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Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple profibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor nuclear factor of activated T cells 1 (NFAT1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key profibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/--deficient mice subjected to bleomycin injury demonstrated improved survival and protection from lung fibrosis and collagen deposition as compared with bleomycin-injured wild-type (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WTâWT and Nfat1-/-âWT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibroprotection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/platelet-derived growth factor receptor alpha (PDGFRα)pos MCs demonstrated decreased MC numbers, proliferation [↓ cyclin D1 and 5-ethynyl-2'-deoxyuridine (EdU) incorporation], myofibroblast differentiation [↓ α-smooth muscle actin (α-SMA)], and survival (↓ Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed using pharmacological and genetic inhibition. Our findings identify NFAT1 as a critical mediator of profibrotic processes, contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.NEW & NOTEWORTHY Idiopathic pulmonary fibrosis (IPF) is a fatal disease with hallmarks of fibroblastic foci and exuberant matrix deposition, unknown etiology, and ineffective therapies. Several profibrotic/proinflammatory pathways are implicated in accelerating tissue remodeling toward a honeycombed end-stage disease. NFAT1 is a transcriptional factor activated in IPF tissues. Nfat1-deficient mice subjected to chronic injury are protected against fibrosis independent of immune influxes, with suppression of profibrotic mesenchymal phenotypes including proliferation, differentiation, resistance to apoptosis, and autotaxin-related migration.
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Fibrose Pulmonar Idiopática , Pulmão , Animais , Humanos , Camundongos , Bleomicina/farmacologia , Diferenciação Celular/genética , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
We report a case of unresectable advanced esophageal cancer with an esophageal fistula that was treated with pembrolizumab plus CDDP plus 5-FU therapy and the fistula was closed. A 73-year-old male was diagnosed with cervical-upper thoracic esophageal cancer and esophago-bronchial fistula on CT and esophagogastroduodenoscopy. He underwent chemotherapy containing pembrolizumab. The fistula was closed after 4 cycles and oral intake became possible. Six months have passed since the first visit and chemotherapy is ongoing. The prognosis of esophago-bronchial fistula is extremely poor, and there is no established treatment, including fistula closure. Chemotherapy containing immune checkpoint inhibitors could considered to be expected not only for local control but also for long-term survival.
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Fístula Brônquica , Fístula Esofágica , Neoplasias Esofágicas , Masculino , Humanos , Idoso , Fístula Brônquica/etiologia , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fístula Esofágica/tratamento farmacológico , Fístula Esofágica/etiologia , CisplatinoRESUMO
BACKGROUND: Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predominant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon monoxide (CO) is a critical endogenous signaling transducer with known anti-inflammatory and anti-fibrotic effects but its therapeutic potential in CLAD remains to be fully elucidated. METHODS: Here we investigate the effect of inhaled CO in modulating chronic lung allograft rejection pathology in a murine orthotopic lung transplant model of BO (B6D2F1/JâDBA/2J). Additionally, the effects of CO on the activated phenotype of mesenchymal cells isolated from human lung transplant recipients with CLAD were studied. RESULTS: Murine lung allografts treated with CO (250 ppm × 30 minutes twice daily from days 7 to 40 post-transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytometry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels comparable to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm × 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and ß-catenin expression as well as an inhibitory effect on ERK1/2 MAPK, and mTORC1/2 signaling. Sildenafil, a phosphodiesterase 5 inhibitor, partially mimicked the effects of CO on CLAD mesenchymal cells and was partially effective in decreasing collagen deposition in murine allografts, suggesting the contribution of cGMP-dependent and -independent mechanisms in mediating the effect of CO. CONCLUSION: These results suggest a potential role for CO in alleviating allograft fibrosis and mitigating chronic rejection pathology post-lung transplant.
