The immune tumour microenvironment of neuroendocrine tumours and its implications for immune checkpoint inhibitors

Immunotherapy in the form of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape in numerous types of advanced cancer. However, the majority of patients do not benefit from this treatment modality. Although data are scarce, in general, patients with low-grade neuroendocrine tumours (NETs) do not benefit from treatment with ICIs in contrast to patients with neuroendocrine carcinoma, in which a small subgroup of patients may benefit. Low- and intermediate-grade NETs predominantly lack factors associated with response to ICIs treatment, like immune cell infiltration and have an immunosuppressive tumour metabolism and microenvironment. In addition, because of its potential influence on the response to ICIs, major interest has been shown in the tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). These enzymes work along the kynurenine pathway that deplete tryptophan in the tumour microenvironment. IDO and TDO are especially of interest in NETs since some tumours produce serotonin but the majority do not, which potentially deplete the precursor tryptophan. In this review we summarize the current knowledge on the immune tumour microenvironment of neuroendocrine tumours and implications for treatment with immune checkpoint inhibitors. We also discuss (targetable) factors in the NET tumour microenvironment that potentially modulate the anti-cancer immune response

Treatment of iron deficiency in patients scheduled for pancreatic surgery:implications for daily prehabilitation practice in pancreatic surgery

BACKGROUND: Preoperative anemia is a frequent complication in pancreatic surgical patients, and it adversely affects morbidity, mortality, and postoperative red blood cell (RBC) transfusion rates. Iron deficiency (ID) is often the underlying cause of anemia and constitutes a modifiable risk factor.METHODS: Single-center, longitudinal prospective cohort study conducted between May 2019 and August 2022 at the University Medical Center Groningen in the Netherlands. Patients scheduled for pancreatic surgery were referred to the outpatient prehabilitation clinic for preoperative optimization of patient-related risk factors. Patients were screened for anemia (&lt; 12.0 g/dL in women and &lt; 13.0 g/dL in men) and ID (either absolute [ferritin &lt; 30 µg/L] or functional [ferritin ≥ 30 µg/L + transferrin saturation &lt; 20% + C-reactive protein &gt; 5 mg/L]). Intravenous iron supplementation (IVIS) (1,000 mg ferric carboxymaltose) was administered to patients with ID at the discretion of the consulting internist. Pre- and postoperative hemoglobin (Hb) levels were assessed, and perioperative outcomes were compared between patients receiving IVIS (IVIS-group) or standard care (SC-group).RESULTS: From 164 screened patients, preoperative anemia was observed in 55 (33.5%) patients, and in 23 (41.8%) of these patients, ID was the underlying cause. In 21 patients, ID was present without concomitant anemia. Preoperative IVIS was administered to 25 patients, out of 44 patients with ID. Initial differences in mean Hb levels (g/dL) between the IVIS-group and SC-group at the outpatient clinic and one day prior to surgery (10.8 versus 13.2, p &lt; 0.001, and 11.8 versus 13.4, p &lt; 0.001, respectively) did not exist at discharge (10.6 versus 11.1, p = 0.13). Preoperative IVIS led to a significant increase in mean Hb levels (from 10.8 to 11.8, p = 0.03). Fewer SSI were observed in the IVIS-group (4% versus 25.9% in the SC-group, p = 0.02), which remained significant in multivariable regression analysis (OR 7.01 (1.68 - 49.75), p = 0.02).CONCLUSION: ID is prevalent in patients scheduled for pancreatic surgery and is amendable to preoperative correction. Preoperative IVIS increased Hb levels effectively and reduced postoperative SSI. Screening and correction of ID is an important element of preoperative care and should be a standard item in daily prehabilitation practice.</p

Diagnostic performance of preoperative CT in differentiating between benign and malignant origin of suspicious gallbladder lesions

