Extrahepatic Sites Research Articles

Patterns and Predictors of Recurrence After Curative Resection of Colorectal Liver Metastasis (CRLM).

Our study aims to determine the predictors and patterns of relapses after curative colorectal liver metastasis (CRLM) resection. A single-centre, retrospective study of CRLM patients operated between 2010 and 2022 was performed. The site of first recurrence was either hepatic (marginal (≤ 1cm) or extramarginal), extrahepatic, or both. Factors that predicted relapse patterns and overall survival were determined by multivariable Cox regression analysis with backward elimination of variables. The study consisted of 258 patients, with a similar proportion of synchronous (144; 56%) and metachronous(114; 43%) metastasis. At a 43-month median follow-up, 156 patients (60.4%) developed recurrences with 33 (21.1%) in the liver, 62(24.03%) extra-hepatic recurrences, and 58 (22.48%) having both. Isolated marginal liver relapses were seen in seven (9.89%) liver recurrence patients. The median overall and relapse-free survivals were 38months (30-54) and 13months (11-16), respectively. The 3-year liver-relapse-free survival was 54.4% (44.9-60.6). Size of liver metastases > 5cm (HR 2.06 (1.34-3.17), involved surgical margins (HR 2.16 (1.27-3.68)), and adjuvant chemotherapy (HR 1.89 (1.07-3.35)) were predictors of hepatic recurrences. Node positivity of primary (HR 1.61 (1.02-2.56)), presence of baseline extra-hepatic metastases (HR 0.30 (0.18-0.51)), size of liver metastases > 5cm (HR 2.02 (1.37-2.99)), poorly differentiated histology (HR 2.25 (1.28-3.49)), presence of LVI (HR 2.25 (1.28-3.94)), and adjuvant chemotherapy (HR 2.15 (1.28-3.61)) were predictors of extra-hepatic recurrences. The study found majority relapses occurred at extrahepatic sites whilst isolated marginal recurrences were few. The consistent predictors of recurrence were size and inability to deliver adjuvant therapy. A tailored adjuvant therapy might improve outcomes after liver metastasectomy in colorectal cancers.

Enormous ectopic liver tissue at the gastrohepatic ligament: a rare entity at Muhimbili National Hospital, Tanzania

BackgroundEctopic liver tissue (ELT) is a developmental abnormality in which liver tissue develops at an extrahepatic site without connection to the true liver. It is a rare entity with an incidence of 0.24–0.56% according to data described in laparoscopic or autopsy studies. The detailed mechanism behind the development of ELT is poorly understood. ELT predominantly has an asymptomatic nature, even by means of radiological studies the diagnosis of ELT without surgery or autopsy is difficult. ELT has been reported mostly to be found frequently on the gallbladder and rarely on the gastrohepatic ligament. ELT has increased the potential risk of HCC which makes the resection crucial. Due to its variations anatomically, ELT recognition should gain clinical importance and surgeons need to be aware of these possible disparities.Case presentation.We present a 59-year-old female from Western Tanzania was presented to us with 2-month history of painless upper abdominal swelling. An abdominal CT scan was performed, and it revealed a large mass located at the gastrohepatic region with blood supply mainly from the left hepatic artery and omentum. Technically difficult excision of 17 × 12 cm tumor at gastrohepatic ligament was performed, with uneventful recovery. Post-operative histology results revealed capsulated hepatic parenchyma without the biliary components and limited sinusoids with tissue degeneration. To date, no complications happened during follow-up for one year.ConclusionELT is a rare entity with a predominantly asymptomatic nature. Preoperatively diagnosis is difficult even with images. It has anatomical variation and is hardly found along the gastrohepatic ligament. ELT has increased the potential risk of HCC which makes the resection crucial. Increased awareness of this congenital anomaly may result in increased detection rates.

Role of point-of-care ultrasound (POCUS) in clinical hepatology.

