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BACKGROUND: Mantle cell lymphomas (MCL) represent a rare subclass of Non-Hodgkin Lymphoma affecting the lacrimal gland (GL). AIM: To extensively describe the immunohistochemical profile of GL-MCL. MATERIAL UND METHODS: Single center, retrospective electronic records review of 3 patients with biopsy proven LG-MCL. RESULTS: The herein presented case series of three patients comprises a focal case involving solely the lacrimal gland, a symptomatic LG-MCL manifesting as the first sign of a systemic disease as well as a case of LG-MCL presenting as a relapsed systemic lymphoma. The three patients presented positive CD19 and CD20, negative CD10 and CD23. One patient showed an uncommon negativity for CD5. The increased expression of cyclin D1 caused by the classical translocation t(11;14) (q13;q32) in the fluorescence-in-situ-hybridisation were observed in all cases. B-cell-lymphoma-2 protein (BCL-2) and transcription factor SOX-11 (SOX-11) were also overexpressed. DISCUSSION: LG-MCL show an immunohistochemical profile corresponding to the classical profile of MCL. Overexpression of molecules for target therapies was found in all cases (CD20 for rituximab, BCL2 for Bruton-kinase-inhibitors and CD19 for CAR-T cell therapy). The removal of the GL can potentially drive to severe complications, even if aimed to confirm diagnosis. Therefore, the choice between GL-biopsy and exstirpation should be carefully evaluated, especially in cases of suspected lymphoma.
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Aparato Lagrimal , Linfoma de Células B , Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/metabolismo , Estudios Retrospectivos , Linfoma de Células B/patología , Biología MolecularRESUMEN
T-lymphocytic enteral leiomyositis (T-lel) is a rare disorder causing chronic intestinal pseudo-obstruction (CIPO), with cases predominantly being reported in the field of veterinary and pediatric medicine. Here, we present a case of T-lel-associated CIPO in an adult female, who initially presented with a paralytic ileus 2 weeks after a common gastroenteritis. The histological diagnosis was established through full-thickness bowel biopsy, exhibiting a dense lymphocytic infiltrate in the lamina muscularis of the intestinal wall. This case shows that T-lel can be a cause of chronic intestinal pseudo-obstruction not only in children but also in adults. A subsequent induction of an immunosuppressive therapy with steroids, azathioprine, and ultimately TNF-alpha-inhibiting antibodies led to a slow recovery and stable disease.
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Gastroenteritis/diagnóstico , Seudoobstrucción Intestinal/diagnóstico , Intestino Delgado/patología , Adulto , Biopsia , Enfermedad Crónica , Femenino , Humanos , Seudoobstrucción Intestinal/etiologíaRESUMEN
Background: Necrotizing enterocolitis (NEC) is an often-fatal neonatal disease involving intestinal hyperinflammation leading to necrosis. Despite ongoing research, (1) conflicting results and (2) comorbidities of NEC patients make early NEC detection challenging and may complicate therapy development. Most research suggests that NEC pathogenesis is multifactorial, involving a combination of (1) gut prematurity; (2) abnormal bacterial colonization; and (3) ischemia-reperfusion (I/R) injury. As neutrophil extracellular traps (NETs) partially mediate I/R injury and drive inflammation in NEC, we hypothesized that NETs contribute to NEC development; particularly in cardiac patients. Methods: A retrospective analysis of baseline characteristics, clinical signs, laboratory parameters, and imaging was conducted for surgically verified NEC cases over 10 years. Patients were stratified into two groups: (1) prior medically or surgically treated cardiac disease (cardiac NEC) and (2) no cardiac comorbidities (inflammatory NEC). Additionally, histology was reassessed for neutrophil activation and NETs formation. Results: A total of 110 patients (cNEC 43/110 vs. iNEC 67/110) were included in the study, with cNEC neonates being significantly older than iNEC neonates (p = 0.005). While no significant differences were found regarding clinical signs and imaging, laboratory parameters revealed that cNEC patients have significantly increased leucocyte (p = 0.024) and neutrophil (p < 0.001) counts. Both groups also differed in pH value (p = 0.011). Regarding histology: a non-significant increase in staining of myeloperoxidase within the cNEC group could be found in comparison to iNEC samples. Neutrophil elastase (p = 0.012) and citrullinated histone H3 stained (p = 0.041) slides showed a significant markup for neonates diagnosed with cNEC in comparison to neonates with iNEC. Conclusion: The study shows that many standardized methods for diagnosing NEC are rather unspecific. However, differing leucocyte and neutrophil concentrations for iNEC and cNEC may indicate a different pathogenesis and may aid in diagnosis. As we propose that iNEC is grounded rather in sepsis and neutropenia, while cNEC primarily involves I/R injuries, which involves neutrophilia and NETs formation, it is plausible that I/R injury due to interventions for cardiac comorbidities results in pronounced neutrophil activation followed by a hyperinflammation reaction and NEC. However, prospective studies are necessary to validate these findings and to determine the accuracy of the potential diagnostic parameters.
