RESUMO
In Gram-negative bacteria, outer membrane-associated lipoproteins can either face the periplasm or protrude out of the bacterial surface. The mechanisms involved in lipoprotein transport through the outer membrane are not fully elucidated. Some lipoproteins reach the surface by using species-specific transport machinery. By contrast, a still poorly characterized group of lipoproteins appears to always cross the outer membrane, even when transplanted from one organism to another. To investigate such lipoproteins, we tested the expression and compartmentalization in E. coli of three surface-exposed lipoproteins, two from Neisseria meningitidis (Nm-fHbp and NHBA) and one from Aggregatibacter actinomycetemcomitans (Aa-fHbp). We found that all three lipoproteins were lipidated and compartmentalized in the E. coli outer membrane and in outer membrane vesicles. Furthermore, fluorescent antibody cell sorting analysis, proteolytic surface shaving, and confocal microscopy revealed that all three proteins were also exposed on the surface of the outer membrane. Removal or substitution of the first four amino acids following the lipidated cysteine residue and extensive deletions of the C-terminal regions in Nm-fHbp did not prevent the protein from reaching the surface of the outer membrane. Heterologous polypeptides, fused to the C termini of Nm-fHbp and NHBA, were efficiently transported to the E. coli cell surface and compartmentalized in outer membrane vesicles, demonstrating that these lipoproteins can be exploited in biotechnological applications requiring Gram-negative bacterial surface display of foreign polypeptides.
Assuntos
Aggregatibacter actinomycetemcomitans/metabolismo , Escherichia coli/genética , Lipoproteínas/metabolismo , Neisseria meningitidis/metabolismo , Aggregatibacter actinomycetemcomitans/genética , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/metabolismo , Membrana Celular/metabolismo , Escherichia coli/citologia , Escherichia coli/metabolismo , Lipoproteínas/genética , Neisseria meningitidis/genética , Transporte Proteico , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transformação BacterianaRESUMO
BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are maximally effective in early-stage colorectal cancer peritoneal metastases (CRC-PM); however, the use of HIPEC to treat subclinical-stage PM remains controversial. This prospective two-center study assessed adjuvant HIPEC in CRC patients at high risk for metachronous PM ( www.clinicaltrials.gov NCT02575859). METHODS: During 2006-2012, a total of 22 patients without systemic metastases were prospectively enrolled to receive HIPEC simultaneously with curative surgery, plus adjuvant systemic chemotherapy (oxaliplatin/irinotecan-containing ± biologics), based on primary tumor-associated criteria: resected synchronous ovarian (n = 2) or minimal peritoneal (n = 6) metastases, primaries directly invading other organs (n = 4) or penetrating the visceral peritoneum (n = 10). A control group retrospectively included 44 matched (1:2) patients undergoing standard treatments and no HIPEC during the same period. The cumulative PM incidence was calculated in a competing-risks framework. RESULTS: Patient characteristics were comparable for all groups. Median follow-up was 65.2 months [95 % confidence interval (CI) 50.9-79.5] in the HIPEC group and 34.5 months (95 % CI 21.1-47.9) in the control group. The 5-year cumulative PM incidence was 9.3 % in the HIPEC group and 42.5 % in the control group (p = 0.004). Kaplan-Meier estimated 5-year overall survival (OS) was 81.3 % in the HIPEC group versus 70.0 % in the control group (p = 0.047). No operative death occurred. Grade 3-4 [National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4] morbidity rates were 18.2 % in the HIPEC group and 25 % in controls (p = 0.75). At multivariate analysis, HIPEC correlated to lower PM cumulative incidence [hazard ratio (HR) 0.04, 95 % CI 0.01-0.31; p = 0.002], and better OS (HR 0.25, 95 % CI 0.07-0.89; p = 0.039) and progression-free survival (HR 0.31, 95 % CI 0.11-0.85; p = 0.028). CONCLUSION: Adjuvant HIPEC may benefit CRC patients at high-risk for peritoneal failure. These results warrant confirmation in phase III trials.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Hipertermia Induzida , Segunda Neoplasia Primária/secundário , Neoplasias Peritoneais/secundário , Adulto , Idoso , Terapia Combinada , Feminino , Humanos , Hipertermia Induzida/métodos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
Epithelial-to-mesenchymal transition (EMT) is an embryonic program used by cancer cells to acquire invasive capabilities becoming metastatic. ΔRon, a constitutively active isoform of the Ron tyrosine kinase receptor, arises from skipping of Ron exon 11 and provided the first example of an alternative splicing variant causatively linked to the activation of tumor EMT. Splicing of exon 11 is controlled by two adjacent regulatory elements, a silencer and an enhancer of splicing located in exon 12. The alternative splicing factor and oncoprotein SRSF1 directly binds to the enhancer, induces the production of ΔRon and activates EMT leading to cell locomotion. Interestingly, we now find an important role for hnRNP A1 in controlling the activity of the Ron silencer. HnRNP A1 is able to antagonize the binding of SRSF1 and prevent exon skipping. Notably, hnRNP A1, by inhibiting the production of ΔRon, activates the reversal program, namely the mesenchymal-to-epithelial transition, which instead occurs at the final metastasis sites. Also, hnRNP A1 affects Ron splicing by regulating the expression level of hnRNP A2/B1, which similarly to SRSF1 can promote ΔRon production. These results shed light on how splicing regulation contributes to the tumor progression and provide potential targets to develop anticancer therapies.
