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1.
Br J Cancer ; 130(9): 1552-1560, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38461170

RESUMEN

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.


Asunto(s)
Autoanticuerpos , Biomarcadores , Colitis Ulcerosa , Inhibidores de Puntos de Control Inmunológico , Integrinas , Humanos , Masculino , Femenino , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/sangre , Persona de Mediana Edad , Integrinas/inmunología , Integrinas/antagonistas & inhibidores , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Biomarcadores/sangre , Adulto , Antígenos de Neoplasias/inmunología , Colitis/inducido químicamente , Colitis/inmunología
2.
J Pathol ; 261(1): 28-42, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37345534

RESUMEN

The prognosis of gallbladder cancer (GBC) remains poor, and a better understanding of GBC molecular mechanisms is important. Genome sequencing of human GBC has demonstrated that loss-of-function mutations of E74-like ETS transcription factor 3 (ELF3) are frequently observed, with ELF3 considered to be a tumour suppressor in GBC. To clarify the underlying molecular mechanisms by which ELF3 suppresses GBC development, we performed in vivo analysis using a combination of autochthonous and allograft mouse models. We first evaluated the clinical significance of ELF3 expression in human GBC tissues and found that low ELF3 expression was associated with advanced clinical stage and deep tumour invasion. For in vivo analysis, we generated Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3f/f (KPCE) mice and Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3wt/wt (KPC) mice as a control and analysed their gallbladders histologically. KPCE mice developed larger papillary lesions in the gallbladder than those developed by KPC mice. Organoids established from the gallbladders of KPCE and KPC mice were analysed in vitro. RNA sequencing showed upregulated expression of epiregulin (Ereg) in KPCE organoids, and western blotting revealed that EGFR/mechanical targets of rapamycin complex 1 (mTORC1) were upregulated in KPCE organoids. In addition, ChIP assays on Elf3-overexpressing KPCE organoids showed that ELF3 directly regulated Ereg. Ereg deletion in KPCE organoids (using CRISPR/Cas9) induced EGFR/mTORC1 downregulation, indicating that ELF3 controlled EGFR/mTORC1 activity through regulation of Ereg expression. We also generated allograft mouse models using KPCE and KPC organoids and found that KPCE organoid allograft tumours exhibited poorly differentiated structures with mTORC1 upregulation and mesenchymal phenotype, which were suppressed by Ereg deletion. Furthermore, EGFR/mTORC1 inhibition suppressed cell proliferation and epithelial-mesenchymal transition in KPCE organoids. Our results suggest that ELF3 suppresses GBC development via downregulation of EREG/EGFR/mTORC1 signalling. EGFR/mTORC1 inhibition is a potential therapeutic option for GBC with ELF3 mutation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Neoplasias de la Vesícula Biliar , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas p21(ras)/genética , Epirregulina/genética , Epirregulina/metabolismo , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/patología , Regulación hacia Abajo , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas Proto-Oncogénicas c-ets/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética
3.
Hepatol Res ; 54(8): 719-726, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38884591

RESUMEN

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI-induced liver injury) as an immune-related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R-value is useful in deciding treatment strategies for ICI-induced liver injury. Histologically, the most representative feature is an acute hepatitis-like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8-positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non-obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI-induced cholangitis are classified as non-hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI-induced liver injury.

4.
Gastroenterology ; 163(6): 1613-1629.e12, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36075324

RESUMEN

BACKGROUND & AIMS: The Notch signaling pathway is an important pathway in the adult pancreas and in pancreatic ductal adenocarcinoma (PDAC), with hairy and enhancer of split-1 (HES1) as the core molecule in this pathway. However, the roles of HES1 in the adult pancreas and PDAC formation remain controversial. METHODS: We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions. RESULTS: The loss of Hes1 expression in the adult pancreas did not induce phenotypic alterations. However, regeneration was impaired after caerulein-induced acute pancreatitis. In a pancreatic intraepithelial neoplasia (PanIN) mouse model, PanINs rarely formed when Hes1 deletion preceded PanIN formation, whereas more PanINs were formed when Hes1 deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced by Hes1 deletion after PanIN/PDAC development; therefore, Hes1 promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that Hes1 deletion enhanced epithelial-to-mesenchymal transition via Muc5ac up-regulation in PDAC progression. The results indicated that HES1 is not required for maintaining the adult pancreas under normal conditions, but is important for regeneration during recovery from pancreatitis; moreover, Hes1 plays different roles, depending on the tumor condition. CONCLUSIONS: Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.


