Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial.

BACKGROUND: The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma. METHODS: This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0-2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60-70 Gy in ten fractions or 52·5-67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611. FINDINGS: 30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2-24·6), median progression-free survival was 22·7 months (95% CI 10·4-not reached; 1-year progression-free survival 64% [95% CI 48-85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths. INTERPRETATION: Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma. FUNDING: Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.

Natural History of T1N0M0 Hepatocellular Carcinoma: Large-Scale Study in the United States.

BACKGROUND: Hepatocellular carcinoma (HCC) prognosis depends on clinicopathological features in addition to the treatment provided. We aimed to assess the natural history of TNM stage I HCC tumors which received different treatment over a period of 20 years. METHODS: Between 1992 and 2011, a total of 397 stage I HCC patients were included. Detailed information was retrieved from MD Anderson Cancer Center patients' medical records. The Kaplan-Meier method was used to calculate patients' overall survival (OS). Cox regression analysis was used to calculate the estimated hazard ratio and 95% confidence interval of different prognostic factors. RESULTS: Out of 397 patients, 67.5% were males, 42.8% had hepatitis-related HCC, and 59.7% had underlying cirrhosis. After adjustment for confounding factors, we found that all therapeutic modalities were associated with a significant mortality rate reduction with an OS of 63, 42.03, 34.3, and 22.1 months among patients treated with surgery, ablation, local, and systemic therapy, respectively. A restricted analysis of cirrhotic and noncirrhotic patients showed that ablative and local therapy were significantly associated with a longer OS compared to systemic therapy. CONCLUSION: TNM stage I HCC patients have a favorable prognosis regardless of the type of treatment. Notably, ablative and local therapy significantly improved OS compared to systemic therapy.

Prognostic value of incidental hypervascular micronodules detected on cone-beam computed tomography angiography of patients with liver metastasis.

PURPOSE: To determine the clinical relevance of incidentally-found hypervascular micronodules (IHM) on cone-beam computed tomography angiography (CBCTA) in patients with liver metastasis undergoing transarterial (chemo)embolization (TACE/TAE). MATERIAL AND METHODS: This was a HIPAA-compliant institutional review board-approved single-institution retrospective review of 95 non-cirrhotic patients (52 men; mean age, 60 years) who underwent CBCTA prior to (chemo)embolic delivery. IHM were defined by the presence of innumerable subcentimetre hepatic parenchymal hypevascular foci not detected on pre-TACE/TAE contrast-enhanced cross-sectional imaging. Multivariate analysis was performed to compare time to tumour progression (TTP) between patients with and without IHM. RESULTS: IHM were present in 21 (22%) patients. Patients with IHM had a significantly shorter intrahepatic TTP determined by a higher frequency of developing new liver metastasis (hazard ratio [HR]: 1.99; 95% confidence interval [CI] 1.08-3.67, P= 0.02). Patients with IHM trended towards a shorter TTP of the tumour(s) treated with TACE/TAE (HR: 1.72; 95% CI: 0.98-3.01, P= 0.056). Extrahepatic TTP was not significantly different between the two cohorts (P= 0.27). CONCLUSION: Patients with IHM on CBCTA have worse prognosis due to a significantly higher risk of developing new hepatic tumours. Further work is needed to elucidate its underlying mechanisms of pathogenesis. KEY POINTS: • 21% of liver metastasis patients undergoing TACE/TAE have IHM on CBTA. • IHM are associated with a high risk of developing new hepatic tumours. • IHA are also associated with a trend toward poorer response to TACE/TAE.

Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma.

OBJECTIVE: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. METHODS: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. RESULTS: RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. CONCLUSIONS: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Lutein protects retinal pigment epithelium from cytotoxic oxidative stress.

