Appropriate and mindful measurement of serum calcitonin in patients with thyroid nodules. A white paper.

Medullary thyroid carcinoma (MTC) is an infrequent thyroid malignancy that is often diagnosed at advanced stage with consequent poor prognosis. Thus, the earlier the diagnosis of MTC, the better the prognosis. Unfortunately, the preoperative detection of MTC remains challenging in clinical practice. In fact, while ultrasound and fine-needle aspiration cytology have suboptimal performance in this context, measuring serum calcitonin (Ctn), fully recognized as the most reliable test to detect MTC, is not universally accepted as routine test in all patients with thyroid nodule(s). The authors of this paper reappraise critically the matter of Ctn measurement in view of the recent advancements in the literature to point out the essential information to be known, and then to prepare an easy-to-use guide for clinicians to appropriately consider the measurement of serum Ctn during clinical practice.

Clinical efficacy of thermal ablation for the treatment of pulmonary carcinoid tumor: a propensity-matched analysis.

OBJECTIVE: To investigate the clinical efficacy of thermal ablation in the treatment of pulmonary carcinoid (PC) tumor. METHODS: Data of patients with inoperable PC diagnosed from 2000 to 2019 were obtained from the SEER database and analyzed according to different therapeutic modality: thermal ablation vs non-ablation. Propensity score matching (PSM) was used to reduce intergroup differences. Kaplan-Meier curves and the log-rank test were used to compare intergroup differences of overall survival (OS) and lung cancer-specific survival (LCSS). Cox proportional risk models were used to reveal prognostic factors. RESULTS: After PSM, the thermal ablation group had better OS (p < .001) and LCSS (p < .001) than the non-ablation group. Subgroup analysis stratified by age, sex, histologic type and lymph node status subgroups showed similar survival profile. In the subgroup analysis stratified by tumor size, the thermal ablation group showed better OS and LCSS than those of the non-ablation group for tumors ≤3.0 cm, not statistically significant for tumors >3.0 cm. Subgroup analysis by M stage showed that thermal ablation was superior to non-ablation in OS and LCSS for patients with M0 stage, but no significant difference was found in subgroups with distant metastatic disease. Multivariate analysis showed that thermal ablation was an independent prognostic factor for OS (HR: 0.34, 95% CI: 0.25-0.46, p < .001) and LCSS (HR: 0.23, 95%CI: 0.12-0.43, p < .001). CONCLUSION: For patients with inoperable PC, thermal ablation might be a potential treatment option, especially in M0-stage with tumor size ≤3 cm.

Optimal postoperative surveillance strategies for cancer survivors with gastric neuroendocrine carcinoma based on individual risk: a multicenter real-world cohort study.

BACKGROUND: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC. MATERIALS AND METHODS: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines. RESULTS: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines. CONCLUSIONS: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC.

Mixed Primary Hepatocellular Carcinoma and Hepatic Neuroendocrine Carcinoma: Case Report and Literature Review.

Mixed hepatocellular carcinoma with neuroendocrine carcinoma (HCC-NEC) is extremely rare, comprising about 0.46% of primary hepatic tumors. A 63-year-old man who was a chronic alcoholic presented with a nine-centimeter-sized hepatic mass. His serum alpha-fetoprotein and protein induced by vitamin K antagonist-II levels were 22,815 ng/mL and 183 mAU/mL, respectively. The patient underwent a right hemihepatectomy, including the middle hepatic vein. The tumor consisted of poorly differentiated HCC (20%) and large- and small-cell-type NEC (80%) components as per the pathological examination. Immunohistochemically chromogranin and synaptophysin were positive in the areas of NEC and negative in the areas of HCC. Adjuvant chemotherapy with a combination of cisplatin and etoposide was administered after surgery. At postoperative 5 months, the patient complained of right flank pain, and CT showed a new mass measuring 7.3 cm in the right adrenal gland. Postoperatively, after 6.5 months, more recurred masses were noted on the posterior aspect of the right kidney and both lungs. Although the regimen was changed from etoposide to irinotecan, additional recurred masses were developed in the liver, lung, and brain. He passed away 12 months after the surgery. After reviewing and analyzing previous literature, the 1 and 2 year overall survival rates are 57.3 and 43.6%, respectively, and the 1 and 2 year disease-free survival rates are 36.2 and 29.0%, respectively. Mixed HCC-NEC is a very rare tumor, and the surgical outcome is poor.

Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities.