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Bronquiolite Obliterante , Transplante de Pulmão , Humanos , Animais , Camundongos , Monóxido de Carbono , Aloenxertos/patologia , Transplante de Pulmão/efeitos adversos , Fibrose , Pulmão/patologia , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/prevenção & controle , Colágeno , Rejeição de EnxertoRESUMO
Morgagni hernia is a rare form of diaphragmatic hernia. It is located at the anterior edge of the diaphragm and does not have an anterior rim. It is difficult to achieve a secure closure and maintain the tension of closure with laparoscopic surgery. We have performed laparoscopic resection of colorectal cancer and hernia repair simultaneously. An 89-year-old woman underwent laparoscopic hernia repair and ileocecal resection simultaneously. Regarding hernia repair, we considered that it would be difficult to use a mesh from the viewpoint of infection due to the colectomy. Therefore, we have done the extra-abdominal suture method. After laparoscopic ileocecal resection, a small incision was made in the epigastric region, and Morgagni hernia repair was performed with extra-abdominal sutures. She had no recurrence of either colon cancer or hernia for 22 months post-operatively. The extra-abdominal suture method can provide secure closure of the hernia orifice for Morgagni hernia.
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Distal gastrectomy (DG) with lymph node dissection is considered as the standard treatment for gastric cancer. Ischemic necrosis of the gastric remnant is a rare but serious complication of DG that requires careful consideration for early diagnosis and treatment to lower the associated mortality rate. A 71-year-old male presented to our hospital with hyperglycemia and was evaluated for suspected diabetes. The patient's medical history was otherwise unremarkable. Computed tomography (CT) revealed a thickening of the stomach wall, with follow-up esophagogastroduodenoscopy revealing type 3 gastric cancer in the greater curvature of the antrum. Biopsy specimen confirmed a pathological diagnosis of mucinous adenocarcinoma, with a clinical diagnosis of cT3N0M0, cStageIIB. An open DG with Billroth I reconstruction was performed, without incident. On postoperative day 1, the patient developed a high fever, abdominal pain, and elevated white blood cell count (12,200/µL). On postoperative day 2, his C-reactive protein level increased to >30 mg/dL. CT revealed an edematous thickening of the stomach wall, with poor mucosal enhancement of the remnant stomach and thinning of the anastomosis wall, with air nearby. Emergency surgery was performed for suspected leakage. Intraoperative findings showed no evidence of leakage. Intraoperative endoscopy revealed a necrotic gastric remnant, and we performed a total remnant gastrectomy with Roux-en Y reconstruction. The patient was discharged in a stable condition, 25 days after the first surgery. Although ischemic necrosis of the gastric remnant is a rare complication, its possibility should be carefully considered after DG, for early diagnosis and treatment.
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In this study, we demonstrate that forkhead box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, was retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as key players in lung allograft remodeling and fibrosis. Using Foxf1-tdTomato BAC (Foxf1-tdTomato) and Foxf1-tdTomato Col1a1-GFP mice, we show that Lin-Foxf1+ cells encompassed the stem cell antigen 1+CD34+ (Sca1+CD34+) subset of collagen 1-expressing mesenchymal cells (MCs) with a capacity to generate CFU and lung epithelial organoids. Histologically, FOXF1-expressing MCs formed a 3D network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA-Seq confirmed distinct transcriptional signatures of Foxf1+ and Foxf1- MCs, with Foxf1-expressing cells delineated by their high expression of the transcription factor glioma-associated oncogene 1 (Gli1) and low expression of integrin α8 (Itga), versus other collagen-expressing MCs. FOXF1+Gli1+ MCs showed proximity to Sonic hedgehog-expressing (Shh-expressing) bronchial epithelium, and mesenchymal expression of Foxf1 and Gli1 was found to be dependent on paracrine Shh signaling in epithelial organoids. Using a murine lung transplant model, we show dysregulation of epithelial-mesenchymal SHH/GLI1/FOXF1 crosstalk and expansion of this specific peribronchial MC population in chronically rejecting fibrotic lung allografts.