Assuntos
Processamento Alternativo , Transição Epitelial-Mesenquimal/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/fisiologia , Receptores Proteína Tirosina Quinases/genética , Linhagem Celular Tumoral , Éxons , Células HEK293 , Células HeLa , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Humanos , Degradação do RNAm Mediada por Códon sem Sentido , Receptores Proteína Tirosina Quinases/metabolismo , Sequências Reguladoras de Ácido RibonucleicoRESUMO
BACKGROUND: We assessed the learning curve (LC) of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treating peritoneal surface malignancies (PSM) in two centers and evaluated in which extent surgical tutoring could abbreviate the learning process. METHODS: Six hundred and forty-one cases submitted to CRS using peritonectomy procedures and HIPEC were considered. After having overcome its own LC, the NCI of Milan has provided technical assistance to Bentivoglio's centre for the development of a new PSM program since 2003. The risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of the two centers. Outcomes were incomplete cytoreduction, G3-5 morbidity (NCI-CTCAE.v3) and procedure-related mortality (PRM). RESULTS: Rates of incomplete cytoreduction, G3-5 morbidity, and PRM were 8.4%, 30.1%, and 3.9%, respectively, in the entire series. The breaking points of the LC concerning incomplete cytoreduction, G3-5 morbidity, and PRM were achieved at 141, 158, and 144 cases, in the Milan's experience, and at 126, 134, and 60 cases in the Bentivoglio's experience. CONCLUSIONS: Surgical tutoring could substantially shorten the steep LC associated with CRS and HIPEC. Our data should be confirmed by further studies on LC focusing oncological outcomes. Other factors that could influence the length of learning process should be identified.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional/educação , Procedimentos Cirúrgicos do Sistema Digestório/educação , Hipertermia Induzida , Curva de Aprendizado , Mentores , Neoplasia Residual/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Adulto , Idoso , Quimioterapia Adjuvante/métodos , Quimioterapia do Câncer por Perfusão Regional/métodos , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Bolsas de Estudo , Feminino , Humanos , Itália , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Neoplasias Peritoneais/mortalidade , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Estados UnidosRESUMO
Alternative splicing generates multiple mRNAs from a single transcript and is a major contributor to proteomic diversity and to the control of gene expression in complex organisms. Not surprisingly, this post-transcriptional event is tightly regulated in different tissues and developmental stages. An increasing body of evidences supports a causative role of aberrant alternative splicing in cancer. However, very little is known about its impact on cellular processes crucially involved in tumor progression. The aim of this review is to discuss the link between alternative splicing and the epithelial-to-mesenchymal transition (EMT), one of the major routes by which cancer cells acquire invasive capabilities and become metastatic. We begin with a brief overview of alternative splicing. Next, we discuss alternative splicing factors that regulate EMT. Finally, we provide examples of target genes presenting alternative splicing changes that contribute to the morphological conversions in the EMT process.