BACKGROUND: Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC. MATERIALS AND METHODS: Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20 815 genes. RESULTS: All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern. CONCLUSIONS: These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE).

Interception Targets of Angelica Gigas Nakai Root Extract versus Pyranocoumarins in Prostate Early Lesions and Neuroendocrine Carcinomas in TRAMP Mice.

We reported efficacy of Angelica gigas Nakai (AGN) root ethanol extract and equimolar decursin (D)/decursinol angelate (DA) through daily gavage starting at 8 weeks of age (WOA) to male transgenic adenocarcinoma of mouse prostate (TRAMP) mice such that these modalities suppressed precancerous epithelial lesions in their dorsolateral prostate (DLP) to similar extent, but AGN extract was better than the D/DA mixture at promoting the survival of mice bearing prostate neuroendocrine carcinomas to 28 WOA. Here, we compared by microarray hybridization the mRNA levels in pooled DLP tissues and individual neuroendocrine carcinomas to characterize potential molecular targets of AGN extract and D/DA. Clustering and principal component analyses supported distinct gene expression profiles of TRAMP DLP versus neuroendocrine carcinomas. Pathway Enrichment, Gene Ontology, and Ingenuity Pathway Analyses of differential genes indicated that AGN and D/DA affected chiefly processes of lipid and mitochondrial energy metabolism and oxidation-reduction in TRAMP DLP, while AGN affected neuronal signaling, immune systems and cell cycling in neuroendocrine carcinomas. Protein-Protein Interaction Network analysis predicted and reverse transcription-PCR verified multiple hub genes common in the DLP of AGN- and D/DA-treated TRAMP mice at 28 WOA and select hub genes attributable to the non-D/DA AGN components. The vast majority of hub genes in the AGN-treated neuroendocrine carcinomas differed from those in TRAMP DLP. In summary, the transcriptomic approach illuminated vastly different signaling pathways and networks, cellular processes, and hub genes of two TRAMP prostate malignancy lineages and their associations with the interception efficacy of AGN and D/DA. PREVENTION RELEVANCE: This study explores potential molecular targets associated with in vivo activity of AGN root alcoholic extract and its major pyranocoumarins to intercept precancerous epithelial lesions and early malignancies of the prostate. Without an ethically-acceptable, clearly defined cancer initiation risk reduction strategy available for the prostate, using natural products like AGN to delay formation of malignant tumors could be a plausible approach for prostate cancer prevention.

Surgery with Radical Intent: Is There an Indication for G3 Neuroendocrine Neoplasms?

BACKGROUND: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. PATIENTS AND METHODS: Multicenter analysis of a series of stage I-III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. RESULTS: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23 months (5-187 months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14 months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. CONCLUSIONS: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma.

Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers.

Vitamin D and vitamin B12 deficiencies in patients with small intestinal carcinoid tumour: is opioid use disorder a confounding factor in the diagnosis?

Carcinoid tumours have the ability to secrete various peptides and bioamines that lead to carcinoid syndrome manifested as cutaneous flushing, diarrhoea, bronchial constriction and cardiac involvement. The deficiencies of vitamins D and B12 have previously been reported in patients with carcinoid tumours presumably due to chronic diarrhoea associated with the carcinoid syndrome. Herein, we chronicle the case of a patient with opioid use disorder who presented with small bowel obstruction that was found to be caused by a midgut carcinoid tumour. Laboratory studies revealed deficiencies of vitamins D and B12 even though he denied diarrhoea and had no other aetiology of deficiencies of these vitamins. Additionally, this paper presents a review of the published medical literature pertaining to clinical features, diagnostic investigations and treatment of intestinal carcinoid tumours and explores possible explanations for the observed deficiencies in these patients.

Urothelial carcinoma with villoglandular differentiation (UCVGD) with small cell neuroendocrine carcinoma of urinary bladder.

Urothelial carcinoma with villoglandular differentiation (UCVGD) is a rare aggressive variant of urothelial carcinoma. It is usually associated with high-grade urothelial carcinoma or rarely adenocarcinoma. There is only one other previous report of UCVGD associated with small cell neuroendocrine carcinoma of urinary bladder. We report the second case of UCVGD with small cell neuroendocrine carcinoma of urinary bladder in a 74-year-old non-smoker male patient. The mass was muscle invasive and also invaded the prostate. This entity needs to be confidently diagnosed due to its prognostic and therapeutic implications.

