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BackgroundDeveloping 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.MethodsImmunocompetent 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.ResultsHistotripsy 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.ConclusionsThese 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.

BackgroundThe role of routine lymphadenectomy in the surgical treatment of pancreatic neuroendocrine tumors (pNET) remains poorly defined. The objective of the current study was to investigate trends in the number of lymph nodes (LN) evaluated for pNET treatment at a nationwide level.MethodsPatients undergoing surgery for pNET between 2000 and 2016 were identified in the U.S. Neuroendocrine Tumor Study Group (US-NETSG) database as well as the Surveillance, Epidemiology, and End Results (SEER) database. The number of LNs examined was evaluated over time.ResultsThe median number of evaluated LNs increased roughly fourfold over the study period (US-NETSG, 2000: 3 LNs vs. 2016: 13 LNs; SEER, 2000: 3 LNs vs. 2016: 11 LNs, both p < 0.001). While no difference in 5-year OS and RFS was noted among patients who had 1–3 lymph node metastases (LNM) vs. ≥ 4 LNM between 2000–2007 (OS 73.5% vs. 69.9%, p = 0.12; RFS: 64.9% vs. 40.1%, p = 0.39), patients who underwent resection and LN evaluation during the period 2008–2016 had an incrementally worse survival if the patient had node negative disease, 1–3 LNM and ≥ 4 LNM (OS 86.8% vs. 82.7% vs. 74.9%, p < 0.001; RFS: 86.3% vs. 64.7% vs. 50.4%, p < 0.001). On multivariable analysis, a more recent year of diagnosis, pancreatic head tumor location, and tumor size > 2 cm were associated with 12 or more LNs evaluated in both US-NETSG and SEER databases.ConclusionThe number of LNs examined nearly quadrupled over the last decade. The increased number of LNs examined suggested a growing adoption of the AJCC staging manual recommendations regarding LN evaluation in the treatment of pNET.

Background Radiographic calcifications and cystic morphology are associated with higher and lower tumor grade, respectively, in pancreatic neuroendocrine tumors (PNETs). Whether calcifications and/or cystic morphology could be used preoperatively to predict post-resection survival in patients with PNETs remains elusive. Methods Patients undergoing curative-intent resection of well-differentiated PNETs from 2000 to 2017 at eight academic institutions participating in the US Neuroendocrine Tumor Study Group were identified. Preoperative cross-sectional imaging reports were reviewed to identify the presence of calcifications and of a cystic component occupying >50% of the total tumor area. Clinicopathologic characteristics and recurrence-free survival (RFS) were compared. Results Of 981 patients studied, 18% had calcifications and 17% had cystic tumors. Tumors with calcifications were more commonly associated with Ki-67 ≥3% (47% vs. 33%; p  = 0.029), lymph node metastasis (36% vs. 24%; p  = 0.011), and distant metastasis (13% vs. 4%; p  < 0.001). In contrast, cystic tumors were less commonly associated with lymph node metastasis (12% vs. 30%; p  < 0.001). Five-year RFS after resection was most favorable for cystic tumors without calcifications (91%), intermediate for solid tumors without calcifications (77%), and least favorable for any calcified PNET (solid 69%, cystic 67%; p  = 0.043). Calcifications remained an independent predictor of RFS on multivariable analysis ( p  = 0.043) controlling for nodal ( p  < 0.001) and distant metastasis ( p  = 0.001). Conclusions Easily detectable radiographic features, such as calcifications and cystic morphology, can be used preoperatively to stratify prognosis in patients with PNETs and possibly inform the decision to operate or not, as well as guide the extent of resection and potential use of neoadjuvant therapy.

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.

Background Appendiceal neuroendocrine tumors (A-NETs) are rare neoplasms of the GI tract. They are typically managed according to tumor size; however, the impact of surgical strategy on the short- and long-term outcomes is unknown. Methods All patients who underwent resection of A-NET at 8 institutions from 2000 to 2016 were analyzed retrospectively. Patient clinicopathologic features and outcomes were stratified according to resection type. Results Of 61 patients identified with A-NET, mean age of presentation was 44.7 ± 16.0 years and patients were predominantly Caucasian (77%) and female (56%). Mean tumor size was 1.2 ± 1.3 cm with a median of 0.8 cm. Thirty-one patients (51%) underwent appendectomy and 30 (49%) underwent colonic resection. The appendectomy group had more T1 tumors (87% vs 42%, p < 0.01) than the colon resection group. Of patients in the colon resection group, 27% had positive lymph nodes and 3% had M1 disease. R0 resections were achieved in 90% of appendectomy patients and 97% of colon resection patients. Complications occurred with a higher frequency in the colon resection group (30%) compared with those in the appendectomy group (6%, p = 0.02). The colon resection group also had a longer length of stay, higher average blood loss, and longer average OR time. Median RFS and OS were similar between groups. Conclusion A-NET RFS and OS are equivalent regardless of surgical strategy. Formal colon resection is associated with increased length of stay, OR time, higher blood loss, and more complications. Further study is warranted to identify patients that are likely to benefit from more aggressive surgery.

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 (T mem ) has been shown to have superior efficacy compared to traditional ACT with effector CD8+ T cells (T eff ). T eff and T mem have complementary physiological advantages for immunotherapy, but previous publications have not examined ACT using a combination of T eff and T mem . 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 T eff , T mem , or a combination of T eff  + T mem . 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 T mem ACT and a stronger systemic T cell responsiveness to tumor antigen. In vitro assays revealed rapid but transient melanoma inhibition with T eff and gradual but prolonged melanoma inhibition with T mem ; the addition of T mem enhanced the ability of T eff to inhibit melanoma in a manner that could be reproduced using conditioned media from activated T mem 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 T eff and T mem may be a way to optimize the efficacy of adoptive immunotherapy.

