Platelet-derived peripheral serotonin has pleiotropic effects on coagulation, metabolism, tissue regeneration, and cancer growth; however, the effect of serotonin on the tumor microenvironment ...remains understudied. Peripheral serotonin–deficient (
) mice displayed reduced growth of subcutaneous and orthotopically injected syngeneic murine pancreatic and colorectal cancers with enhanced accumulation of functional CD8
T cells compared to control C57BL/6 mice, resulting in extended overall survival. Subcutaneous and orthotopic syngeneic tumors from
mice expressed less programmed cell death 1 ligand 1 (PD-L1), suggesting serotonin-mediated regulation. Serotonin enhanced expression of PD-L1 on mouse and human cancer cells in vitro via serotonylation, which is the formation of covalent bonds between glutamine residues and serotonin, resulting in activation of small G proteins. Serotonin concentrations in metastases of patients with abdominal tumors negatively correlated to the number of CD8
tumor-infiltrating T cells. Depletion of serotonin cargo or inhibition of serotonin release from thrombocytes decreased growth of syngeneic pancreatic and colorectal tumors in wild-type mice, increased CD8
T cell influx, and decreased PD-L1 expression. Pharmacological serotonin depletion with oral fluoxetine or intraperitoneal injection of the TPH1 inhibitor telotristat augmented the effects of programmed cell death protein 1 (PD-1) checkpoint blockade and triggered long-term tumor control in mice subcutaneously inoculated with syngeneic colorectal and pancreatic tumors. Overall, peripheral serotonin weakens effector functions of CD8
T cells within tumors. Clinically approved serotonin targeting agents alone or in combination with PD-1 blockade provided long-term control of established tumors in murine models, warranting further investigation of the clinical translatability of these findings.
BACKGROUND:Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful ...long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear.
METHODS:Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction.
RESULTS:Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range3–12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI hazard ratio (HR)1.08, N1 stage (HR2.15), N2 stage (HR2.57), G3 stage (HR1.80) as well as KRAS (HR1.46) and BRAF (HR3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination development area under the curve (AUC) = 0.72, validation AUC = 0.70, calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes.
CONCLUSION:RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors with a broad range of local and systemic treatment options. Still a lack of data regarding treatment ...sequences exists. The aim of this study was to analyse outcomes in GEP-NETs depending on stage and treatment steps and compare our treatment decisions to the latest treatment recommendations of European Society of Medical Oncology (ESMO) 2020 for GEP-NETs.
Patients were included in this retrospective single-center analysis from 2012-2016. All patients suffering from a GEP-NET, who were screened, treated or evaluated at ENETS Center in Zurich, Switzerland were included in analysis. Patients with any other diagnosis of NET were not included. We used Kaplan Meier estimator as well as Cox regression to compare survival rates between different sites of localization, grades or stages and treatment sequences.
Overall, we identified 256 GEP-NETs, most in advanced stage (62%) and located in small intestine tract or pancreatic gland. Survival depended on stage, grade, primary site and duration of response for the early systemic treatment. On average patients underwent 2.6 different treatment modalities, mostly depending on stage and higher tumor grade. Surgery was performed early but also in advanced stages, usually followed by Somatostatine-Agonist modalities. In distant disease (Stage IV), we investigated a positive effect of PFS after treatment with Somatostatine Analogues (SSA) (hazard ratio HR, 0.45; 95% confidence interval CI, 0.21 - 0.97; p = 0.04) and systemic treatment (HR, 0.51; 95% CI, 0.26 - 0.99; p = 0.047) if patients underwent prior surgery or endoscopic resection. Kaplan Meier distributions predict shorter OS in distant disease (Stage IV), (Figure. 1; HR, 2.06; 95% CI, 1.46 - 2.89; log-rank test, p < 0.001).
This retrospective analysis presents a great overview of all patients', disease and treatment characteristics of GEP-NETs at ENETS Center in Zurich, Switzerland. We illustrated survival (PFS) depending on implemented therapies. According to these findings, we formed a suggested treatment algorithm for advanced GEP-NETs, which does not differ from the latest treatment recommendation by ESMO guidelines for GEP-NETs. The results of this project may define GEP-NET patients' selection for upcoming clinical prospective studies.
