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1.
Eur J Cancer ; 205: 114100, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38729055

RESUMO

OBJECTIVES: This study aimed to assess the consistency and replicability of treatment recommendations provided by ChatGPT 3.5 compared to gastrointestinal tumor cases presented at multidisciplinary tumor boards (MTBs). It also aimed to distinguish between general and case-specific responses and investigated the precision of ChatGPT's recommendations in replicating exact treatment plans, particularly regarding chemotherapy regimens and follow-up protocols. MATERIAL AND METHODS: A retrospective study was carried out on 115 cases of gastrointestinal malignancies, selected from 448 patients reviewed in MTB meetings. A senior resident fed patient data into ChatGPT 3.5 to produce treatment recommendations, which were then evaluated against the tumor board's decisions by senior oncology fellows. RESULTS: Among the examined cases, ChatGPT 3.5 provided general information about the malignancy without considering individual patient characteristics in 19% of cases. However, only in 81% of cases, ChatGPT generated responses that were specific to the individual clinical scenarios. In the subset of case-specific responses, 83% of recommendations exhibited overall treatment strategy concordance between ChatGPT and MTB. However, the exact treatment concordance dropped to 65%, notably lower in recommending specific chemotherapy regimens. Cases recommended for surgery showed the highest concordance rates, while those involving chemotherapy recommendations faced challenges in precision. CONCLUSIONS: ChatGPT 3.5 demonstrates potential in aligning conceptual approaches to treatment strategies with MTB guidelines. However, it falls short in accurately duplicating specific treatment plans, especially concerning chemotherapy regimens and follow-up procedures. Ethical concerns and challenges in achieving exact replication necessitate prudence when considering ChatGPT 3.5 for direct clinical decision-making in MTBs.


Assuntos
Neoplasias Gastrointestinais , Humanos , Estudos Retrospectivos , Neoplasias Gastrointestinais/terapia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Tomada de Decisão Clínica , Oncologia , Adulto
2.
Brain Spine ; 4: 102779, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38560042

RESUMO

Introduction: Predicting the pre-morbid sagittal profile of the spine or segmental angles could enhance the process of planning the extent of fracture reduction. There is evidence that spinopelvic parameters may be suitable for this purpose. Research question: Is it possible to determine the inflection point and the mono- and bi-segmental endplate angles (EPA) in the thoracolumbar transition (from Th9 to L2) based on age, gender, spinopelvic parameters, and the adjacent EPA in the supine position? Material and methods: Based on Polytrauma CT scans in the supine position, the following spinopelvic parameters were measured using non-fractured spines: pelvic incidence (PI), sacral slope (SS), lumbar lordosis (LL), and the apex of the LL. Results: In this study, a total of 287 patients with a mean age of 42±16 years were included. Age-related changes were observed, where LL, thoracic kyphosis (TK), and PI increase with age. Gender-related comparisons showed that females had a more pronounced LL and reduced TK. Significant correlations between IP and spinopelvic parameters, with the apex of LL providing the best prediction, were found. However, the overall model quality remained low. Predicting mEPA and bEPA showed positive correlations. The prediction for mEPA L2/3 demonstrated the highest correlation. For bisegmental angles, the most caudal bEPA (L2) exhibited the highest correlation, albeit with some notable absolute differences in the values between measured and predicted values. Discussion and conclusion: While this study highlights the complexity of the relationship between the pelvis and thoracolumbar parameters, finding a predictive tool for thoracolumbar reduction and stabilization was not possible.

3.
Contemp Clin Trials Commun ; 38: 101273, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38425423

RESUMO

Background: Patients affected by lumbar spinal stenosis (LSS) suffer from a multifactorial degeneration of the lumbar spine resulting in narrowing of the neuroforamina and spinal canal, leading to various functional limitations. It remains unclear whether LSS patients after surgery would benefit from early post-operative rehabilitation, or if a delayed rehabilitation would be more advantageous. The purpose of this partially randomized patient preference trial is to evaluate the impact of post-operative rehabilitation timing as well as surgical intervention type on psychometric properties and functional outcomes in patients with LSS. Methods: Data for this patient preference trial are collected before and after surgical (decompression only or decompression and fusion) and rehabilitative interventions as well as six, 12 and 24 months after completing rehabilitation. The study participants are patients diagnosed with LSS who are at least 18 years old. After a medical check-up, participants will complete patient-reported outcome measures (PAREMO-20, SIBAR, FREM-8, SF-12, SFI, ODI) and different functional assessments (functional reach test, loaded reach test, handgrip strength, standing balance control, 6-min walk test). Ethics and dissemination: The results of this study will be published through peer-reviewed publications and scientific contributions at national and international conferences. This research has been approved by the Institutional Review Board of Martin Luther University Halle-Wittenberg (reference number: 2022-128).

