The Clinical Significance of MicroRNAs in Colorectal Cancer Signaling Pathways: A Review.

Colorectal carcinoma (colon and rectum) is currently considered among the most prevalent malignancies of Western societies. The pathogenesis and etiological mechanisms underlying colorectal cancer (CRC) development remain complex and heterogeneous. The homeostasis and function of normal human intestinal cells is highly regulated by microRNAs. Therefore, it is not surprising that mutations and inactivation of these molecules appear to be linked with progression of colorectal tumors. Recent studies have reported significant alterations of microRNA expression in adenomas and CRCs compared with adjacent normal tissues. This observed deviation has been proposed to correlate with the progression and survival of disease as well as with choice of optimal treatment and drug resistance. MicroRNAs can adopt either oncogenic or tumor-suppressive roles during regulation of pathways that drive carcinogenesis. Typically, oncogenic microRNAs termed oncomirs, target and silence endogenous tumor-suppressor genes. On the other hand, tumor-suppressive microRNAs are critical in downregulating genes associated with cell growth and malignant capabilities. By extensively evaluating robust studies, we have emphasized and distinguished a discrete set of microRNAs that can modulate tumor progression by silencing specific driver genes crucial in signaling pathways including Wnt/b-catenin, epidermal growth factor receptor, P53, mismatch repair DNA repair, and transforming-growth factor beta.

Helicobacter pylori, gastric microbiota and gastric cancer relationship: Unrolling the tangle.

Helicobacter pylori infection (Hp-I) represents a typical microbial agent intervening in the complex mechanisms of gastric homeostasis by disturbing the balance between the host gastric microbiota and mucosa-related factors, leading to inflammatory changes, dysbiosis and eventually gastric cancer. The normal gastric microbiota shows diversity, with Proteobacteria [Helicobacter pylori (H. pylori) belongs to this family], Firmicutes, Actinobacteria, Bacteroides and Fusobacteria being the most abundant phyla. Most studies indicate that H. pylori has inhibitory effects on the colonization of other bacteria, harboring a lower diversity of them in the stomach. When comparing the healthy with the diseased stomach, there is a change in the composition of the gastric microbiome with increasing abundance of H. pylori (where present) in the gastritis stage, while as the gastric carcinogenesis cascade progresses to gastric cancer, the oral and intestinal-type pathogenic microbial strains predominate. Hp-I creates a premalignant environment of atrophy and intestinal metaplasia and the subsequent alteration in gastric microbiota seems to play a crucial role in gastric tumorigenesis itself. Successful H. pylori eradication is suggested to restore gastric microbiota, at least in primary stages. It is more than clear that Hp-I, gastric microbiota and gastric cancer constitute a challenging tangle and the strong interaction between them makes it difficult to unroll. Future studies are considered of crucial importance to test the complex interaction on the modulation of the gastric microbiota by H. pylori as well as on the relationships between the gastric microbiota and gastric carcinogenesis.

Pancreatic cancer and oligonucleotide therapy: Exploring novel therapeutic options and targeting chemoresistance.

Pancreatic cancer (PC) represents a malignancy with increased mortality rate, as less than 10% of patients survive for 5 years after diagnosis. Current evolution in basic sciences has revealed promising results by decrypting genetic loci vulnerable to mutations, as potential targets of novel treatment choices. In this regard, the "Oligonucleotide therapeutics", based on synthetic nucleotides, modify the function and expression of their targets. Antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNAs (miRNAs), aptamers, CpG oligodeoxynucleotides and decoys comprise the main representatives of this emerging technology, by regulating oncogenes' expression, restoring DNA repairment mechanisms, sensitizing cancer cells in chemotherapy, and inhibiting PC progress. A plethora of genetic treatment molecules and respective targets have been described and are currently studied, thus providing a broad range of probable pharmaceutical options. This narrative review illuminates the main parameters of genetic treatment molecules for PC and underlines their deficiencies, to clarify the upcoming future and trigger further investigation in PC management.

Prevalence of inflammatory bowel disease in young Greek Army male recruits from 2006 to 2018: a 13-year retrospective study from a tertiary center.