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Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/metabolismo , Transplante de Pulmão , Células-Tronco Mesenquimais/metabolismo , Alvéolos Pulmonares/metabolismo , Fibrose Pulmonar/metabolismo , Aloenxertos , Animais , Doença Crônica , Fatores de Transcrição Forkhead/genética , Rejeição de Enxerto/genética , Rejeição de Enxerto/patologia , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Transgênicos , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologiaRESUMO
Black esophagus is a rare condition referred from acute necrosis of the esophagus, with characteristic endoscopic finings of circumferential black appearance of the mucosa. Black esophagus is associated with systemic dysfunction, such as massive bleeding, or severe dehydration. Although the duodenal mucosa is also susceptible to ischemia, reports of black esophagus with duodenal involvement, such as bleeding or perforation, are limited. Here, we present the case of a 61-year-old male who developed the typical black esophagus with duodenal involvement following severe dehydration. The patient was treated conservatively and recovered from the acute phase. In the chronic stage, transthoracic esophagectomy was performed because of esophageal stricture, and the patient then returned to his daily life. Although the etiological mechanism of acute esophageal necrosis is unknown, it is thought to be associated with the presence of an underlying severe systemic condition. Our case is not exceptional for these systemic conditions demonstrating extreme dehydration. However, it remains unclear why our case showed duodenal involvement. Although the reason is unknown, the presence of a celiac aneurysm located near the bifurcation to duodenal blood flow might explain the impaired blood flow to the duodenum.
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Duodeno , Estenose Esofágica , Doença Aguda , Humanos , Masculino , Pessoa de Meia-Idade , NecroseRESUMO
Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.
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Interleucina-6 , Transplante de Pulmão , Aloenxertos , Animais , Fibrose , Humanos , Pulmão/patologia , Transplante de Pulmão/efeitos adversos , Camundongos , Receptores de Interleucina-6RESUMO
Forkhead box F1 (FOXF1) is a lung embryonic mesenchyme-associated transcription factor that demonstrates persistent expression into adulthood in mesenchymal stromal cells. However, its biologic function in human adult lung-resident mesenchymal stromal cells (LR-MSCs) remain to be elucidated. Here, we demonstrate that FOXF1 expression acts as a restraint on the migratory function of LR-MSCs via its role as a novel transcriptional repressor of autocrine motility-stimulating factor Autotaxin (ATX). Fibrotic human LR-MSCs demonstrated lower expression of FOXF1 mRNA and protein, compared to non-fibrotic controls. RNAi-mediated FOXF1 silencing in LR-MSCs was associated with upregulation of key genes regulating proliferation, migration, and inflammatory responses and significantly higher migration were confirmed in FOXF1-silenced LR-MSCs by Boyden chamber. ATX is a secreted lysophospholipase D largely responsible for extracellular lysophosphatidic acid (LPA) production, and was among the top ten upregulated genes upon Affymetrix analysis. FOXF1-silenced LR-MSCs demonstrated increased ATX activity, while mFoxf1 overexpression diminished ATX expression and activity. The FOXF1 silencing-induced increase in LR-MSC migration was abrogated by genetic and pharmacologic targeting of ATX and LPA1 receptor. Chromatin immunoprecipitation analyses identified three putative FOXF1 binding sites in the 1.5 kb ATX promoter which demonstrated transcriptional repression of ATX expression. Together these findings identify FOXF1 as a novel transcriptional repressor of ATX and demonstrate that loss of FOXF1 promotes LR-MSC migration via the ATX/LPA/LPA1 signaling axis.
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Fatores de Transcrição Forkhead/metabolismo , Pulmão/metabolismo , Lisofosfolipídeos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Sítios de Ligação/genética , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Imunoprecipitação da Cromatina , Citocinas/metabolismo , Fatores de Transcrição Forkhead/genética , Ontologia Genética , Inativação Gênica , Humanos , Pulmão/citologia , Camundongos , Diester Fosfórico Hidrolases/genética , Regiões Promotoras Genéticas , Interferência de RNA , Transdução de Sinais/genética , Ativação Transcricional/genética , Regulação para CimaRESUMO
Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 â parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into µMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory µ-chain (µs) double-KO (AID-/-µs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.