Asunto(s)
Carcinoma in Situ , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pancreatitis , Animales , Ratones , Enfermedad Aguda , Pancreatitis/inducido químicamente , Pancreatitis/genética , Páncreas , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Factor de Transcripción HES-1/genética , Neoplasias Pancreáticas
6.
Histopathology ; 73(2): 247-258, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29660164

RESUMEN

AIMS: This study aimed to identify the pathological features of high-grade PanIN that presents with imaging-detectable abnormalities. METHODS AND RESULTS: Ten cases of isolated, main-duct, high-grade PanIN as the primary clinical presentation were identified. All patients presented with stenosis of the main pancreatic duct, with two being associated with extensive upstream duct dilatation (>5 mm in diameter). Pancreatic juice cytology suggested adenocarcinoma in all seven cases examined. In resected specimens, high-grade PanIN was present chiefly in the main pancreatic duct, with longitudinal extension ranging between 3 and 40 mm in length (median = 18 mm). In four cases, in which hypoechoic or hypovascular masses were observed on imaging, radiopathology correlations suggested that they represented parenchymal atrophy and subsequent fibrosis around affected ducts, but not invasive malignancy. On immunohistochemistry, the loss of p16 expression was found in five (50%), p53 overexpression in two (20%) and loss of SMAD4 expression in none (0%). KRAS mutations were detected in nine cases, with two dominant clones being found in three by ultrasensitive droplet digital polymerase chain reaction, suggesting the genetic heterogeneity of dysplastic cells composing individual lesions. Mutant GNAS was also observed in one case. CONCLUSIONS: Isolated high-grade PanIN may present with pancreatic duct stenosis. Therefore, intensive investigations including pancreatic juice cytology will be required for patients with unexplained pancreatic duct stenosis. The abnormal expression of p53 and SMAD4 is infrequent, while GNAS may be mutated in premalignant lesions mainly affecting the main pancreatic duct, similar to KRAS.


Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma in Situ/patología , Detección Precoz del Cáncer/métodos , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Anciano , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Cromograninas/genética , Constricción Patológica/patología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética
7.
Nihon Shokakibyo Gakkai Zasshi ; 115(6): 563-572, 2018.
Artículo en Japonés | MEDLINE | ID: mdl-29887592

RESUMEN

A referring hospital diagnosed a 57-year-old man with a pancreatic head mass. The initial endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) was inconclusive because of the small sample size. Endoscopic ultrasonography elastography (EUS-EG) and contrast-enhanced harmonic endoscopic ultrasonography (CE-EUS), conducted at our institute, raised the possibility of mass-forming pancreatitis or autoimmune pancreatitis (AIP). A repeat EUS-FNA revealed inflammatory changes, including a neutrophilic duct injury suggestive of type 2 AIP. The pancreatic lesion responded well to the steroid therapy. The present case suggests that EUS-EG and CE-EUS may be useful for diagnostic exclusion of pancreatic cancers, and the combined use of EUS-EG and CE-EUS, with EUS-FNA, may help characterize inflammatory pancreatic lesions.


Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Diagnóstico por Imagen de Elasticidad , Endosonografía , Pancreatitis/diagnóstico , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas
13.
Hepatol Res ; 45(7): 814-7, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25088083

RESUMEN

Acetaminophen (paracetamol), a widely used antipyretic/analgesic, is a well-known agent causing acute hepatic injury. Whereas most cases are caused by its intrinsic hepatotoxicity, idiosyncratic hepatitis by the allergic mechanism is extremely rare. We herein report a case of late-onset acetaminophen-induced allergic hepatitis with progression to chronicity. This unique case extends the spectrum of acetaminophen-induced liver injury. Clinicians should be aware of this unusual clinical manifestation. The mechanism underlying the immunological reaction to acetaminophen remains to be elucidated.

