Liver Transplantation in a Woman with Mahvash Disease.

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

Efficient killing of tumor cells by CAR-T cells requires greater number of engaged CARs than TCRs.

Although CAR-T cells are widely used to treat cancer, efficiency of CAR-T cell cytolytic responses has not been carefully examined. We engineered CAR specific for HMW-MAA (high-molecular-weight melanoma-associated antigen) and evaluated potency of CD8+ CAR-T cells to release cytolytic granules and to kill tissue-derived melanoma cells, which express different levels of HMW-MAA. CAR-T cells efficiently killed melanoma cells expressing high level of HMW-MAA, but not melanoma cells with lower levels of HMW-MAA. The same melanoma cells presenting significantly lower level of stimulatory peptide-MHC ligand were readily lysed by T cells transduced with genes encoding α,ß-TCR specific for the peptide-MHC ligand. The data suggest that higher level of targeted molecules is required to engage a larger number of CARs than TCRs to induce efficient cytolytic granule release and destruction of melanoma cells. Understanding the difference in molecular mechanisms controlling activation thresholds of CAR- versus TCR-mediated responses will contribute to improving efficiency of CAR T cells required to eliminate solid tumors presenting low levels of targeted molecules.

Development and optimization of orthotopic liver metastasis xenograft mouse models in uveal melanoma.

BACKGROUND: Patients with metastatic uveal melanoma (MUM) in the liver usually die within 1 year. The development of new treatments for MUM has been limited by the lack of diverse MUM cell lines and appropriate animal models. We previously reported that orthotopic xenograft mouse models established by direct injection of MUM cells into the liver were useful for the analysis associated with tumor microenvironment in the liver. However, considering that patients with UM metastasize to the liver hematogenously, direct liver injection model might not be suitable for investigation on various mechanisms of liver metastasis. Here, we aim to establish new orthotopic xenograft models via hematogenous dissemination of tumor cells to the liver, and to compare their characteristics with the hepatic injection model. We also determine if hepatic tumors could be effectively monitored with non-invasive live imaging. METHODS: tdtTomate-labeled, patient-derived MUM cells were injected into the liver, spleen or tail vein of immunodeficient NSG mice. Tumor growth was serially assessed with In Vivo Imaging System (IVIS) images once every week. Established hepatic tumors were evaluated with CT scan and then analyzed histologically. RESULTS: We found that splenic injection could consistently establish hepatic tumors. Non-invasive imaging showed that the splenic injection model had more consistent and stronger fluorescent intensity compared to the hepatic injection model. There were no significant differences in tumor growth between splenic injection with splenectomy and without splenectomy. The splenic injection established hepatic tumors diffusely throughout the liver, while the hepatic injection of tumor cells established a single localized tumor. Long-term monitoring of tumor development showed that tumor growth, tumor distribution in the liver, and overall survival depended on the number of tumor cells injected to the spleen. CONCLUSION: We established a new orthotopic hepatic metastatic xenograft mouse model by splenic injection of MUM cells. The growth of orthotopic hepatic tumors could be monitored with non-invasive IVIS imaging. Moreover, we evaluated the therapeutic effect of a MEK inhibitor by using this model. Our findings suggest that our new orthotopic liver metastatic mouse model may be useful for preclinical drug screening experiments and for the analysis of liver metastasis mechanisms.

First-in-Human Phase I Study of Merestinib, an Oral Multikinase Inhibitor, in Patients with Advanced Cancer.

BACKGROUND: The purpose of this nonrandomized, open-label, phase I study (NCT01285037) was to evaluate the safety and tolerability of merestinib, an oral antiproliferative and antiangiogenic kinase inhibitor, and to determine a recommended phase II dose and schedule for patients with advanced cancer. MATERIALS AND METHODS: This was a multicenter, nonrandomized, open-label, phase I study of oral merestinib consisting of six parts: dose escalation (part A), followed by a four-cohort dose-confirmation study (part B) and subsequently a four-part dose expansion and combination safety testing of merestinib with standard doses of cetuximab (part C), cisplatin (part D), gemcitabine and cisplatin (part E), and ramucirumab (part F) in patients with specific types of advanced cancers. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated in all cohorts. RESULTS: The dose escalation, confirmation, and expansion results support the dosing of merestinib at 120 mg once daily, based on acceptable exposure and safety at this dose. One complete response was observed in a patient with cholangiocarcinoma, and three patients with cholangiocarcinoma achieved a partial response. Overall, 60 (32%) of the 186 patients enrolled in the study had a best response of stable disease. CONCLUSION: This study demonstrates that merestinib has a tolerable safety profile and potential anticancer activity and warrants further clinical investigation. IMPLICATIONS FOR PRACTICE: Merestinib treatment in patients with advanced cancer demonstrated an acceptable safety profile and potential antitumor activity, supporting its future development in specific disease populations as a monotherapy and/or in combination with other therapies.