Hospitalized patients with cirrhosis frequently require critical care management for sepsis, HE, respiratory failure, acute variceal bleeding, acute kidney injury (AKI), shock, and optimization for liver transplantation, while outpatients have unique care considerations. Point-of-care ultrasonography (POCUS) enhances bedside examination of the hepatobiliary system and relevant extrahepatic sites. POCUS includes cardiac US and is used to assess volume status and hemodynamic parameters like cardiac output, systemic vascular resistance, cardiac contractility, and pulmonary artery pressure, which aid in the early and accurate diagnosis of heart failure, cirrhotic cardiomyopathy, porto-pulmonary hypertension, hepatopulmonary syndrome, arrhythmia, and pulmonary embolism. This also helps in fluid management and vasopressor use in the resuscitation of patients with cirrhosis. Lung ultrasound (LUS) can help in differentiating pneumonia, effusion, and edema. Further, US guides interventions such as line placement, drainage of abdominal collections/abscesses, relief of tension pneumothorax, drainage of pleural and pericardial effusions, and biliary drainage in cholangitis. Additionally, its role is essential to assess liver masses foci of sepsis, for appropriate sites for paracentesis, and to assess for vascular disorders such as portal vein or hepatic vein thrombosis. Renal US can identify renal and postrenal causes of AKI and aid in diagnosis of prerenal AKI through volume assessment. In this review, we address the principles and methods of POCUS in hospitalized patients and in outpatients with cirrhosis and discuss the application of this diverse modality in clinical hepatology.

Performance of sofosbuvir and NITD008 in extrahepatic neuronal cells against HEV

Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach mortality rates up to 25% in pregnant women or become chronic in immunocompromised patients. Hepatitis E virus (HEV) infection have been associated with a range of extrahepatic manifestations, including a spectrum of neurological symptoms. Current therapy options are limited to non-specific antivirals like ribavirin, but recently, repurposed viral polymerase inhibitors like sofosbuvir and NITD008 were described to inhibit HEV replication. Here, we evaluated the efficacy of these drugs in various neuronal-derived cell lines to determine their potency outside the liver. Our findings indicate that both drugs, especially sofosbuvir, exhibited reduced efficacy in neuronal cells compared to hepatic cells. These results should be taken into account in the development of direct-acting antivirals for HEV and their potency at extrahepatic replication sites.

Simultaneous gastric, pancreatic, and renal metastasis from poorly differentiated hepatocellular carcinoma

Common extrahepatic metastasis sites of hepatocellular carcinoma (HCC) are the lungs, adrenal glands, and bones. Herein, we report a rare case of metastatic gastric, pancreatic, and renal tumors from HCC simultaneously, and review the relevant literature. A 75-year-old woman presented with right hypochondralgia, appetite loss, and weight loss. Computed tomography revealed suspected metastatic liver, lung, and renal tumors. A blood test revealed a leukocyte count of 26,210/μL and a high inflammatory reaction. As sepsis was suspected, the patient was referred to our hospital. Gadolinium–ethoxybenzyl–diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed a hypovascular liver tumor that was suspected to be metastatic. Upper gastrointestinal endoscopy revealed two suspected metastatic gastric tumors. Liver and gastric tumor biopsies revealed poor carcinoma in both. The patient’s condition gradually worsened and she died on day 8 of the illness. Based on autopsy findings, the patient was finally diagnosed with metastatic gastric and renal tumors originating from HCC. Additionally, a metastatic pancreatic tumor originating from the HCC was identified during autopsy. The pathological diagnosis of the pulmonary lesion was primary lung adenocarcinoma. In conclusion, HCC should be suspected in cases with multiple metastases of unknown primary lesions.

Local Therapy Improves Survival for Early Recurrence After Resection of Colorectal Liver Metastases.