14.
J Gastroenterol ; 58(8): 778-789, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37310456

RESUMEN

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) possess autoantibodies against biliary epithelial cells. However, the target molecules remain unknown. METHODS: The sera of patients with PSC and controls were subjected to enzyme-linked immunosorbent assays to detect autoantibodies using recombinant integrin proteins. Integrin αvß6 expression in the bile duct tissues was examined using immunofluorescence. The blocking activity of the autoantibodies was examined using solid-phase binding assays. RESULTS: Anti-integrin αvß6 antibodies were detected in 49/55 (89.1%) patients with PSC and 5/150 (3.3%) controls (P < 0.001), with a sensitivity and specificity of 89.1% and 96.7%, respectively, for PSC diagnosis. When focusing on the presence or absence of IBD, the proportion of the positive antibodies in PSC with IBD was 97.2% (35/36) and that in PSC alone was 73.7% (14/19) (P = 0.008). Integrin αvß6 was expressed in bile duct epithelial cells. Immunoglobulin (Ig)G from 15/33 patients with PSC blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif. CONCLUSIONS: Autoantibodies against integrin αvß6 were detected in most patients with PSC; anti-integrin αvß6 antibody may serve as a potential diagnostic biomarker for PSC.


Asunto(s)
Colangitis Esclerosante , Enfermedades Inflamatorias del Intestino , Humanos , Autoanticuerpos , Células Epiteliales/metabolismo , Ensayo de Inmunoadsorción Enzimática
15.
Pancreas ; 51(9): 1258-1262, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37078954

RESUMEN

ABSTRACT: Pancreatic cancer and its rare subtype, acinar cell carcinoma (PACC), frequently harbor germline and/or somatic variants in homologous recombinant genes, including BRCA2. Individuals possessing germline pathogenic BRCA2 variants are known to have a higher risk of developing various cancers, including breast, ovarian, pancreatic, and bile duct cancers (BDCs). It has been reported that tumors positive for BRCA1/2 variants are sensitive to platinum-based agents. Thus, BRCA1/2 germline testing and comprehensive genomic profiling are recommended to identify genetic susceptibility and to indicate optimal targeted therapy. Here, we report familial occurrence of PACC and BDC associated with BRCA2; both tumors responded exceptionally well to platinum-based chemotherapy. A 37-year-old man was diagnosed with unresectable PACC with a germline BRCA2 variant. He was treated with oxaliplatin-containing chemotherapy and conversion surgery, and remains alive without tumor recurrence after more than 36 months. His father also possessed the identical germline BRCA2 variant and was diagnosed with extrahepatic BDC with lymph node metastases. The tumors showed marked shrinkage upon treatment with cisplatin-containing chemotherapy. Our cases underscore the importance of comprehensive genomic profiling and genetic testing for BRCA2 to ensure optimal therapeutic options for PACC as well as to identify high-risk individuals with various cancers in the family.


Asunto(s)
Neoplasias de los Conductos Biliares , Carcinoma de Células Acinares , Neoplasias Pancreáticas , Masculino , Humanos , Adulto , Proteína BRCA2/genética , Proteína BRCA1/genética , Platino (Metal)/uso terapéutico , Carcinoma de Células Acinares/tratamiento farmacológico , Recurrencia Local de Neoplasia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Mutación de Línea Germinal , Predisposición Genética a la Enfermedad , Células Germinativas , Neoplasias Pancreáticas
16.
Diagnostics (Basel) ; 11(5)2021 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-33923064

RESUMEN

Autoimmune pancreatitis (AIP) is a pancreatic manifestation of an IgG4-related disease (IgG4-RD). AIP lacks disease-specific biomarkers, and therefore, it is difficult to distinguish AIP from malignancies, especially pancreatic cancer. In this review, we have summarized the latest findings on potential diagnostic biomarkers for AIP. Many investigations have been conducted, but no specific biomarkers for AIP are identified. Therefore, further studies are required to identify accurate diagnostic biomarkers for AIP.

17.
Pancreas ; 50(3): 399-404, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33835972

RESUMEN

OBJECTIVES: This study aimed to evaluate the pathological features and imaging findings of pancreatic carcinoma in situ (PCIS). METHODS: Twenty patients with PCIS were categorized as flat (F) (n = 6) and low papillary (LP) (n = 14) types. RESULTS: None of F type and 8 (57%) of 14 with LP type lesions showed intraductal infiltrations of the main pancreatic duct (MPD) greater than 10 mm. None of F type and 3 (21%) of 14 with LP type lesions showed skip lesions in the MPD. Magnetic resonance cholangiopancreatography showed irregular MPD stenoses in 5 (83%) of 6 with F and 13 (100%) of 13 with LP type lesions. Magnetic resonance cholangiopancreatography determined that the median lengths of the irregular MPD stenoses were 3.6 mm for F, and 11.6 mm for LP type lesions. Endoscopic retrograde cholangiopancreatography determined that the median lengths of the irregular MPD stenoses were 2.8 mm for F, and 14.3 mm for LP type lesions. Pancreatic cancer recurrences limited to the remnant pancreas occurred in 2 patients with LP type lesions. CONCLUSIONS: In LP type PCIS, intraductal infiltration of the MPD occurs frequently. There may be multiple lesions, and lesions may recur in the remnant pancreas. Long-term strict follow-up assessments should be implemented for LP type PCIS.


