Quality of Life and Independent Factors Associated with Poor Digestive Function after Ivor Lewis Esophagectomy.

Transthoracic esophagectomy results in a radical change in foregut anatomy with multiple consequences for digestive physiology. The aim of this study was to identify factors associated with poor functional outcomes by assessing multiple dimensions of digestive performance and health-related quality of life (HRQL). Patients with cancer-free survival after Ivor Lewis esophagectomy were included. Four functional syndromes (dysphagia, gastroesophageal reflux disease (GERD), delayed gastric conduit emptying (DGCE), and dumping syndrome (DS)) and HRQL were assessed using specifically designed questionnaires. Patient outcomes were compared with healthy controls. Independent factors associated with poor digestive performance were identified through multivariable analysis. Sixty-five postoperative patients and 50 healthy volunteers participated in this study. Compared with controls, patients had worse outcomes for dysphagia, GERD, DS, and HRQL, but not for DGCE. A multivariate analysis showed a significant correlation of reduced digestive performance with ASA score, squamous cell carcinoma, open or hybrid surgical approach, and (neo)adjuvant therapy. In contrast, no individual patient factor was found to be associated with dumping syndrome. Digestive function and HRQL are substantially impaired after Ivor Lewis esophagectomy for cancer. Comorbid patients undergoing multimodal treatment and open access surgery for squamous cell carcinoma have the highest risk of poor functional outcome.

First-in-human Use of a Microsurgical Robotic System for Central Lymphatic Reconstruction.

Advances in the development of robotic systems have recently enabled the use of robotic technology in reconstructive lymphatic surgery. Although the advantages of microsurgical robots must be weighed carefully against the costs, their use may allow for smaller surgical approaches and easier access to anatomically deeper structures or even smaller vessels. We report on a case of a patient with central lymphatic dilation causing abdominal pain and severely reduced physical capacity. Sonography-assisted intranodal injection of indocyanine green allowed for localization of the lymphatic cyst and anastomosis with the left ovarian vein, applying robotic-assisted microsurgery for the first time on the central lymphatic system. Following the successful reconstruction of lymphatic drainage and decompression of the cyst, the patient reported a complete regression of her preoperative symptoms. From a surgical point of view, the Symani Surgical System improved precision and allowed significantly smaller surgical access. Considering the high morbidity and rarity of pathologies of the central lymphatic system, central lymphatic surgery is to date rarely performed. With improved precision and significantly smaller surgical access, robotic-assisted microsurgery has great potential to expand the treatment options for central lymphatic lesions.

Routine Endoscopy Prior to Surgical Ostomy Closure: An Obsolete Concept.

BACKGROUND: Closure of temporary diverting ostomies is commonly preceded by an endoscopic study of the colonic mucosa and anastomosis, despite lacking evidence of its relevance and impact on subsequent operative management. AIM: We sought to determine the incidence of pathological findings and therefore evaluate the clinical benefit of routine pre-operative endoscopy in asymptomatic patients, hypothesizing sole evaluation of the anastomotic integrity to be sufficient in these cases. METHODS: We retrospectively identified all adult patients with ostomy installations who were followed up for potential reversal surgery between 2002 and 2020 at the University Hospital of Zurich, Switzerland. Main outcome measures were the incidence of endoscopically identified pathological findings in the asymptomatic case cohort and their impact on the subsequent course of treatment. RESULTS: Pre-procedural endoscopic data of 187 cases evaluated for ostomy closure were evaluated. Relevant mucosal findings in the asymptomatic cohort were documented in 26.3% and findings at the anastomotic site detected in 8.7%. A change in subsequent surgical management was noted in 10 patients of the entire cohort (5.3%) and in 9 (5.1%) of all asymptomatic cases. Upon multivariate analyses, the age range of 51 to 60 years old was found to be significantly linked to the presence of endoscopic findings entailing a change in patient management. CONCLUSION: Our findings strongly suggest ostomy closure surgery without previous assessment of the bowel mucosa by means of endoscopy to be acceptable in asymptomatic patients. However, we found it to be indicated in all patients meeting the screening criteria for colorectal carcinoma.

Early Postoperative Serum Phosphate Drop Predicts Sufficient Hypertrophy After Liver Surgery.

