Toll-like receptors 1-9 in small bowel neuroendocrine tumors-Clinical significance and prognosis.

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immunity. TLRs are known to mediate both antitumor effects and tumorigenesis. TLRs are abundant in many cancers, but their expression in small bowel neuroendocrine tumors (SB-NETs) is unknown. We aimed to characterize the expression of TLRs 1-9 in SB-NETs and lymph node metastases and evaluate their prognostic relevance. The present study included 125 patients with SB-NETs, of whom 95 had lymph node metastases, from two Finnish hospitals. Tissue samples were stained immunohistochemically for TLR expression, assessed based on cytoplasmic and nucleic staining intensity and percentage of positively stained cells. Statistical methods for survival analysis included Kaplan-Meier method and Cox regression adjusted for confounding factors. Disease-specific survival (DSS) was the primary outcome. TLRs 1-2 and 4-9 were expressed in SB-NETs and lymph node metastases. TLR3 showed no positive staining. In primary SB-NETs, TLRs 1-9 were not associated with survival. For lymph node metastases, high cytoplasmic TLR7 intensity associated with worse DSS compared to low cytoplasmic intensity (26.4% vs. 84.9%, p = 0.028). Adjusted mortality hazard (HR) was 3.90 (95% CI 1.07-14.3). The expression of TLRs 1-6 and 8-9 in lymph node metastases were not associated with survival. SB-NETs and their lymph node metastases express cytoplasmic TLR 1-2 and 4-9 and nucleic TLR5. High TLR7 expression in SB-NET lymph node metastases was associated with worse prognosis. The current research has future perspective, as it can help create base for clinical drug trials to target specific TLRs with agonists or antagonists to treat neuroendocrine tumors.

A nomogram incorporating treatment data for predicting overall survival in gastroenteropancreatic neuroendocrine tumors: a population-based cohort study.

BACKGROUND: Over the last few decades, the annual global incidence of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) has steadily increased. Because of the complex and inconsistent treatment of GEP-NETs, the prognosis of patients with GEP-NETs is still difficult to assess. The study aimed to construct and validate the nomograms included treatment data for prediction overall survival (OS) in GEP-NETs patients. METHODS: GEP-NETs patients determined from the Surveillance, Epidemiology, and End Results (SEER)-13 registry database (1992-2018) and with additional treatment data from the SEER-18 registry database (1975-2016). In order to select independent prognostic factors that contribute significantly to patient survival and can be included in the nomogram, multivariate Cox regression analysis was performed using the minimum value of Akaike information criterion (AIC) and we analyzed the relationship of variables with OS by calculating hazard ratios (HRs) and 95% CIs. In addition, we also comprehensively compared the nomogram using to predict OS with the current 7th American Joint Committee on Cancer (AJCC) staging system. RESULTS: From 2004 to 2015, a total of 42 662 patients at diagnosis years with GEP-NETs were determined from the SEER database. The results indicated that the increasing incidence of GEP-NETs per year and the highest incidence is in patients aged 50-54. After removing cases lacking adequate clinicopathologic characteristics, the remaining eligible patients ( n =7564) were randomly divided into training (3782 patients) and testing sets (3782 patients). In the univariate analysis, sex, age, race, tumour location, SEER historic stage, pathology type, TNM, stage, surgery, radiation, chemotherapy, and CS tumour size were found to be significantly related to OS. Ultimately, the key factors for predicting OS were determined, involving sex, age, race, tumour location, SEER historic stage, M, N, grade, surgery, radiation, and chemotherapy. For internal validation, the C-index of the nomogram used to estimate OS in the training set was 0.816 (0.804-0.828). For external validation, the concordance index (C-index) of the nomogram used to predict OS was 0.822 (0.812-0.832). In the training and testing sets, our nomogram produced minimum AIC values and C-index of OS compared with AJCC stage. Decision curve analysis (DCA) indicated that the nomogram was better than the AJCC staging system because more clinical net benefits were obtained within a wider threshold probability range. CONCLUSION: A nomogram combined treatment data may be better discrimination in predicting overall survival than AJCC staging system. The authors highly recommend to use their nomogram to evaluate individual risks based on different clinical features of GEP-NETs, which can improve the diagnosis and treatment outcomes of GEP-NETs patients and improve their quality of life.

