RESUMO
Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.
RESUMO
By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.
Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Cristalografia por Raios X , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Desenho de Fármacos , LigantesRESUMO
AIM: Black esophagus, or acute esophageal necrosis, is a rare entity with multifactorial aetiology. Modern theories suggest a combination of ischemia, compromised mucosa defences and corrosive agent's injury. MATERIAL AND METHODS: We investigated black esophagus by means of a retrospective review of 26 cases in literature. A Medline overview is performed until May 2021 by considering the Italian results. The search terms were "black esophageal syndrome in Italy", "black esophagus in Italy", "black esophageal necrosis in Italy", and "Gurvits syndrome in Italy". To complete these case reports, we illustrate our first experience of the syndrome successfully treated with esophagectomy, cervical diversion and gastrostomy. RESULTS: Black esophagus is common in adult males (M/F: 21/5) (Range: 47-89 years; Average: 70.6 year-old). The most common symptoms are hematemesis, epigastric pain and dysphagia. Endoscopically, diffuse involvement of acute esophageal necrosis is diagnosed in 42.3% of cases. The treatment consisted on red blood cell transfusions, sucralfate administration, proton pump-inhibition, enteral nutrition and antimicrobial agents. Overall mortality was 38.4% and only one case underwent surgery for acute bleeding. CONCLUSIONS: Black esophagus is often reversible both anatomically and functionally. Its treatment is based on supported therapies and hemodynamic resuscitation. This syndrome shows high mortality related to the coexisted medical conditions rather than acute esophageal necrosis. Only in selected cases, surgical treatment is indicated. KEY WORDS: Acute necrotizing esophagitis, Black esophagus, Ischemia.
Assuntos
Doenças do Esôfago , Esofagite , Adulto , Idoso , Humanos , Masculino , Doença Aguda , Doenças do Esôfago/etiologia , Doenças do Esôfago/cirurgia , Esofagite/etiologia , Esofagite/terapia , Esofagite/diagnóstico , Isquemia , NecroseRESUMO
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nicotinamida N-Metiltransferase/antagonistas & inibidores , Regulação Enzimológica da Expressão Gênica , Humanos , Estrutura Molecular , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Intestinal microbiota dysbiosis may enhance the carcinogenicity of colon cancer (CC) by the proliferation and differentiation of epithelial cells. Oral Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) have the ability to invade the gut epithelium, promoting tumor progression. The aim of the study was to assess whether the abundance of these odontopathogenic bacteria was associated with colon cancer. We also investigated how lifestyle factors could influence the oral Fn and Pg abundance and CC. METHODS: Thirty-six CC patients were included in the study to assess the Pg and Fn oral and colon tissue abundance by qPCR. Oral health data, food habits and lifestyles were also recorded. RESULTS: Patients had a greater quantity of Fn in the oral cavity than matched CC and adjacent non-neoplastic mucosa (adj t) tissues (p = 0.004 and p < 0.001). Instead, Pg was not significantly detected in colonic tissues. There was an association between the Fn quantity in the oral and CC tissue and a statistically significant relation between the Fn abundance in adenocarcinoma (ADK) and staging (p = 0.016). The statistical analysis revealed a tendency towards a greater Fn quantity in CC (p = 0.073, η2p = 0.12) for high-meat consumers. CONCLUSION: In our study, Pg was absent in colon tissues but was correlated with the oral inflammation gingival and plaque indices. For the first time, there was evidence that the Fn oral concentration can influence colon tissue concentrations and predict CC prognosis.
RESUMO
AIM: Pathological complete response (pCR) and clinical outcomes [overall survival (OS), disease-free survival (DFS), locoregional control (LC)] were evaluated in a single-institution experience of different schedules of neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Data for 322 patients with LARC were retrospectively analyzed. pCR was evaluated according to Mandard tumor regression grade (TRG). The Kaplan-Meier method was used to estimate OS, DFS and LC. RESULTS: Three hundred and three (94.1%) patients underwent surgery. pCR was observed in 81 patients (26.7%), with TRG1-2 rate of 41.8%. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively. CONCLUSION: Neoadjuvant CRT in LARC patients resulted in favorable long-term oncological outcomes, with a high pCR rate and acceptable toxicity.
Assuntos
Neoplasias Retais/patologia , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/mortalidade , Resultado do TratamentoRESUMO
Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.
Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/química , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Proteínas Proto-Oncogênicas c-bcl-6/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel.
