Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy.

BACKGROUND: Developing the ability to use tumor-directed therapies to trigger potentially therapeutic immune responses against cancer antigens remains a high priority for cancer immunotherapy. We hypothesized that histotripsy, a novel non-invasive, non-thermal ablation modality that uses ultrasound-generated acoustic cavitation to disrupt tissues, could engender adaptive immune responses to tumor antigens. METHODS: Immunocompetent C57BL/6 mice inoculated with flank melanoma or hepatocellular carcinoma tumors were treated with histotripsy, thermal ablation, radiation therapy, or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) blockade checkpoint inhibition. Lymphocyte responses were measured using flow cytometric and immunohistochemical analyses. The impact of histotripsy on abscopal immune responses was assessed in mice bearing bilateral tumors, or unilateral tumors with pulmonary tumors established via tail vein injection. RESULTS: Histotripsy ablation of subcutaneous murine melanoma tumors stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations. The magnitude of this immunostimulation was stronger than that seen with tumor irradiation or thermal ablation. Histotripsy also promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity, and this immunostimulatory effect was associated with calreticulin translocation to the cellular membrane and local and systemic release of high mobility group box protein 1. Histotripsy ablation potentiated the efficacy of checkpoint inhibition immunotherapy in murine models of melanoma and hepatocellular carcinoma. CONCLUSIONS: These preclinical observations suggest that non-invasive histotripsy ablation can be used to stimulate tumor-specific immune responses capable of magnifying the impact of checkpoint inhibition immunotherapy.

Predictive Value of Chromogranin A and a Pre-Operative Risk Score to Predict Recurrence After Resection of Pancreatic Neuroendocrine Tumors.

INTRO: Chromogranin A (CgA) may be prognostic for patients with neuroendocrine tumors; however, the clinical utility of this test is unclear. METHODS: Patients undergoing resection for pancreatic neuroendocrine tumors (pNET) were selected from the eight institutions of the US Neuroendocrine Tumor Study Group database. Cox regression was used to identify pre-operative variables that predicted recurrence-free survival (RFS), and those with p < 0.1 were included in a risk score. The risk score was tested in a unique subset of the overall cohort. RESULTS: In the entire cohort of 287 patients, median follow-up time was 37 months, and 5-year RFS was 73%. Cox regression analysis identified four variables for inclusion in the risk score: CgA > 5x ULN (HR 4.3, p = 0.01), tumor grade 2/3 (HR 3.7, p = 0.01), resection for recurrent disease (HR 6.2, p < 0.01), and tumor size > 4 cm (HR 4.5, p = 0.1). Each variable was assigned 1 point. Risk-score testing in the unique validation cohort of 63 patients revealed a 95% negative predictive value for recurrence in patients with zero points. DISCUSSION: This simple pre-operative risk scoring system resulted in a high degree of specificity for identifying patients at low-risk for tumor recurrence. This test can be utilized pre-operatively to aid informed decision-making.

Evaluating the ACS-NSQIP Risk Calculator in Primary GI Neuroendocrine Tumor: Results from the United States Neuroendocrine Tumor Study Group.

The ACS established an online risk calculator to help surgeons make patient-specific estimates of postoperative morbidity and mortality. Our objective was to assess the accuracy of the ACS-NSQIP calculator for estimating risk after curative intent resection for primary GI neuroendocrine tumors (GI-NETs). Adult patients with GI-NET who underwent complete resection from 2000 to 2017 were identified using a multi-institutional database, including data from eight academic medical centers. The ability of the NSQIP calculator to accurately predict a particular outcome was assessed using receiver operating characteristic curves and the area under the curve (AUC). Seven hundred three patients were identified who met inclusion criteria. The most commonly performed procedures were resection of the small intestine with anastomosis (N = 193, 26%) and partial colectomy with anastomosis (N = 136, 18%). The majority of patients were younger than 65 years (N = 482, 37%) and ASA Class III (N = 337, 48%). The most common comorbidities were diabetes (N = 128, 18%) and hypertension (N = 395, 56%). Complications among these patients based on ACS NSQIP definitions included any complication (N = 132, 19%), serious complication (N = 118, 17%), pneumonia (N = 7, 1.0%), cardiac complication (N = 1, 0.01%), SSI (N = 80, 11.4%), UTI (N = 17, 2.4%), venous thromboembolism (N = 18, 2.5%), renal failure (N = 16, 2.3%), return to the operating room (N = 27, 3.8%), discharge to nursing/rehabilitation (N = 22, 3.1%), and 30-day mortality (N = 9, 1.3%). The calculator provided reasonable estimates of risk for pneumonia (AUC = 0.721), cardiac complication (AUC = 0.773), UTI (AUC = 0.716), and discharge to nursing/rehabilitation (AUC = 0.779) and performed poorly (AUC < 0.7) for all other complications Fig. 1). The ACS-NSQIP risk calculator estimates a similar proportion of risk to actual events in patients with GI-NET but has low specificity for identifying the correct patients for many types of complications. The risk calculator may require modification for some patient populations.

Co-transfer of tumor-specific effector and memory CD8+ T cells enhances the efficacy of adoptive melanoma immunotherapy in a mouse model.