Purpose: To determine diagnostic performance of preoperative CT in differentiating between benign and malignant suspicious gallbladder lesions and to develop a preoperative risk score. Method: All patients referred between January 2007 and September 2018 for suspicion of gallbladder cancer (GBC) or incidentally found GBC were retrospectively analyzed. Patients were excluded when preoperative CT or histopathologic examination was lacking. Two radiologists, blinded to histopathology results, independently reviewed CT images to differentiate benign disease from GBC. Multivariable analysis and internal validation were used to develop a risk score for GBC. Model discrimination, calibration, and diagnostic performance were assessed. Results: In total, 118 patients with 39 malignant (33 %) and 79 benign (67 %) lesions were included. Sensitivity of CT for diagnosing GBC was 90 % (95 % confidence interval [CI]: 76?97). Specificity rates were 61 % (95 % CI: 49?72) and 59 % (95 % CI: 48?70). Three predictors of GBC (irregular lesion aspect, absence of fat stranding, and locoregional lymphadenopathy) were included in the risk score ranging from -1 to 4. Adequate performance was found (AUC: 0.79, calibration slope: 0.89). In patients allocated >0 points, the model showed higher performance in excluding GBC than the radiologists (sensitivity 92 % [95 % CI: 79?98]). Moreover, when allocated >3 points, the risk score was superior in diagnosing GBC (specificity 99 % [95 % CI: 93?100]). Conclusions: Sensitivity rates of CT for differentiation between benign and malignant gallbladder lesions are high, however specificity rates are relatively low. The proposed risk score may facilitate differentiation between benign and malignant suspicious gallbladder lesions

Diagnostic Laparoscopy as a Selection Tool for Patients with Colorectal Peritoneal Metastases to Prevent a Non-therapeutic Laparotomy During Cytoreductive Surgery

OBJECTIVE: The aim of this study was to evaluate the introduction of diagnostic laparoscopy (DLS) in patients with colorectal peritoneal metastases (PM) to prevent non-therapeutic laparotomies during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). METHODS: Patients with histologically proven colorectal PM who underwent a laparotomy for potential CRS + HIPEC from January 2006 to January 2019 were retrospectively identified from a prospectively maintained database. In 2012, DLS was introduced in the preoperative work-up for CRS + HIPEC in our academic center. The rates of non-therapeutic laparotomies, major postoperative complications (Clavien-Dindo grade III or higher), and survival outcomes were investigated for patients who underwent a laparotomy before (cohort A) and after (cohort B) the introduction of DLS. In cohort B, the reasons to refrain from DLS were retrospectively explored from medical records. RESULTS: Overall, 172 patients were included [cohort A: 48 patients (27.9%); cohort B: 124 patients (72.1%)]. A significant drop in the rate of non-therapeutic laparotomies occurred in cohort B compared with cohort A (21.0 vs. 35.4%: p = 0.044), despite only 85 patients (68.5%) from cohort B undergoing DLS in our academic center. The most important reason to refrain from DLS was a recently performed DLS or laparotomy in the referring hospital (48.7%). Major postoperative complications, in-hospital mortality, and survival outcomes were similar for both cohorts. CONCLUSIONS: Performing DLS during the preoperative work-up for CRS + HIPEC prevents non-therapeutic laparotomies in patients with colorectal PM. We recommend performing this laparoscopic screening in an experienced HIPEC center

Gallbladder Cancer:Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

SIMPLE SUMMARY: Knowledge of genetic alterations in gallbladder cancer (GBC) continues to increase. This systematic review provides an overview of frequently occurring genetic alterations in GBC and describes their possible therapeutic implications. We detected three frequently (>5%) altered genes (ATM, ERBB2 and PIK3CA) for which targeted therapies are available in other cancer types. For solid cancers with microsatellite instability or a high tumor mutational burden pembrolizumab is FDA-approved. Altogether, these five biomarkers might be used in future molecular panels to enable precision medicine for patients with GBC. We found only nine clinical trials evaluating targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials. ABSTRACT: Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials

Delta peritoneal cancer index (Delta PCI):A new dynamic prognostic parameter for survival in patients with colorectal peritoneal metastases

Background: The peritoneal cancer index (PCI) calculated during exploratory laparotomy is a strong prognostic factor for overall survival (OS) in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Progression of the PCI between diagnostic laparoscopy (DLS) and potential CRS + HIPEC (Delta PCI) might be a more dynamic prognostic factor for OS after CRS + HIPEC. Materials and methods: Between 2012 and 2018, all colorectal PM patients who underwent an exploratory laparotomy for potential CRS + HIPEC after DLS were retrospectively identified from a prospectively maintained database. Patients were divided into stable disease (Delta PCI 0-3), mild progression (Delta PCI 4-9), or severe progression (Delta PCI >= 10). Kaplan-Meier analysis and a multivariate Cox regression were performed. Results: Eighty-four patients (Delta PCI 0-3, n = 35; Delta PCI 4-9, n = 34; and Delta PCI >= 10, n = 15) were analysed. Median OS after CRS + HIPEC was significantly decreased in patients with a Delta PCI of 4-9 (35.1 [95% CI 25.5-44.6]) or Delta PCI >= 10 (24.1 [95% CI 11.7-36.5]) compared to patients with a Delta PCI of 0-3 (47.9 [95% CI 40.0-55.7], p = 0.004). In multivariate regression analysis, Delta PCI remained an independent risk factor for OS: Delta PCI 4-9 HR 3.1 (95% CI 1.4-7.2, p = 0.007) and Delta PCI >= 10 HR 4.4 (95% CI 1.5-13.1, p = 0.007). Conclusion: A high Delta PCI is an independent dynamic prognostic factor for OS and might reflect a more aggressive tumour biology in patients with colorectal PM. HIPEC surgeons should be aware of a high-Delta PCI-associated diminished prognosis and should reconsider CRS + HIPEC when confronted with a Delta PCI >= 10. (C) 2019 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved

Risk factors for complications after surgery for pancreatic neuroendocrine tumors

BACKGROUND: Surgical resection is the only potentially curative treatment for pancreatic neuroendocrine tumors. The choice for the type of procedure is influenced by the expected oncological benefit and the anticipated risk of procedure-specific complications. Few studies have focused on complications in these patients. This cohort study aimed to assess complications and risk factors after resections of pancreatic neuroendocrine tumors. METHODS: Patients undergoing resection of a pancreatic neuroendocrine tumor were identified within 2 centers of excellence. Complications were assessed according to the Clavien-Dindo classification and the comprehensive complication index. Logistic regression was performed to compare surgical procedures with adjustment for potential confounders (Clavien-Dindo ≥3). RESULTS: The cohort comprised 123 patients, including 12 enucleations, 50 distal pancreatectomies, 51 pancreatoduodenectomies, and 10 total/combined pancreatectomies. Mortality was 0.8%, a severe complication occurred in 41.5%, and the failure-to-rescue rate was 2.0%. The median comprehensive complication index was 22.6 (0-100); the comprehensive complication index increased after more extensive resections. After adjustment, a pancreatoduodenectomy, as compared to a distal pancreatectomy, increased the risk for a severe complication (odds ratio 3.13 [95% confidence interval 1.32-7.41]). Of the patients with multiple endocrine neoplasia type 1 or von Hippel-Lindau, 51.9% developed a severe complication vs 38.5% with sporadic disease. After major resections, morbidity was significantly higher in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau (comprehensive complication index 45.1 vs 28.9, P = .029). CONCLUSION: Surgery for pancreatic neuroendocrine tumors is associated with a high rate of complications but low failure-to-rescue in centers of excellence. Complications are procedure-specific. Major resections in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau appear to increase the risk of complications

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors

Background: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. Methods: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. Results: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). Conclusions: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com

A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms:An International Multicenter Cohort Study

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off >= 0.2 mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size >= 3.0 cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p <0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival