Vidutolimod in Combination With Atezolizumab With and Without Radiation Therapy in Patients With Programmed Cell Death Protein 1 or Programmed Death-Ligand 1 Blockade-Resistant Advanced NSCLC.

Introduction: Vidutolimod, a CpG-A TLR9 agonist, was investigated in a phase 1b study (CMP-001-003; ClinicalTrials.gov, NCT03438318) in combination with atezolizumab with and without radiation therapy (RT) in patients with advanced NSCLC. Methods: Patients with progressive disease after anti-programmed cell death protein 1 or programmed death-ligand 1 therapy received either vidutolimod and atezolizumab (part A) or vidutolimod, atezolizumab, and RT (part B). The primary objective was to evaluate the safety of vidutolimod and atezolizumab with and without RT. Key secondary end point was best objective response rate per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Between March 28, 2018, and July 25, 2019, a total of 29 patients were enrolled and received at least one dose of vidutolimod (part A, n = 13; part B, n = 16). Intratumoral injections of vidutolimod were administered successfully, including injection of visceral lesions. The most common treatment-related adverse events (≥30%) were flu-like symptoms and hypotension. No objective responses were observed; 23.1% and 50.0% of the patients in parts A and B, respectively, had stable disease as best response. In parts A and B, 15.4% and 25.0% of the patients, respectively, had tumor shrinkage (<30% decrease in tumor size, nonirradiated). Enrollment was stopped owing to lack of objective responses. In the two patients with initial tumor shrinkage in part A, a strong serum induction of C-X-C motif chemokine ligand 10 was observed. Conclusions: Vidutolimod and atezolizumab with and without RT had a manageable safety profile, with minimal clinical activity in heavily pretreated patients with programmed cell death protein 1 or programmed death-ligand 1 blockade-resistant NSCLC.

A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy.

The accumulation of immune-suppressive myeloid cells is a critical determinant of resistance to anti-programmed death-1 (PD-1) therapy in advanced clear cell renal cell carcinoma (ccRCC). In preclinical models, the tyrosine kinase inhibitor sitravatinib enhanced responses to anti-PD-1 therapy by modulating immune-suppressive myeloid cells. We conducted a phase 1-2 trial to choose an optimal sitravatinib dose combined with a fixed dose of nivolumab in 42 immunotherapy-naïve patients with ccRCC refractory to prior antiangiogenic therapies. The combination demonstrated no unexpected toxicities and achieved an objective response rate of 35.7% and a median progression-free survival of 11.7 months, with 80.1% of patients alive after a median follow-up of 18.7 months. Baseline peripheral blood neutrophil-to-lymphocyte ratio correlated with response to sitravatinib and nivolumab. Patients with liver metastases showed durable responses comparable to patients without liver metastases. In addition, correlative studies demonstrated reduction of immune-suppressive myeloid cells in the periphery and tumor microenvironment following sitravatinib treatment. This study provides a rationally designed combinatorial strategy to improve outcomes of anti-PD-1 therapy in advanced ccRCC.

The Impact of the Use of C-Arm Cone-Beam CT During Chemoembolization for Hepatocellular Carcinoma.

OBJECTIVE: The objective of the study was to investigate the consequences of using CArm Cone-Beam computed Tomography (CBCT) on super-selective catheterization of Hepatic Artery (HA) branches during chemoembolization of hepatocellular carcinoma. METHODS: Two groups of patients were created according to the dates of their treatment sessions. Group A and Group B included patients who had their treatment sessions in 2004 - 2005 and 2008 - 2010, respectively. The sessions performed in 2006 and 2007 were excluded to allow for the adoption and incorporation of CBCT imaging into clinical practice. All chemoembolized HA branches were categorized according to selection order (0-1, 2, or ≥3). Other procedure variables were documented. RESULTS: A total of 58 and 183 sessions were included in Groups A and B, respectively, for 144 patients. C-arm CBCT was used in 2 (3%) sessions and 142 (78%) sessions in groups A and B, respectively. The average number of vessels treated was significantly higher in group B (1.8) compared to group A (1.3) (P < .0001). A shift to an increased selection order in group B (0-1, 44 [24%]; 2, 85 [46%]; ≥3, 54 [30%]) was more significant (P = .0004) than that in group A (0-1, 32 [55%]; 2, 18 [31%]; ≥3, 8 [14%]). The average duration of the procedure was significantly longer in group B (P = .0002). CONCLUSION: Using C-arm CBCT during chemoembolization has a positive impact on increasing the number and order of HA selected and chemoembolized. This comes at the expense of an increase in the duration of the procedure.

Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma.

Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies. Here we report a pilot study of anti-CTLA-4 (tremelimumab) with (n = 15) or without (n = 14) cryoablation in patients with metastatic renal cell carcinoma (NCT02626130), 18 patients with clear cell and 11 patients with non-clear cell histologies. The primary endpoint is safety, secondary endpoints include objective response rate, progression-free survival, and immune monitoring studies. Safety data indicate ≥ grade 3 treatment-related adverse events in 16 of 29 patients (55%) including 6 diarrhea/colitis, 3 hepatitis, 1 pneumonitis, and 1 glomerulonephritis. Toxicity leading to treatment discontinuation occurs in 5 patients in each arm. 3 patients with clear cell histology experience durable responses. One patient in the tremelimumab arm experiences an objective response, the median progression-free survival for all patients is 3.3 months (95% CI: 2.0, 5.3 months). Exploratory immune monitoring analysis of baseline and post-treatment tumor tissue samples shows that treatment increases immune cell infiltration and tertiary lymphoid structures in clear cell but not in non-clear cell. In clear cell, cryoablation plus tremelimumab leads to a significant increase in immune cell infiltration. These data highlight that treatment with tremelimumab plus cryotherapy is feasible and modulates the immune microenvironment in patients with metastatic clear cell histology.

An analysis of research biopsy core variability from over 5000 prospectively collected core samples.

Factors correlated with biopsy tissue adequacy and the prevalence of within-biopsy variability were evaluated. Totally, 1149 research biopsies were performed on 686 patients from which 5090 cores were assessed. Biopsy cores were reviewed for malignant percentage (estimated percentage of cells in the core that were malignant) and malignant area (estimated area occupied by malignant cells). Linear mixed models and generalized linear mixed models were used for the analysis. A total of 641 (55.8%) biopsies contained a core with <10% malignant percentage (inadequate core). The chance of an inadequate core was not influenced by core order, though the malignant area decreased with each consecutive core (p < 0.001). Younger age, bone biopsy location, appendiceal tumor pathology, and responding/stable disease prior to biopsy increased the odds of a biopsy containing zero adequate cores. Within-biopsy variability in core adequacy is prevalent and suggests the need for histological tumor quality assessment of each core in order to optimize translational analyses.

Society of Interventional Radiology Multidisciplinary Position Statement on Percutaneous Ablation of Non-small Cell Lung Cancer and Metastatic Disease to the Lungs: Endorsed by the Canadian Association for Interventional Radiology, the Cardiovascular and Interventional Radiological Society of Europe, and the Society of Interventional Oncology.

PURPOSE: To state the Society of Interventional Radiology's position on the use of image-guided thermal ablation for the treatment of early stage non-small cell lung cancer, recurrent lung cancer, and metastatic disease to the lung. MATERIALS AND METHODS: A multidisciplinary writing group, with expertise in treating lung cancer, conducted a comprehensive literature search to identify studies on the topic of interest. Recommendations were drafted and graded according to the updated SIR evidence grading system. A modified Delphi technique was used to achieve consensus agreement on the recommendation statements. RESULTS: A total of 63 studies, including existing systematic reviews and meta-analysis, retrospective cohort studies, and single-arm trials were identified. The expert writing group developed and agreed on 7 recommendations on the use of image-guided thermal ablation in the lung. CONCLUSION: SIR considers image-guided thermal ablation to be an acceptable treatment option for patients with inoperable Stage I NSCLC, those with recurrent NSCLC, as well as patients with metastatic lung disease.

