Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behaviour and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage and grading. The effect of liposomal clodronate on TAM cell viability was analysed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human insulinomas TAM density was correlated with invasiveness and malignant behaviour. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80 positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET in particular in insulinomas and correlate with metastatic behaviour. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET. This article is protected by copyright. All rights reserved.
First line options for palliative chemotherapy in pancreatic cancer For years, gemcitabine has been the standard of care and the only therapeutic option in patients with metastatic pancreatic cancer (mPC). The benefit of gemcitabine treated patients in stage IV pancreatic cancer was very limited with 5.65 months (1). Subsequent phase II and phase III studies that aimed to improve the outcome of gemcitabine in combination with different compounds over gemcitabine monotherapy failed. The first positive trial was published in 2007. In this study gemcitabine with erlotinib, a potent and selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, revealed a statistically, albeit clinically not really meaningful benefit of 0.33 months (2). However, patients that developed a skin rash showed a hitherto unknown extension of overall survival with up to 11 months (3). This association has been confirmed in subsequent studies. In 2011 and 2013 data of two phase III studies were released showing a statistically relevant and clinically meaningful improvement in the overall survival of mPC patients thus providing two first line chemotherapeutic options. The PRODIGE-4/ACCORD-11 trial investigated the benefits of therapy with FOLFIRINOX compared with gemcitabine. In this study the treatment with FOLFIRINOX showed an objective response rate of approximately 31.6% and a median overall survival of 11.1 versus 6.8 months in the gemcitabine mono cohort (4) (Table 1). These data were very encouraging demonstrating for the first time not only a nearly doubling of the overall survival, but also high objective response rates. And yet, it has to be noted that in this PRODIGE trial a highly selective patient cohort was chosen with patients included who were under an age of 76 years with an ECOG of 0 or
<b><i>Background:</i></b> Pancreatic adenocarcinoma is an extremely aggressive tumor which is supposed to become the second deadliest malignancy in 2030. For a long time the possibilities to treat this complex disease were very limited. <b><i>Summary:</i></b> In the last years the development of new chemotherapeutic regimens has led to a better outcome in the adjuvant, neoadjuvant, and palliative setting. Furthermore, progress in sequencing technologies has enabled a detailed investigation of the genetic alterations, mutational burden, expression pattern, and stroma composition in pancreatic cancer and led to the identification of subtypes of this disease. <b><i>Messages:</i></b> This analysis will increase our understanding of tumor heterogeneity and hopefully translate into new potential targets, biomarkers, and the development of individual therapeutic approaches in the future.
Secondary sclerosing cholangitis in critically ill patients (SC-CIP) is a rare disease characterized by chronic cholestasis. The underlying pathophysiology of SC-CIP is not fully understood, and prognosis in severe cases remains poor with liver transplantation remaining the only curative treatment option. There is a growing amount of literature describing patients with chronic cholangiopathy after COVID-19 infection. The vast majority of the patients described in these reports were male and had a poor outcome. While the exact percentage of patients with COVID-19-related SC-CIP cannot be estimated accurately due to a lack of larger studies, an increase in patients with long-term complications of chronic cholestatic liver disease after severe COVID19-pneumonia can be expected in the upcoming years. Treatment options remain limited and further research is needed to improve the dismal prognosis of SC-CIP. Here, we present the cases of two patients who developed SC-CIP after prolonged intensive care unit stay due to severe COVID-19 pneumonia. Both patients required invasive ventilation for 31 and 141 days, respectively, as well as extra-corporal membrane oxygenation for 23 and 87 days. The patients suffered from jaundice and severe pruritus, and typical features of SC-CIP were present by MRCP and ERC. Repeated removal of biliary casts resulted in some alleviation of their clinical symptoms, but cholestasis parameters remain elevated. Furthermore, an increased liver stiffness was indicative of advanced fibrosis in both patients. In addition to these two case reports, we provide a concise review of the literature of SC-CIP after COVID-19 infection and discuss risk factors, treatment options and prognosis.
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