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Pediatric histiocytic sarcoma (HS) clonally related to anteceding leukemia is a rare malignancy with poor outcome. We performed a molecular characterization of HS and the corresponding leukemia by methylation arrays and whole-exome sequencing and found a variety of aberrations in both entities with deletions of CDKN2A/B as a recurrent finding. Furthermore, data from genome-wide mutation analysis from one patient allowed the reconstruction of a sequence of tumorigenesis of leukemia and HS lesions including the acquisition of a putatively activating KRAS frameshift deletion (p.A66fs). Our results provide an insight into the genetic landscape of pediatric HS clonally related to anteceding leukemia.
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Análisis Mutacional de ADN/métodos , Genoma Humano , Sarcoma Histiocítico/genética , Leucemia Mieloide Aguda/genética , Niño , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Mutación del Sistema de Lectura , Sarcoma Histiocítico/patología , Humanos , Leucemia Mieloide Aguda/patología , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Eliminación de Secuencia , Secuenciación Completa del GenomaAsunto(s)
Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Atrofia Muscular Espinal/tratamiento farmacológico , Acetaminofén/administración & dosificación , Administración Intravenosa , Adulto , Analgésicos no Narcóticos/administración & dosificación , Biopsia , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Humanos , Hígado/diagnóstico por imagen , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Tomografía Computarizada por Rayos XRESUMEN
Persistently elevated eosinophil granulocytes in the peripheral blood in children is challenging because of a complex diagnosis especially after solid organ transplantation and can lead to difficulties in finding an underlying causative factor.We report a 12-year-old boy who developed severe hypereosinophilia 11 years after liver transplantation due to biliary atresia. Accompanying symptoms were recurrent fever, fatigue, elevated liver enzymes, abdominal pain, and significant weight loss. After exclusion of secondary causes of eosinophilia, an idiopathic hypereosinophilic syndrome (I-HES) was diagnosed. Treatment with prednisolone resulted in an immediate response with rapid reduction of eosinophils, normalization of liver enzymes, and amelioration of any clinical symptoms. A hypereosinophilic syndrome in patients after liver transplantation is rare, and a broad differential diagnosis has to be considered. Prednisolone may lead to a prompt amelioration of eosinophilia and associated symptoms.
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Síndrome Hipereosinofílico/etiología , Trasplante de Hígado , Complicaciones Posoperatorias , Niño , Humanos , Síndrome Hipereosinofílico/diagnóstico , Masculino , Complicaciones Posoperatorias/diagnósticoRESUMEN
OBJECTIVE: To evaluate the effects of thrombolysis and/or anticoagulation on testicular viability after testicular tortion (TT) was the aim of this study. It has been suggested that alterations of circulation during TT result in thrombus formation that might prevent sufficient perfusion after detorsion. Due to the narrow safety margin of testicular perfusion, even moderate disturbances in blood supply can cause major testicular damage. METHODS: In 112 rats, the right testicle was torsed for 3 or 6 hours. After detorsion and randomization, they received either enoxaparin, alteplase, both, or placebo, according to their subgroup. Thrombus formation was accessed via D-dimers, pDNA, oxidative testicular damage was evaluated via glutathione peroxidase and malondialdehyde, and cellular damage via inhibin B, testosterone, histological analysis (Johnsen score, Cosetino grading), and TUNEL assay. RESULTS: One hundred and twelve rats were included in the study. The treatment with alteplase or enoxaparin showed significantly less testicular damage and significantly improved Sertoli cell function. Enoxaparin significantly reduced oxidative impairment. CONCLUSION: The results of the study indicate that TT induces thrombus formation and demonstrate that modulation of thrombosis significantly ameliorates testicular damage in rats. Hence, this treatment option after TT ought to be evaluated in humans.