Musculoskeletal Oncologic Interventions: Proceedings from the Society of Interventional Radiology and Society of Interventional Oncology Research Consensus Panel.

Musculoskeletal interventions are increasingly used with palliative and curative intent in the multidisciplinary treatment of oncology patients with bone and soft-tissue tumors. There is an unmet need for high-quality evidence to guide broader application and adoption of minimally invasive interventional technologies to treat these patients. Therefore, the Society of Interventional Radiology Foundation and the Society of Interventional Oncology collaborated to convene a research consensus panel to prioritize a research agenda addressing the gaps in the current evidence. This article summarizes the panel's proceedings and recommendations for future basic science and clinical investigation to chart the course for interventional oncology within the musculoskeletal system. Key questions that emerged addressed the effectiveness of ablation within specific patient populations, the effect of combination of ablation with radiotherapy and/or immunotherapy, and the potential of standardization of techniques, including modeling and monitoring, to improve the consistency and predictability of treatment outcomes.

Safety and efficacy of percutaneous transabdominal and transesophageal decompression gastric catheters for palliation of malignant bowel obstruction.

PURPOSE: To evaluate the safety and primary technical success rate of gastric decompression via percutaneous transabdominal gastrostomy (PTAG) or percutaneous transesophageal gastric (PTEG) catheter placement for management of malignant bowel obstruction (MBO). A secondary purpose was to evaluate the safety and success rate for PTAG catheter placement in patients with both MBO and ascites. METHODS: A single-institution retrospective review of 385 patients who underwent attempted decompression gastric catheter placement from March 2013 to August 2018 was performed. Medical records and imaging studies were reviewed. A subgroup of patients with concomitant MBO and ascites were identified. The primary outcome measures were procedural technical success and procedural complications. RESULTS: 394 decompression gastrostomy catheters were attempted from 2013 to 2018, n = 353 PTAG and n = 41 PTEG. The success rate was 95.5% (n = 337 of 353) for PTAG and 97.6% (n = 40 of 41) for PTEG. There were 63 total complications involving 47 (13.9%) patients following PTAG and 13 total complications involving 9 (22.5%) patients following PTEG, P = 0.16. For the subgroup of patients with MBO and ascites, the success rate was 94.8% (n = 182 of 192 patients), and there were 20 complications involving 17 (12.9%) of 132 patients. CONCLUSION: Gastric decompression for patients with MBO via PTAG or PTEG catheter placement is associated with high success rates and low complications.

A novel irinotecan-lipiodol nanoemulsion for intravascular administration: pharmacokinetics and biodistribution in the normal and tumor bearing rat liver.

Colorectal cancer is one of the most common cancers in the United States and treatment options are limited for patients who develop liver metastases. Several chemotherapeutic regimens have been used for transvascular liver-directed therapy in the treatment of colorectal liver metastases without clear evidence of superiority of one therapy over another. We describe the development of a novel nanoemulsion through combining irinotecan (IRI), a first line systemic agent used for the treatment of colon cancer, with lipiodol, an oily contrast medium derived from poppy seed oil, and evaluated its pharmacokinetic and biodistribution profile as a function of portal venous chemoembolization (PVCE) versus transarterial chemoembolization (TACE) delivery. The Tessari technique was used to create a stable emulsion (20 mg IRI mixed with 2 mL lipiodol) with resultant particle size ranging from 28.9 nm to 56.4 nm. Pharmacokinetic profile established through venous sampling in Buffalo rats demonstrate that the area under the curve (AUC0-∞) of IRI was significantly less after PVCE with IRI-lipiodol as compared to IRI alone (131 vs. 316 µg*min/mL, p-value = .023), suggesting significantly higher amounts of IRI retention in the liver with the IRI-lipiodol nanoemulsion via first-pass extraction. Subseqent biodistribution studies in tumor-bearing WAG/Rjj rats revealed more IRI present in the tumor following TACE versus PVCE (29.19 ± 12.33 µg/g versus 3.42 ± 1.62; p-value = .0033) or IV (29.19 ± 12.33 µg/g versus 1.05 ± 0.47; p-value = .0035). The IRI-lipiodol nanoemulsion demonstrated an acceptable hepatotoxicity profile in all routes of administration. In conclusion, the IRI-lipiodol nanoemulsion via TACE showed promise and warrants further investigation as an option for the treatment of metastatic colorectal cancer.