4.
BMC Musculoskelet Disord ; 25(1): 200, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38443864

RESUMO

INTRODUCTION: The assessment of bone density has gained significance in recent years due to the aging population. Accurate assessment of bone density is crucial when deciding on the appropriate treatment plan for spinal stabilization surgery. The objective of this work was to determine the trabecular bone density values of the subaxial cervical, thoracic and lumbar spine using Hounsfield units. MATERIAL AND METHODS: Data from 200 patients who underwent contrast-enhanced polytrauma computed tomography at a maximum care hospital over a two-year period were retrospectively analyzed. HUs were measured with an elliptical measurement field in three different locations within the vertebral body: below the upper plate, in the middle of the vertebral body, and above the base plate. The measured Hounsfield units were converted into bone density values using a validated formula. RESULTS: The mean age of the patient collective was 47.05 years. Mean spinal bone density values decreased from cranial to caudal (C3: 231.79 mg/cm3; L5: 155.13 mg/cm3; p < 0.001), with the highest values in the upper cervical spine. Bone density values generally decreased with age in all spinal segments. There was a clear decrease in values after age 50 years (p < 0.001). CONCLUSIONS: In our study, bone density decreased from cranial to caudal with higher values in the cervical spine. These data from the individual spinal segments may be helpful to comprehensively evaluate the status of the spine and to design a better preoperative plan before instrumentation.


Assuntos
Densidade Óssea , Vértebras Lombares , Humanos , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Tomografia Computadorizada por Raios X
5.
Gut ; 73(5): 787-796, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38267201

RESUMO

OBJECTIVE: To describe the long-term consequences of necrotising pancreatitis, including complications, the need for interventions and the quality of life. DESIGN: Long-term follow-up of a prospective multicentre cohort of 373 necrotising pancreatitis patients (2005-2008) was performed. Patients were prospectively evaluated and received questionnaires. Readmissions (ie, for recurrent or chronic pancreatitis), interventions, pancreatic insufficiency and quality of life were compared between initial treatment groups: conservative, endoscopic/percutaneous drainage alone and necrosectomy. Associations of patient and disease characteristics during index admission with outcomes during follow-up were assessed. RESULTS: During a median follow-up of 13.5 years (range 12-15.5 years), 97/373 patients (26%) were readmitted for recurrent pancreatitis. Endoscopic or percutaneous drainage was performed in 47/373 patients (13%), of whom 21/47 patients (45%) were initially treated conservatively. Pancreatic necrosectomy or pancreatic surgery was performed in 31/373 patients (8%), without differences between treatment groups. Endocrine insufficiency (126/373 patients; 34%) and exocrine insufficiency (90/373 patients; 38%), developed less often following conservative treatment (p<0.001 and p=0.016, respectively). Quality of life scores did not differ between groups. Pancreatic gland necrosis >50% during initial admission was associated with percutaneous/endoscopic drainage (OR 4.3 (95% CI 1.5 to 12.2)), pancreatic surgery (OR 3.2 (95% CI 1.1 to 9.5) and development of endocrine insufficiency (OR13.1 (95% CI 5.3 to 32.0) and exocrine insufficiency (OR6.1 (95% CI 2.4 to 15.5) during follow-up. CONCLUSION: Acute necrotising pancreatitis carries a substantial disease burden during long-term follow-up in terms of recurrent disease, the necessity for interventions and development of pancreatic insufficiency, even when treated conservatively during the index admission. Extensive (>50%) pancreatic parenchymal necrosis seems to be an important predictor of interventions and complications during follow-up.


