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Immunotherapy in biliary tract cancers:Current evidence and future perspectives

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World Journal of Gastrointestinal Oncology 2022年第8期14卷 1446-1455页

作者： Pedro Luiz Serrano Uson Junior raphael lc araujo Center for Personalized Medicine Hospital Israelita Albert EinsteinSão Paulo 05652-900Brazil Department of Surgery Universidade Federal de São PauloSão Paulo 04039-002Brazil Department of Oncology Hospital Israelita Albert EinsteinSão Paulo 05652-900Brazil

Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder *** are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall *** are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant *** Food and Drug Administration approvals of immune checkpoint inhibitors(ICI)for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct *** limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease,drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.

关键词： Biliary tract cancer Cholangiocarcinoma Anti-programmed cell death protein-1 Anti-programmed death ligand-1 Microsatellite instability high Tumor mutational burden high

Recurrence-free survival as a putative surrogate for overall survival in phase Ⅲ trials of curative-intent treatment of colorectal liver metastases:Systematic review

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World Journal of Clinical Oncology 2017年第3期8卷 266-272页

作者： raphael lc araujo Paulo Herman Rachel P Riechelmann Department of Upper Gastrointestinal and Hepato-Pancreato-Bliliary Sugery Barretos Cancer Hospital Department of Gastroenterology University of S?o Paulo Instituto do Cancer do Estado de S?o Paulo Universidade de S?o Paulo

AIM To verify whether recurrence-free survival(RFS) surrogates overall survival(OS) in phase Ⅲ trials for resectable colorectal liver metastases(CRLM).METHODS MEDLINE,EMBASE,and Scopus databases were *** studies were phase Ⅲ trials testing any type of systemic therapy(neoadjuvant,adjuvant or perioperative) added to surgery in patients with resectable CRLM.A linear regression model based on hazard ratios(HR) of OS and RFS was *** Of 3059 studies,5 phase Ⅲ trials(1162 patients) were included for analyses.A linear regression weighted by each trial was used to estimate the association between each HR and *** originated formula was:OS HR =(0.93 × RFS HR) + 0.14;with RFS 95%CI(0.48-1.38),with P = *** This association suggests that RFS could work as a putative surrogate endpoint of OS in this population,avoiding bigger,longer and more resource-consuming *** OS could be assumed based on RFS and our model could be useful to better estimate sample size calculations of phase Ⅲ trials of CRLM aiming for OS.

关键词： Colorectal liver metastases Surgery Chemotherapy Clinical trial Long-term outcomes Surrogate endpoints

Does autologous blood transfusion during liver transplantation for hepatocellular carcinoma increase risk of recurrence?

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World Journal of Gastrointestinal Surgery 2016年第2期8卷 161-168页

作者： raphael lc araujo Carlos Andrés Pantanali Luciana Haddad Joel Avancini Rocha Filho Luiz Augusto Carneiro D’Albuquerque Wellington Andraus Liver Surgery Unit Department of Gastroenterology University of Sao Paulo School of MedicineSao Paulo CEP 05403-900 Brazil DiviGastroenterology University of Sao Paulo School of Medicine Sao Paulo CEP 05403-900 Brazil Department of Anesthesiology University of Sao Paulo School of MedicineSao Paulo CEP 05403-900 Brazil

AIM: To analyze outcomes in patients who underwent liver transplantation(LT) for hepatocellular carcinoma(HCC) and received autologous intraoperative blood salvage(IBS). METHODS: Consecutive HCC patients who underwent LT were studied retrospectively and analyzed according to the use of IBS or not. Demographic and surgical data were collected from a departmental prospective maintained database. Statistical analyses were performed using the Fisher's exact test and the Wilcoxon rank sum test to examine covariate differences between patients who underwent IBS and those who did not. Univariate and multivariate Cox regression models were developed to evaluate recurrence and death,and survival probabilities were estimated using the Kaplan-Meier method and compared by the log-rank ***: Between 2002 and 2012,158 consecutive patients who underwent LT in the same medical center and by the same surgical team were identified. Among these patients,122(77.2%) were in the IBS group and 36(22.8%) in the non-IBS group. The overall survival(OS) and recurrence free survival(RFS) at 5 years were 59.7% and 83.3%,respectively. No differences in OS(P=0.51) or RFS(P=0.953) were detected between the IBS and non-IBS groups. On multivariate analysis for OS,degree of tumor differentiation remained as the only independent predictor. Regarding patients who received IBS,no differences were detected in OS or RFS(P=0.055 and P=0.512,respectively) according to the volume infused,even when outcomes at 90 d or longer were analyzed separately(P=0.518 for both outcomes).CONCLUSION: No differences in RFS or OS were detected according to IBS use. Trials addressing this question are justified and should be designed to detect small differences in long-term outcomes.

