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Highly tumorigenic, drug-resistant cancer stem-like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem-like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem-like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem-like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug-resistant phenotype.
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Plasticidade Celular/genética , Metilação de DNA/genética , Fator de Transcrição E2F3/genética , Células-Tronco Neoplásicas/patologia , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Cromatina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F3/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Background: Palliative care can enhance quality of life during a terminal hospitalization. Despite advances in diagnostic and treatment tools, blood cancers lag behind solid malignancies in palliative use. It is not clear what factors affect palliative care use in blood cancer. Methods: We used the 2016 to 2019 National Inpatient Sample to identify demographic and socioeconomic factors associated with receiving palliative care among patients over age 18 with any malignant hematological diagnosis during a terminal hospitalization lasting at least 3 days, excluding those receiving a stem cell transplant. Results: Palliative care use was documented 54% of the time among 49,720 weighted cases (9944 distinct individual hospitalizations), approximately evenly distributed across the years 2016-2019. Palliative care use was lowest in 2016 (51%) and highest in 2018 (58%), and increased with age, reaching 58% for those 80 years and older. Men and women were similarly likely to receive care. Patients of Hispanic ethnicity and African Americans received less palliative care (47% and 49%, respectively), as did those insured by Medicaid (48%), and those admitted to small or rural hospitals (52% and 47%, respectively). Charges for hospitalizations with palliative care were 19% lower than for those without it. Conclusions: This study highlights disparities in palliative care use among blood-cancer patients who died in the hospital. It seems likely that many of the 46% who did not receive palliative care could have benefitted from it. Interventions are likely needed to achieve equitable access to ideal levels of palliative care services in late-stage blood cancer.
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BACKGROUND Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin, which can lead to a prothrombotic state. Prompt cessation of heparin and initiation of non-heparin anticoagulation is the standard of care for HIT. Nevertheless, the treatment can pose challenges, particularly in refractory HIT, in patients with contraindications to anticoagulation, or those requiring urgent surgery. Additionally, in rare cases, conventional anticoagulation therapy is not effective, necessitating alternative treatments such as plasma exchange (PLEX) and intravenous immunoglobulin (IVIG). CASE REPORT Here, we report the case of a 57-year-old male patient who developed mild acute cellular rejection, refractory HIT, and disseminated intravascular coagulation after liver transplant surgery. Heparin was stopped and argatroban was initiated for thromboembolism treatment, but hepatic artery thrombosis occurred in the setting of refractory HIT and caused transplant failure. The patient underwent a second liver transplant 1 month after the first surgery. He had 2 sessions of PLEX and received 1 dose of IVIG before and 1 dose during the operation. Despite advanced treatment with PLEX and IVIG, the refractory HIT persisted. Hepatic artery thrombosis recurred within 2 weeks and the transplant failed again despite catheter-directed intra-arterial thrombolysis and argatroban therapy. CONCLUSIONS Recently perioperative PLEX and IVIG have been used a few times for the treatment of refractory HIT. This is the first reported case of a liver transplant recipient with refractory HIT who underwent this treatment strategy. Further investigation is required to determine the efficacy and safety of preoperative and intraoperative administration of PLEX and IVIG, especially in liver transplant recipients with HIT.
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Transplante de Fígado , Trombocitopenia , Trombose , Masculino , Humanos , Pessoa de Meia-Idade , Imunoglobulinas Intravenosas/uso terapêutico , Troca Plasmática , Transplante de Fígado/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia , Heparina/efeitos adversos , Trombose/tratamento farmacológico , Anticoagulantes/efeitos adversosRESUMO
ABSTRACT: Polyactide (PLA) barrier is one of the most commonly used materials to prevent the formation of postoperative adhesion. Even though previous studies supported the anti-adhesion efficacy of PLA barrier, there have been limited reports focusing on the associated foreign body reaction. We sought to investigate the potential complication of PLA barrier placement that could lead to unnecessary intervention.This is a retrospective study of colorectal cancer patients with laparoscopic surgery. Cases with stage IV unresectable disease, poor Eastern Cooperative Oncology Group Performance, death within 3 months after the surgery, and insufficient record were excluded. A total of 296 cases were identified in our study and 220 patients received PLA film placement. We compared the incidence of foreign body reaction between the patients with and without PLA film.Among PLA film group, 16 cases had signs of local recurrence on the follow-up image studies. The subsequent operation found 10 patients had no cancerous lesions but only foreign-body-associated granulomas. The incidence of foreign body reaction mimicking local recurrence on image study was 4.5% with high false positive rate of 62.5% on positron emission tomography scan in patients with PLA film. There were only 2 cases without the antiadhesive barrier developed signs of recurrence during active surveillance. Both cases were later confirmed to have malignant peritoneal seeding.The PLA film was associated with rare foreign body reaction that could interfere the accuracy of follow-up program and result in unnecessary surgical intervention. Hence, we recommend avoiding the use of the PLA barrier.
