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Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.
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Lenvatinib is a clinically effective multikinase inhibitor approved for first-line therapy of advanced hepatocellular carcinoma (HCC). Although resistance against lenvatinib often emerges and limits its antitumor activity, the underlying molecular mechanisms involved in endogenous and acquired resistance remain elusive. In this study, we identified focal adhesion kinase (FAK) as a critical contributor to lenvatinib resistance in HCC. The elevated expression and phosphorylation of FAK were observed in both acquired and endogenous lenvatinib-resistant (LR) HCC cells. Furthermore, inhibition of FAK reversed lenvatinib resistance in vitro and in vivo. Mechanistically, FAK promoted lenvatinib resistance through regulating lysine-deficient kinase 1 (WNK1). Phosphorylation of WNK1 was significantly increased in LR-HCC cells. Further, WNK1 inhibitor WNK463 resensitized either established or endogenous LR-HCC cells to lenvatinib treatment. In addition, overexpression of WNK1 desensitized parental HCC cells to lenvatinib treatment. Conclusively, our results establish a crucial role and novel mechanism of FAK in lenvatinib resistance and suggest that targeting the FAK/WNK1 axis is a promising therapeutic strategy in HCC patients showing lenvatinib resistance.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Lisina/uso terapêutico , Linhagem Celular TumoralRESUMO
PURPOSE: To compare pathologic tumor necrosis rates after locoregional therapies (LRTs) for hepatocellular carcinoma (HCC) prior to liver transplantation and evaluate radiologic-pathologic correlation along with posttransplant HCC recurrence. MATERIALS AND METHODS: Consecutive patients with solitary HCC bridged or downstaged with LRT from 2010 to 2022 were included. LRTs were transarterial chemoembolization (TACE), radioembolization (yttrium-90 [90Y]), ablation, and stereotactic body radiotherapy (SBRT). Upfront combination therapy options were TACE/ablation and TACE/SBRT. Subsequent therapy crossover due to local recurrence was allowed. Posttreatment imaging closest to the time of transplant, explant histopathologic necrosis, and tumor recurrence after transplant were reviewed. RESULTS: Seventy-three patients met inclusion criteria, of whom 5 (7%) required downstaging. 90Y alone (n = 36) and multimodal therapy (pooled upfront combination and crossover therapy, n = 23) resulted in significantly greater pathologic necrosis compared with TACE alone (n = 14; P = .01). High dose 90Y radiation segmentectomy (≥190 Gy; n = 27) and TACE/ablation (n = 7) showed highest rates of complete pathologic necrosis (CPN)-63% (n = 17) and 71% (n = 5), respectively. Patients with CPN had a mean lesion size of 2.5 cm, compared with 3.2 cm without CPN (P = .04), irrespective of LRT modality. HCC recurrence was more common in patients without CPN (16%, 6/37) than in those with CPN (3%, 1/36; P = .11). Using Liver Imaging Reporting and Data System (LI-RADS), a nonviable imaging response was 75% sensitive and 57% specific for CPN. CONCLUSIONS: Radiation segmentectomy and multimodal therapy significantly improved CPN rates compared with TACE alone. A LI-RADS treatment response of nonviable did not confidently predict CPN.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Necrose/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) represents a spectrum of alcohol use-related liver diseases. Outside of alcohol abstinence, there are currently no Food and Drug Administration-approved treatments for advanced ALD, necessitating a greater understanding of ALD pathogenesis and potential molecular targets for therapeutic intervention. The ABL-family proteins, including ABL1 and ABL2, are non-receptor tyrosine kinases that participate in a diverse set of cellular functions. We investigated the role of the ABL kinases in alcohol-associated liver disease. METHODS: We used samples from patients with ALD compared with healthy controls to elucidate a clinical phenotype. We established strains of liver-specific Abl1 and Abl2 knockout mice and subjected them to the National Institute on Alcohol Abuse and Alcoholism acute-on-chronic alcohol feeding regimen. Murine samples were subjected to RNA sequencing, AST, Oil Red O staining, H&E staining, Western blotting, and quantitative polymerase chain reaction to assess phenotypic changes after alcohol feeding. In vitro modeling in HepG2 cells as well as primary hepatocytes from C57BL6/J mice was used to establish this mechanistic link of ALD pathogenesis. RESULTS: We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well as in liver tissues from mice subjected to an alcohol feeding regimen. We found that the liver-specific knockout of Abl2, but not Abl1, attenuated alcohol-induced