BACKGROUND: Among patients undergoing colonoscopy, anticoagulants are usually stopped and are sometimes substituted by a heparin bridge (hep-bridge). We aimed to assess adverse events associated with hep-bridge compared to temporary cessation of anticoagulants (no-bridge). METHODS: This was a single-center, retrospective cohort study that included anticoagulated patients undergoing colonoscopy between 2013 and 2016 at a Veterans Affairs Medical Center. In the no-bridge cohort, warfarin was stopped for 5 days and novel anticoagulants for 2 days pre-procedure. In the hep-bridge cohort, anticoagulants were stopped and were substituted by subcutaneous enoxaparin. The primary outcome was post-polypectomy bleeding. Secondary outcomes included cardiovascular events, all-cause adverse events and emergency department or unscheduled ambulatory office visits within 30 days. The predictive values of the HAS-BLED and CHADS2 scores were evaluated. RESULTS: A total of 662 patients were included, of whom 551 underwent polypectomy (mean age 68.6 years; 97.6% male). Four hundred seventy colonoscopies were performed with no-bridge and 192 with hep-bridge. Post-polypectomy bleeding occurred in 6.0% of procedures: 5.7% in the no-bridge cohort compared to 13.0% of hep-bridge procedures (P=0.0038). Cardiovascular or thrombotic events occurred after 2.6% of the no-bridge and 5.2% of the hep-bridge procedures (P=0.1176). Emergency department or unscheduled office visits within 30 days were reported after 18.7% of the no-bridge procedures and 29.7% of the hep-bridge procedures (P<0.0001). Neither CHADS2 nor HASBLED scores predicted bleeding. CONCLUSION: The use of hep-bridge was associated with a greater incidence of post-polypectomy bleeding and more emergency department and unscheduled office visits compared with cessation of all anticoagulants.

7.
J Surg Res ; 246: 379-383, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31676146

RESUMO

BACKGROUND: Lymphocytes have become the target of cancer interventions through engineering or immune checkpoint antibodies. We previously found decreased lymphocyte counts to be a predictor of mortality and complications in trauma and cardiac surgery patients. We hypothesized lack of lymphocyte count recovery postoperatively would predict outcomes in esophagectomy patients. METHODS: A retrospective review of all patients undergoing esophagectomy for adenocarcinoma performed over 13 y at our center by a single surgeon after institutional review board approval was performed. Patients were grouped by postoperative lymphocytes counts: never low, low with recovery, and low without recovery. Resolution of lymphopenia was assessed by day 4. Primary end points were overall and recurrence-free survival. RESULTS: In total, 198 patients were included with a minimum 6-mo follow-up. Collectively the 5-y recurrence and overall survival rates were 36% and 50%, respectively. Recurrence was significantly higher at 5 y in patients with persistent lymphopenia (43%) compared with those who recovered (14% P = 0.0017) and those who never dropped (0% P = 0.0009). The persistent lymphopenia group had significantly lower survival (45%) compared with the two other groups (67% P = 0.0232). CONCLUSIONS: There is a significant decrease in the overall and recurrence-free survival in those patients whose lymphocyte count drops without recovery after their esophagectomy. These data imply differences in immune responses to the stress of surgery that can be measured with routine postoperative laboratory values and are indicative of overall outcomes.


Assuntos
Neoplasias Esofágicas/mortalidade , Esofagectomia/efeitos adversos , Linfócitos , Linfopenia/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Intervalo Livre de Doença , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/cirurgia , Feminino , Seguimentos , Humanos , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/etiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/epidemiologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
8.
Mol Cancer Ther ; 18(11): 2021-2029, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31341031

RESUMO

Chondrosarcoma is a highly aggressive primary malignant bone tumor mostly occurring in adults. There are no effective systemic treatments, and patients with this disease have poor survival. miR-181a is an oncomiR that is overexpressed in high-grade chondrosarcoma and promotes tumor progression. Regulator of G-protein signaling 16 (RGS16) is a target of miR-181a. Inhibition of RGS16 expression by miR-181a enhances CXC chemokine receptor 4 signaling, which in turn increases MMP1 and VEGF expression, angiogenesis, and metastasis. Here, we report the results of systemic treatment with anti-miRNA oligonucleotides (AMO) directed against miR-181a utilizing a nanopiece delivery platform (NPs). NPs were combined with a molecular beacon or anti-miR-181a oligonucleotides and are shown to transfect chondrosarcoma cells in vitro and in vivo Intratumoral injection and systemic delivery had similar effects on miR-181a expression in nude mice bearing chondrosarcoma xenografts. Systemic delivery of NPs carrying anti-miR-181a also restored RGS16 expression, decreased expression of VEGF and MMP1, MMP activity, and tumor volume by 32% at day 38, and prolonged survival from 23% to 45%. In conclusion, these data support that systemic delivery of AMO shows promise for chondrosarcoma treatment.