Background The optimal treatment in patients with gastric cancer and peritoneal disease remains controversial. Some guidelines indicate palliative treatment only, while others consider surgical ...treatment in case of positive lavage cytology (CY+) or limited peritoneal disease. Here, we analyzed the role of peritoneal disease in patients with gastric cancer, and the prognostic relevance of response to neoadjuvant therapy. Methods In this retrospective cohort analysis, we analyzed patients with adenocarcinoma of the stomach or esophago-gastric junction from a single center operated between 2011 and 2019. According to histology and lavage cytology, patients were classified into four risk groups: (A) no peritoneal disease, (B) CY+ who converted to negative lavage cytology (CY-) after neoadjuvant chemotherapy, (C) CY+ without conversion after chemotherapy, and (D) patients with visible peritoneal metastasis. Results Overall, n = 172 patients were included. At initial presentation, n = 125 (73%) had no peritoneal disease, and about a third of patients (n = 47, 27%) had microscopic or macroscopic peritoneal disease. Among them, n = 14 (8%) were CY+ without visible peritoneal metastasis, n = 9 converted to CY- after chemotherapy, and in n = 5 no conversion was observed. Median overall survival was not reached in patients who had initially no peritoneal disease and in patients who converted after chemotherapy, resulting in 3-year survival rates of 65% and 53%. In contrast, median overall survival was reduced to 13 months (95% CI 8.7-16.7) in patients without conversion and was 16 months (95% CI 12-20.5) in patients with peritoneal metastasis without difference between the two groups (p = .364). The conversion rate from CY+ to CY- was significantly higher after neoadjuvant treatment with FLOT (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel) compared to ECF (epirubicin, cisplatin, and 5-fluorouracil) (p = 0.027). Conclusion Conversion of CY+ to CY- after neoadjuvant chemotherapy with FLOT is a significant prognostic factor for a better overall survival. Surgical treatment in well-selected patients should therefore be considered. However, peritoneal recurrence remains frequent despite conversion, urging for a better local control. Keywords: Gastric cancer, Peritoneal lavage cytology, Peritoneal metastasis, Neoadjuvant chemotherapy
AIM: Haemophilic pseudotumours are complications in patients with haemophilia A or B and result from locally repetitive bleeding, mainly in the musculoskeletal system. Abdominal haemophilic ...pseudotumours are exceptionally rare but may cause severe complications. This systematic review aimed to evaluate therapy strategies for symptomatic abdominal haemophilic pseudotumours.
METHODS: We systematically searched three databases (Medline PubMed, Web of Science and EMBASE) for publications published between 1995 and 2023. Two reviewers independently selected the studies, extracted data and performed a quality assessment using the JBI critical appraisal checklist.
RESULTS: From a total of 1199 articles, 39 articles describing 41 cases were included for final analysis. Conservative or interventional treatment was performed in 12 cases. In eight cases, a step-up to surgical therapy after interventional treatment was indicated. Primary surgical therapy was performed in 21 cases. Failure to cure was documented in 50% (n = 6) of patients treated in the first group, with a mortality rate of 16.6% (n = 2). Interventional therapy with a step-up to surgery showed no morbidity or mortality. Primary surgical resection documented favourable results in 66.6% (n = 14), with failure to cure in 9.5% (n = 2) and a mortality rate of 14.3% (n = 3).
CONCLUSION: Primary surgical resection can be a first-line therapy for symptomatic, abdominal haemophilic pseudotumours, whereas preoperative embolisation could be used as a bridging therapy before surgery, especially in emergency settings. Diagnostic biopsy and percutaneous drainage should be avoided to prevent complications.
Background & Aims Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the ...mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms. Methods Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw264-7 macrophage-like cells were investigated in vitro . Sirt1 and HMGB1 were inhibited using Ex527 and neutralizing antibodies, respectively. Results Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating HMGB1 associated with cytoplasmic HMGB1 translocation, aggregate formation, and autophagy. Inhibition of autophagy re-elevated circulating HMGB1 and abolished protection in fasted mice, as did supplementation with HMGB1. In vitro , Sirt1 inhibition prevented HMGB1 translocation, leading to elevated HMGB1 in the supernatant. In vivo , Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing HMGB1 antibody. Conclusions Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating HMGB1. The reduction in serum HMGB1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, HMGB1, and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.