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Aloenxertos/imunologia , Aloenxertos/patologia , Imunidade Humoral/imunologia , Animais , Fibrose , Rejeição de Enxerto/imunologia , Pulmão/patologia , Transplante de Pulmão/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Órgãos , FenótipoRESUMO
BACKGROUND: The clinical significance of lymph node (LN) status determined by preoperative 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) has not been investigated in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (NCRT) followed by surgery (trimodal therapy). METHODS: This study reviewed 132 consecutive patients with ESCC who had been preoperatively evaluated using FDG-PET before and after NCRT to analyze associations among LN status according to PET findings, pathologic LN metastasis, and prognosis of ESCC after trimodal therapy. RESULTS: Lymph nodes that were PET-positive both before and after NCRT comprised significant predictive markers of pathologic LN metastasis in station-by-station analyses (sensitivity, specificity, and accuracy respectively 41.7%, 95.0%, and 92.7% before, and 12.0%, 99.4%, and 95.6% after NCRT; both p < 0.0001). The numbers of LNs evaluated using PET before and after NCRT were significantly associated with those of pathologic metastatic LNs. Uni- and multivariable analyses selected LN status determined by PET before NCRT as a significant independent predictor of both recurrence-free [LN-negative vs LN-positive: hazard ratio (HR) 1.90; 95% confidence interval (CI) 1.02-3.23; p = 0.045] and overall survival (HR 2.62; 95% CI 1.29-5.30; p = 0.01). CONCLUSIONS: The status of LN determined by preoperative FDG-PET is significantly associated with pathologic LN status and the prognosis of ESCC with trimodal therapy. Thus, FDG-PET is a useful diagnostic tool for preoperative prediction of pathologic LN metastasis and survival among patients with ESCC.
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Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia/mortalidade , Neoplasias Esofágicas/mortalidade , Esofagectomia/mortalidade , Linfonodos/patologia , Terapia Neoadjuvante/mortalidade , Tomografia por Emissão de Pósitrons/métodos , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Fluordesoxiglucose F18 , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
The current study aimed to understand the developmental mechanisms regulating bud tip progenitor cells in the human fetal lung, which are present during branching morphogenesis, and to use this information to induce a bud tip progenitor-like population from human pluripotent stem cells (hPSCs) in vitro. We identified cues that maintained isolated human fetal lung epithelial bud tip progenitor cells in vitro and induced three-dimensional hPSC-derived organoids with bud tip-like domains. Bud tip-like domains could be isolated, expanded, and maintained as a nearly homogeneous population. Molecular and cellular comparisons revealed that hPSC-derived bud tip-like cells are highly similar to native lung bud tip progenitors. hPSC-derived epithelial bud tip-like structures survived in vitro for over 16 weeks, could be easily frozen and thawed, maintained multilineage potential, and successfully engrafted into the airways of immunocompromised mouse lungs, where they persisted for up to 6 weeks and gave rise to several lung epithelial lineages.
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Feto , Pulmão , Células-Tronco Pluripotentes , Animais , Feto/citologia , Feto/metabolismo , Xenoenxertos , Humanos , Pulmão/citologia , Pulmão/embriologia , Camundongos , Camundongos Transgênicos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/transplanteRESUMO
Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and ß-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear ß-catenin expression that was dependent on autocrine ATX secretion and LPA signaling. We found that NFAT1 upstream of ATX regulated expression of ATX as well as ß-catenin. Silencing NFAT1 in BOS MCs suppressed ATX expression, and sustained overexpression of NFAT1 increased ATX expression and activity in non-fibrotic MCs. LPA signaling induced NFAT1 nuclear translocation, suggesting that autocrine LPA synthesis promotes NFAT1 transcriptional activation and ATX secretion in a positive feedback loop. In an in vivo mouse orthotopic lung transplant model of BOS, antagonism of the LPA receptor (LPA1) or ATX inhibition decreased allograft fibrosis and was associated with lower active ß-catenin and dephosphorylated NFAT1 expression. Lung allografts from ß-catenin reporter mice demonstrated reduced ß-catenin transcriptional activation in the presence of LPA1 antagonist, confirming an in vivo role for LPA signaling in ß-catenin activation.