Early recurrence following hepatectomy for colorectal liver metastases (CLM) is associated with worse survival; yet, impact of further local therapy is unclear. We sought to evaluate whether local therapy benefits patients with early recurrence following hepatectomy for CLM. Clinicopathologic and survival outcomes of patients managed with hepatectomy for CLM (1/2001-12/2020) were queried from a prospectively maintained database. Timing of recurrence was stratified as early (recurrence-free survival [RFS] < 6months), intermediate (RFS 6-12months), and later (RFS > 12months). Local therapy was defined as ablation, resection, or radiation. Of 671 patients, 541 (81%) recurred with 189 (28%) early, 180 (27%) intermediate, and 172 (26%) later recurrences. Local therapy for recurrence resulted in improved survival, regardless of recurrence timing (early 78 vs. 32months, intermediate 72 vs. 39months, later 132 vs. 65months, all p < 0.001). Following recurrence, treatment with local therapy (hazard ratio [HR] = 0.24), liver and extrahepatic recurrence (HR = 1.81), RAS + TP53 co-mutation (HR = 1.52), and SMAD4 mutation (HR = 1.92) were independently associated with overall survival (all p ≤ 0.002). Among patients with recurrence treated by local therapy, patients older than 65years (HR 1.79), liver and extrahepatic recurrence (HR 2.05), primary site or other recurrence (HR 1.90), RAS-TP53 co-mutation (HR 1.63), and SMAD4 mutation (HR 2.06) had shorter post-local therapy survival (all p ≤ 0.04). While most patients recur after hepatectomy for CLM, local therapy may result in long-term survival despite early recurrence. Somatic mutational profiling may help to guide the multidisciplinary consideration of local therapy after recurrence.

Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic colorectal cancer: Subgroup analysis of patients treated within the PanaMa trial (AIO KRK 0212).

Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.

Adipose-Derived Stromal Cells Preserve Pancreatic Islet Function in a Transplantable 3D Bioprinted Scaffold.

Intra-portal islet transplantation is currently the only clinically approved beta cell replacement therapy, but its outcome is hindered by limited cell survival due to a multifactorial reaction against the allogeneic tissue in liver. Adipose-derived stromal cells (ASCs) can potentially improve the islet micro-environment by their immunomodulatory action. The challenge is to combine both islets and ASCs in a relatively easy and consistent long-term manner in a deliverable scaffold. Manufacturing the 3D bioprinted double-layered scaffolds with primary islets and ASCs using a mix of alginate/nanofibrillated cellulose (NFC) bioink is reported. The diffusion properties of the bioink and the supportive effect of human ASCs on islet viability, glucose sensing, insulin secretion, and reducing the secretion of pro-inflammatory cytokines are demonstrated. Diabetic mice transplanted with islet-ASC scaffolds reach normoglycemia seven days post-transplantation with no significant difference between this group and the group received islets under the kidney capsules. In addition, animals transplanted with islet-ASC scaffolds stay normoglycemic and show elevated levels of C-peptide compared to mice transplanted with islet-only scaffolds. The data present a functional 3D bioprinted scaffold for islets and ASCs transplanted to the extrahepatic site and suggest a possible role of ASCs on improving the islet micro-environment.

Perioperative Chemotherapy is Associated with Superior Overall Survival in Patients with Synchronous Colorectal Liver Metastases.

The sequence of localized and systemic treatment for colorectal liver metastases (CRLM) remains debated. Our objective is to analyze the effect of treatment sequence on overall survival (OS) in patients with CRLM using a large cancer database. The national cancer database (NCDB) was utilized to identify patients with stage IV colorectal cancer (CRC) diagnosed between 2004 and 2016. OS was analyzed using standard univariate and multivariate methods. We identified 72,376 patients with synchronous CRLM, of whom 43,039 had liver-only metastases. Patients with liver-only CRLM had a median OS of 18.9 months, versus those with CRLM plus extrahepatic sites (11.3 months). In patients with liver-only CRLM, resection of both the primary and metastatic site was associated with median OS 38.9 months versus 30.2 months after resection of the metastatic site alone, and resection of the primary tumor alone (22.3 months, all p < 0.001). Receipt of perioperative chemotherapy correlated with a median OS of 44.7 months versus preoperative chemotherapy only (38.4 months) or postoperative chemotherapy only (27.9 months, all p < 0.001). Patients who received chemotherapy alone had a median OS of 16.4 months versus those who underwent resection without chemotherapy (9.5 months, p < 0.001). This study reveals a correlation between perioperative chemotherapy and superior OS in patients with liver-only CRLM, and shows that resection of the metastatic site was linked to better OS. Despite obvious cohort heterogeneity, the data can support a resection approach with additional, preferably peri- or preoperative systemic therapy for patients with CRLM.