Assuntos
Antagomirs/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Condrossarcoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , MicroRNAs/genética , Animais , Antagomirs/farmacologia , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Condrossarcoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Camundongos Nus , MicroRNAs/antagonistas & inibidores , Nanopartículas , Proteínas RGS/genética , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Orthop Rev (Pavia) ; 11(1): 7757, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30996839

RESUMO

Transcranial motor-evoked potentials (TcMEPs) are used to monitor the descending motor pathway during scoliosis surgery. By comparing potentials before and after correction, surgeons may prevent postoperative functional loss in distal muscles. There is currently no consensus as to which muscles should be monitored. The purpose of this study is to determine the least invasive monitoring protocol with the best localization of potential neurologic deficit. A retrospective review of 125 patients with TcMEP monitoring during surgery for thoracolumbar scoliosis between 2008 and 2015 was conducted. 18 patients had postoperative neurologic consult due to deficit. The remaining 107 patients were a consecutive cohort without postoperative neurologic consult. TcMEPs were recorded from vastus lateralis (VL), tibialis anterior (TA), peroneus longus (PL), adductor hallucis (AH) and abductor pollicis brevis (APB) bilaterally. The effectiveness of each muscle combination was evaluated independently and then compared to other combinations using Akaike Information Criterion (AIC). Monitoring of VL, TA, PL, and AH yielded sensitivity of 77.8% and specificity of 92.5% (AIC=66.7). Monitoring of TA, PL and AH yielded sensitivity of 77.8% and specificity of 94.4% (AIC=62.4). Monitoring of VL, TA and PL yielded sensitivity of 72.2% and specificity of 93.5% (AIC=70.1). Monitoring of TA and PL yielded sensitivity of 72.2% and specificity of 96.3% (AIC=63.9). TcMEP monitoring of TA, PL, and AH provided the highest sensitivity and specificity and best predictive power for postoperative lower extremity weakness.

10.
Orthop J Sports Med ; 7(3): 2325967119830139, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30886876

RESUMO

BACKGROUND: Achilles tendon tears are potentially career-ending injuries for professional athletes. For players in the National Football League (NFL), return requires not only surgery and extensive rehabilitation but also the ability to compete in a market with limited positions that annually introduces new recruits. PURPOSE/HYPOTHESIS: We authors sought to evaluate factors related to return to play (RTP) and changes in performance following a primary Achilles tear. Our hypothesis was that "skilled" position players and those drafted in later rounds would return at a lower rate as compared with "unskilled" position players and higher draft-round players. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: From a previously established database, 80 NFL players were identified as having primary Achilles tendon tears between the 2009 and 2014 seasons. RTP was defined as playing in a regular season or postseason game following injury. Probability of RTP was modeled as a function of time after injury in Kaplan-Meier analysis with demographic variables assessed via generalized linear models. Twelve players (15%) experienced a subsequent Achilles tendon tear during or after the study period and were included in the overall RTP rate but were excluded from performance analyses owing to the confounding effects of an ipsilateral retear or contralateral tear. RESULTS: The overall RTP rate was 61.3%. Age, number of prior seasons, position type, or draft round status did not significantly affect RTP when evaluated with Kaplan-Meier analysis. In the season before their injury, players who did RTP played in a significantly greater number of regular season games (13.7) compared with players who did not RTP (8.71) (P = .011). Players who did not RTP exhibited a significant decrease in performance in the season preceding injury (12.7 regular season games played 2 seasons preinjury vs 8.71 regular season games played 1 season prior preinjury;, P = .019). Players who returned did not display a significant change in the number of games played or started in seasons following injury when >1 season after return was evaluated. CONCLUSION: Rate of RTP following primary Achilles tendon tears may be lower than previously published. However, for those able to return, performance only in the season immediately following injury appears to be affected; players return to preinjury levels if given the opportunity to play >1 season after injury.

