RESUMO
We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67+ tumor cells and CD3+ cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.
Assuntos
Infiltração Leucêmica/imunologia , Modelos Estatísticos , Neoplasias/imunologia , Carga Tumoral/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Most studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomic data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking. METHODS: To characterise the spatial transcriptomics of gallbladder cancer tumourigenesis in individual patients, we selected two patients with distinct cancer aetiology and whose samples simultaneously displayed multiple areas of normal epithelium, BilINs and adenocarcinoma. Using GeoMx digital spatial profiling, we characterised the whole transcriptome of a high number of regions of interest (ROIs) per sample in the two patients (24 and 32 ROIs respectively), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Human gallbladder organoids and cell line-derived tumours were used to investigate the tumour-promoting role of genes. RESULTS: Spatial transcriptomics revealed that each type of lesion displayed limited intra-patient transcriptomic variability. Our data further suggest that adenocarcinoma derived from high-grade BilIN in one patient and from low-grade BilIN in the other patient, with co-existing high-grade BilIN evolving via a distinct process in the latter case. The two patients displayed distinct sequences of signalling pathway activation during tumour progression, but Semaphorin 4 A (SEMA4A) expression was repressed in both patients. Using human gallbladder-derived organoids and cell line-derived tumours, we provide evidence that repression of SEMA4A promotes pseudostratification of the epithelium and enhances cell migration and survival. CONCLUSION: Gallbladder adenocarcinoma can develop according to patient-specific processes, and limited intra-patient variability of precursor and cancer lesions was noticed. Our data suggest that repression of SEMA4A can promote tumour progression. They also highlight the need to gain gene expression data in addition to histological information to avoid understimating the risk of low-grade preneoplastic lesions.
Assuntos
Adenocarcinoma , Progressão da Doença , Neoplasias da Vesícula Biliar , Perfilação da Expressão Gênica , Humanos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Transcriptoma , Masculino , Regulação Neoplásica da Expressão Gênica , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Feminino , Linhagem Celular Tumoral , Organoides/patologia , Vesícula Biliar/patologia , Idoso , Pessoa de Meia-IdadeRESUMO
BACKGROUND: While outcomes after spleen-preserving distal pancreatectomy (SP-DP) have been widely reported, impacts on splenic parenchyma have not been well studied. This study aimed to compare postoperative outcomes, particularly spleen-related outcomes, by assessing splenic imaging after SP-DP with or without splenic vessels removal. METHODS: Data for all patients who underwent SP-DP with splenic vessels removal (Warshaw technique, WDP) or preservation (Kimura technique, KDP) between 2010 and 2022 in two tertiary centres were retrospectively analysed. Splenic ischemia and volume at early/late imaging and postoperative outcomes were reviewed. RESULTS: Eighty-seven patients were included, 51 in the WDP and 36 in the KDP groups. Median Charlson's Comorbidity Index was significantly higher in the WDP group compared with the KDP group. Postoperative morbidity was similar between groups. There was more splenic ischemia at early imaging in the WDP group compared to the KDP group (55% vs. 14%, p = 0.018), especially severe ischemia (23% vs. 0%). Partial splenic atrophy was observed in 29% and 0% in the WDP and KDP groups, respectively (p = 0.002); no complete splenic atrophy was observed. Platelet levels at POD 1, 2 and 6 were significantly higher in the WDP group compared to KDP group. At univariate analysis, age, Charlson Comorbidity Index, platelet levels at POD 6, and early splenic infarction were prognostic factors for development of splenic atrophy. No episodes of overwhelming post-splenectomy infection or secondary splenectomy were recorded after a median follow-up of 9 and 11 months in the WDP and KDP groups, respectively. CONCLUSIONS: Splenic ischemia appeared in one-half of patients undergoing SP-DP with splenic vessels removal at early imaging, and partial splenic atrophy in almost 30% at late imaging, without clinical impact or complete splenic atrophy. Age, Charlson Comorbidity Index, platelet levels at POD 6, and early splenic infarction could help to predict the occurrence of splenic atrophy.
