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INTRODUCTION: Cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG) regimen activity was assessed in a single institution phase II trial (PACT-19) on pancreatic ductal adenocarcinoma (PDAC). The PACT-31 study explored the external validity of PACT-19 results. MATERIALS AND METHODS: Patients aged ≥18 and ≤75 years with KPS ≥70, and PDAC diagnosis receiving PAXG in the participating institutions were eligible and categorized as follows: A) PACT-19; B) PACT-31-HSR; C) PACT-31-non-HSR. With a sample of 175 patients, assuming a target 1-year overall survival of 60 % for metastatic and of 80 % for non-metastatic patients, the trial will be considered successful with the 1-year OS falling into the 95 % CI. RESULTS: Data from 68 PACT-19 and 168 PACT-31 patients were retrieved. After 124 events, 1yOS was 52.5 % (95 %CI: 44.6-60.4 %) for metastatic and 80.5 % (95 %CI: 71.9-89.1 %) for non-metastatic patients. Survival overlapped between PACT-19 and PACT-31-HSR (median 17.6 and 17.4 months, p = 0.21) and was significantly shorter in PACT-31-non-HSR (median 11.3 months; p = 0.03). Differences of dose-intensity, use of maintenance therapy, and treatment after progression between PACT-31-HSR and non-HSR were evidenced. DISCUSSION: PACT-19 results have external validity. The outcome difference between HSR and non-HSR centers endorses the need of creating a hub-and-spoke network aimed at sharing the expertise on rare-diseases.
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BACKGROUND AND AIM: Germline BRCA1-2 test is routinely recommended in Pancreatic Cancer (PC) patients, due to its clinical-epidemiological relevance. Data on the prevalence of germline pathogenic variants (gPV) in other cancer predisposition and DNA Damage Repair (DDR) system-related genes in unselected PC cases are sparce in Italy. We assessed this prevalence in a multicentre cohort, to derive recommendations for PC patients. METHODS: Clinical data of 1200 consecutive PC patients, of any age and stage, tested with a multigene germline panel were collected. A descriptive analysis of gPV frequency and clinical variables was performed both in 1092 patients tested for an 18 genes core-panel (CP-18 cohort) and in 869 patients screened only for CDKN2A. RESULTS: 11.5 % (126/1092) of CP-18 cohort patients harbored a gPV in ≥ 1 gene. Highest gPV frequencies were detected in ATM (3.1 %), BRCA2 (2.9 %), BRCA1 (1.6 %), CHEK2 (1.1 %). Patients harboring any CP-18 gene and BRCA1-2 gPV were younger and with a higher rate of personal (PH) or family history (FH) of cancer when compared to no gPV patients. The risk of having a gPV was ≥ 7 % in all subgroups of patients, including those aged > 73, with tumor stage I-III and negative FH/PH. CDKN2A gPV were detected in 2.6 % (23/869) of patients. CONCLUSIONS: A remarkable prevalence of gPV in cancer predisposition and DDR genes is reported in this large multicentre cohort of consecutive and unselected PC patients. Therefore, we recommend multigene germline testing (at least including BRCA1-2, ATM, CDKN2A, PALB2) for all PC patients, irrespective of age, stage, PH/FH.
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Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Masculino , Feminino , Itália/epidemiologia , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Quinase do Ponto de Checagem 2RESUMO
Pancreatic and periampullary cancers pose significant challenges in oncological care due to their complexity and diagnostic difficulties. Global experiences underscore the crucial role of multidisciplinary collaboration and centralized care in improving patient outcomes in this context. Recognizing these challenges, Lombardy, Italy's most populous region, embarked on establishing pancreas units across its territory to enhance clinical outcomes and organizational efficiency. This initiative, driven by a multistakeholder approach involving the Lombardy Welfare Directorate, clinicians, and a patient association, emphasizes the centralization of complex care in high-volume hospitals, adopting a hub-and-spoke model and a multidisciplinary approach. This article outlines the process and criteria set forth for pancreas unit implementation, aiming to provide a structured framework for enhancing pancreatic cancer care. Central to this initiative is the establishment of structured criteria and minimal requirements, not only for surgery but also for other essential components of care, ensuring a comprehensive approach to pancreatic cancer management. The Lombardy model offers a structured framework for enhancing pancreatic cancer care, with potential applicability to other regions and countries seeking to improve their cancer care infrastructure.