Assuntos
Pontos de Checagem do Ciclo Celular , Pirimidinas/farmacologia , Fuso Acromático/metabolismo , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Disponibilidade Biológica , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Segregação de Cromossomos/efeitos dos fármacos , Cromossomos Humanos/genética , Sinergismo Farmacológico , Humanos , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/química , Fuso Acromático/efeitos dos fármacos , Triazóis/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4- d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4- d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Descoberta de Drogas , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Masculino , Metilação , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição Tecidual , Triazóis/farmacocinéticaRESUMO
This study analyses the utility of right colectomy as a learning procedure at the beginning of a robotic surgical program. The hypothesis is that right colectomy contains all the technical steps necessary to acquire basic abilities in robotics surgery. The first 23 consecutive robotic right colectomy performed at the beginning of a robotic program were analysed. All surgical times were recorded in the operating room and second checked on a dedicated video-database. Specific robotic times were analysed using CUSUM method to evaluate the learning curve. CUSUM-derived learning phases were compared. Fourteen males and nine females with a mean age of 68.7 (46-84) underwent robotic right colectomy. The mean overall time was 265.3 min (180-320 min), docking time was 7 min (5-12 min), console time was 205.9 min (145-260 min), and anastomotic time was 43.6 (25-60 min). CUSUM analyses identified two learning phases: "starting phase" and "consolidation phase". Interphase comparison confirmed the significant (p < 0.05) differences between the two phases. Robotic technology facilitates the training process in minimally invasive colorectal surgery. At the beginning of the learning curve, right colectomy could represent a complete procedure to be proficient in robotic colorectal surgery.
Assuntos
Colectomia/educação , Educação de Pós-Graduação em Medicina/métodos , Curva de Aprendizado , Procedimentos Cirúrgicos Robóticos/educação , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Colectomia/efeitos adversos , Colectomia/métodos , Neoplasias do Colo/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Procedimentos Cirúrgicos Robóticos/efeitos adversosRESUMO
BACKGROUND: A high rate of association between neuroendocrine tumors (NETs) and secondary primary malignancy (SPM) has been described in literature and this association can occur either in a synchronous or a metachronous presentation. A wide range of hypothesis has been postulated to explain the high rate of association between NETs and SPM, without definitive conclusions. CASE PRESENTATION: We report a case of an ileal neuroendocrine tumor found incidentally at the histologic examination of the surgical specimen in a 72 years old male underwent to right hemi colectomy for two colic adenomatous polips with high grade dysplasia. CONCLUSION: Large multicentric epidemiological studies should be considered to assess the association between NETs and SPM. KEY WORDS: Neuroendocrine tumors (NETs), Progression-Free Survival (PFS), Secondary primary malignancy (SPM).
Assuntos
Pólipos Adenomatosos/epidemiologia , Tumor Carcinoide/epidemiologia , Neoplasias do Colo/epidemiologia , Pólipos do Colo/epidemiologia , Neoplasias do Íleo/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Adenoma Viloso/patologia , Adenoma Viloso/cirurgia , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/cirurgia , Idoso , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/secundário , Tumor Carcinoide/cirurgia , Causalidade , Neoplasias do Ceco/patologia , Neoplasias do Ceco/cirurgia , Colectomia/métodos , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Pólipos do Colo/patologia , Pólipos do Colo/cirurgia , Colonoscopia , Comorbidade , Predisposição Genética para Doença , Humanos , Neoplasias do Íleo/diagnóstico , Neoplasias do Íleo/cirurgia , Incidência , Achados Incidentais , Metástase Linfática , Masculino , Gradação de Tumores , Neoplasias Primárias Múltiplas/diagnósticoRESUMO
BACKGROUND: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers. METHODS: To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment. RESULTS: CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model. CONCLUSIONS: CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850.