Revisited role of the placenta in bile acid homeostasis.

To date, the discussion concerning bile acids (BAs) during gestation is almost exclusively linked to pregnancy complications such as intrahepatic cholestasis of pregnancy (ICP) when maternal serum BA levels reach very high concentrations (>100μM). Generally, the placenta is believed to serve as a protective barrier avoiding exposure of the growing fetus to excessive amounts of maternal BAs that might cause detrimental effects (e.g., intrauterine growth restriction and/or increased vulnerability to metabolic diseases). However, little is known about the precise role of the placenta in BA biosynthesis, transport, and metabolism in healthy pregnancies when serum BAs are at physiological levels (i.e., low maternal and high fetal BA concentrations). It is well known that primary BAs are synthesized from cholesterol in the liver and are later modified to secondary BA species by colonic bacteria. Besides the liver, BA synthesis in extrahepatic sites such as the brain elicits neuroprotective actions through inhibition of apoptosis as well as oxidative and endoplasmic reticulum stress. Even though historically BAs were thought to be only "detergent molecules" required for intestinal absorption of dietary fats, they are nowadays acknowledged as full signaling molecules. They modulate a myriad of signaling pathways with functional consequences on essential processes such as gluconeogenesis -one of the principal energy sources of the fetus- and cellular proliferation. The current manuscript discusses the potential multipotent roles of physiologically circulating BAs on developmental processes during gestation and provides a novel perspective in terms of the importance of the placenta as a previously unknown source of BAs. Since the principle "not too much, not too little" applicable to other signaling molecules may be also true for BAs, the risks associated with fetal exposure to excessive levels of BAs are discussed.

ALBI and APRI score as prognostic factors for predicting the FABIB complications after liver resection in metastatic colorectal cancer.

e15577 Background: Previous studies and this study demonstrate that liver resection, even with subsequent extrahepatic relapse, may be associated with long-term survival, are very encouraging for future studies of the effectiveness of liver cytoreduction in conditions of minimal extrahepatic disease. These data also contribute to selective cytoreduction in extrahepatic sites. If it is necessary to achieve an oncological result (maximally extended liver resection), sometimes the surgical result suffers in the form of postoperative complications. The most serious complication of liver resection due to colorectal cancer metastases is postoperative liver failure, characterized by high levels of INR and bilirubin by day 5 after surgery. Methods: To classify the most frequent postoperative complications, the FABIB system has been developed, which includes Failure, Ascites, Bile leakage, Infection, Bleeding. We tried to evaluate the possibilities of using the ALBI and APRI indicators as one of the factors that must be taken into account when predicting the development of complications from the FABIB group. ALBI score is used in predicting the development of liver failure in patients with hepatocellular cancer. APRI score is a predictor of fibrosis and cirrhosis in patients suffering from hepatitis. Results: We have analyzed the results of liver resections in 174 patients with metastatic liver damage in colorectal cancer. Among them 57% are women, 43% are men. Metastatic lesion of the right lobe – 38 (21.8%), the left lobe – 78 (44.8%), right and left lobes – 58 (33.4%). Right–sided tumors - 25% - 43 patients, left–sided tumors - 75% - 131 patients. According to the FABIB classification, liver insufficiency was observed in 25 patients (14%), ascites in 4 patients (2.3%), bile leakage in 8 (4.6%), infectious complications in 9 (5%), bleeding in 15 patients (8%). A single-factor analysis of the variance of ALBI and APRI indicators on the day of surgery, the day after surgery and on the 5th day after surgery did not show a statistically significant difference in the groups with all FABIB complications and without FABIB complications. However, statistical analysis separately in each subgroup of complications revealed a statistically significant difference in ALBI and APRI in the groups with and without postoperative liver failure, as well as a statistically significant difference in the groups with and without bleeding. Conclusions: Thus, it can be concluded that ALBI score and APRI score can be used in the early postoperative period to predict the development of postoperative liver failure and hemorrhagic complications not only in patients with hepatocellular cancer or cirrhosis, but also in patients with colorectal cancer with liver metastases. It could be useful in patients who have undergone several lines of chemotherapy before liver resection or with a large tumor lesion of the liver.