BACKGROUND: The prevalence and incidence of inflammatory bowel diseases (IBDs) vary among countries. Data regarding prevalence of IBD in Greece are limited or outdated. METHODS: We reviewed the medical records of IBD patients from a population of 551,808 Greek Army recruits in a 13-year period (2006-2018). Study population consisted of males 18-37 of age from Northwest, Central Greece (including Attica), Peloponnese, and Aegean Sea Islands. Age, disease distribution, pharmaceutical treatment and IBD-related surgery at the time of patients' admission were recorded. RESULTS: The prevalence of IBD among male recruits during the studied period was 0.15% (839/551 808, 95% confidence interval 0.14-0.16%). Of these, 448 (53.4%) had Crohn's disease (CD) and 391 (46.6%) ulcerative colitis (UC). Although 32.1% of CD patients had been treated with biologics, most often infliximab (60% of them), azathioprine was the most common as monotherapy (27% of patients). Among UC patients, mesalamine was the most often prescribed treatment (64.2%), whereas treatment with biologics as monotherapy or in combination with azathioprine was used in a ratio 1:2 compared to CD patients. A gradual reduction in steroid use was noted from 2006 to 2018, coinciding with the advent and increasing use of biologics. IBD-related surgery had been performed in 8% and 2.8% of CD and UC patients, respectively. CONCLUSION: The prevalence of IBD in Greek male recruits was 0.15% with a slight CD predominance. Remarkable changes in therapeutic trends were noted with an increasing use of biologics and reduced prescription of steroids, especially for CD.

Room for improvement in the treatment of pancreatic cancer: Novel opportunities from gene targeted therapy.

Pancreatic cancer is one of the highest and in fact, unchanged mortality-associated tumor, with an exceptionally low survival rate due to its challenging diagnostic approach. So far, its treatment is based on a combination of approaches (such as surgical resection with or rarely without chemotherapeutic agents), but with finite limits. Thus, looking for additional space to improve pancreatic tumorigenesis therapeutic approach, research has focused on gene therapy with unexpectedly growing horizons not only for the treatment of inoperable pancreatic disease, but also for its early stages. In vivo gene delivery viral vectors, despite few disadvantages (possible immunogenicity, toxicity, mutagenicity, or high cost), could be one of the most efficient cancer gene therapeutic strategies for clinical application due to their superiority compared with other systems (ex vivo delivery strategies). Their dominance consists of simple preparation, easy operation and a wide range of functions. Adenoviruses are one of the most common used vectors, inducing strong immune as well as inflammatory reactions. Oncolytic virotherapy, using the above mentioned in vivo viral vectors, is one of the most promising non-pathogenic, highly-selective cytotoxic anti-cancer therapy using anti-cancer agents with high anti-tumor potency and strong oncolytic effect. There have been a variety of targeted therapeutic and pre-clinical strategies tested for gene therapy in pancreatic cancer such as gene-editing systems (e.g., clustered regularly interspaced palindromic repeats-Cas9), RNA interference technology (e.g., microRNAs, short hairpin RNA or small interfering RNA), adoptive immunotherapy and vaccination (e.g., chimeric antigen receptor T-cell therapy) with encouraging results.

Laboratory manifestations and pathophysiological aspects of coronavirus disease 2019 pandemic: focusing on the digestive system.

Since December 2019, the severe acute respiratory syndrome coronavirus 2 has constituted a serious threat to global health. So far, there is little published evidence on the laboratory features of coronavirus disease 2019 (COVID-19). We have reviewed laboratory findings from multiple studies, mostly relating to the digestive system, since the virus outbreak. Laboratory data from older coronaviruses endemics, as well as other RNA viruses, were also reported. Although the main route of transmission is considered to be respiratory droplets, the distribution of ACE2 receptors in the gastrointestinal tract in combination with the detection of the virus in feces may imply a potential fecal-oral transmission route, and thus, emphasis should be given to patients with gastrointestinal symptoms. Interestingly, there is evidence that severe acute respiratory syndrome coronavirus 2 displays similar laboratory and clinical findings with older members of the coronavirus family, and so, comparable diagnostic and therapeutic approaches may be used. Regarding laboratory abnormalities, lymphopenia appears to be the most common finding, together with coagulation disorders and inflammatory markers elevation, reflecting a sustained systemic response. Abnormal liver and, occasionally, pancreatic tests are also common and even more severe in patients with gastrointestinal symptoms or diseases. Thus, the aim of this study is to focus on the laboratory and pathophysiologic side of this novel disease in order to strengthen current knowledge and urge further research. Detailed investigation of numerous studies may suggest a common laboratory pattern between COVID-19 patients. It is important for clinicians not to underestimate patients with gastrointestinal comorbidities, as they have been associated with severe COVID-19 disease.