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Comunicação Autócrina , Lisofosfolipídeos/fisiologia , Fibrose Pulmonar/metabolismo , beta Catenina/metabolismo , Aloenxertos , Animais , Bronquiolite Obliterante/metabolismo , Células Cultivadas , Colágeno/biossíntese , Feminino , Rejeição de Enxerto/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Transplante de Pulmão , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Fatores de Transcrição NFATC/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Ativação TranscricionalRESUMO
Anal metastasis of colorectal cancer is rare, and no standardized effective therapeutic strategy exists. We report a case of abdominoperineal resection for anal metastasis of rectal cancer. A 65-year-old man underwent laparoscopic low anterior resection for rectal cancer in August 2013. Histopathological examination revealed a moderately differentiated adenocarcinoma( tub2, pSS, ly3, v2, pN1, H0, P0, M0, Stage III a, Cur A). In February 2015, he complained of anal discomfort, and tumor markers were elevated. Enhanced CT revealed a 15-mm high-density solid tumor in the anal canal. The results of needle biopsy indicated a moderately differentiated adenocarcinoma. This tumor was suspected to be metastasis from rectal cancer, and we performed abdominoperineal resection. Histopathological examination revealed a moderately differentiated adenocarcinoma, which was the same histological type as the primary rectal cancer and was covered with normal anal epithelium. Collectively, the findings indicated anal metastasis from rectal cancer. The patient is alive without recurrence for 18 months after resection. Anal metastasis should be considered as a differential diagnosis in patients with anal discomfort who have a history of colon/rectal cancer. Abdominoperineal resection may be an effective treatment modality for this condition.
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Adenocarcinoma/cirurgia , Neoplasias do Ânus/cirurgia , Neoplasias Peritoneais/cirurgia , Neoplasias Retais/patologia , Adenocarcinoma/secundário , Idoso , Neoplasias do Ânus/secundário , Humanos , Metástase Linfática , Masculino , Neoplasias Peritoneais/secundário , Prognóstico , Neoplasias Retais/cirurgiaRESUMO
Bronchiolitis obliterans is the leading cause of chronic graft failure and long-term mortality in lung transplant recipients. Here, we used a novel murine model to characterize allograft fibrogenesis within a whole-lung microenvironment. Unilateral left lung transplantation was performed in mice across varying degrees of major histocompatibility complex mismatch combinations. B6D2F1/J (a cross between C57BL/6J and DBA/2J) (Haplotype H2b/d) lungs transplanted into DBA/2J (H2d) recipients were identified to show histopathology for bronchiolitis obliterans in all allogeneic grafts. Time course analysis showed an evolution from immune cell infiltration of the bronchioles and vessels at day 14, consistent with acute rejection and lymphocytic bronchitis, to subepithelial and intraluminal fibrotic lesions of bronchiolitis obliterans by day 28. Allografts at day 28 showed a significantly higher hydroxyproline content than the isografts (33.21 ± 1.89 versus 22.36 ± 2.33 µg/mL). At day 40 the hydroxyproline content had increased further (48.91 ± 7.09 µg/mL). Flow cytometric analysis was used to investigate the origin of mesenchymal cells in fibrotic allografts. Collagen I-positive cells (89.43% ± 6.53%) in day 28 allografts were H2Db positive, showing their donor origin. This novel murine model shows consistent and reproducible allograft fibrogenesis in the context of single-lung transplantation and represents a major step forward in investigating mechanisms of chronic graft failure.