steatosis, liver injury, and inflammation. Subsequent RNA sequencing and gene set enrichment analyses of mouse liver tissues revealed that relative to wild-type alcohol-fed mice, Abl2 knockout alcohol-fed mice exhibited numerous pathway changes, including significantly decreased peroxisome proliferator activated receptor (PPAR) signaling. Further examination revealed that PPARγ, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in Abl2 knockout mice. In vitro analyses revealed that shRNA-mediated knockdown of ABL2 abolished the alcohol-induced accumulation of PPARγ as well as subsequent lipid accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARγ protein expression. Furthermore, we demonstrated that the regulation of hypoxia inducible factor 1 subunit alpha (HIF1α) by ABL2 is required for alcohol-induced PPARγ expression. Furthermore, treatment with ABL kinase inhibitors attenuated alcohol-induced PPARγ expression, lipid droplet formation, and liver injury. CONCLUSIONS: On the basis of our current evidence, we propose that alcohol-induced ABL2 activation promotes ALD through increasing HIF1α and the subsequent PPARγ expression, and ABL2 inhibition may serve as a promising target for the treatment of ALD.
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Hepatopatias Alcoólicas , PPAR gama , Humanos , Animais , Camundongos , Hepatopatias Alcoólicas/patologia , Etanol/toxicidade , Camundongos Knockout , TirosinaRESUMO
Malignant neoplasms arising from the Brunner gland are exceedingly rare. A 62-year-old man with a history of surgical resection of Brunner gland adenocarcinoma presented with upper extremity cellulitis. Hospital course was complicated by atrial fibrillation and hematochezia. Bidirectional endoscopy was negative; however, small bowel enteroscopy revealed recurrence of Brunner gland adenocarcinoma 6 years after surgical resection. To our knowledge, this is the first reported case of recurrent Brunner gland adenocarcinoma after curative resection.
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Background and Objective: Esophageal carcinoma cuniculatum (CC) is a rare variant of a well-differentiated squamous cell carcinoma (SCC). Unlike other forms of esophageal cancers, CC of the esophagus is difficult to diagnose on endoscopic biopsies. This can lead to a delay in the diagnosis and increases morbidity. We reviewed the available literature to shed light on the etiopathogenesis, diagnosis, treatment, and outcomes of this disease. Our aim is to create a better understanding of this rare disease entity and contribute to a timely diagnosis to reduce the associated morbidity and mortality. Methods: Extensive review of PubMed, Embase, Scopus, Google Scholar was conducted. We identified the published literature on Esophageal CC from inception till date. We report epidemiological trends, clinical presentation, diagnostic and treatment strategies to correctly identify the cases to reduce the likelihood of a missed diagnosis of esophageal CC. Key Content and Findings: Associated risk factors for esophageal CC are chronic reflux esophagitis, smoking, alcohol consumption, immunosuppression, and achalasia. Dysphagia is the most common presentation. Primary diagnostic modality is an esophagogastroduodenoscopy (EGD), but diagnosis can be easily missed. To favor an early diagnosis, a histological scoring system has been proposed by Chen et al. where authors describe specific histological features that appear to be common based on the numerous mucosal biopsies examined from patients with CC. Conclusions: A high clinical suspicion for the disease along with close endoscopic follow-up with repeat biopsies is needed for an early diagnosis. Surgery remains the gold standard for treatment and is associated with a favorable prognosis when the patients are diagnosed early.
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Despite the high lethality of colorectal cancers (CRCs), only a limited number of genetic risk factors are identified. The mammalian ssDNA-binding protein complex CTC1-STN1-TEN1 protects genome stability, yet its role in tumorigenesis is unknown. Here, we show that attenuated CTC1/STN1 expression is common in CRCs. We generated an inducible STN1 knockout mouse model and found that STN1 deficiency in young adult mice increased CRC incidence, tumor size, and tumor load. CRC tumors exhibited enhanced proliferation, reduced apoptosis, and elevated DNA damage and replication stress. We found that STN1 deficiency down-regulated multiple DNA glycosylases, resulting in defective base excision repair (BER) and accumulation of oxidative damage. Collectively, this study identifies STN1 deficiency as a risk factor for CRC and implicates the previously unknown STN1-BER axis in protecting colon tissues from oxidative damage, therefore providing insights into the CRC tumor-suppressing mechanism.
