Carboplatin in Combination with Oral or Intravenous Etoposide for Extra-Pulmonary, Poorly-Differentiated Neuroendocrine Carcinomas.

BACKGROUND: Carboplatin-etoposide (CarboEtop) is a 1st-line option for patients with advanced extra-pulmonary (EP), poorly-differentiated (PD) neuroendocrine carcinoma (NEC). Different schedules are used in clinical practice and randomised evidence is lacking. OBJECTIVES: To provide real-life outcomes of carboplatin combined with oral or intravenous (IV) etoposide (Etop) in advanced EP-PD-NEC, from 2 specialist centres. METHODS: Activity/efficacy/toxicity data of CarboEtop were collected retrospectively and analysed. RESULTS: We identified 113 patients; median age: 65.8 years; male: 64%; gastro-entero-pancreatic origin: 54%; stage IV: 90%; median Ki-67: 70%; median follow-up: 11.5 months. A total of 123 courses of CarboEtop (oral: 45%; IV: 55%) were administered; 106 (86%) 1st-line, 16 (13%) 2nd-line, and 1 (1%) 3rd-line. Disease control rate: 74.5% in 1st-line and 69.2% in 2nd/3rd-line, with no significant difference between oral and IV Etop in 1st-line (69.8 vs. 80.8%, p = 0.237). Median progression-free survival (PFS): 6.0 and 4.5 months in 1st-line and 2nd/3rd-line, respectively. Overall survival (OS): 11.5 and 12.5 months in 1st-line and 2nd/3rd-line, respectively. The schedule (oral versus IV Etop) did not impact on 1st-line PFS (5.6 vs. 6.2 months, p = 0.179), although there was a trend towards shorter OS (8.9 vs. 12.1 months, p = 0.069). Liver metastases correlated with worse 1st-line PFS (p = 0.015) and 1st-line OS (p < 0.001) on multivariable analysis. The commonest grade 3-4 adverse event was myelosuppression (49%), with comparable toxicity between oral and IV Etop, except for venous thromboembolism (12.5 vs. 1.7%, p = 0.04). CONCLUSIONS: CarboEtop for advanced EP-PD-NEC is active, effective, and well-tolerated. Oral and IV Etop schedules are associated with comparable toxicity; activity should be compared in larger cohorts.

Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = -0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.

Relevant Study: Patient and Clinician Perspectives on Clinically-Meaningful Outcomes in Advanced Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis and significant symptom burden. This prospective observational study aimed to evaluate expectations and priorities of patients with advanced PDAC and their clinicians through a study survey and two quality of life (QoL) questionnaires (QLQ-C30 and PAN26) at three time-points: baseline (T1), before (T2) and after (T3) their 1st on-treatment CT scan. Over a 1-year period, 106 patients were approached, 71 patients and 12 clinicians were recruited. Choosing between treatment options, patients prioritised: 54% overall survival (OS), 26% balance between side-effects and OS, 15% could not choose and 5% favoured symptom control. These were significantly different from the clinician's answers (p < 0.001). Patients who prioritised OS had higher symptom burden (p = 0.03) and shorter OS compared to those who prioritised balance (p = 0.01). Most (86%) patients had personal goals they wanted to reach; clinicians knew of these in 12% of instances. Patient and clinicians' views regarding survival improvement from chemotherapy were significantly different: 81% of clinicians and 12% of patients thought 1-2 or 3-6 months extension, 58% of patients and 0% physicians thought 1-5 or >5 years (p < 0.001). At T1, patients had low QoL and worst symptoms were: 'Future worries', 'planning of activities', fatigue and pain. Patients were willing to accept significantly higher amounts of side-effects as a trade-off for extra time, than clinicians thought (p < 0.001). Overall, there are significant discrepancies between patient and clinicians' views about the aims, priorities and expected extension of life.

Molecular Profiling of Well-Differentiated Neuroendocrine Tumours: The Role of ctDNA in Real-World Practice.