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Background and purpose: To assess feasibility, toxicity and outcome of moderately hypofractionated radiotherapy concomitant to capecitabine after induction chemotherapy for advanced pancreatic cancer. Materials and methods: Patients with advanced pancreatic cancer without distant progression after induction chemotherapy (CHT) were considered. Radiochemotherapy (RCT) consisted of 44.25 Gy in 15 fractions to the tumor and involved lymph-nodes concomitant to capecitabine 1250 mg/m2/day. Feasibility and toxicity were evaluated in all pts. Overall survival (OS), progression free survival (PFS), distant PFS (DPFS) and local PFS (LPFS) were assessed only in stage III patients. Results: 254 patients, 220 stage III, 34 stage IV, were treated. Median follow up was 19 months. Induction CHT consisted of Gemcitabine (35 patients), or drug combination (219 patients); median duration was 6 months.Four patients (1.6 %) did not complete RT (1 early progression, 3 toxicity), median duration of RT was 20 days, 209 patients (82 %) received ≥ 75 % of capecitabine dose.During RCT G3 gastrointestinal toxicity occurred in 3.2% of patients, G3-G4 hematologic toxicity in 5.4% of patients. Subsequently, G3, G4, G5 gastric or duodenal lesions occurred in 10 (4%), 2 (0.8%) and 1 patients (0.4%), respectively.Median PFS, LPFS, and DPFS were 11.9 months (95 % CI:11.4-13), 16 months (95 % CI:14.2-17.3) and 14.0 months (95 % CI:12.6-146.5), respectively.Median OS was 19.5 months (95 % CL:18.1-21.3). One- and two-year survival were 85.2 % and 36 %, respectively. Conclusions: The present schedule of hypofractionated RT after induction CHT is feasible with acceptable toxicity rate and provides an outcome comparable with that achievable with standard doses and fractionation.
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Carcinoma Ductal Pancreático , Recidiva Local de Neoplasia , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Pancreatectomia/métodosRESUMO
PURPOSE: Very early recurrence after radical surgery for pancreatic ductal adenocarcinoma (PDAC) has been poorly investigated. This study was designed to evaluate this group of patients who developed recurrence, within 12 weeks after surgery, defined as "biological R2 resections (bR2)." METHODS: Data from patients who underwent surgical resection as upfront procedure or after neoadjuvant treatment for PDAC between 2015 and 2019 were analyzed. Disease-free, disease-specific survival, and independent predictors of early recurrence were examined. The same analysis was performed separately for upfront and neoadjuvant treated patients. RESULTS: Of the 573 patients included in the study, 63 (11%) were classified as bR2. The rate of neoadjuvant treatment was similar in bR2 and in the remaining patients (44 vs. 42%, p = 0.78). After a median follow-up of 27 months, median DFS and DSS for the entire cohort were 17 and 43 months, respectively. Median DSS of bR2 group was 13 months. The only preoperative identifiable independent predictor of very early recurrence was body-tail site lesion, whereas all other were pathological: higher pT (8th classification), G3 differentiation, and high lymph node ratio. These predictors were confirmed for patients undergoing upfront surgery, whereas in the neoadjuvant group the only independent predictor was pT. CONCLUSIONS: One of ten patients with "radical" resected PDAC relapses very early after surgery (bR2); hence, imaging must be routinely repeated within 12 weeks. Despite higher biological aggressiveness and worse pathology, this bR2 cluster eludes our preoperative examinations.
