Background and Aims Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease—the principal causes of cancer mortality—have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE‐induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. Approach and Results In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE‐induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13carbon‐labeled substrates. Under TAE‐induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP‐MRSI of 1‐13C‐pyruvate and its downstream metabolites, 1‐13C‐lactate and 1‐13C‐alanine, predicted histological viability. Conclusions These studies provide a paradigm for imaging latent, treatment‐refractory cancer cells, suggesting that DNP‐MRSI provides a technology for this application.

Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.

Minimally invasive ablation strategies enable locoregional treatment of tumors. One such strategy, electrolytic ablation, functions through the local delivery of direct current without thermal effects, facilitating enhanced precision. However, the clinical application of electrolytic ablation is limited by an incompletely characterized mechanism of action. Here we show that acid and base production at the electrodes precipitates local pH changes causing the rapid cell death that underlies macroscopic tumor necrosis at pH > 10.6 or < 4.8. The extent of cell death can be modulated by altering the local buffering capacity and antioxidant availability. These data demonstrate that electrolytic ablation is distinguished from other ablation strategies via its ability to induce cellular necrosis by directly altering the tumor microenvironment. These findings may enable further development of electrolytic ablation as a curative therapy for primary, early stage tumors.

BackgroundRefugees living with HIV in sub-Saharan Africa suffer unique hardships that may increase their vulnerability to interruptions in antiretroviral therapy (ART).MethodsTo investigate refugees’ experiences adhering to ART, we conducted inperson interviews with refugees on ART (n = 73) and HIV clinic staff (n = 4) in Nakivale Refugee Settlement in southwest Uganda from March to July 2011. Three analysts used a conventional content analysis approach to evaluate these data.ResultsRefugees described profound motivation to adhere to ART and employed adherence strategies to facilitate success despite the austere setting. However, refugees spoke of specific hardships living in Nakivale that served as barriers to ART adherence, including difficulty accessing clinic when ill, food insecurity, drug stockouts, and violence and unrest in the settlement. For some refugees, need for ART inextricably linked them to the HIV clinic and prevented them from transitioning permanently away from the settlement.ConclusionsBy learning about refugees’ experiences we can design informed interventions to enhance ART adherence, thus minimizing morbidity and mortality, preventing transmission of HIV, and supporting refugees’ abilities to move freely toward repatriation, resettlement or integration in their host country.

Background Gastroparesis is a complex and poorly understood disease. The literature is lacking with respect to the epidemiology of patient comorbidities and their effect on gastric emptying. We aimed to describe the most common comorbid conditions among patients with gastroparesis in an urban population and quantify the effect of these comorbidities on the severity of delayed gastric emptying (DGE). MethodsWe examined the medical records of all patients diagnosed with gastroparesis at a quaternary care center between 2014 and 2015. The severity of DGE was analyzed after patients were stratified for possible causative etiologies. Likelihood ratio tests were used to assess the significance of demographic and scintigraphic variation in this population. ResultsOf the 221 patients, 56.1% were Caucasian and 31.7% were African American. Among these patients, 29.4% had evidence of medication-associated gastroparesis, 29.0% had diabetesassociated gastroparesis, and 31.7% had idiopathic disease. African American patients with gastroparesis were more likely to have diabetic gastroparesis than patients of other races (P=0.01). There was a statistically significant relationship between the number of major risk factors and the severity of a patient's DGE (P=0.004).Conclusions Among a diverse urban population, patients with DGE often carry multiple comorbid conditions that serve as risk factors for the development of gastroparesis, including prescriptions for narcotic medications. Greater numbers of these comorbid conditions are associated with more severe disease. Demographics are significantly associated with the etiology and severity of gastroparesis; in particular, African American patients are more likely to have diabetic gastroparesis than patients of other races.

While patient-derived xenograft (PDX) models of hepatocellular carcinoma (HCC) have been successfully generated from resected tissues, no reliable methods have been reported for the generation of PDXs from patients who are not candidates for resection and represent the vast majority of patients with HCC. Here we compare two methods for the creation of PDXs from HCC biopsies and find that implantation of whole biopsy samples without the addition of basement membrane matrix favors the formation of PDX tumors that resemble Epstein-Barr virus (EBV)-driven B-cell lymphomas rather than HCC tumors. In contrast, implantation with Matrigel supports growth of HCC cells and leads to a high rate of HCC tumor formation from these biopsies. We validate the resulting PDXs, confirm their fidelity to the patients’ disease and conclude that minimally invasive percutaneous liver biopsies can be used with relatively high efficiency to generate PDXs of HCC.

◥Purpose: Targeted therapies for cancer have accelerated the need for functional imaging strategies that inform therapeutic efficacy. This study assesses the potential of functional genetic screening to integrate therapeutic target identification with imaging probe selection through a proof-of-principle characterization of a therapyprobe pair using dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI).Experimental Design: CRISPR-negative selection screens from a public dataset were used to identify the relative dependence of 625 cancer cell lines on 18,333 genes. Follow-up screening was performed in hepatocellular carcinoma with a focused CRISPR library targeting imaging-related genes. Hyperpolarized [1-13 C]-pyruvate was injected before and after lactate dehydrogenase inhibitor (LDHi) administration in male Wistar rats with autochthonous hepatocellular carcinoma. MRSI evaluated intratumoral pyruvate metabolism, while T 2 -weighted segmentations quantified tumor growth.Results: Genetic screening data identified differential metabolic vulnerabilities in 17 unique cancer types that could be imaged with existing probes. Among these, hepatocellular carcinoma required lactate dehydrogenase (LDH) for growth more than the 29 other cancer types in this database. LDH inhibition led to a decrease in lactate generation (P < 0.001) and precipitated dose-dependent growth inhibition (P < 0.01 overall, P < 0.05 for dose dependence). Intratumoral alanine production after inhibition predicted the degree of growth reduction (P < 0.001).Conclusions: These findings demonstrate that DNP-MRSI of LDH activity using hyperpolarized [1-13 C]-pyruvate is a theranostic strategy for hepatocellular carcinoma, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening informs imaging probe selection to quantify therapeutic efficacy on a cancer-bycancer basis.

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