Peritoneal metastasis (PM) originating from gastrointestinal cancer was considered a terminal disease until recently. The advent of better systemic treatment, a better understanding of prognostic ...factors, and finally, the advent of novel loco-regional therapies, has opened the door for the multimodal treatment of PM. These strategies, including radical surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) showed surprisingly good results, leading to the prolonged survival of patients with peritoneal metastasis. This has triggered a significant body of research, leading to the molecular characterization of PM, which may further help in the development of novel treatments. This review summarizes current evidence on peritoneal metastasis and explores potential novel mechanisms and therapeutic approaches to treat patients with peritoneal metastasis.
γ-radiation is an effective treatment for cancer. There is evidence that radiotherapy supports tumor-specific immunity. It was described that irradiation induces de novo protein synthesis and ...enhances antigen presentation, we therefore investigated whether γ-radiation results in increased expression of cancer-testis (CT) antigens and MHC-I, thus allowing efficient immunological control. This is relevant because the expression of CT-antigens and MHC-I on tumor cells is often heterogeneous. We found that the changes induced by γ-radiation promote the immunological recognition of the tumor, which is illustrated by the increased infiltration by lymphocytes after radiotherapy.
We compared the expression of CT-antigens and MHC-I in various cancer cell lines and fresh biopsies before and after in vitro irradiation (20 Gy). Furthermore, we compared paired biopsies that were taken before and after radiotherapy from sarcoma patients. To investigate whether the changed expression of CT-antigens and MHC-I is specific for γ-radiation or is part of a generalized stress response, we analyzed the effect of hypoxia, hyperthermia and genotoxic stress on the expression of CT-antigens and MHC-I. In vitro irradiation of cancer cell lines and of fresh tumor biopsies induced a higher or de novo expression of different CT-antigens and a higher expression of MHC-I in a time- and dose-dependent fashion. Importantly, we show that irradiation of cancer cells enhances their recognition by tumor-specific CD8+ T cells. The analysis of paired biopsies taken from a cohort of sarcoma patients before and after radiotherapy confirmed our findings and, in addition showed that irradiation resulted in higher infiltration by lymphocytes. Other forms of stress did not have an impact on the expression of CT-antigens or MHC-I.
Our findings suggest that γ-radiation promotes the immunological recognition of the tumor. We therefore propose that combining radiotherapy with treatments that support tumor specific immunity may result in increased therapeutic efficacy.
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improve the survival of selected patients with peritoneal metastasis. A major cause of treatment-related morbidity ...after CRS/HIPEC is infection and sepsis. HIPEC alters the diagnostic sensitivity and specificity of blood and serum markers and therefore has an impact on early diagnosis of postoperative complications. This study aimed to assess the sensitivity and specificity of blood and serum markers after CRS/HIPEC.
Patients from two centers, operated between 2009 and 2017, were enrolled in this study. Perioperative blood samples were analyzed for white blood cells (WBC), C-reactive protein (CRP), and procalcitonin (PCT); postoperative complications were graded according to Clavien-Dindo and infectious complications according to CDC criteria.
Overall, n=248 patients were included with peritoneal metastasis from different primary tumors treated by CRS/HIPEC. Depending on the applied HIPEC protocol, patients presented a suppressed WBC response to infection. In addition, a secondary and unspecific CRP elevation in absence of an underlining infection, and pronounced after prolonged perfusion for more than 60 min. PCT was identified as a highly specific - although less sensitive - marker to diagnose infectious complications after CRS/HIPEC.
Sensitivity and specificity of WBC counts and CRP values to diagnose postoperative infection are limited in the context of HIPEC. PCT is helpful to specify suspected infection. Overall, diagnosis of postoperative complications remains a clinical diagnosis, requiring surgical expertise and experience.
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