12.
PLoS One ; 13(6): e0199019, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29949619

RESUMO

OBJECTIVE: Recent studies in the US and abroad suggest that boys are undergoing puberty at a younger age. It is unknown if this secular trend extends to boys with central precocious puberty (CPP), who sit at the extreme end of the pubertal spectrum, and if neuroimaging should remain a standard diagnostic tool. STUDY DESIGN: Retrospective chart review of all boys with CPP seen by Endocrinology at a US pediatric hospital from 2001-2010. RESULTS: Fifty boys had pubertal onset at an average age of 7.31 years (95CI 6.83-7.89), though many did not present until nearly one year thereafter, by which time 30% were mid-to-late pubertal. Boys were predominantly non-Hispanic White and 64% were overweight/obese. The majority (64%) of boys had neurogenic CPP (CNS-CPP) with neurofibromatosis type I being the most common diagnosis. Diagnosis of CPP led to discovery of a neurogenic lesion in only 3 of 32 (9%) CNS-CPP cases. The remaining boys, with idiopathic CPP (36%), were indistinguishable from those with CNS-CPP aside from four boys who endorsed a family history of PP (22% vs. 0% among CNS-CPP cases). Importantly, there was no change in the incidence of male CPP after accounting for the increase in clinic volume during this time period. CONCLUSION: In this contemporary Boston-based cohort of 50 boys with CPP, most cases were neurogenic, consistent with older literature. Several idiopathic cases had a family history of PP but were otherwise indistinguishable from CNS-CPP cases. Thus, neuroimaging remains a critical diagnostic tool. We find no evidence for an increase in the prevalence of male CPP.


Assuntos
Puberdade Precoce/epidemiologia , Boston/epidemiologia , Criança , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Puberdade Precoce/sangue , Estudos Retrospectivos , Testosterona/sangue
13.
Histopathology ; 73(1): 124-136, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29489025

RESUMO

AIMS: The tumour microenvironment is increasingly important in several tumours. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas. METHODS AND RESULTS: Tissue microarrays were constructed from gastrectomy specimens, 2004-13. Immunohistochemistry was performed for programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate-binding protein 5 (GBP5), tumour-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1 and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6. Clinicopathological parameters and clinical follow-up were recorded. The study included 86 patients; median follow-up was 34 months (0-148). Tumour types were 45% tubular, 38% diffuse, 17% mixed. PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53% and stromal GBP5 in 71%. MMR-deficiency was found in 22%. There was no difference in biomarker expression by histological subtype, with the exception of fewer diffuse-type being MMR-deficient. Low stromal IDO was associated with decreased progression-free, overall and disease-specific survival. PD-L1-positive tumours were larger with MMR-deficiency and with increasing TILs, and had significantly higher FoxP3TILs. CONCLUSIONS: PD-L1 is expressed in a large proportion of gastric carcinomas, suggesting that therapy targeting this pathway could be relevant to many patients. PD-L1 expression and MMR-deficiency are associated with increased TILs and larger tumour size, emphasising their role in tumour biology. Higher stromal IDO expression is associated with better prognosis. Finally, we observed that immune modulators WARS and GBP5 are expressed highly in gastric adenocarcinomas, suggesting an important role in tumour pathobiology.


Assuntos
Adenocarcinoma/imunologia , Antígeno B7-H1/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Neoplasias Gástricas/imunologia , Microambiente Tumoral/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Biomarcadores Tumorais , Intervalo Livre de Doença , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
14.
Clin Gastroenterol Hepatol ; 16(9): 1467-1473, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29486253

RESUMO

BACKGROUND & AIMS: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, ≤16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (<3 mo of diagnosis) affected risk of disease progression. RESULTS: The 10-year risk of first bowel surgery was 26%. The 5-year risk of bowel surgery did not change from 2002 through 2014, and remained between 13% and 14%. Most surgeries occurred within 3 years from diagnosis. The only predictor of surgery was disease behavior at diagnosis. CD with inflammatory behavior had the lowest risk of surgery compared to stricturing disease, penetrating disease, or both. We associated slowing of disease progression to stricturing or penetrating disease (but not surgery) with early use of biologics, but this effect only became evident after 5 years of disease. Our results indicate that biologics slow disease progression over time (hazard ratio, 0.85; 95% CI, 0.76-0.95). CONCLUSIONS: In an analysis of data from a registry of pediatric patients with CD, we found that among those with significant and progressing disease at or shortly after presentation, early surgery is difficult to prevent, even with early use of biologics. Early use of biologics (<3 mo of diagnosis) can delay later disease progression to stricturing and/or penetrating disease, but this affect could become evident only years after initial management decisions are made.