Antiproliferative Effect of Above-Label Doses of Somatostatin Analogs for the Management of Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. OBJECTIVE: To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. METHODS: Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. RESULTS: The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9-33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, p = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. CONCLUSIONS: Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach.

Origin and genomic characteristics of SARS-CoV-2 and its interaction with angiotensin converting enzyme type 2 receptors, focusing on the gastrointestinal tract.

The emergence of coronavirus disease-2019 induced by a newly identified b-coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has constituted a public health emergency. Even though it was considered a zoonotic disease, the virus has also spread among humans via respiratory secretions. The expression and distribution of angiotensin converting enzyme type 2 (ACE2) in various human organs might also show other possible infection routes. High ACE2 ribonucleic acid expression has been identified in the gastrointestinal tract (GI) indicating its importance as a possible infection pathway of SARS-CoV-2. ACE2 induces viral entry into the host and most importantly has been found to be associated with the function of the gut. Its deficiency has been implicated in several pathologies such as colorectal inflammation. The renin-angiotensin system (RAS) is an essential regulatory cascade operating both at a local tissue level and at the systemic or circulatory level. The RAS may be important in the pathogenesis of chronic liver disease and is associated with the up-regulation of ACE2. Thus, the aim of this review is firstly, the analysis of some important general and genome characteristics of SARS-CoV-2 and secondly, and most importantly, to focus on the utility of ACE2 receptors in both SARS-CoV-2 replication and pathogenesis, especially in the GI tract.

COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract.

The pandemic of coronavirus disease 2019 (COVID-19), caused by a newly identified ß-coronavirus (SARS-CoV-2) has emerged as a dire health problem, causing a massive crisis for global health. Primary method of transmission was firstly thought to be animal to human transmission. However, it has been observed that the virus is transmitted from human to human via respiratory droplets. Interestingly, SARS-CoV-2 ribonucleic acid (RNA) has been isolated from patient stools, suggesting a possible gastrointestinal (GI) involvement. Most commonly reported clinical manifestations are fever, fatigue and dry cough. Interestingly, a small percentage of patients experience GI symptoms with the most common being anorexia, diarrhea, nausea and vomiting. The presence of viral RNA in stools is also common and fecal tests can be positive even after negative respiratory samples. The exact incidence of digestive symptoms is a matter of debate. The distribution of Angiotensin converting enzyme type 2 receptors in multiple organs in the body provides a possible explanation for the digestive symptoms' mechanism. Cases with solely GI symptoms have been reported in both adults and children. Viral RNA has also been detected in stool and blood samples, indicating the possibility of liver damage, which has been reported in COVID-19 patients. The presence of chronic liver disease appears to be a risk factor for severe complications and a poorer prognosis, however data from these cases is lacking. The aim of this review is firstly, to briefly update what is known about the origin and the transmission of SARS-CoV-2, but mainly to focus on the manifestations of the GI tract and their pathophysiological background, so that physicians on the one hand, not to underestimate or disregard digestive symptoms due to the small number of patients exhibiting exclusively this symptomatology and on the other, to have SARS-CoV-2 on their mind when the "gastroenteritis" type symptoms predominate.

Real world data regarding the management of cancer-associated thrombosis.

PURPOSE OF REVIEW: Patients with cancer are at high risk for thrombotic events, mainly deep vein thrombosis and pulmonary embolism. Low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) are among the current treatment options for cancer-associated thrombosis (CAT). We assessed real world data (RWD) regarding treatment patterns of CAT from 1 September 2018 to 31 January 2020. RECENT FINDINGS: RWD showed that LMWHs were the most common initial anticoagulation treatment for CAT. Based on these data DOACs had a lower risk of recurrent venous thromboembolism compared with LMWHs and warfarin. However, the selection bias and the small number of patients in these studies might explain this difference and these limitations should be taken into consideration. Moreover, there was no statistical difference regarding adverse events during anticoagulant treatment between LMWHs and DOACs with the limitations of RWD. As far as the duration of the treatment is concerned, the adherence ranged from 100% to 67.3% at 6 months. SUMMARY: The current review of RWD illustrates that LMWHs and DOACs are used for the treatment of CAT. LMWHs are most commonly used for the initial management of CAT. Data regarding recurrence of CAT, adverse events, compliance and duration of anticoagulant treatment should be analyzed with caution as RWD are observational studies with many limitations. Further research is needed to elucidate the best algorithm for the management of CAT.

