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OBJECTIVE: To describe the rate of occult carcinoma deposits in total hepatectomy specimens from patients treated with liver transplant (LT) for colorectal liver metastases (CRLM). BACKGROUND: Previous studies have shown that patients with CRLM treated with systemic therapy demonstrate a high rate of complete radiographic response or may have disappearing liver metastases. However, this does not necessarily translate into a complete pathologic response, and residual invasive cancer may be found in up to 80% of the disappearing tumors after resection. METHODS: Retrospective review of 14 patients who underwent LT for CRLM, at 2 centers. Radiographic and pathologic correlation of the number of tumors and their viability before and after LT was performed. RESULTS: The median (interquartile range) number of tumors at diagnosis was 11 (4-23). The median number of chemotherapy cycles was 24 (16-37). Hepatic artery infusion was used in 5 patients (35.7%); 6 (42.9%) underwent surgical resection, and 5 (35.7%) received locoregional therapy. The indication for LT was unresectability in 8 patients (57.1%) and liver failure secondary to oncologic treatment in the remaining 6 (42.9%). Before LT, 7 patients (50%) demonstrated fluorodeoxyglucose-avid tumors and 7 (50%) had a complete radiographic response. Histopathologically, 11 patients (78.6%) had a viable tumor. Nine (64.2%) of the 14 patients were found to have undiagnosed metastases on explant pathology, with at least 22 unaccounted viable tumors before LT. Furthermore, 4 (57.1%) of the 7 patients who demonstrated complete radiographic response harbored viable carcinoma on explant pathology. CONCLUSIONS: A complete radiographic response does not reliably predict a complete pathologic response. In patients with unresectable CRLM, total hepatectomy and LT represent a promising treatment options to prevent indolent disease progression from disappearing CRLM.
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Neoplasias Colorretais , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Neoplasias Colorretais/patologia , Hepatectomia , Incidência , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/secundárioRESUMO
BACKGROUND: Current success in transplant oncology for select liver tumors, such as hepatocellular carcinoma, has ignited international interest in liver transplantation (LT) as a therapeutic option for nonresectable colorectal liver metastases (CRLM). In the United States, the CRLM LT experience is limited to reports from a handful of centers. This study was designed to summarize donor, recipient, and transplant center characteristics and posttransplant outcomes for the indication of CRLM. METHODS: Adult, primary LT patients listed between December 2017 and March 2022 were identified by using United Network Organ Sharing database. LT for CRLM was identified from variables: "DIAG_OSTXT"; "DGN_OSTXT_TCR"; "DGN2_OSTXT_TCR"; and "MALIG_TY_OSTXT." RESULTS: During this study period, 64 patients were listed, and 46 received LT for CRLM in 15 centers. Of 46 patients who underwent LT for CRLM, 26 patients (56.5%) received LTs using living donor LT (LDLT), and 20 patients received LT using deceased donor (DDLT) (43.5%). The median laboratory MELD-Na score at the time of listing was statistically similar between the LDLT and DDLT groups (8 vs. 9, P = 0.14). This persisted at the time of LT (8 vs. 12, P = 0.06). The 1-, 2-, and 3-year, disease-free, survival rates were 75.1, 53.7, and 53.7%. Overall survival rates were 89.0, 60.4, and 60.4%, respectively. CONCLUSIONS: This first comprehensive U.S. analysis of LT for CRLM suggests a burgeoning interest in high-volume U.S. transplant centers. Strategies to optimize patient selection are limited by the scarce oncologic history provided in UNOS data, warranting a separate registry to study LT in CRLM.
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Neoplasias Colorretais , Neoplasias Hepáticas , Transplante de Fígado , Adulto , Humanos , Estados Unidos , Estudos Retrospectivos , Neoplasias Hepáticas/cirurgia , Doadores Vivos , Neoplasias Colorretais/cirurgia , Receptores de Antígenos de Linfócitos T , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: To summarize the current state of liver transplantation (LT) for unresectable colorectal liver metastases (uCRLM), and to address future directions. RECENT FINDINGS: The Norwegian secondary cancer (SECA) I and SECA II studies demonstrated that after LT the 5-year survival of a highly selected group of patients with uCRLM could be as high as 60% and 83%, respectively. After long-term follow-up, the 5- and 10-year survival was shown to be 43% and 26%, respectively. Furthermore, data has accumulated in other countries and a North American study reported a 1.5-year survival of 100%. In addition, steady growth has been demonstrated in the US, with 46 patients transplanted to date and 19 centers enrolling patients for this indication. Lastly, although recurrence is almost universal in patients with a high tumor burden, it has not been an accurate surrogate for survival, reflecting the relatively indolent nature of recurrence after LT. SUMMARY: Growing evidence has shown that excellent survival and even cure can be achieved in highly selected patients with uCRLM, with survival rates far superior than in patients treated with chemotherapy. The next step is to create national registries to standardize selection criteria and establish the optimal approach and best practices for incorporating LT for uCRLM into the treatment armamentarium.