Asunto(s)
Carcinoma in Situ/diagnóstico por imagen , Pancreatocolangiografía por Resonancia Magnética/métodos , Páncreas/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Carcinoma in Situ/mortalidad , Carcinoma in Situ/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Páncreas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de Supervivencia
18.
J Hepatobiliary Pancreat Sci ; 28(9): 788-797, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34174030

RESUMEN

BACKGROUND/PURPOSE: The purpose of the present study was to investigate the possibility of reducing clinical impacts of acute necrotic collection (ANC) on patients with acute pancreatitis (AP) using recombinant human soluble thrombomodulin (rTM). METHODS: In this retrospective multicenter study, 233 consecutive AP patients with ANC and acute peripancreatic fluid collection (APFC) from 2012 to 2016 were enrolled. To assess clinical impacts of ANC, severity on admission (JPN score, JPN CT grade, and Modified CT severity index), development of walled-off necrosis (WON), imaging costs for follow-up, and mortality were recorded. Finally, we investigated whether rTM could reduce the clinical impacts, adjusting the severity using propensity analysis with Inverse probability of treatment weighting. RESULTS: Patients with ANC developed WON with higher ratio than APFC (58/98 [59.2%] vs 20/135 [14.8%], OR = 8.3, P < .01]. Severity on admission and imaging costs for follow-up in ANC patients were significantly higher than those in APFC (P < .01). However, regarding mortality, there was no significant difference between patients with ANC and APFC (P = .41). Adjusting severity, it was revealed that rTM administration significantly reduced the risk of ANC developed WON (OR = 0.23, P = .01). CONCLUSIONS: While ANC had a higher clinical impact than that of APFC, we found that early administration of rTM may reduce the impact.


Asunto(s)
Pancreatitis , Trombomodulina , Enfermedad Aguda , Humanos , Necrosis , Estudios Retrospectivos
19.
Mol Clin Oncol ; 11(5): 488-492, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31602301

RESUMEN

The current study indicates the case of intracholecystic papillary neoplasm (ICPN) protruding into the common bile duct (CBD) without superficial spread. A 58-year-old woman presented to hospital with a fever that lasted for three days. Laboratory tests revealed elevated hepatobiliary enzyme levels. CT, MRI and endoscopic ultrasonography revealed a polypoid, papillary tumor inside the gallbladder cavity, which also extended to the CBD. On peroral cholangioscopy, a papillary tumor with mucin production was found at the middle bile duct. Biliary biopsy and bile cytology indicated adenocarcinoma. Based on a diagnosis of ICPN extending to the CBD, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy and gallbladder bed resection. However, pathological examination revealed that the ICPN was confined to the gallbladder and cystic duct, whereas the CBD was tumor-free. The present case indicates that when ICPN increases in size, it may protrude into the CBD due to an increased intracholecystic pressure, which increases the risk of overestimation of tumor extension and may result in unnecessary additional bile duct resection.

20.
Intern Med ; 57(20): 2945-2949, 2018 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-29877276

RESUMEN

A 90-year-old man was referred to our hospital because of a positive fecal occult blood test. Colonoscopy revealed a lesion with multiple nodules covered with abundant mucus at the hepatic flexure. Computed tomography showed a dilated appendix attached distally to the hepatic flexure. Right hemicolectomy was performed, and the pathological examination revealed a mucinous appendiceal adenocarcinoma infiltrating the hepatic flexure without pseudomyxoma peritonei. The patient is doing well without recurrence 12 months postoperatively. Extraperitoneal drainage of the malignant ascites caused by the fistula may allow for an early diagnosis, while also making it possible to successfully resect the lesion, thus resulting in a favorable outcome.


Asunto(s)
Adenocarcinoma Mucinoso/complicaciones , Adenocarcinoma Mucinoso/cirugía , Neoplasias del Apéndice/complicaciones , Neoplasias del Apéndice/cirugía , Fístula/etiología , Recurrencia Local de Neoplasia/complicaciones , Recurrencia Local de Neoplasia/cirugía , Adenocarcinoma Mucinoso/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Apéndice/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/fisiopatología , Pronóstico , Resultado del Tratamiento
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