Background: The role of tumour genomic profiling in the clinical management of well-differentiated neuroendocrine tumours (WdNETs) is unclear. Circulating tumour DNA (ctDNA) may be a useful surrogate for tumour tissue when the latter is insufficient for analysis. Methods: Patients diagnosed with WdNETs underwent ctDNA genomic profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly-differentiated neuroendocrine carcinoma) were used for comparison. The aim was to determine the rate of: test failure (primary end-point), "pathological alterations" (PAs) (secondary end-point) and patients for whom ctDNA analysis impacted management (secondary end-point). Results: Forty-five patients were included. A total of 15 patients with WdNETs (18 ctDNA samples) were eligible: 8 females (53.3%), median age 63.2 years (range 23.5-86.8). Primary: small bowel (8; 53.3%), pancreas (5; 33.3%), gastric (1; 6.7%) and unknown primary (1; 6.7%); grade (G)1 (n = 5; 33.3%), G2 (9; 60.0%) and G3 (1; 6.7%); median Ki-67: 5% (range 1-30). A total of 30 patients with non-WdNETs (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs. 17.65% in non-WdNETs; p-value 0.395). Of the 13 WdNET samples with successful ctDNA analyses, PAs were detected in 6 (46.15%) (vs. 82.14% in non-WdNETs; p-value 0.018). In WdNETs, the PA rate was independent of concomitant administration anti-cancer systemic therapies (2/7; 28.57% vs. 4/6; 66.67%; p-value 0.286) at the time of the ctDNA analysis: four, one and one samples had one, two and three PAs, respectively. These were: CDKN2A mutation (mut) (one sample), CHEK2mut (one), TP53mut (one), FGFR2 amplification (one), IDH2mut (one), CTNNB1mut (one), NF1mut (one) and PALB2mut (one). None were targetable (0%) or impacted clinical management (0%). There was a lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs. non-WdNETs (mean 26.99), even though differences did not reach statistical significance (p-value 0.0584). Conclusions: Although feasible, mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. The rates of PAs and mMAFs were higher in non-WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients' expectations regarding the likelihood of the results impacting their treatment.

The Management and Outcomes of Patients with Extra-Pulmonary Neuroendocrine Neoplasms and Brain Metastases.

BACKGROUND: Brain metastases (BMs) in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) are rare, and limited clinical information is available. The aim of this study was to detail the clinicopathological features, management and outcomes in patients with EP-NENs who developed BMs. METHODS: A retrospective single-centre analysis of consecutive patients with EP-NENs (August 2004-February 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis was estimated (Kaplan-Meier). RESULTS: Of 730 patients, 17 (1.9%) had BMs, median age 61 years (range 15-77); 8 (53%) male, unknown primary NEN site: 40%. Patients with BMs had grade 3 (G3) EP-NENs 11 (73%), G2: 3 (20%), G1: 1 (7%). Eight (53%) had poorly differentiated NENs, 6 were well-differentiated and 1 was not recorded. Additionally, 2 (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. The relative risk of developing BMs was 7.48 in patients with G3 disease vs. G1 + G2 disease (p = 0.0001). Median time to the development of BMs after NEN diagnosis: 15.9 months (range 2.5-139.5). Five patients had a solitary BM, 12 had multiple BMs. Treatment of BMs were surgery (n = 3); radiotherapy (n = 5); 4: whole brain radiotherapy, 1: conformal radiotherapy (orbit). Nine (53%) had best supportive care. Median OS from NEN diagnosis was 23.6 months [95% CI 15.2-31.3]; median time to death from BMs diagnosis was 3.0 months [95% CI 0.0-8.3]. CONCLUSION: BMs in patients with EP-NENs are rare and of increased risk in G3 vs. G1 + G2 EP-NENs. Survival outcomes are poor, and a greater understanding is needed to improve therapeutic outcomes.

Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma.

Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of "NE lineage plasticity," whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type-agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how "NE lineage plasticity" can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.