Peptide-Based Nanoparticles for Systemic Extrahepatic Delivery of Therapeutic Nucleotides.

Peptide-based nanoparticles (PBN) for nucleotide complexation and targeting of extrahepatic diseases are gaining recognition as potent pharmaceutical vehicles for fine-tuned control of protein production (up- and/or down-regulation) and for gene delivery. Herein, we review the principles and mechanisms underpinning self-assembled formation of PBN, cellular uptake, endosomal release, and delivery to extrahepatic disease sites after systemic administration. Selected examples of PBN that have demonstrated recent proof of concept in disease models in vivo are summarized to offer the reader a comparative view of the field and the possibilities for clinical application.

Retinoids in marine mammals and their use as biomarkers of organochlorine compounds

Retinoids, also known as vitamin A, are non-endogenous molecules that are essential for a number of physiological processes in mammals. Imbalance of retinoids has been associated with reproductive impairment, embryonic mortality, growth retardation and bone deformities, pathologies in skin and the nervous system, and immune suppression. Mammals cannot produce retinoids so their primary source is dietary. They are absorbed by the small intestine and packaged as retinyl esters in chylomicrons, which enter the circulation and end up mostly in the liver and fatty tissues. Plasma retinoid levels are homeostatically regulated, so they remain constant despite variations in dietary supply or tissue stores. Therefore body depletion of retinoids cannot be reliably assessed through levels in blood, and should be evaluated through concentrations in depot tissues. In marine mammals, the main storage sites for retinoids are liver and blubber. Although not a universal rule, the concentration of retinoids often increases with age in both sexes because of progressive build-up of retinyl esters. In addition, sex often affects retinoid levels, but the nature and magnitude of this effect varies between species and populations. Taxonomic, life-style (particularly dietary) and climatic differences may explain dissimilarities in the effect of age and sex on retinoid levels. For this reason, retinoids can be used to distinguish populations or population components showing distinct dietary, behavioural, or other traits. Disease, particularly when affecting organs of physiological importance or inducing malnutrition, may affect retinoid tissue levels, so care should be taken when studying concentrations in stranded animals. Organochlorine compounds, particularly PCBs, dioxin (TCDDs) and DDTs, increase mobilisation of retinoids from hepatic and extrahepatic storage sites into serum, accompanied by enhanced degradation and elimination of retinoids through urine. In terrestrial mammals, this effect increases retinoid concentration. Conversely, in some species of marine mammals plasma retinoid levels have been reported to decrease when exposure to organochlorines increases, although the physiological mechanisms are unclear. However, given the homeostatic regulation of retinoids in blood, variation in plasma is expected to be less than that in liver or blubber. Because retinoid tissue levels vary in marine mammals even at moderate exposure to organochlorines, and original levels are restored when such exposure decreases or disappears, retinoids may be used as a biomarker of the impact of pollutants on populations. Further research is needed to validate their use, particularly in cetaceans.

Aptamer-Based Targeted Delivery of Functional Nucleic Acids.

Functional nucleic acid (NA)-based drugs have a broad range of applications since they allow the alteration and control of gene/protein expression patterns in cells. In principle, functional NAs need to be transported precisely and efficiently to target cells to guarantee both functionality and safety. Owing to their negative charges, it is difficult for natural NAs to cross the cell membrane composed of lipid bilayer and enter targeted cells. Worse still, the delivery of undirected functional NAs to nontargeted healthy cells and/or tissues would induce unpredictable adverse effects. Therefore, the precisely targeted delivery of functional NAs to specific cells/organs, particularly in extrahepatic sites, is required. Since aptamers can bind to various proteins on the cell surface with high specificity and selectivity, they can serve as the molecular recognition units to accurately bind target cells and subsequently enable the efficient delivery of cargo. In this perspective, we summarize the original, proof-of-concept aptamer-based strategies for the targeted delivery of functional NAs. A few specific examples are then discussed, followed by our perspectives on some of the challenges and opportunities that lie ahead.