Percutaneous retrograde left external carotid artery coil embolization for management of hemorrhage from a persistent proatlantal intersegmental artery type 2.

Persistent fetal communications between the carotid and vertebrobasilar systems are rare and most often discovered incidentally. We present the case of a patient with oropharyngeal cancer status post chemotherapy, radiation therapy, and surgical resection who developed acute oropharyngeal hemorrhage on postoperative day 36, originating from branches of the ligated external carotid artery stump by retrograde flow through a proatlantal intersegmental artery type 2. This hemorrhage was successfully controlled with coil embolization through percutaneous access of the external carotid artery without recurrence at 1-year follow-up.

Durability of partial splenic artery embolization on platelet counts for cancer patients with hypersplenism-related thrombocytopenia.

PURPOSE: Partial splenic artery embolization (PSAE) has shown promise in increasing platelet counts in cancer patients with hypersplenism-related thrombocytopenia. The purpose of this study was to identify response predictors and to longitudinally evaluate PSAE efficacy and durability in a large cohort of cancer patients with hypersplenism-related thrombocytopenia. METHODS: A single-institution, IRB-approved, HIPAA-compliant retrospective review of all PSAEs for thrombocytopenia between 2012 and 2015 was performed. Patients were classified as complete responders (CR, no platelet value < 100 × 109/L following PSAE), partial responders (PR, initial increase in platelets but subsequent decrease in platelets < 100 × 109/L), and non-responders (NR, platelets never > 100 × 109/L following PSAE). RESULTS: Of the 98 patients included in the study, 58 had CR (59%), 28 had PR (29%), and 12 patients had NR (12%). The percent splenic tissue embolized was significantly greater in the CR group compared to the PR group (P = 0.001). The percent volume of splenic tissue embolized was linearly correlated with the magnitude of platelet increase without a minimum threshold. At least one line of chemotherapy was successfully restarted in 97% of patients, and 41% of patients did not experience recurrence of thrombocytopenia for the duration of their survival. The major complication rate was 8%, with readmission following initial hospitalization for persistent "post-embolization syndrome" symptoms the most common. CONCLUSIONS: In cancer patients with hypersplenism-related thrombocytopenia, PSAE is a safe intervention that effects a durable elevation in platelet counts across a range of malignancies and following the re-initiation of chemotherapy.

Changes in inferior vena cava filter placement and retrieval practice patterns from a population health perspective.

PURPOSE: Inferior vena cava (IVC) filters are placed to reduce venous thromboembolism (VTE)-related morbidity and mortality, though the evidence supporting this practice is limited. In 2010, the Food and Drug Administration (FDA) released a device safety advisory due to the risk of filter migration, fracture, and thrombosis with long-term use. The purpose of this study was to evaluate trends and predictors for IVCF placement and retrieval over a 10-year time period from a population health perspective. MATERIALS AND METHODS: De-identified patient information from the State Inpatient Databases (SID) and the States Ambulatory Surgery and Services Databases (SASD) for Florida and California were used to identify all patients who underwent IVC filter placement from 2005 to 2014 and 2005 to 2011, respectively. Hospital practice patterns were assessed as a function of time as well as IVC filter placement and retrieval volume. Temporal trends were evaluated for statistical significance using the Cochran-Armitage test. RESULTS: A total of 181,260 IVC filters were placed in 178,327 patients over the study period. IVC filter placements peaked in 2010; following the FDA advisory in 2010, however, IVC filter placements monotonically decreased each subsequent year. The proportion of IVCF placement patients with both acute DVT and PE (17.6% vs 11.8%, P < 0.001) at the time of hospitalization increased; likewise, the proportion of IVCF patients with acute DVT or PE with a concomitant acute contraindication to anticoagulation at the time of hospitalization increased as well following 2010 (17.0% vs 11.9%, P < 0.001). From 2005 to 2014, there was a continual increase in both filter retrieval procedures as well overall percentage of filters retrieved. However, estimated retrieval rates remained low, with a retrieval rate of less than 6% in 2014. CONCLUSION: Following the FDA warning in 2010, there was a significant decrease in IVC filter placements, with filter placements more frequently performed in patients with poorer health. While retrieval rates increased over time, they remained low.