Assuntos
Esplenopatias , Infarto do Baço , Humanos , Pancreatectomia , Estudos Retrospectivos , AtrofiaRESUMO
BACKGROUND: The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to elucidate the outcome of the liver-first approach and to identify patients who benefit at most from this approach. METHODS: Patients with synchronous CRLM included in the LiverMetSurvey registry between 2000 and 2017 were considered. Three strategies were analyzed, i.e. liver-first approach, colorectal resection followed by liver resection (primary-first), and simultaneous resection, and three groups of patients were analyzed, i.e. solitary metastasis, multiple unilobar CRLM, and multiple bilobar CRLM. In each group, patients from the three strategy groups were matched by propensity score analysis. RESULTS: Overall, 7360 patients were analyzed: 4415 primary-first, 552 liver-first, and 2393 simultaneous resections. Compared with the other groups, the liver-first group had more rectal tumors (58.0% vs. 31.2%) and higher hepatic tumor burden (more than three CRLMs: 34.8% vs. 24.0%; size > 50 mm: 35.6% vs. 22.8%; p < 0.001). In patients with solitary and multiple unilobar CRLM, survival was similar regardless of treatment strategy, whereas in patients with multiple bilobar metastases, the liver-first approach was an independent positive prognostic factor, both in unmatched patients (3-year survival 65.9% vs. primary-first 60.4%: hazard ratio [HR] 1.321, p = 0.031; vs. simultaneous resections 54.4%: HR 1.624, p < 0.001) and after propensity score matching (vs. primary-first: HR 1.667, p = 0.017; vs. simultaneous resections: HR 2.278, p = 0.003). CONCLUSION: In patients with synchronous CRLM, the surgical strategy should be decided according to the hepatic tumor burden. In the presence of multiple bilobar CRLM, the liver-first approach is associated with longer survival than the alternative approaches and should be evaluated as standard.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Colorretais/cirurgia , Hepatectomia , Humanos , Fígado , Neoplasias Hepáticas/cirurgia , Sistema de Registros , Estudos RetrospectivosRESUMO
Background: Management of bile duct injury (BDI) after cholecystectomy is challenging. The authors analyzed their center's 49-year experience.Methods: From 1968 to 2016, 120 consecutive patients were managed in a tertiary HBP center, 105 referred from other centers (Group A), 15 from our center (Group B). Surgical strategies and long-term outcomes were retrospectively reviewed.Results: Primary cholecystectomy approach was open in 35% and laparoscopic in 65%. In Group A, intraoperative BDI diagnosis was made in 25/105 patients, including 13 via intraoperative cholangiography (IOC) which was used in 21% of cases. Median time from BDI to referral was 148 days (range 0-10,758), and 3 patients had BDI-related secondary cirrhosis. Ninety-four patients underwent secondary surgical repair, mostly a complex biliary procedure (97%). Postoperative overall and severe morbidity rates were 26% and 6%, respectively. One patient with biliary cirrhosis at referral died postoperatively from hepatic failure. Nine patients (9.6%) developed a secondary biliary stricture after a median of 54 months from repair (6-228 months). In Group B, IOC was performed in 14/15 in whom BDI were intraoperatively detected and immediately repaired. There were 13 minor and 2 major BDIs, all repaired by uncomplex procedures with uneventful postoperative course. One patient had a secondary biliary stricture after 5 months, successfully treated by temporary endoprosthesis.Conclusion: Late follow-up after primary or secondary repair of BDI is recommended to detect recurrent biliary stricture. Bile duct injuries may occur in a tertiary center, but are intraoperatively detected with routine IOC and immediately repaired resulting in satisfactory outcome.
Assuntos
Ductos Biliares/lesões , Doenças Biliares/cirurgia , Colecistectomia/efeitos adversos , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colangiografia , Feminino , Humanos , Complicações Intraoperatórias/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: While distal pancreatectomy with splenectomy (DPS) is the reference treatment for pancreatic body and tail neoplasia, oncological benefits of splenectomy have never been demonstrated. Involvement of spleen, splenic hilum and lymph nodes (LN) was therefore assessed on DPS specimens. METHODS: All DPS pancreatic neoplasia specimens obtained in 2 Brussels University Hospitals over 15 years (2004-2018) were reviewed retrospectively, using both preoperative radiological imaging and postoperative pathological analyses of splenic parenchyma, hilar tissue and LN. RESULTS: The total of 130 DPS specimens included 85 adenocarcinomas, 37 neuroendocrine neoplasms and 8 other carcinomas. Tumours involved the pancreatic body without tail invasion for 59 specimens (B, Body group), and the pancreatic tail with/without body for 71 (T, Tail group). At pathology, direct splenic and/or hilar involvement was observed in 13 T specimens (13/71, 18.3%), but in none belonging to the Body group. The observed numbers of splenic hilar LN (only reported in 49/130 patients) were low, only one T adenocarcinoma had positive splenic LN in addition to direct splenic involvement. CONCLUSION: Splenectomy remains justified during pancreatectomy for neoplasia involving the pancreatic tail, but in case of pancreatic body tumours, its benefits should be questioned in the light of absent splenic LN/parenchymal involvement.