CONTEXT: Lutein (LUT) and zeaxanthin (ZEA) are currently under investigation in clinical trials as prophylactic nutritional agents for age-related macular degeneration (AMD). However, dose used in these trials is empirical and not been investigated in in vitro studies. OBJECTIVE: In this study, we investigated the dose-response effect of LUT and ZEA in protecting retinal pigment epithelium (RPE) from oxidative stress, a common underlying pathology in AMD. METHODS: Three thousand cultured human retinal pigment epithelial cells (ARPE-19) were plated in 72-well plate and after 24 h were exposed to increasing concentrations of hydrogen peroxide (H2O2). ARPE-19 cells were exposed to four different concentrations of LUT (0.5, 1, 2 and 4 µg/mL) and ZEA (0.1, 0.2, 0.4 and 0.8 µg/mL). After 24 h incubation, cells were subjected to oxidative stress induced with H2O2. Cultures containing saline solution and dichloromethane served as controls. Cell viability was assessed using the WST-1 assay. Pathophysiological pathways were evaluated by measuring caspase-3 levels as an indicator of apoptosis induction. Reactive oxygen species (ROS) levels were measured using dihydrorhodamine-123. RESULTS: Cell viability as a percentage of control was 81.3%, 81.1%, and 88.8% at 0.5, 1, and 2 µg/ml, respectively of LUT (p < 0.001). The maximum cytoprotective effect was seen with LUT at 2 µg/mL. ZEA did not show any cytoprotective effect at all concentrations used in the study. Caspase-3 showed a corresponding decrease in levels with LUT (1 and 2 µg/ml). Significant decrease in ROS levels were measured only with LUT at 4 µg/ml (p = 0.02). DISCUSSION AND CONCLUSIONS: Results from our study provide in vitro data to support the epidemiologic studies, which are currently underway to provide evidence that lutein may act as cofactor that modulates processes implicated in AMD pathogenesis.

Resveratrol inhibits proliferation of hypoxic choroidal vascular endothelial cells.

PURPOSE: Resveratrol, a polyphenolic phytoalexin present in red wine, has a protective role against tumor-induced angiogenesis. Exudative age-related macular degeneration is characterized by hypoxia-induced choroidal vascular endothelial cell (CVEC) proliferation. In this study, we evaluated the effect of resveratrol on hypoxic CVECs and the underlying signaling pathways involved. METHODS: CVECs (RF/6A) after induction of hypoxia with cobalt chloride (CoCl2, 200 µM) were exposed to increasing doses of resveratrol (2, 4, 6, 8, 10, and 12 µg/ml). Cell viability was measured with 4-[3-(4Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1, 3-benzene disulfonate (WST-1) colorimetric assay. The effect of resveratrol on hypoxia-induced vascular endothelial growth factor (VEGF) release was analyzed with enzyme-linked immunosorbent assay. The mechanistic pathway was further evaluated by analyzing phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) using immunoblot and cleaved caspase-3 with In-Cell enzyme-linked immunosorbent assay. RESULTS: Resveratrol inhibited hypoxic CVEC proliferation. Hypoxia-induced VEGF release (30.9±2.6 pg/ml) was inhibited in a dose-dependent fashion by 2, 4, 6, 8, 10, and 12 µg/ml resveratrol to 12.4±2.1, 11.0±1.9, 10.3±3.0, 7.5±1.9, 5.5±2.0, and 5.5±2.3 pg/ml, respectively. SAPK/JNK increased by 1.8-fold and 3.9-fold after treatment with 4 and 12 µg/ml resveratrol, respectively. Significant increase in caspase-3 levels was observed with 12 µg/ml resveratrol. CONCLUSIONS: Our study demonstrates that resveratrol suppresses hypoxic CVEC proliferation through activation of the SAPK/JNK pathway. Resveratrol, a nutritional supplement and inhibitor of CVECs, may be a useful adjunct to current anti-VEGF therapy in wet age-related macular degeneration.

Gastroduodenal artery recanalization after transcatheter fibered coil embolization for prevention of hepaticoenteric flow: incidence and predisposing technical factors in 142 patients.

BACKGROUND: Prophylactic occlusion of extrahepatic vessels prior to radioembolization or chemotherapy infusion is an effective method to prevent gastrointestinal complications. Unfortunately, vascular recanalization can occur. PURPOSE: To retrospectively determine the rate and technical factors associated with gastroduodenal artery (GDA) recanalization after transcatheter occlusion with fibered coils. MATERIAL AND METHODS: Patients with hepatic malignancy who underwent fibered coil occlusion of the GDA origin for radioembolization or hepatic arterial chemotherapy infusion with at least one subsequent hepatic angiogram between March 2006 and January 2011 were included. One hundred and forty-two patients (men, 71; women, 71) met study criteria. Hepatic arteriograms were reviewed to determine the frequency of arterial recanalization. Additional parameters included: patients' demographics, GDA diameter, length of coil pack, distance between GDA origin and most cephalad coil, persistent flow at the conclusion of the initial GDA occlusion procedure, platelet count, and international normalized ratio (INR). Chi-square test and pooled t-test were used to compare the two groups. Prospective multivariate analysis was performed with a logistic regression model. RESULTS: Twenty-nine of 142 patients (20.4%) experienced GDA recanalization. The distance between the GDA origin and most cephalad coil was significantly greater in the recanalization group than in the non-recanalization group (9.6 mm vs. 12.6 mm, P = 0.01). A prospective multivariate analysis established that the further the coil was from the origin the more likely the GDA was to recanalize. The two groups did not differ on the basis of any other factors examined. CONCLUSION: GDA origin recanalization after fibered coil occlusion is common. The distance between the GDA origin and most cephalad coil appears to be a predisposing factor for recanalization. Familiarity with this phenomenon is beneficial to reduce the likelihood of gastrointestinal tract complications during hepatic locoregional therapy.