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Neoplasias Colorretais , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Transplante de Fígado/efeitos adversos , Resultado do Tratamento , Neoplasias Hepáticas/patologia , Neoplasias Colorretais/patologiaRESUMO
OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA. METHODS: Blood and tumours were analysed from iCCA patients and controls. Treatment and correlative studies were performed in mice with autochthonous and established orthotopic iCCA tumours treated with anti-GM-CSF monoclonal antibody. RESULTS: Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68+ TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. CONCLUSIONS: iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity.
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Colangiocarcinoma , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Animais , Anticorpos Monoclonais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Camundongos , Mielopoese , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
INTRODUCTION: Socioeconomic disadvantage has been associated with increased complicated appendicitis rates. Our purpose was to analyze the complex interactions between social determinants of health (SDOH) and postoperative outcomes in pediatric appendicitis. MATERIALS AND METHODS: Children who underwent appendectomy at our institution (1/2015-12/2020) were retrospectively reviewed. We used home addresses to determine composite measures of neighborhood/area-level socioeconomic advantage (Area Deprivation Index [ADI] and Social Deprivation Index [SDI]), and other area-level indicators. We created a novel, composite outcome score computed as a weighted average of eight outcome measures. Feature selection and exploratory factor analysis were used to create a multivariate model predictive of outcomes. RESULTS: Of 1117 children with appendicitis, 20.59% had complicated (perforated) appendicitis. Factor analysis identified two multivariate latent factors; Factor 1 contained SDI, ADI, and % unemployed in the population, and Factor 2 contained % Hispanic and % foreign-born in the population. Low Factor 2 scores (communities with more Hispanic/foreign-born residents) were associated with increased length of stay, more frequent postoperative percutaneous drainage, and increased postoperative imaging. CONCLUSIONS: Interactions between SDOH and pediatric surgical care go beyond the individual patient and suggest that vulnerable populations are exposed to contextual conditions that may impact outcomes. Specifically, neighborhood-level factors, including the prevalence of Hispanic ethnicity and foreign-born individuals, are associated with outcomes in pediatric patients with complicated appendicitis. Reducing disparities in complicated appendicitis outcomes may involve addressing neighborhood-level SDOH through strategic reallocation of healthcare resources and developing targeted interventions to improve access to pediatric surgical care in underserved communities.
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Apendicite , Apendicectomia/efeitos adversos , Apendicectomia/métodos , Apendicite/complicações , Apendicite/epidemiologia , Apendicite/cirurgia , Criança , Humanos , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Determinantes Sociais da SaúdeRESUMO
INTRODUCTION: Pernicious health disparities have been reported in patients with hepatocellular carcinoma (HCC). Few tools exist to screen patients in order to facilitate educational and outreach initiatives. We hypothesize that neighborhood-level socioeconomic metrics such as the Area Deprivation Index (ADI) can predict inferior outcomes in patients with early-stage HCC. METHODS: A single institution's retrospective review of patients with Surveillance, Epidemiology, and End Results Stage I HCC between 2000 and 2020 was conducted. Univariate and multivariate models were constructed to identify clinical and socioeconomic variables correlated with treatment-specific survival. Kaplan-Meier analysis was performed to compare survival differences between cohorts. RESULTS: A total of 558 patients were included in this study with newly diagnosed Surveillance, Epidemiology, and End Results Stage I HCC. Multivariate models demonstrated native model of end-stage liver disease, largest tumor size, insurance type, the distance to our transplant center, and the ADI score, a validated metric for a patient's socioeconomic status, are independent risk factors for worse overall survival (all P-values < 0.05). Concerningly, despite similar maximal tumor size, number of tumors, and native model of end-stage liver disease scores, patients from high ADI neighborhoods are 20% less likely to receive surgical treatment, especially liver transplantation. CONCLUSIONS: The ADI is a useful tool for identifying patients at the time of presentation who are at risk for inferior treatment for early stage HCC, and the ADI should be incorporated as a social vital sign.