OBJECTIVE: The aim of this study was to assess the impact of postoperative hypophosphatemia on liver regeneration after major liver surgery in the scenario of Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) and living liver donation (LLD). BACKGROUND: Hypophosphatemia has been described to reflect the metabolic demands of regenerating hepatocytes. Both ALPPS and LLD are characterized by an exceptionally strong liver regeneration and may be of particular interest in the context of posthepatectomy hypophosphatemia. METHODS: Serum phosphate changes within the first 7 postoperative days after ALPPS (n=61) and LLD (n=54) were prospectively assessed and correlated with standardized volumetry after 1 week. In a translational approach, postoperative phosphate changes were investigated in mice and in vitro . RESULTS: After ALPPS stage 1 and LLD, serum phosphate levels significantly dropped from a preoperative median of 1.08 mmol/L [interquartile range (IQR) 0.92-1.23] and 1.07 mmol/L (IQR 0.91-1.21) to a postoperative median nadir of 0.68 and 0.52 mmol/L, respectively. A pronounced phosphate drop correlated well with increased liver hypertrophy ( P <0.001). Patients with a low drop of phosphate showed a higher incidence of posthepatectomy liver failure after ALPPS (7% vs 31%, P =0.041). Like in humans, phosphate drop correlated significantly with degree of hypertrophy in murine ALPPS and hepatectomy models ( P <0.001). Blocking phosphate transporter (Slc20a1) inhibited cellular phosphate uptake and hepatocyte proliferation in vitro. CONCLUSION: Phosphate drop after hepatectomy is a direct surrogate marker for liver hypertrophy. Perioperative implementation of serum phosphate analysis has the potential to detect patients with insufficient regenerative capacity at an early stage.

The Role of Pancreatic Stone Protein (PSP) as a Biomarker of Pregnancy-Related Diseases.

Background: Pancreatic stone protein (PSP) is a biochemical serum marker that contains levels that are elevated in various inflammatory and infectious diseases. The role of PSP in the diagnosis of these diseases seems to be more important compared to clinically established biochemical serum markers in discriminating the severity of the same diseases. Standard values for PSP in pregnant women in relation to gestational age have been reported recently. Additionally, increased PSP levels have been observed to be associated with renal dysfunction in pregnant women. The aim of this study is to evaluate the diagnostic role of PSP in pregnancy-related diseases, such as pre-eclampsia (PE), hemolysis-elevated liver enzymes, and low platelet (HELLP) syndrome. In addition, the study aims to assess its diagnostic role in inflammation-triggered diseases as preterm premature rupture of membranes (PPROM) or COVID-19-positive pregnant women. Materials and Methods: In this single-centred prospective study performed at a tertiary university hospital between 2013 and 2021, we included 152 pregnant women who were diagnosed with either PE, HELLP syndrome, or PPROM. In December 2020, in the context of the COVID-19 pandemic, the Independent Ethics Committee (IEC) approved an amendment to the study protocol. Depending on the underlying disease, single or serial-serum PSP measurements were assessed. These PSP values were compared to PSP levels of women with normal pregnancies. Results: Pregnant women diagnosed with pre-eclampsia or HELLP syndrome had significantly increased PSP values (mean 9.8 ng/mL, SD 2.6) compared to healthy singleton pregnant women (mean 7.9 ng/mL, SD 2.6, p ≤ 0.001). There was no difference in serum PSP in pregnant women with PPROM compared to women with uncomplicated singleton pregnancies (mean in PPROM: 7.9 ng/mL; SD 2.9 versus mean in healthy pregnancies: 7.9 ng/mL; SD 2.6, p = 0.98). Furthermore, no difference in the PSP values in women with or without intra-amniotic infection was observed (infection: mean 7.9 ng/mL; SD 2.8 versus no infection: mean 7.8 ng/mL; SD 3, p = 0.85). The mean value of PSP in COVID-19-infected women during pregnancy (8.5 ng/mL, SD 2.3) was comparable to healthy singleton pregnancies (mean 7.9 ng/mL, SD 2.6), p = 0.24. Conclusions: The novel serum biomarker PSP is significantly upregulated in pregnant women with pre-eclampsia and HELLP syndrome. Our observations call for the further evaluation of PSP in randomized controlled clinical trials to demonstrate the actual role of PSP in pregnancy-related diseases and whether it may provide new approaches for the management and discrimination of the severity of these gestational conditions.

Self-expandable metallic stent as bridge to surgery vs. emergency resection in obstructive right-sided colon cancer: a systematic review and meta-analysis.