A Prospective Phase II Trial of Radioembolization for Treatment of Uveal Melanoma Hepatic Metastasis.

Background Overall survival (OS) for patients with uveal melanoma (UM) hepatic metastases is extremely poor. Therefore, stabilization of hepatic metastases is essential to prolonging OS. Purpose To assess the safety and effectiveness of radioembolization (RE) for treatment of UM hepatic metastases. Materials and Methods Enrollment for this prospective phase II trial began November 2011 and concluded January 2017. Treatment-naïve participants (group A) and participants who progressed after immunoembolization (group B) with hepatic tumor burden less than 50% underwent RE. Participants were followed for 1 month and every 3 months for acute and delayed toxicities, respectively. MRI, CT, and PET were performed every 3 months to evaluate for tumor response and extrahepatic disease. Participants were followed for at least 2 years or until death. Kaplan-Meier method and multivariable Cox proportional hazard models were used for data analysis. Results In group A, 24 participants (mean age ± standard deviation, 59 years ± 13; 13 men and 11 women) underwent unilobar (n = 7), fractionated whole-liver (n = 1), or sequential lobar (n = 16) RE. One participant was excluded from the trial. Complete response (n = 0), partial response (n = 9), or stable disease (n = 11) was achieved in 20 of 23 (87.0%; 95% confidence interval [CI]: 66.4%, 97.2%) participants. Median progression-free survival from liver metastasis was 8.1 months (95% CI: 6.4, 11.8; range, 3.3-33.7 months). Median OS was 18.5 months (95% CI: 11.3, 23.5; range, 6.5-73.7 months). In group B, 24 participants (mean age, 58 years ± 10; nine men and 15 women) underwent unilobar (n = 5) or sequential lobar (n = 19) RE. Complete response (n = 0), partial response (n = 8), or stable disease (n = 6) was achieved in 14 of 24 (58.3%; 95% CI: 36.3%, 77.9%) participants. Median progression-free survival from liver metastasis was 5.2 months (95% CI: 3.7, 9.8; range, 2.9-22.0 months). Median OS was 19.2 months (95% CI: 11.5, 24.0; range, 4.8-76.6 months). Grade 3 treatment-related toxicities included transient lymphopenia (group A, n = 1; group B, n = 1), pain (group A, n = 2) and nausea or vomiting (group A, n = 1). Conclusion Radioembolization is a promising treatment for patients with uveal melanoma hepatic metastases. © RSNA, 2019 Online supplemental material is available for this article.

Adjuvant Sunitinib in High-Risk Patients with Uveal Melanoma: Comparison with Institutional Controls.

PURPOSE: To compare overall survival in high-risk patients with primary uveal melanoma who received adjuvant sunitinib with institutional controls. DESIGN: Retrospective cohort. PARTICIPANTS: Selection criteria were (1) monosomy 3 and 8q amplification by cytogenetic or DecisionDx-UM Class 2 and (2) monosomy 3 and large tumor size (T3-4 by American Joint Committee on Cancer classification). Exclusion criteria were date of diagnosis before 2007 or after 2013 and age <18 years. METHODS: A cohort of patients who intended to receive adjuvant sunitinib for 6 months was compared with institutional historical controls with the same risk factors. Kaplan-Meier and Cox proportional hazards models were used to analyze the outcome. Propensity score was used to adjust for nonrandom assignment to sunitinib. MAIN OUTCOME MEASURES: Overall survival. RESULTS: From the Wills Eye Hospital Oncology Service Uveal Melanoma Cytogenetic Database (N = 1172), 128 patients fulfilled the selection and exclusion criteria. Median follow-up was 52.7 months (range, 0.26-108 months). A total of 54 patients received sunitinib. Their median age was 56 years (range, 29-81 years), and 48% were men. A total of 74 historical controls in the same risk category were identified. Their median age was 62 years (21-80 years), and 48% were men. Patients in the sunitinib group had worse cytogenetic or molecular features (monosomy 3 and 8q amplification or class 2 87% vs. 57%; P < 0.001), had smaller tumor sizes (T3-4 56% vs. 83%; P = 0.001), and were younger. There were 51 deaths, 14 (26%) in the sunitinib group and 37 (50%) in the control group. In the univariate analysis, the sunitinib group had longer overall survival (hazard ratio, 0.53; 95% confidence interval, 0.29-0.99; P = 0.041). In multivariate Cox regression analysis, interaction between use of sunitinib and age as a dichotomous variable was highly significant (P = 0.003). The following variables were statistically associated with prediction of overall survival: cytogenetic/molecular status (P = 0.015), T-size category (P = 0.022), gender (P = 0.040), and adjuvant sunitinib in patients aged <60 years (P = 0.004). Results were confirmed by propensity score analysis. CONCLUSIONS: In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better overall survival.

CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects.

PURPOSE: To review immune checkpoint inhibitor indications and ophthalmic side effects. METHODS: A literature review was performed using a PubMed search for publications between 1990 and 2017. RESULTS: Immune checkpoint inhibitors are designed to treat system malignancies by targeting one of three ligands, leading to T-cell activation for attack against malignant cells. These ligands (and targeted drug) include cytotoxic T-lymphocyte antigen-4 (CTLA-4, ipilimumab), programmed death protein 1 (PD-1, pembrolizumab, nivolumab), and programmed death ligand-1 (PD-L1, atezolizumab, avelumab, durvalumab). These medications upregulate the immune system and cause autoimmune-like side effects. Ophthalmic side effects most frequently manifest as uveitis (1%) and dry eye (1-24%). Other side effects include myasthenia gravis (n = 19 reports), inflammatory orbitopathy (n = 11), keratitis (n = 3), cranial nerve palsy (n = 3), optic neuropathy (n = 2), serous retinal detachment (n = 2), extraocular muscle myopathy (n = 1), atypical chorioretinal lesions (n = 1), immune retinopathy (n = 1), and neuroretinitis (n = 1). Most inflammatory side effects are managed with topical or periocular corticosteroids, but advanced cases require systemic corticosteroids and cessation of checkpoint inhibitor therapy. CONCLUSION: Checkpoint inhibitors enhance the immune system by releasing inhibition on T cells, with risk of autoimmune-like side effects. Ophthalmologists should include immune-related adverse events in their differential when examining cancer patients with new ocular symptoms.

Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis.

BACKGROUND: Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice. RESULTS: By using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice. CONCLUSIONS: Surgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies.

Establishment and Characterization of Orthotopic Mouse Models for Human Uveal Melanoma Hepatic Colonization.

Uveal melanoma (UM) is a rare type of melanoma, although it is the most common primary ocular malignant tumor in adults. Nearly one-half the patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, no treatment is effective for UM hepatic metastasis, and the prognosis is universally poor. The main challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We developed two orthotopic mouse models for human UM hepatic metastases: direct hepatic implantation model (intrahepatic dissemination model) and splenic-implantation model (hematogenous dissemination model) and investigated the tumorgenesis in the liver. A human UM cell line, established from a hepatic metastasis and nonobese diabetic severe combined immunodeficient γ mice, were used for development of in vivo tumor models. In the direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about one-half of cases. However, in the splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently seeded intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. These orthotopic mouse models offer useful tools to investigate the biological behavior of human UM cells in the liver.

Autologous melanoma cell vaccine using monocyte-derived dendritic cells (NBS20/eltrapuldencel-T).

Targeted therapy and immunotherapy have revolutionized the treatment of advanced melanoma. Despite recent advances, lack of long-term efficacy from targeted therapy and serious immune-related toxicity are major concerns. There is unmet need for 'durable' and 'safe' treatment options for advanced melanoma. Cancer vaccine therapy in melanoma has been investigated for many years with modest clinical efficacy. More recently, dendritic cell-based vaccine products have become available for clinical use and have been the focus of investigation. CLBS20 (NBS20/eltrapuldencel-T) is a novel dendritic cell-based vaccine product that has shown promising results in early phase trials in advanced melanoma. This cancer vaccine approach could play an important role in providing a sustainable survival benefit, targeting cancer cells themselves and avoiding off-target immune-related toxicity.