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Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Pancreatectomia , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/patologia , Feminino , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Idoso , Pancreatectomia/métodos , Taxa de Sobrevida , Pessoa de Meia-Idade , Seguimentos , Prognóstico , Estudos Retrospectivos , Estudo de Prova de Conceito , Adulto , Idoso de 80 Anos ou maisRESUMO
Background and study aims Besides increasing adequacy, rapid on-site evaluation (ROSE) during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) may impact choices and timing of subsequent therapeutic procedures, yet has been unexplored. Patients and methods This was a retrospective evaluation of a prospectively maintained database of a tertiary, academic centre with availability of ROSE and hybrid EUS-ERCP suites. All consecutive patients referred for pathological confirmation of suspected malignancy and jaundice or gastric outlet obstruction (GOO) between Jan-2020 and Sep-2022 were included. Results Of 541 patients with underlying malignancy, 323 (59.7%) required same-session pathological diagnosis (male: 54.8%; age 70 [interquartile range 63-78]; pancreatic cancer: 76.8%, biliary tract adenocarcinoma 16.1%). ROSE adequacy was 96.6%, higher for EUS versus ERCP. Among 302 patients with jaundice, ERCP-guided stenting was successful in 83.1%, but final drainage was completed in 97.4% thanks to 43 EUS-guided biliary drainage procedures. Twenty-one patients with GOO were treated with 15 EUS-gastroenterostomies and six duodenal stents. All 58 therapeutic EUS procedures occurred after adequate ROSE. With ERCP-guided placement of stents, the use of plastic stents was significantly higher among patients with inadequate ROSE (10/11; 90.9%) versus adequate sampling (14/240; 5.8%) P <0.0001; OR 161; 95%CI 19-1352). Median hospital stay for diagnosis and palliation was 3 days (range, 2-7) and median time to chemotherapy was 33 days (range, 24-47). Conclusions Nearly two-thirds of oncological candidates for endoscopic palliation require contemporary pathological diagnosis. ROSE adequacy allows, since the index procedure, state-of-the-art therapeutics standardly restricted to pathologically confirmed malignancies (e.g. uncovered SEMS or therapeutic EUS), potentially reducing hospitalization and time to oncological treatments.
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BACKGROUND: Objectives: To investigate communication clarity and understanding at the time of pancreatic adenocarcinoma (PDAC) diagnosis and whether they can influence patient engagement and compliance. METHODS: Consecutive PDAC patients were enrolled at the time of diagnosis after obtaining informed consent in a single-center study. The patients completed a validated scale (PHE-s®), and the understanding rate was assessed using standardized tools. Patient compliance was evaluated, and the correlation between the PHE-s®, understanding, and compliance was calculated. RESULTS: Thirty patients were enrolled (15 female) with a mean age 64.4, 13 were metastatic. The mean visit time was 31 min, being longer if visiting doctor was an oncologist (p = 0.002). The engagement level was high in 70% of the patients, and all but one were compliant. The analysis of doctor-patient interactions showed a median of 121 conversational turns for doctors, 75 for patients, and 20 for caregivers (p < 0.0001), and the median percentage of speaking time was 77% for doctors, 13% for patients, and 2% for caregivers (p < 0.0001). Female caregivers spent more time speaking than did male caregivers (median 11.6% vs. 1.3%; p = 0.06). There were 290 instances of problematic understanding, most of which occurred during the taking of patients' personal medical history for doctors, while for patients and caregivers, these occurred mainly during the discussion of diagnosis/treatment (p < 0.0001). In a multivariable analysis, only origin from central or southern Italy was associated with high engagement (p = 0.0087). CONCLUSION: In this first attempt to measure clarity of communication and engagement in patients with PDAC, typical features of conversation and problematic understanding emerged, which deserves further investigation.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Masculino , Feminino , Comunicação , Cooperação do Paciente , ItáliaRESUMO
BACKGROUND: Data on the proper post-surgical chemotherapy (PSC) in pancreatic ductal adenocarcinoma (PDAC) patients already treated with neoadjuvant therapy (NAT) are lacking, especially for stage ypIA. AIM AND METHODS: We retrospectively analyzed ypT1N0M0 (ypIA) PDAC patients resected after NAT between 2015 and 2020 at our Institution. Primary endpoint was median disease free-survival (DFS) according to PSC treatment. RESULTS: Seventy-five out of 363 patients achieved a pathological ypIA after NAT (20.6%) and 72 were analyzed. Among the study population 34 patients (47%) were treated with NAT ≤4 months and 38 (53%) >4 months. After surgery, 10 patients (14%) received PSC using the same multidrug NAT regimen (Group A); 35 (49%) received PSC with a different regimen (Group B), with either single agents in 24 patients (68.5%) or combination schedules in 11 (31.5%); 27 patients (14%) did not receive any PSC (Group C). DFS was longer in group A and C as opposed to group B (p = 0.006). CONCLUSION: Patients affected by ypIA PDAC treated with a proper multi-agent chemotherapy for more than 4 months show an improved DFS, regardless of the perioperative or totally pre-surgical administration of treatment.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologiaRESUMO
BACKGROUND: Administering chemotherapy until progression to metastatic pancreatic ductal adenocarcinoma (PDAC) patients lacks of supporting evidence and causes cumulative toxicity. We explored the role of cyclophosphamide as maintenance therapy. METHODS: PDAC germline BRCA1-2 wild-type patients who were progression-free after ≥6 months of any regimen and line of chemotherapy and received maintenance cyclophosphamide (mCTX) (50 mg/day), were included in the analysis. RESULTS: 42 patients were included in the analysis. Thirty-nine patients had progression of disease. Median PFS was 3.5 (range 1.0-31+) months. PFS rates at 6 and 12 months were 26.2% and 11.9%. At a median follow-up of 20.0 months (range 12.1-31.0 months), 20 patients died and 22 are alive. Median OS was 20.0 months (range 2.2-31.0+). OS at 6 and 12 months was 97.6% (95%CI: 93.4-100), and 73.8% (95% CI: 61.1-86.5), respectively. Only 2 patients receiving mCTX had Grade 3 toxicity. CONCLUSIONS: mCTX therapy yielded promising PFS and OS outcome in PDAC patients who were progression-free after induction chemotherapy, with unremarkable toxicity. Accordingly, this approach warrants further investigation.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêuticoRESUMO
In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetal-antigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal-antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a regulatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetal-maternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials.