BACKGROUND: Emergency resection is common for malignant right-sided obstructive colon cancer. As there is evidence showing a potential benefit of self-expandable metal stents as a bridge to surgery, a new debate has been initiated. OBJECTIVE: The aim of this study was to compare self-expandable metal stents with emergency resection in right-sided obstructive colon cancer. DATA SOURCE: A systematic search was conducted accessing Medline/PubMed, Scopus, Embase, and the Cochrane Database of Systematic Reviews. STUDY SELECTION: Studies reporting either emergency surgery or stent placement in right-sided obstructive colon cancer were included. INTERVENTION: Stent or emergency resection in right-sided obstructive colon cancer. MAIN OUTCOME MEASURES: Morbidity rate, mortality rate, stoma rate, laparoscopic resection rate, anastomotic insufficiency rate, success rate of stent. RESULTS: A total of 6343 patients from 16 publications were analyzed. The stent success rate was 0.92 (95% CI, 0.87 to 0.95) with perforation of 0.03 (95% CI, 0.01 to 0.06). Emergency resection was performed laparoscopically at a rate of 0.15 (95% CI, 0.09 to 0.24). Primary anastomosis rate in emergency resection was 0.95 (95% CI, 0.91 to 0.97) with an anastomotic insufficiency rate of 0.07 (95% CI, 0.04 to 0.11). The mortality rate after emergency resection was 0.05 (95% CI, 0.02 to 0.09). Primary anastomosis and anastomotic insufficiency rate were similar between the two groups (RR: 1.02; 95% CI, 0.95 to 1.1; p = 0.56 and RR: 0.53; 95% CI, 0.14 to 1.93; p = 0.33). The mortality rate in emergency resection was higher compared to stent (RR: 0.51, 95% CI 0.30 to 10.89, p = 0.016). LIMITATION: No randomized controlled trials are available. CONCLUSION: Stent is a safe and successful alternative to emergency resection and may increase the rate of minimally invasive surgery. Emergency resection, however, remains safe and did not result in higher rate of anastomotic insufficiency. Further high-quality comparative studies are warranted to assess long-term outcomes.

Serum Pancreatic Stone Protein Reference Values in Healthy Pregnant Women: A Prospective Cohort Study.

BACKGROUND: In non-pregnant populations, pancreatic stone protein (PSP) has been reported to have a higher diagnostic performance for identifying severe inflammatory and infectious disease than other established biomarkers. OBJECTIVE: To generate reference values for serum PSP in pregnancy and compare them to the values of the general healthy population. DESIGN: A prospective cohort study. SETTING: A single center. POPULATION: Healthy women with singleton and multiple pregnancies. METHODS: This is a prospective single-center cohort study. Between 2013 and 2021, samples of 5 mL peripheral blood were drawn from 440 healthy pregnant women. Therein, 393 cases were singletons and 47 were multiple pregnancies. Serum PSP levels were measured by specific enzyme-linked immunosorbent assay. The main outcome measures were serum PSP level (ng/mL) reference values in healthy pregnant women. RESULTS: The mean PSP reference values in women with singleton pregnancies were 7.9 ± 2.6 ng/mL (95% CI; 2.69-13.03 ng/mL). The PSP values in women with multiple pregnancies (9.17 ± 3.06 ng/mL (95% CI; 3.05-15.28 ng/mL)) were significantly higher (p = 0.001). The PSP values in the first trimester (6.94 ± 2.53 ng/mL) were lower compared to the second (7.42 ± 2.21 ng/mL) and third trimesters (8.33 ± 2.68 ng/mL, p = 0.0001). Subgroup analyses in singletons revealed no correlations between PSP values, maternal characteristics, and pre-existing medical conditions. CONCLUSION: The PSP values in healthy pregnant women (4-12 ng/mL) were in the range of the reference values of the general healthy population (8-16 ng/mL). This insight blazes a trail for further clinical studies on the use of PSP as a potential novel biomarker for the early detection of pregnancy-related diseases such as chorioamnionitis.

FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review.

BACKGROUND: Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC. METHODS: We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based. RESULTS: A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC. CONCLUSIONS: In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Controversy Over Liver Transplantation or Resection for Neuroendocrine Liver Metastasis: Tumor Biology Cuts the Deal.