Integrin receptors on tumor cells facilitate NK cell-mediated antibody-dependent cytotoxicity.

NK cells that mediate ADCC play an important role in tumor-specific immunity. We have examined factors limiting specific lysis of tumor cells by CD16.NK-92 cells induced by CNTO 95LF antibodies recognizing αV integrins that are overexpressed on many tumor cells. Although all tested tumor cells were killed by CD16.NK-92 effectors in the presence of the antibodies, the killing of target cells with a low level of ICAM-1 expression revealed a dramatic decrease in their specific lysis at high antibody concentration, revealing a dose limiting effect. A similar effect was also observed with primary human NK cells. The effect was erased after IFN-γ treatment of tumor cells resulting in upregulation of ICAM-1. Furthermore, killing of the same tumor cells induced by Herceptin antibody was significantly impaired in the presence of CNTO 95Ala-Ala antibody variant that blocks αV integrins but is incapable of binding to CD16. These data suggest that αV integrins on tumor cells could compensate for the loss of ICAM-1 molecules, thereby facilitating ADCC by NK cells. Thus, NK cells could exercise cytolytic activity against ICAM-1 deficient tumor cells in the absence of proinflammatory cytokines, emphasizing the importance of NK cells in tumor-specific immunity at early stages of cancer.

Double-blinded, randomized phase II study using embolization with or without granulocyte-macrophage colony-stimulating factor in uveal melanoma with hepatic metastases.

PURPOSE: To investigate the effects of immunoembolization with granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with uveal melanoma (UM) with liver-only metastasis. MATERIALS AND METHODS: In this double-blind phase II clinical trial, patients were randomized to undergo immunoembolization or bland embolization (BE). Lobar treatment was performed with GM-CSF or normal saline solution mixed with ethiodized oil followed by embolization with gelatin sponge emulsified with iodinated contrast medium. Fifty-two patients (immunoembolization, n = 25; BE, n = 27) were enrolled. Response was assessed after every two treatments. The primary endpoint was overall response rate (ORR) of liver metastases. Progression-free survival (PFS), overall survival (OS), and immunologic responses were secondary endpoints. RESULTS: There were five partial responses in the immunoembolization group (ORR, 21.2%; 90% confidence interval [CI], 10.3%-30.5%) and three in the BE group (ORR, 16.7%; 90% CI, 6.3%-26.9%). Stable disease was seen in 12 patients in the immunoembolization group and 19 in the BE group. OS times were 21.5 months (95% CI, 18.5-24.8 mo) with immunoembolization and 17.2 months (95% CI, 11.9-22.4 mo) with BE. The degree of proinflammatory cytokine production was more robust after immunoembolization and correlated with time to "systemic" extrahepatic progression. In the immunoembolization group, interleukin (IL)-6 levels at 1 hour (P = .001) and IL-8 levels at 18 hours after the procedure (P < .001) were significant predictors of longer systemic PFS. Moreover, a dose-response pattern was evident between posttreatment serum cytokine concentrations and systemic PFS. CONCLUSIONS: Immunoembolization induced more robust inflammatory responses, which correlated with the delayed progression of extrahepatic systemic metastases.

Uveal Melanoma Metastatic to the Liver: Chemoembolization With 1,3-Bis-(2-Chloroethyl)-1-Nitrosourea.