Comparing Somatostatin Analogs in the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study's objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. RESULTS: A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6-18 months) and 10.8 months (95% CI, 6-15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. CONCLUSIONS: Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.

Gastroenteropancreatic grade 3 neuroendocrine tumors: a single entity or a heterogeneous group? A retrospective analysis.

PURPOSE: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. PATIENTS AND METHODS: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. RESULTS: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). CONCLUSION: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.

Effect of primary tumour resection without curative intent in patients with metastatic neuroendocrine tumours of the small intestine and right colon: meta-analysis.

BACKGROUND: Patients with small intestinal neuroendocrine tumours (siNETs) usually present with advanced disease. Primary tumour resection without curative intent is controversial in patients with metastatic siNETs. The aim of this meta-analysis was to investigate survival after primary tumour resection without curative intent compared with no resection in patients with metastatic siNETs. METHODS: A systematic literature search was performed, using MEDLINE® (PubMed), Embase®, Web of Science, and the Cochrane Library up to 25 February 2021. Studies were included if survival after primary tumour resection versus no resection in patients with metastatic siNETs was reported. Results were pooled in a random-effects meta-analysis, and are reported as hazard ratios (HRs) with 95 per cent confidence intervals. Sensitivity analyses were undertaken to enable comment on the impact of important confounders. RESULTS: After screening 3659 abstracts, 16 studies, published between 1992 and 2021, met the inclusion criteria, with a total of 9428 patients. Thirteen studies reported HRs adjusted for important confounders and were included in the meta-analysis. Median overall survival was 112 (i.q.r. 82-134) months in the primary tumour resection group compared with 60 (74-88) months in the group without resection. Five-year overall survival rates were 74 (i.q.r. 67-77) and 44 (34-45) per cent respectively. Primary tumour resection was associated with improved survival compared with no resection (HR 0.55, 95 per cent c.i. 0.47 to 0.66). This effect remained in sensitivity analyses. CONCLUSION: Primary tumour resection is associated with increased survival in patients with advanced, metastatic siNETs, even after adjusting for important confounders.

Relevant prognostic factors in patients with stage IV small intestine neuroendocrine neoplasms.

There are few, but controversial data on the prognostic role of upfront primary tumour resection and mesenteric lymph node dissection (PTR) in patients with diffuse metastatic small intestinal neuroendocrine neoplasia (SI-NEN). Therefore, the prognostic role of PTR and other factors was determined in this setting. This retrospective cohort study included patients with stage IV SI-NETs with unresectable distant metastases without clinical and radiological signs of acute bowel obstruction or ischaemia. Patients diagnosed from January 2002 to May 2020 were retrieved from a prospective SI-NEN database. Disease specific overall survival (OS) was analysed with regard to upfront PTR and a variety of other clinical (e.g., gender, age, Hedinger disease, carcinoid syndrome, diarrhoea, laboratory parameters, metastatic liver burden, extrahepatic and extra-abdominal metastasis) and pathological (e.g., grading, mesenteric gathering) parameters by uni- and multivariate analysis. A total of 138 patients (60 females, 43.5%) with a median age of 60 years, of whom 101 (73%) underwent PTR and 37 (27%) did not, were included in the analysis. Median OS was 106 (95% CI: 72.52-139.48) months in the PTR group and 52 (95% CI: 30.55-73.46) in the non-PTR group (p = 0.024), but the non-PTR group had more advanced metastatic disease (metastatic liver burden ≥50% 32.4% vs. 13.9%). There was no significant difference between groups regarding the rate of surgery for bowel complications during a median follow-up of 51 months (PTR group 10.9% and non-PTR group 16.2%, p = 0.403). Multivariate analysis revealed age < 60 years, normal C-reactive protein (CRP) at baseline, absence of diarrhoea, less than 50% of metastatic liver burden, and treatment with PRRT as independent positive prognostic factors, whereas PTR showed a strong tendency towards better OS, but level of significance was missed (p = 0.067). However, patients who underwent both, PTR and peptide radioreceptor therapy (PRRT) had the best survival compared to the rest (137 vs. 73 months, p = 0.013). PTR in combination with PRRT significantly prolongs survival in patients with stage IV SI-NEN. Prophylactic PTR does also not result in a lower reoperation rate compared to the non-PTR approach regarding bowel complications.