关键词： Cell saver Cancer Hepatocellular carcinoma Liver transplantation Recurrence

Combination approaches in hepatocellular carcinoma:How systemic treatment can benefit candidates to locoregional modalities

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World Journal of Gastroenterology 2022年第28期28卷 3573-3585页

作者： Leonardo Gomes da Fonseca raphael L C araujo Department of Medical Oncology Instituto do Cancer do Estado de Sao PauloUniversity of Sao PauloSão Paulo 01246-000São PauloBrazil Hospital e Maternidade Brasil-Rede D'Or São Luiz Santo André09030-590São PauloBrazil Department of Digestive Surgery Escola Paulista de Medicina-UNIFESPSão Paulo 04023-062São PauloBrazil

The management of hepatocellular carcinoma(HCC)is challenging because most patients have underlying cirrhosis,and the treatment provides,historically,a limited impact on the natural history of patients with advanced-stage ***,recurrence rates are high for those patients who receive local and locoregional modalities,such as surgical(resection and transplantation)or imageguided(ablation and intra-arterial)*** research has led to new concepts that are reshaping the current clinical *** advancements were achieved in the understanding of the hallmarks that drive *** has primed a successful incorporation of novel agents with different targets,such as anti-angiogenic drugs,targeted-therapies,and immune-checkpoint *** clinical trials have proven efficacy of systemic agents in advanced stage disease,there is no conclusive evidence to support their use in combination with loco-regional *** novel local modalities are being incorporated(e.g.,radioembolization,microwave ablation,and irreversible electroporation),emerging data indicate that locoregional treatments may induce tumor microenvironment changes,such as hyperexpression of growth factors,release of tumor antigens,infiltration of cytotoxic lymphocytes,and modulation of adaptative and innate immune *** trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial *** efforts are directed to investigate the role of immunotherapy-based regimens in this *** present review aims to describe the current landscape of systemic and locoregional treatments for HCC,present evidence to support combination approaches,and address future perspectives.

关键词： Liver cancer Hepatocellular carcinoma Immunotherapy Systemic therapy Ablation Embolization

Molecular profiling and patient selection for the multimodal approaches for patients with resectable colorectal liver metastases

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Hepatobiliary Surgery and Nutrition 2024年第2期13卷 273-292页

作者： raphael L.C.araujo Leonardo G.Fonseca raphael Oliveira Silva Marcelo Moura Linhares Pedro L.S.Uson Junior Department of Surgery Universidade Federal de São PauloSão PauloSPBrazil Hospital e Maternidade Brasil-Rede D’Or São Luiz Santo AndréSPBrazil Department of Oncology Hospital Israelita Albert EinsteinSão PauloSPBrazil Department of Oncology Instituto do Cancer do Estado de São PauloUniversity of Sao PauloSão PauloSPBrazil Department of Oncology Hospital Ministro Costa CavalcantiFoz do IguaçuPRBrazil Center for Personalized Medicine Hospital Israelita Albert EinsteinSão PauloSPBrazil

Colorectal cancer represents the third most common cancer and about 20%are diagnosed with synchronous metastatic *** a historical point of view,surgery remains the mainstream treatment for resectable colorectal liver metastases(CRLM).Furthermore,disease outcomes are improving due significant advances in systemic treatments and diagnostic ***,the optimal timing for neoadjuvant chemotherapy or upfront surgery for CRLM has not yet been established and remains an open ***,patient selection combining image workouts,time of recurrence,positive lymph nodes,and molecular biomarkers can improve the decision-making ***,molecular profiling is rising as a promising field to be incorporated in the multimodal approach and guide patient selection and sequencing of *** biomakers,genetic profiling,and circulating tumor DNA have been used to offer as much personalized treatment as possible,based on the precision oncology concept of tailored care rather than a guideline-based *** review article discusses the role of molecular pathology and biomarkers as prognostic and predictor factors in the diagnosis and treatment of resectable CRLM.