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Anticoagulantes/uso terapéutico , Enoxaparina/uso terapéutico , Fibrinolíticos/uso terapéutico , Torsión del Cordón Espermático/terapia , Testículo/irrigación sanguínea , Trombosis/terapia , Activador de Tejido Plasminógeno/uso terapéutico , Animales , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Torsión del Cordón Espermático/complicaciones , Trombosis/etiologíaRESUMEN
BACKGROUND: The pathogenesis of intestinal dysmotility in gastroschisis is not completely understood. Peel formation and disorganization of interstitial Cajal cells (ICC) have been proposed in humans. The aim of this study was to evaluate the impact of prenatal coverage of gastroschisis on gut inflammation and expression of ICC in a fetal lamb model. METHODS: Twenty-one German blackhead sheep with an abdominal wall defect that was created fetoscopically on day 77 of 145 days gestation were used in this study. Intrauterine surgery with the aim to cover the defect was performed 3 weeks later; two fetuses were covered completely, 5 partially and 11 remained uncovered. Three fetuses without gastroschisis were used as controls. All fetuses were retrieved by cesarean section at day 135. Samples of the small intestine were stained with hematoxylin and eosin for histologic analysis of peel formation and serosal and muscular thickness. For ICC detection, immunohistochemistry using anti-CD117 (c-Kit) antibody was used. RESULTS: In all samples with exposure to amniotic fluid, peel formation and significantly decreased ICC were found. Complete coverage reduced peel formation and disorganization of ICC compared to uncovered animals almost to the level of controls. CONCLUSIONS: Peel formation and ICC derangement were significantly reduced by prenatal coverage of gastroschisis. Moreover, this animal model mimics the histopathological bowel changes as seen in human gastroschisis and may, therefore, be used for further research on the pathophysiology and fetal therapy of this malformation.
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Fetoscopía , Gastrosquisis/cirugía , Inflamación/patología , Células Intersticiales de Cajal/metabolismo , Animales , Recuento de Células , Modelos Animales de Enfermedad , Femenino , Gastrosquisis/patología , Inmunohistoquímica , Inflamación/metabolismo , Mucosa Intestinal/patología , Embarazo , OvinosAsunto(s)
Parasitosis Hepáticas/diagnóstico , Enfermedades Parasitarias/diagnóstico , Pentastomida/genética , Emigrantes e Inmigrantes , Resultado Fatal , Alemania , Humanos , Hígado/parasitología , Hígado/patología , Parasitosis Hepáticas/parasitología , Masculino , Técnicas de Diagnóstico Molecular , Enfermedades Parasitarias/parasitología , Togo/etnología , Adulto JovenRESUMEN
We describe and discuss autopsy findings of bowel wall hemorrhage in a study population comprising cases of suicidal death by hanging. Intramural hemorrhages were seen in approximately 12% of the cases examined; no preexisting bowel diseases were found. In hanging deaths with a longer agonal phase, we opine that abdominal congestion during the hanging process provides a viable pathophysiological explanation for bowel wall hemorrhage. Though we are not dealing here with obligatory autopsy findings, the detection of bowel wall hemorrhage might be used as another sign of vital hanging after considering differential diagnostic aspects.
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Asfixia/patología , Hemorragia/patología , Intestinos/irrigación sanguínea , Suicidio , Adolescente , Adulto , Asfixia/complicaciones , Femenino , Humanos , Intestinos/patología , Masculino , Persona de Mediana EdadAsunto(s)
Anemia de Células Falciformes/virología , Hepatitis Autoinmune/virología , Infecciones por Parvoviridae/complicaciones , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/fisiopatología , Preescolar , ADN Viral/sangre , Femenino , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/fisiopatología , Humanos , Infecciones por Parvoviridae/sangre , Infecciones por Parvoviridae/fisiopatología , Infecciones por Parvoviridae/virología , Parvovirus B19 Humano , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , ViremiaAsunto(s)
Antineoplásicos/efectos adversos , Bencenosulfonatos/efectos adversos , Carcinoma Hepatocelular/cirugía , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Hepatitis C/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/inmunología , Piridinas/efectos adversos , Enfermedad Aguda , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Bilirrubina/sangre , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/uso terapéutico , Sorafenib , Resultado del TratamientoRESUMEN
BACKGROUND: We aimed to compare two techniques of heterotopic heart transplantation in rats. Non-volume-loaded (NL) and volume-loaded (VL) models were tested for their physiologic and immunologic properties to assess their suitability for transplant studies. METHODS: Syngeneic heterotopic heart transplants were performed according to the techniques previously described by Ono (NL) and Yokoyama (VL). Grafts were followed over 90 days with sequential echocardiography. Ex-vivo Langendorff perfusion was used to gain functional data. Allogeneic heart transplants were done to determine whether chronic allograft vasculopathy (CAV) develops at a different pace in both transplant models. RESULTS: The ischemic time during surgery was significantly longer using the VL model (p<0.001). The LV diameter of NL hearts decreased over time while that of the VL model significantly increased (p=0.004 on POD 90). Mean LV developed pressure and (dP/dt)max were significantly higher with the NL model (61.1+/-8.5 mmHg and 4261.7+/-419.6 mmHg/s) than with VL hearts (19.9+/-16.5 mmHg; p=0.011 and 924.8+/-605.6 mmHg/s; p<0.001). The mean weight of NL hearts (0.45+/-0.03 g) was significantly less than that of VL hearts (1.21+/-0.16 g, p<0.001). Histology of syngeneic NL grafts showed healthy, but partly atrophic myocardium, whereas the LV myocardium of VL hearts showed dilation and scarring typical for chronic ischemic injury. Heart allografts similarly developed CAV with luminal narrowing of 37.2+/-16.6% (NL) and 34.4+/-21.4% (VL), respectively by POD 90 (p=0.807). CONCLUSIONS: Since the coronary arteries in the VL model get perfused with partly deoxygenated blood, the myocardium suffers from chronic ischemic injury. We recommend using the NL model in preclinical transplant studies.
