TNM Staging of Neoplasms of the Endocrine Pancreas: Results From a Large International Cohort Study

BackgroundThe prognostic nutritional index (PNI), alkaline phosphatase (ALP), and lymph node ratio (LNR) are reportedly related to prognosis. The aim of this study was to elucidate the clinical importance of the LNR and hematological parameters in patients with high grade rectal neuroendocrine neoplasms (HG-RNENs) who were undergoing radical resection.MethodsWe reviewed the medical records of patients with HG-RNENs from 17 large-scale medical centers in China (January 1, 2010–April 30, 2022). A nomogram was constructed by using a proportional hazard model. Bootstrap method was used to draw calibration plots to validate the reproducibility of the model. Concordance index (C-Index), decision curve analysis (DCA), and time-dependent area under the receiver operating characteristic curve (TD-AUC) analysis were used to compare the prognostic predictive power of the new model with American Joint Committee on Cancer (AJCC) TNM staging and European Neuroendocrine Tumor Society (ENETS) TNM staging.ResultsA total of 85 patients with HG-RNENs were enrolled in this study. In the 45 patients with HG-RNENs who underwent radical resection, PNI ≤ 49.13 (HR: 3.997, 95% CI: 1.379–11.581, P = 0.011), ALP > 100.0 U/L (HR: 3.051, 95% CI: 1.011–9.205, P = 0.048), and LNR > 0.40 (HR: 6.639, 95% CI: 2.224–19.817, P = 0.0007) were independent predictors of relapse-free survival. The calibration plots suggested that the nomogram constructed based on the three aforementioned factors had good reproducibility. The novel nomogram revealed a C-index superior to AJCC TNM staging (0.782 vs 0.712) and ENETS TNM staging (0.782 vs 0.657). Also, the new model performed better compared to AJCC TNM staging and ENETS TNM staging in DCA and TD-AUC analyses.ConclusionsLNR, ALP, and PNI were independent prognostic factors in patients with HG-RNENs after radical resection, and the combined indicator had better predictive efficacy compared with AJCC TNM staging and ENETS TNM staging.

Neuroendocrine gastroenteropancreatic tumors: ESMO Clinical Recommendation for diagnosis, treatment and follow-up

BackgroundLung adenocarcinoma (LUAD) is the most common pathological subtype of lung cancer. Ferroptosis, an oxidative, iron-dependent form of necrotic cell death, is highly associated with tumorigenesis and cancer progression. However, the prognostic value of ferroptosis progress in LUAD was still rarely be investigated.MethodsHerein, we collected three mRNA expression profiles and 85 ferroptosis-related genes from public databases. The “limma” package was used to identify ferroptosis-related differentially expressed genes (DEGs). Univariate Cox regression analysis and LASSO regression analysis were applied to screen and develop a ferroptosis-related gene signature (FRGS) and a formula to calculate the risk score. Multivariate Cox regression analysis was implemented to determine independent prognostic predictors of overall survival (OS). The area under the receiver operating characteristic curve (AUC) and calibration plot were used to evaluate the predictive accuracy of the FRGS and nomogram.ResultsWe developed a FRGS with five genes (CYBB, CISD1, FADD, SAT2, VDAC2). The AUC of the FRGS in TCGA cohort was 0.777 at 1-year, 0.721 at 3-year and 0.725 at 5-year, significantly superior to the AUC of TNM stage (1-year: 0.701, 3-year: 0.691, 5-year: 0.686). A similar phenomenon was observed in GEO cohort 1 and 2. Multivariate Cox regression analysis indicted TNM stage and risk score were independent prognostic predictors. Finally, we built a nomogram with TNM stage and FRGS, the AUCs of which markedly higher than that of FRGS or TNM stage alone.ConclusionWe constructed a prognostic FRGS with five ferroptosis-related genes and a nomogram for predicting the 1-, 3- and 5-year survival rate of LUAD patients, which may provide a new understanding of the prognostic value of ferroptosis progress in LUAD and will benefit prognosis assessment of LUAD patients.

Are Neuroendocrine Tumors Going Mainstream?