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Neoplasias do Colo , Proteínas de Ligação a Telômeros , Animais , Camundongos , Neoplasias do Colo/genética , Reparo do DNA , Replicação do DNA , Mamíferos/genética , Telômero/metabolismo , Proteínas de Ligação a Telômeros/genéticaRESUMO
Background and Aims: The preponderance of microscopic colitis (MC) in females may be associated with postmenopausal increased risk of atherosclerosis. The aim of this study was to describe the prevalence of atherosclerotic diseases in adults with MC. Methods: Retrospective observational study of patients with a diagnosis of MC or incomplete MC at our institution from 2008 to 2018. We performed a chart review and extracted data on demographics, comorbidities, medications, diagnosis, imaging, and endoscopy. Data were analyzed descriptively. Logistic regression was used to estimate the unadjusted effects of different variables on MC. Results: Of 269 patients, 265 had a MC diagnosis; 236 (89.06%) had collagenous colitis or lymphocytic colitis; and 29 (10.94%) were diagnosed with incomplete MC. Majority were female (79.55%), ≥ 65 years (59.11%), and white (88.81%). Majority had the following risk factors for atherosclerosis, smoking (52.04%), hypertension (58.21%), and hyperlipidemia (59.5%). The prevalence of coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease (CVD) was 16.79% (12.32, 21.27), 8.58% (5.23-11.94), and 7.49% (4.33-10.65), respectively. There was no difference in the prevalence of CAD and CVD after adjusting for sex. Females with MC had reduced odds of PAD compared with males. Conclusion: The prevalence of CAD, PAD, and CVD was 16.79%, 8.58%, and 7.49%, respectively. Similar to the general population, smoking, hypertension, and hyperlipidemia are risk factors for atherosclerosis in MC.
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FXR regulates bile acid metabolism, and FXR null (Fxr-/-) mice have elevated bile acid levels and progressive liver injury. The inositol-requiring enzyme 1α/X-box binding protein 1 (XBP1) pathway is a protective unfolded protein response pathway activated in response to endoplasmic reticulum stress. Here, we sought to determine the role of the inositol-requiring enzyme 1α/XBP1 pathway in hepatic bile acid toxicity using the Fxr-/- mouse model. Western blotting and quantitative PCR analysis demonstrated that hepatic XBP1 and other unfolded protein response pathways were activated in 24-week-old Fxr-/- compared with 10-week-old Fxr-/- mice but not in WT mice. To further determine the role of the liver XBP1 activation in older Fxr-/- mice, we generated mice with whole-body FXR and liver-specific XBP1 double KO (DKO, Fxr-/-Xbp1LKO) and Fxr-/-Xbp1fl/fl single KO (SKO) mice and characterized the role of hepatic XBP1 in cholestatic liver injury. Histologic staining demonstrated increased liver injury and fibrosis in DKO compared with SKO mice. RNA sequencing revealed increased gene expression in apoptosis, inflammation, and cell proliferation pathways in DKO mice. The proapoptotic C/EBP-homologous protein pathway and cell cycle marker cyclin D1 were also activated in DKO mice. Furthermore, we found that total hepatic bile acid levels were similar between the two genotypes. At age 60 weeks, all DKO mice and no SKO mice spontaneously developed liver tumors. In conclusion, the hepatic XBP1 pathway is activated in older Fxr-/- mice and has a protective role. The potential interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses.
