The Significance of Circulating Tumor Cells in Pancreatic Cancer.

The notion that technically resectable pancreatic ductal adenocarcinoma presents as localized disease is now known to be inaccurate. Evidence supports that most patients have subclinical systemic dissemination at the time of diagnosis. It is now widely accepted that both a local and systemic component of disease coexist, each requiring treatment of improved survival and potential cure. The advent of multiagent chemotherapy regimens has resulted in a modest improvement in survival. Consequently, this article will emphasize the expanding potential and significance of circulating tumor cells in the prognostication and management of patients with pancreatic cancer.

Evolution and improved outcomes in the era of multimodality treatment for extended pancreatectomy.

BACKGROUND: The evolution and outcomes of extended pancreatectomies at a single institute over 15 years are presented in this study. METHODS: A retrospective analysis of the institutional database was performed from 2015 to 2022 (period B). Patients undergoing extended pancreatic resections, as defined by the International Study Group for Pancreatic Surgery, were included. Perioperative and survival outcomes were compared with data from 2007-2015 (period A). Regression analyses were used to identify factors affecting postoperative and long-term survival outcomes. RESULTS: A total of 197 (16.1%) patients underwent an extended resection in period B compared to 63 (9.2%) in period A. Higher proportions of borderline resectable (5 (18.5%) versus 51 (47.7%), P = 0.011) and locally advanced tumours (1 (3.7%) versus 24 (22.4%), P < 0.001) were resected in period B with more frequent use of neoadjuvant therapy (6 (22.2%) versus 79 (73.8%), P < 0.001). Perioperative mortality (4 (6.0%) versus 12 (6.1%), P = 0.81) and morbidity (23 (36.5%) versus 83 (42.1%), P = 0.57) rates were comparable. The overall survival for patients with pancreatic adenocarcinoma was similar in both periods (17.5 (95% c.i. 6.77 to 28.22) versus 18.3 (95% c.i. 7.91 to 28.68) months, P = 0.958). Resectable, node-positive tumours had a longer disease-free survival (DFS) in period B (5.81 (95% c.i. 1.73 to 9.89) versus 14.03 (95% c.i. 5.7 to 22.35) months, P = 0.018). CONCLUSION: Increasingly complex pancreatic resections were performed with consistent perioperative outcomes and improved DFS compared to the earlier period. A graduated approach to escalating surgical complexity, multimodality treatment, and judicious patient selection enables the resection of advanced pancreatic tumours.

Digital subtraction angiography-guided pancreatic arterial infusion of GEMOX chemotherapy in advanced pancreatic adenocarcinoma: a phase II, open-label, randomized controlled trial comparing with intravenous chemotherapy.

BACKGROUND: Advanced pancreatic adenocarcinoma lacks effective treatment options, and systemic gemcitabine-based chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. New therapeutic options with better drug availability are warranted. This study aims to evaluate the safety and efficacy of digital subtraction angiography (DSA)-guided pancreatic arterial infusion (PAI) versus intravenous chemotherapy (IVC) using the gemcitabine and oxaliplatin (GEMOX) regimen in unresectable locally advanced or metastatic pancreatic cancer (PC) patients. MATERIALS AND METHODS: This study prospectively enrolled 51 eligible treatment-naive patients with unresectable PC to receive GEMOX treatment via PAI or IVC (1:1 ratio randomization) from December 2015 to December 2019. Cycles were repeated monthly, and each process consisted of two treatments administered bi-weekly. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, 6-month survival, tumor-site subgroup survival, and incidences of adverse events were compared. RESULTS: The median OS of the PAI and IVC groups were 9.93 months and 10.07 months, respectively (p = 0.3049). The median PFS of the PAI and IVC groups were 5.07 months and 4.23 months (p = 0.1088). No significant differences were found in the ORR (11.54% vs. 4%, p = 0.6312), DCR (53.85% vs. 44%, p = 0.482), and 1-year OS rate (44% vs. 20.92%, p = 0.27) in PAI and IVC groups. The 6-month OS rate was significantly higher in the PAI group (100%) than in the IVC group (83.67%) (p = 0.0173). The median OS of patients in PAI group with pancreatic head and neck tumors were significantly higher than those of body and tail tumors (12.867 months vs. 9 months, p = 0.0214). The incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group (p < 0.05). CONCLUSION: GEMOX PAI therapy presented a higher 6-month OS rate and fewer adverse events than IVC in advanced pancreatic adenocarcinoma patients. Those with pancreatic head and neck tumors may yield a superior treatment outcome from PAI treatment. TRIAL REGISTRATION NUMBER: NCT02635971. DATE OF REGISTRATION: 21/12/2015.