First Line Sorafenib Treatment for Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

BACKGROUND: Medullary thyroid cancer (MTC) is a rare disease, the prognosis of advanced and metastatic disease is poor and few therapeutic options are available in this setting. Based on the results of phase II and III studies with sorafenib in differentiated thyroid cancer and the lack of availability of registered tyrosine kinase inhibitors, vandetabin and cabozantinib in Hungary, we designed a uncontrolled, prospective efficacy and safety study of patients with metastatic MTC treated with first-line sorafenib in five Hungarian oncology centers. METHODS: Ten consecutive patients with progressive or symptomatic metastatic MTC were included and started sorafenib 400  mg twice a day between June 2012 and March 2016. The primary end point was median progression-free survival (mPFS). Secondary endpoints included disease control rate, biochemical response, symptomatic response and toxicity. RESULTS: Four patients achieved partial remission (40%) according to RECIST 1.1 evaluation. Five patients had stable disease beyond 12 months (50%) and one patient had progressive disease (10%). Median PFS was 19.1 months. The disease control rate was 90%. Association between radiologic response and biochemical or symptomatic response was inconsistent. Most common side effects were Grade 1-2 fatigue (60%), palmar-plantar erythrodysesthesia, rash/dermatitis 50-50%, alopecia 40%. CONCLUSIONS: In our prospective case series in patients with MTC first-line sorafenib showed at least similar efficacy as in other small phase II trials and case reports. Based on comparable efficacy with registered tyrosine kinase inhibitors and it's manageable toxicity profile, we believe that sorafenib has role in the sequential treatment of MTC.

Primary large cell neuroendocrine carcinoma of the prostate in a hormone naive patient: A case report from Taiwan.

Large cell neuroendocrine carcinoma (LCNEC) of the prostate is extremely rare. Previously reported cases in the literature were almost exclusively developed in men receiving androgen deprivation therapy for prostate adenocarcinoma. We herein present a case of de novo LCNEC: A 66-year-old male was incidentally diagnosed as LCNEC after he underwent transurethral resection of prostate. The stage was T4N1M1. Therefore, the patient was treated with 6 cycles of cisplatin and etoposide in the following 6 months, which achieved a partial remission. He gave up the chance to eradicate the residual mass. Three months later, the tumor progressed rapidly. In conclusion, LCNEC is a rare prostate cancer. Our experience shows that chemotherapy with etoposide and cisplatin is effective to achieve a significant remission. However, LCNEC is highly malignant in nature, postchemotherapy surgery for the residual mass should be considered.

Association of PD-L1 Expression with Tumor-Infiltrating Immune Cells and Mutation Burden in High-Grade Neuroendocrine Carcinoma of the Lung.

INTRODUCTION: The immune microenvironment of high-grade neuroendocrine carcinoma of the lung, including programmed death ligand 1 (PD-L1) expression, has not been well characterized. METHODS: On the basis of immunohistochemistry (IHC) results, PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) was scored as follows: TC0 and IC0 were defined as PD-L1 expression less than 1%, TC1 and IC1 as at least 1% but less than 10%, TC2 and IC2 as 10% or more but less than 50%, and TC3 and IC3 as 50% or more. Phosphatase and tensin homolog (PTEN) IHC was scored as either lost or retained expression. The Ion AmpliSeq Comprehensive Cancer Panel (ThermoFisher Scientific, Waltham, MA) was used to identify mutations in all coding exons of 409 cancer-related genes. RESULTS: A total of 192 patients with large cell neuroendocrine carcinoma (LCNEC) (n = 72) and SCLC (n = 120) were studied. The prevalence of PD-L1 expression on TCs was 15.1% (29 of 192). IC infiltration and PD-L1 expression on ICs were observed in 34.4% of patients (66 of 192) and 31.3% of patients (60 of 192), respectively. The prevalence of IC infiltration and PD-L1 expression on IC were more strongly correlated with LCNEC than with SCLC (57.6% versus 23.3%, p < 0.01; 45.8% versus 22.5%, p < 0.01) and high nonsynonymous mutations (p = 0.05 and .04). PTEN loss was found in 9.5% of patients (18 of 189) and showed no correlation with PD-L1 expression. Progression-free survival was better in patients with IC infiltration than in those without IC infiltration (median 11.3 versus 6.8 months [p < 0.01]) and in patients with PD-L1 expression of IC1/2/3 than in those with expression of IC0 (median 11.3 versus 7.0 months [p = 0.03]). CONCLUSION: These findings suggest that the PD-1/PD-L1 pathway is activated in the microenvironment of pulmonary high-grade neuroendocrine carcinoma and correlated with a higher mutation burden.

Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer.

Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately 73-fold higher concentration of AdVince is needed to induce a similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET.

Ursolic acid from Trailliaedoxa gracilis induces apoptosis in medullary thyroid carcinoma cells.

Medullary thyroid carcinoma (MTC) originates from the C­cells of the thyroid and is not sensitive to radiation or chemotherapy. Therefore, surgical removal of the tumor tissue in its entirety is the only curative treatment for MTC. The present study aimed to examine the potential mechanisms of action of extracts of Trailliaedoxa gracilis (TG; WW Smith & Forrest), a plant from the province of Sichuan, China, and of ursolic acid (UA), a pentacyclic triterpen present in TG, on the MTC­SK MTC cell line. A total of 13 TG fractions and UA were examined in vitro for their effects on cell morphology, cell number, proliferation and rates of apoptosis. Reverse transcription­quantitative polymerase chain reaction of nuclear factor­κB essential modifier (NEMO) was performed to delineate the role of the apoptotic pathway following treatment with UA. TG and UA were examined in vivo in xenotransplanted MTC­bearing severe combined immunodeficient mice. The TG fractions exhibited antiproliferative effects, with inhibition of mitochondrial activity in the tumor cells at concentrations, which caused no impairment of the normal control cells. The apoptotic rates of the MTC­SK cells treated with the TG fractions and UA were determined, in which no marked tumor inhibition was observed in the treated MTC­mice, and no change in the expression of NEMO was detected in the treated MTC­SK cells. The observation of early­onset activation of caspase 8 suggested that the responsible factor was linked to NEMO, an anti­apoptotic protein. However, no differences in the mRNA transcription levels of NEMO were detected in MTC­SK cells treated with UA, suggesting that this protein was not associated with the signal transducer and activator of transcription 3 pathway.

Nintedanib Is a Highly Effective Therapeutic for Neuroendocrine Carcinoma of the Pancreas (PNET) in the Rip1Tag2 Transgenic Mouse Model.

PURPOSE: Pancreatic neuroendocrine tumors (PNET) represent a rare but challenging heterogeneous group of cancers with an increasing incidence over the last number of decades. Herein, we report an in-depth evaluation of the new antiangiogenic small-molecule tyrosine kinase inhibitor (TKI) nintedanib in the preclinical Rip1Tag2 transgenic mouse model of neuroendocrine carcinoma of the pancreas (insulinoma). EXPERIMENTAL DESIGN: We have assessed the antiangiogenic and antitumor activity of nintedanib, in comparison with other antiangiogenic TKI, by treating Rip1Tag2 transgenic mice with different treatment schedules complemented with histopathologic, cell biologic, and biochemical analyses. RESULTS: Prolonged nintedanib treatment of Rip1Tag2 mice has led to a strong suppression of angiogenesis, accompanied by a reduced tumor burden, which translated into a significant prolongation of survival. Despite nintedanib's inhibitory action on perivascular cells, the blood vessels remaining after therapy displayed a considerably mature phenotype with tight perivascular cell coverage and preserved perfusion. Nintedanib treatment did not increase local tumor invasiveness or metastasis to the liver and pancreatic lymph nodes--a phenomenon that has been observed with antiangiogenic treatments of Rip1Tag2 transgenic mice in other laboratories. In contrast with the strong reduction in blood microvessel densities, nintedanib did not have any impact on tumor lymphangiogenesis. CONCLUSIONS: Based on our findings, we propose the clinical evaluation of the antiangiogenic drug nintedanib as a new treatment modality for PNET patients, notably in a direct comparison with already established therapeutic regimens, such as sunitinib.

Adjuvant radiotherapy for gastric carcinoma: 10 years follow-up of 244 cases from a single institution.