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Colestase , Fígado , Proteína 1 de Ligação a X-Box , Animais , Camundongos , Ácidos e Sais Biliares/metabolismo , Colestase/genética , Inositol/metabolismo , Fígado/metabolismo , Fígado/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 1 de Ligação a X-Box/genéticaRESUMO
Nodular histiocytic/mesothelial hyperplasia (NHMH) is a rare histologic entity, characterized by localized benign reactive proliferation of histiocytes and mesothelial cells. The presence of this rare entity poses a challenge in differential diagnosis, both in radiological findings and pathological interpretations under certain circumstances, and consequently has been misdiagnosed as malignancy. Here, we report a case of mesenteric NHMH in a patient with colonic mucinous adenocarcinoma. Histology shows numerous large calretinin (+) mesothelial cells mixed with CD68 (+) histiocytes by immunohistochemistry. In contrast to almost all previously reported cases with typical features of histiocytic predominance, the current case of NHMH mainly consists of mesothelial cells with intermixed histiocytes. The findings expand the histologic spectrum of NHMH and contribute to awareness of this entity in the differential diagnosis.
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Lenvatinib is a multikinase inhibitor approved as a first-line therapy for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common, and the underlying mechanisms governing this resistance are largely unknown. In this study, we established two lenvatinib-resistant (LR) HCC cell lines and identified integrin subunit beta 8 (ITGB8) as a critical contributor to lenvatinib resistance in HCC. The elevated expression of ITGB8 was observed in LR HCC cells. Furthermore, silencing of ITGB8 reversed lenvatinib resistance in vitro and in vivo, whereas ectopic expression of ITGB8 in lenvatinib-sensitive parental HCC cells exhibited increased resistance to lenvatinib. Mechanistically, ITGB8 regulated lenvatinib resistance through an HSP90-mediated stabilization of AKT and enhanced AKT signaling. In support of this model, either an AKT inhibitor MK-2206 or an HSP90 inhibitor 17-AAG resensitized LR HCC cells to lenvatinib treatment. Conclusion: Collectively, our results establish a crucial role of ITGB8 in lenvatinib resistance, and suggest that targeting the ITGB8/HSP90/AKT axis is a promising therapeutic strategy in patients with HCC exhibiting lenvatinib resistance.
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Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Cadeias beta de Integrinas , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Cadeias beta de Integrinas/genética , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia , Proteínas Proto-Oncogênicas c-akt/genética , QuinolinasRESUMO
Extramedullary gastrointestinal tract involvement in plasma cell dyscrasias is rare and represents a diagnostic challenge. We present a 66-year-old man with an unusual presentation of multiple myeloma. He presented with chronic diarrhea, and extensive biopsies in the jejunum allowed for the presumptive diagnosis of multiple myeloma to be made and the weighted decision to treat without a definitive diagnosis. Plasma cell dyscrasias can have highly varied presentations, unclear differentiation, and require a multidisciplinary approach for diagnosis and management. Adequate tissue sampling of the small bowel is critical in assessing patients with chronic diarrhea.
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Microscopic colitis (MC) is a common cause of chronic diarrhea with limited long-term data. We searched the pathology records at our institution from 2008 to 2018 to identify cases of MC. Total sample included patients with either a diagnosis of MC or incomplete MC (MCi).Chart review was performed and data were summarized for descriptive statistics. Logistic regression was used to estimate the unadjusted effects of predictors on MC. A total of 216 patients (88.32% white, 80.56% females, mean age 67.12 +/- 15.79) were studied; 50.00% had CC, 40.28% had LC and 9.72% had MCi. Majority (52.31%) were smokers and 21.84% of females were using some form of hormonal therapy. The odds of LC in reference to CC were significantly higher for those using tricyclic antidepressants (TCAs) (OR: 3.23, 95% C.I: 1.18-8.80, p = 0.02). The odds of smoking, statins, aspirin and beta-blocker use were decreased in MCi in reference to CC (all p < 0.05), 29 (74.35%) patients with unresolved symptoms underwent repeat colonoscopies with biopsies. One case of MCi resolved, 8 (72.73%) out of 11 cases of LC resolved, 2 (18.18%) continued to be LC and 1 (9.09%) transformed to CC, 8 (47.06%) out of 17 cases of CC resolved, 8 (47.06%) continued to be CC and 1 (5.88%) transformed to LC. Majority of patients had CC. TCA use resulted in increased odds of LC in reference to CC. Biopsies from repeat colonoscopies in some patients revealed changes in the pathological diagnoses raising the question of interchangeability of MC (CC to LC and vice versa).