318 Background: Pancreatic neuroendocrine tumors (pNETs) comprise a spectrum of neoplasm with variable biological behaviour and heterogeneous prognosis. The European Neuroendocrine Tumor Society (ENETS) and the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) TNM staging systems have been recently published. The aim of this study was to evaluate the consistency of both staging systems on outcomes for patients with pNETs. Methods: A retrospective clinico-pathological study of 77 consecutive patients with pNETs who were surgically treated from 1993 to 2014 was carried out. Results: The male to female ratio was 1.0 (38 men, 39 women); 56 tumors were non-functionating and 21 functionating. Most of the tumors were G1 (57) and 20 were classified as G2-G3. The AJCC/UICC stage was IA in 29 patients, IB in 14, IIA in 10, IIB in 7 and IV in 17. Meanwhile, according with the ENETS staging system was: stage I in 30, IIa in 14, IIb in 3, IIIa in 6, IIIb in 7 and IV in 17. We found 18 (23.3%) cases of ENETS - AJCC/UICC discrepancies regarding the primary tumor. They included 6 cases (33%) disagreement between IIA (T3 N0 M0) and IIIa (T4 N0 M0); and 7 cases (38.8%) between IIB (T1-T3 N1 M0) and IIIb (anyT N1 M0). Conclusions: The AJCC and ENETS TNM classification staging for pNETs provide meaninful prognostic value of long-term survival por patients with pNETs. The T staging discrepancies between AJCC/UICC and ENETS are relative frequent and should be strictly recognized.

This study concerns clinical characteristics and survival of renal cell carcinoma (RCC) patients in University Malaya Medical Centre (UMMC), as well as the prognostic significance of presenting symptoms. The clinical characteristics, presenting symptoms and survival of RCC patients (n=151) treated at UMMC from 2003-2012 were analysed. Symptoms evaluated were macrohaematuria, flank pain, palpable abdominal mass, fever, lethargy, loss of weight, anaemia, elevated ALP, hypoalbuminemia and thrombocytosis. Univariate and multivariate Cox regression analyses were performed to determine the prognostic significance of these presenting symptoms. Kaplan Meier and log rank tests were employed for survival analysis. The 2002 TNM staging was a prognostic factor (p<0.001) but Fuhrman grading was not significantly correlated with survival (p=0.088). At presentation, 76.8% of the patients were symptomatic. Generally, symptomatic tumours had a worse survival prognosis compared to asymptomatic cases (p=0.009; HR 4.74). All symptoms significantly affect disease specific survival except frank haematuria and loin pain on univariate Cox regression analysis. On multivariate analysis adjusted for stage, only clinically palpable abdominal mass remained statistically significant (p=0.027). The mean tumour size of palpable abdominal masses, 9.5±4.3cm, was larger than non palpable masses, 5.3±2.7cm (p<0.001). This is the first report which includes survival information of RCC patients from Malaysia. Here the TNM stage and a palpable abdominal mass were independent predictors for survival. Further investigations using a multicentre cohort to analyse mortality and survival rates may aid in improving management of these patients.

