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Supplementary Figure from A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

Purpose:A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC.Patients and Methods:In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers.Results:Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders.Conclusions:The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Supplementary Table from A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

Purpose: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. Patients and Methods: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Objective Thyroid nodules are prevalent in over half the general population. Several multidisciplinary societies have management recommendations. However, the majority of data to support these guidelines are derived from studies of predominantly younger and female populations. This study’s aim was to evaluate characteristics of thyroid nodules in a largely older and male Veteran population and apply these findings prospectively to reduce unnecessary thyroid fine needle aspiration (FNA). Materials and Methods Over a 4-year period, all ultrasound-guided FNA of thyroid nodules performed in our department were reviewed. Sonographic features, patterns, and histopathology were evaluated. A prospective strategy of avoiding FNA in all lesions matching imaging patterns of benignity was implemented and positive predictive value (PPV) of malignancy was calculated and compared to the retrospective data. Results Retrospectively, FNA was performed on 351 successive thyroid nodules, 9 of which were malignant. Statistically significant malignant features include presence of microcalcifications, irregular or amorphous morphology, taller-than-wide shape, spiculated margins, vascularity, and lymphadenopathy. PPV of thyroid FNA was 2.6% in this period. Four sonographic patterns were 100% specific for benignity, including: “spongiform,” “cyst with a colloid clot,” “giraffe,” and “white knight” patterns. Over 23 months, prospective avoidance of FNA of lesions characterized as a benign pattern (159 nodules) was implemented and PPV was calculated as 7.2% resulting in a cost savings of $477,000. Conclusion Four sonographic patterns were 100% specific for benignity in the older and predominantly male Veteran population. Strict prospective application of avoiding biopsy in these benign patterns resulted in a decrease of unnecessary biopsies, decrease in patient morbidity, and improved allocation of health care resources.

Uveal melanoma has in the liver the most common site of metastases. Although there is no clear consensus about the management of metastatic uveal melanoma, therapy directed specifically toward secondary liver lesions has been associated with notable clinical utility.

9115 Background: The introduction of immunotherapy has altered the treatment paradigm for metastatic non-small cell cancer (mNSCLC). Unfortunately, many patients with mNSCLC have limited or no benefit from immune checkpoint inhibitors (ICIs). A variety of approaches have been explored to augment the efficacy of ICIs. Our study’s aim was to determine whether the addition of stereotactic body radiation therapy (SBRT) and intratumoral injection of the oncolytic virus ADV/HSV-tk (adenovirus-mediated expression of herpes simplex virus thymidine kinase) to a monoclonal antibody targeting programmed cell death-1 (PD-1) would improve the ICI’s efficacy in the treatment of mNSCLC. Methods: In this single-arm, open-label phase II study, patients with mNSCLC (squamous or non-squamous) who were ICI-naive or who were previously treated with a maximum of one line of therapy that included an ICI received an intratumoral injection of ADV/HSV-tk (5 x 1011 vp) followed by SBRT (30 Gy in 5 fractions) to the same tumor. An anti-PD-1 agent (pembrolizumab 200 mg IV every 3 weeks or nivolumab 240 mg IV every 2 weeks) was then given for up to 24 months (pembrolizumab) or 12 months (nivolumab), or until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A secondary endpoint was clinical benefit rate (CBR). Results: A total of 35 patients were enrolled, with 28 (80%) receiving pembrolizumab and 7 (20%) receiving nivolumab; 14 (40%) had previous ICI therapy while 21 (60%) were ICI-naive. The ORR and CBR were 28.5% and 61.9% in the ICI-naive group, and 14.2% and 64.2% in the group that previously received an ICI, respectively. Grade 3 or higher toxicity was seen in five patients (26.3%) in the ICI-naive group and in one patient (7.1%) in the previously ICI-treated group. No treatment-related deaths were observed. Conclusions: The addition of SBRT and intratumor injection of ADV/HSV-tk to anti-PD-1 therapy in mNSCLC resulted in a CBR of over 60% for both ICI-naive and previously ICI-treated patients without the use of chemotherapy. The combination was able to reinstitute sensitivity to ICIs in patients previously treated with an ICI, and also benefited some patients whose tumors did not express PD-L1. These findings should be further explored in a larger study population. Clinical trial information: NCT03004183. [Table: see text]