Assuntos
Pancreatectomia , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Baço , EsplenectomiaRESUMO
In the context of the flat-rate reimbursements in healthcare, we reviewed physicians' behavior towards laboratory test ordering. We demonstrated how it could be improved when a specific stage of the patient management is considered. We took a multi-step approach to analyze the laboratory test orders in the context of planned laparoscopic cholecystectomy in a general teaching hospital. A reference order set was defined through a collaborative analysis between clinicians and laboratory physicians. The clinical and financial impacts were then evaluated over a period of 24 months. After the introduction of the reference order set, the number of laboratory tests per order decreased significantly for patients with cholecystitis of low severity. Above the monitoring of repeated orderings during a single stay, the major impacts were achieved by a drastic reduction of inappropriate orders, particularly in the field of bacteriology. The main effects of the order set were maintained throughout a follow-up period of 24 months. Our study demonstrated that, when considering laboratory test ordering optimization, reference order sets could achieve high levels of efficiency. To ensure high compliance to reference order sets, extensive collaboration between clinicians and laboratory physician is mandatory even if very sophisticated information systems are available.
Assuntos
Testes Diagnósticos de Rotina/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Hospitais de Ensino/economia , Padrões de Prática Médica/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/economia , Antibacterianos/uso terapêutico , Bélgica , Colecistectomia Laparoscópica/economia , Colecistectomia Laparoscópica/métodos , Colecistectomia Laparoscópica/reabilitação , Testes Diagnósticos de Rotina/ética , Feminino , Hospitais de Ensino/ética , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Médicos/psicologia , Projetos Piloto , Padrões de Prática Médica/éticaRESUMO
BACKGROUND: Laparoscopic liver surgery (LLS) gained popularity bringing several advantages including decreased morbidity and reduction of length of hospital stay compared to open. METHODS: To understand practice and evolution of LLS in Belgium, a 20-questions survey was sent to all members of the Royal Belgian Society for Surgery, the Belgian Section of Hepato-Pancreatic and Biliary Surgery and the Belgian Group for Endoscopic Surgery. RESULTS: Thirty-seven surgical units representing 61 surgeons performing LLS in Belgium responded: 50% from regional hospitals, 28% from university and 22% from peripheral hospitals. Replies from high volume centers (>50 liver-surgery/year) were 19%. More than 25% of liver procedures were performed laparoscopically in 35% of centers. LLS is adopted since more than 15-years in 14.5% of centers with an increasing rate reported in 59%. Low relevance of LLS in the hospital organization (26.5%) and lack of time in surgical schedules (12%) or of specific training (9%) are the main barriers for further diffusion. More than 80% of the responders agreed to participate to a national prospective registry. CONCLUSION: LLS is mainly performed in experienced HPB units with an increasing interest in peripheral centers. A prospective national registry will be useful by providing real data in terms of indications, morbidity and overall evolution.
Assuntos
Hepatectomia , Laparoscopia , Hepatopatias/diagnóstico , Hepatopatias/cirurgia , Padrões de Prática Médica , Bélgica , Humanos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The combination of liver resection and chemotherapy has become the standard of care for colorectal liver metastases (LM). The objective of the present study was to evaluate the impact of two-stage hepatectomy (TSH) on the long-term survival of patients with bilobar LM. METHODS: We included adult (over-18) patients from the LiverMetSurvey registry with confirmed multiple colorectal LM and having undergone either one-stage hepatectomy or TSH with curative intent. The "TSH (2/2)" group (n = 625) comprised patients having completed both stages of TSH; the "TSH (1/2)" group (n = 244) comprised patients having undergone only the first stage of TSH; the "hepatectomy" group. The primary outcome criterion was the overall survival (OS). The secondary outcomes were the morbidity and mortality rates. RESULTS: The 30- and 90-day mortality rates were respectively 3.8% and 9.3% in the TSH (2/2) group, 9.4% and 16.4% in the TSH (1/2) group, and 5.4% and 9.1% in the "hepatectomy" group. The three-year OS rate was 45% in the TSH (2/2) group, 30% in the TSH (1/2) group and 50.7% in the hepatectomy group. CONCLUSION: The LiverMetSurvey registry's data indicate that TSH is associated with rather good long-term survival and acceptable morbidity and mortality rates.