Survival in cases of intestinal tumors

Objective: To assess the survival rate of patients with colorectal cancer at Hospital Universitário Alzira Vellano, in the municipality of Alfenas, state of Minas Gerais (MG), Brazil, from 2007 to 2016. Methodology: A search was conducted in the laboratory files and medical records of patients diagnosed with colorectal cancer and cared for during the aforementioned period. Results: In total, 128 cases were found: 52.3% were men, and 47.7% were women, with ages ranging from 25 to 91 years. The most common types of cancer in both genders were of the colon, rectum and sigmoid. The most common stages were T3N1Mx, followed by T3N0Mx and T3N2Mx. Patients with T1 or T2 cancers had a 100% survival rate, whereas the rate for those with grade 4 (T4) was of 0%. An association (p<0.05) of the location of the tumor with the survival rate was confirmed. Conclusion: There was a high mortality rate among patients diagnosed with colorectal cancer at Hospital Universitário Alzira Vellano from 2007 to 2016. (AU)

The impact of surgery on long-term survival of patients with primary intestinal non-Hodgkin lymphomas based on SEER database.

Evidence regarding the need for surgery for primary intestinal non-Hodgkin lymphoma (PINHL) patients with chemotherapy is limited and controversial. We aimed to investigate the specific impact of surgery on survival of PINHL patients. Data from PINHL patients (aged > 18 years) with chemotherapy between 1983 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We concerned about overall survival (OS) and improved cancer-specific survival (CSS). Propensity score matching (PSM) analysis was also used to explore the reliability of the results to further control for confounding factors. Finally, we screened 3537 patients. Multivariate regression analysis showed that patients with surgery and chemotherapy had better OS (hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.75-0.93; p = 0.0009) and CSS (HR 0.87; 95% CI 0.77-0.99; p = 0.0404) compared with the non-operation group after adjusting for confounding factors. After PSM analysis, compared with non-surgery, surgery remained associated with improved OS (HR 0.77; 95% CI 0.68-0.87; p < 0.0001) and improved CSS (HR 0.82; 95% CI 0.72-0.95; p = 0.008) adjusted for baseline differences. In the large cohort of PINHL patients with chemotherapy older than 18 years, surgery was associated with significantly improved OS and CSS before and after PSM analysis.

Second-line Chemotherapy for Previously Treated Metastatic Small Bowel Adenocarcinoma: A Retrospective Analysis.

BACKGROUND/AIM: Metastatic small bowel adenocarcinoma (SBA) is a rare disease with poor prognosis. This study aimed to explore the efficacy and safety of second-line chemotherapy for patients with SBA. PATIENTS AND METHODS: We retrospectively reviewed the clinical characteristics of 27 metastatic patients with SBA after progression on first-line chemotherapy. The patients were divided into Cohort A, receiving second-line chemotherapy, and Cohort B, receiving best supportive care. RESULTS: Patients in Cohort B had higher age, worse performance status, and higher neutrophil-to-lymphocyte ratio compared with those in Cohort A. Cohort A showed significantly better overall survival (OS) compared with Cohort B (median OS, 15.6 vs. 3.4 months; p=0.002). Objective response rate, disease control rate, and median progression-free survival (PFS) for Cohort A were 7%, 74%, and 5.0 months, respectively. Patients who underwent irinotecan-based chemotherapy showed longer PFS and OS compared with those who underwent taxane-based chemotherapy. No significant adverse events were reported. CONCLUSION: Second-line chemotherapy for metastatic SBA demonstrated clinical activity with acceptable toxicities.