Assuntos
Produtos Biológicos/administração & dosagem , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Progressão da Doença , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Resultado do Tratamento
15.
Histopathology ; 72(3): 405-413, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28871595

RESUMO

AIMS: The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment, including tumour-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumours (GISTs) is largely unknown. METHODS AND RESULTS: Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO and WARS was correlated with tumour size, mitoses and outcomes. TILs expressing CD3, CD4, CD8, FoxP3 and GBP5 were counted. A total of 129 GISTs were analysed. Mean patient age was 62.5 years; 52.0% were male. Tumour location included 89 stomach (69.0%), 33 small bowel (25.6%) and seven other (5.4%). Mean tumour size was 5.6 cm; mean mitoses were 7.2 per 50 high-power field. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n = 8), liver (n = 6) and elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumour samples (69.0%), 114 of 127 tumours were IDO-positive (89.8%) and 60 of 127 were positive for WARS (47.2%). PD-L1 was associated with increased size (P = 0.01), necrosis (P = 0.018) and mitoses (P = 0.006). Disease progression was not associated with PD-L1 (P = 0.44), IDO (P = 0.14) or WARS (P = 0.36) expression. PD-L1-positive GISTs with CD8+ or CD3+ TILs were significantly smaller than tumours with CD8+ or CD3+ TILs. CONCLUSIONS: PD-L1 expression was associated with increased size and mitoses. High CD8+ or CD3+ TIL counts were associated with decreased PD-L1/IDO+ GIST size. PD-L1 and IDO could be significant in GIST tumour biology, which invites consideration of immunotherapy as a potential treatment option.


Assuntos
Biomarcadores Tumorais/imunologia , Neoplasias Gastrointestinais/imunologia , Tumores do Estroma Gastrointestinal/imunologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígeno B7-H1/análise , Antígeno B7-H1/biossíntese , Feminino , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Interpretação de Imagem Assistida por Computador , Indolamina-Pirrol 2,3,-Dioxigenase/análise , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Triptofano-tRNA Ligase/análise , Triptofano-tRNA Ligase/biossíntese
16.
Arthroscopy ; 33(2): 436-444, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28160934

RESUMO

PURPOSE: To investigate whether arthroscopy or stress radiography can identify instability resulting from single-ligament injury of the ankle syndesmosis and to determine whether either modality is capable of differentiating between various levels of ligament injury. METHODS: Syndesmotic/deltoid ligament sectioning was performed in 10 cadaver legs. Arthroscopic evaluation and fluoroscopic stress testing were completed after each sectioning. In group 1 (n = 5), sectioning began with anteroinferior tibiofibular ligament (AITFL), then interosseous membrane (IOM), posteroinferior tibiofibular ligament (PITFL), and deltoid. In group 2 (n = 5), this order was reversed. Measurements were made by determining the largest-sized probe that would fit in the anterior and posterior syndesmosis. Radiographic parameters included tibiofibular overlap/clear space and medial clear space. RESULTS: No radiographic measurement proved useful in distinguishing between intact and transected AITFL. Anterior probe (AP) size reached significance when distinguishing between intact and AITFL-transected specimens (P < .0001). AP detected significant differences comparing single with 2-, 3-, and 4-ligament (AITFL, IOM, PITFL, deltoid) disruptions (P = .05, <.0001, and <.0001, respectively). Significant differences were observed between 2- and 3/4-ligament (P = .02) transections. Posterior probe (PP) size detected significant differences between intact and single-, double-, triple-, and complete ligament transections (P values .0006, <.0001, <.0001, <.001, respectively). PP detected significant differences between single- and double-, triple-, and complete ligament transection models (P = .0075, .0010, and .0010, respectively). PP distinguished between 2- and 3/4-ligament (P = .03) transections. CONCLUSIONS: Stress radiography did not distinguish between intact and single-ligament disruption, and was unreliable in distinguishing between sequential transection models. Arthroscopy significantly predicted isolated disruption of the AITFL or deltoid ligaments. Also, probing was able to differentiate between most patterns of ligament injury, including sequential transections. CLINICAL RELEVANCE: These data can aid surgeons during arthroscopy of the ankle when attempting to correlate intraoperative syndesmotic evaluation findings with the extent of ligament injury.