Assuntos
Proteínas de Ciclo Celular/genética , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Células HCT116 , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fibromyalgia, a chronic syndrome of diffuse musculoskeletal pain and somatic hyperalgesia from central sensitization, is very often comorbid with visceral pain conditions. In fibromyalgia patients with gallbladder calculosis, this study assessed the short and long-term impact of laparoscopic cholecystectomy on fibromyalgia pain symptoms. Fibromyalgia pain (VAS scale) and pain thresholds in tender points and control areas (skin, subcutis and muscle) were evaluated 1week before (basis) and 1week, 1,3,6 and 12months after laparoscopic cholecystectomy in fibromyalgia patients with symptomatic calculosis (n = 31) vs calculosis patients without fibromyalgia (n. 26) and at comparable time points in fibromyalgia patients not undergoing cholecystectomy, with symptomatic (n = 27) and asymptomatic (n = 28) calculosis, and no calculosis (n = 30). At basis, fibromyalgia+symptomatic calculosis patients presented a significant linear correlation between the number of previously experienced biliary colics and fibromyalgia pain (direct) and muscle thresholds (inverse)(p<0.0001). After cholecystectomy, fibromyalgia pain significantly increased and all thresholds significantly decreased at 1week and 1month (1-way ANOVA, p<0.01-p<0.001), the decrease in muscle thresholds correlating linearly with the peak postoperative pain at surgery site (p<0.003-p<0.0001). Fibromyalgia pain and thresholds returned to preoperative values at 3months, then pain significantly decreased and thresholds significantly increased at 6 and 12months (p<0.05-p<0.0001). Over the same 12-month period: in non-fibromyalgia patients undergoing cholecystectomy thresholds did not change; in all other fibromyalgia groups not undergoing cholecystectomy fibromyalgia pain and thresholds remained stable, except in fibromyalgia+symptomatic calculosis at 12months when pain significantly increased and muscle thresholds significantly decreased (p<0.05-p<0.0001). The results of the study show that biliary colics from gallbladder calculosis represent an exacerbating factor for fibromyalgia symptoms and that laparoscopic cholecystectomy produces only a transitory worsening of these symptoms, largely compensated by the long-term improvement/desensitization due to gallbladder removal. This study provides new insights into the role of visceral pain comorbidities and the effects of their treatment on fibromyalgia pain/hypersensitivity.
Assuntos
Colecistectomia Laparoscópica , Fibromialgia/complicações , Doenças da Vesícula Biliar/cirurgia , Hiperalgesia/complicações , Litíase/cirurgia , Dor Musculoesquelética/complicações , Adolescente , Adulto , Idoso , Colecistectomia Laparoscópica/efeitos adversos , Estimulação Elétrica , Feminino , Doenças da Vesícula Biliar/complicações , Doenças da Vesícula Biliar/fisiopatologia , Humanos , Litíase/complicações , Litíase/fisiopatologia , Masculino , Pessoa de Meia-Idade , Limiar da Dor , Dor Pós-Operatória/etiologia , Pressão , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Descoberta de Drogas , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/químicaRESUMO
AIM: Describe a rare case of intestinal obstruction due to sigmoid colon incarceration into a right Spigelian hernia and provide a literature review about its surgical management. MATERIAL OF STUDY: An 88 year-old man presented with a 3-day history of right lower quadrant pain and abdominal distension. Clinical examination revealed a not reducible palpable mass on right side of the anterior abdominal wall. Computed tomography shown signs of intestinal obstruction and a Spigelian hernia of about 3 cm. RESULTS: Sigmoid colon was incarcerated in the defect but no signs of intestinal ischemia was found during the surgical exploration. The hernia content was reduced and the defect was repaired with a polypropylene mesh placed in the pre-peritoneal space. Postoperative period was uneventful and the patient was discharged on the fourth postoperative day. DISCUSSION: Spigelian hernia occurs through congenital or acquired defects in the Spigelian fascia at the level of the semicircular line. Clinical presentation depends on the size and the pattern of the hernia defect. In some cases, symptoms are no specific and uncommon findings have been reported so far. Preoperative establishment of the hernia content and the location of the sac is mandatory to plan a correct surgical strategy. Intestinal incarceration often occurs and suggests a prompt surgical exploration. CONCLUSIONS: Colonic obstruction secondary to an incarcerated Spigelian hernia is a rare but dangerous occurrence. Surgical approach is selected based on patient's conditions and surgeon's expertise. In a non-contaminated surgical field, the use of prosthesis is recommended. KEY WORDS: Intestinal obstruction, Mesh repair, Spigelian hernia.