The clinical courses of patients with medullary thyroid carcinoma (MTC) vary, and a number of prognostic factors have been studied, but the significance of some of these factors remains controversial. The study group consisted of 104 patients with MTC or C-cell hyperplasia managed at the hospitals of the University of California, San Francisco, between January 1960 and December 1998. Patients were classified as having sporadic MTC, familial non-multiple endocrine neoplasia (MEN) MTC, MEN 2A, or MEN 2B. The TNM, European Organization for Research and Treatment of Cancer (EORTC), National Thyroid Cancer Treatment Cooperative Study (NTCTCS), and Surveillance, Epidemiology, and End Results (SEER) extent-of-disease stages were determined for each patient. The predictive values of these staging or prognostic scoring systems were compared by calculating the proportion of variance explained (PVE) for each system. Fifty-six percent of the patients had sporadic MTC, 22% had familial MTC, 15% had MEN 2A, and 7% had MEN 2B. The overall average age at diagnosis was 38 years, and patients with sporadic MTC presented at an older age (P < 0.05). Thirty-two percent of the patients with hereditary MTC were diagnosed by screening (genetic and/or biochemical). These patients had a lower incidence of cervical lymph node metastasis (P < 0.05) and 94.7% were cured at last follow-up (P < 0.0001) compared with patients not screened. Patients with sporadic MTC who had systemic symptoms (diarrhea, bone pain, or flushing) had widely metastatic MTC and 33.3% of those patients died within 5 years. Overall, 49.4% of the patients were cured, 12.3% had recurrent MTC, and 38.3% had persistent MTC. The mean follow-up time was 8.6 years (median, 5.0 years) with 10.7% (n=11) and 13.5% (n=14) cause specific mortality at 5 and 10 years, respectively. Patients with persistent or recurrent MTC who died of MTC lived for an average of 3.6 years (ranging from 1 month to 23.7 years). Patients who had total or subtotal thyroidectomy were less likely to have persistent or recurrent MTC (P < 0.05), and patients who had total thyroidectomy with cervical lymph node clearance required fewer reoperations for persistent or recurrent MTC (P < 0.05) than patients who underwent lesser procedures. In univariate analysis, age, gender, clinical presentation, TNM stage, sporadic/hereditary MTC, distant metastasis, and extent of thyroidectomy were significant prognostic factors. Only age and stage, however, remained independent prognostic factors in multivariate analysis. The TNM, EORTC, NTCTCS, and SEER staging systems were all accurate predictors of survival, but the EORTC prognostic scoring system had the highest PVE in this cohort. Screening for MTC and early treatment (total thyroidectomy with central neck lymph node clearance) had nearly a 100% cure rate. Patients with postoperative hypercalcitoninemia without clinical or radiologic evidence of residual tumor after apparently curative surgery may enjoy long term survival but have occult MTC. Only patient age at presentation and TNM stage were independent predictors of survival. The EORTC criteria, which included the greatest number of significant prognostic factors in our cohort, had the highest predictive value.

628 THE NEW TNM STAGING SYSTEM FOR RENAL CELL CARCINOMA DOES NOT IMPROVE ACCURACY IN PREDICTING CANCER-SPECIFIC MORTALITY

Objective: Albeit controversial, serum uric acid (SUA) seems to convey a prognostic significance in women. Yet data over the long run are limited in hypertension. The aim of the present study was to confirm the prognostic significance over the long-term particularly in hypertensive women. Design and method: 1897 hypertensive patients with an assessment of SUA at baseline during their work-up for hypertension were followed according to tertile of SUA: < 339, 339 to 428 and >428 micromol/L. All-cause and cardiovascular mortalities were assessed after a 20 year-follow-up period. Results: Baseline characteristics were age 45.1 ± 13.4 years, systolic/diastolic blood pressure 180 ± 32/104 ± 20 mmHg, women 39.1% and eDFG 83.3 ± 29.5 mL/min. SUA was independently correlated with age, gender, BMI, previous cardiovascular events, eGFR, thiazide diuretics and beta-blockers use, and diabetes. At 20 years of follow-up, 748 deaths were observed, 442 of which were from cardiovascular causes. As shown in Kaplan-Meier curves, tertiles of SUA were predictor of all-cause and cardiovascular death in the whole cohort (p < 0.001 for both, Figure). In multivariate Cox regression analysis, patients in the third tertile have an increased risk of all-cause death (HR 1.34 (1.09–1.65) vs. tertile 1, HR 1.30 (1.09–1.55) vs. tertile 2) but only a trend was observed for cardiovascular death (HR 1.33 (1.00–1.76) vs. tertile 1, HR 1.16 (0.92–1.53) vs. tertile 2). A strong interaction with gender was observed for all-cause and cardiovascular mortality (p = 0.006 and p = 0.013 respectively). In subgroup analysis with the same Cox regression analysis, tertile 3 predicts mortality only in women: all-cause death HR 1.86 (1.34–2.58) vs. tertile 1, HR 1.76 (1.25–2.48) vs. tertile 2; cardiovascular death HR 1.77 (1.13–2.79) vs. tertile 1, HR 1.52 (0.96–2.38) vs. tertile 2. The information gain after addition of tertiles of SUA was significant in the multivariable Cox regression model (likelihood ratio test p = 0.009 and p = 0.025 for all-cause and cardiovascular mortality, respectively) with an increment of the C-index of 0.003 for the two different endpoints.Conclusions: After a long-term follow-up period, SUA improves death stratification in hypertensive women on top of traditional risk factors and target organ damages.