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Carcinoma Hepatocelular , Doença Hepática Terminal , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Estudos Retrospectivos , Classe SocialRESUMO
BACKGROUND: Deep venous thrombosis (DVT) prophylaxis is often employed to prevent the potentially serious complication of pulmonary embolism (PE). However, little data exist regarding the optimal DVT prophylaxis strategy for living donors undergoing hepatectomy for living donor liver transplantation. Here we present our consensus statement on DVT prophylaxis for living donors undergoing hepatectomy. OBJECTIVES: To identify the optimal DVT prophylaxis strategy, which reduces, risk of complications in living liver donors, and enhances recovery. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. Of interest was the impact of DVT prophylaxis or lack of prophylaxis on living donors undergoing hepatectomy and subsequent rates of DVT, PE, and hemorrhagic complications. PROSPERO ID: CRD42021260720 RESULTS: The review of the literature identified three studies, which directly addressed thrombogenesis following living donor hepatectomy. All studies were observational in nature without randomization into treatments. The rate of DVT-PE in unscreened living donors with chemoprophylaxis was 5%. Furthermore, thromboelastography of living donors demonstrated sustained hypercoagulability for 50% of donors 10 days postoperatively. In line with CHEST (The American College of Chest Physicians) guidelines of chemoprophylaxis for surgical procedures with 3% or greater risk of DVT-PE, we conclude that a minimum of 10 days of postoperative chemoprophylaxis with unfractionated heparin or low-molecular weight heparin is recommended for patients undergoing living donor hepatectomy. The quality of evidence (QOE) for these recommendations based on the GRADE criteria is low, with a Grade of Recommendation of Strong. CONCLUSIONS: Chemoprophylaxis for DVT following living donor hepatectomy is associated with reduced adverse thrombotic events, (Quality of Evidence; Low | Grade of Recommendation; Strong).
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Transplante de Fígado , Embolia Pulmonar , Trombose Venosa , Humanos , Heparina , Transplante de Fígado/efeitos adversos , Doadores Vivos , Trombose Venosa/etiologia , Trombose Venosa/prevenção & controle , Heparina de Baixo Peso Molecular/uso terapêutico , Embolia Pulmonar/etiologia , Anticoagulantes/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/tratamento farmacológicoRESUMO
BACKGROUND: Enhanced recovery after surgery (ERAS) components for liver resection lack standardization and compliance. We evaluated our ERAS protocol and describe the association of postoperative ERAS compliance with length of stay (LOS) and complications. METHODS: We retrospectively reviewed patients undergoing liver resection at our institution from 2016 to 2020. Pre- and post-ERAS outcomes and compliance at 72 h were compared with LOS and complications. LOS beyond 72 h was defined as LOS72. RESULTS: 210 patients were included. Post-ERAS patients had significantly shorter LOS (5.1 vs. 7.3 days, p = 0.0014) with no difference in 30-day mortality, morbidity, or readmissions. ERAS components associated with shorter LOS72 were regular diet (HR 1.73), fluid discontinuation (HR 1.63), drain removal (HR 1.94), multimodal and oral analgesia (HR 1.51), and ambulation >100 ft (HR 2.23). LOS72 was 1-day for ≥9 ERAS component compliance, 4-days for 6-8 components, and 6-days for <6 components. 30-day complication rates for patients with ≥9 components by postoperative day 3 (POD3) were significantly lower than those with 6-8 (12 vs 32%). CONCLUSION: ERAS decreases LOS after liver resection. Nutritional advancement, drain discontinuation, multimodal and oral analgesia, and ambulation >100 ft by POD3 are associated with decreased LOS72. Achieving ≥6 components by POD3 predicts decreased LOS72 and complications.