Assuntos
Insuficiência Pancreática Exócrina , Pancreatite Necrosante Aguda , Pancreatite Crônica , Humanos , Pancreatite Necrosante Aguda/complicações , Pancreatite Necrosante Aguda/cirurgia , Seguimentos , Qualidade de Vida , Estudos Prospectivos , Insuficiência Pancreática Exócrina/etiologia , Pancreatite Crônica/complicações , Drenagem/efeitos adversos , Necrose , Resultado do Tratamento
6.
Ann Surg ; 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38275104

RESUMO

BACKGROUND: Recent retrospective studies suggest a role for distinct microbiota in the perioperative morbidity and mortality of pancreatic head resections. OBJECTIVE: We aimed to prospectively investigate the microbial colonization of critical operative sites of pancreatic head resections to identify microbial stratification factors for surgical and long-term oncologic outcomes. METHODS: Prospective biomarker study applying 16S rRNA sequencing and microbial culturing to samples collected from various sites of the GI tract and surgical sites of patients during pancreatic head resections at a German single high-volume pancreatic center. RESULTS: A total of 101 patients were included (38 non-cancer, 63 cancer patients [50 PDAC patients]) in the study. In a first data analysis series, 16S rRNA sequencing data were utilized from 96 patients to assess associations of microbiome profiles with clinical parameters and outcomes. In general, microbiome composition varied according to sampling site, cancer, age or preoperative ERCP intervention, notably for the bile microbiome. In the PDAC subcohort, compositional variance of the bile or periampullary microbiome was significantly associated with postoperative complications such as ICU admission; on a taxonomic level we observed Enterococcus spp. to be significantly more abundant in patients developing deep or organ-space surgical site infections (SSI). Elevated Enterococcus relative abundances in the upper GI tract, in turn, were associated with 6-months mortality rates. In a second step, we focused on microbiological cultures collected from bile aspirates during surgery and investigated associations with perioperative complications and long-term survival. Notably, Enterococcus spp. were among the most prevalent pathobiont isolates observed in cancer patient bile specimens that were associated with severe SSIs, and thereby elevated mortality rates up to 24 months. Clinically relevant postoperative pancreatic fistulas or severe SSI were found as other major variables determining short-term mortality in this cancer patient cohort. In the context of adverse microbiological factors, a preoperative ERCP was also observed to segregate long-term survival, and it appeared to interact with the presence of Enterococcus spp. as highest mortality rates were observed in PDAC patients with both preoperative ERCP and presence of E. faecalis in bile aspirates. CONCLUSIONS: The presence of Enterococcus spp. in bile ducts of PDAC patients undergoing pancreatic surgery represents a significant risk factor for perioperative infections and, thereby, elevated postoperative and long-term mortality. This finding supports previous data on the use of the antibiotic drug piperacillin-tazobactam as appropriate perioperative antibiotic prophylaxis for preventing adverse outcomes after pancreatoduodenectomy.

7.
Surgery ; 175(2): 491-497, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38044240

RESUMO

BACKGROUND: Postoperative pancreatic fistulas are the most frequent major complications after pancreatoduodenectomy. The soft pancreatic texture is a critical, independent risk factor for postoperative pancreatic fistulas after pancreatoduodenectomy. The current gold standard for postoperative pancreatic fistula risk evaluation consists of the surgeon's intraoperative palpation of the pancreatic texture and, thus, lacks objectivity. In this prospective study, we used ultrasound-based shear-wave elastography, image data analysis, and a fistula risk score calculator to correlate the stiffness of pancreatic tissue with the occurrence of clinically relevant postoperative pancreatic fistulas. METHODS: We included 100 patients with pancreatic pathologies (71% pancreatic ductal adenocarcinoma) and 100 healthy individuals who were preoperatively assessed via real-time tissue ultrasound-based shear-wave elastography on a Philips EPIQ 7 ultrasound device and had pancreatic parenchyma histologically evaluated with manually stained images. RESULTS: We found a significant difference in the mean elasticity between the soft (1.22 m/s) and the hard pancreas group (2.10 m/s; P < .0001). The mean elasticity significantly correlated with the pancreatic fibrosis rate and the appearance of a postoperative pancreatic fistula after pancreatoduodenectomy. Low elasticity (≤1.2 m/s, mean) correlated with soft and high elasticity (>2.0 m/s, mean) with hard pancreatic parenchyma, as assessed by pathologic evaluation. Multivariate analysis revealed a mean elasticity of <1.3 m/s as a significant cut-off predictor for clinically relevant postoperative pancreatic fistulas (P = .003; Youden-Index = 0.6945). CONCLUSION: Preoperative ultrasound-based shear-wave elastography is a feasible and objective clinical diagnostic modality in evaluating pancreatic tissue stiffness. A mean pancreatic elasticity of <1.3 m/s was a significant independent risk predictor of clinically relevant postoperative pancreatic fistulas after pancreatoduodenectomy.