BACKGROUND: Adoptive cell transfer (ACT) is a promising cancer immunotherapeutic strategy that remains ineffective for a large subset of patients. ACT with memory CD8+ T cells (Tmem) has been shown to have superior efficacy compared to traditional ACT with effector CD8+ T cells (Teff). Teff and Tmem have complementary physiological advantages for immunotherapy, but previous publications have not examined ACT using a combination of Teff and Tmem. METHODS: Splenocytes harvested from Ly5.1+/C57BL/6 mice during and after infection with lymphocytic choriomeningitis virus (LCMV) were used to generate bona fide effector and memory CD8+ T cells specific for the LCMV epitope peptide GP33. Congenic Ly5.2+/C57BL/6 mice were inoculated with B16F10 melanoma cells transfected to express very low levels of GP33, then treated with ACT 7 days later with GP33-specific Teff, Tmem, or a combination of Teff + Tmem. RESULTS: Inhibition of melanoma growth was strongest in mice receiving combinatorial ACT. Although combinatorial ACT and memory ACT resulted in maximal intratumoral infiltration of CD8+ T cells, combinatorial ACT induced stronger infiltration of endogenous CD8+ T cells than Tmem ACT and a stronger systemic T cell responsiveness to tumor antigen. In vitro assays revealed rapid but transient melanoma inhibition with Teff and gradual but prolonged melanoma inhibition with Tmem; the addition of Tmem enhanced the ability of Teff to inhibit melanoma in a manner that could be reproduced using conditioned media from activated Tmem and blocked by the addition of anti-IL-2 blocking antibody. CONCLUSIONS: These findings suggest that a novel combinatorial approach that takes advantage of the unique and complementary strengths of tumor-specific Teff and Tmem may be a way to optimize the efficacy of adoptive immunotherapy.

Race, insurance status, and traumatic brain injury outcomes before and after enactment of the Affordable Care Act.

BACKGROUND: The Affordable Care Act aims to improve patient outcomes. Race/ethnicity and insurance status impact outcomes after traumatic brain injury. We sought to gauge the Affordable Care Act's effect on outcomes after traumatic brain injury, as graded by race/ethnicity and insurance status. METHODS: The National Trauma Data Bank was utilized to identify traumatic brain injury patients before and after the Affordable Care Act. Patient outcomes comprised of hospital duration of stay, in-hospital mortality, discharge to rehabilitation, and surgical procedures. Using regression analysis, we evaluated the impact of race/ethnicity and insurance status on traumatic brain injury outcomes, then compared them before and after the Affordable Care Act. RESULTS: Mortality decreased for blacks (odds ratio = 0.96 [confidence interval 0.83-1.10] to odds ratio = 0.79 [confidence interval = 0.70-0.89], and Hispanics (odds ratio = 1.03 [confidence interval = 0.90-1.17] to odds ratio = 0.79 [confidence interval = 0.70-0.89]). Mortality increased for the uninsured (odds ratio = 1.28 [confidence interval = 1.11-1.47] to odds ratio = 1.40 [confidence interval = 1.24-1.58]). Medicaid patients underwent decreased duration of stay, (coefficient = 2.75 [confidence interval = 2.49-3.02] to coefficient = 2.17, [confidence interval = 1.98-2.37]), discharge to rehabilitation (odds ratio = 1.15, [confidence interval = 1.04-1.26] to odds ratio = 0.95 [confidence interval = 0.87-1.03]), and surgical procedures (odds ratio = 1.28 [confidence interval = 1.13-1.45] to odds ratio = 1.18, [confidence interval = 1.07-1.30]), while mortality remained unchanged. CONCLUSION: After the Affordable Care Act traumatic brain injury mortality decreased for blacks and Hispanics, but increased for the uninsured. Decreasing trends in resource consumption were also evident, especially for Medicaid patients. These results may illustrate altered delivery of care.

Number of rib fractures thresholds independently predict worse outcomes in older patients with blunt trauma.

BACKGROUND: There have been conflicting reports regarding whether the number of rib fractures sustained in blunt trauma is associated independently with worse patient outcomes. We sought to investigate this risk-adjusted relationship among the lesser-studied population of older adults. METHODS: A retrospective review of the National Trauma Data Bank was performed for patients with blunt trauma who were ≥65 years old and had rib fractures between 2009 and 2012 (N = 67,695). Control data were collected for age, sex, injury severity score, injury mechanism, 24 comorbidities, and number of rib fractures. Outcome data included hospital mortality, hospital and intensive care unit durations of stay, duration of mechanical ventilation, and the occurrence of pneumonia. Multiple logistic and linear regression analyses were performed. RESULTS: Sustaining ≥5 rib fractures was associated with increased intensive care unit admission (odds ratio: 1.14, P < .001) and hospital duration of stay (relative duration: 105%, P < .001). Sustaining ≥7 rib fractures was associated with an increased incidence of pneumonia (odds ratio: 1.32, P < .001) and intensive care unit duration of stay (relative duration: 122%, P < .001). Sustaining ≥8 rib fractures was associated with increased mortality (odds ratio: 1.51, P < .001) and duration of mechanical ventilation (relative duration: 117%, P < .001). CONCLUSION: In older patients with trauma, sustaining at least 5 rib fractures is a significant predictor of worse outcomes independent of patient characteristics, comorbidities, and trauma burden.