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Recuperação Pós-Cirúrgica Melhorada , Hepatectomia/efeitos adversos , Humanos , Tempo de Internação , Fígado , Complicações Pós-Operatórias/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVE: The opioid epidemic has stimulated initiatives to reduce the number of unnecessary narcotic prescriptions. We adopted an opt-in prescription system for patients undergoing ambulatory cervical endocrine surgery (CES). We hypothesized that empowering patients to decide whether or not to receive narcotics for pain control would result in fewer unnecessary opioid prescriptions. METHODS: We enrolled all patients scheduled for outpatient CES between July 2017 and June 2018 in a narcotic opt-in program. Patient demographics, procedure characteristics, and postoperative pain scores were collected prospectively. Statistical analyses were performed to correlate clinical predictors with narcotic request. Results were compared against a historical control group. The study was approved by the University IRB. RESULTS: A total of 216 consecutive patients underwent outpatient CES following implementation of the program. Only nine (4%) requested prescription narcotic medication at discharge, and no patient called after discharge to request analgesic medications. Compared with our prior treatment paradigm, we achieved a 96.6% reduction in the number of narcotic tablets prescribed, and a 98% reduction in unconsumed tablets. Univariate analysis suggested history of substance abuse (P < 0.001), anxiety (P = 0.01), depression (P < 0.001), baseline narcotic use (P = 0.004), highest pain postoperatively (P = 0.004), and incision length (P = 0.007) as predictive for narcotic request. Multivariate analysis retained significance with incision length and history of substance abuse. CONCLUSION: By empowering patients undergoing ambulatory CES to accept or decline a prescription, we reduced the number of prescribed narcotic tablets by 96.6%. Although longer incisions and prior substance abuse predict higher likelihood of requesting pain medication on discharge, 207 of 216 patients were treated with acetaminophen alone.
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Acetaminofen/uso terapêutico , Procedimentos Cirúrgicos Ambulatórios , Analgésicos Opioides/uso terapêutico , Doenças do Sistema Endócrino/cirurgia , Pescoço/cirurgia , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Enhanced recovery after surgery (ERAS) is an evidence-based clinical pathway designed to standardize and optimize care. We studied the impact of ERAS and sought to identify the most important recommendations to predict shorter length of stay (LOS) after pancreaticoduodenectomy (PD). METHODS: We retrospectively reviewed all patients undergoing PD at our institution between January 2014 and June 2018. We compared clinicopathologic outcomes for patients before and after ERAS implementation. We defined "A-recommendations" as those that were graded "strong" and had "moderate" or "high" levels of evidence. We then compared outcomes of the ERAS group with adherence to "A-recommendations" and performed a subset analysis of "A-recommendations" over the first 72 h after surgery, which we termed "early factors". RESULTS: A total of 191 patients underwent PD during the study period. We excluded 87 patients who had minimally invasive PD (22), vascular reconstruction (53), or both (12). Of the 104 patients studied, 56 (54%) were pre-ERAS and 48 (46%) were ERAS. There were no differences in comorbidities or demographics between these groups, and morbidity, mortality, and readmission rates were also similar (P > 0.6). Median LOS was 3.5 d shorter in the ERAS group (7 versus 10.5 d, P < 0.001). Adherence to "A-recommendations" within ERAS was associated with a decreased LOS (r = -0.52 P = 0.0001). Patients with >5 "early factors" had a median LOS of 6 d, whereas patients with <5 "early factors" had a median LOS of 9 d (P = 0.008). CONCLUSIONS: ERAS is an effective protocol that standardizes care and reduces LOS after PD. Implementation of ERAS resulted in a 3.5-day reduction in our LOS with no change in morbidity, mortality, or readmissions. Adherence to ERAS protocol "A-recommendations" and ≥5 "early factors" may be predictive of shortened LOS.
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Recuperação Pós-Cirúrgica Melhorada , Tempo de Internação/estatística & dados numéricos , Pancreaticoduodenectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Regras de Decisão Clínica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos RetrospectivosRESUMO
There has been a recent increase in enthusiasm for expansion of living donor liver transplantation (LDLT) programmes. Using all adults initially placed on the waiting list in the United States, we estimated the risk of overall mortality under national strategies which differed in their utilization of LDLT. We used a generalization of inverse probability weighting which can estimate the effect of interventions in the setting of finite resources. From 2005 to 2015, 93 812 eligible individuals were added to the waitlist: 51 322 received deceased donor grafts while 1970 underwent LDLT. Individuals who underwent LDLT had more favourable prognostic factors, including lower mean MELD score at transplant (14.6 vs. 20.5). The 1-year, 5-year and 10-year cumulative incidence of death under the current level of LDLT utilization were 18.0% (95% CI: 17.8, 18.3%), 41.2% (95% CI: 40.8, 41.5%) and 57.4% (95% CI: 56.9, 57.9%) compared to 17.9% (95% CI: 17.7, 18.2%), 40.6% (95% CI: 40.2, 40.9%) and 56.4% (95% CI: 55.8, 56.9%) under a strategy which doubles LDLT utilization. Expansion of LDLT utilization would have a measurable, modest effect on the risk of mortality for the entire cohort of individuals who begin on the transplant waiting list.