Assuntos
Técnicas de Imagem por Elasticidade , Fístula Pancreática , Humanos , Fístula Pancreática/diagnóstico por imagem , Fístula Pancreática/etiologia , Fístula Pancreática/epidemiologia , Pancreaticoduodenectomia/efeitos adversos , Estudos Prospectivos , Técnicas de Imagem por Elasticidade/efeitos adversos , Técnicas de Imagem por Elasticidade/métodos , Pâncreas/diagnóstico por imagem , Pâncreas/cirurgia , Pâncreas/patologia , Fatores de Risco , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia
8.
J Am Coll Surg ; 238(1): 70-80, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37870235

RESUMO

BACKGROUND: Intestinal homeostasis is a crucial factor for complication-free short- and long-term postoperative recovery. The brush border enzyme intestinal alkaline phosphatase (IAP) is an important regulator of gut barrier function and intestinal homeostasis and prevents endotoxemia by detoxifying lipopolysaccharides (LPSs). As IAP is predominantly secreted by enterocytes in the duodenum, we hypothesized that pancreaticoduodenectomy (PD) leads to a significantly stronger decrease in IAP than other major abdominal surgery. STUDY DESIGN: Pre- and postoperative blood, stool, and intestinal samples were collected from patients undergoing PD, as well as other major surgical procedures without duodenectomy. The samples were analyzed using enzyme histochemistry, the para -nitrophenyl phosphate method for IAP, and the limulus amebocyte lysate assay for LPS. RESULTS: Overall, 88 patients were prospectively enrolled in the study. Fecal IAP activity negatively correlated with serum LPS (r = -0.3603, p = 0.0006). PD led to a significant decline in IAP compared to preoperative baseline levels (p < 0.0001). The decline in IAP correlated with the length of proximal small intestinal resection (r = 0.4271, p = 0.0034). Compared to controls, PD was associated with a much more pronounced reduction in IAP-also after adjusting for surgical trauma (operative time, blood loss; r = 0.4598, p = 0.0086). Simultaneously, PD triggered a clearly more prominent increase in serum LPS compared to controls (p = 0.0001). Increased postoperative LPS was associated with an elongated hospitalization (r = 0.7534, p = 0.0062) and more prominent in pancreatic cancer (p = 0.0009). CONCLUSIONS: Based upon the functional roles for IAP, supplementation with exogenous IAP might be a new treatment option to improve short- and long-term outcome after PD.


Assuntos
Fosfatase Alcalina , Lipopolissacarídeos , Pancreaticoduodenectomia , Humanos , Fosfatase Alcalina/metabolismo , Fosfatase Alcalina/fisiologia , Homeostase , Mucosa Intestinal , Período Pós-Operatório , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/reabilitação
9.
ArXiv ; 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37214132

RESUMO

Two major challenges in time-of-flight positron emission tomography (TOF-PET) are low spatial resolution and high radioactive dose to the patient, both of which result from limitations in detection technology rather than fundamental physics. A new type of TOF-PET detector employing low-atomic number (low-Z) scintillation media and large-area, high-resolution photodetectors to record Compton scattering locations in the detector has been proposed as a promising alternative, but the minimum technical requirements for such a system have not yet been established. Here we present a simulation study evaluating the potential of a proposed low-Z detection medium, linear alkylbenzene (LAB) doped with a switchable molecular recorder, for next-generation TOF-PET detection. We developed a custom Monte Carlo simulation of full-body TOF-PET using the TOPAS Geant4 software package. By quantifying contributions and tradeoffs for energy, spatial, and timing resolution of the detector, we show that at reasonable combination of specifications, our likelihood-based identification of pairs of first interaction locations in the simulated detector identifies 87.1% of pairs with zero or negligible error, and correctly rejects 90% of all in-patient scatters. The same specifications give TOF-PET sensitivity of ~66.7% and PSF width 4.6 mm with clear contrast. A detector with these specifications provides a clear image of a brain phantom simulated at less than 1% of a standard radiotracer dose.