BACKGROUND: In patients with neuroendocrine liver metastasis (NELM), liver transplantation (LT) is an alternative to liver resection (LR), although the choice of therapy remains controversial. In this multicenter study, we aim to provide novel insight in this dispute. METHODS: Following a systematic literature search, 15 large international centers were contacted to provide comprehensive data on their patients after LR or LT for NELM. Survival analyses were performed with the Kaplan-Meier method, while multivariable Cox regression served to identify factors influencing survival after either transplantation or resection. Inverse probability weighting and propensity score matching was used for analyses with balanced and equalized baseline characteristics. RESULTS: Overall, 455 patients were analyzed, including 230 after LR and 225 after LT, with a median follow-up of 97 months [95% confidence interval (CI): 85-110 months]. Multivariable analysis revealed G3 grading as a negative prognostic factor for LR [hazard ratio (HR)=2.22, 95% CI: 1.04-4.77, P =0.040], while G2 grading (HR=2.52, 95% CI: 1.15-5.52, P =0.021) and LT outside Milan criteria (HR=2.40, 95% CI: 1.16-4.92, P =0.018) were negative prognostic factors in transplanted patients. Inverse probability-weighted multivariate analyses revealed a distinct survival benefit after LT. Matched patients presented a median overall survival (OS) of 197 months (95% CI: 143-not reached) and a 73% 5-year OS after LT, and 119 months (95% CI: 74-133 months) and a 52.8% 5-year OS after LR (HR=0.59, 95% CI: 0.3-0.9, P =0.022). However, the survival benefit after LT was lost if patients were transplanted outside Milan criteria. CONCLUSIONS: This multicentric study in patients with NELM demonstrates a survival benefit of LT over LR. This benefit depends on adherence to selection criteria, in particular low-grade tumor biology and Milan criteria, and must be balanced against potential risks of LT.

Prognostic factors in patients with acute mesenteric ischemia-novel tools for determining patient outcomes.

BACKGROUND: Acute mesenteric ischemia (AMI) is a devastating disease with poor prognosis. Due to the multitude of underlying factors, prediction of outcomes remains poor. We aimed to identify factors governing diagnosis and survival in AMI and develop novel prognostic tools. METHODS: This monocentric retrospective study analyzed patients with suspected AMI undergoing imaging between January 2014 and December 2019. Subgroup analyses were performed for patients with confirmed AMI undergoing surgery. Nomograms were calculated based on multivariable logistic regression models. RESULTS: Five hundred and thirty-nine patients underwent imaging for clinically suspected AMI, with 216 examinations showing radiological indication of AMI. Intestinal necrosis (IN) was confirmed in 125 undergoing surgery, 58 of which survived and 67 died (median 9 days after diagnosis, IQR 22). Increasing age, ASA score, pneumatosis intestinalis, and dilated bowel loops were significantly associated with presence of IN upon radiological suspicion. In contrast, decreased pH, elevated creatinine, radiological atherosclerosis, vascular occlusion (versus non-occlusive AMI), and colonic affection (compared to small bowel ischemia only) were associated with impaired survival in patients undergoing surgery. Based on the identified factors, we developed two nomograms to aid in prediction of IN upon radiological suspicion (C-Index = 0.726) and survival in patients undergoing surgery for IN (C-Index = 0.791). CONCLUSION: As AMI remains a condition with high mortality, we identified factors predicting occurrence of IN with suspected AMI and survival when undergoing surgery for IN. We provide two new tools, which combine these parameters and might prove helpful in treatment of patients with AMI.

Trends in pancreatic surgery in Switzerland: a survey and nationwide analysis over two decades.

BACKGROUND: Centralisation of highly specialised medicine (HSM) has changed practice and outcome in pancreatic surgery (PS) also in Switzerland. Fewer hospitals are allowed to perform pancreatic surgery according to nationally defined cut-offs. OBJECTIVE: We aimed to examine trends in PS in Switzerland. First, to assess opinions and expected trends among Swiss pancreatic surgeons in regard of PS practice and second, to assess the evolution of PS performance in Switzerland by a nationwide retrospective analysis. METHODS: First, a 26-item survey among all surgeons who performed PS in 2016 in Switzerland was performed. Then, nationwide data from 1998 to 2018 from all hospitals performing PS was analysed including centre volume, perioperative morbidity and mortality, surgical indications and utilisation of minimally invasive pancreatic surgery (MIPS). The national cut-off for regulatory accredited volume centres (AVC) was ≥ 12. Additionally, an international benchmark definition for high volume (≥ 20 surgeries/year) was used. RESULTS: Among 25 surgeons from 15 centres (response rate 51%), the survey revealed agreement that centralisation is important to improve perioperative outcomes. Respondents agreed on a minimum case load per surgeon or centre. Within the nationwide database, 8534 pancreatic resections were identified. Most resections were performed for pancreatic ductal adenocarcinoma (58.9%). There was a significant trend towards centralisation of PS with fewer non-accredited volume centres (nAVC) (36 in 1998 and 17 in 2018, p < 0.001) and more AVC (2 in 1998 and 18 in 2018, p < 0.001). A significantly higher adjusted mortality after pancreatoduodenectomy (PD) was observed in low-volume compared to high-volume hospitals (OR 1.45 [95% CI 1.15-1.84], p = 0.002) and a similar trend compared among AVC and nAVC (OR 1.25 [95% CI 0.98-1.60], p = 0.072), while mortality after distal pancreatectomy (DP) was not influenced by centre volume. CONCLUSIONS: Over the last two decades, centralisation of PS towards higher-volume centres was observed in Switzerland with a decrease of mortality after PD and low mortality after DP. Further centralisation is supported by most pancreatic surgeons. However, the ideal metric and outcome measures for the allocation of highly specialised medicine need further discussion to allow a fair and outcome-focused allocation.