Assuntos
Neoplasias Colorretais/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Metastasectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Pesquisas sobre Atenção à Saúde , Hepatectomia/efeitos adversos , Hepatectomia/mortalidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Metastasectomia/efeitos adversos , Metastasectomia/mortalidade , Pessoa de Meia-Idade , Análise Multivariada , Complicações Pós-Operatórias/etiologia , Pontuação de Propensão , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Catalysts are a vital part of synthetic chemistry. However, there are still many important reactions for which catalysts have not been developed. The use of enzymes as biocatalysts for synthetic chemistry is growing in importance due to the drive towards sustainable methods for producing both bulk chemicals and high value compounds such as pharmaceuticals, and due to the ability of enzymes to catalyse chemical reactions with excellent stereoselectivity and regioselectivity. Such challenging transformations are a common feature of natural product biosynthetic pathways. In this mini-review, we discuss the potential to use biosynthetic pathways as a starting point for biocatalyst discovery. We introduce the reader to natural product assembly and tailoring, then focus on four classes of enzyme that catalyse CâH bond activation reactions to functionalize biosynthetic precursors. Finally, we briefly discuss the challenges involved in novel enzyme discovery.
Assuntos
Produtos Biológicos/metabolismo , Vias Biossintéticas , Enzimas/metabolismo , Biologia Sintética/métodosRESUMO
BACKGROUND: Chemotherapeutic advances have enabled successful cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) expansion in treating metastatic colorectal cancer. OBJECTIVES: The aims of this study were to evaluate the safety of combining liver surgery (LS) with HIPEC and CRS (which remains controversial) and its impact on overall survival (OS) rates. METHODS: From 2007 to 2015, a total of 77 patients underwent CRS/HIPEC for peritoneal carcinomatosis (PC) of colorectal cancer. Twenty-five of these patients underwent concomitant LS for suspicion of liver metastases (LM; group 2), and were compared with patients who underwent CRS/HIPEC only (group 1). Demographic and clinical data were reviewed retrospectively. RESULTS: Among the group 2 patients, two underwent major hepatectomies, six underwent multiple wedge resections, 16 underwent single wedge resections (one with radiofrequency ablation), and one underwent radiofrequency ablation alone. For groups 1 and 2, median peritoneal cancer index was 6 and 10 (range 0-26; p = 0.08), complication rates were 15.4 and 32.0 % (Dindo-Clavien ≥3; p = 0.15), and median follow-up was 34.2 and 25.5 months (range 0-75 and 3-97), respectively. One group 2 patient died of septic shock after 66 days. Pathology confirmed LM in 21 patients in group 2 (four with benign hepatic lesions were excluded from long-term outcome analysis). Two-year OS rates were 89.5 and 70.2 % (p = 0.04), and 2-year recurrence-free survival rates were 38.3 and 13.4 % (p = 0.01) in groups 1 and 2, respectively. CONCLUSIONS: Simultaneous surgery for colorectal LM and PC is both feasible and safe, with low postoperative morbidity. Further longer-term studies would help determine its impact on patient survival.