10.
J Transl Med ; 21(1): 876, 2023 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-38041179

RESUMO

BACKGROUND: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. METHODS: Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways. RESULTS: Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment. CONCLUSION: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Neoplásicas Circulantes , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Tigeciclina/farmacologia , Tigeciclina/metabolismo , Tigeciclina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular , Células Neoplásicas Circulantes/metabolismo , Proliferação de Células/genética , Células Hep G2 , Mitocôndrias/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Apoptose , Regulação Neoplásica da Expressão Gênica , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/farmacologia
11.
J Clin Med ; 12(21)2023 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-37959391

RESUMO

(1) Background: The clinical assessment of attention-deficit/hyperactivity disorder (ADHD) in adulthood is known to show non-trivial base rates of noncredible performance and requires thorough validity assessment. (2) Objectives: The present study estimated base rates of noncredible performance in clinical evaluations of adult ADHD on one or more of 17 embedded validity indicators (EVIs). This study further examines the effect of the order of test administration on EVI failure rates, the association between cognitive underperformance and symptom overreporting, and the prediction of cognitive underperformance by clinical information. (3) Methods: A mixed neuropsychiatric sample (N = 464, ADHD = 227) completed a comprehensive neuropsychological assessment battery on the Vienna Test System (VTS; CFADHD). Test performance allows the computation of 17 embedded performance validity indicators (PVTs) derived from eight different neuropsychological tests. Further, all participants completed several self- and other-report symptom rating scales assessing depressive symptoms and cognitive functioning. The Conners' Adult ADHD Rating Scale and the Beck Depression Inventory-II were administered to derive embedded symptom validity measures (SVTs). (4) Results and conclusion: Noncredible performance occurs in a sizeable proportion of about 10% up to 30% of individuals throughout the entire battery. Tests for attention and concentration appear to be the most adequate and sensitive for detecting underperformance. Cognitive underperformance represents a coherent construct and seems dissociable from symptom overreporting. These results emphasize the importance of performing multiple PVTs, at different time points, and promote more accurate calculation of the positive and negative predictive values of a given validity measure for noncredible performance during clinical assessments. Future studies should further examine whether and how the present results stand in other clinical populations, by implementing rigorous reference standards of noncredible performance, characterizing those failing PVT assessments, and differentiating between underlying motivations.

12.
Aging (Albany NY) ; 15(20): 10897-10914, 2023 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-37770230

RESUMO

The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells' WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional in vitro assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Via de Sinalização Wnt/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas
13.
Cell Stem Cell ; 30(8): 1091-1109.e7, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37541213

RESUMO

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Fator Trefoil-2/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Pâncreas/metabolismo , Células Acinares/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo
14.
J Cancer Res Clin Oncol ; 149(14): 13051-13064, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37470855

RESUMO

PURPOSE: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs). METHODS: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs. RESULTS: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4+, CD8+ and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids. CONCLUSION: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future.