1079 Background: Pembrolizumab, stereotactic body radiotherapy (SBRT), and viral vector-based gene therapy such as adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus ganciclovir have each shown antitumor immune activity. The combination of those modalities may represent a window of opportunity to enhance pembrolizumab efficacy in mTNBC patients. Methods: In this single-arm, open-label phase II trial, mTNBC patients were treated with in situ oncolytic ADV/HSV-tk (5 x 1011 vp) intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab until progression or intolerable toxicity. Response was assessed in non-irradiated metastatic sites. The primary end point was clinical benefit rate (CR, PR and SD per RECIST version1.1). Secondary endpoints included duration on treatment (DoT) and safety. Immune correlative analysis with peripheral blood CYTOF (D1 baseline, D7 and D38), and tissue imaging mass cytometry (IMC) with 35 cell surface markers was performed on paired biopsies (D1 baseline and D17). Results: 28 mTNBC patients were enrolled; 18 (64.3%) had PD-L1 negative tumors. Median age was 54 years (range 34-78). Median prior lines of chemotherapy were 2 (range 0-6), with 8 (28.6%) having received >3. 3 (10.7%) had brain metastases. Clinical benefit was seen in 6 (21.43%) patients; 2 CR (7.1%),1 PR (3.57%) and 3 SD (10.7%). Patients who had clinical benefits had durable responses, with median DoT of 383 days (range 195-1195). One patient who had CR, but discontinued pembrolizumab due to Grade 3 pneumonitis, has remained disease free without any systemic therapy for 39 months. The combination was well tolerated; 9 (32.1%) patients had Grade 3- 4 AEs. Pre- and post-therapy CYTOF analysis showed significant association between immune biomarkers with clinical responses (AUC 0.75, Cohen’s Kappa 0.364). Tumor PDL1 was independently associated with response (AUC 0.70, Cohen’s Kappa 0.347); AUC for PDL1 together with immune biomarkers is 0.85. Conclusions: ADV/HSV-tk gene therapy followed by radiation therapy and then pembrolizumab is a well-tolerated promising treatment in heavily pretreated mTNBC patients. Early detection of increased effector and effector memory CD8 T cells and nonclassical monocytes correlates with response and non-response respectively. Clinical trial information: NCT03295916 .[Table: see text]

Background Transarterial chemoembolization (TACE) is the most common treatment for patients with unresectable hepatocellular carcinoma (HCC). Post‐embolization syndrome (PES) is a common post‐TACE complication. The goal of this study was to evaluate PES as an early predictor of the long‐term outcome. Methods A retrospective cohort study of HCC patients treated with TACE at a tertiary referral centre was performed (2008–2014). Patients were categorized on the basis of PES, defined as fever with or without abdominal pain within 14 days of TACE. The primary outcome was overall survival (OS). Multivariate Cox regression was done to examine the association between PES and OS. Results Among 144 patients, 52 (36.1%) experienced PES. The median follow‐up for the cohort was 11.4 months. The median and 3‐year OS rates were 16 months and 18% in the PES group versus 25 months and 41% in the non‐PES group (log rank, P = 0.027). After multivariate analysis, patients with PES had a significantly increased risk of death [hazard ratio 2.0 (95%CI 1.2–3.3), P = 0.011]. Conclusions PES is a common complication after TACE and is associated with a two‐fold increased risk of death. Future studies should incorporate PES as a relevant early predictor of OS and examine the biological basis of this association.

Preoperative portal vein embolization (PVE) is used to extend the indications for major hepatic resection, and it has become the standard of care for selected patients with hepatic malignancies treated at major hepatobiliary centers. To date, various techniques with different embolic materials have been used with similar results in the degree of liver hypertrophy. Regardless of the specific strategy used, both surgeons and interventional radiologists must be familiar with each other’s techniques to be able to create the optimal plan for each individual patient. Knowledge of the segmental anatomy of the liver is paramount to fully understand the liver segments that need to be embolized and resected. Understanding the portal vein anatomy and the branching variations, along with the techniques used to transect the portal vein during hepatic resection, is important because these variables can affect the PVE procedure and the eventual surgical resection. Comprehension of the advantages and disadvantages of approaches to the portal venous system and the various embolic materials used for PVE is essential to best tailor the procedures for each patient and to avoid complications. Before PVE, meticulous assessment of the portal vein branching anatomy is performed with cross-sectional imaging, and embolization strategies are developed based on the patient’s anatomy. The PVE procedure consists of several technical steps, and knowledge of these technical tips, potential complications, and how to avoid the complications in each step is of great importance for safe and successful PVE and ultimately successful hepatectomy. Because PVE is used as an adjunct to planned hepatic resection, priority must always be placed on safety, without compromising the integrity of the future liver remnant, and close collaboration between interventional radiologists and hepatobiliary surgeons is essential to achieve successful outcomes.

We searched the electronic patient database at The University of Texas M. D. Anderson Cancer Center for patients who underwent computed tomography (CT)-guided needle biopsy between January 2001 and December 2005. Inclusion criteria were a known history of haematologic malignancy and a newly detected, undiagnosed pulmonary lesion on chest CT that required tissue sampling for diagnosis; 213 met these criteria. We analysed the biopsy results for diagnostic yield, factors affecting diagnostic yield and effect on treatment. Of 213 procedures, 191 (89.7%) yielded sufficient material for pathologic analysis; 130 (60%) yielded specific diagnoses, while 61 (28.6%) yielded nonspecific benign diagnoses. Lesions larger than 1 cm, cavitary lesions and lung masses were more likely to yield a specific diagnosis than were lesions smaller than 1 cm, lung nodules and consolidations. The most common specific diagnoses were malignancy (62.8%) and infection (34.3%). The latter was more common in patients with leukaemia, cavitary lung lesions or consolidations, active underlying malignancy, neutropenia, respiratory signs and symptoms and/or fever, bone marrow transplant recipients, and in patients receiving chemotherapy. Lung lesions discovered upon follow-up imaging in patients who did not have any respiratory signs/symptoms or fever were mostly malignant. Therapeutic changes were more likely after a specific diagnosis than after a nonspecific diagnosis or a nondiagnostic biopsy (88.4% vs. 18.1%; p