关键词： Colorectal liver metastases(CRLM) surgery chemotherapy molecular pathology circulating tumor DNA tumor markers

Oncologic aspects of the decision-making process for surgical approach for colorectal liver metastases progressing during chemotherapy

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World Journal of Gastrointestinal Surgery 2022年第9期14卷 877-886页

作者： raphael L C araujo Camila G C Y Carvalho Carlos T Maeda Jean Michel Milani Diogo G Bugano Pedro Henrique Z de Moraes Marcelo M Linhares Department of Surgery Universidade Federal de São PauloSão Paulo 04024-002Brazil Department of Oncology Hospital Israelita Albert EinsteinSão Paulo 05652-900Brazil Department of Surgical Oncology Hospital e Maternidade Brasil Rede D'Or São LuizSanto André09030-590São PauloBrazil

Colorectal cancer represents the third most diagnosed malignancy in the *** liver is the main site of metastatic disease,affected in 30%of patients with newly diagnosed *** resection is considered the only potentially curative treatment for colorectal liver metastasis(CRLM),with a 5-year survival rate ranging from 35%to 58%.However,up to 80%of patients have initially unresectable disease,due to extrahepatic disease or bilobar multiple liver *** availability of increasingly effective systemic chemotherapy has contributed to converting patients with initially unresectable liver metastases to resectable disease,improving long-term outcomes,and accessing tumor *** recent years,response to preoperative systemic chemotherapy before liver resection has been established as a major prognostic *** studies have demonstrated that patients with regression of hepatic metastases while on chemotherapy have improved outcomes when compared to patients with stabilization or progression of the *** if disease progression during chemotherapy represents an independent negative prognostic factor,some patients may still benefit from surgery,given the role of this modality as the main treatment with curative intent for patients with *** selected cases,based on size,the number of lesions,and tumor markers,surgery may be offered despite the less favorable prognosis and as an option for non-chemo responders.

关键词： Colorectal liver metastases Oncology Disease progression Surgery Liver resection Hepatectomy

Staggered Lagrangian Discretization Based on Cell-Centered Riemann Solver and Associated Hydrodynamics Scheme

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Communications in Computational Physics 2011年第9期10卷 940-978页

作者： Pierre-Henri Maire raphael Loubere Pavel Vachal CEA-CESTA BP 233114Le BarpFrance Institut de Mathematiques de Toulouse(IMT)Universite Paul-Sabatier and CNRS ToulouseFrance FNSPE Czech Technical University(CTU)in PragueCzech Republic

The aim of the present work is to develop a general formalism to derive staggered discretizations for Lagrangian hydrodynamics on two-dimensional unstructured *** this end,we make use of the compatible discretization that has been initially introduced by *** et al.,in ***.,146(1998).Namely,momentum equation is discretized by means of subcell forces and specific internal energy equation is obtained using total energy *** main contribution of this work lies in the fact that the subcell force is derived invoking Galilean invariance and thermodynamic *** is,we deduce a general form of the sub-cell force so that a cell entropy inequality is *** subcell force writes as a pressure contribution plus a tensorial viscous contribution which is proportional to the difference between the nodal velocity and the cell-centered *** cell-centered velocity is a supplementary degree of freedom that is solved by means of a cell-centered approximate Riemann *** satisfy the second law of thermodynamics,the local subcell tensor involved in the viscous part of the subcell force must be symmetric positive *** subcell tensor is the cornerstone of the *** particular expression of this tensor is given.A high-order extension of this discretization is *** tests are presented in order to assess the efficiency of this *** results obtained for various representative configurations of one and two-dimensional compressible fluid flows show the robustness and the accuracy of this scheme.