Assuntos
Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/patologia , Artroscopia , Fluoroscopia , Instabilidade Articular/diagnóstico , Traumatismos do Tornozelo/diagnóstico , Cadáver , Feminino , Humanos , Instabilidade Articular/etiologia , Ligamentos Articulares/diagnóstico por imagem , Ligamentos Articulares/lesões , Ligamentos Articulares/patologia , Masculino , Pessoa de Meia-Idade
17.
Neuroophthalmology ; 40(4): 171-180, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27928403

RESUMO

This is a 25-year observational retrospective review of 372 consecutive participants with optic disc drusen or resolved papilloedema from idiopathic intracranial hypertension. The prevalence of optic disc drusen at 19% among eyes with resolved papilloedema was approximately 10 times higher and significantly increased (p < 0.001) as compared with the occurrence in the general population. Eyes with both resolved papilloedema and optic disc drusen had similar visual acuity and visual field outcome as compared with resolved papilloedema alone. Eyes with exposed drusen had significantly worse visual acuity and visual field outcome (p < 0.001) than buried drusen. The high prevalence of optic disc drusen after papilloedema has resolved suggests a non-coincidental relationship. Optic disc drusen formation can be a sequela of papilloedema.

18.
Ann Intern Med ; 165(9): 609-616, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27547925

RESUMO

BACKGROUND: To date, evidence for the efficacy of fecal microbiota transplantation (FMT) in recurrent Clostridium difficile infection (CDI) has been limited to case series and open-label clinical trials. OBJECTIVE: To determine the efficacy and safety of FMT for treatment of recurrent CDI. DESIGN: Randomized, controlled, double-blind clinical trial. (ClinicalTrials.gov: NCT01703494). SETTING: Two academic medical centers. PATIENTS: 46 patients who had 3 or more recurrences of CDI and received a full course of vancomycin for their most recent acute episode. INTERVENTION: Fecal microbiota transplantation with donor stool (heterologous) or patient's own stool (autologous) administered by colonoscopy. MEASUREMENTS: The primary end point was resolution of diarrhea without the need for further anti-CDI therapy during the 8-week follow-up. Safety data were compared between treatment groups via review of adverse events (AEs), serious AEs (SAEs), and new medical conditions for 6 months after FMT. Fecal microbiota analyses were performed on patients' stool before and after FMT and also on donors' stool. RESULTS: In the intention-to-treat analysis, 20 of 22 patients (90.9%) in the donor FMT group achieved clinical cure compared with 15 of 24 (62.5%) in the autologous FMT group (P = 0.042). Resolution after autologous FMT differed by site (9 of 10 vs. 6 of 14 [P = 0.033]). All 9 patients who developed recurrent CDI after autologous FMT were free of further CDI after subsequent donor FMT. There were no SAEs related to FMT. Donor FMT restored gut bacterial community diversity and composition to resemble that of healthy donors. LIMITATION: The study included only patients who had 3 or more recurrences and excluded those who were immunocompromised and aged 75 years or older. CONCLUSION: Donor stool administered via colonoscopy seemed safe and was more efficacious than autologous FMT in preventing further CDI episodes. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases.


Assuntos
Clostridioides difficile , Infecções por Clostridium/terapia , Diarreia/terapia , Transplante de Microbiota Fecal , Infecções por Clostridium/microbiologia , Colonoscopia , Diarreia/microbiologia , Método Duplo-Cego , Transplante de Microbiota Fecal/efeitos adversos , Transplante de Microbiota Fecal/métodos , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Resultado do Tratamento
19.
J Trauma Acute Care Surg ; 81(4): 729-34, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27488489

