RESUMO
BACKGROUND: The highly metastatic nature of pancreatic ductal adenocarcinoma (PDAC) and the difficulty to achieve favorable patient outcomes emphasize the need for novel therapeutic solutions. For preclinical evaluations, genetically engineered mouse models are often used to mimic human PDAC but frequently fail to replicate synchronous development and metastatic spread. This study aimed to develop a transplantation model to achieve synchronous and homogenous PDAC growth with controlled metastatic patterns in the liver. METHODS: To generate an orthotopic PDAC model, the DT6606 cell line was injected into the pancreas head of C57BL/6 mice, and their survival was monitored over time. To generate a heterotopic transplantation model, growing doses of three PDAC cell lines (DT6606, DT6606lm, and K8484) were injected into the portal vein of mice. Magnetic resonance imaging (MRI) was used to monitor metastatic progression, and histologic analysis was performed. RESULTS: Orthotopically injected mice succumbed to the tumor within an 11-week period (average survival time, 78.2 ± 4.45 days). Post-mortem examinations failed to identify liver metastasis. In the intraportal model, 2 × 105 DT6606 cells resulted in an absence of liver metastases by day 21, whereas 5 × 104 DT6606lm cells and 7 × 104 K8484 cells resulted in steady metastatic growth. Higher doses caused significant metastatic liver involvement. The use of K8484 cells ensured the growth of tumors closely resembling the histopathologic characteristics of human PDAC. CONCLUSIONS: This report details the authors' efforts to establish an "optimal" murine model for inducing metastatic PDAC, which is critical for advancing our understanding of the disease and developing more effective treatments.
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Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas , Animais , Camundongos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/secundário , Carcinoma Ductal Pancreático/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Humanos , Células Tumorais Cultivadas , Modelos Animais de Doenças , Taxa de Sobrevida , Transplante de NeoplasiasRESUMO
PURPOSE: Accurate identification of lymph node (LN) metastases is pivotal for surgical planning of pancreatic neuroendocrine tumours (PanNETs); however, current imaging techniques have sub-optimal diagnostic sensitivity. Aim of this study is to investigate whether [68Ga]Ga-DOTATOC PET radiomics might improve the identification of LN metastases in patients with non-functioning PanNET (NF-PanNET) referred to surgical intervention. METHODS: Seventy-two patients who performed preoperative [68Ga]Ga-DOTATOC PET between December 2017 and March 2022 for NF-PanNET. [68Ga]Ga-DOTATOC PET qualitative assessment of LN metastases was measured using diagnostic balanced accuracy (bACC), sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV). SUVmax, SUVmean, Somatostatin receptor density (SRD), total lesion SRD (TLSRD) and IBSI-compliant radiomic features (RFs) were obtained from the primary tumours. To predict LN involvement, these parameters were engineered, selected and used to train different machine learning models. Models were validated using tenfold repeated cross-validation and control models were developed. Models' bACC, SN, SP, PPV and NPV were collected and compared (Kruskal-Wallis, Mann-Whitney). RESULTS: LN metastases were detected in 29/72 patients at histology. [68Ga]Ga-DOTATOC PET qualitative examination of LN involvement provided bACC = 60%, SN = 24%, SP = 95%, PPV = 78% and NPV = 65%. The best-performing radiomic model provided a bACC = 70%, SN = 77%, SP = 61%, PPV = 60% and NPV = 83% (outperforming the control model, p < 0.05*). CONCLUSION: In this study, [68Ga]Ga-DOTATOC PET radiomics allowed to increase diagnostic sensitivity in detecting LN metastases from 24 to 77% in NF-PanNET patients candidate to surgery. Especially in case of micrometastatic involvement, this approach might assist clinicians in a better patients' stratification.