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Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide. One major obstacle to treatment is a lack of effective molecular-targeted therapies. In this study, we find that EphA2 expression and signaling are enriched in human HCC and associated with poor prognosis. Loss of EphA2 suppresses the initiation and growth of HCC both in vitro and in vivo. Furthermore, CRISPR/CAS9-mediated EphA2 inhibition significantly delays tumor development in a genetically engineered murine model of HCC. Mechanistically, we discover that targeting EphA2 suppresses both AKT and JAK1/STAT3 signaling, two separate oncogenic pathways in HCC. We also identify a small molecule kinase inhibitor of EphA2 that suppresses tumor progression in a murine HCC model. Together, our results suggest EphA2 as a promising therapeutic target for HCC.
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Antineoplásicos/farmacologia , Benzamidas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Janus Quinase 1/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor EphA2/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 1/genética , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Niacinamida/farmacologia , Fosforilação , Receptor EphA2/genética , Receptor EphA2/metabolismo , Estudos Retrospectivos , Fator de Transcrição STAT3/genética , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Alcohol can potentiate disease in a mouse model of dextran sodium sulfate (DSS) colitis; however, the underlying mechanism remains to be established. In this study, we assessed whether the potentiated disease could be related to Enterobacteriaceae and Lactobacillus, as changes in their relative abundance can impact intestinal health. We also assessed whether the intestinal barrier is compromised after alcohol and DSS as it may increase bacterial translocation and liver inflammation. Mice were administered DSS followed by binge ethanol or water vehicle, generating four experimental groups: (Control+Vehicle, Control+Ethanol, DSS+Vehicle, DSS+Ethanol). DNA was isolated from colon and cecal contents followed by qPCR for levels of Enterobacteriaceae and Lactobacillus. Colon and liver sections were taken for histology. Intestinal epithelial cells were isolated from the colon for RNA expression. DSS+Ethanol cecal contents exhibited a 1 log increase in Enterobacteriaceae (p < .05), a 0.5 log decrease in Lactobacillus, and a 1.5 log decrease (p < .05) in the Lactobacillus:Enterobacteriaceae ratio compared to DSS+Vehicle, with similar trends in colon contents. These changes correlated with shorter colons and more weight loss. Irrespective of ethanol administration, DSS compromised the mucosal barrier integrity, however only DSS+Ethanol exhibited significant increases in circulating endotoxin. Furthermore, the livers of DSS+Ethanol mice had significantly increased levels of triglycerides, mononuclear cells, yet exhibited significantly depressed expression of liver inflammatory pathways, suggestive of tolerance induction, compared to mice receiving DSS+Vehicle. Our results suggest that ethanol after DSS colitis increases the intestinal burden of Enterobacteriaceae which may contribute to intestinal and liver damage, and the induction of immune tolerance.
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Colite/imunologia , Enterobacteriaceae/isolamento & purificação , Etanol/farmacologia , Tolerância Imunológica/imunologia , Mucosa Intestinal/imunologia , Lactobacillus/isolamento & purificação , Animais , Carga Bacteriana , Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana , Modelos Animais de Doenças , Endotoxinas/sangue , Mucosa Intestinal/microbiologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Junções Íntimas/fisiologia , Triglicerídeos/sangueRESUMO
Microscopic colitis (MC) is a chronic inflammation condition of the colon characterized by watery diarrhea and normal appearing mucosa. A 75-year-old female presented with one-year history of chronic diarrhea while taking cannabidiol (CBD) for pain. Colonoscopy with random colon biopsies revealed collagenous colitis. She started budesonide and stopped CBD. At six-week follow-up, her diarrhea improved, and the budesonide dose was decreased. She restarted CBD oil twice but had diarrhea both times. Her diarrhea resolved after taking budesonide and stopping CBD. We report a case of CBD-associated MC to make clinicians aware of this potential adverse effect in patients who chronically use CBD.