Assuntos
Hérnia Ventral/complicações , Obstrução Intestinal/etiologia , Doenças do Colo Sigmoide/etiologia , Abdome Agudo/etiologia , Idoso de 80 Anos ou mais , Aponeurose/anormalidades , Emergências , Hérnia Ventral/diagnóstico por imagem , Hérnia Ventral/cirurgia , Herniorrafia , Humanos , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , Masculino , Doenças do Colo Sigmoide/diagnóstico por imagem , Doenças do Colo Sigmoide/cirurgia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Circulating pentraxin 3 (PTX3), the main regulator of the inflammatory response, rapidly increases following cardiovascular events, and low PTX3 is associated with high body mass index. METHODSâANDâRESULTS: We conducted a 12-month longitudinal study, to test the hypothesis that laparoscopic adjustable gastric banding (LAGB)-induced weight loss was associated with changes in platelet activation markers and PTX3. Twelve obese patients, scheduled to undergo LAGB, were enrolled at the University Obesity Center. Urinary 11-dehydro-thromboxane (Tx)B2excretion rate was measured on radioimmunoassay, and PTX3 and CD40L were determined on immunoassay. Plasma PTX3 increased by 178.8 and 214.9% (P<0.0001), respectively, 6 and 12 months after LAGB. High-sensitivity CRP decreased by 24 and 29.7% (P<0.0001), whereas CD40L decreased by 64.3 and 58.6% (P=0.002), respectively. Urinary 11-dehydro-TxB2decreased from 1,443 to 715 and 564 pg/mg creatinine, respectively 6 months and 12 months after LAGB (P<0.0001). PTX3 was inversely related to platelet activation markers, 11-dehydro-TxB2and CD40L. Moreover, multiple regression analysis on pooled data showed that plasma PTX3 was an independent predictor of urinary 11-dehydro-TxB2. CONCLUSIONS: There is an association between inflammation, platelet activation and metabolic dysfunction in obesity, and PTX3 is a key player within these circuits.
Assuntos
Proteína C-Reativa/metabolismo , Derivação Gástrica , Obesidade/sangue , Obesidade/cirurgia , Ativação Plaquetária , Componente Amiloide P Sérico/metabolismo , Adulto , Ligante de CD40/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/urina , Tromboxano B2/análogos & derivados , Tromboxano B2/urinaRESUMO
Neuroblastoma is a childhood malignancy that has not yet benefitted from the rapid progress in the development of small-molecule therapeutics for cancer. An opportunity to take advantage of pharmaceutical innovation in this area arose when the identification of ALK fusion proteins in non-small cell lung cancer (NSCLC) occurred in parallel to the discovery of point mutations of ALK in neuroblastomas. ALK is now known to be a marker of poor outcome in neuroblastoma, and therefore, urgent development of specific ALK inhibitors to treat this devastating disease is a necessity. However, the translation of small molecules from adult directly into pediatric practice has thus far been challenging, due to mutation-specific structural variances in the ALK kinase domain. We discuss how the most recent structural and biological characterizations of ALK are directing preclinical and clinical studies of ALK inhibitors for both NSCLC and neuroblastoma.
Assuntos
Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Adulto , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Criança , Crizotinibe , Descoberta de Drogas/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Receptores Proteína Tirosina Quinases/fisiologiaRESUMO
AIM: Main endpoint was a response rate to therapy; secondary endpoints were disease-free survival, overall survival, acute and late toxicities, specially in terms of anorectal and urinary continence. BACKGROUND: Radiochemotherapy for anal cancer achieves a good clinical response, locoregional control, anal function preservation. However, oncologic outcomes can differ using radiotherapy plus fluorouracil and mytomicin vs. cisplatin and fluorouracil. METHODS: Between 2000 and 2012, 27 anal cancer patients receiving radiotherapy combined with two different radiochemotherapy schedules, fluorouracil and mytomicin (group A) and cisplatin plus fluorouracil (group B). The Kaplan-Meier method was also used to estimate local control, overall survival and disease free survival. Statistical significance between curves was evaluated using the Log-rank test. RESULTS: Complete pathological response was found in 85.2% of patients, with higher rates of response in the group A (100% vs. 63.6%, p = 0.039). No significantly difference was found between the two groups for the other endpoints. Low rates of both acute and late toxicities were recorded. CONCLUSION: Radiotherapy plus fluorouracil and mytomicin provide a better complete pathological response than radiotherapy plus cisplatin and fluorouracil and a greater rate of anal sphincter function preservation. Globally, radiochemotherapy of the anal cancer provides excellent clinical outcomes with a good profile of acute and late toxicity, without difference between the two groups studied.
RESUMO
Fused pyrimidine cores are privileged kinase scaffolds, yet few examples of the 2-amino-pyrido[3,4-d]pyrimidine chemotype have been disclosed in the context of kinase inhibitor programs. Furthermore, no general synthetic route has been reported to access 2-amino-pyrido[3,4-d]pyrimidine derivatives. Here we report a versatile and efficient chemical approach to this class of molecules. Our strategy involves the concise preparation of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine intermediates and their efficient derivatisation to give novel compounds with potential as kinase inhibitors.