Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials

Sarcopenia Is a Negative Prognostic Factor in Patients Undergoing Transarterial Chemoembolization (TACE) for Hepatic Malignancies

Background and Aims: While transarterial chemoembolization (TACE) represents a standard of therapy for intermediate-stage hepatocellular carcinoma (HCC) and is also routinely performed in patients with liver metastases, it is still debated which patients represent the ideal candidates for TACE therapy in terms of overall survival. Sarcopenia, the degenerative loss of skeletal muscle mass and strength, has been associated with an adverse outcome for various malignancies, but its role in the context of TACE has largely remained unknown. Here, we evaluated the role of sarcopenia on the outcome of patients undergoing TACE for primary and secondary liver cancer. Methods: The patients’ psoas muscle size was measured on axial computed tomography (CT) scans and normalized for the patients’ height squared. This value was referred to as the psoas muscle index (PMI). The PMI was correlated with clinical and laboratory markers. Results: While pre-interventional sarcopenia had no impact on the direct tumor response to TACE, sarcopenic patients with a pre-interventional PMI below our ideal cut-o value of 13.39 mm/m2 had a significantly impaired long-term outcome with a median overall survival of 491 days compared to 1291 days for patients with a high PMI. This finding was confirmed by uni- and multivariate Cox-regression analyses. Moreover, a progressive rapid decline in muscle mass after TACE was a predictor for an unfavorable prognosis. Conclusion: Our data suggest that sarcopenia represents a previously unrecognized prognostic factor for patients undergoing TACE therapy which might yield important information on the patients’ post-interventional outcome and should therefore be implemented into clinical stratification algorithms

A case report of an excellent response to interferon- α in a patient with functional metastasized neuroendocrine tumor refractory to other treatments

Introduction: Interferon alpha (IFNα) has been used for a long time in patients with functionally active neuroendocrine tumors (NET). However, due to the unfavorable toxicity profile of interferon, the perceived limited efficacy as well as the development of novel substances, IFNα is only used sparingly in the treatment of NET to date. Patients concerns and diagnosis: We describe the case of a 63-year-old male patient with highly differentiated, functional NET of the ileum and synchronous liver metastasis. Interventions: After failure of classical therapies including dose-intensified somatostatin analog treatment and palliative primary tumor resection, a therapy with pegylated IFNα2a (135 μg/wk) was initiated. Following this treatment, the patient fully recovered from signs of hypersecretion and demonstrated an impressive tumor response. Outcomes: Thirty months after initiating IFNα, the patient is still free of clinical symptoms and shows a sustained tumor response. Notably, no relevant side effects were observed. Conclusion: Our case report supports the use of IFNα in patients with functional NET refractory to classical treatments

Mouse models of hepatocarcinogenesis: What can we learn for the prevention of human hepatocellular carcinoma?

There is growing evidence that chronic inflammatory processes are involved in triggering the sequence from chronic liver injury to liver fibrosis, ultimately leading to liver cancer. In the last years this process has been recapitulated in a growing number of different mouse models. However, it has remained unclear whether and how these mouse models reflect the clinical reality of human hepatocellular carcinoma (HCC)

A Combined Score of Circulating miRNAs Allows Outcome Prediction in Critically Ill Patients

Background and aims: Identification of patients with increased risk of mortality represents an important prerequisite for an adapted adequate and individualized treatment of critically ill patients. Circulating micro-RNA (miRNA) levels have been suggested as potential biomarkers at the intensive care unit (ICU), but none of the investigated miRNAs displayed a sufficient sensitivity or specificity to be routinely employed as a single marker in clinical practice. Methods and results: We recently described alterations in serum levels of 7 miRNAs (miR-122, miR-133a, miR-143, miR-150, miR-155, miR-192, and miR-223) in critically ill patients at a medical ICU. In this study, we re-analyzed these previously published data and performed a combined analysis of these markers to unravel their potential as a prognostic scoring system in the context of critical illness. Based on the Youden’s index method, cut-off values were systematically defined for dysregulated miRNAs, and a “miRNA survival score” was calculated. Patients with high scores displayed a dramatically impaired prognosis compared to patients with low values. Additionally, the predictive power of our score could be further increased when the patient’s age was additionally incorporated into this score. Conclusions: We describe the first miRNA-based biomarker score for prediction of medical patients’ outcome during and after ICU treatment. Adding the patients’ age into this score was associated with a further increase in its predictive power. Further studies are needed to validate the clinical utility of this score in risk-stratifying critically ill patients

Results from a real-life study

Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN

In Vivo Models for Cholangiocarcinoma—What Can We Learn for Human Disease?

Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the last decade to better understand the complex processes of biliary carcinogenesis, it was only recently that new therapeutic advances have been achieved. Animal models are a crucial bridge between in vitro findings on molecular or genetic alterations, pathophysiological understanding, and new therapeutic strategies for the clinic. Nevertheless, it is inherently difficult to recapitulate simultaneously the stromal microenvironment (e.g., immune-competent cells, cholestasis, inflammation, PSC-like changes, fibrosis) and the tumor biology (e.g., mutational burden, local growth, and metastatic spread) in an animal model, so that it would reflect the full clinical reality of CCA. In this review, we highlight available data on animal models for CCA. We discuss if and how these models reflect human disease and whether they can serve as a tool for understanding the pathogenesis, or for predicting a treatment response in patients. In addition, open issues for future developments will be discussed

The spectrum of comorbidities at the initial diagnosis of heart failure a case control study

The prognosis of heart failure (HF) patients is determined to a decisive extent by comorbidities. The present study investigates the association between a broad spectrum of diseases and the occurrence of HF in a large collective of outpatients. This retrospective case control study assessed the prevalence of 37 cardiac and extracardiac diseases in patients with an initial diagnosis of heart failure (ICD-10: I50) in 1,274 general practices in Germany between January 2005 and December 2019. The study is based on the Disease Analyzer database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data. Patients with and without heart failure were matched by sex, age, and index year. Hazard regression models were conducted to evaluate the association between different disease entities and heart failure. The present study included 162,246 patients with heart failure and 162,246 patients without heart failure. Mean age [SD] was 73.7 [12.1] years; 52.6% were women. Out of 37 predefined diagnoses, 36 were more prevalent in HF patients. The highest prevalence was primary hypertension (63.4% in HF patients vs. 53.3% in controls, p < 0.001) followed by lipid metabolism disorders (34.6% in HF patients vs. 29.1% in HF patients p < 0.001) and diabetes mellitus type II (32.2% in HF patients vs. 25.2% in controls, p < 0.001). In the regression analysis, 19 diseases were significantly associated with heart failure. Non-cardiovascular diagnoses strongly associated with HF were obesity (HR = 1.46), chronic bronchitis and COPD (HR = 1.41), gout (HR: 1.41), and chronic kidney disease (HR = 1.27). In the present study, we identified a variety of cardiac and extracardiac diseases associated with heart failure. Our data underscore the immense importance of comorbidities, even as early as at the stage of initial diagnosis of heart failure

Circulating MicroRNA-223 Serum Levels Do Not Predict Sepsis or Survival in Patients with Critical Illness

Background and Aims. Dysregulation of miR-223 was recently linked to various diseases associated with systemic inflammatory responses such as type 2 diabetes, cancer, and bacterial infections. However, contradictory results are available on potential alterations of miR-223 serum levels during sepsis. We thus aimed to evaluate the diagnostic and prognostic value of miR-223 serum concentrations in patients with critical illness and sepsis. Methods. We used i.v. injection of lipopolysaccharide (LPS) as well as cecal pole ligation and puncture (CLP) for induction of polymicrobial sepsis in mice and measured alterations in serum levels of miR-223. These results from mice were translated into a large and well-characterized cohort of critically ill patients admitted to the medical intensive care unit (ICU). Finally, results from analysis in patients were correlated with clinical data and extensive sets of routine and experimental biomarkers. Results. Although LPS injection induced moderately elevated serum miR-223 levels in mice, no significant alterations in miR-223 serum levels were found in mice after CLP-induced sepsis. In accordance with these results from animal models, serum miR-223 levels did not differ between critically ill patients and healthy controls. However, ICU patients with more severe disease (APACHE-II score) showed moderately reduced circulating miR-223. Strikingly, no differences in miR-223 levels were found in critically ill patients with or without sepsis, and serum levels of miR-223 did not correlate with classical markers of inflammation or bacterial infection. Finally, low miR-223 serum levels were moderately associated with an unfavorable prognosis of patients during the ICU treatment but did not predict long-term mortality. Conclusion. Recent reports on alterations in miR-223 serum levels during sepsis revealed contradictory results, preventing a potential use of this miRNA in clinical routine. We clearly show that miR-223 serum levels do not reflect the presence of sepsis neither in mouse models nor in a large cohort of ICU patients and do not indicate clinical outcome of critically ill patients. Thus miR-223 serum levels should not be used as a biomarker in this setting