Evaluation of the Direct Economic Cost per Eradication Treatment Regimen against Helicobacter pylori Infection in Greece: Do National Health Policy-Makers Need to Care?

Helicobacter pylori (Hp) management has undoubtedly resulted in a notable economic burden on healthcare systems globally, including Greece. Its cost has never been estimated so far, especially during the recent 10-year unprecedented financial crisis. Direct medical and procedural costs for one attempt "outpatient" Hp eradication treatment were estimated as the following: (I) first-line regimens: 10 and 14 days standard triple, 10 and 14 days sequential, 10 and 14 days concomitant non-bismuth quadruple, 14 days hybrid, (II) second-line salvage regimens: 10 and 14 days levofloxacin-containing triple regimens. Treatment costs using prototypes and/or generic drugs were calculated. Drug prices were collected and confirmed from two official online medical databases including all medicines approved by the Greek National Organization for Medicines. Regimens based on generics were more affordable than prototypes and those including pantoprazole yielded the lowest prices (mean: 27.84 €). Paradoxically, 10-day concomitant and 14-day hybrid regimens (currently providing good (90-94%) first-line eradication rates in Greece) cost the same (mean: 34.76 €). The expenditures for Hp eradication treatment regimens were estimated thoroughly for the first time in Greece. These data should be taken into account by Public Health policymakers both in Greece and the European Union, aiming for a better and less expensive therapeutic approach.

Helicobacter pylori eradication regimens in an antibiotic high-resistance European area: A cost-effectiveness analysis.

INTRODUCTION: Helicobacter pylori infection (H pylori-I) affects more than half of the global population and consists an important burden to public health and healthcare expenditures, by contributing to many diseases' pathogenesis. AIM: This study aimed to evaluate the current nonbismuth quadruple eradication regimens in a high antibiotic resistance area, such as Greece, concerning their cost-effectiveness, especially during financial crisis period. MATERIALS AND METHODS: Eight hundred and nine patients who received eradication treatment against H pylori-I were included to evaluate five different regimens, using amoxicillin, clarithromycin, and metronidazole as antibiotics and one proton-pump inhibitor, based on their current eradication rates. Regimes compared 10-day concomitant use of (a) pantoprazole or (b) esomeprazole; 10-day sequential use of (c) pantoprazole or (d) esomeprazole; and 14-day hybrid using esomeprazole. Cost-effectiveness analysis ratio (CEAR) and incremental cost-effectiveness ratios were calculated taking into account all direct costs and cases who needed second-line treatment. Additionally, sensitivity analysis was performed to predict all potential combinations. RESULTS: Ten-day concomitant regimen with esomeprazole was characterized by the lowest CEAR (179.17€) followed by the same regimen using pantoprazole (183.27€). Hybrid regimen, although equivalent in eradication rates, was found to have higher CEAR (187.42€), whereas sequential regimens were not cost-effective (CEAR: 204.12€ and 216.02€ respectively). DISCUSSION: This is the first study evaluating the cost-effectiveness of H pylori-I treatment regimens in a high clarithromycin-resistance (≈26.5%) European area, suggesting the 10-day concomitant regimen with generics using esomeprazole 40 mg as the most appropriate one. National and regional guidelines should include cost-effectiveness in their statements, and further studies are required to clarify the necessity of a wide "test and treat" policy for H pylori-I.

Challenging the Current Risk Factors of Appendiceal Neuroendocrine Neoplasms: Can They Accurately Predict Local Lymph Nodal Invasion? Results from a Large Case Series.