16.
BMC Gastroenterol ; 23(1): 214, 2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37337197

RESUMO

BACKGROUND: The sole presence of deep submucosal invasion is shown to be associated with a limited risk of lymph node metastasis. This justifies a local excision of suspected deep submucosal invasive colon carcinomas (T1 CCs) as a first step treatment strategy. Recently Colonoscopy-Assisted Laparoscopic Wedge Resection (CAL-WR) has been shown to be able to resect pT1 CRCs with a high R0 resection rate, but the long term outcomes are lacking. The aim of this study is to evaluate the safety, effectiveness and long-term oncological outcomes of CAL-WR as primary treatment for patients with suspected superficial and also deeply-invasive T1 CCs. METHODS: In this prospective multicenter clinical trial, patients with a macroscopic and/or histologically suspected T1 CCs will receive CAL-WR as primary treatment in order to prevent unnecessary major surgery for low-risk T1 CCs. To make a CAL-WR technically feasible, the tumor may not include > 50% of the circumference and has to be localized at least 25 cm proximal from the anus. Also, there should be sufficient distance to the ileocecal valve to place a linear stapler. Before inclusion, all eligible patients will be assessed by an expert panel to confirm suspicion of T1 CC, estimate invasion depth and subsequent advise which local resection techniques are possible for removal of the lesion. The primary outcome of this study is the proportion of patients with pT1 CC that is curatively treated with CAL-WR only and in whom thus organ-preservation could be achieved. Secondary outcomes are 1) CAL-WR's technical success and R0 resection rate for T1 CC, 2) procedure-related morbidity and mortality, 3) 5-year overall and disease free survival, 4) 3-year metastasis free survival, 5) procedure-related costs and 6) impact on quality of life. A sample size of 143 patients was calculated. DISCUSSION: CAL-WR is a full-thickness local resection technique that could also be effective in removing pT1 colon cancer. With the lack of current endoscopic local resection techniques for > 15 mm pT1 CCs with deep submucosal invasion, CAL-WR could fill the gap between endoscopy and major oncologic surgery. The present study is the first to provide insight in the long-term oncological outcomes of CAL-WR. TRIAL REGISTRATION: CCMO register (ToetsingOnline), NL81497.075.22, protocol version 2.3 (October 2022).


Assuntos
Carcinoma , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Qualidade de Vida , Estudos Prospectivos , Neoplasias do Colo/cirurgia , Colonoscopia , Endoscopia Gastrointestinal , Resultado do Tratamento , Neoplasias Colorretais/patologia , Estudos Retrospectivos , Estudos Multicêntricos como Assunto
17.
Cancers (Basel) ; 15(9)2023 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-37173928

RESUMO

The globally increasing incidence of cutaneous malignancies leads, in parallel, to increasing numbers of locally advanced skin cancer resulting in reconstructive surgery. Reasons for locally advanced skin cancer may be a patient's neglect or aggressive tumor growth, such as desmoplastic growth or perineural invasion. This study investigates characteristics of cutaneous malignancies requiring microsurgical reconstruction with the aim of identifying possible pitfalls and improving diagnostic and therapeutic processes. A retrospective data analysis from 2015 to 2020 was conducted. Seventeen patients (n = 17) were included. The mean age at reconstructive surgery was 68.5 (±13) years. The majority of patients (14/17, 82%) presented with recurrent skin cancer. The most common histological entity was squamous cell carcinoma (10/17, 59%). All neoplasms showed at least one of the following histopathological characteristics: desmoplastic growth (12/17, 71%), perineural invasion (6/17, 35%), or tumor thickness of at least 6 mm (9/17, 53%). The mean number of surgical resections until cancer-free resection margins (R0) were achieved was 2.4 (±0.7). The local recurrence rate and the rate of distant metastases were 36%. Identified high-risk neoplastic characteristics, such as desmoplastic growth, perineural invasion, and a tumor depth of at least 6 mm, require a more extensive surgical treatment without concerns about defect size.

18.
Global Spine J ; 13(1_suppl): 36S-43S, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37084347

RESUMO

STUDY DESIGN: Multicenter prospective cohort study. OBJECTIVE: To analyse therapeutical strategies applied to osteoporotic thoracolumbar OF 4 injuries, to assess related complications and clinical outcome. METHODS: A multicenter prospective cohort study (EOFTT) including 518 consecutive patients who were treated for an Osteoporotic vertebral compression fracture (OVCF). For the present study, only patients with OF 4 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale, Oswestry Disability Questionnaire, Timed Up & Go test, EQ-5D 5L, and Barthel Index after a minimum follow-up of 6 weeks. RESULTS: A total of 152 (29%) patients presented with OF 4 fractures with a mean age of 76 years (range 41-97). The most common treatment was short-segment posterior stabilization (51%; hybrid stabilization in 36%). Mean follow up was 208 days (±131 days), mean ODI was 30 ± 21. Dorsoventral stabilized patients were younger compared to the other groups (P < .001) and had significant better TuG compared to hybrid stabilization (P = .049). The other clinical outcomes did not differ in the therapy strategies (VAS pain: P = 1.000, ODI: P > .602, Barthel: P > .252, EQ-5D 5L index value: P > .610, VAS-EQ-5D 5L: P = 1.000). The inpatient complication rate was 8% after conservative and 16% after surgical treatment. During follow-up period 14% of conservatively treated patients and 3% of surgical treated patients experienced neurological deficits. CONCLUSIONS: Conservative therapy of OF 4 injuries seems to be viable option in patients with only moderate symptoms. Hybrid stabilization was the dominant treatment strategy leading to promising clinical short-term results. Stand-alone cement augmentation seems to be a valid alternative in selected cases.