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Transplante de Fígado , Adulto , Estudos de Coortes , Humanos , Incidência , Doadores Vivos , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos , Listas de EsperaRESUMO
Eyeblink conditioning in restrained rabbits has served as an excellent model of cerebellar-dependent motor learning for many decades. In mice, the role of the cerebellum in eyeblink conditioning is less clear and remains controversial, partly because learning appears to engage fear-related circuits and lesions of the cerebellum do not abolish the learned behavior completely. Furthermore, experiments in mice are performed using freely moving systems, which lack the stability necessary for mapping out the essential neural circuitry with electrophysiological approaches. We have developed a novel apparatus for eyeblink conditioning in head-fixed mice. Here, we show that the performance of mice in our apparatus is excellent and that the learned behavior displays two hallmark features of cerebellar-dependent eyeblink conditioning in rabbits: (1) gradual acquisition; and (2) adaptive timing of conditioned movements. Furthermore, we use a combination of pharmacological inactivation, electrical stimulation, single-unit recordings, and targeted microlesions to demonstrate that the learned behavior is completely dependent on the cerebellum and to pinpoint the exact location in the deep cerebellar nuclei that is necessary. Our results pave the way for using eyeblink conditioning in head-fixed mice as a platform for applying next-generation genetic tools to address molecular and circuit-level questions about cerebellar function in health and disease.
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Piscadela , Cerebelo/fisiologia , Condicionamento Clássico , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Restrição Física/instrumentação , Restrição Física/métodosRESUMO
BACKGROUND: Outcomes after non-accidental trauma (NAT) have been shown to be impacted by social determinants of health. Our study aims to investigate the association between NAT, patient demographics, neighborhood disadvantage as measured by the Area Deprivation Index (ADI), and patient disposition. METHODS: An 8-year retrospective chart review was conducted in pediatric patients presenting to our level I trauma center with suspected NAT. Patient demographics, ADI, injury severity score (ISS), Glasgow coma scale (GCS), length of stay, and discharge disposition were analyzed using univariate and multivariate techniques to evaluate associations between patient demographics, injury severity, and patient outcomes. RESULTS: A total of 84 patients were admitted with suspected NAT. Of our study population, 45% of patients were White and 26% were Black. Black children were overrepresented in this cohort compared to general population means, while White children were underrepresented (p < 0.05). Median ADI was 6.5 (IQR 4.0-8.0). Of our cohort, 65 patients were discharged home, and 18 patients to foster care. One patient in our cohort died. An ADI >6 was the only factor significantly associated with discharge to foster care. This association held on both univariate (OR 1.4; 95% CI 1.07-1.84, p = 0.02) and multivariate (OR 1.4; 95% CI 1.05-1.86, p = 0.02) analyses. CONCLUSION: Our study found that neighborhood disadvantage, as measured by ADI, is an independent predictor of discharge to foster care. Additionally, Black children remain over-represented in the NAT population referred to our institution, including those discharged to foster care. Efforts to address healthcare disparities and community-based NAT prevention and reunification programs are necessary. TYPE OF STUDY: Prognosis Study (Retrospective Case-Control Study). LEVEL OF EVIDENCE: Level III.
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Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFß/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.
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Neoplasias dos Ductos Biliares , Proteínas Proto-Oncogênicas c-myc , Animais , Camundongos , Transdução de Sinais , Carcinogênese/genética , Proliferação de Células , Ductos Biliares Intra-HepáticosRESUMO
BACKGROUND: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. METHODS: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. RESULTS: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. CONCLUSIONS: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Proteína-Lisina 6-Oxidase , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Animais , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Camundongos , Humanos , Microambiente Tumoral/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Masculino , Aminoácido Oxirredutases/antagonistas & inibidores , Modelos Animais de Doenças , Linhagem Celular TumoralRESUMO
BACKGROUND: Child physical abuse is a significant cause of pediatric injury and death. Previous studies have described disparities in outcomes for physically abused children according to insurance status. We hypothesized that children treated for physical abuse would be more likely to live in neighborhoods with increased socioeconomic deprivation. STUDY DESIGN: We performed a retrospective review of children who were admitted with suspected physical abuse from 2011 to 2021. Home addresses at the time of admission were used to assign an Area Deprivation Index (ADI) of the neighborhood. Clinicopathologic and outcome variables were compared between children from neighborhoods in the top 10th and bottom 90th national neighborhood ADI percentile. Univariate and multivariate logistic models were constructed. RESULTS: One hundred eighty-four children were included for analysis. Children from the top 10th (more impoverished) ADI percentile presented with more severe injuries, had higher area injury scores in the abdomen and extremities, and required admission to the intensive care unit more often, compared with children from the bottom 90th ADI percentile (all p Values <0.05). Children from high ADI neighborhoods were more likely to be discharged to a different caretaker than children from low ADI neighborhoods (71% caretaker change vs 49% caretaker change, p = 0.005). Univariate and multivariate logistic regression demonstrated statistically significant association between the ADI score and the need for caretaker change at the time of discharge (p = 0.004). CONCLUSIONS: Community-level social determinants of health are closely associated with child physical abuse. Child abuse reduction strategies might consider increased support for families with fewer resources and social support systems.