Extrahepatic Replication Sites of Hepatitis E Virus (HEV)

Hepatitis E virus (HEV) is an emerging viral disease known to cause acute viral hepatitis globally. Various genotypes of HEV have been identified that produce genotype specific lesions depending on the HEV targeted population. Pregnant or immunosuppressed individuals develop significantly more severe hepatitis E in comparison to the general population. In the last 40 years, we discovered that the tropism of HEV is not restricted to the liver, and virus replication was demonstrated in multiple organs. Out of the 10 body systems described in humans, HEV produces lesions causing a broad range of extrahepatic clinical manifestations in each of them. Affected body systems include nervous and musculoskeletal, cardiovascular, digestive, endocrine, integumentary, renal, respiratory, immune, and reproductive systems producing systemic lesions. All extrahepatic signs are caused by either direct HEV replication in these tissues, or indirectly by various immune mediated mechanisms. Extrahepatic replication features of HEV allowed it to cross the placental barrier, blood–brain barrier (BBB), and blood–testis barrier (BTB) that do not typically grant entry to viruses in general. Thus, in this review, we summarized the extrahepatic replication sites of HEV, listed the body systems where HEV invaded, and described multiple animal models including immunocompetent and immunosuppressed that were used to study the extrahepatic replication sites of HEV.

Bioengineered omental transplant site promotes pancreatic islet allografts survival in non-human primates

The transplanting islets to the liver approach suffers from an immediate posttransplant loss of islets of more than 50%, progressive graft dysfunction over time, and precludes recovery of grafts should there be serious complications such as the development of teratomas with grafts that are stem cell-derived islets (SC-islets). The omentum features an attractive extrahepatic alternative site for clinical islet transplantation. We explore an approach in which allogeneic islets are transplanted onto the omentum, which is bioengineered with a plasma-thrombin biodegradable matrix in three diabetic non-human primates (NHPs). Within 1week posttransplant, each transplanted NHP achieves normoglycemia and insulin independence and remains stable until termination of the experiment. Success was achieved in each case with islets recovered from a single NHP donor. Histology demonstrates robust revascularization and reinnervation of the graft. This preclinical study can inform the development of strategies for β cell replacement including the use of SC-islets or other types of novel cells in clinical settings.

Primary Hepatic Extra-gastrointestinal Stromal Tumors: Molecular Pathogenesis, Immunohistopathology, and Treatment.

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract. They originate from the interstitial cells of Cajal and are usually found in extrahepatic gastrointestinal sites. However, a small subset are derived from the liver and are known as primary hepatic gastrointestinal stromal tumors (PHGIST). They have a poor prognosis and are historically difficult to diagnose. Our objective was to review and update the latest evidence-based knowledge concerning PHGIST, with a focus on epidemiology, etiology, pathophysiology, clinical presentation, histopathology, and treatment. These tumors are usually found incidentally, occur sporadically, and are associated with mutations of KIT and PDGFRA genes. PHGIST is a diagnosis of exclusion, as it has the same molecular, immunochemistry and histological appearance as gastrointestinal stromal tumors (GIST). Thus, imaging, such as positron emission tomography-computed tomography (PET-CT) must be used to rule out metastatic GIST before a diagnosis can be made. However, with mutation analysis and pharmacological advances, tyrosine kinase inhibitors are typically pursued with or without surgical intervention. Other potential treatments include transcatheter arterial chemoembolization and tumor ablation. However, these are typically considered palliative options. As there are only a limited number of publications regarding PHGIST, data concerning morbidity and mortality are not yet available. Immunohistopathology can help develop screening guidelines and evaluating resistance to treatment.

Outcomes Following Treatment with FOLFOX for Patients with Resectable or Potentially Resectable Metastatic Colorectal Cancer: A Population-based Cohort Study