Deep learning predicts the 1-year prognosis of pancreatic cancer patients using positive peritoneal washing cytology.

Peritoneal washing cytology (CY) in patients with pancreatic cancer is mainly used for staging; however, it may also be used to evaluate the intraperitoneal status to predict a more accurate prognosis. Here, we investigated the potential of deep learning of CY specimen images for predicting the 1-year prognosis of pancreatic cancer in CY-positive patients. CY specimens from 88 patients with prognostic information were retrospectively analyzed. CY specimens scanned by the whole slide imaging device were segmented and subjected to deep learning with a Vision Transformer (ViT) and a Convolutional Neural Network (CNN). The results indicated that ViT and CNN predicted the 1-year prognosis from scanned images with accuracies of 0.8056 and 0.8009 in the area under the curve of the receiver operating characteristic curves, respectively. Patients predicted to survive 1 year or more by ViT showed significantly longer survivals by Kaplan-Meier analyses. The cell nuclei found to have a negative prognostic impact by ViT appeared to be neutrophils. Our results indicate that AI-mediated analysis of CY specimens can successfully predict the 1-year prognosis of patients with pancreatic cancer positive for CY. Intraperitoneal neutrophils may be a novel prognostic marker and therapeutic target for CY-positive patients with pancreatic cancer.

Role of glycosylation-related gene MGAT1 in pancreatic ductal adenocarcinoma.

Background: pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a very poor prognosis and a complex tumor microenvironment, which plays a key role in tumor progression and treatment resistance. Glycosylation plays an important role in processes such as cell signaling, immune response and protein stability. Materials and methods: single-cell RNA sequencing data and spatial transcriptome data were obtained from GSE197177 and GSE224411, respectively, and RNA-seq data and survival information were obtained from UCSC Xena and TCGA. Multiple transcriptomic data were comprehensively analyzed to explore the role of glycosylation processes in tumor progression, and functional experiments were performed to assess the effects of MGAT1 overexpression on PDAC cell proliferation and migration. Results: In PDAC tumor samples, the glycosylation level of macrophages was significantly higher than that of normal samples. MGAT1 was identified as a key glycosylation-related gene, and its high expression was associated with better patient prognosis. Overexpression of MGAT1 significantly inhibited the proliferation and migration of PDAC cells and affected intercellular interactions in the tumor microenvironment. Conclusion: MGAT1 plays an important role in PDAC by regulating glycosylation levels in macrophages, influencing tumor progression and improving prognosis.MGAT1 is a potential therapeutic target for PDAC and further studies are needed to develop targeted therapeutic strategies against MGAT1 to improve clinical outcomes.

Partial pancreatoduodenectomy versus total pancreatectomy in patients with preoperative diabetes mellitus: Comparison of surgical outcomes and quality of life.

PURPOSE: To reduce perioperative risks among patients with a preoperative diabetes mellitus (DM) a total pancreatectomy (TP) might be a alternative to pancreatoduodenectomy (PD). This study aimed to compare the postoperative quality of life (QoL) of patients with preoperative DM undergoing PD or TP. METHODS: A single-centre retrospective study was conducted, all consecutive patients with preoperative DM undergoing PD or TP between 2011 and 2023 were identified in a prospective database. The primary endpoint was QoL, prospectively assessed using EORTC QLQ-C30 questionnaires at 3, 6, and 12 months after surgery and then annually until death. Secondary endpoints were morbidity and mortality. RESULTS: Seventy-one patients were included, 17 after TP and 54 after PD. Insulin-dependent DM occurred in 21 (39%) of the PD patients. QoL was worse after TP, especially in terms of physical functioning (-31.7 points; 95% CI: -50.0 to -13.3; P < 0.001), role functioning (-41.3 points; 95% CI: -61.3 to -21.3; P < 0.001), emotional functioning (-27.5 points; 95% CI: -50.4 to -4.6; P = 0.019), fatigue symptoms (20 points; 95% CI: 2.7 to 37.4; P = 0.024) and pain symptoms (30.2 points; 95% CI: 4.1 to 56.3; P = 0.024). The rates of postoperative major complications (29% vs. 35%; P = 0.853) and mortality (11% vs. 7%; P = 0.857) were similar between TP and PD. CONCLUSION: Postoperative morbidity and mortality were comparable between PD and TP, however QoL is significantly lower after TP. Importantly, patients with preoperative DM have a 60% chance of remaining noninsulin-dependent after PD.