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Neoplasias , Caracteres Sexuais , Gravidez , Humanos , Feminino , Animais , Camundongos , Imunoterapia , Especificidade de Anticorpos , Microambiente Tumoral , Neoplasias/terapiaRESUMO
BACKGROUND: In non-small cell lung cancer (NSCLC), the immune checkpoint inhibitors (ICI) revolution is rapidly moving from metastatic to early-stage, however, the impact of clinicopathological variables and optimal treatment sequencing remain unclear. METHODS: Randomized controlled trials (RCTs) in patients with early-stage NSCLC treated with ICI as single agent or in combination with platinum-based chemotherapy (PCT) were included. Primary outcomes were pathological complete response (pCR), event free survival (EFS) (neoadjuvant/perioperative), and disease-free survival (DFS) (adjuvant). Secondary outcomes were major pathological response (MPR), overall survival (OS), toxicity, surgical outcomes (neoadjuvant/perioperative); OS and toxicity (adjuvant). An additional secondary endpoint was to compare EFS and OS between neoadjuvant and perioperative strategies. RESULTS: 8 RCTs (2 neoadjuvant, 4 perioperative, 2 adjuvant) (4661 participants) were included. Neoadjuvant/perioperative ICI+PCT significantly improved pCR, EFS, OS, MPR and R0 resection compared to PCT. Adjuvant ICI significantly improved DFS compared to placebo. There was a significant subgroup interaction by PD-L1 status (χ2 = 10.72, P = 0.005), pCR (χ2 = 17.80, P < 0.0001), and stage (χ2 = 4.46, P = 0.003) for EFS. No difference according to PD-L1 status was found for pCR, with 14% of patients having PD-L1 negative tumors still experiencing a pCR. No interaction by PD-L1 status was found for DFS upon adjuvant ICI. Indirect comparison showed no difference in EFS and OS between neoadjuvant and perioperative ICI+PCT. CONCLUSIONS: PD-L1 status, pCR and stage impact on survival upon neoadjuvant/perioperative ICI. The restriction of neoadjuvant/perioperative ICI to PD-L1 + patients could preclude pCR and long-term benefit in the PD-L1- subgroup. Neoadjuvant and perioperative could be equivalent strategies.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Terapia Neoadjuvante , Adjuvantes Imunológicos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown. METHODS: We carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies. FINDINGS: We identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor-draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E2. INTERPRETATION: Our results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh-B cell interactions and facilitate more effective treatment. FUNDING: Research grants from the Italian Association for Cancer Research (AIRC) IG-19119 to MPP and the AIRC Special Program in Metastatic disease: the key unmet need in oncology, 5 per Mille no. 22737 to CB, MF, CD, MR and MPP; the ERA-NET EuroNanoMed III (a collaborative european grant financed by the Italian Ministry of Health, Italy) project PANIPAC (JTC2018/041) to MPP; the Fondazione Valsecchi to SC.