Thymic carcinoma (TC) and thymic carcinoid (TCD) are aggressive thymic epithelial neoplasms with a poor prognosis. Due to rarity, little is known about their comparative clinical characteristics, treatment outcomes and patterns of relapse. A retrospective cohort study was performed on 287 patients with TC and 56 patients with TCD who were treated at the Shanghai Chest Hospital between February 2003 and April 2014. Patient demographics, tumour stage, treatment, pathologic findings and postoperative outcomes were compared between the two tumour types using both multivariable Cox regression analysis and propensity-matched analysis. Compared to patients with TC, significantly more patients with TCD were male, had larger tumours, and displayed a greater proportion of lymph node metastases. However, overall survival was similar (60.7% 5-year survival for TC, 80.7% for TCD, P = 0.159), as was disease-free survival (41.1% 5-year survival for TC, 37.6% for TCD, P = 0.696) and patterns of relapse. Multiple Cox regression analysis identified younger patients [hazard ratio (HR) 1.018; 95% confidence interval (CI) 1.000-1.035; P = 0.047], more completeness of resection (HR 1.424; 95% CI 1.105-1.836; P = 0.006), adjuvant radiotherapy (HR 0.455; 95% CI 0.276-0.751; P = 0.002), and no adjuvant chemotherapy (HR 1.799; 95% CI 1.017-3.183; P = 0.044) as independent factors predicting better overall survival. Completeness of resection (HR 1.258; 95% CI 1.022-1.548; P = 0.031) and TNM stage (HR 1.479; 95% CI 1.107-1.977; P = 0.008) were independent predictors of disease-free survival. Propensity matching produced 46 patients in each group and no significant difference on overall survival or disease-free survival was found. Patients with TCD have discrete features but share a similar clinical course to those with TC. The importance of complete resection in both of these thymic malignancies is emphasized. Further investigation at multiple centers with the longer follow-up data is required to substantiate our conclusion.

Background and ObjectiveTools for the non-invasive assessment of colorectal cancer (CRC) prognosis have profound significance. Although plasma coagulation tests have been investigated in a variety of tumours, the prognostic value of the prothrombin time (PT) and activated partial thromboplastin time (APTT) in CRC has not been discussed. Our study objective was to explore the prognostic significance of preoperative PT and APTT in CRC patients.Patients and MethodsA retrospective analysis of preoperative coagulation indexes including PT, PTA, INR, APTT, FIB, TT, PLT, NLR and PLR in 250 patients with CRC was performed. Kaplan–Meier and multivariate Cox regression analysis were used to demonstrate the prognostic value of these preoperative coagulation indexes.ResultsThe overall survival (OS, p<0.05) and disease-free survival (DFS, p<0.05) of CRC patients with lower PT and APTT levels were significantly prolonged. Based on univariate analysis, PT levels (p<0.001, p<0.001), PTA levels (p=0.001, p=0.001), APTT levels (p=0.001, p<0.001), INR levels (p<0.001, p<0.001), fibrinogen levels (p=0.032, p=0.036), tumour status (p=0.005, p=0.003), nodal status (p<0.001, p<0.001), metastasis status (p<0.001, p<0.001) and TNM stages (p<0.001, p<0.001) were remarkably associated with DFS and OS. Multivariate Cox regression analysis suggested that the levels of PT (HR: 2.699, p=0.006) and APTT (HR: 1.942, p=0.015), metastasis status (HR: 2.091, p= 0.015) and TNM stage (HR: 7.086, p=0.006) were independent predictors of survival in CRC. In the whole cohort, the enrolled patients were then divided into three groups according to their PT and APTT levels. The OS and DFS differed notably among the low-risk (PT<11.85 sec and APTT<25.85 sec), medium-risk (PT≥11.85 sec or APTT≥25.85 sec), and high-risk (PT≥11.85 sec and APTT≥25.85 sec) groups.ConclusionElevated levels of preoperative PT and APTT were predictors of poor outcomes in CRC patients. Moreover, the combination of preoperative PT and APTT can be a new prognostic stratification approach for more precise clinical staging of CRC.