Assuntos
Processamento Alternativo , Transição Epitelial-Mesenquimal/genética , Animais , Carcinoma/etiologia , Carcinoma/genética , Humanos , Receptores de Hialuronatos/genética , Modelos Genéticos , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas Nucleares/genética , Proto-Oncogenes , Proteínas de Ligação a RNA/genética , Receptores Proteína Tirosina Quinases/genética , Fatores de Processamento de Serina-Arginina , Microambiente Tumoral/genética , Proteínas rac1 de Ligação ao GTP/genéticaRESUMO
OBJECTIVE: The primary end-point of this multi-institutional phase-II trial was to assess results in terms of overall survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment-naive epithelial ovarian cancer (EOC) with advanced peritoneal involvement. Secondary end-points were treatment morbi-mortality and outcome effects of time to subsequent adjuvant systemic chemotherapy (TTC). METHODS: Twenty-six women with stage III-IV EOC were prospectively enrolled in 4 Italian centers to undergo CRS and closed-abdomen HIPEC with cisplatin and doxorubicin. Then they received systemic chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m(2)) for 6 cycles. RESULTS: Macroscopically complete cytoreduction was achieved in 15 patients; only minimal residual disease (≤2.5 mm) remained in 11. Major complications occurred in four patients and postoperative death in one. After a median follow-up of 25 months, 5-year overall survival was 60.7% and 5-year progression-free survival 15.2% (median 30 months). Excluding operative death, all the patients underwent systemic chemotherapy at a median of 46 days from combined treatment (range: 29-75). The median number of cycles per patient was 6 (range: 1-8). The time to chemotherapy did not affect the OS or PFS. CONCLUSIONS: In selected patients with advanced stage EOC, upfront CRS and HIPEC provided promising results in terms of outcome. Morbidity was comparable to aggressive cytoreduction without HIPEC. Postoperative recovery delayed the initiation of adjuvant systemic chemotherapy but not sufficiently to impact negatively on survival. These data warrant further evaluation in a randomized clinical trial.
Assuntos
Antineoplásicos/administração & dosagem , Hipertermia Induzida/métodos , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário , Terapia Combinada , Feminino , Humanos , Injeções Intraperitoneais , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundárioRESUMO
Alternative splicing is a key molecular mechanism for increasing the complexity of the human transcriptome. Nearly all human genes are regulated by alternative splicing and the deregulation of this process has a causative role in various human diseases, including cancer. The discovery that alternatively spliced isoforms of several genes are expressed selectively in tumor cells opened the exciting possibility that pharmacological treatment of aberrant splicing could lead to new anti-cancer therapeutic approaches. An alternatively spliced isoform of a scatter factor receptor and proto-oncogene, Ron, accumulates during tumor progression of epithelial tissues and is able to confer an invasive phenotype to the expressing cells. This isoform, called ΔRon, originates from skipping of exon 11, and this specific splicing event is controlled by the expression level of the splicing factor and proto-oncogene SF2/ASF. Over-expression of SF2/ASF, which occurs frequently in various human tumors, induces the production of ΔRon and activates the epithelial to mesenchymal transition (EMT), leading to increased cell motility. In this paper, we have used targeted oligonucleotide enhancers of splicing (TOES) to recruit positive splicing factors to Ron exon 11 and thereby stimulate its inclusion. As an alternative approach, we have used selected indole derivatives that target ASF/SF2 splicing activity. Both treatments correct aberrant ΔRon splicing, restoring the incorporation of Ron exon 11. Notably, indole derivatives are also able to affect the invasive phenotype of the cells. Thus, these treatments may have therapeutic applications for anti-cancer purposes.
Assuntos
Indóis/farmacologia , Metástase Neoplásica/genética , Metástase Neoplásica/terapia , Oligonucleotídeos/farmacologia , Splicing de RNA/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/genética , Linhagem Celular Tumoral , Células HeLa , Humanos , Proto-Oncogene MasRESUMO
The treatment of patients at high risk of developing colorectal peritoneal carcinomatosis is still debated since the absence of peritoneal disease synchronous with the primitive cancer makes the application of aggressive treatments less obvious. In this subset of patients hyperthermic intraperitoneal chemotherapy (HIPEC), after the resection of the primitive cancer, may improve long-term survival. Over the period from December 2003 to June 2008 142 patients affected by different kinds of cancers underwent HIPEC in the surgical division of Bentivoglio Hospital, A.U.S.L. Bologna. In 13 patients HIPEC was combined only with the resection of the primitive cancer and no major cytoreductive surgery was performed. Nine of these 13 patients were affected by colorectal cancer and at high risk of developing carcinomatosis. The average surgical time was 420 min (range: 300-510). No intraoperative complications occurred, but 3 cases of postoperative morbidity were reported; only 1 of these was a major complication At an average follow-up of 22 months 1 patient with a liver metastasis died of complications unrelated to progression of the disease, 1 patient had a lymph node relapse and is currently on systemic chemotherapy, while the remaining 7 patients are alive and free from peritoneal disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/terapia , Neoplasias Colorretais/terapia , Hipertermia Induzida , Neoplasias Peritoneais/terapia , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Colectomia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Peritoneal carcinomatosis has always been regarded as a contraindication in traditional cancer surgery treatment; however, good results have been reported by using new combined medical-surgical loco-regional