AimsTo evaluate the safety and effectiveness of oxaliplatin-based combination chemotherapy for patients with metastatic colorectal cancer (mCRC) to extrahepatic sites. Materials and methodsWe conducted a population-based retrospective study examining the safety and effectiveness of perioperative oxaliplatin for resectable or potentially resectable colorectal metastases in Ontario, Canada. Outcomes were also compared with patients with liver-only metastases. Patients received oxaliplatin for mCRC between 1 January 2013 and 30 June 2020. ResultsIn total, 192 patients had extrahepatic metastases. Seventy per cent had R0 metastasectomy. The 3-year disease-free survival and overall survival were 62% and 79%, respectively; <4% of patients died within 60 days of metastasectomy and 74–90% of patients received treatment according to recommendations from a multidisciplinary setting. Compared with liver-only controls (n = 1306), patients had mCRC to the lung only (n = 115), lung and liver (n = 55) and liver with non-pulmonary site (n = 22). Extrahepatic metastases were more likely to be found for patients whose primary colorectal resection had positive margins (14% versus 7%, P = 0.005) and primary tumours located in the rectum [odds ratio 4.01 (2.31–6.97)]. After adjustment, there was no difference in overall survival between liver-only controls and patients with lung-only [hazard ratio 0.82 (0.59–1.15)] or liver and lung metastases [hazard ratio 1.26 (0.85–1.87)] (P = 0.24). In total, 79/115 (69%) of patients with lung-only metastases had a metastasectomy compared with 645/1306 (49%) and 15/55 (27%) of patients with liver-only and liver and lung metastases, respectively. Hospital visits were similar between patients with liver-only and extrahepatic metastases. ConclusionOxaliplatin-based chemotherapy for patients with resectable or potentially resectable mCRC with extrahepatic metastases was safe and resulted in similar outcomes in appropriately selected patients when compared with patients with liver-only metastases.

Extrahepatic transplantation of 3D cultured stem cell-derived islet organoids on microporous scaffolds.

Stem cell differentiation methods have been developed to produce cells capable of insulin secretion which are showing promise in clinical trials for treatment of type-1 diabetes. Nevertheless, opportunities remain to improve cell maturation and function. Three-dimensional (3D) culture has demonstrated improved differentiation and metabolic function in organoid systems, with biomaterial scaffolds employed to direct cell assembly and facilitate cell-cell contacts. Herein, we investigate 3D culture of human stem cell-derived islet organoids, with 3D culture initiated at the pancreatic progenitor, endocrine progenitor, or immature β-cell stage. Clusters formed by reaggregation of immature β-cells could be readily seeded into the microporous poly(lactide-co-glycolide) scaffold, with control over cell number. Culture of islet organoids on scaffolds at the early to mid-stage beta cell progenitors had improved in vitro glucose stimulated insulin secretion relative to organoids formed at the pancreatic progenitor stage. Reaggregated islet organoids were transplanted into the peritoneal fat of streptozotocin-induced diabetic mice, which resulted in reduced blood glucose levels and the presence of systemic human C-peptide. In conclusion, 3D cell culture supports development of islet organoids as indicated by insulin secretion in vitro and supports transplantation to extrahepatic sites that leads to a reduction of hyperglycemia in vivo.

Fas Ligand-Modified Scaffolds Protect Stem Cell Derived β-Cells by Modulating Immune Cell Numbers and Polarization.

Stem cell derived β-cells have demonstrated the potential to control blood glucose levels and represent a promising treatment for Type 1 diabetes (T1D). Early engraftment post-transplantation and subsequent maturation of these β-cells are hypothesized to be limited by the initial inflammatory response, which impacts the ability to sustain normoglycemia for long periods. We investigated the survival and development of immature hPSC-derived β-cells transplanted on poly(lactide-co-glycolide) (PLG) microporous scaffolds into the peritoneal fat, a site being considered for clinical translation. The scaffolds were modified with biotin for binding of a streptavidin-FasL (SA-FasL) chimeric protein to modulate the local immune cell responses. The presence of FasL impacted infiltration of monocytes and neutrophils and altered the immune cell polarization. Conditioned media generated from SA-FasL scaffolds explanted at day 4 post-transplant did not impact hPSC-derived β-cell survival and maturation in vitro, while these responses were reduced with conditioned media from control scaffolds. Following transplantation, β-cell viability and differentiation were improved with SA-FasL modification. A sustained increase in insulin positive cell ratio was observed with SA-FasL-modified scaffolds relative to control scaffolds. These results highlight that the initial immune response can significantly impact β-cell engraftment, and modulation of cell infiltration and polarization may be a consideration for supporting long-term function at an extrahepatic site.