关键词： Lagrangian scheme Riemann solver artificial viscosity hydrodynamics compressible flow

Brain tumor surgery:supplemental intra-operative imaging techniques and future challenges

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Journal of Cancer Metastasis and Treatment 2016年第1期2卷 70-79页

作者： Telmo Augusto Barba Belsuzarri raphael Martinelli Anson Sangenis João Flavio Mattos araujo Department of Neurosurgery Pontifical Catholic University of CampinasCampinasSão Paulo 13060-803Brazil

Modern brain tumor surgery stands in the pillar of maximum safe *** borders are always challenging,especially infiltration zones in malignant brain *** technologies are designed for a better delineation and to increase the extent of resection(EOR)in brain tumor surgery,such as:cortical and sub-cortical mapping strategies with somatosensory-evoked potentials,awake stimulation mapping and cortical/sub-cortical stimulation for motor pathways,important for resection in eloquent areas;intra-operative imaging as functional and intra-operative magnetic resonance imaging,diffusion tensor imaging and intra-operative ultrasound are important for the tumor borders and to achieve the gross total resection;neurochemical navigation methods as 5-aminolevulinic and sodium fluorescein are important for the non-contrast-enhanced tumor border;future methods can be achieved with augmented reality surgery,new intra-operative chemical markers,and visualization *** all these techniques seem to be promising,the real challenge in the future will be held in how to apply them and how they really affect the prognosis of the ***,new concepts in tumor genetics will provide knowledge for the tumor behavior and will guide *** all limitations,the increasing importance of safe EOR shows the possible benefits of the novel technologies and surgical advances in brain tumor surgery,taking it to a new step of the neuronavigation era.

关键词： Brain tumor fluorescein intra-operative neuronavigation novel technology

Is it possible to adopt the same oncological approach in urgent surgery for colon cancer?

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World Journal of Clinical Oncology 2022年第11期13卷 896-906页

作者： Bruno Yuki Yoshida raphael L C araujo José Francisco M Farah Alberto Goldenberg Goldenberg Department of Surgery Federal University of Sao PauloSao Paulo 04024-002Sao PauloBrazil Department of General and Oncological Surgery Sao Paulo State Employee HospitalSao Paulo 04029-000Sao PauloBrazil

BACKGROUND Locoregional complications may occur in up to 30%of patients with colon *** they are frequent events in the natural history of this disease,there should be a concern in offering an oncologically adequate surgical treatment to these *** To compare the oncological radicality of surgery for colon cancer between urgent and elective *** One-hundred and eighty-nine consecutive patients with non-metastatic colon adenocarcinoma were studied over two years in a single institution,who underwent surgical resection as the first therapeutic approach,with 123 elective and 66 urgent *** assessment of oncological radicality was performed by analyzing the extension of the longitudinal margins of resection,the number of resected lymph nodes,and the percentage of surgeries with 12 or more resected lymph *** clinicopathological variables were compared between the two groups in terms of sex,age,tumor location,type of urgency,surgical access,staging,compromised lymph nodes rate,differentiation grade,angiolymphatic and perineural invasion,and early *** There was no difference between the elective and urgency group concerning the longitudinal margin of resection(average of 6.1 in elective vs 7.3 cm in urgency,P=0.144),number of resected lymph nodes(average of 17.7 in elective vs 16.6 in urgency,P=0.355)and percentage of surgeries with 12 or more resected lymph nodes(75.6%in elective vs 77.3%in urgency,P=0.798).It was observed that the percentage of patients aged 80 and over was higher in the urgency group(13.0%in elective vs 25.8%in urgency,P=0.028),and the early mortality was 4.9%in elective vs 15.2%in urgency(P=0.016,OR:3.48,95%CI:1.21–10.06).Tumor location(P=0.004),surgery performed(P=0.016)and surgical access(P<0.001)were also different between the two *** was no difference in other clinicopathological variables *** Oncological radicality of colon cancer surgery may be achieved in both emergency and

关键词： Colorectal cancer Intestinal obstruction Intestinal perforation Surgical oncology Lymph node excision