Is the Morphological Subtype of Extra-Pulmonary Neuroendocrine Carcinoma Clinically Relevant?

Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in "real-world" treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted-p = 0.021) and OS (adjusted-p = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.

Clinical and Translational Research Challenges in Biliary Tract Cancers.

BACKGROUND: Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. OBJECTIVE: This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. FINDINGS: The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. CONCLUSION: Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.

Current Translational and Clinical Challenges in Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated deaths worldwide. Reversing this trend is complicated by the varied aetiological factors leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined with frequent presentation at advanced stage. Large-scale genomic studies have identified alterations in key signalling pathways for HCC development and progression, but these findings have not yet directly influenced patient management in the clinical setting. Despite these translational challenges, a small number of anti-angiogenic systemic therapy agents have succeeded in recent randomized trials enriching the repertoire of available treatments for advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the cusp of delivering changes to standard systemic therapy algorithms. This review focuses on recent translational and clinical developments that have advanced. current practice and explores the challenges encountered in attempting to improve the outcomes and experience of patients diagnosed with advanced HCC.

Second-line treatment in patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma: a systematic review and meta-analysis.

BACKGROUND: There is no standard second-line treatment for patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC). This study explored data evaluating second-line treatment in these patients. METHODS: A search of MEDLINE and EMBASE identified studies reporting survival and/or response data for patients with EP-PD-NEC receiving second-line therapy. Association between various factors (age, gender, ECOG performance status, primary tumour location, morphology, Ki-67, treatment and grade 3/4 haematological toxicity) and response rate (RR), progression-free (PFS) and overall survival (OS) were assessed with a mixed effects meta-regression weighted by individual study sample size. Due to a small sample size, associations were reported quantitatively, based on magnitude of beta coefficient rather than statistical significance. RESULTS: Of 83 identified studies, 19 were eligible, including 4 prospective and 15 retrospective studies. Analysis comprised 582 patients, with a median number of 19 patients in each study (range 5-100). Median age was 59 years (range 53-66). Median RR was 18% (range 0-50; 0% for single-agent everolimus, temozolomide, topotecan; 50% with amrubicin), median PFS was 2.5 months (range 1.15-6.0) and median OS was 7.64 months (range 3.2-22.0). Studies with a higher proportion of patients with a Ki-67>55% had lower RR (ß = -0.73) and shorter OS (ß = -0.82). CONCLUSION: Second-line therapy for patients with advanced EP-PD-NEC has limited efficacy and the variety of regimens used is diverse. Ki-67>55% is associated with worse outcomes. Prospective randomised studies are warranted to enable exploration of new treatment strategies.

Fibrolamellar carcinoma: Challenging the challenge.

Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon α-2B (IFN-α-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-α-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-α-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC.

Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: A Systematic Review of a Controversial and Underestimated Diagnosis.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare diagnosis of the gastro-entero-pancreatic tract. Evidence from the current literature regarding their epidemiology, biology, and management is of variable quality and conflicting. Based on available data, the MiNEN has an aggressive biological behaviour, mostly driven by its (often high-grade) neuroendocrine component, and a dismal prognosis. In most cases, the non-neuroendocrine component is of adenocarcinoma histology. Due to limitations in diagnostic methods and poor awareness within the scientific community, the incidence of MiNENs may be underestimated. In the absence of data from clinical trials, MiNENs are commonly treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin, based on the assumption of a biological similarity to their pure counterparts. However, little is known about the molecular aberrations of MiNENs, and their pathogenesis remains controversial; molecular/genetic studies conducted so far point towards a common monoclonal origin of the two components. In addition, mutations in tumour-associated genes, including TP53, BRAF, and KRAS, and microsatellite instability have emerged as potential drivers of MiNENs. This systematic review (91 full manuscripts or abstracts in English language) summarises the current reported literature on clinical, pathological, survival, and molecular/genetic data on MiNENs.