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Volumen Cardíaco/fisiología , Trasplante de Corazón/métodos , Trasplante Heterotópico , Animales , Aorta Abdominal/trasplante , Aorta Torácica/diagnóstico por imagen , Diástole , Ecocardiografía , Corazón/fisiopatología , Masculino , Modelos Animales , Miocardio/patología , Ratas , Vena Cava Inferior/patologíaRESUMEN
We report a Caucasian neonate with chronic non-spherocytic hemolytic anemia due to a class I G6PD deficiency. A novel mutation missense mutation in exon eight of the G6PD gene was detected (c.827C>T p.Pro276Leu). Bilirubin peaked on day 5 at 24 mg/dl with a conjugated bilirubin of 17 mg/dl. Jaundice resolved within 4 weeks. A detailed work-up failed to reveal other specific factors contributing to cholestasis. Severe hemolytic disease of the newborn may cause cholestasis even in the absence of associated primary hepato-biliary disease.
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Anemia Hemolítica Congénita no Esferocítica/complicaciones , Colestasis/etiología , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Recien Nacido Prematuro , Ictericia Neonatal/etiología , Kernicterus/complicaciones , Mutación Missense , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/patología , Colestasis/patología , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Deficiencia de Glucosafosfato Deshidrogenasa/patología , Humanos , Recién Nacido , Ictericia Neonatal/patología , Kernicterus/genética , Kernicterus/patología , MasculinoAsunto(s)
Proctoscopía/efectos adversos , Recto/microbiología , Sepsis/microbiología , Choque Séptico/microbiología , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/patogenicidad , Adulto , Antibacterianos/uso terapéutico , Biopsia , Humanos , Masculino , Membrana Mucosa/microbiología , Membrana Mucosa/patología , Pelvis , Recto/patología , Sepsis/tratamiento farmacológico , Choque Séptico/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/transmisión , Streptococcus pyogenes/aislamiento & purificaciónRESUMEN
BACKGROUND: Interleukin-12 (IL-12) is well characterized to induce cellular antitumoral immunity by activation of NK-cells and T-lymphocytes. However, systemic administration of recombinant human IL-12 resulted in severe toxicity without perceptible therapeutic benefit. Even though intratumoral expression of IL-12 leads to tumor regression and long-term survival in a variety of animal models, clinical trials have not yet shown a significant therapeutic benefit. One major obstacle in the treatment with IL-12 is to overcome the relatively low expression of the therapeutic gene without compromising the safety of such an approach. Our objective was to generate an adenoviral vector system enabling the regulated expression of very high levels of bioactive, human IL-12. RESULTS: High gene expression was obtained utilizing the VP16 herpes simplex transactivator. Strong regulation of gene expression was realized by fusion of the VP16 to a tetracycline repressor with binding of the fusion protein to a flanking tetracycline operator and further enhanced by auto-regulated expression of its fusion gene within a bicistronic promoter construct. Infection of human colon cancer cells (HT29) at a multiplicity of infection (m.o.i.) of 10 resulted in the production of up to 8000 ng/106 cells in 48 h, thus exceeding any published vector system so far. Doxycycline concentrations as low as 30 ng/ml resulted in up to 5000-fold suppression, enabling significant reduction of gene expression in a possible clinical setting. Bioactivity of the human single-chain IL-12 was similar to purified human heterodimeric IL-12. Frozen sections of human colon cancer showed high expression of the coxsackie adenovirus receptor with significant production of human single chain IL-12 in colon cancer biopsies after infection with 3*107 p.f.u. Ad.3r-scIL12. Doxycycline mediated suppression of gene expression was up to 9000-fold in the infected colon cancer tissue. CONCLUSION: VP16 transactivator-mediated and doxycycline-regulated expression of the human interleukin-12 gene enables highly efficient and tightly controlled cytokine expression in human cancer. These data illustrate the potential of the described adenoviral vector system for the safe and superior expression of therapeutic genes in the treatment of colorectal cancer and other malignancies.