A Sticky Situation: Glue Migration during Hepatic Vein Embolization.

The addition of hepatic venous embolization to portal venous embolization to achieve ipsilateral liver venous deprivation before major hepatectomy has been suggested to increase the extent of hypertrophy of the future liver remnant. The presented case discusses a hepatic vein embolization procedure complicated by the unintended migration of a glue cast used to achieve hepatic venous occlusion and subsequent management with endovascular retrieval of the glue cast from the inferior vena cava. The emerging role of hepatic venous embolization and associated complications are also discussed.

Temporary balloon occlusion of the common hepatic artery for administration of yttrium-90 resin microspheres in a patient with patent hepatoenteric collaterals.

The most common serious complication of yttrium-90 ((90)Y) therapy is gastrointestinal ulceration caused by extrahepatic microsphere dispersion. The authors describe the use of a balloon catheter for temporary occlusion of the common hepatic artery to reverse hepatoenteric flow for lobar administration of resin microspheres when coil embolization of a retroportal artery was impossible. At 9 months after treatment, the patient had no gastrointestinal side effects and showed a partial response.

Evaluation of proton beam radiation sensitivity of proliferating choroidal endothelial and retinal ganglion cells with clonogenic assay.

CONTEXT: Proton beam therapy offers the advantage of precise delivery with limited damage to the healthy tissue and is being tested in the management of exudative age-related macular degeneration (AMD). However, the dosages tested are empirical and not based on preclinical studies. OBJECTIVE: In this study we evaluated the effects of varying doses of proton beam radiation on choroidal endothelial cells (CECs) and retinal ganglion cells (RGCs) using clonogenic assay to determine differential sensitivity. MATERIALS AND METHODS: Each cell type has different efficiency to replicate (plating efficiency (PE)). PE of CEC (RF/6A) and RGC (RGC-5) grown in culture flasks was determined by plating 250 cells each (without any treatment) and counting the number of colonies after 13 days. Radiation induced sensitivity was determined by exposing the semi-confluent RF/6A and RGC-5 cells to proton beam at the doses of 0 (control), 2, 4, 8 and 12 cobalt gray equivalent (CGE). The ability of the cells to repair and replicate to form colonies were analyzed 13 days after radiation with crystal violet stain and the survival ratio was calculated. The significance of survival was analyzed using ANOVA (Graphpad Instat.3). RESULTS: The PE of CEC and RGC was 12.96 ± 0.29% and 40.7 ± 1.48%, respectively. A survival ratio of CEC at 2, 4, 8 and 12 CGE proton radiation was 66.0 ± 8.6%, 44.3 ± 6.5%, 7.6 ± 0.3% and 1.14 ± 0.06% on exposure to 2, 4, 8 and 12 CGE proton radiation, respectively, p < 0.01). Survival ratio of RGC was 71.1 ± 22.4% (p = 0.05), 40.2 ± 7.9%, 8.89 ± 2.6% and 0.78 ± 0.31% at 2, 4, 8 and 12 CGE dosages (p < 0.001). DISCUSSION: CEC showed dose-dependent decrease in survival rate with values attaining significance at all radiation dosages. In contrast, RGC was comparatively radio resistant and were able to replicate at lower doses and sensitive at higher doses after proton beam radiation. CONCLUSION: Since CECs proliferate during neovascularization, this clonogenic assay is a useful assay to assess the sensitivity of CEC to radiation. This study identified that CEC were more sensitive to proton beam radiation than RGC at all doses. This may provide a therapeutic window for administration of proton beam radiation in the management of AMD.

Temporary Reversal of Hepatoenteric Collaterals during 90Y Radioembolization Planning and Administration.