Comparing clinical and genomic features based on the tumor location in patients with resected pancreatic cancer.

BACKGROUND: Pancreatic cancer is anatomically divided into pancreatic head and body/tail cancers, and some studies have reported differences in prognosis. However, whether this discrepancy is induced from the difference of tumor biology is hotly debated. Therefore, we aimed to evaluate the differences in clinical outcomes and tumor biology depending on the tumor location. METHODS: In this retrospective cohort study, we identified 800 patients with pancreatic ductal adenocarcinoma who had undergone upfront curative-intent surgery. Cox regression analysis was performed to explore the prognostic impact of the tumor location. Among them, 153 patients with sufficient tumor tissue and blood samples who provided informed consent for next-generation sequencing were selected as the cohort for genomic analysis. RESULTS: Out of the 800 patients, 500 (62.5%) had pancreatic head cancer, and 300 (37.5%) had body/tail cancer. Tumor location in the body/tail of the pancreas was not identified as a significant predictor of survival outcomes compared to that in the head in multivariate analysis (hazard ratio, 0.94; 95% confidence interval, 0.77-1.14; P = 0.511). Additionally, in the genomic analyses of 153 patients, there were no significant differences in mutational landscapes, distribution of subtypes based on transcriptomic profiling, and estimated infiltration levels of various immune cells between pancreatic head and body/tail cancers. CONCLUSIONS: We could not find differences in prognosis and tumor biology depending on tumor location in pancreatic ductal adenocarcinoma. Discrepancies in prognosis may represent a combination of lead time, selection bias, and clinical differences, including the surgical burden between tumor sites.

[Sex differences in pancreatic cancer]. / Geschlechtsunterschiede beim Pankreaskarzinom.

This review article discusses the currently available evidence on the importance of biological and social sex in pancreatic cancer in the context of the operative, perioperative and multimodal treatment. In pancreatic cancer there are gender differences with respect to the incidence, treatment response and prognosis. Sex significantly influences both innate and adaptive immune responses, thereby affecting treatment response and survival rates. Women are less likely to receive systemic treatment and tend to wait longer for surgery but have better perioperative outcomes after pancreatic resection. Overall, female pancreatic cancer patients seem to have longer survival under treatment; however, they report a subjectively lower quality of life and higher disease burden.

Nivolumab plus platinum-doublet chemotherapy in treatment-naive patients with advanced grade 3 Neuroendocrine Neoplasms of gastroenteropancreatic or unknown origin: The multicenter phase 2 NICE-NEC trial (GETNE-T1913).

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m2/d iv on days 1-3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H0 50%, H1 72%, ß 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.

Driver mutation subtypes involve with differentiated immunophenotypes influencing pancreatic cancer outcomes.