BACKGROUND: Appendiceal neuroendocrine neoplasms (ANEN) are uncommon entities, which run mostly an indolent course. Appendicectomy alone is usually curative, except for in a selected group of patients that are deemed to be at risk of loco-regional metastases, in whom a completion right hemicolectomy (RHC) is recommended. The current "Guidelines" criteria for the latter have been controversial, and may result in overtreatment, which is concerning for a young patient population. OBJECTIVE: The aim of this study is to evaluate the prognostic value of the current criteria in identifying more accurately those at-risk patients. METHODS: This was a retrospective study of the 263 cases of ANEN referred for advice or management to a tertiary referral unit over a 10-year period. Seventy-two patients underwent RHC, based on criteria, suggested by International Guidelines. Each one of those was assessed to identify whether it correlated with lymph node invasion (LNI) at the RHC surgical specimen. RESULTS: Tumour grade (p < 0.001), vascular (p = 0.044) and lymph vessel invasion (p < 0.001) were all found to be statistically significant independent risk factors for LNI identified following RHC, whilst tumour size (p = 0.375) and mesoappendiceal invasion (MAI) (p = 0.317) were not statistically significant. However, deep MAI and tumour size >2 cm showed a correlation with each other on LNI positive subgroup analysis. Location in appendiceal base made LNI more likely but again was not significant (p = 0.133). CONCLUSIONS: Higher tumour grade and lymphovascular invasion should be considered as the most important risk prognosticators. Surprisingly, tumour size was not found to be significant in our cohort. Further international multicentre studies with large numbers of patients are needed to fully validate those data.

Impact of occupational stress on irritable bowel syndrome pathophysiology and potential management in active duty noncombat Greek military personnel: a multicenter prospective survey.

INTRODUCTION: Irritable bowel syndrome (IBS) is one of the gut-brain axis interaction disorders. It has global distribution with varying prevalence and particular financial and psychological consequences. IBS has been associated with stress and anxiety, conditions that are usually prevalent in the army. There are scarce data investigating the impact of IBS on noncombat active duty military without reports of Greek military or stress in the occupational environment. MATERIALS AND METHODS: The main exclusion criteria in our noncombat military multicenter prospective survey were gastrointestinal pathologies, malignancies, hematochezia, recent infections and antibiotics prescription, and pregnancy. Questionnaires included a synthesis of baseline information, lifestyle, and diet, psychological and stress-investigating scales and the IBS diagnosis checklist. Hospital Anxiety and Depression Scale and Rome IV criteria were utilized. RESULTS: Among 1605 participants included finally, the prevalence of IBS was 8% and 131 cases were identified. Women were more vulnerable to IBS, although male sex was prevalent at a ratio of 3.5 : 1 (male:female) in the entire sample. The mean age of all participants was 23.85 years; most of the IBS patients were older than thirty. Abnormal anxiety scores and high levels of occupational stress were related to an IBS diagnosis. DISCUSSION: This prospective multicenter survey showed, for the first time, the potential impact of occupational stress on IBS in active duty noncombat Greek Military personnel. The diagnosis of IBS by questionnaire is a quick, affordable way that can upgrade, by its management, the quality of life and relieve from the military burden. Our results are comparable with previous studies, although large-scale epidemiological studies are required for the confirmation of a possible causative relationship.

Screening and surveillance methods for dysplasia in inflammatory bowel disease patients: Where do we stand?

Patients with long-standing ulcerative colitis (UC) and extensive Crohn's colitis (CC) are at increased risk for dysplasia and colorectal cancer (CRC). Several studies have shown that UC extending proximal to the rectum, CC involving at least 1/3 of the colon, co-existence of primary sclerosing cholangitis, undetermined or unclassified colitis, family history of CRC and young age at diagnosis appear to be independent risk factors for inflammatory bowel disease (IBD) - related CRC. Therefore, screening and surveillance for CRC in IBD patients is highly recommended by international and national guidelines, whilst colonoscopy remains the unequivocal tool in order to detect potentially resectable dysplastic lesions or CRC at an early stage. Although the importance of screening and surveillance is widely proven, there is a controversy regarding the time of the first colonoscopy and the criteria of who should undergo surveillance. In addition, there are different recommendations among scientific societies concerning which endoscopic method is more efficient to detect dysplasia early, as well as the terminology for reporting visible lesions and the management of those lesions. This article concisely presents the main endoscopic methods and techniques performed for detecting dysplasia and CRC surveillance in patients with IBD focusing on their evidence-based accuracy and efficiency, as well as their cost-effectiveness. Finally, newer methods are mentioned, highlighting their applicability in daily endoscopic practice.