Assuntos
Neoplasias Colorretais/patologia , Hipertermia Induzida , Neoplasias Hepáticas/cirurgia , Neoplasias Peritoneais/terapia , Adolescente , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Ablação por Cateter/efeitos adversos , Terapia Combinada/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Hepatectomia/efeitos adversos , Humanos , Hipertermia Induzida/efeitos adversos , Infusões Parenterais , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Peritoneais/secundário , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: The use of neo-adjuvant chemotherapy in resectable synchronous liver metastasis is ill defined. The aim of this study was to evaluate neo-adjuvant chemotherapy on outcomes following liver resection for synchronous CLM. METHODS: An analysis of a multi-centric cohort from the LiverMetSurvey International Registry, who had undergone curative resections for synchronous CLM was undertaken. Patients who received neo-adjuvant chemotherapy prior to liver surgery (group NAS; n = 693) were compared with those treated by surgery alone (group SG; n = 608). Baseline clinicopathological variables were compared. Predictors of overall (OS) and disease free survival (DFS) were subsequently identified. RESULTS: Clinicopathological comparison of the groups revealed a greater proportion of solitary metastasis in the SG compared to the NAS group (58.8% versus 38.4%; P < 0.001) therefore a separate analysis of solitary versus multi-centric analysis was performed. N-stage (> N1), number of metastasis (> 3), serum CEA (> 5 ng/ml) and no adjuvant chemotherapy independently predicted poorer OS, while N-stage (> N1), serum CEA (> 5 ng/ml) and no adjuvant chemotherapy independently predicted poorer DFS. Neo-adjuvant chemotherapy did not independently affect outcome. CONCLUSION: We present an analysis of a large multi-center series of the role of neo-adjuvant chemotherapy in resectable CLM and demonstrate no survival advantage in this setting.
Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Terapia Neoadjuvante , Antígeno Carcinoembrionário/sangue , Quimioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Sistema de Registros , Estudos RetrospectivosRESUMO
Splenectomy is the only potentially curative treatment for chronic immune thrombocytopenic purpura (ITP) in adults. However, one-third of the patients relapse without predictive factors identified. We evaluate the predictive value of the site of platelet sequestration on the response to splenectomy in patients with ITP. Eighty-two consecutive patients with ITP treated by splenectomy between 1992 and 2013 were retrospectively reviewed. Platelet sequestration site was studied by (111)Indium-oxinate-labeled platelets in 93% of patients. Response to splenectomy was defined at last follow-up as: complete response (CR) for platelet count (PC) ≥100 × 10(9)/L, response (R) for PC≥30 × 10(9)/L and <100 × 10(9)/L with absence of bleeding, no response (NR) for PC<30 × 10(3)/L or significant bleeding. Laparoscopic splenectomy was performed in 81 patients (conversion rate of 16%), and open approach in one patient. Median follow-up was 57 months (range, 1-235). Platelet sequestration study was performed in 93% of patients: 50 patients (61%) exhibited splenic sequestration, 9 (11%) hepatic sequestration and 14 patients (17%) mixed sequestration. CR was obtained in 72% of patients, R in 25% and NR in 4% (two with splenic sequestration, one with hepatic sequestration). Preoperative PC, age at diagnosis, hepatic sequestration and male gender were significant for predicting CR in univariate analysis, but only age (HR = 1.025 by one-year increase, 95% CI [1.004-1.047], p = 0.020) and pre-operative PC (HR = 0.112 for > 100 versus <=100, 95% CI [0.025-0.493], p = 0.004) were significant predictors of recurrence-free survival in multivariate analysis. Response to splenectomy was independent of the site of platelet sequestration in patients with ITP. Pre-operative platelet sequestration study in these patients cannot be recommended.
Assuntos
Plaquetas/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/cirurgia , Esplenectomia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Esplenectomia/métodos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Postoperative pancreatic fistula (POPF) is a major complication after pancreatic surgery and results from an impaired healing of the pancreatic enteric anastomosis. Whether perioperative hemodynamic fluid management aiming to provide an adequate tissue perfusion could influence the occurrence of POPF is unknown. Serum lactate level is a well-recognized marker of decreased tissue perfusion and is known to be associated with higher morbidity and mortality in various postoperative settings. We aimed to determine in a retrospective high-volume center's cohort whether postoperative hyperlactatemia could predict POPF occurrence. METHOD: We conducted a retrospective analysis of 96 consecutive patients admitted in the intensive care unit (ICU) after pancreaticoduodenectomy or distal pancreatectomy. Univariate analysis was conducted to compare lactate levels at 6 h between patients evolving with versus without POPF. A logistic regression model was developed and included potential confounding factors. RESULTS: POPF occurred in 28 patients (29 %). Serum lactate level 6 h after admission was significantly higher in the POPF group (2.8 mmol/L [95 % confidence interval (CI): 2.1-3.5] versus 1.8 mmol/L [95 % CI: 1.8-2.4], p-value = 0.04) whereas it did not differ at ICU admission or at 12 h. Despite similar cumulative fluid balance, fluid intake and vasopressor use, hyperlactatemia > 2.5 mmol/L (Odds ratio (OR): 3.58; 95 % CI: 1.22-10.48; p-value = 0.020) and red blood cells transfusion (OR: 1.24; 95 % CI: 1.03-1.49; p-value = 0.022) were found to be independent predictive factors of POPF occurrence. CONCLUSION: In patients undergoing partial pancreatectomy, hyperlactatemia measured 6 h after ICU admission is a predictive factor for the occurrence of POPF. Inflammatory changes after surgery may account for this observation and should be further evaluated.