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Neoplasias Colorretais , Reação a Corpo Estranho , Laparoscopia , Poliésteres/efeitos adversos , Neoplasias Colorretais/cirurgia , Diagnóstico Diferencial , Reação a Corpo Estranho/diagnóstico por imagem , Reação a Corpo Estranho/etiologia , Humanos , Recidiva Local de Neoplasia , Estudos Retrospectivos , Aderências Teciduais/prevenção & controleRESUMO
Introduction Influenza causes significant morbidity and mortality annually in the United States (US) and people with chronic medical conditions are thought to be at higher risk for severe disease and death. Infection is a leading cause of death for patients with end-stage kidney disease (ESKD). We used a national-level inpatient database to study the trend of influenza hospitalizations and in-hospital mortality for patients without and with ESKD. Methods The National Inpatient Sample (NIS) 2010-2019 was used. A primary diagnosis of influenza was identified using ICD-9-CM (487.X, 488.X) and ICD-10-CM codes (J09.X, J10.X, J11.X). ESKD was identified using a validated algorithm identifying patients with a diagnosis of ESKD or procedure code for dialysis and excluding patients with a diagnosis of acute kidney injury. Other diagnoses and procedures were identified using validated algorithms based on ICD-9-CM, ICD-10-CM, and ICD-10-PCS codes. Discharge-level weights were used to estimate the total number of admissions in the NIS universe. Weighted multivariable logistic regression was performed to study the association between ESKD and in-hospital death. Results 131,942 admissions with a primary diagnosis of influenza with 4,647 admissions for ESKD patients among them were included in our analysis. Admissions varied by influenza season and ESKD patients accounted for 2.91% to 3.65% of all influenza admissions each season. 2,081 influenza patients (1.58%) died in the hospital and 115 patients with influenza and ESKD (2.47%) died in the hospital. Age-adjusted in-hospital mortality varied from season to season but was consistently higher in ESKD patients (2.25% vs 1.38%). ESKD was a risk factor for in-hospital death (OR 1.26, 95% CI 1.15-1.38) after adjusting for age, gender, primary payer, heart failure, chronic lung disease, obesity, drug abuse, immunocompromised status, bacterial pneumonia, the Charlson Comorbidity Index, and the influenza season. Conclusion ESKD patients accounted for a significant proportion of influenza hospitalizations in the US from 2010-11 to the 2018-19 influenza season. Among people hospitalized primarily for influenza, age-adjusted in-hospital mortality varied from season to season and was consistently higher in ESKD patients. For people hospitalized primarily for influenza, ESKD was an independent risk factor for in-hospital death.
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Chemotherapy resistance is traditionally attributed to DNA mutations that confer a survival advantage under drug selection pressure. However, in bladder cancer and other malignancies, we and others have previously reported that cancer cells can convert spontaneously to an aggressive drug-resistant phenotype without prior drug selection or mutational events. In the current work, we explored possible epigenetic mechanisms behind this phenotypic plasticity. Using Hoechst dye exclusion and flow cytometry, we isolated the aggressive drug-resistant cells and analyzed their chromatin accessibility at regulatory elements. Compared to the rest of the cancer cell population, the aggressive drug-resistant cells exhibited enhancer accessibility changes. In particular, we found that differentially accessible enhancers were enriched for the FOXC1 transcription factor motif, and that FOXC1 was the most significantly overexpressed gene in aggressive drug-resistant cells. ChIP-seq analysis revealed that differentially accessible enhancers in aggressive drug-resistant cells had a higher FOXC1 binding, which regulated the expression of adjacent cancer-relevant genes like ABCB1 and ID3. Accordingly, cisplatin treatment of bladder cancer cells led to an increased FOXC1 expression, which mediated cell survival and conversion to a drug-resistant phenotype. Collectively, these findings suggest that FOXC1 contributes to phenotypic plasticity by binding enhancers and promoting a mutation-independent shift towards cisplatin resistance in bladder cancer.