techniques. Peritonectomy and chemohyperthermic perfusion with cisplatinum (CIIP) seem to play a central role in obtaining a better survival rate than with the traditional procedures, even though there is a cisplatinum nephrotoxic effect. The aim of this study was to investigate entity and type of renal injury after CIIP. Forty-two patients (12 males and 30 females) with recurrent or primary peritoneal carcinomatosis who underwent peritonectomy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy with cisplatin were enrolled. A significant worsening in renal function was observed on the third post-operative day and this condition then persisted for three months. A reduction in estimated-Glomerular Filtration Rate (e-GFR) and an alteration in the albumin:creatinine ratio proved tubular injury. On the third post-operative day after cisplatinum administration, a high toxicity peak was found following platinum free fraction excretion. Proximal tubular injury was confirmed even at the three month analysis. A significant correlation between the total protein reduction rate and the decrease in renal function was established. In relation to that, the platinum free fraction could increase because of a binding protein shortage and the nephrotoxic effect could be enhanced due to platinum accumulation within the post-operative period. This finding suggests that the higher the protein reduction is, the lower the e-GFR determination is at three months.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma/terapia , Cisplatino/efeitos adversos , Nefropatias/induzido quimicamente , Túbulos Renais/efeitos dos fármacos , Neoplasias Peritoneais/tratamento farmacológico , Peritônio/cirurgia , Albuminúria/diagnóstico , Albuminúria/urina , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Creatina/urina , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertermia Induzida , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family.
Assuntos
Processamento Alternativo/fisiologia , Antígenos de Neoplasias/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/fisiologia , Neovascularização Fisiológica/fisiologia , Proteínas de Ligação a RNA/metabolismo , Animais , Antígenos de Neoplasias/genética , Células Cultivadas , Camundongos , Antígeno Neuro-Oncológico Ventral , Proteínas de Ligação a RNA/genéticaRESUMO
Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events.
RESUMO
AIMS AND BACKGROUND: The prognosis of peritoneal metastases from colorectal cancer has recently improved with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Although outcomes are further improved when early stage peritoneal metastases are treated, adjuvant hyperthermic intraperitoneal chemotherapy has never been thoroughly addressed. This prospective pilot study assessed feasibility, safety and efficacy of hyperthermic intraperitoneal chemotherapy combined with primary curative surgery in colorectal cancer at high risk for peritoneal metastases. METHODS: Twelve patients were prospectively selected according to predetermined risk factors for the development of peritoneal metastases. Patients underwent conventional colon surgery, closed-abdomen mitomycin-C plus cisplatin-based hyperthermic intraperitoneal chemotherapy, and cytoreductive surgical procedures, as needed. RESULTS: Preoperative tumor-related risk factors were confirmed by intraoperative findings and pathological examination in all patients: minimal synchronous peritoneal metastases (n = 2), synchronous ovarian metastases (n = 1), positive peritoneal washing cytology (n = 2), primary tumor directly invading other organs (n = 6), or penetrating visceral peritoneum (n = 1). Major morbidity occurred in 2 patients and operative death in none. Median follow-up was 49 months (range, 22-72). Peritoneal metastases occurred in 1 patient and distant metastases in 2. Five-year overall survival was 83.3%. CONCLUSIONS: Preoperative/early intraoperative assessment can reliably identify colorectal cancer patients at high risk for peritoneal metastases. Adjuvant hyperthermic intraperitoneal chemotherapy is well tolerated and safe. These preliminary results would support the design of future phase-III trials of adjuvant hyperthermic intraperitoneal chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Hipertermia Induzida , Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Quimioterapia Adjuvante , Quimioterapia do Câncer por Perfusão Regional/métodos , Cisplatino/administração & dosagem , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Neoplasias Ovarianas/prevenção & controle , Neoplasias Ovarianas/secundário , Neoplasias Peritoneais/prevenção & controle , Neoplasias Peritoneais/secundário , Projetos Piloto , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.
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AIMS AND BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare clinical entity characterized by diffuse intraabdominal gelatinous collections with mucinous implants on the peritoneal surfaces and omentum. This condition should be considered a borderline malignancy with disease progression over time. Encouraging treatment results have been recently reported with the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: . From December 2003 to December 2010, 18 patients with PMP were referred to our institution. All patients underwent peritonectomy and CRS combined with HIPEC in accordance with Sugarbaker's procedure. RESULTS: The mean Peritoneal Cancer Index score was 27.6 (range, 5-39). Twelve (67%) patients had disseminated peritoneal adenomucinosis and 6 (33%) peritoneal mucinous carcinomatosis. Optimal cytoreduction with no visible residual disease or residual disease ≤2.5 mm in diameter was achieved in all patients. The mean duration of the surgical procedure including HIPEC was 9 hours and 30 minutes (range, 5-13 hours); major morbidity occurred in 30% of patients and the mortality was 11%. The mean follow-up was 27 months (range, 1-72) and the 5-year overall survival 66%. CONCLUSIONS: In line with the existing literature, our experience suggests that patients with PMP could benefit from CRS + HIPEC in terms of survival and locoregional disease control.
Assuntos
Quimioterapia do Câncer por Perfusão Regional , Hipertermia Induzida , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Pseudomixoma Peritoneal/tratamento farmacológico , Pseudomixoma Peritoneal/cirurgia , Adulto , Idoso , Quimioterapia do Câncer por Perfusão Regional/métodos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Peritônio/patologia , Peritônio/cirurgia , Pseudomixoma Peritoneal/mortalidade , Pseudomixoma Peritoneal/patologia , Qualidade de Vida , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Hepatobiliary cystoadenoma is a rare cystic tumor of the liver that can undergo malignant change and become lethal. Accurate diagnosis of such lesions, even though not always possible, is of importance as the management is totally different from that of other nonneoplastic cysts. We report a case of a 60-year-old woman with aspecific symptoms, which was diagnosed using ultrasound scan and CT scan and treated with hepatic resection, and review the main features of this tumor.
Assuntos
Cistadenoma , Lobos , Animais , Vestuário , Cistadenoma/diagnóstico , Cistos/cirurgia , Diagnóstico Diferencial , Humanos , Ovinos , Tomografia Computadorizada por Raios XRESUMO
Epithelial-to-mesenchymal transition (EMT) and its reversal (MET) are crucial cell plasticity programs that act during development and tumor metastasis. We have previously shown that the splicing factor and proto-oncogene SF2/ASF impacts EMT/MET through production of a constitutively active splice variant of the Ron proto-oncogene. Using an in vitro model, we now show that SF2/ASF is also regulated during EMT/MET by alternative splicing associated with the nonsense-mediated mRNA decay pathway (AS-NMD). Overexpression and small interfering RNA experiments implicate the splicing regulator Sam68 in AS-NMD of SF2/ASF transcripts and in the choice between EMT/MET programs. Moreover, Sam68 modulation of SF2/ASF splicing appears to be controlled by epithelial cell-derived soluble factors that act through the ERK1/2 signaling pathway to regulate Sam68 phosphorylation. Collectively, our results reveal a hierarchy of splicing factors that integrate splicing decisions into EMT/MET programs in response to extracellular stimuli.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Processamento Alternativo , Códon sem Sentido/fisiologia , Proteínas de Ligação a DNA/fisiologia , Proteínas Nucleares/genética , Estabilidade de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , Regiões 3' não Traduzidas , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Bases , Diferenciação Celular , Proteínas de Ligação a DNA/química , Células Epiteliais/citologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Mesoderma/citologia , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Proto-Oncogene Mas , RNA Mensageiro/química , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Processamento de Serina-ArgininaRESUMO
We describe a case of a 76-year-old man with a giant ileal gastrointestinal stromal tumour (GIST) causing an intestinal subocclusion and a subsequent haemoperitoneum. During his hospital stay for a sudden hypovolemic shock, the patient underwent an urgent laparotomy and a 20 cm × 15 cm ruptured ileal GIST causing haemoperitoneum was found. Only 13 cases of ileal GIST causing peritoneal bleeding have been described since 2000, the one we presented is the largest. Although rare this pathological entity should be kept in mind in case of sudden abdominal pain and hypovolemic shock in patients with a large intraabdominal mass.
Assuntos
Tumores do Estroma Gastrointestinal , Hemoperitônio , Humanos , Íleo , LaparotomiaRESUMO
INTRODUCTION: Stump appendicitis is a rare complication of appendectomy due to recurrent inflammation of the residual appendix. The diagnosis is often delayed due to low index of suspicious, which may result in serious complications. CASE PRESENTATION: We describe a case of stump appendicitis occurred 12 months after appendectomy in 25 years old man. Despite past medical history of appendectomy the diagnosis was made by means of ultrasound scan and an high degree of clinical suspicion. CONCLUSIONS: Stump appendicitis is a rare but important complication of appendectomy, often misdiagnosed. Prompt recognition is important to avoid serious complications. This pathologic entity should always be kept in mind on case of right lower quadrant pain.