Despite many studies focusing on the prognostic biomarkers in pancreatic adenocarcinomas (PAADs), there is ill-informed about the relationships between their genomic features and immune characteristics. Herein, we deeply investigated the involvement of major driver mutation subtypes with immunophenotypes impacting PAAD outcomes. Based on public data analyses of RNA expression-based immune subtypes in PAAD, in contrast to KRAS G12D & TP53 co-mutant patients with poor outcomes, the best immune subtype C3 (inflammatory) characterized by high Th1/Th2 ratio was relatively enriched in KRASnon-G12DTP53wt patients with better survival, whereas the inferior subtype C2 (IFN-γ dominant) with low Th1/Th2 ratio was more common in the former than in the latter. Moreover, contrary to the highly immunosuppressive microenvironment (high Treg, high ratio of Treg to tumor-specific CD4+ T cell) in KRASG12DTP53mut patients, KRASG12VTP53wt individuals exhibited an inflamed context profiled by multiplex immunohistochemistry. It could be responsible for their outstanding survival advantage over others in postsurgical PAAD patients receiving adjuvant chemotherapy as shown by our cohort. Together, KRASG12VTP53wt may be a promising biomarker for prognostic evaluation and screening certain candidates with PAAD to get desirable survival benefit from adjuvant chemotherapy.

Stereotactic body radiation therapy for the primary tumor and oligometastases versus the primary tumor alone in patients with metastatic pancreatic cancer.

BACKGROUND: Local therapies may benefit patients with oligometastatic cancer. However, there were limited data about pancreatic cancer. Here, we compared the efficacy and safety of stereotactic body radiation therapy (SBRT) to the primary tumor and all oligometastases with SBRT to the primary tumor alone in patients with metastatic pancreatic cancer. METHODS: A retrospective review of patients with synchronous oligometastatic pancreatic cancer (up to 5 lesions) receiving SBRT to all lesions (including all oligometastases and the primary tumor) were performed. Another comparable group of patients with similar baseline characteristics, including metastatic burden, SBRT doses, and chemotherapy regimens, receiving SBRT to the primary tumor alone were identified. The primary endpoint was overall survival (OS). The secondary endpoints were progression frees survival (PFS), polyprogression free survival (PPFS) and adverse events. RESULTS: There were 59 and 158 patients receiving SBRT to all lesions and to the primary tumor alone. The median OS of patients with SBRT to all lesions and the primary tumor alone was 10.9 months (95% CI 10.2-11.6 months) and 9.3 months (95% CI 8.8-9.8 months) (P < 0.001). The median PFS of two groups was 6.5 months (95% CI 5.6-7.4 months) and 4.1 months (95% CI 3.8-4.4 months) (P < 0.001). The median PPFS of two groups was 9.8 months (95% CI 8.9-10.7 months) and 7.8 months (95% CI 7.2-8.4 months) (P < 0.001). Additionally, 14 (23.7%) and 32 (20.2%) patients in two groups had grade 3 or 4 treatment-related toxicity. CONCLUSIONS: SBRT to all oligometastases and the primary tumor in patients with pancreatic cancer may improve survival, which needs prospective verification.

Diagnosis, treatment, and prognosis of adult pancreatoblastoma.

BACKGROUND: Pancreatoblastoma (PB) is one of the rare malignant tumors that typically occurs in children. Cases of PB in adults are highly unusual. This disease often presents with subtle symptoms and lacks characteristic clinical manifestations, leading to diagnostic challenges. OBJECTIVE: This study integrates the relevant literature on adult PB, conducting data analysis on clinical features, laboratory and imaging results, pathological characteristics, and treatments according to inclusion and exclusion criteria. Kaplan-Meier univariate analysis and Log-rank tests are employed to analyze survival data from adult PB follow-up, exploring factors influencing prognosis. RESULTS: A total of 65 articles were included, encompassing 103 cases of adult PB. The average age of PB patients was 41.78 years (range 19-81 years), and the male-to-female ratio was 1.06:1. Patients frequently presented with abdominal pain as the initial symptom. Laboratory results lacked specificity and imaging findings often presented as large, well-defined masses. PB exhibited distinctive pathological features, including squamous corpuscles (n = 76, 89.41%) and acinar differentiation (n = 34, 40%), with frequent positive expression of Trypsin, Chymotrypsin, and AACT (Alpha-1-Antichymotrypsin). APC (Adenomatous Polyposis Coli) gene mutation was the most common molecular alteration in adult PB. During the follow-up period, 43.59% of patients died (range 3 days to 348 months). The primary factors affecting prognosis were the presence of metastasis (χ2 = 3.996, p = 0.046) and incomplete surgical resection (χ2 = 5.586, p = 0.018), with mean survival times of 48 months and 27 months, respectively. CONCLUSIONS: PB in adults is an invasive tumor. The key to distinguishing PB from other pancreatic tumors lies in recognizing its unique pathological feature, the squamous corpuscles. Timely and complete surgical resection is the preferred treatment following diagnosis. Patients with incomplete resection or the presence of lymph nodes or (and) distant metastases have a poor prognosis.