Prognostic importance of lymph node yield after curative resection of gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: The prognostic significance of lymph nodes (LNs) metastases and the optimum number of LN yield in gastroenteropancreatic neuroendocrine tumours (GEP NETs) undergoing curative resection is still debatable. Many studies have demonstrated that cure rate for patients with GEP NETs can be improved by the resection of the primary tumour and regional lymphadenectomy. AIM: To evaluate the effect of lymph node (LN) status and yield on relapse-free survival (RFS) and overall survival (OS) in patients with resected GEP NETs. METHODS: Data on patients who underwent curative resection for GEP NETs between January 2002 and March 2017 were analysed retrospectively. Grade 3 tumours (Ki67 > 20%) were excluded. Univariate Cox proportional hazard models were computed for RFS and OS and assessed alongside cut-point analysis to distinguish a suitable binary categorisation of total LNs retrieved associated with RFS. RESULTS: A total of 217 patients were included in the study. The median age was 59 years (21-97 years) and 51% (n = 111) were male. Primary tumour sites were small bowel (42%), pancreas (25%), appendix (18%), rectum (7%), colon (3%), gastric (2%), others (2%). Median follow up times for all patients were 41 mo (95%CI: 36-51) and 71 mo (95%CI: 63-76) for RFS and OS respectively; 50 relapses and 35 deaths were reported. LNs were retrieved in 151 patients. Eight or more LNs were harvested in 106 patients and LN positivity reported in 114 patients. Three or more positive LNs were detected in 62 cases. The result of univariate analysis suggested perineural invasion (P = 0.0023), LN positivity (P = 0.033), LN retrieval of ≥ 8 (P = 0.047) and localisation (P = 0.0049) have a statistically significant association with shorter RFS, but there was no effect of LN ratio on RFS: P = 0.1 or OS: P = 0.75. Tumour necrosis (P = 0.021) and perineural invasion (P = 0.016) were the only two variables significantly associated with worse OS. In the final multivariable analysis, localisation (pancreas HR = 27.33, P = 0.006, small bowel HR = 32.44, P = 0.005), and retrieval of ≥ 8 LNs (HR = 2.7, P = 0.036) were independent prognostic factors for worse RFS. CONCLUSION: An outcome-oriented approach to cut-point analysis can suggest a minimum number of adequate LNs to be harvested in patients with GEP NETs undergoing curative surgery. Removal of ≥ 8 LNs is associated with increased risk of relapse, which could be due to high rates of LN positivity at the time of surgery. Given that localisation had a significant association with RFS, a prospective multicentre study is warranted with a clear direction on recommended surgical practice and follow-up guidance for GEP NETs.

Follow-Up Recommendations after Curative Resection of Well-Differentiated Neuroendocrine Tumours: Review of Current Evidence and Clinical Practice.

The incidence of neuroendocrine neoplasms (NENs) is increasing, especially for patients with early stages and grade 1 tumours. Current evidence also shows increased prevalence, probably reflecting earlier stage diagnosis and improvement of treatment options. Definition of adequate postsurgical follow-up for NENs is a current challenge. There are limited guidelines, and heterogeneity in adherence to those available is notable. Unfortunately, the population of patients at greatest risk of recurrence has not been defined clearly. Some studies support that for patients with pancreatic neuroendocrine tumours (PanNETs), factors such as primary tumour (T), stage, grade (Ki-67), tumour size, and lymph node metastases (N) are of relevance. For bronchial neuroendocrine tumours (LungNETs) and small intestinal neuroendocrine tumours (siNETs), similar factors have been identified. This review summarises the evidence supporting the rationale behind follow-up after curative resection in well-differentiated PanNETs, siNETs, and LungNETS. Published evidence informing relapse rate, disease-free survival, and relapse patterns are discussed, together with an overview of current guidelines informing postsurgical investigations and duration of follow-up.

Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres.

