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2.
Eur J Cancer ; 206: 114128, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38805957

RESUMO

Duodenal adenocarcinoma is a rare digestive cancer, often diagnosed at a late stage and harbours a poor prognosis. The arrival of immunotherapy has changed the prognosis of many neoplasia, including digestive adenocarcinomas with MSI-H status. Hereby, we describe three cases of MSI-H locally advanced duodenal adenocarcinoma who received neoadjuvant treatment with a PD1 inhibitor, pembrolizumab. A partial metabolic and endoscopic response was observed in all patients after 2 cycles. Duodenopancreatectomy was performed at the end of treatment (4-6 cycles), and anatomopathological analysis demonstrated pathological complete response in all patients. Our case series paves the way for prospectively exploring neoadjuvant immunotherapy in duodenal MSI-H adenocarcinoma and raises the question of organ sparing surgery in case of complete clinical response as observed in gastric and colo-rectal adenocarcinomas.


Assuntos
Adenocarcinoma , Anticorpos Monoclonais Humanizados , Neoplasias Duodenais , Instabilidade de Microssatélites , Terapia Neoadjuvante , Humanos , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adenocarcinoma/patologia , Neoplasias Duodenais/genética , Neoplasias Duodenais/patologia , Neoplasias Duodenais/terapia , Terapia Neoadjuvante/métodos , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Resultado do Tratamento
3.
Clin Res Hepatol Gastroenterol ; 47(4): 102108, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36878461

RESUMO

BACKGROUND: Trop-2 is overexpressed in tumor cells of various cancers, including pancreatic ductal adenocarcinoma (PDAC), and has emerged as a potent therapeutic target. We evaluated Trop-2 expression both at the transcriptomic and protein levels, and its correlation with tumor features and patients' outcomes in a large cohort of PDAC. METHODS: We included patients undergoing pancreatic resection for PDAC in 5 academic hospitals in France and Belgium. Transcriptomic profiles were obtained from FFPE tissue samples, with paired primary -25and metastatic lesions when available. Protein expression was evaluated by immunohistochemistry (IHC) using tissue micro-arrays. RESULTS: 495 patients (male 54%, median age 63 years) were included between 1996 and 2012. Trop-2 mRNA expression was significantly associated to tumor cellularity, but no association with survival nor with any clinical or pathological features was observed, with tumor cells showing an overall high expression among every subgroup. Trop-2 mRNA expression was maintained between primary and metastatic lesion in all 26 paired samples evaluated. In 50 tumors assessed by IHC, 30%, 68% and 2% harbored a high, medium, or low Trop-2 expression score, respectively. Trop-2 staining was significantly associated to mRNA expression, but not to survival or any pathological features. CONCLUSIONS: Our results suggest Trop-2 overexpression as a ubiquitous marker of PDAC tumor cells and thus a promising therapeutic target to evaluate in these patients.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , RNA Mensageiro/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Neoplasias Pancreáticas
4.
ESMO Open ; 7(1): 100386, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35124465

RESUMO

Pancreatic exocrine insufficiency (PEI) is a common condition in patients with pancreatic cancer (PC). PEI can be due to the tumor, which, if located in the head, causes obstruction of the pancreatic duct with subsequent atrophy of the pancreatic parenchyma, or it can be the consequence of pancreatic surgical resection. The standard treatment of PEI is pancreatic enzyme replacement therapy (PERT). Clinical data to support the use of PERT in PC are however limited. There are very few randomized clinical trials that evaluated PERT in PC. Most data come from observational studies. Despite this limited clinical evidence, PERT treatment for PEI is an essential part of supportive therapy to ensure optimal nutritional status in PC patients who will receive surgery, neoadjuvant/adjuvant or palliative treatment. The objective of this review is to increase the awareness about PEI in PC patients and to provide expert recommendations on the use of PERT in resected, borderline resectable and unresectable patients, based on clinical experience and literature review.


Assuntos
Insuficiência Pancreática Exócrina , Neoplasias Pancreáticas , Terapia de Reposição de Enzimas/efeitos adversos , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/terapia , Prova Pericial , Humanos , Pâncreas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/terapia
5.
Transl Oncol ; 16: 101315, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34906890