The Problem of Appendiceal Carcinoids.

Appendiceal neuroendocrine neoplasms are uncommon, mostly discovered coincidentally during appendectomy. They usually show a benign clinical course and appendectomy alone is curative. However, some cases may harbor malignant potential; therefore, additional/prophylactic operations, such as right hemicolectomy, are offered. Current international guidelines are based on heterogeneous and retrospective series. Thus, there is lack of robust evidence, mainly in terms of accurate factors, that could identify patients at risk, requiring more extensive surgical treatment. In this article, we highlight controversies in the epidemiology, workup assessment, and management algorithms of appendiceal neuroendocrine neoplasms, but also to explore future developments and advances.

Advanced small cell lung cancer (SCLC): new challenges and new expectations.

Small cell lung cancer (SCLC) remains one of the most lethal malignancies and a major health riddle. The therapeutic options are limited. The combination of etoposide or irinotecan with platinum chemotherapy is the standard of care at any stage. The last decade systemic efforts have been done to reveal specific therapeutic targets for small cell lung carcinomas. In this review, we focus on the new therapeutic strategies of SCLC, including immune-related treatment that may change the prognosis of the disease. The main genetic mutations observed in SCLC are TP53 and RB1 mutations; however, it is well known that these molecules are not yet targetable. In recent years, research has revealed other frequent genetic alterations and activated signaling pathways that might be an effective treatment target. Loss of PTEN, activating PI3K mutations, inhibition of NOTCH pathway and aurora kinase activation are among them. Moreover, FDGFR1 amplification, activation of the Hedgehog pathway and repair-protein PARP1 seem to participate in SCLC tumorigenesis. These new findings have identified some interesting targets. Moreover, immunotherapy tries to find its place in the treatment of SCLC. Immune checkpoint inhibitors are under investigation in phase I to III clinical trials. We hope that in next years the treatment of SCLC patients will be improved with the administration of targeting therapy and the introduction of immunotherapy.

Advances on systemic treatment for lung neuroendocrine neoplasms.

Lung well-to-moderately differentiated neuroendocrine tumors (also known as carcinoids) and large cell neuroendocrine lung carcinoma (poorly differentiated neuroendocrine tumor) are rare neuroendocrine neoplasms, which account for less than 4% of all lung neoplasms. Due to their low incidence, their systemic treatment is greatly influenced by therapeutic evidence derived from the more frequent gastroenteropancreatic neuroendocrine neoplasms and/or small cell lung carcinoma leading to significant bias. Currently, employed systemic therapies for lung carcinoids, aiming at controlling tumor growth include long acting somatostatin analogues (SSAs), peptide receptor radionuclide therapy, chemotherapy and molecular-targeted therapy. In this review, each of those treatments is presented based upon available clinical evidence from retrospective and prospective studies particularly focused on the role of everolimus in the advanced setting and on ongoing clinical trials reflecting our expectations in the near future. In addition, we critically analyse currently employed treatment of large cell neuroendocrine carcinoma where the appropriate chemotherapeutic regimen is still a matter of debate.

Secondary metastatic lesions to colon and rectum.

Metastatic lesions of the colon are a rare clinical entity that may present difficulties in management. The incidence of these metastases appears to be increasing, as a result of physicians' greater awareness during follow-up investigations of a primary neoplasm. Furthermore, the presence of a greater proportion of these abnormalities at autopsy should be a triggering factor for further investigation for doctors dealing with colorectal oncology. Their clinical presentation may vary from asymptomatic to signs similar to those of colorectal cancer. However, immunohistological analysis is considered the cornerstone for differentiating metastases to the colon, originating from other primaries, from primary colorectal neoplasms. Survival reports and treatment options vary. This article concisely presents the main characteristics of the secondary lesions to the colon from neoplasms that metastasize to the large intestine (namely, lung, ovary, breast, prostate, kidney, and melanoma) focusing on their incidence, their clinical presentation and the workup investigation. Physicians aware of this uncommon entity are much better prepared to apply an efficient diagnosis and workup, as well as an appropriate treatment strategy.