State of the Art: Toward Improving Outcomes of Lung and Liver Tumor Biopsies in Clinical Trials-A Multidisciplinary Approach.

PURPOSE: National Cancer Institute (NCI)-sponsored clinical trial network studies frequently require biopsy specimens for pharmacodynamic and molecular biomarker analyses, including paired pre- and post-treatment samples. The purpose of this meeting of NCI-sponsored investigators was to identify local institutional standard procedures found to ensure quantitative and qualitative specimen adequacy. METHODS: NCI convened a conference on best biopsy practices, focusing on the clinical research community. Topics discussed were (1) criteria for specimen adequacy in the personalized medicine era, (2) team-based approaches to ensure specimen adequacy and quality control, and (3) risk considerations relevant to academic and community practitioners and their patients. RESULTS AND RECOMMENDATIONS: Key recommendations from the convened consensus panel included (1) establishment of infrastructure for multidisciplinary biopsy teams with a formalized information capture process, (2) maintenance of standard operating procedures with regular team review, (3) optimization of tissue collection and yield methodology, (4) incorporation of needle aspiration and other newer techniques, and (5) commitment of stakeholders to use of guideline documents to increase awareness of best biopsy practices, with the goal of universally improving tumor biopsy practices.

Diagnostic efficacy and molecular testing by combined fine-needle aspiration and core needle biopsy in patients with a lung nodule.

BACKGROUND: Combined image-guided fine-needle aspiration biopsy (FNA) and core needle biopsy (CNB) has become the standard of care for diagnosis and/or molecular testing for patients with a solitary lung nodule at our institution. Our purpose was to evaluate the efficacy of this practice. METHODS: We identified patients who underwent combined lung FNA/CNB during 2012 at our institution. A total of 667 patients who underwent 682 combined lung FNA/CNB procedures were included in the study, including 355 men and 312 women. Combined lung FNA/CNB procedures were performed by a radiologist. The adequacy of FNA specimens was assessed immediately by a cytopathologist. The FNA and CNB specimens were interpreted separately by a cytopathologist and a surgical pathologist, respectively. The diagnostic accuracy of the combined technique was determined. RESULTS: The rate of diagnostic consistency between FNA and CNB was 83.4%, and the rate of diagnostic accuracy for malignancy was 98.5% for combined FNA/CNB. Combined FNA/CNB showed a high diagnostic efficacy for malignancy (sensitivity, 97.6%; specificity, 100%). Combined FNA/CNB had a lower false-negative rate for malignancy (2.2%) than either FNA (7.2%) or CNB (6.2%) alone. FNA contributed to 10.3% of molecular analyses as a complementary tissue source. CONCLUSIONS: Combined lung FNA/CNB has high diagnostic efficacy for malignancy and a lower false-negative rate than either procedure alone. FNA was a valuable complement to CNB for molecular testing, potentially reducing patient inconvenience and morbidity associated with repeated lung needle biopsy.

Hepatic Arterial Bland Embolization Increases Th17 Cell Infiltration in a Syngeneic Rat Model of Hepatocellular Carcinoma.