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Bronquiolite Obliterante/patologia , Rejeição de Enxerto/patologia , Transplante de Pulmão/efeitos adversos , Pulmão/patologia , Células-Tronco Mesenquimais/patologia , Animais , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/imunologia , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Pulmão/imunologia , Linfócitos/imunologia , Linfócitos/patologia , Macrófagos/imunologia , Macrófagos/patologia , Células-Tronco Mesenquimais/imunologia , CamundongosRESUMO
BACKGROUND: In T4 esophageal cancer with tracheobronchial invasion, an esophagorespiratory fistula (ERF) often occurs during or after chemoradiotherapy. We have performed esophageal bypass operations prior to definitive chemoradiotherapy for these patients to increase the chemoradiotherapy completion rate by minimizing the potential effect of an ERF. The aim of this study was to examine the clinical outcome of esophageal bypass surgery prior to chemoradiotherapy. METHODS: Between 1997 and 2010, 17 patients underwent esophageal bypass surgery followed by definitive chemoradiotherapy for esophageal cancer with tracheobronchial invasion (bypass group). Ten patients in the same circumstances were treated with chemoradiotherapy alone (control group). Overall survival, the clinical effect of chemoradiotherapy, the ERF incidence rate, and the safety of esophageal bypass surgery were assessed. RESULTS: The overall response rate to chemoradiotherapy was 64.7% in the bypass group and 90.0% in the control group. Except for 2 patients with ERF at initial diagnosis, 4 (26.7%) of the 15 patients developed ERF in the bypass group, and 3 (30.0%) of the 10 patients developed ERF in the control group during or after chemoradiotherapy. The 2-year and 3-year overall survival rates were 17.6% and 17.6% in the bypass group and 20.0% and 0% in the control group, respectively (p = 0.924); long-term survival of more than 3 years was seen only in the bypass group. CONCLUSIONS: Esophageal bypass surgery prior to definitive chemoradiotherapy could be performed safely, and this strategy contributed to long-term survival in the patients who achieved a good response to chemoradiotherapy but developed an ERF.
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Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/métodos , Neoplasias Esofágicas/terapia , Esôfago/cirurgia , Terapia Neoadjuvante/métodos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Brônquicas/mortalidade , Neoplasias Brônquicas/secundário , Neoplasias Brônquicas/terapia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Estudos de Casos e Controles , Quimiorradioterapia/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Fístula Esofágica/prevenção & controle , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Valores de Referência , Fístula do Sistema Respiratório/prevenção & controle , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Taxa de Sobrevida , Neoplasias da Traqueia/mortalidade , Neoplasias da Traqueia/secundário , Neoplasias da Traqueia/terapia , Resultado do TratamentoRESUMO
Poly (ADP-ribose) polymerase (PARP) plays a critical role in responding to DNA damage, by activating DNA repair pathways responsible for cellular survival. Inhibition of PARP is used to treat certain solid cancers, such as breast and ovarian cancers. However, its effectiveness with other solid cancers, such as esophageal squamous cell carcinoma (ESCC), has not been clarified. We evaluated the effects of PARP inhibition on the survival of human esophageal cancer cells, with a special focus on the induction and repair of DNA double-strand breaks. The effects were monitored by colony formation assays and DNA damage responses, with immunofluorescence staining of γH2AX and RAD51. We found that PARP inhibition synergized with cisplatin, and the cells were highly sensitive, in a similar manner to the combination of cisplatin and 5-fluorouracil (5-FU). Comparable increases in RAD51 foci formation were observed after each combined treatment with cisplatin and either 3-aminobenzamide (3-AB) or 5-FU in three human esophageal cancer cell lines, TE11, TE14, and TE15. In addition, decreasing the amount of RAD51 by RNA interference rendered the TE11 cells even more hypersensitive to these treatments. Our findings suggested that the homologous recombinational repair pathway may be involved in the synergism between cisplatin and either 3-AB or 5-FU, and that 3-AB and 5-FU may similarly modify the cisplatin-induced DNA damage to types requiring the recruitment of RAD51 proteins for their repair. Understanding these mechanisms could be useful for improving the clinical outcome of ESCC patients who suffer from aggressive disease that presently lacks effective treatment options.