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Metástase Linfática , Tumores Neuroendócrinos , Octreotida , Compostos Organometálicos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Feminino , Pessoa de Meia-Idade , Masculino , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Octreotida/análogos & derivados , Metástase Linfática/diagnóstico por imagem , Idoso , Adulto , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Período Pré-Operatório , RadiômicaRESUMO
OBJECTIVE: To investigate whether revision of pancreatic neck margin based on intraoperative frozen section analysis has oncologic value in post-neoadjuvant pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: The role of intraoperative neck margin revision has been controversial, with little information specific to post-neoadjuvant PD. METHODS: Patients who underwent post-neoadjuvant PD (2013-2019) for conventional PDAC with frozen section analysis of neck margin at three academic institutions were included. Overall survival (OS) and recurrence-free survival (RFS) were compared across three groups: complete resection achieved en-bloc (CR-EB), complete resection achieved non-en-bloc (CR-NEB), and incomplete resection (IR). RESULTS: Among the 671 patients included, 524 (78.1%) underwent CR-EB, 119 (17.7%) CR-NEB and 28 (4.2%) IR. Patients undergoing CR-NEB and IR exhibited larger tumors and lower rates of RECIST response, requiring vascular resections more often. Likewise, CR-NEB and IR were associated with a worse pathological profile than CR-EB. The incidence of postoperative complications and access to adjuvant treatment were comparable among groups. A CR-EB was associated with the longest OS duration (34.3 mo). In patients with positive neck margin, obtaining a CR-NEB via re-excision was associated with a comparable OS relative to patients with an IR (26.9 vs. 27.1 mo, P=0.901). Similar results were observed for RFS. At multivariable analysis, neck margin status was not independently associated with survival and recurrence. CONCLUSION: Conversion of an initially positive pancreatic neck margin by additional resection is not associated with oncologic benefits in post-neoadjuvant PD and cannot be routinely recommended.
Assuntos
Metástase Linfática , Micrometástase de Neoplasia , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Prognóstico , Metástase Linfática/patologia , Micrometástase de Neoplasia/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/secundário , Idoso , Adulto , Linfonodos/patologiaRESUMO
INTRODUCTION: Pancreatic Neuroendocrine Neoplasms (PanNENs) are characterized by a highly heterogeneous clinical and biological behavior, making their diagnosis challenging. PanNENs diagnostic work-up mainly relies on biochemical markers, pathological examination, and imaging evaluation. The latter includes radiological imaging (i.e. computed tomography [CT] and magnetic resonance imaging [MRI]), functional imaging (i.e. 68Gallium [68 Ga]Ga-DOTA-peptide PET/CT and Fluorine-18 fluorodeoxyglucose [18F]FDG PET/CT), and endoscopic ultrasound (EUS) with its associated procedures. AREAS COVERED: This review provides a comprehensive assessment of the recent advancements in the PanNENs diagnostic field. PubMed and Embase databases were used for the research, performed from inception to October 2023. EXPERT OPINION: A deeper understanding of PanNENs biology, recent technological improvements in imaging modalities, as well as progresses achieved in molecular and cytological assays, are fundamental players for the achievement of early diagnosis and enhanced preoperative characterization of PanNENs. A multimodal diagnostic approach is required for a thorough disease assessment.
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Endossonografia , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico , Biomarcadores Tumorais/análise , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos RadiofarmacêuticosRESUMO
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.
Assuntos
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: Autoimmune Pancreatitis (AIP) is a rare chronic inflammatory disease affecting the pancreas. Chronic pancreatic inflammation represents a risk factor for pre-neoplastic conditions such as Intraductal Papillary Mucinous Neoplasia (IPMN). Due to the rarity of AIP, the incidence, and clinical features of IPMN occurring in AIP patients remains unknown. AIMS: In the present study we aimed to explore the relationship between AIP and IPMN and to characterize the clinical features and outcomes of IPMN occurring in the context of AIP. METHODS: We retrospectively (2008-2020) analyzed the clinical and radiological records of a large single center cohort of patients with AIP and investigated the prevalence of IPMN. We then compared the clinical, laboratory and radiological characteristics of patients with IPMN and AIP with a cohort of patients with isolated IPMN. RESULTS: Five hundred and nineteen patients were included in this retrospective study. Sixteen patients had concomitant IPMN and AIP(3%); 61 patients had isolated AIP (12%); 442 patients had isolated IPMN (85%). The prevalence of IPMN in patients with AIP was higher than that observed in the general population (21%vs8-10%). Worrisome Features and High-Risk Stigmata were more frequently observed in IPMN occurring together with AIP compared to isolated IPMN(p < 0.05). Based on radiological features IPMN in the context of AIP was more frequently of main-duct type compared to isolated IPMN(p < 0.05). CONCLUSION: Our data suggest that AIP represents a chronic inflammatory condition that might favor IPMN development with high-risk features. Prolonged surveillance of these patients and longitudinal studies are required to further test the association with AIP and malignant and pre-malignant conditions.