BACKGROUND: Postoperative chemoradiotherapy (CRT) of gastric carcinoma improves survival among high- risk patients. This study was undertaken to analyse long-term survival probability and the impact of certain covariates on the survival outcome in affected individuals. MATERIALS AND METHODS: Between January 2000 and December 2005, 244 patients with gastric cancer underwent adjuvant radiotherapy (RT) in our institution. Data were retrieved retrospectively from patient files and analysed with SPSS version 21.0. RESULTS: A total of 244 cases, with a male to female ratio of 2.2:1, were enrolled in the study. The median age of the patients was 52 years (range, 20-78 years). Surgical margin status was positive or close in 72 (33%) out of 220 patients. Postoperative adjuvant RT dose was 46 Gy. Median follow-up was 99 months (range, 79-132 months) and 23 months (range, 2-155 months) for surviving patients and all patients, respectively. Actuarial overall survival (OS) probability for 1-, 3-, 5- and 10-year was 79%, 37%, 24% and 16%, respectively. Actuarial progression free survival (PFS) probability was 69%, 34%, 23% and 16% in the same consecutive order. AJCC Stage I-II disease, subtotal gastrectomy and adjuvant CRT were significantly associated with improved OS and PFS in multivariate analyses. Surgical margin status or lymph node dissection type were not prognostic for survival. CONCLUSIONS: Postoperative CRT should be considered for all patients with high risk of recurrence after gastrectomy. Beside well-known prognostic factors such as stage, lymph node status and concurrent chemotherapy, the type of gastrectomy was an important prognostic factor in our series. With our findings we add to the discussion on the definition of required surgical margin for subtotal gastrectomy. We consider that our observations in gastric cancer patients in our clinic can be useful in the future randomised trials to point the way to improved outcomes.

Current concepts in the diagnosis and management of poorly differentiated gastrointestinal neuroendocrine carcinomas.

Poorly differentiated neuroendocrine carcinomas (PDNEC) are rare tumours that can originate from any site of the gastrointestinal tract exhibiting an overall aggressive behaviour that may vary between tumours according to the degree of cellular proliferation. The majority of PDNEC are locally advanced or metastatic at presentation, and are only infrequently associated with secretory hormonal syndromes. PDNEC exhibit aggressive histological features (high mitotic rate, high Ki67 labelling index and presence of necrosis) and are further subdivided into two morphological subgroups, small and large cell variants. As PDNEC express somatostatin receptors less frequently, somatostatin receptor scintigraphy is usually negative, whereas 18F-fluorodeoxyglucose positron emission tomography appears to be the best method of evaluating disease spread and guiding further treatment. PDNEC have traditionally been treated similarly to small cell lung carcinoma, although they show a number of different clinical and histopathologic features. First line systemic chemotherapy with a platinum-based agent and etoposide is used for patients with metastatic disease, leading to variable response rates that are often of relative short duration. Sequential or concurrent chemoradiation is recommended for patients with locoregional disease. In patients with localised disease, complete surgical resection should be offered followed by adjuvant treatment (chemotherapy with or without radiotherapy); the value of neoadjuvant chemotherapy has not been evaluated as yet. The role of second line therapies is evolving, with temozolomide being a promising agent. However, the majority of data regarding PDNEC is hampered by the small number of series and their retrospective nature, making it important that multicentre co-operative studies be performed.

Thiocoraline alters neuroendocrine phenotype and activates the Notch pathway in MTC-TT cell line.

Medullary thyroid cancer (MTC) is an aggressive neuroendocrine tumor (NET). Previous research has shown that activation of Notch signaling has a tumor suppressor role in NETs. The potential therapeutic effect of thiocoraline on the activation of the Notch pathway in an MTC cell line (TT) was investigated. Thiocoraline was isolated from a marine bacterium Verrucosispora sp. MTT assay (3-[4, 5-dimethylthiazole-2-yl]-2, 5-diphenyltetrazolium bromide) was used to determine the IC50 value and to measure cell proliferation. Western blot revealed the expression of Notch isoforms, NET, and cell cycle markers. Cell cycle progression was validated by flow cytometry. The mRNA expression of Notch isoforms and downstream targets were measured using real-time PCR. The IC50 value for thiocoraline treatment in TT cells was determined to be 7.6 nmol/L. Thiocoraline treatment decreased cell proliferation in a dose- and time-dependent manner. The mechanism of growth inhibition was found to be cell cycle arrest in G1 phase. Thiocoraline activated the Notch pathway as demonstrated by the dose-dependent increase in mRNA and protein expression of Notch isoforms. Furthermore, treatment with thiocoraline resulted in changes in the expression of downstream targets of the Notch pathway (HES1, HES2, HES6, HEY1, and HEY2) and reduced expression of NET markers, CgA, and ASCL1. Thiocoraline is a potent Notch pathway activator and an inhibitor of MTC-TT cell proliferation at low nanomolar concentrations. These results provide exciting evidence for the use of thiocoraline as a potential treatment for intractable MTC.