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Imunoglobulina G , Neoplasias Pancreáticas , Humanos , Dinoprostona , Imunoglobulina E , Anti-Inflamatórios , RNA , Microambiente TumoralRESUMO
BACKGROUND: Real-world data on treatment patterns/outcomes for metastatic pancreatic cancer (mPAC) are limited. This study aims to assess real-world treatment patterns, survival outcomes, and prognostic/predictive factors in patients with mPAC. METHODS: Retrospective, observational, chart-review involving medical oncologists and gastroenterologists from five European countries. Physicians reported information on disease and patient characteristics, diagnosis, and treatment for patients diagnosed with mPAC from January-October 2016. Outcomes included median progression-free survival (mPFS), median overall survival (mOS), and the impact of baseline performance status on survival. Univariate/multivariate regression analyses were undertaken to identify prognostic/predictive factors. RESULTS: Three hundred four physicians and 3432 patients were included. First-line therapies included modified (m)FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%). Frequent second-line therapies were gemcitabine monotherapy (25.0%), fluorouracil (5-FU) + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). Most frequent first- to second-line treatment sequences were gemcitabine + nab-paclitaxel followed by fluoropyrimidine combinations. Longest unadjusted estimated mOS was observed with (m)FOLFIRINOX followed by gemcitabine-based combinations (19.1 months). Multivariate analysis identified significant prognostic/predictive factors for OS and PFS including performance status and carbohydrate antigen 19-9 (CA 19-9) levels. CONCLUSIONS: Treatment and treatment sequences were generally in accordance with guidelines at the time of the study. Identification of prognostic/predictive factors for survival may help inform the individualised management of mPAC patients in the future.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Europa (Continente)/epidemiologia , Gencitabina , Análise Multivariada , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Neoplasias PancreáticasRESUMO
PURPOSE: The clinical outcome and the efficacy of chemotherapy in pancreatic cancer patients with BRCA1/2 Variants of Unknown Significance (VUS) is unknown. We explored the effects of chemotherapy with or without Platinum in non metastatic and metastatic pancreatic cancer patients with BRCA1/2 VUS. METHODS: A retrospective analysis of non-metastatic or metastatic pancreatic cancer patients with gBRCA1/2 VUS treated in 13 Italian centers between November 2015 and December 2020 was performed. All patients were assessed for toxicity and RECIST 1.1 response. Metastatic patients were evaluated for survival outcome. RESULTS: 30 pancreatic cancer patients with gBRCA1/2 VUS were considered: 20 were M+ and 10 were non-M+. Pl-CT was recommended to 16 patients: 10 M+ (6 FOLFIRINOX and 4 PAXG) and 6 non-M+ (3 FOLFIRINOX and 3 PAXG); 11 patients received Nabpaclitaxel-Gemcitabine (AG; 8 M+) and 3 patients (2 M+) were treated with Gemcitabine (G). The RECIST 1.1 response rate was 27% for AG and 44% for Pl-CT (22% for (m) FOLFIRINOX and 71% PAXG). 1 year Progression-Free Survival was 37.5% for patients treated with AG and 33% in the Pl-CT subgroup. Median Overall Survival (OS) was 23.5 months for patients treated with AG and 14 months for the Pl-CT subgroup. 1 Year and 2 Year OS were numerically better for AG (1 Year OS: 75% vs 60% and 2 Year OS: 50% and 20% in AG and Pl-CT subgroups, respectively) as well. CONCLUSIONS: Pl-CT does not seem to be associated with a better outcome compared to AG chemotherapy in PDAC patients with BRCA 1/2 VUS.
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Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Genes BRCA2 , Proteína BRCA1/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Proteína BRCA2/genética , Neoplasias PancreáticasRESUMO
Immunological consequences of endoscopic ultrasound (EUS)-local thermal ablation (LTA) for pancreatic ductal adenocarcinoma (PDAC) have not been extensively assessed. We aimed to explore EUS-LTA effects on the systemic immune response in PDAC. Peripheral blood was collected from 10 treatment-naïve patients with borderline resectable and locally advanced PDAC, randomly allocated to Nab-paclitaxel plus Gemcitabine chemotherapy (CT-arm, n = 5) or EUS-LTA with HybridTherm Probe plus CT (HTP + CT-arm, n = 5). Twenty healthy donors were included as controls. Flow-cytometry and multiplex assays were used to profile immune cell subsets and measure serum cytokines/chemokines, respectively. At baseline, PDAC patients showed increased circulating monocytes and lower circulating lymphocytes and CD19+ B cells counts compared to healthy controls. After 4 months, CT induced decrease of B regulatory cells, CD4+ cytotoxic T cells and IL-1ß. The addition of EUS-HTP to CT selectively decreased the serum levels of APRIL/TNFSF13 as well as T regulatory cells, total, classic and inflammatory monocytes. Serum levels of APRIL/TNFSF13 and total, classic and inflammatory monocytes counts at baseline were associated with worse overall survival. EUS-HTP has the potential to selectively impact on immune cells and cytokines associated with poor outcomes in PDAC.