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.

BackgroundPancreatic neuroendocrine tumors (PNETs) are often indolent; however, identifying patients at risk for rapidly progressing variants is critical, particularly for those with small tumors who may be candidates for expectant management. Specific growth rate (SGR) has been predictive of survival in other malignancies but has not been examined in PNETs.MethodsA retrospective cohort study of adult patients who underwent PNET resection from 2000 to 2016 was performed utilizing the multi-institutional United States Neuroendocrine Study Group database. Patients with ≥ 2 preoperative cross-sectional imaging studies at least 30 days apart were included in our analysis (N = 288). Patients were grouped as “high SGR” or “low SGR.” Demographic and clinical factors were compared between the groups. Kaplan–Meier and log-rank analysis were used for survival analysis. Cox proportional hazard analysis was used to assess the impact of various clinical factors on overall survival (OS).ResultsHigh SGR was associated with higher T stage at resection, shorter doubling time, and elevated HbA1c (all P ≤ 0.01). Patients with high SGR had significantly decreased 5-year OS (63 vs 80%, P = 0.01) and disease-specific survival (72 vs 91%, P = 0.03) compared to those with low SGR. In patients with small (≤ 2 cm) tumors (N = 106), high SGR predicted lower 5-year OS (79 vs 96%, P = 0.01). On multivariate analysis, high SGR was independently associated with worse OS (hazard ratio 2.67, 95% confidence interval 1.05–6.84, P = 0.04).ConclusionHigh SGR is associated with worse survival in PNET patients. Evaluating PNET SGR may enhance clinical decision-making, particularly when weighing expectant management versus surgery in patients with small tumors.

BackgroundInsurance status predicts access to medical care in the USA. Previous studies have shown uninsured patients with some malignancies have worse outcomes than insured patients. The impact of insurance status on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is unclear.Patients and MethodsA retrospective cohort study of adult patients with resected GEP-NETs was performed using the US Neuroendocrine Tumor Study Group (USNETSG) database (2000–2016). Demographic and clinical factors were compared by insurance status. Patients ≥ 65 years were excluded, as these patients are almost universally covered by Medicare. Kaplan–Meier and log-rank analyses were used for survival analysis. Logistic regression was used to assess factors associated with overall survival (OS).ResultsThe USNETSG database included 2022 patients. Of those, 1425 were aged 18–64 years at index operation and were included in our analysis. Uninsured patients were more likely to have an emergent operation (7.9% versus 2.5%, p = 0.01) and less likely to receive postoperative somatostatin analog therapy (1.6% versus 9.9%, p = 0.03). OS at 1, 5, and 10 years was significantly higher for insured patients (96.3%, 88.2%, and 73.8%, respectively) than uninsured patients (87.7%, 71.9%, and 44.0%, respectively) (p < 0.01). On Cox multivariate regression analysis controlling for T/M stage, tumor grade, ASA class, and income level, being uninsured was independently associated with worse OS [hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.32–5.48, p = 0.006].ConclusionsInsurance status is an independent predictor of survival in patients with GEP-NETs. Our study highlights the importance of access to medical care, disparities related to insurance status, and the need to mitigate these disparities.

Background The scarcity of physicians in sub-Saharan Africa – particularly in rural clinics staffed only by non-physician health workers – is constraining access to HIV treatment, as only they are legally allowed to start antiretroviral therapy in the HIV-positive patient. Here we present a pilot study from Uganda assessing agreement between non-physician clinicians (nurses and clinical officers) and physicians in their decisions as to whether to start therapy. Methods We conducted the study at 12 government antiretroviral therapy sites in three regions of Uganda, all of which had staff trained in delivery of antiretroviral therapy using the WHO Integrated Management of Adult and Adolescent Illness guidelines for chronic HIV care. We collected seven key variables to measure patient assessment and the decision as to whether to start antiretroviral therapy, the primary variable of interest being the Final Antiretroviral Therapy Recommendation. Patients saw either a clinical officer or nurse first, and then were screened identically by a blinded physician during the same clinic visit. We measured inter-rater agreement between the decisions of the non-physician health workers and physicians in the antiretroviral therapy assessment variables using simple and weighted Kappa analysis. Results Two hundred fifty-four patients were seen by a nurse and physician, while 267 were seen by a clinical officer and physician. The majority (> 50%) in each arm of the study were in World Health Organization Clinical Stages I and II and therefore not currently eligible for antiretroviral therapy according to national antiretroviral therapy guidelines. Nurses and clinical officers both showed moderate to almost perfect agreement with physicians in their Final Antiretroviral Therapy Recommendation (unweighted κ = 0.59 and κ = 0.91, respectively). Agreement was also substantial for nurses versus physicians for assigning World Health Organization Clinical Stage (weighted κ = 0.65), but moderate for clinical officers versus physicians (κ = 0.44). Conclusion Both nurses and clinical officers demonstrated strong agreement with physicians in deciding whether to initiate antiretroviral therapy in the HIV patient. This could lead to immediate benefits with respect to antiretroviral therapy scale-up and decentralization to rural areas in Uganda, as non-physician clinicians – particularly clinical officers – demonstrated the capacity to make correct clinical decisions to start antiretroviral therapy. These preliminary data warrant more detailed and multicountry investigation into decision-making of non-physician clinicians in the management of HIV disease with antiretroviral therapy, and should lead policy-makers to more carefully explore task-shifting as a shorter-term response to addressing the human resource crisis in HIV care and treatment.