RESUMO

BACKGROUND: Limited data exist on how to develop resident leadership and communication skills during actual trauma resuscitations. METHODS: An evaluation tool was developed to grade senior resident performance as the team leader during full-trauma-team activations. Thirty actions that demonstrated the Accreditation Council for Graduate Medical Education core competencies were graded on a Likert scale of 1 (poor) to 5 (exceptional). These actions were grouped by their respective core competencies on 5 × 7-inch index cards. In Phase 1, baseline performance scores were obtained. In Phase 2, trauma-focused communication in-services were conducted early in the academic year, and immediate, personalized feedback sessions were performed after resuscitations based on the evaluation tool. In Phase 3, residents received only evaluation-based feedback following resuscitations. RESULTS: In Phase 1 (October 2009 to April 2010), 27 evaluations were performed on 10 residents. In Phase 2 (April 2010 to October 2010), 28 evaluations were performed on nine residents. In Phase 3 (October 2010 to January 2012), 44 evaluations were performed on 13 residents. Total scores improved significantly between Phases 1 and 2 (p = 0.003) and remained elevated throughout Phase 3. When analyzing performance by competency, significant improvement between Phases 1 and 2 (p < 0.05) was seen in all competencies (patient care, knowledge, system-based practice, practice-based learning) with the exception of "communication and professionalism" (p = 0.56). Statistically similar scores were observed between Phases 2 and 3 in all competencies with the exception of "medical knowledge," which showed ongoing significant improvement (p = 0.003). CONCLUSIONS: Directed resident feedback sessions utilizing data from a real-time, competency-based evaluation tool have allowed us to improve our residents' abilities to lead trauma resuscitations over a 30-month period. Given pressures to maximize clinical educational opportunities among work-hour constraints, such a model may help decrease the need for costly simulation-based training. LEVEL OF EVIDENCE: Therapeutic study, level III.


Assuntos
Competência Clínica , Educação de Pós-Graduação em Medicina , Avaliação Educacional , Liderança , Ressuscitação/educação , Traumatologia/educação , Adulto , Comunicação , Retroalimentação , Feminino , Humanos , Internato e Residência , Masculino
20.
Orthop J Sports Med ; 4(3): 2325967116638341, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27069948

RESUMO

BACKGROUND: Psychological factors may have underappreciated effects on surgical outcomes after anterior cruciate ligament (ACL) reconstruction; however, few studies have investigated the relationship between specific psychological factors, objective clinical data, and patient-oriented outcomes. PURPOSE: Psychological factors are significantly associated with patient perceptions and functional outcomes after ACL reconstruction. The purpose of this study was to demonstrate relationships between self-esteem, health locus of control, and psychological distress with objective clinical outcomes, patient-oriented outcomes, and return to sport. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Twenty-seven patients who were 6 to 24 months post-computer-assisted ACL reconstruction by a single surgeon consented to participate in the study (52% response rate). Participants had a 1-time visit with a physician consisting of: a physical examination, a single-leg hop test, KT-1000 arthrometer measurements, and survey completion. Psychological measures included the Multidimensional Health Locus of Control Scale, Rosenberg Self-Esteem Scale, and Brief Profile of Mood States. Outcome measures included the Tegner activity scale, International Knee Documentation Committee (IKDC) Subjective Knee Score, Knee injury and Osteoarthritis Outcome Score-Quality of Life subscale (KOOS-QOL), and Short Form-36 (SF-36). Patient charts were also reviewed for pertinent operative details. RESULTS: The mean age of patients (±SD) was 25.7 ± 8.4 years, and the mean duration of time since surgery was 16.5 ± 5.9 months. The majority (89%) of the patients identified themselves as athletes, and of these, 65% reported returning to sports at a competitive level. Sport returners were found to have higher levels of self-esteem (P = .002) and higher reported KOOS-QOL scores (P = .02). Self-esteem was significantly associated with IKDC scores (r = 0.46, P < .05), KOOS-QOL scores (r = 0.45, P < .05), and SF-36 subscales of general health (r = 0.45, P < .05) and physical functioning (r = 0.42, P < .05). Internal locus of control was significantly correlated with performance on single-leg hop test (r = 0.4, P < .05). Objective knee stability measurements did not correlate with subjective outcomes. CONCLUSION: Self-esteem levels and locus of control had significant relationships with functional test performance and validated outcome measures after ACL reconstruction. Sport returners had significantly higher self-esteem levels than those who did not return to sports, without observable differences in knee stability or time since surgery.

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