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BACKGROUND: Nivolumab and pembrolizumab-two monoclonal antibodies that block human programmed cell death-1 (PD-1)-have been successfully used to treat patients with multiple advanced malignancies. The histologic patterns of hepatic toxicity induced by anti-PD-1 treatment have not been well studied and the aim of this study was to explore them. METHODS: Eight patients with advanced malignancies who were treated with either nivolumab or pembrolizumab were identified from five institutions. These patients had no history of underlying liver disease and a viral hepatitis panel was negative in all patients. RESULTS: Seven of eight patients exhibited mild to moderate gastrointestinal symptoms such as abdominal pain, fatigue, nausea, vomiting, and jaundice after anti-PD-1 treatment. Significant elevations in liver-chemistry tests were detected in all patients. Six cases (6/8) demonstrated an acute lobular hepatitis pattern of histologic injury. The remaining two cases showed different histologic patterns of injury: steatohepatitis with mild cholestasis (1/8) and pure acute cholestatic injury (1/8). No case showed typical features of autoimmune hepatitis. The liver function recovered in all eight cases after cessation of anti-PD-1 agents and with immunosuppressive therapy. CONCLUSIONS: Our study suggests that screening patients for abnormal liver-function tests prior to anti-PD-1 therapy as well as periodic monitoring of liver-function tests are necessary to prevent severe liver injury. Rather than causing classical autoimmune hepatitis, PD-1 inhibitors appear to produce an immune-mediated nonspecific acute hepatitis. Drug cessation, without steroid therapy, may therefore be sufficient in some patients.
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BACKGROUND & AIMS: We investigated whether ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) is involved in development of hepatocellular carcinoma (HCC). METHODS: We analyzed clinical and gene expression data from The Cancer Genome Atlas. Albumin-Cre (HepWT) mice and mice with hepatocyte-specific disruption of Abl1 (HepAbl-/- mice) were given hydrodynamic injections of plasmids encoding the Sleeping Beauty transposase and transposons with the MET gene and a catenin ß1 gene with an N-terminal truncation, which induces development of liver tumors. Some mice were then gavaged with the ABL1 inhibitor nilotinib or vehicle (control) daily for 4 weeks. We knocked down ABL1 with short hairpin RNAs in Hep3B and Huh7 HCC cells and analyzed their proliferation and growth as xenograft tumors in mice. We performed RNA sequencing and gene set enrichment analysis of tumors. We knocked down or overexpressed NOTCH1 and MYC in HCC cells and analyzed proliferation. We measured levels of phosphorylated ABL1, MYC, and NOTCH1 by immunohistochemical analysis of an HCC tissue microarray. RESULTS: HCC tissues had higher levels of ABL1 than non-tumor liver tissues, which correlated with shorter survival times of patients. HepWT mice with the MET and catenin ß1 transposons developed liver tumors and survived a median 64 days; HepAbl-/- mice with these transposons developed tumors that were 50% smaller and survived a median 81 days. Knockdown of ABL1 in human HCC cells reduced proliferation, growth as xenograft tumors in mice, and expression of MYC, which reduced expression of NOTCH1. Knockdown of NOTCH1 or MYC in HCC cells significantly reduced cell growth. NOTCH1 or MYC overexpression in human HCC cells promoted proliferation and rescued the phenotype caused by ABL1 knockdown. The level of phosphorylated (activated) ABL1 correlated with levels of MYC and NOTCH1 in human HCC specimens. Nilotinib decreased expression of MYC and NOTCH1 in HCC cell lines, reduced the growth of xenograft tumors in mice, and slowed growth of liver tumors in mice with MET and catenin ß1 transposons, reducing tumor levels of MYC and NOTCH1. CONCLUSIONS: HCC samples have increased levels of ABL1 compared with nontumor liver tissues, and increased levels of ABL1 correlate with shorter survival times of patients. Loss or inhibition of ABL1 reduces proliferation of HCC cells and slows growth of liver tumors in mice. Inhibitors of ABL1 might be used for treatment of HCC.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Receptor Notch1/metabolismo , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Fosforilação , Prognóstico , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor Notch1/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Autoimmune enteropathy is a rare disorder of the immune system. We present a 75-year-old woman with rheumatoid arthritis who presented with 4 months of intractable vomiting, diarrhea, and unexplained weight loss. Initial workup was negative for infection and celiac disease, but her symptoms progressed. Repeat esophagogastroduodenoscopy showed duodenal scalloping and friability. Biopsies of the duodenum and terminal ileum showed glandular destruction, epithelial apoptosis, and goblet cell depletion. Colonoscopic examination was normal, and random colon biopsies did not show evidence of microscopic colitis. She was diagnosed with autoimmune enteropathy, and treatment consisted of an extended corticosteroid taper, with the resolution of symptoms.