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

6.
Acta Gastroenterol Belg ; 84(3): 451-455, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34599570

RESUMO

BACKGROUND AND AIMS: Endoscopic ultrasound fine-needle aspiration/biopsy (EUS-FNA/FNB) is highly accurate, but discrepancies between cytological and surgical diagnoses are still observed. We aimed to determine its accuracy and monitor quality indicators in our facilities. PATIENTS AND METHODS: We performed a retrospective review of all cases of pancreatic solid lesions evaluated by EUS-FNA/FNB, between July 2015 and June 2018, in two centers. Cytological and surgical findings were categorized into five groups: benign, malignant, suspect of malignancy, undetermined and insufficient for diagnosis. Final diagnosis was based on surgical diagnosis and, in patients who did not undergo surgery, on clinical outcome after 6 months follow-up. RESULTS: Altogether, 142 patients were included. FNA was the preferred tissue acquisition method (88%), with a predilection for the FNA 22G needle (57%). Cytology was insufficient for diagnosis in 2 cases, therefore a full diagnostic sample was available in 98.6% of the patients (>90%, ESGE target). Fifty-five (38.7%) patients underwent surgery. In term of cancer diagnosis, comparison with final surgical pathology (n=55) revealed 89% true positives, 5.5% true negatives, 3.6% false positives and 1.8% false negatives. When combining surgical diagnosis and clinical outcomes together, EUS-guided sampling sensitivity was 97.4% (92.5-99.5), specificity was 92.3% (74.9-99.1), positive predictive value was 98.2% (93.6- 99.5), negative predictive value was 88.9% (72.3-96.1) and accuracy was 96.4% (91.9-98.8). Post-procedural acute pancreatitis was reported in 2 patients (1.4%). CONCLUSIONS: These results reveal a performance for diagnostic tissue sampling well above the ESGE proposed target standard. Also, the uncommon high specificity illustrates the determining role of the pathologist's final interpretation and diagnosis.


Assuntos
Neoplasias Pancreáticas , Pancreatite , Doença Aguda , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Endoscopia , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Indicadores de Qualidade em Assistência à Saúde , Estudos Retrospectivos
7.
Ann Oncol ; 32(2): 250-260, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33188873

RESUMO

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Quimioterapia Adjuvante , Desoxicitidina/análogos & derivados , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Estudos Retrospectivos , Transcriptoma , Gencitabina
9.
Ann Oncol ; 31(9): 1169-1177, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32464280

RESUMO

BACKGROUND: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).


Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ductos Biliares Intra-Hepáticos , Neoplasias do Sistema Biliar/tratamento farmacológico , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Humanos , Compostos de Fenilureia , Platina/uso terapêutico , Piridinas , Resultado do Tratamento , Gencitabina
10.
Ann Oncol ; 30(9): 1428-1436, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31161208

RESUMO

BACKGROUND: Different histological and molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different molecular composition and survival statistics, have recently been recognised. MATERIALS AND METHODS: This review describes the currently available studies regarding molecular and histological subtypes in PDAC. Studies from major cohorts such as International Cancer Genome Consortium as well as smaller cohorts are reviewed. We discuss where the described subtypes overlap, where the discrepancies are and which paths forward could be taken regarding diagnosis, ontogeny and therapy. RESULTS: Four molecular subtypes with strong overlap among the different studies can be found, next to a list of mixed findings. Two of the four subtypes (epithelial classical and mesenchymal basal-like) were represented in every study and were often discriminated in other solid tumours as well. These two subtypes differ substantially in prognosis. One biomarker has been discovered, only discriminating these two subtypes, and insights into subtype-specific therapeutic vulnerabilities are scarce. CONCLUSION: Subtypes can be reproducibly detected in cohorts of PDAC patients and two of them directly relate with prognosis. A consensus on the subtypes is warranted. Further discovery and validation studies are needed to identify strong biomarkers, to comprehend subtype ontogeny and to define strategies for precision medicine.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Transcriptoma/genética , Adenocarcinoma/classificação , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/classificação , Carcinoma Ductal Pancreático/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Medicina de Precisão/tendências , Prognóstico
11.
J Immunol Res ; 2018: 4874193, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854838

RESUMO

BACKGROUND: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. METHOD: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. RESULTS: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) (p < 0.05). CONCLUSIONS: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neuroimunomodulação , Neoplasias Pancreáticas/diagnóstico , Nervo Vago/fisiologia , Idoso , Idoso de 80 Anos ou mais , Bélgica , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Frequência Cardíaca , Humanos , Imunomodulação , Inflamação , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
12.
Ann Oncol ; 28(7): 1473-1483, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28459988