Assuntos
Hiperlactatemia/epidemiologia , Pancreatectomia/efeitos adversos , Fístula Pancreática/epidemiologia , Pancreaticoduodenectomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pancreatectomia/métodos , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
PURPOSE: The aims of this study were to assess the risk of early recurrence after liver resection for colorectal metastases (CRLM) and its prognostic value; identify early recurrence predictive factors; clarify the effect of perioperative chemotherapy on its occurrence; and elucidate the best early recurrence management. METHODS: Patients of the LiverMetSurvey registry who underwent complete liver resection (R0/R1) between 1998 and 2009 were reviewed. Early recurrence was defined as any recurrence that occurred within 6 months after resection. RESULTS: A total of 6,025 patients were included; 2,734 (45.4 %) had recurrence, including 639 (10.6 %) early recurrences. Early recurrence was mainly hepatic (59.5 vs. 54.4 % for late recurrences; p = 0.023). Independent risk factors of early recurrence were: T3-4 primary tumor (p = 0.0002); synchronous CRLM (p = 0.0001); >3 CRLM (p < 0.0001); 0-mm margin liver resection (p = 0.003); and associated intraoperative radiofrequency ablation (p = 0.0005). Response to preoperative chemotherapy (complete/partial) and administration of adjuvant chemotherapy reduced early recurrence risk (p = 0.003 and p < 0.0001, respectively). Intraoperative ultrasonography reduced hepatic early recurrence rate (p = 0.025). Early recurrence negatively affected prognosis: 5-year survival 26.9 versus 49.4 % for the late recurrence group (p < 0.0001, median follow-up 34.4 months). Overall, 234 (36.6 %) patients with early recurrence underwent re-resection. These patients had survival rates higher than non-re-resected patients (5-year survival 47.2 vs. 8.9 %; p < 0.0001) and similar to re-resected patients for late recurrence (48.7 %). Chemotherapy before early recurrence resection improved later survival (5-year survival 61.5 vs. 43.7 %; p = 0.028). CONCLUSIONS: Early recurrence risk is enhanced for extensive disease after poor preoperative disease control and inadequate surgical treatment, but is reduced after adjuvant chemotherapy. Although early recurrence negatively affects prognosis, re-resection may restore better survival. Chemotherapy before early recurrence resection is advocated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/terapia , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/etiologia , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours. METHODS: Patients aged 18-85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (≤3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778. FINDINGS: Between June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19.8%) patients in the pancreaticojejunostomy group and 13 (8.0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2.86, 95% CI 1.38-6.17; p=0.002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade ≥3a than in the pancreaticogastrostomy group (39 vs 35). INTERPRETATION: In patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula. FUNDING: Funding Johnson & Johnson Medical Devices, Belgium.