Outcomes of minimally invasive vs. open pancreatoduodenectomies in pancreatic adenocarcinoma: analysis of ACS-NSQIP data.

INTRODUCTION: Pancreatoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) presents a significant challenge owing to its aggressive nature. Traditionally performed as open surgery, the advent of minimally invasive surgery (MIS) including laparoscopic and robotic techniques, offers a potential alternative. This study assessed the use and outcomes of MIS and open PD for PDAC treatment. METHODS: We analyzed ACS-NSQIP data (2015-2021) using regression models to compare patient outcomes across open PD, MIS PD, and conversions from MIS to open (MIS-O). RESULTS: Of 19,812 PDAC patients, 1,293 (6.53%) underwent MIS, 18,116 (91.44%) underwent open PD, and 403 (2.03%) underwent MIS converted to open PD (MIS-O). The MIS rate increased from 6.1% to 9.2%. Black patients had a higher MIS-O rate (RR, 1.55; p = 0.025). Open PD was associated with more severe conditions (ASA ≥ III, malnutrition) and prior radiation therapy. MIS patients more often had neoadjuvant chemotherapy. Complex procedures, such as vein resection, favored open PD. Need for arterial resection was associated with MIS-O (RR, 2.11; p = 0.012), and operative time was significantly associated with MIS (OR: 4.32, 95% CI: 3.43-5.43, p-value: < 0.001) No differences in the overall morbidity or 30-day mortality were observed. MIS led to shorter stays but higher risks of reoperation and pulmonary embolism. MIS-O increased the delayed gastric emptying rate (RR, 1.79; p < 0.001). CONCLUSION: During 2015-2021, an increasing number of patients with PDAC are undergoing MIS PD. Morbidity and mortality did not differ between open and MIS PD. MIS was performed more frequently in patients with better nutritional status and lower ASA, or when vascular resection was not anticipated. In well selected patients, short-term outcomes of MIS and open PD seem similar.

Deep-Transfer-Learning-Based Natural Language Processing of Serial Free-Text Computed Tomography Reports for Predicting Survival of Patients With Pancreatic Cancer.

PURPOSE: To explore the predictive potential of serial computed tomography (CT) radiology reports for pancreatic cancer survival using natural language processing (NLP). METHODS: Deep-transfer-learning-based NLP models were retrospectively trained and tested with serial, free-text CT reports, and survival information of consecutive patients diagnosed with pancreatic cancer in a Korean tertiary hospital was extracted. Randomly selected patients with pancreatic cancer and their serial CT reports from an independent tertiary hospital in the United States were included in the external testing data set. The concordance index (c-index) of predicted survival and actual survival, and area under the receiver operating characteristic curve (AUROC) for predicting 1-year survival were calculated. RESULTS: Between January 2004 and June 2021, 2,677 patients with 12,255 CT reports and 670 patients with 3,058 CT reports were allocated to training and internal testing data sets, respectively. ClinicalBERT (Bidirectional Encoder Representations from Transformers) model trained on the single, first CT reports showed a c-index of 0.653 and AUROC of 0.722 in predicting the overall survival of patients with pancreatic cancer. ClinicalBERT trained on up to 15 consecutive reports from the initial report showed an improved c-index of 0.811 and AUROC of 0.911. On the external testing set with 273 patients with 1,947 CT reports, the AUROC was 0.888, indicating the generalizability of our model. Further analyses showed our model's contextual interpretation beyond specific phrases. CONCLUSION: Deep-transfer-learning-based NLP model of serial CT reports can predict the survival of patients with pancreatic cancer. Clinical decisions can be supported by the developed model, with survival information extracted solely from serial radiology reports.

Dual and triple gene combinations of KRT5, KRT17, and S100A2 identify basal-like subtype of pancreatic ductal adenocarcinoma and correlate with survival outcome.