Neoplasias neuroendocrinas del intestino: serie de casos / Intestinal neuroendocrine tumors: case series

RESUMEN: Los tumores neuroendocrinos (TNE) intestinales representan el mayor porcentaje de este tipo de lesiones a nivel del aparato digestivo. El tratamiento de elección es la extirpación de la lesión primaria y sus linfonodos regionales. El objetivo de este estudio es reportar el resultado de pacientes portadores de TNE intestinales, tratados quirúrgicamente, en términos de morbilidad postoperatoria (MPO) y mortalidad. Serie de casos de pacientes con TNE intestinales intervenidos de forma consecutiva en Clínica RedSalud Mayor Temuco, entre 2006 y 2020. Las variables resultado fueron MPO y mortalidad. Otras variables de interés fueron localización y diámetro del tumor, tipo de cirugía y estancia hospitalaria. Se utilizó estadística descriptiva. Se trató a 11 pacientes (54,5 % mujeres), con una mediana de edad de 56 años. El 54,5 % de los tumores se localizó en yeyuno-íleon. La mediana del diámetro tumoral, tiempo quirúrgico y estancia hospitalaria fueron 2 cm, 75 min y 4 días, respectivamente. El tipo de resección más frecuente fue hemicolectomía derecha (63,6 %). La MPO fue 9,1 % (seroma en un paciente). No hubo reintervenciones ni mortalidad operatoria. Con una mediana de seguimiento de 18 meses, no se verificaron recurrencias. Los resultados reportados en relación a MPO y mortalidad, son adecuados en relación con la evidencia publicada.

SUMMARY: Intestinal neuroendocrine tumors (INETs) represent the highest percentage of this type of lesion in the digestive system. The treatment of choice is removal of the primary lesion and its regional lymph nodes. The aim of this study is to report the results of patients with INETs treated surgically, in terms of postoperative morbidity (POM) and mortality. Series of cases of patients with intestinal INETs operated consecutively at Clínica RedSalud Mayor Temuco, between 2006 and 2020. Result variables were POM and mortality. Other variables of interest were location and diameter of the tumor, type of surgery, and hospital stay. Descriptive statistics were used. Eleven patients (54.5 %) were treated, with a median age of 56 years. 54.5 % of the tumors were located in the jejunum-ileum. The median tumor diameter, surgical time, and hospital stay were 2 cm, 75 min, and 4 days, respectively. The most frequent type of resection was right hemicolectomy (63.6 %). The MPO was 9.1 % (seroma in one patient). There were no reoperations or operative mortality. With a median follow-up of 18 months, there were no recurrences. Reported results in relation to POM and mortality are adequate in relation to the published evidence.

Epidemiologic Trends of and Factors Associated With Overall Survival for Patients With Gastroenteropancreatic Neuroendocrine Tumors in the United States.

Importance: Although the incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have been thought to have increased during the past decades, updated epidemiologic and survival data are lacking. Objectives: To conduct an epidemiologic and survival analysis of the largest cohort of patients with GEP-NETs using the latest data and to establish a novel nomogram to predict the survival probability of individual patients with GEP-NETs. Design, Setting, and Participants: In this cohort study, 43 751 patients with GEP-NETs diagnosed from January 1, 1975, to December 31, 2015, were identified from the Surveillance, Epidemiology, and End Results Program. Associated data were used for epidemiologic and survival analysis, as well as the establishment and validation of a nomogram to predict the survival probability of individual patients with GEP-NETs. The study cutoff date was December 31, 2018. Statistical analysis was performed from February 1 to April 30, 2020. Main Outcomes and Measures: Incidence, factors associated with overall survival, and a nomogram model for patients with GEP-NETs. Results: A total of 43 751 patients received a diagnosis of GEP-NETs from 1975 to 2015 (22 398 women [51.2%], 31 976 White patients [73.1%], 7097 Black patients [16.2%], 3207 Asian and Pacific Islander patients [7.3%], 270 American Indian and Alaska Native patients [0.6%], and 4546 patients of unknown race [10.4%]; mean [SD] age at diagnosis, 58 [15] years). The age-adjusted incidence rate of GEP-NETs increased 6.4-fold from 1975 to 2015 (annual percentage change [APC], 4.98; 95% CI, 4.75-5.20; P < .001). Furthermore, among site groups, the incidence of GEP-NETs in the rectum increased most significantly (APC, 6.43; 95% CI, 5.65-7.23; P < .001). As for stage and grade, the incidence increased the most in localized GEP-NETs (APC, 6.53; 95% CI, 6.08-6.97; P < .001) and G1 GEP-NETs (APC, 18.93; 95% CI, 17.44-20.43; P < .001). During the study period, the mean age at diagnosis for localized disease increased by 9.0 years (95% CI, 3.3-14.7 years; P = .002), which remained unchanged for regional and distant cases. On multivariable analyses, age, sex, marital status, and tumor size, grade, stage, and site were significantly associated with overall survival for patients with GEP-NETs (eg, patients with distant vs localized disease: hazard ratio, 10.32; 95% CI, 8.56-12.43; G4 vs G1 GEP-NET: hazard ratio, 6.37; 95% CI, 5.39-7.53). Furthermore, a nomogram comprising age, size, grade, stage, and site was established to predict the 3-year and 5-year survival probability, with the concordance indexes of 0.893 (95% CI, 0.883-0.903) for the internal validations and 0.880 (95% CI, 0.866-0.894) for the external validations. The receiver operating characteristic curve demonstrated that the nomogram exhibited better discrimination power than TNM classification (area under the curve for 3-year overall survival, 0.908 vs 0.795; for 5-year overall survival, 0.893 vs 0.791). Conclusions and Relevance: In this study, the incidence and prevalence of GEP-NETs have continued to increase over 40 years, especially among patients with rectal GEP-NETs. In addition, this study suggests that a nomogram with 5 prognostic parameters may accurately quantify the risk of death among patients with GEP-NETs, indicating that it has satisfactory clinical practicality.

Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort.

Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Molecular profiling and identification of prognostic factors in Chinese patients with small bowel adenocarcinoma.

Small bowel adenocarcinoma (SBA) is a rare malignancy with a poor prognosis and limited treatment options. Despite prior studies, molecular characterization of this disease is not well defined, and little is known regarding Chinese SBA patients. In this study, we conducted multigene next-generation sequencing and 16S ribosomal RNA gene sequencing on samples from 76 Chinese patients with surgically resected primary SBA. Compared with colorectal cancer and Western SBA cohorts, a distinctive genomic profile was revealed in Chinese SBA cohorts. According to the levels of clinical actionability to targetable alterations stratified by OncoKB system, 75% of patients harbored targetable alterations, of which ERBB2, BRCA1/2, and C-KIT mutations were the most common targets of highest-level actionable alterations. In DNA mismatch repair-proficient (pMMR) patients, significant associations between high tumor mutational burden and specific genetic alterations were identified. Moreover, KRAS mutations/TP53 wild-type/nondisruptive mutations (KRASmut /TP53wt/non-dis ) were independently associated with an inferior recurrence-free survival (hazard ratio [HR] = 4.21, 95% confidence interval [CI] = 1.94-9.14, P < .001). The bacterial profile revealed Proteobacteia, Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Cyanobacteria were the most common phyla in SBA. Furthermore, patients were clustered into three subgroups based on the relative abundance of bacterial phyla, and the distributions of the subgroups were significantly associated with the risk of recurrence stratified by TP53 and KRAS mutations. In conclusion, these findings provided a comprehensive molecular basis for understanding SBA, which will be of great significance in improving the treatment strategies and clinical management of this population.

Postoperative morbidity and mortality after surgical resection of small bowel neuroendocrine neoplasms: A systematic review and meta-analysis.

Although small bowel resection is generally considered a low risk gastrointestinal procedure, this might not be true for small bowel neuroendocrine neoplasms (SB-NEN) as a result of potential central mesenteric involvement. We aimed to determine the reported morbidity and mortality after resection of SB-NEN in the literature and assess the effect of hospital volume on postoperative morbidity and mortality. A systematic review was performed by searching MEDLINE and Embase in March 2021. All studies reporting morbidity and/or mortality after SB-NEN resection were included. Pooled proportions of overall morbidity (Clavien-Dindo I-IV), severe morbidity (Clavien-Dindo III-IV), 30-day mortality, 90-day mortality and in-hospital mortality were calculated, as well as the association with hospital volume (high volume defined as the fourth quartile). Thirteen studies were included, with a total of 1087 patients. Pooled proportions revealed an overall morbidity of 13% (95% confidence interval [CI] = 7%-24%, I2  = 90%), severe morbidity of 7% (95% CI = 4%-14%, I2  = 70%), 30-day mortality of 2% (95% CI = 1%-3%, I2  = 0%), 90-day mortality of2% (95% CI = 2%-4%, I2  = 35%) and in-hospital mortality of 1% (95% CI = 0%-2%, I2  = 0%). An annual hospital volume of nine or more resections was associated with lower overall and severe morbidity compared to lower volume: 10% vs 15% and 4% vs 9%, respectively. Thirty-day mortality was similar (2% vs 1%) and 90-day mortality was higher in high-volume hospitals: 4% vs 1%. This systematic review with meta-analyses showed severe morbidity of 7% and low mortality rates after resection of SB-NEN. The currently available literature suggests a certain impact of hospital volume on postoperative outcomes, although heterogeneity among the included studies constrains interpretation.