OBJECTIVE: The purpose of this study is to evaluate whether chemoembolization with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) is a safe and effective treatment for bulky uveal melanoma liver metastasis. MATERIALS AND METHODS: Over a 7-year period, 63 treatment-naïve patients presented with uveal melanoma metastasis replacing 50% or more of the normal liver parenchyma. Patients with Eastern Cooperative Oncology Group 0-2 performance status, no extensive extrahepatic metastases, and adequate liver and renal function were treated with BCNU (200 mg) chemoembolization. Pretreatment tumor burdens were classified by MRI as 50-75% and more than 75%. Lactate dehydrogenase (LDH) levels were divided into less than or equal to 500 and more than 500 IU/L (i.e., more than twice the normal level). Treatment toxicity was assessed using Common Terminology Criteria for Adverse Events (version 4.0). CT and MRI were used to determine best radiologic response (Response Evaluation Criteria in Solid Tumors). Overall survival (OS) and progression-free survival (PFS) were compared with tumor burden and LDH levels. RESULTS: Fifty patients (31 men; mean age, 59.1 years; range, 30-88 years) met the inclusion criteria. A total of 271 chemoembolization procedures were performed. Grade 3 thrombocytopenia occurred in two patients, grade 3 hyperbilirubinemia (n = 2) was attributed to disease progression, and asymptomatic grade 4 transaminitis occurred after 16 treatments. Best radiologic response was as follows: partial response, n = 3; stable disease, n = 33; and disease progression, n = 12 (no follow-up imaging, n = 2). The median OS was 7.1 months (range, 1.2-32.3 months), and the median PFS was 5.0 months (range, 1.1-32.3 months). Eleven patients (22%) survived longer than 12 months (range, 12.2-32.3) with one patient alive at follow-up. Tumor burden and LDH levels showed no statistically significant effect on OS (p = 0.20 and p = 0.14, respectively) or PFS (p = 0.10 and p = 0.34, respectively). CONCLUSION: BCNU chemoembolization should be considered as a treatment option for patients with bulky uveal melanoma hepatic metastases.

Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial.

IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.

Early arterial stasis during resin-based yttrium-90 radioembolization: incidence and preliminary outcomes.

OBJECTIVES: This study was conducted to determine the incidence of early stasis in radioembolization using resin yttrium-90 (Y-90) microspheres, to evaluate potential contributing factors, and to review initial imaging outcomes. METHODS: Patients in whom early stasis occurred were compared with those in whom complete delivery was achieved for tumour type and vascularity, tumour : normal liver ratio (T : N ratio) at technetium-99m-macroaggregated albumin (Tc-99m-MAA) angiography, previous intra-arterial therapy, and infusion site (left, right or whole liver). Tumour response was evaluated at 3 months and defined according to whether a partial response and stable disease versus progressive disease were demonstrated. RESULTS: A total of 71 patients underwent 128 Y-90 infusions in which 26 (20.3%) stasis events occurred. Hypervascular and hypovascular tumours had similar rates of stasis (17.4% versus 27.8%; P = NS). The mean ± standard deviation T : N ratio was 3.03 ± 1.54 and 3.66 ± 2.79 in patients with and without stasis, respectively (P = NS). Stasis occurred in 14 of 81 (17.3%) and 12 of 47 (25.5%) infusions following previous intra-arterial therapy and in therapy-naïve territories, respectively (P = NS). Early stasis occurred in 15 of 41 (36.6%) left, 10 of 65 (15.4%) right and one of 22 (4.5%) whole liver infusions (P < 0.001). Rates of partial response and stable disease were similar in the stasis (88.3%) and non-stasis (76.0%) groups (P = NS). CONCLUSIONS: Early stasis occurred in approximately 20% of infusions with similar incidences in hyper- and hypovascular tumours. Whole-liver therapy reduced the incidence of stasis. Stasis did not appear to affect initial imaging outcomes.

A cluster of Candida parapsilosis displaying fluconazole-trailing in a neonatal intensive care unit successfully contained by multiple infection-control interventions.

Objective: This study aimed to investigate and contain a cluster of invasive candidiasis cases caused by fluconazole-resistant Candida parapsilosis (FRC) in a neonatal intensive care unit. Methods: Active surveillance was initiated. Direct observations of hand-hygiene compliance (HHC) among staff were conducted before and after the implementation of hand-hygiene (HH) education. Thirty-five environmental cultures were obtained. Phylogenetic analysis of FRC was performed using Fourier-transform infrared spectroscopy and microsatellite genotyping. Results: A total of 14 patients (mean birth weight = 860 g, gestational age = 25 weeks) infected with FRC were identified using the fully automated analyzer, including 5 with clinical infection (three with catheter-related bloodstream infection, one with cutaneous infection, and one with fatal peritonitis) and 9 with colonization. The HHC rate in nurses before performing a sterile or aseptic procedure significantly improved after the HH education (P < .05). Sinks near the patients were contaminated with FRC. All FRC strains were confirmed to be susceptible to fluconazole using the CLSI method, and the microdilution procedure indicated a trailing effect. Phylogenetic analysis showed that all the fluconazole-trailing isolates from patients were clustered together and had the same genotype. Sinks were successfully decontaminated using accelerated hydrogen peroxide and drainage pipes were replaced. Ultraviolet-C decontamination was applied in the milk preparation room. No new cases were detected after the education and disinfection interventions. Conclusions: Sinks are an important reservoir of C. parapsilosis. Active surveillance, environmental hygiene, and constant staff education on maintaining a high level of HHC are necessary to limit the spread of C. parapsilosis.