There is a significant difference in prognosis and response to chemotherapy between basal and classical subtypes of pancreatic ductal adenocarcinoma (PDAC). Further biomarkers are required to identify subtypes of PDAC. We selected candidate biomarkers via review articles. Correlations between these candidate markers and the PDAC molecular subtype gene sets were analyzed using bioinformatics, confirming the biomarkers for identifying classical and basal subtypes. Subsequently, 298 PDAC patients were included, and their tumor tissues were immunohistochemically stratified using these biomarkers. Survival data underwent analysis, including Cox proportional hazards modeling. Our results indicate that the pairwise and triple combinations of KRT5/KRT17/S100A2 exhibit a higher correlation coefficient with the basal-like subtype gene set, whereas the corresponding combinations of GATA6/HNF4A/TFF1 show a higher correlation with the classical subtype gene set. Whether analyzing unmatched or propensity-matched data, the overall survival time was significantly shorter for the basal subtype compared with the classical subtype (p < .001), with basal subtype patients also facing a higher risk of mortality (HR = 4.017, 95% CI 2.675-6.032, p < .001). In conclusion, the combined expression of KRT5, KRT17, and S100A2, in both pairwise and triple combinations, independently predicts shorter overall survival in PDAC patients and likely identifies the basal subtype. Similarly, the combined expression of GATA6, HNF4A, and TFF1, in the same manner, may indicate the classical subtype. In our study, the combined application of established biomarkers offers valuable insights for the prognostic evaluation of PDAC patients.

Distinct clinicopathological features of neuroendocrine liver metastases originating from the pancreas and rectum.

INTRODUCTION: Survival comparisons among patients with liver metastases from pancreatic and rectal neuroendocrine tumors (NETs) were limited, and the efficacy of observation rules in patients undergoing hepatectomy for neuroendocrine liver metastases (NELMs) was unknown. This study aims to distinguish these characteristics and clarify the effects of the observation rules on NELMs. METHODS: Clinical data were separately collected from patients with pancreatic and rectal NELMs at medical centers in both Japan and China. The Japanese cohort followed the observation rules for the resection of NELMs. A comparative analysis was conducted on clinical characteristics and prognosis features such as overall survival time (OS) and disease-free survival interval (DFS-I). RESULTS: Enrollment included 47 and 34 patients from Japan and China, respectively. Of these, 69 and 12 patients had tumors originating from the pancreas and rectum, respectively. The OS time in patients undergoing primary tumor resection was significantly longer; however, the OS time between the patients undergoing and not undergoing radical resection of liver metastasis was the same. In asynchronous NELMs, patients with rectal (R)-NELMs showed a significantly higher proportion of type III NELMs. Additionally, the median DFS-I of asynchronous R-NELMs was longer than the recommended follow-up time, with 71.4% of them classified as G2. In the Japanese cohort, patients who adhered to the observation rules exhibited a longer median DFS after hepatectomy for NELMs compared with their counterparts. CONCLUSION: Although curative surgery is crucial for primary lesions, personalized approaches are required to manage NELMs. Extended overall follow-ups and shortened follow-up intervals are recommended for G2 stage rectal NETs. The observation rules for NELMs require further validation with a larger sample size.

Critical appraisal of the adequacy of surgical indications for non-functioning pancreatic neuroendocrine tumours.

BACKGROUND: The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness. METHODS: A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002-2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse). RESULTS: A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001). CONCLUSIONS: Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment.

Metabolic Tumor Volume on 18-Fluorodeoxyglucose Positron Emission Tomography as a Prognostic Marker of Survival in Patients With Locally Advanced or Metastatic Neuroendocrine Neoplasms Treated With 177Lutetium-DOTA-Octreotate Peptide Receptor Radionuclide Therapy.