Prognostic features of gastro-entero-pancreatic neuroendocrine neoplasms in primary and metastatic sites: Grade, mesenteric tumour deposits and emerging novelties.

Updates in classification of gastro-entero-pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty-four cases of neuroendocrine tumours of gastro-entero-pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki-67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki-67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96-14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56-6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25-3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27-5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro-entero-pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci.

Socioeconomic disparities in cancer incidence and mortality in England and the impact of age-at-diagnosis on cancer mortality.

BACKGROUND: We identify socioeconomic disparities by region in cancer morbidity and mortality in England for all-cancer and type-specific cancers, and use incidence data to quantify the impact of cancer diagnosis delays on cancer deaths between 2001-2016. METHODS AND FINDINGS: We obtain population cancer morbidity and mortality rates at various age, year, gender, deprivation, and region levels based on a Bayesian approach. A significant increase in type-specific cancer deaths, which can also vary among regions, is shown as a result of delay in cancer diagnoses. Our analysis suggests increase of 7.75% (7.42% to 8.25%) in female lung cancer mortality in London, as an impact of 12-month delay in cancer diagnosis, and a 3.39% (3.29% to 3.48%) increase in male lung cancer mortality across all regions. The same delay can cause a 23.56% (23.09% to 24.30%) increase in male bowel cancer mortality. Furthermore, for all-cancer mortality, the highest increase in deprivation gap happened in the East Midlands, from 199 (186 to 212) in 2001, to 239 (224 to 252) in 2016 for males, and from 114 (107 to 121) to 163 (155 to 171) for females. Also, for female lung cancer, the deprivation gap has widened with the highest change in the North West, e.g. for incidence from 180 (172 to 188) to 272 (261 to 282), whereas it has narrowed for prostate cancer incidence with the biggest reduction in the South West from 165 (139 to 190) in 2001 to 95 (72 to 117) in 2016. CONCLUSIONS: The analysis reveals considerable disparities in all-cancer and some type-specific cancers with respect to socioeconomic status. Furthermore, a significant increase in cancer deaths is shown as a result of delays in cancer diagnoses which can be linked to concerns about the effect of delay in cancer screening and diagnosis during the COVID-19 pandemic. Public health interventions at regional and deprivation level can contribute to prevention of cancer deaths.

Initiation of Somatostatin analogues for neuroendocrine tumor patients: a cost-effectiveness analysis.

BACKGROUND & AIMS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous neoplasms. Although some have a relatively benign and indolent natural history, others can be aggressive and ultimately fatal. Somatostatin analogues (SSAs) improve both quality of life and survival for these patients once they develop metastatic disease. However, these drugs are costly and their cost-effectiveness is not known. METHODS: A decision-analytic model was developed and analyzed to compare two treatment strategies for patients with Stage IV GEP-NETs. The first strategy had all patients start SSA immediately while the second strategy waited, reserving SSA initiation until the patient showed signs of progression. Sensitivity analysis was performed to explore model parameter uncertainty. RESULTS: Our model of patients age 60 with metastatic GEP-NETs suggests empiric initiation of SSA led to an increase 0.62 unadjusted life-years and incremental increase in quality-adjusted life years (QALYs) of 0.44. The incremental costs were $388,966 per QALY and not cost-effective at a willingness-to-pay threshold of $100,000. Death was attributed to GEP-NETs for 94.1% of patients in the SSA arm vs. 94.9% of patients in the DELAY SSA arm. Sensitivity analysis found that the model was most sensitive to costs of SSAs. Using probabilistic sensitivity analysis, the SSA strategy was only cost-effective 1.4% of the time at a WTP threshold of $100,000 per QALY. CONCLUSIONS: Our modeling study finds it is not cost-effective to initiate SSAs at time of presentation for patients with metastatic GEP-NETs. Further clinical studies are needed to identify the optimal timing to initiate these drugs.