Assuntos
Ampola Hepatopancreática/cirurgia , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias Duodenais/cirurgia , Gastrostomia/efeitos adversos , Fístula Pancreática/diagnóstico , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticojejunostomia/efeitos adversos , Complicações Pós-Operatórias , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ampola Hepatopancreática/patologia , Neoplasias do Ducto Colédoco/complicações , Neoplasias do Ducto Colédoco/patologia , Neoplasias Duodenais/complicações , Neoplasias Duodenais/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fístula Pancreática/etiologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Prognóstico , Procedimentos de Cirurgia Plástica , Adulto JovemRESUMO
OBJECTIVES: The most frequent presentation of chemotherapy-related toxicity in colorectal liver metastases (CRLM) is sinusoidal obstruction syndrome (SOS). The purpose of the present study was to identify preoperative factors predictive of SOS and to establish associations between type of chemotherapy and severity of SOS. METHODS: A retrospective study was carried out in a tertiary academic referral hospital. Patients suffering from CRLM who had undergone resection of at least one liver segment were included. Grading of SOS on the non-tumoral liver parenchyma was accomplished according to the Rubbia-Brandt criteria. A total of 151 patients were enrolled and divided into four groups according to the severity of SOS (grades 0-3). RESULTS: Multivariate analysis identified oxaliplatin and 5-fluorouracil as chemotherapeutic agents responsible for severe SOS lesions (P < 0.001 and P = 0.005, respectively). Bevacizumab was identified as having a protective effect against the occurrence of SOS lesions (P = 0.005). Univariate analysis identified the score on the aspartate aminotransferase : platelets ratio index (APRI) as the most significant biological factor predictive of severe SOS lesions. Splenomegaly is also significantly associated with the occurrence of severe SOS lesions. CONCLUSIONS: The APRI score and splenomegaly are effective as factors predictive of SOS. Bevacizumab has a protective effect against SOS.
Assuntos
Antineoplásicos/efeitos adversos , Aspartato Aminotransferases/sangue , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Hepatopatia Veno-Oclusiva/induzido quimicamente , Neoplasias Hepáticas/secundário , Esplenomegalia/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/prevenção & controle , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Esplenomegalia/diagnóstico , Resultado do Tratamento , Adulto JovemRESUMO
Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.
Assuntos
Neoplasias da Mama , Humanos , Camundongos , Animais , Feminino , Neoplasias da Mama/metabolismo , Ácido Pantotênico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , VitaminasRESUMO
BACKGROUND: Liver-first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver-directed chemotherapy, the resection of the CRLM, and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80% of patients can successfully undergo a complete RM, whereas less than 30% of those undergoing classical management (CM) do so. This registry-based study compared the 2 approaches. METHODS: The study was based on the LiverMetSurvey (January 1, 2000 to December 31, 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin-based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. RESULTS: A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM, P = 0.231) and Fong scores of 3 or more (79% vs 87%, P = 0.164). Rectal cancer, neoadjuvant rectal radiotherapy, and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001), whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease-free survival were similar in the RM and CM groups (48% vs 46% at 5 years, P = 0.965 and 30% vs 26%, P = 0.992). CONCLUSIONS: Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed.
Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Distribuição de Qui-Quadrado , Neoplasias Colorretais/tratamento farmacológico , Terapia Combinada , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/tratamento farmacológico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Pontuação de Propensão , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Laparoscopic cholecystectomy is considered nowadays as the standard management of acute cholecystitis (AC). However, results from multicentric studies in the general surgical community are still lacking. METHODS: A prospective multicenter survey of surgical management of AC patients was conducted over a 2-year period in Belgium. Operative features and patients' clinical outcome were recorded. The impact of independent predictive factors on the choice of surgical approach, the risk of conversion, and the occurrence of postoperative complications was studied by multivariate logistic regression analysis. RESULTS: Fifty-three surgeons consecutively and anonymously included 1,089 patients in this prospective study. A primary open approach was chosen in 74 patients (6.8%), whereas a laparoscopic approach was the first option in 1,015 patients (93.2%). Independent predictive factors for a primary open approach were previous history of upper abdominal surgery [odds ratio (OR) 4.13, p < 0.001], patient age greater than 70 years (OR 2.41, p < 0.05), surgeon with more than 10 years' experience (OR 2.08, p = 0.005), and gangrenous cholecystitis (OR 1.71, p < 0.05). In the laparoscopy group, 116 patients (11.4%) required conversion to laparotomy. Overall, 38 patients (3.5%) presented biliary complications and 49 had other local complications (4.5%). Incidence of bile duct injury was 1.2% in the whole series, 2.7% in the open group, and 1.1% in the laparoscopy group. Sixty patients had general complications (5.5%). The overall mortality rate was 0.8%. All patients who died were in poor general condition [American Society of Anesthesiologists (ASA) III or IV]. CONCLUSIONS: Although laparoscopic cholecystectomy is currently considered as the standard treatment for acute cholecystitis, an open approach is still a valid option in more advanced disease. However, overall mortality and incidence of bile duct injury remain high.