RESUMO
BACKGROUND & AIMS: Patient-derived organoids (PDOs) are promising tumor avatars that could enable ex vivo drug tests to personalize patients' treatments in the frame of functional precision oncology. However, clinical evidence remains scarce. This study aims to evaluate whether PDOs can be implemented in clinical practice to benefit patients with advanced refractory pancreatic ductal adenocarcinoma (PDAC). METHODS: During 2021 to 2022, 87 patients were prospectively enrolled in an institutional review board-approved protocol. Inclusion criteria were histologically confirmed PDAC with the tumor site accessible. A panel of 25 approved antitumor therapies (chemogram) was tested and compared to patient responses to assess PDO predictive values and map the drug sensitivity landscape in PDAC. RESULTS: Fifty-four PDOs were generated from 87 pretreated patients (take-on rate, 62%). The main PDO mutations were KRAS (96%), TP53 (88%), and CDKN2A/B (22%), with a 91% concordance rate with their tumor of origin. The mean turnaround time to chemogram was 6.8 weeks. In 91% of cases, ≥1 hit was identified (gemcitabine (n = 20 of 54), docetaxel (n = 18 of 54), and vinorelbine (n = 17 of 54), with a median of 3 hits/patient (range, 0-12). Our cohort included 34 evaluable patients with full clinical follow-up. We report a chemogram sensitivity of 83.3% and specificity of 92.9%. The overall response rate and progression-free survival were higher when patients received a hit treatment as compared to patients who received a nonhit drug (as part of routine management). Finally, we leveraged our PDO collection as a platform for drug validation and combo identification. We tested anti-KRASG12D (MRTX1133), alone or combined, and identified a specific synergy with anti-EGFR therapies in KRASG12D variants. CONCLUSIONS: We report the largest prospective study aiming at implementing PDO-based functional precision oncology and identify very robust predictive values in this clinical setting. In a clinically relevant turnaround time, we identify putative hits for 91% of patients, providing unexpected potential survival benefits in this very aggressive indication. Although this remains to be confirmed in interventional precision oncology trials, PDO collection already provides powerful opportunities for drugs and combinatorial treatment development.
RESUMO
Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early-onset pancreatic cancer (EOPC, defined by an age at diagnosis <50 years old) is increasing. Here, we conducted a study of all PDAC patients followed at our institution. Patients were classified as EOPC or non-early onset (nEOPC, >50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence-free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I-III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal-like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.
Assuntos
Colecistectomia Laparoscópica , Neoplasias da Vesícula Biliar , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/cirurgia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Achados Incidentais , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
BACKGROUND: KRAS mutation is the most common molecular alteration in pancreatic adenocarcinoma (PDAC), and around 10% of patients harbor KRAS wild-type tumors (KRASWT). METHODS: A retrospective chart review of clinical/molecular data was performed including all PDAC patients with a determined KRAS status (tumor molecular profiling on tissue or liquid biopsy). RESULTS: 342 patients were included with 54 KRASWT PDAC (16%) compared to 288 patients with KRASm PDAC. Median age was 61 years [IQR:54.0;67.0] and 164 pts (48%) were female. At diagnosis, KRASWT patients (63%) were more frequently diagnosed at a non-metastatic stage compared to KRASm patients (41%) (p = 0.003). Regarding metastatic sites, liver was less frequent in KRASWT (39%, p < 0.0001). Median overall survival (mOS) from initial diagnosis was significantly higher in the KRASWT group compared to KRASm (50.8 months, CI95% [32.0-NR] vs 21.1 months, CI95% [18.9-23.4] (p < 0.004 after adjustment on age, ECOG and stage at diagnosis). In first-line systemic treatment, (mostly FOLFIRINOX) progression-free survival (PFS) was also higher in KRASWT. Based on ESCAT classification, a putative actionable alteration (ESCAT I-III) was identified in 19 (36%) KRASWT pts and 46 (16%) KRASm patients (p < 0.0001) with more alterations in FGFR2, BRAF(V600E), NRTK and more MSI tumors. KRASWT harbored also fewer alterations in TP53, CDKN2A, and SMAD4. 12 KRASWT patients received a molecularly-matched treatment with clinical benefit and improved outcomes compared to KRASm patients. CONCLUSIONS: KRASWT patients display distinct disease characteristics and outcomes with prolonged overall survival. KRASWT patients also harbor more actionable molecular alterations, leading to higher survival rates after receiving molecularly matched treatments.
Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Medicina de Precisão , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , IdosoRESUMO
The number of robotic-assisted procedures for rectal cancer is rising. The risk of this procedure when performed by surgeon with limited robotic experience is unknown and the precise duration of the learning curve debated. We, therefore, aimed to analyze the learning curve and its related safety in a single center before the development of mentoring programs. We prospectively recorded all robotic procedures performed for colorectal cancer between 2015 and 2020 by a single surgeon. Operative times for partial and total proctectomy were analyzed. The learning curve was defined by comparison with the standard duration of the laparoscopic procedure performed in expert centers (published in GRECCAR 5 and GRECCAR 6 trials) and calculated using a cumulative summation for learning curve test (LC-CUSUM). Among the 174 patients operated for colorectal cancer, we analyzed the outcomes of the 89 patients operated by partial and total robotic proctectomy. To reach repeatedly the same surgical duration as laparoscopic procedure for partial or complete proctectomy, the LC-CUSUM identified a learning curve of 57 patients. A severe morbidity in this population, defined by Clavien-Dindo classification ≥ 3, was observed in 15 cases (16.8%) with an anastomotic leak rate of 13.5%. The rate of completeness of mesorectal excision was 90% and the mean number of harvested lymph nodes was 15 (± 9). Using operative time as end-point, the learning curve of rectal cancer robotic surgery identified a cut-off of 57 patients. The technic remained safe with acceptable morbidity and oncological outcomes.
Assuntos
Laparoscopia , Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Curva de Aprendizado , Resultado do Tratamento , Neoplasias Retais/cirurgia , Reto/cirurgia , Laparoscopia/métodos , Estudos RetrospectivosRESUMO
BACKGROUND The characteristics of liver donors have changed over the last decade owing to the shortage of organs and high mortality on the waiting list, leading to wider use of extended-criteria donors, including older donors. The aim of this study was to evaluate the effect of matching donor-recipient age on morbidity at 1 year post-transplant and on long-term patient and graft survival. MATERIAL AND METHODS Retrospective study from a prospectively-obtained database including adult patients who had received a primary liver transplant (LT) from whole graft of brain-dead donors. Recipients were divided into 2 age groups: <60 years and ≥60 years. Both groups were sub-divided according to donor age (younger than 60 years and 60 years or older). A propensity score analysis was performed to further adjust for baseline differences between recipients and donors. RESULTS We analyzed 642 patients who had LT performed between January 2000 and December 2013. No differences were observed in 1-year morbidity (hospital stay, rejection, surgical complications, and retransplant) between groups. Although patient and graft survival was significantly impaired in the older donor/older recipient group on Kaplan-Meier analysis (p=0.004), the propensity score analysis showed that donor age ≥60 years did not increase the risk of death for recipients aged ≥60 (HR1.40, p 0.074) and <60 years (HR 1.47, p 0.070). CONCLUSIONS Older donor age did not negatively affect survival regardless of recipient age, and comparable outcomes were achieved without an increased rate of complications.
Assuntos
Seleção do Doador , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto , Transplante de Fígado/métodos , Adulto , Fatores Etários , Idoso , Bases de Dados Factuais , Feminino , Humanos , Tempo de Internação , Falência Hepática/cirurgia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
Cholangiocarcinoma is a malignant tumor of the biliary system that can be classified into intrahepatic (iCCA), perihiliar (phCCA) and distal. Initial experiences with orthotopic liver transplantation (OLT) for patients with iCCA and phCCA had very poor results and this treatment strategy was abandoned. In the last decade, thanks to a strict selection process and a neoadjuvant chemoradiation protocol, the results of OLT for patients with non-resectable phCCA have been shown to be excellent and this strategy has been extended worldwide in selected transplant centers. Intrahepatic cholangiocarcinoma is a growing disease in most countries and can be diagnosed both in cirrhotic and in non-cirrhotic livers. Even though OLT is contraindicated in most centers, recent investigations analyzing patients that were transplanted with a misdiagnosis of HCC and were found to have an iCCA have shown encouraging results. There is some information suggesting that patients with early stages of the disease could benefit from OLT. In this review we analyze the current state-of-the-art of OLT for cholangiocarcinoma as well as the new insights and future perspectives.
RESUMO
INTRODUCTION: Primary aorto-enteric fistula (AEF) is an uncommon life-threating condition. Only 4% of them involve the jejunum or ileum and its mortality ranges from 33 to 85%. PRESENTATION OF CASE: A 54-year-old female was admitted to the Emergency Department with syncope and hematemesis. The esophagogastroduodenoscopy found a pulsatile vessel in the second portion of the duodenum. A computed tomography scan showed an AEF with an infrarenal aortic aneurysm and iliac artery thrombosis. During surgery, an infrarenal aortic aneurysm complicated with an aorto-jejunal fistula was found. An axilo-bifemoral bypass, open repair of the aneurysm and segmental small bowel resection with primary suture of the jejunal defect were performed. DISCUSSION: Depending on previous aortic grafting, AEF can be classified as primary or secondary. Primary AEF is usually caused by an untreated abdominal aortic aneurysm, commonly presenting an infectious etiology. The main clinical sign is a "herald" hemorrhage. The EGD is considered as the first step in diagnosing AEF. The treatment of choice for AEF is emergent surgery. Use of broad-spectrum antibiotics is mandatory in the postoperative period to avoid fistula recurrence. CONCLUSION: AEF is a rare entity with a high mortality. High clinical suspicion is essential to make a correct diagnosis, which is crucial for the prognosis of these patients, such is the case of our patient. If hemodynamic stability is achieved, it allows to employ surgical strategies in which extra-abdominal bypass is performed before fistula is treated.
RESUMO
No disponible