PURPOSE: To determine the tumor immune cell landscape after transcatheter arterial bland embolization (TAE) in a clinically relevant rat hepatocellular carcinoma (HCC) model. MATERIALS AND METHODS: Buffalo rats (n = 21) bearing syngeneic McArdle RH-7777 rat hepatoma cells implanted into the left hepatic lobe underwent TAE using 70-150 µm beads (n = 9) or hepatic artery saline infusion (n = 12). HCC nodules, peritumoral margin, adjacent non-cancerous liver, and splenic parenchyma were collected and disaggregated to generate single-cell suspensions for immunological characterization 14 d after treatment. Changes in tumor-infiltrating immune subsets including CD4 T cells (Th17 and Treg), CD8 cytotoxic T cells (IFNγ), and neutrophils were evaluated by multiparameter flow cytometry. Migration and colony formation assays were performed to examine the effect of IL-17, a signature cytokine of Th17 cells, on McArdle RH-7777 hepatoma cells under conditions simulating post-embolization environment (i.e., hypoxia and nutrient privation). Statistical significance was determined by the Student unpaired t test or one-way ANOVA. RESULTS: TAE induces increased infiltration of Th17 cells in liver tumors when compared with controls 14 d after treatment (0.29 ± 0.01 vs. 0.19 ± 0.02; p = 0.02). A similar pattern was observed in the spleen (1.41 ± 0.13 vs. 0.57 ± 0.08; p < 0.001), indicating both local and systemic effect. No significant differences in the percentage of FoxP3 + Tregs, IFNγ-producing CD4 T cells, and CD8 T cells were observed between groups (p > 0.05). In vitro post-embolization assays demonstrated that IL-17 reduces McA-RH7777 cell migration at 24-48 h (p = 0.003 and p = 0.002, respectively). CONCLUSION: Transcatheter hepatic arterial bland embolization induces local and systemic increased infiltration of Th17 cells and expression of their signature cytokine IL-17. In a simulated post-embolization environment, IL-17 significantly reduced McA-RH7777 cell migration.

Ethical Framework for Including Research Biopsies in Oncology Clinical Trials: American Society of Clinical Oncology Research Statement.

In contrast to clinical biopsies, where tissue is collected to inform patient care, research biopsies are performed for scientific purposes to potentially enhance understanding of the biologic bases of cancer and drug action, thereby improving diagnosis and treatment, but they may offer no direct benefit to participants and have known risks. The widespread use of research biopsies that do not have the potential to directly benefit participants has come under scrutiny, with critics raising ethical concerns related to the adequacy of participant protections, informed consent, and participant understanding of the risks and benefits, as well as the scientific impact of research biopsies on drug development and treatment. This manuscript presents the American Society of Clinical Oncology's (ASCO's) ethical framework for incorporation of research biopsies in trials. The framework provides guidance on the circumstances to include optional and mandatory biopsies, as well as provides recommendations to stakeholders on necessary steps for improving the conduct of research biopsies overall.

Local Recurrence After Microwave Ablation of Lung Malignancies: A Systematic Review.

BACKGROUND: Microwave ablation is a therapeutic option for patients with lung malignancies who are not surgical candidates. However, reports on local recurrence have been limited to small case series or retrospective reports. This review was conducted to synthesize the evidence regarding local recurrence and adverse events after microwave ablation for primary non-small cell lung cancer or pulmonary metastases. METHODS: The PubMed, Embase, and Scopus databases were searched to identify peer-reviewed studies investigating microwave ablation of lung malignancies with local recurrence or adverse events as a primary outcome. Articles were appraised using the Critical Appraisal Skills Programme criteria. RESULTS: Twelve studies met the eligibility criteria, representing 985 patients and 1,336 treated lung nodules. Studies were limited by infrequent reporting of censoring and by short follow-up. Estimates of local recurrence by the end of the study varied substantially, from 9% to 37%. Tumor size was consistently shown to increase the risk of local recurrence. Among four studies that stratified results by tumor size, local recurrence among tumors smaller than 3 to 4 cm was 5% to 19%. Studies with accrual after 2011 showed recurrence rates between 9% and 26%, whereas earlier studies showed recurrence rates between 22% and 37%. The most common complication was pneumothorax, with grade III or higher complications infrequently encountered. CONCLUSIONS: Microwave ablation of primary and secondary lung malignancies is a reasonable therapeutic approach for select patients. Estimates of local failure after treatment are highly variable, with newer reports and smaller tumors having more favorable treatment efficacy rates.