RESUMO

Pancreatic adenocarcinoma is a frequent and severe disease, either diagnosed as metastatic pancreatic adenocarcinoma (MPA) or as locally advanced pancreatic carcinoma (LAPC). Though no improvement in patients outcome have been made between 1996 and 2011, since 5 years new treatment options have become available to treat our patients. New standard first line regimens, such as FOLFIRINOX and gemcitabine combined with nab-paclitaxel, have improved overall survivals and second line treatments have been tested and validated. Other first-line treatments have failed, but research remains active and trials are ongoing with promising new anti-cancer agents. These new effective regimens used for MPA have yielded promising results in LAPC patients in open cohorts or phase II trials and a recent trial have failed to demonstrate the added value of classical external radiotherapy in this setting. Here, we review current standards of care in LAPC and MPA, consider the latest challenges and strategic questions, and examine what we may hope for in the future.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/radioterapia , Fatores de Tempo , Resultado do Tratamento
13.
Ann Oncol ; 28(4): 824-830, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28031175

RESUMO

Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab/administração & dosagem , Quimioterapia Adjuvante/métodos , Neoplasias do Colo/tratamento farmacológico , Adenocarcinoma/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Neoplasias do Colo/genética , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Adulto Jovem , Proteínas ras/genética
14.
Br J Cancer ; 115(10): 1245-1252, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27755532

RESUMO

BACKGROUND: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins. RESULTS: High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort. CONCLUSIONS: Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Desoxicitidina/análogos & derivados , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação ao Cálcio , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante/métodos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/patologia , Prognóstico , Receptor Notch1/metabolismo , Receptor Notch3/metabolismo , Gencitabina
15.
Dig Liver Dis ; 48(11): 1283-1289, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27590840

RESUMO

BACKGROUND AND SCOPE: The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. METHODOLOGY: Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. RESULTS: Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. CONCLUSION: GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.


Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Junção Esofagogástrica/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Congressos como Assunto , Tratamento Farmacológico , Endoscopia Gastrointestinal , Esofagostomia , Medicina Baseada em Evidências , Gastrectomia , Humanos , Oncologia , Estadiamento de Neoplasias , Apoio Nutricional , Cuidados Paliativos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sociedades Médicas , Espanha , Organização Mundial da Saúde
16.
Ann Oncol ; 27(4): 648-53, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26802153

RESUMO

BACKGROUND: In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial. PATIENTS AND METHODS: Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity. RESULTS: PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001). CONCLUSION: Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response. CLINICALTRIALSGOV: NCT00844649.


Assuntos
Adenocarcinoma/tratamento farmacológico , Albuminas/administração & dosagem , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Gencitabina
17.
Rev Med Suisse ; 11(483): 1543-8, 2015 Aug 26.
Artigo em Francês | MEDLINE | ID: mdl-26502580

RESUMO

Pancreatic ductal adenocarcinoma is characterized by a high rate of early metastatic relapse. Surgical resection is still recognized as the cornerstone upfront therapy. However, reported 5 years survival rates are inferior to 20-25% even when surgery is followed by chemotherapy. Margins involvement on the surgical specimen (50 to 85%) and lymph node involvement (around 70%) both strongly impact survival. Median survivals are close to those of locally advanced diseases treated by chemotherapy or chemoradiotherapy, 15 to 16 months. This review focuses on adverse prognostic factors, post-operative outcomes and their impact on multimodality therapy completion rates and survivals in patients undergoing upfront surgery. Current data and emerging results from neoadjuvant series could lead to a change in the therapeutic strategy.


Assuntos
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Humanos , Neoplasias Pancreáticas
19.
Ann Oncol ; 26(5): 921-927, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25609246

RESUMO

BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , Gencitabina
20.
Rev Med Liege ; 70(11): 540-5, 2015 Nov.
Artigo em Francês | MEDLINE | ID: mdl-26738264

RESUMO

Surgical resection followed by chemotherapy is the actual standard of care for localized, deemed resectable, pancreatic ductal adenocarcinoma. Despite a better selection of surgical candidates and the actual performance of expert teams, the proportion of patients with a prolonged survival has not been ameliorated during the last three decades. The morphological determinants of resectability are the subject of limitations. In the future, only a better understanding of the biological process, an earlier diagnosis of purely localized disease and more efficient systemic therapies may lead to a better prognosis. Meanwhile, taking into account the prognostic factors associated with a lower chance of cure is currently a matter of debate. The optimal therapeutic sequence, being a surgery-first or a neoadjuvant approach is controversial. The theoretical advantages of preoperative chemotherapy eventually associated with chemo-radiation are demonstrated in other tumours and applicable to pancreatic cancer without any excess of operative mortality, early progression rates and, on the contrary with positive survival data. The completion rates of multi-modal therapy are in favour of the preoperative approach, which also gives the opportunity to select the best candidates for surgical resection.


Assuntos
Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidade , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/mortalidade , Humanos , Terapia Neoadjuvante , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Seleção de Pacientes , Prognóstico
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