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Maus-Tratos Infantis , Abuso Físico , Criança , Humanos , Características de Residência , Estudos Retrospectivos , Determinantes Sociais da SaúdeRESUMO
BACKGROUND AND OBJECTIVES: Premature infants are often given glycerin suppositories or enemas to facilitate meconium evacuation and the transition to enteral feeds. We reviewed the best-available evidence for the use of glycerin suppositories and enemas in premature infants. METHODS: We searched MEDLINE, Embase, and Cochrane Central for randomized controlled trials (RCTs) of premature infants treated with glycerin suppositories or enemas through January 2022. Studies were screened and data extracted independently and in duplicate. We included RCTs of premature infants <32 weeks gestation and/or birth weight <1500 g who were treated with glycerin suppositories or enemas. Meta-analysis was performed using random effects and reported as relative risk or mean difference. RESULTS: We identified 6 single-center, RCTs of 389 premature infants treated with glycerin suppositories (n = 207) or enemas (n = 182). Mortality rates ranged from 0% to 17%, and the meta-analysis revealed no differences between treatment groups (P = .86). Active treatment was associated with earlier meconium evacuation (mean, 1.5 days; 95% confidence interval, 3.0 to 0.01; P = .05) but not a faster time to enteral feeds (mean, 0.5 days; P = .48). We identified 1 ongoing trial with a target recruitment of 220 premature infants. The quality of evidence was very low to moderate because of inadequate statistical power and other methodologic issues. CONCLUSIONS: The use of glycerin suppositories and enemas in premature infants is associated with earlier meconium evacuation, but the clinical significance of this finding is uncertain. Treatment has no definitive effects on mortality, necrotizing enterocolitis, or enteral feeds.
Assuntos
Glicerol , Recém-Nascido de muito Baixo Peso , Enema , Glicerol/uso terapêutico , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Supositórios , Fatores de TempoRESUMO
Importance: Colorectal cancer is a leading cause of cancer-related death, and nearly 70% of patients with this cancer have unresectable colorectal cancer liver metastases (CRLMs). Compared with chemotherapy, liver transplant has been reported to improve survival in patients with CRLMs, but in North America, liver allograft shortages make the use of deceased-donor allografts for this indication problematic. Objective: To examine survival outcomes of living-donor liver transplant (LDLT) for unresectable, liver-confined CRLMs. Design, Setting, and Participants: This prospective cohort study included patients at 3 North American liver transplant centers with established LDLT programs, 2 in the US and 1 in Canada. Patients with liver-confined, unresectable CRLMs who had demonstrated sustained disease control on oncologic therapy met the inclusion criteria for LDLT. Patients included in this study underwent an LDLT between July 2017 and October 2020 and were followed up until May 1, 2021. Exposures: Living-donor liver transplant. Main Outcomes and Measures: Perioperative morbidity and mortality of treated patients and donors, assessed by univariate statistics, and 1.5-year Kaplan-Meier estimates of recurrence-free and overall survival for transplant recipients. Results: Of 91 evaluated patients, 10 (11%) underwent LDLT (6 [60%] male; median age, 45 years [range, 35-58 years]). Among the 10 living donors, 7 (70%) were male, and the median age was 40.5 years (range, 27-50 years). Kaplan-Meier estimates for recurrence-free and overall survival at 1.5 years after LDLT were 62% and 100%, respectively. Perioperative morbidity for both donors and recipients was consistent with established standards (Clavien-Dindo complications among recipients: 3 [10%] had none, 3 [30%] had grade II, and 4 [40%] had grade III; donors: 5 [50%] had none, 4 [40%] had grade I, and 1 had grade III). Conclusions and Relevance: This study's findings of recurrence-free and overall survival rates suggest that select patients with unresectable, liver-confined CRLMs may benefit from total hepatectomy and LDLT.