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma.

The mechanisms driving late relapse in uveal melanoma (UM) patients remains a medical mystery and major challenge. Clinically it is inferred that UM disseminated cancer cells (DCCs) persist asymptomatic for years-to-decades mainly in the liver before they manifest as symptomatic metastasis. Here we reveal using Gαq/11 mut /BAP wt human uveal melanoma models and human UM metastatic samples, that the neural crest lineage commitment nuclear receptor NR2F1 is a key regulator of spontaneous UM DCC dormancy in the liver. Using a quiescence reporter, RNA-seq and multiplex imaging we revealed that rare dormant UM DCCs upregulate NR2F1 expression and genes related to neural crest programs while repressing gene related to cell cycle progression. Gain and loss of function assays showed that NR2F1 silences YAP1/TEAD1 transcription downstream of Gαq/11 signaling and that NR2F1 expression can also be repressed by YAP1. YAP1 expression is repressed by NR2F1 binding to its promoter and changing the histone H3 tail activation marks to repress YAP1 transcription. In vivo CRISPR KO of NR2F1 led dormant UM DCCs to awaken and initiate relentless liver metastatic growth. Cut&Run and bulk RNA sequencing further confirmed that NR2F1 epigenetically stimulates neuron axon guidance and neural lineage programs, and it globally represses gene expression linked to G-protein signaling to drive dormancy. Pharmacological inhibition of Gαq/11 mut signaling resulted in NR2F1 upregulation and robust UM growth arrest, which was also achieved using a novel NR2F1 agonist. Our work sheds light on the molecular underpinnings of UM dormancy revealing that transcriptional programs driven by NR2F1 epigenetically short-circuit Gαq/11 signaling to its downstream target YAP1. Highlights: Quiescent solitary uveal melanoma (UM) DCCs in the liver up- and down-regulate neural crest and cell cycle progression programs, respectively.NR2F1 drives solitary UM DCC dormancy by antagonizing the Gαq/11-YAP1 pathway; small molecule Gαq/11 inhibition restores NR2F1 expression and quiescence. NR2F1 short-circuits oncogenic YAP1 and G-protein signaling via a chromatin remodeling program. Loss of function of NR2F1 in dormant UM DCCs leads to aggressive liver metastasis.

A rat-based preclinical platform facilitating transcatheter hepatic arterial infusion in immunodeficient rats with liver xenografts of patient-derived pancreatic ductal adenocarcinoma.

Liver metastases from pancreatic ductal adenocarcinoma (PDAC) are highly fatal. A rat-based patient-derived tumor xenograft (PDX) model is available for transcatheter therapy. This study aimed to create an immunodeficient rat model with liver xenografts of patient-derived primary PDAC and evaluate efficacy of hepatic arterial infusion chemotherapy with cisplatin in this model. Three patient-derived PDACs were transplanted into the livers of 21 rats each (totally, 63 rats), randomly assigned into hepatic arterial infusion, systemic venous infusion, and control groups (n = 7 each) four weeks post-implantation. Computed tomography evaluated tumor volumes before and four weeks after treatment. Post-euthanasia, resected tumor specimens underwent histopathological examination. A liver-implanted PDAC PDX rat model was established in all 63 rats, with first CT identifying all tumors. Four weeks post-treatment, arterial infusion groups exhibited significantly smaller tumor volumes than controls for all three tumors on second CT. Xenograft tumors histologically maintained adenocarcinoma features compared to original patient tumors. Ki67 expression was significantly lower in arterial infusion groups than in the other two for the three tumors, indicating reduced tumor growth in PDX rats. A liver-implanted PDAC PDX rat model was established as a rat-based preclinical platform. Arterial cisplatin infusion chemotherapy represents a potential therapy for PDAC liver metastasis.

Slow proliferation of BAP1-deficient uveal melanoma cells is associated with reduced S6 signaling and resistance to nutrient stress.

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, BAP1 mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in BAP1 mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.