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Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.
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Cisplatino , Neoplasias da Bexiga Urinária , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Células Epiteliais , Humanos , Fosforilação Oxidativa , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genéticaRESUMO
BACKGROUND: In-hospital cardiac arrest (IHCA) carries a high mortality and significant morbidity in survivors. Gastrointestinal bleeding (GIB) can complicate cardiac arrests. We aim to study the association between GIB and the in-hospital outcomes of patients with IHCA. METHODS AND RESULTS: The National Inpatient Sample 2016-2018 databases were used. IHCA were identified using ICD-10-PCS code for cardiopulmonary resuscitation. Other diagnoses including GIB were identified using ICD-10-CM codes. Multivariate logistic regression was used to study the effect of GIB on in-hospital mortality. Gamma regression with log link was used to determine the effect of GIB on length of stay and cost of admission. In patients with IHCA, GIB as a secondary diagnosis is associated with an increased in hospital mortality (unadjusted 74.2% vs 68.3%, adjusted OR 1.17, 95% confidence interval [CI] 1.09-1.25, p < 0.001), longer length of stay (unadjusted median 16 vs 10 days, IQR 9-27 vs 5-17 days, exponentiated coefficient 1.45, 95% CI 1.36-1.54, p < 0.001 for survivors; unadjusted median 4 vs 3 days, IQR 1-10 vs 1-7 days, exponentiated coefficient 1.27, 95% CI 1.22-1.34, p < 0.001 for patients who died in hospital), and higher cost for hospital stay (unadjusted median $226065 vs $151459, IQR $117551-434003 vs $76197-287846, exponentiated coefficient 1.40, 95% CI 1.32-1.49, p < 0.001 for survivors; unadjusted median $87996 vs $77056, IQR $42566-186677 vs $34066-149009, exponentiated coefficient 1.26, 95% CI 1.20-1.32, p < 0.001 for patients who died in hospital) adjusted for baseline characteristics and other comorbidities. CONCLUSIONS: In patients with IHCA, GIB as a secondary diagnosis is associated with a higher in-hospital mortality, longer length of stay and higher cost for the admission.
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INTRODUCTION: Breast metastases from primary colorectal carcinoma are extremely rare, with only 45 cases being reported previously. Since the most common malignancy in the breast and axilla is primary breast cancer regardless of cancer history, non-hematologic metastases may be misdiagnosed initially. Nevertheless, differentiating breast metastases from primary breast cancer is crucial because of their differences in prognosis and management. PATIENT CONCERNS: We present a case of a 44-year-old Asian woman who noticed a new right breast lump after undergoing surgery and chemotherapy for her primary sigmoid colon cancer. DIAGNOSIS: Image and immunohistochemistry findings were consistent with breast metastasis from primary colorectal adenocarcinoma. INTERVENTIONS: The patient underwent breast tumor excision and reinitiated chemotherapy. OUTCOMES: The patient's disease progressed despite the interventions. She passed away 7 months after the detection of breast metastasis. CONCLUSION: When a new breast lesion is detected in patients with colorectal cancer history, the physician should consider the possibility of breast metastasis due to the poor prognosis. If a biopsy is necessary, cancer history should be provided to the clinicians to prevent incorrect pathological interpretation. In establishing the diagnosis, certain immunohistochemical markers have been shown to be sensitive and specific in previously reported cases. The combination of tumor excision and chemotherapy was the most common strategy in managing this condition with inconsistent clinical outcomes.