Synthesis of coagulation factors during long-term ex situ liver perfusion.

Robust viability assessment of grafts during normothermic liver perfusion is a prerequisite for organ use. Coagulation parameters are used commonly for liver assessment in patients. However, they are not yet included in viability assessment during ex situ perfusion. In this study, we analysed coagulation parameters during one week ex situ perfusion at 34℃. Eight discarded human livers were perfused with blood-based, heparinised perfusate for one week; perfusions in a further four livers were terminated on day 4 due to massive ongoing cell death. Coagulation parameters were well below the physiologic range at perfusion start. Physiologic levels were achieved within the first two perfusion days for factor V (68.5 ± 35.5%), factor VII (83.5 ± 26.2%), fibrinogen (2.1 ± 0.4 g/L) and antithrombin (107 ± 26.5%) in the livers perfused for one week. Despite the increased production of coagulation factors, INR was detectable only at 24h of perfusion (2.1 ± 0.3) and prolonged thereafter (INR > 9). The prolongation of INR was related to the high heparin level in the perfusate (anti-FXa > 3 U/mL). Intriguingly, livers with ongoing massive cell death also disclosed synthesis of factor V and improved INR. In summary, perfused livers were able to produce coagulation factors at a physiological level ex situ. We propose that single coagulation factor analysis is more reliable for assessing the synthetic function of perfused livers as compared to INR when using a heparinised perfusate.

Treatment of cylindrospermopsin by hydroxyl and sulfate radicals: Does degradation equal detoxification?

Drinking water treatment ultimately aims to provide safe and harmless drinking water. Therefore, the suitability of a treatment process should not only be assessed based on reducing the concentration os a pollutant concentration but, more importantly, on reducing its toxicity. Hence, the main objective of this study was to answer whether the degradation of a highly toxic compound of global concern for drinking water equals its detoxification. We, therefore, investigated the treatment of cylindrospermopsin (CYN) by •OH and SO4-• produced in Fenton and Fenton-like reactions. Although SO4-• radicals removed the toxin more effectively, both radical species substantially degraded CYN. The underlying degradation mechanisms were similar for both radical species and involved hydroxylation, dehydrogenation, decarboxylation, sulfate group removal, ring cleavage, and further fragmentation. The hydroxymethyl uracil and tricyclic guanidine moieties were the primary targets. Furthermore, the residual toxicity, assessed by a 3-dimensional human in vitro liver model, was substantially reduced during the treatment by both radical species. Although the results indicated that some of the formed degradation products might still be toxic, the overall reduction of the toxicity together with the proposed degradation pathways allowed us to conclude: "Yes, degradation of CYN equals its detoxification!".

Combination of Antiretroviral Drugs Zidovudine and Efavirenz Impairs Tumor Growths in a Mouse Model of Cancer.

LINE1 retrotransposons, which are thought to be the remnants of ancient integrations of retrovirus-like elements, are aberrantly (re)activated in many cancer cells. Due to LINE1-induced alterations in target gene expression and/or chromosomal rearrangements, they may be important drivers of tumorigenesis. Moreover, LINE1 encoded proteins, Open Reading Frame (ORF)1 and ORF2, may have pro-oncogenic potential through inductors of oncogenic transcription factors or inhibitors of cell cycle suppressors. The current study therefore aimed to investigate in vitro and in vivo anti-tumorigenic effects of two well-known antiretroviral drugs, zidovudine, a nucleoside analogue inhibitor of RT (NRTI), and efavirenz, a non-nucleoside RT inhibitor (NNRTI). Our data demonstrate that both drugs in clinically relevant doses significantly reduced the proliferation of murine and human cancer cell lines, as well as growth of tumors in a murine subcutaneous model. Intriguingly, we found that the combination of both zidovudine and efavirenz almost entirely blocked tumorigenesis in vivo. Because both drugs are FDA-approved agents and the combination was very well tolerated in mice, the combination therapy as presented in our paper might be an opportunity to treat colorectal tumors and metastasis to the liver in an inexpensive way.

Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models.

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 serotonin­deficient (Tph1−/−) 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 Tph1−/− 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.