PURPOSE: This paper aims to evaluate the safety and efficacy of the temporary redirection of blood flow of hepatoenteric collaterals using a balloon catheter in the common hepatic artery (CHA) to prevent the nontarget deposition of 90Y microspheres. MATERIALS AND METHODS: In this retrospective single-center study of patients who received 90Y radioembolization (RE) from September 2010 to September 2015, diagnostic (67 patients) or treatment (72 patients) angiograms with the attempted use of a balloon catheter in the CHA to temporarily direct blood flow away from the hepatoenteric arteries were analyzed. SPECT/CT nuclear scintigraphy was performed after both diagnosis and treatment. RESULTS: Overall, only 12 hepatoenteric arteries in 11 patients required embolization due to persistent hepatoenteric flow despite the use of the balloon occlusion technique in a total of 86 patients. Physicians performed the 90Y RE using balloon occlusion with glass (n = 22) or resin (n = 50) microspheres. Over 80% administration of the prescribed 90Y dose was accomplished in 34 (67%) resin and 20 (95%) glass microsphere patients. Post-treatment 90Y RE scintigraphy confirmed the absence of extrahepatic activity in all patients. One grade 2 gastrointestinal ulcer was present after 90 days of follow-up. CONCLUSION: Temporary CHA occlusion with a balloon catheter is a reliable and reproducible alternative to the conventional coil embolization of hepatoenteric arteries during diagnostic Tc-99m macroaggregated albumin and therapeutic 90Y RE delivery.

Tilsotolimod Exploits the TLR9 Pathway to Promote Antigen Presentation and Type 1 IFN Signaling in Solid Tumors: A Multicenter International Phase I/II Trial (ILLUMINATE-101).

PURPOSE: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors. PATIENTS AND METHODS: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses. RESULTS: Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease. CONCLUSIONS: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment. See related commentary by Punekar and Weber, p. 5007.

Response, survival, and prognostic factors after hepatic arterial chemoembolization in patients with liver metastases from cutaneous melanoma.

We reviewed the medical records of 42 patients with cutaneous melanoma metastatic to the liver who underwent hepatic artery chemoembolization (HACE) at our institution. HACE resulted in radiologic response (38.9%) or disease stabilization (47.2%) in most patients. The median overall survival (OS) and time to progression (TTP) of liver disease were 7.7 and 6 months, respectively. Patient's age, lactate dehydrogenase (LDH) levels, type of treatment, number of extrahepatic metastatic sites, and response to therapy were found to be significant predictors of OS after HACE. Prolonged survival was seen in patients who responded to HACE (p = .034).

Development of a large animal model of cirrhosis and portal hypertension using hepatic transarterial embolization: a study in swine.

PURPOSE: To develop a clinically relevant porcine model of liver cirrhosis with portal hypertension by means of hepatic transarterial embolization. MATERIALS AND METHODS: Institutional animal care and use committee approval was obtained for all experiments. Pigs received transcatheter arterial infusion of a 3:1 mixture of iodized oil and ethanol into the hepatic artery in volumes of 16 mL in group 1 (n = 4), 28 mL in group 2 (n = 4), and 40 mL in group 3 (n = 4) with intent of bilobar distribution. Hepatic venous pressure gradient (HVPG) measurement, liver function tests, and volumetry were performed at baseline, at 2 weeks, and before necropsy. RESULTS: Cirrhosis was successfully induced in three animals that received 16 mL of the embolic mixture and in all four animals that received 28 mL. The animals in the 40-mL group did not recover from the procedure and were euthanized within 48 h. Increases in HVPG after 6-8 weeks versus baseline reached statistical significance (P < .05). Correlation between degree of fibrosis and volume of embolic agent did not reach statistical significance, but there was a trend toward increased fibrosis in the 28-mL group compared with the 16-mL group. CONCLUSIONS: Transcatheter hepatic arterial embolization can be used to create a reliable and reproducible porcine model of liver cirrhosis and portal hypertension.

Comparative in vitro safety analysis of dyes for chromovitrectomy: indocyanine green, brilliant blue green, bromophenol blue, and infracyanine green.