Gender Differences in Gastric Cancer Survival: 99,922 Cases Based on the SEER Database

We aimed to investigate the long-term cardiac mortality and the relationship between cardiac mortality and electrocardiographic abnormalities in patients with diphtheritic myocarditis who survived after hospital discharge. Between 1991 and 1996, 32 patients (all males, mean age 21.00 +/- 3.77 years) surviving diphtheritic myocarditis were included in the study and they were followed up for an average of 16.3 months (range 10.3-26.8 months) after hospital discharge. Clinical evaluation, ECG, and echocardiography were performed on admission, daily while in hospital and at the time of discharge. ECG changes were permanent during the follow-up period. The causes of death of the patients during follow-up period were inferred from the death records of the patients and talking to the people witnessing cardiac arrest. We observed that the patients with left bundle branch block (LBBB) and T wave inversion at hospital discharge had lower survival rates than that of the patients without these ECG changes in the long term. Although univariate Cox regression analysis identified LBBB (P = 0.001) and T wave inversion (P = 0.014) as the predictors of survival, only LBBB was an independent predictor of survival in multivariate Cox regression analysis. Adjusted hazard ratio was calculated as 13.67 for LBBB (P = 0.001; CI = 2.81-66.28). Diphtheritic myocarditis does not only demonstrate a malignant clinical course during acute phase of the disease, but also during the long-term follow-up period, especially in patients with LBBB and T wave inversion. Besides, T wave inversion and LBBB can help us to predict survival rate of the patients in long term. Moreover, LBBB is an independent predictor of long-term survival in diphtheritic myocarditis.

To evaluate the diagnostic and prognostic value of coagulation markers - including activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB), platelet count (PLT), and D-dimer (DD) - and platelet-derived growth factor-BB (PDGF-BB) in patients with nasopharyngeal carcinoma (NPC) undergoing intensity-modulated radiotherapy (IMRT). A total of 210 NPC patients receiving IMRT and 160 healthy controls were enrolled. Baseline levels of PDGF-BB and coagulation markers were compared between groups. The association of PDGF-BB with clinical staging was analyzed, and receiver operating characteristic (ROC) curve analysis was used to assess its diagnostic performance. Cox regression analyses were performed to identify independent predictors of five-year survival. A dynamic nomogram was developed to provide individualized survival predictions. NPC patients exhibited significantly higher levels of PDGF-BB, APTT, PT, FIB, PLT, and DD compared to healthy controls (all P < 0.001). PDGF-BB was positively correlated with TNM stage (stage III/IV vs. I/II, P < 0.001), T stage (P = 0.005), and N stage (P = 0.020). Multivariate Cox regression identified low PDGF-BB (< 628.18) (HR = 0.492, P = 0.009), low DD (< 746.1) (HR = 0.456, P = 0.002), age 51-64 years (HR = 2.057, P = 0.032) and ≥ 65 years (HR = 4.138, P < 0.001), EBV DNA negativity (HR = 0.273, P = 0.012), and TNM stage III/IV (HR = 3.042, P = 0.023) as independent prognostic factors. PDGF-BB and DD, alongside age, EBV DNA status, and TNM stage, are promising biomarkers for NPC prognosis. A dynamic nomogram integrating these factors offers accurate survival prediction and supports personalized treatment strategies in NPC management.

Appendiceal neuroendocrine neoplasms (NENs) are rare and usually incidentally discovered. Most cases are clinically indolent, although the rare aggressive ones are poorly predictable. The aim of this study was to test the applicability and prognostic significance of the new World Health Organization (WHO) classification and to test the several pathologic features and TNM staging systems (American Joint Committee on Cancer and European Neuroendocrine Tumor Society) in these tumors. A multi-institutional retrospective series of 138 appendiceal NENs was selected on the basis of the availability of both pathologic material and clinical information, including follow-up data. All cases were reviewed to record pathologic features and to apply year 2000 and 2010 WHO classifications, as well as European Neuroendocrine Tumor Society and American Joint Committee on Cancer TNM stages. Clinical and pathologic characteristics were compared with disease outcome by contingency, univariate, and multivariate survival analyses. Although up to one third of cases presented several malignancy-associated pathologic features, only 4 patients died of the disease. Adverse outcome was significantly associated with extramural extension (including mesoappendix), well-differentiated carcinoma diagnosis (2000 WHO classification), pT3-4 stage, older age, and presence of positive resection margins, but not with tumor size, mitotic or proliferative indexes, and, consequently, 2010 WHO grading. In the appendix, at variance with midgut/hindgut NENs, the 2000 WHO classification performs better than the grading-based 2010 WHO scheme and, together with tumor stage, is the most relevant parameter associated with clinical aggressiveness.