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Adenoviridae/genética , Clonación Molecular/métodos , Doxiciclina/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interleucina-12/genética , Interleucina-12/metabolismo , Transducción Genética/métodos , Relación Dosis-Respuesta a Droga , Células HT29 , HumanosRESUMEN
BACKGROUND: This study examines the efficacy of FK778 regimens for prevention of different phases of xenograft rejection. METHODS: Antibody and complement tissue depositions were measured by immunofluorescence in a discordant ex vivo rat-to-human heart perfusion model of hyperacute rejection with immunosuppressant-enriched human blood. The concordant hamster-to-rat aortic xenotransplantation model was used to assess host cellular (lymphocyte activation, mixed lymphocyte reaction [MLR]) and humoral responsiveness (xenoantibody production) as well as histologic xenograft rejection. Recipients were treated for 14 days with FK778, tacrolimus, sirolimus or combination regimens at varying doses. RESULTS: Antibody binding during hyperacute rejection was unaffected by the immunosuppressive treatment, but complement deposition was reduced in the following order: tacrolimus > FK778 approximately sirolimus. FK778 most effectively reduced complement factor 5 in vitro. In untreated rats with hamster aortic xenografts, a large infiltrative response was observed within the grafts with extensive myocyte necrosis. Tacrolimus > FK778 approximately sirolimus dose-dependently diminished xenograft infiltration and in the same order reduced vessel-wall myocyte necrosis. Tacrolimus approximately FK778 > sirolimus reduced in vivo lymphocyte CD25 expression and tacrolimus > FK778 approximately sirolimus diminished MLR. Xenoreactive IgM and IgG antibody production levels were vigorously upregulated a few days after transplantation, but were significantly reduced by tacrolimus > FK778 approximately sirolimus. Combination regimens revealed no significant benefit when compared with the corresponding monotherapy groups. CONCLUSIONS: FK778 mildly interfered with hyperacute rejection and markedly suppressed acute humoral and cellular aortic xenograft rejection. However, T-cell-dependent host responses were most potently suppressed by tacrolimus, and the overall efficacy of FK778 was similar to that of sirolimus.
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Alquinos/uso terapéutico , Aorta Abdominal/trasplante , Rechazo de Injerto/prevención & control , Isoxazoles/uso terapéutico , Nitrilos/uso terapéutico , Trasplante Heterólogo/métodos , Alquinos/farmacocinética , Animales , Anticuerpos Antiidiotipos/inmunología , Cricetinae , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Citometría de Flujo , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Isoxazoles/farmacocinética , Masculino , Nitrilos/farmacocinética , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the efficacy of the malononitrilamide FK778 to prevent vascular smooth muscle cell (SMC) migration/proliferation, and vascular fibrosis, the key events in restenosis development using in vivo and in vitro studies. BACKGROUND: Since the high rate of restenosis after percutaneous transluminal coronary angioplasty limited its long-term success, the implementation of locally delivered antiproliferative/immunosuppressive agents became advantageous. METHODS: Rats underwent balloon denudation of the abdominal aorta and received sirolimus, tacrolimus, or FK778 for 28 days in varying doses. Aortas were harvested for histologic evaluation, profibrotic gene expression, and organ chamber studies. Antifibrotic, antiproliferative and antimigratory effects of the immunosuppressants were further evaluated in vitro. RESULTS: Histology of untreated animals revealed marked intimal hyperplasia with moderate luminal obliteration. Neointima formation was dose-dependently attenuated by all three agents with FK778 and sirolimus being most efficacious. Organ chamber relaxation studies showed a leftward shift of the nitroglycerin and the acetylcholine dose-responses in all treatment groups, indicating diminished endothelial dysfunction. In vivo, only FK778 treatment revealed a significant downregulation of the TGF-beta/vasorin system which could be explained by upregulation of the TGF-beta-inhibitory mediator SMAD7. In vitro, FK778 showed most potent antiproliferative and antimigratory effects on SMC compared with sirolimus and tacrolimus. Only the antiproliferative effect of FK778 was due to pyrimidine synthesis blockade and could be reversed by uridine supplementation. CONCLUSIONS: The malononitrilamide FK778 proved highly efficacious against restenosis development by targeting two major components of intimal hyperplasia: SMC proliferation/migration and vascular fibrosis. Thus, the introduction of malononitrilamide-loaded stents may be a promising effort for future strategies.