PURPOSE: Vital dyes such as infracyanine green (IfCG), brilliant blue green (BBG), and bromophenol blue (BPB) have been used as an alternative to indocyanine green (ICG) during chromovitrectomy. We compared the in vitro toxicity of IfCG, BBG, and BPB with ICG on the retinal pigment epithelial cells and retinal ganglion cells at various concentrations to optimize the safe dose and duration of exposure. METHODS: Cultured retinal ganglion cells (RGC-5) and human retinal pigment epithelial cells (ARPE-19) were exposed to 2 concentrations (0.25 and 0.5 mg/mL) of ICG, IfCG, BBG, and BPB at various time intervals (1, 5, 15, and 30 minutes). Cell viability was quantified with neutral red assay, and mode of cell death was evaluated with flow cytometry-based Annexin V and propidium iodide staining. RESULTS: Exposure to ICG resulted in 48%-74% reduction in neutral red uptake in both RGC-5 and ARPE-19 cells, after an exposure time of ≥5 minutes compared with control (P < 0.001). Infracyanine green, BBG, and BPB were significantly less toxic on the 2 cell lines at exposure times <15 minutes. (Reduction in cell viability ranged from 6.9% ± 3.3% to 29.3% ± 7.4% when compared with control, P > 0.5.) However, among the newer dyes, BBG caused necrosis in retinal pigment epithelial cells and retinal ganglion cells as the exposure time period increased beyond 5 minutes. CONCLUSION: Newer vital dyes, IfCG, BBG, and BPB, are significantly less toxic on retinal ganglion cells and retinal pigment epithelial cells' cell lines when compared with ICG. Infracyanine green was least toxic among the three newer dyes studied.

Evaluation of choroidal endothelial cell proliferation after exposure to varying doses of proton beam radiation.

PURPOSE: Focal epiretinal radiation has emerged as a promising tool in the management of choroidal neovascularization associated with age-related macular degeneration. However, the dosages tested are not backed by cell culture studies used in the clinical setting empirically. METHODS: Choroidal endothelial cells (RF6A) were maintained in a log scale and exposed to a single fraction of 2, 4, 8, and 12 cobalt gray-equivalent of proton radiation with an internal control. Cell viability was quantified using Vi-cell XR and neutral red assay at days 5, 9, and 12 after radiation. Mitochondrial viability using WST-1 and reactive oxygen species levels using dihydrorhodamine 123 were measured at similar intervals. RESULTS: By using neutral red assay, on day 12, the percentages of viable cells compared with control were 100.1 ± 5.7%, 96.7 ± 23.3%, 27.6 ± 6.6%, and 19.5 ± 3% at radiation doses of 2, 4, 8, and 12 cobalt gray-equivalent, respectively (P < 0.001). Increase in reactive oxygen species levels correlated with the number of dead cells implicating reactive oxygen species as an intermediary molecule (r = 0.85-0.96). CONCLUSION: Our study shows sensitivity of cultured choroidal endothelial cells to proton beam radiation at doses of 8 and 12 cobalt gray-equivalent in an in vitro model.

Refractory Biliary Catheter Leak Corrected by a Hybrid Closed Loop Catheter-Pump System.

The development of inoperable biliary obstruction in patients with liver, biliary, and pancreatic neoplasia is commonplace particularly in the advanced stages of these diseases. Under these circumstances, restoring bile flow to the gut is paramount in reestablishing homeostasis. Hitherto, this has been achieved by utilizing passive, gravity-dependent bilioenteric conduits with the use of perforated plastic catheters or metallic stents inserted either in a percutaneous transhepatic fashion or via endoscopic techniques. A frequent untoward event of biliary decompression utilizing percutaneous transhepatic catheters (PTC) is the development of pain, cholangitis, hyperbilirubinemia, or pericatheter bile leak due to the suboptimal normalization of bile flow. In some instances, the etiology of PTC malfunction can be correctly ascribed to catheter malposition and/or catheter lumen obstruction; however, in the majority, it remains radiographically occult on transcatheter cholangiography-the "gold standard." Regardless of findings, the management remains fluoroscopic repositioning or exchanges for larger diameter catheters to attempt to seal the pericatheter potential space and prevent bile seepage. Unfortunately, these maneuvers are met with limited and unpredictable levels of success. We present the successful management of an instance of recalcitrant external pericatheter bile leak mitigated by employing a hybrid closed loop biliary catheter-pump system by employing an assortment of FDA approved off-the-shelf medical devices.

Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy.

BACKGROUND: Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy. METHODS: Intratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution. RESULTS: Variations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and 'inflammatory' dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal). CONCLUSIONS: Injection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics.

Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone.This article is highlighted in the In This Issue feature, p. 1861.

Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors.

PURPOSE: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. PATIENTS AND METHODS: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. RESULTS: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. CONCLUSIONS: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.