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BACKGROUND: Systemic chemotherapy (CT) is the treatment of choice for advanced pancreatic ductal adenocarcinoma (PDAC). Biliary obstruction is common in this setting and may interfere with CT administration due to jaundice or cholangitis related to biliary stent malfunction. AIMS: To evaluate the impact of biliary events on CT administration and survival in patients with stage III-IV PDAC. METHODS: Patients enrolled in a randomized trial of nab-paclitaxel plus gemcitabine with/without capecitabine and cisplatin in advanced PDAC were included. Data on management of jaundice, biliary stents/complications and CT were prospectively collected and retrospectively analyzed. Modified overall (mOS) and progression-free (mPFS) survival were evaluated. RESULTS: Eighty-eight patients met the inclusion criteria (50% females; median age 65years). Seven of eight (87.5%) patients who placed plastic stents developed biliary complications versus 14/30 (46.7%) with metallic stents (p = 0.071). Patients without biliary complications completed planned CT in 64.2% versus 47.6% of cases (p = 0.207). CT completion was related to longer mOS (17 vs 12 months, p = 0.005) and mPFS (9 vs 6 months, p = 0.011). mOS was shorter when biliary complications occurred (12 vs 17 months, p = 0.937), as was mPFS (6 vs 8 months, p = 0.438). CONCLUSION: Complications related to biliary obstruction influence chemotherapy completion and survival in patients with advanced PDAC.
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Adenocarcinoma , Colestase , Icterícia , Neoplasias Pancreáticas , Feminino , Humanos , Idoso , Masculino , Gencitabina , Desoxicitidina , Estudos Retrospectivos , Neoplasias Pancreáticas/patologia , Adenocarcinoma/tratamento farmacológico , Colestase/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica , Albuminas , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Retrospective studies on malignant gastric outlet obstruction (mGOO) highlighted several advantages of EUS-guided gastroenterostomy (EUS-GE) over enteral stenting (ES). However, no prospective evidence is available. The aim of this study was to report on clinical outcomes of EUS-GE in a prospective cohort study, with a subgroup comparison versus ES. METHODS: All consecutive patients endoscopically treated for mGOO between December 2020 and December 2022 in a tertiary, academic center were enrolled in a prospective registry (Prospective Registry of Therapeutic Endoscopic Ultrasound [PROTECT]; NCT04813055) and followed up every 30 days to register efficacy/safety outcomes. EUS-GE and ES cohorts were matched according to baseline frailty and oncologic disease. RESULTS: A total of 104 patients were treated for mGOO during the study; 70 (58.6% male subjects; median age, 64 [interquartile range, 58-73] years; 75.7% pancreatic cancer, 60.0% metastatic cancer) underwent EUS-GE via the wireless simplified technique. Technical success was 97.1% and clinical success was 97.1% after a median of 1.5 (interquartile range, 1-2) days. Adverse events occurred in 9 (12.9%) patients. After a median follow-up of 105 (49-187) days, symptom recurrence was 7.6%. In the matched comparison versus ES (28 patients per arm), EUS-GE-treated patients experienced higher and faster clinical success (100% vs 75.0%, P = .006), reduced recurrences (3.7% vs 33.3%, P = .02), and a trend toward shorter time to chemotherapy. CONCLUSIONS: In this first, prospective, single-center comparison, EUS-GE showed excellent efficacy in treating mGOO, with an acceptable safety profile and long-term patency, and several clinically significant advantages over ES. While awaiting randomized trials, these results might endorse EUS-GE as first-line strategy for mGOO, where adequate expertise is available.
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Obstrução da Saída Gástrica , Gastroenterostomia , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Estudos Prospectivos , Gastroenterostomia/métodos , Obstrução da Saída Gástrica/etiologia , Obstrução da Saída Gástrica/cirurgia , Endoscopia , Endossonografia/métodos , StentsAssuntos
Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante , Metanálise em Rede , Fluoruracila/uso terapêutico , Leucovorina/uso terapêuticoRESUMO
Background: Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1. Methods: In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive). Findings: Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval [CI]) OS in the napabucasin and control treatment arms was 11.4 (10.5-12.2) and 11.7 (10.7-12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93-1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%). Interpretation: Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC. Funding: The Sumitomo Pharma Oncology, Inc.