BACKGROUND: Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare diagnosis, mainly encountered in the gastro-entero-pancreatic tract. There is limited knowledge of its epidemiology, prognosis and biology, and the best management for affected patients is still to be defined. AIM: To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN. METHODS: Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable). RESULTS: Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment (vs surgery alone) did not improve RFS (P = 0.375), or OS (P = 0.240). In advanced cases, median progression free survival (PFS); 5.6 mo (95%CI: 4.4-7.4), and median OS; 9.0 mo (95%CI: 5.2-13.4). On univariate analysis, receipt of palliative active treatment (vs best supportive care) prolonged PFS and OS (both, P < 0.001). CONCLUSION: MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.

MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours.

Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18-22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours.

Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis.

BACKGROUND: Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS: A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS: Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION: CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).

Somatostatin analogue-induced pancreatic exocrine insufficiency in patients with neuroendocrine tumors: results of a prospective observational study.

BACKGROUND: Patients with advanced well-differentiated neuroendocrine tumours (Wd-NETs) are commonly treated with somatostatin analogues (SSAs). Some patients may develop SSA-related side effects such as pancreatic exocrine insufficiency (PEI). METHODS: In this prospective, observational study, the frequency of SSA-induced PEI in 50 sequential patients with advanced Wd-NETs treated with SSAs was investigated. Toxicity was assessed monthly and faecal elastase-1 (FE1) and quality of life (QoL) were assessed 3-monthly. RESULTS: The median age was 65.8 years, 58% were male and the majority (92%) of patients had metastatic disease; patients received 4-weekly long acting octreotide (60%) or lanreotide (40%). Twelve patients (24%) developed SSA-related PEI after a median of 2.9 months from SSA initiation; FE1 was a reliable screening tool for PEI, especially in symptomatic (abdominal bloating, flatulence and/or diarrhea) patients (risk ratio 8.25 (95% confidence interval 1.15-59.01)). Most of these patients (11/12; 92%) required PERT. Other SSA-related adverse events (any grade) included flatulence (50%), abdominal pain (32%), diarrhoea (30%) and fatigue (20%). Development of PEI did not significantly worsen overall QoL, however gastrointestinal symptoms and diarrhoea were increased. CONCLUSION: This study demonstrated that PEI occurs at a higher rate than previously reported; clinicians need to diagnose and treat this SSA-related adverse-event which occurs in 1 in 4 patients with Wd-NETs treated with SSAs. Screening with FE1 in symtomatic patients is recommend.

A circulating TH2 cytokines profile predicts survival in patients with resectable pancreatic adenocarcinoma.

Surgery is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC), but metastatic relapse remains common. We hypothesized that the expression levels of inflammatory cytokines could predict recurrence of PDAC, thus allowing to select patients who most likely could benefit from surgical resection. We prospectively collected plasma at diagnosis from 287 patients with pancreatic resectable neoplasms. The expression levels of 23 cytokines were measured in 90 patients with PDAC by using a multiplex analyte profiling assay. Levels higher than cutoff identified of the TH2 cytokines interleukin (IL)4, IL5, IL6 of macrophage inflammatory protein (MIP)1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)1, and of IL17α, IFNγ-induced protein (IP)10, and IL1b were significantly associated with a shorter median OS. In particular, levels of IL4 and IP10 higher than cutoff identified, and level of TH1 cytokines TNFα and INFγ, and of IL9 and IL1Rα lower than cutoff identified were significantly associated with a shorter DFS. In the multivariate analysis, high IP10 was confirmed as negatively associated with OS (HR = 3.097, p = 0.014) and IL4 and TNFα remain negatively (HR = 2.75, p = 0.002) and positively (HR = 0.224, p = 0.049) associated with DFS, respectively. Simultaneous expression of low IL4 and high TNFα identified patients with best prognosis (HR = 0.313, p < 0.0001). In conclusion, we demonstrated that, among a series of cytokines, IL4 is the most significant independent prognostic factor for DFS in resectable PDAC patients, and it could be useful to select patients with high risk of early recurrence who may avoid an unnecessary resection.