OBJECTIVE: We investigated metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on pre-treatment FDG-PET as prognostic markers for survival in patients with metastatic neuroendocrine neoplasms (NENs) receiving peptide receptor radionuclide therapy (PRRT). METHODS: A retrospective review of patients with metastatic NENs receiving PRRT was undertaken. Pre-treatment FDG-PET images were analyzed and variables collected included MTV and TLG (dichotomized by median into high vs low). Main Outcomes were overall survival (OS) and progression-free survival (PFS) by MTV and TLG (high vs low). RESULTS: One hundred five patients were included. Median age was 64 years (50% male). Main primary NEN sites were small bowel (43.8%) and pancreas (40.0%). Median MTV was 3.8 mL and median TLG was 19.9. Dichotomization formed identical cohorts regardless of whether MTV or TLG were used. Median OS was 72 months; OS did not differ based on MTV/TLG high versus low (47.4 months vs not reached; hazard ratio, 0.43; 95% confidence interval [CI], 0.18-1.04; P = 0.0594). Median PFS was 30.4 months; PFS differed based on MTV/TLG high versus low (21.6 months vs 45.7 months; hazard ratio, 0.35; 95% CI, 0.19-0.64; P = 0.007). CONCLUSIONS: Low MTV/TLG on pre-treatment FDG-PET was associated with longer PFS in metastatic NEN patients receiving PRRT.

Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma.

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

The prognostic role of lymphocyte-to-monocyte ratio in patients with resectable pancreatic cancer: a systematic review and meta-analysis.

Objectives: This systematic review and meta-analysis examined whether the lymphocyte-to-monocyte ratio (LMR) can serve as an indicator for predicting the prognosis of patients with resectable pancreatic cancer. Patients and Methods: This meta-analysis was registered with PROSPERO: CRD42023461260. A systematic literature search was conducted in the PubMed, Embase, Cochrane, and Web of Science databases up to September 2023 to assess whether LMR can predict the prognosis of patients with resectable pancreatic cancer. The outcomes measured included subgroup analyses of overall survival (OS) with hazard ratios (HR) and confidence intervals of geographical region, patient population, and LMR threshold. A sensitivity analysis was also performed for OS and HR and confidence intervals were calculated for recurrence-free survival (RFS). Results: A total of 14 eligible articles, comprising 4,019 patients, were included in the comprehensive analysis. The results of this comprehensive analysis indicate that LMR is a robust predictor of OS, demonstrating strong prognostic significance (HR = 0.55, 95% CI [0.44-0.69], I2 = 79%, P < 0.00001). This predictive significance extended to various types of pancreatic cancer, such as pancreatic ductal adenocarcinoma (HR = 0.73, 95% CI [0.57-0.93], I2 = 46%, P = 0.01), pancreatic neuroendocrine neoplasms (HR = 0.81, 95% CI [0.66-0.99], P = 0.04) and other subtypes (HR = 0.40, 95% CI [0.22-0.72], I2 = 89%, P < 0.00001), but not to pancreatic head cancer (HR = 0.46, 95% CI [0.16-1.13], I2 = 59%, P = 0.12). LMR retained its predictive value across different regions, including Asia (HR = 0.62, 95% CI [0.47-0.76], I2 = 68%, P < 0.0001), Europe (HR = 0.78, 95% CI [0.67-0.91], I2 = 0%, P = 0.002), and the Americas (HR = 0.14, 95% CI [0.08-0.24], I2 = 0%, P < 0.00001). Notably, both LMR cut-off values greater than or equal to three (HR = 0.62, 95% CI [0.47-0.82], I2 = 67%, P = 0.0009) and less than three (HR = 0.47, 95% CI [0.32-0.69], I2 = 85%, P = 0.0001) exhibited prognostic significance. The sensitivity analysis for OS confirmed the strong predictive value of LMR, whereas LMR did not exhibit predictive significance for RFS (HR = 0.35, 95% CI [0.09-1.32], I2 = 95%, P = 0.12). In both subgroups categorized by Newcastle-Ottawa Scale (NOS) scores of ≥7 (HR = 0.66, 95% CI [0.54-0.80], I2 = 53%, P = 0.04) and <7 (HR = 0.41, CI [0.23-0.72], I2 = 89%, P < 0.00001), LMR was demonstrated to have predictive value. Conclusion: Despite the observed heterogeneity and potential biases in the included studies, the findings of this study suggest that LMR may serve as a valuable predictor of OS in patients with resectable pancreatic cancer.