Assuntos
Carcinoma de Células Escamosas/enzimologia , Cisplatino/farmacologia , Reparo do DNA/genética , Inibidores Enzimáticos/farmacologia , Neoplasias Esofágicas/enzimologia , Recombinação Homóloga/genética , Inibidores de Poli(ADP-Ribose) Polimerases , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Sinergismo Farmacológico , Carcinoma de Células Escamosas do Esôfago , Fluoruracila/farmacologia , Histonas/metabolismo , Humanos , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismoRESUMO
BACKGROUND/AIM: The status of each patient with advanced esophageal cancer varies widely, and the prognosis is generally poor. We aimed to determine which prognostic factors are involved in the management of locally advanced esophageal cancer with adjacent organ invasion. PATIENTS AND METHODS: We retrospectively investigated the therapeutic outcomes of 74 patients with thoracic esophageal cancer and clinical evidence of adjacent organ invasion but without distant metastasis. The predictive factors for a chemoradiotherapeutic response and survival were evaluated. RESULTS: Definitive chemoradiotherapy (CRT), bypass surgery and CRT, as well as CRT followed by esophagectomy were carried out in 48 (64.9%), 17 (23.0%), and 9 (12.2%) patients, respectively. The median survival time (MST) of patients overall was 11.3 months. The MST of patients after definitive CRT, bypass surgery plus CRT and CRT followed by esophagectomy was 10.4, 11.0 and 16.4 months, respectively; MST did not differ significantly between patients. MST of patients with a complete response (CR), a partial response (PR) and stable (SD)/progressive (PD) disease as clinical outcomes of CRT was 52.6, 11.3 and 6.7 months, respectively; the MST was considerably longer in patients with, than in those without CR (CR vs. SD/PD, p<0.0001; CR vs. PR, p=0.0004). In multivariate analysis, age <60 years [odds ratio (OR)=7.74; 95% confidence interval (CI)=1.85-32.41; p=0.005] and hemoglobin ≥13 g/dl (OR=11.54; 95% CI=1.29-103.21; p=0.03) were independently associated with CR as an outcome of CRT, and serum albumin level ≥3.5 g/dl (OR=2.11; 95% CI=1.09-4.10; p=0.03) was independently associated with prolonged survival. CONCLUSION: Pre-treatment hemoglobin and albumin levels were valuable predictors of the outcome of CRT and survival, respectively. A better response to CRT as well as improved nutritional status prolonged the survival of patients with advanced esophageal cancer.
Assuntos
Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/terapia , Quimiorradioterapia , Neoplasias Esofágicas/diagnóstico por imagem , Feminino , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Especificidade de Órgãos , Prognóstico , Análise de Sobrevida , Neoplasias Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
We describe the case of an 80-year-old man with hepatocellular carcinoma (HCC) who developed tracheal obstruction due to peritracheal lymph node metastasis. A metastatic tumor that protruded into the airway was ablated using a neodymium yttrium-aluminium-garnet laser and then a self-expandable metallic stent (SEMS) was deployed in the trachea. Stenting resolved symptoms of severe dyspnea upon mild exertion and in the supine position. Three months later, the patient is alive and has resumed normal activities as an outpatient, despite having metastatic HCC. Peritracheal lymph node metastasis arising from HCC is very rare and a polypoid tumor growing from a metastatic lymph node into the trachea is also extremely unusual. Tracheal obstruction in this patient was successfully treated by airway stenting.
Assuntos
Obstrução das Vias Respiratórias/terapia , Carcinoma Hepatocelular/complicações , Neoplasias Hepáticas/complicações , Stents , Doenças da Traqueia/terapia , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/etiologia , Carcinoma Hepatocelular/secundário , Humanos , Neoplasias Hepáticas/patologia , Metástase Linfática , Masculino , Doenças da Traqueia/etiologia , Resultado do TratamentoRESUMO
5-Fluorouracil (5-FU) is one of the most well established chemotherapeutic agents in the treatment of esophageal cancer. Ribonucleotide reductase M1 (RRM-1) is the ratelimiting enzyme in de novo DNA synthesis, and has been considered to play an important role in the 5-FU metabolic pathway. However, the means by which RRM-1 participates in the anticancer effects of 5-FU and cisplatin (CDDP) have not been well studied. Here, we show that RRM-1 significantly contributes to the induction of DNA damage by 5-FU in esophageal cancer cell lines. An assay of γ-H2AX focus formation, a marker of DNA damage, after 5-FU treatment revealed good correlation with the levels of RRM-1 protein expression. Moreover, the increased sensitivity and RAD51 focus formation induced by the combination treatment of 5-FU and CDDP were significantly repressed by RRM-1 depletion. These results suggest that RRM-1 is involved not only in the induction of DNA damage by 5-FU but also in the synergistic cytotoxic effect in the combination therapy of 5-FU and CDDP.