Probabilistic linkage without personal information successfully linked national clinical datasets.

BACKGROUND: Probabilistic linkage can link patients from different clinical databases without the need for personal information. If accurate linkage can be achieved, it would accelerate the use of linked datasets to address important clinical and public health questions. OBJECTIVE: We developed a step-by-step process for probabilistic linkage of national clinical and administrative datasets without personal information, and validated it against deterministic linkage using patient identifiers. STUDY DESIGN AND SETTING: We used electronic health records from the National Bowel Cancer Audit and Hospital Episode Statistics databases for 10,566 bowel cancer patients undergoing emergency surgery in the English National Health Service. RESULTS: Probabilistic linkage linked 81.4% of National Bowel Cancer Audit records to Hospital Episode Statistics, vs. 82.8% using deterministic linkage. No systematic differences were seen between patients that were and were not linked, and regression models for mortality and length of hospital stay according to patient and tumour characteristics were not sensitive to the linkage approach. CONCLUSION: Probabilistic linkage was successful in linking national clinical and administrative datasets for patients undergoing a major surgical procedure. It allows analysts outside highly secure data environments to undertake linkage while minimizing costs and delays, protecting data security, and maintaining linkage quality.

Outcomes of small-cell versus large-cell gastroenteropancreatic neuroendocrine carcinomas: A population-based study.

The recent World Health Organization classification for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) classified poorly differentiated GEP-NENs into small cell and large cell categories. The present study aimed to assess the differences in outcomes between patients with both histological categories. The Surveillance, Epidemiology and End Results (SEER) database (1975-2016) was accessed and patients with small cell and large cell GEP-neuroendocrine carcinomas (NECs) were extracted. Differences in survival outcomes were explored through Kaplan-Meier survival estimates and multivariable Cox regression models. In total, 2204 patients with GEP-NEC were identified in the survival cohort, including 1698 patients with small cell NEC (77%) and 506 patients with large cell NEC (23%). Using Kaplan-Meier analysis/log-rank testing, large cell GEP-NEC was associated with better overall survival compared to small cell NEC (P < 0.01). Using multivariable Cox regression analysis, large cell GEP-NEC was associated with better overall survival (large cell GEP-NEC versus small cell GEP-NEC, hazard ratio = 0.77; 95% confidence interval = 0.68-0.86) and cancer-specific survival (large cell GEP-NEC versus small cell GEP-NEC, hazard ratio = 0.79; 95% 95% confidence interval = 0.69-0.91). Patients with small cell GEP-NEC have worse survival outcomes compared to those with large cell GEP-NEC. Further efforts are needed to identify biological differences and treatment sensitivities between both histological categories.

Efficacy of FOLFOX Chemotherapy in Metastatic Enteropancreatic Neuroendocrine Tumors.

BACKGROUND/AIM: FOLFOX (5-Fluorouracile and oxaliplatin) exhibits promising activity in advanced well-differentiated neuroendocrine tumors (NETs). This retrospective study aimed to analyze the outcome of metastatic enteropancreatic NETs patients treated with FOLFOX. PATIENTS AND METHODS: We retrospectively identified patients treated with FOLFOX for NETs of enteropancreatic or unknown origin among those referred to our Regional Multidisciplinary Tumor Board. RESULTS: Among 48 patients, most often pancreatic NETs (n=33, 68.8%), the median Ki67 index was 10%. The median number cycle of FOLFOX was 6 and median follow-up was 34.8 months. Disease control rate (DCR) was 83.3%. Median PFS and OS were 12.6 and 29.4 months respectively. Median chemotherapy break was 14.1 months. No significant difference was observed between PFS and the following criteria: Ki67 index, primary tumor site, alkaline phosphatase levels, primary tumor surgery and 18F-FDG PET positivity. CONCLUSION: FOLFOX exhibits a high DCR and a short duration of treatment with a relative long chemotherapy break in patients with metastatic enteropancreatic NETs.