Assuntos
Adenocarcinoma Mucinoso , Pancreatite Autoimune , Carcinoma Ductal Pancreático , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Pancreatite Autoimune/complicações , Carcinoma Ductal Pancreático/patologia , Atenção Terciária à Saúde , Adenocarcinoma Mucinoso/patologia , Neoplasias Pancreáticas/patologia , Encaminhamento e ConsultaRESUMO
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.
Assuntos
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
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1ß (IL-1ß)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2) and tumour necrosis factor (TNF). Physical proximity with IL-1ß+ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2 or IL-1ß activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2-IL-1ß axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
Assuntos
Inflamação , Interleucina-1beta , Neoplasias Pancreáticas , Macrófagos Associados a Tumor , Humanos , Carcinogênese , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Dinoprostona/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral , Fatores de Necrose Tumoral/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologiaRESUMO
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
We report the case of a paediatric female patient affected by Bannayan-Riley-Ruvalcaba syndrome (BRRS) and congenital hypothyroidism (CH) with homozygous mutation of the TPO gene. She underwent total thyroidectomy at the age of seven years because of the development of a multinodular goiter. BRRS patients present an increased risk of benign and malignant thyroid disease since childhood because of inactivating mutation of PTEN, an onco-suppressor gene. Instead, homozygous mutations in the TPO gene can be associated with severe forms of hypothyroidism with goiter; previous studies have described cases of follicular and papillary thyroid cancer in CH patients with TPO mutation despite a perfectly controlled thyroid function with Levothyroxine therapy. To our knowledge, this is the first case that describes the possible synergic role of coexisting mutation of both TPO and PTEN in the development of multinodular goiter underlining the importance of a tailored surveillance program in these patients, especially during childhood.
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Hipotireoidismo Congênito , Bócio , Síndrome do Hamartoma Múltiplo , Neoplasias da Glândula Tireoide , Humanos , Criança , Feminino , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/genética , Mutação , Bócio/complicações , Bócio/genética , Bócio/cirurgia , PTEN Fosfo-Hidrolase/genéticaRESUMO
Perineural invasion (PNI) is a common feature in pancreatic ductal adenocarcinoma (PDAC) and correlates with an aggressive tumor behavior already at early stages of disease. PNI is currently considered as a "present vs. absent" feature, and a severity score system has not yet been established. The aim of the present study was thus to develop and validate a score system for PNI and to correlate it with other prognostic features. In this monocentric retrospective study, 356 consecutive PDAC patients (61.8% upfront surgery patients, 38.2% received neoadjuvant therapy) were analyzed. PNI was scored as follows: 0: absent; 1: the presence of neoplasia along nerves < 3 mm in caliber; and 2: neoplastic infiltration of nerve fibers ≥ 3 mm and/or massive perineural infiltration and/or the presence of necrosis of the infiltrated nerve bundle. For every PNI grade, the correlation with other pathological features, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed. Uni- and multivariate analysis for DFS and DSS were also performed. PNI was found in 72.5% of the patients. Relevant trends between PNI score and tumor differentiation grade, lymph node metastases, vascular invasion, and surgical margins status were found. The latter was the only parameter statistically correlated with the proposed score. The agreement between pathologists was substantial (Cohen's K 0.61). PNI severity score significantly correlated also with decreased DFS and DSS at univariate analysis (p < 0.001). At multivariate analysis, only the presence of lymph node metastases was an independent predictor of DFS (HR 2.235 p < 0.001). Lymph node metastases (HR 2.902, p < 0.001) and tumor differentiation grade (HR 1.677, p = 0.002) were independent predictors of DSS. Our newly developed PNI score correlates with other features of PDAC aggressiveness and proved to have a prognostic role though less robust than lymph nodes metastases and tumor differentiation grade. A prospective validation is needed.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Metástase Linfática , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias PancreáticasRESUMO
BACKGROUND: It is unclear whether pathological staging is significant prognostically and can inform the delivery of adjuvant therapy after pancreatectomy preceded by neoadjuvant therapy. METHODS: This multicentre retrospective study included patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma after neoadjuvant treatment at two Italian centres between 2013 and 2017. T and N status were assigned in accordance with the seventh and eighth editions of the AJCC staging system, as well as according to a modified system with T status definition combining extrapancreatic invasion and tumour size. Patients were then stratified by receipt of adjuvant therapy. Survival analysis and multivariable interaction analysis of adjuvant therapy with pathological parameters were performed. The results were validated in an external cohort from the USA. RESULTS: The developmental set consisted of 389 patients, with a median survival of 34.6 months. The modified staging system displayed the best prognostic stratification and the highest discrimination (C-index 0.763; 1-, 2- and 3-year time-dependent area under the curve (AUC) 0.746, 0.722, and 0.705; Uno's AUC 0.710). Overall, 67.0 per cent of patients received adjuvant therapy. There was no survival difference by receipt of adjuvant therapy (35.0 versus 36.0 months; P = 0.772). After multivariable adjustment, interaction analysis suggested a benefit of adjuvant therapy for patients with nodal metastases or with tumours larger than 2 cm with extrapancreatic extension, regardless of nodal status. These results were confirmed in the external cohort of 216 patients. CONCLUSION: Modified staging with a T status definition combining extrapancreatic invasion and tumour size is associated with better prognostic segregation after postneoadjuvant pancreatectomy. This system allows identification of patients who might benefit from adjuvant therapy.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Pancreatectomia/métodos , Estudos Retrospectivos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Prognóstico , Carcinoma Ductal Pancreático/patologia , Terapia Neoadjuvante , Quimioterapia Adjuvante , Neoplasias PancreáticasRESUMO
PURPOSE: To evaluate the role of 68Ga-DOTATOC PET parameters in predicting DAXX/ATRX loss of expression in patients with Pancreatic neuroendocrine tumors (PanNET) candidate to surgery. METHODS: This retrospective study included 72 consecutive patients with PanNET (January 2018-March 2022) who underwent to 68Ga-DOTATOC PET for preoperative staging. Image analysis: qualitative assessment and extraction of SUVmax, SUV mean, somatostatin receptor density (SRD), and total lesion somatostatin receptor density (TLSRD) from primary PanNET. Radiological diameter and biopsy information (grade, Ki67) were collected. Loss of expression (LoE) of DAXX/ATRX was assessed by immunohistochemistry on surgical specimen. Student t-test, univariate and multivariate logistic regression and ROC curves have been used to investigate the predictive value of PET parameters on DAXX/ATRX LoE. RESULTS: Forty-two/72 patients had a G1, 28/72 a G2, and 2/72 a G3 PanNET. Seven/72 patients had DAXX LoE, 10/72 ATRX LoE, and 2/72 DAXX/ATRX LoE. SRD and TLSRD could predict DAXX LoE (p = 0.002, p = 0.018, respectively). By evaluating SRD in combination with radiological diameter, only SRD maintained statistical significance (multivariate logistic regression: p = 0.020, OR = 1.05), providing the best prediction (AUC-ROC = 79.01%; cut-off = 46.96; sensitivity = 77.78%; specificity = 88.89%). In the sub-analysis performed on 55 patients with biopsy availability, SRD demonstrated its role in providing useful and additional information (multivariate logistic regression: SRD p = 0.007; grade p = 0.040). CONCLUSION: SRD has a predictive role on DAXX LoE in PanNETs, with higher probability of LoE at increasing SRD values. SRD provides complementary/additional information to grade assessed on biopsy material, and the combined use of these approaches might support patients' management by preoperatively identifying subjects with more aggressive diseases.
Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/metabolismo , Proteína Nuclear Ligada ao X/metabolismo , Receptores de Somatostatina/metabolismo , Radioisótopos de Gálio , Estudos Retrospectivos , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Pancreáticas/metabolismo , Tomografia por Emissão de Pósitrons , Chaperonas Moleculares/metabolismo , Proteínas Correpressoras/metabolismoRESUMO
Objective: Endoscopic ultrasound (US)-guided radiofrequency ablation (RFA) has been investigated for pancreatic ductal adenocarcinoma (PDAC) but studies are limited and heterogeneous. Computed tomography (CT) scan features may predict RFA response after chemotherapy but their role is unexplored. The primary aim was to investigate the efficacy of ex-vivo application of a dedicated RFA system at three power on surgically resected PDAC in patients who underwent neoadjuvant chemotherapy. The secondary aim was to explore the association between pre-treatment CT-based quantitative features and RFA response. Methods: Fifteen ex-vivo PDAC samples were treated by RFA under US control at three power groups (10, 30, and 50 W). Short axis necrosis diameter was measured by two expert blinded pathologists as the primary outcome. Two radiologists independently reviewed preoperative CT images. Results: Eighty percent of specimens showed coagulative necrosis consisting of few millimeters: 5.7 ± 3.9 mm at 10 W, 3.7 ± 2.2 mm at 30 W, and 3.5 ± 2.4 mm at 50 W (p = 0.3), without a significant correlation between power setting and mean necrosis short axis (rho = -0.28; p = 0.30). Good agreement was seen between pathologists (k = 0.76; 95% confidence interval 0.55-0.98). Logistic regression analysis did not show associations between CT features and RFA response. Conclusions: RFA causes histologically evident damage with coagulative necrosis of a few millimeters in 80% of ex-vivo PDAC samples after chemotherapy and no clinical or pre-operative CT features can predict efficacy. Power settings do not correlate with the histological ablation area. These results are of relevance when employing RFA in vivo and planning clinical trials on its role in PDAC patients.
Assuntos
Pancreatectomia , Neoplasias Pancreáticas , Humanos , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Fístula Pancreática/diagnóstico por imagem , Fístula Pancreática/etiologia , Fístula Pancreática/cirurgia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Medição de Risco , Tomografia Computadorizada por Raios X , Estudos Retrospectivos , Fatores de Risco , Pâncreas/diagnóstico por imagem , Pâncreas/cirurgiaRESUMO
BACKGROUND: Data on recurrence after post-neoadjuvant pancreatectomy are scant. This study investigated the incidence and pattern of recurrence in patients with initially resectable and borderline resectable pancreatic ductal adenocarcinoma who received post-neoadjuvant pancreatectomy. Furthermore, preoperative predictors of recurrence-free survival (RFS) and their interactions were determined. PATIENTS AND METHODS: Patients undergoing post-neoadjuvant pancreatectomy at two academic facilities between 2013 and 2017 were analyzed using standard statistics. The possible interplay between preoperative parameters was scrutinized including interaction terms in multivariable Cox models. RESULTS: Among 315 included patients, 152 (48.3%) were anatomically resectable. The median RFS was 15.7 months, with 1- and 3-year recurrence rates of 41.9% and 74.2%, respectively. Distant recurrence occurred in 83.3% of patients, with lung-only patterns exhibiting the most favorable prognostic outlook. Normal posttreatment CA19.9, ΔCA19.9 (both in patients with normal and elevated baseline levels), and posttreatment tumor size were associated with RFS. Critical thresholds for ΔCA19.9 and tumor size were set at 50% and 20 mm, respectively. Interaction between ΔCA19.9 and posttreatment CA19.9 suggested a significant risk reduction in patients with elevated values when ΔCA19.9 exceeded 50%. Moreover, posttreatment tumor size interacted with posttreatment CA19.9 and ΔCA19.9, suggesting an increased risk in the instance of elevated posttreatment CA19.9 values and a protective effect associated with CA19.9 response in patients with tumor size >20 mm. CONCLUSION: Recurrence following post-neoadjuvant pancreatectomy is common. Preoperative tumor size <20 mm, normal posttreatment CA19.9 and ΔCA19.9 > 50% were associated with longer RFS. These variables should not be taken in isolation, as their interaction significantly modulates the recurrence risk.