19.
Global Spine J ; 13(1_suppl): 44S-51S, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37084351

RESUMO

STUDY DESIGN: Subgroup analysis of a multicenter prospective cohort study. OBJECTIVE: To analyse surgical strategies applied to osteoporotic thoracolumbar osteoporotic fracture (OF) 5 injuries with anterior or posterior tension band failure and to assess related complications and clinical outcome. METHODS: A multicenter prospective cohort study (EOFTT) was conducted at 17 spine centers including 518 consecutive patients who were treated for an osteoporotic vertebral fracture (OVF). For the present study, only patients with OF 5 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale (VAS), Oswestry Disability Questionnaire (ODI), Timed Up & Go test (TUG), EQ-5D 5L, and Barthel Index. RESULTS: In total, 19 patients (78 ± 7 years, 13 female) were analysed. Operative treatment consisted of long-segment posterior instrumentation in 9 cases and short-segment posterior instrumentation in 10 cases. Pedicle screws were augmented in 68 %, augmentation of the fractured vertebra was performed in 42%, and additional anterior reconstruction was done in 21 %. Two patients (11 %) received short-segment posterior instrumentation without either anterior reconstruction or cement-augmentation of the fractured vertebra. No surgical or major complications occurred, but general postoperative complications were observed in 45%. At a follow-up of mean 20 ± 10 weeks (range, 12 to 48 weeks), patients showed significant improvements in all functional outcome parameters. CONCLUSIONS: In this analysis of patients with type OF 5 fractures, surgical stabilization was the treatment of choice and lead to significant short-term improvement in terms of functional outcome and quality of life despite a high general complication rate.

20.
Global Spine J ; 13(1_suppl): 6S-12S, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37084354

RESUMO

OBJECTIVES: Osteoporotic vertebral compression fractures (OVCF) are a common increasing entity in elderly patients and represent a tremendous economic burden. Surgical treatment is related to high complication rates and little is known about patient-specific and internal risk factors associated with poor clinical results. METHODS: We carried out a comprehensive, systematic literature search according to the PRISMA checklist and algorithm. Risk factors for perioperative complications, for early inpatient readmission, for the duration of the hospital stay, the hospital mortality, the total mortality and the clinical result were analyzed. RESULTS: A total of 739 potentially usable studies were identified. After considering all inclusion and exclusion criteria, 15 studies with 15,515 patients were included. Non-adjustable risk factors were age >90 years (OR 3.27), male gender (OR 1.41), BMI less than 18.5 kg/m2 (OR 3.97), ASA score >3 (OR 2.7), activity of daily live (ADL) (OR 1.52), dependence (OR 5.68), inpatient admission status (OR 3.22), Parkinson disease (OR 3.63) and disseminated cancer (OR 2.98). Adjustable factors were insufficient kidney function (GFR <60 mL/min, and Creatinine Clearance below 60 mg/dl) (OR 4.4), nutrition status (hypalbuminemia (<3.5 g/dl)), liver function (OR 8.9) and further cardiac and pulmonary comorbidities. DISCUSSION: We identified a couple of non-adjustable risk factors, which should be considered preoperatively in terms of risk assessment. However, even more important were adjustable factors that can be influenced preoperatively. In conclusion, we recommend a perioperative interdisciplinary cooperation, especially with geriatricians, to achieve the best possible clinical results in geriatric patients undergoing surgery for OVCF.

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