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Background The 8th edition of the AJCC staging system for pancreatic cancer incorporated several significant changes. This study sought to evaluate this staging system and assess its strengths and weaknesses relative to the 7th edition AJCC staging system. Methods Using the Surveillance, Epidemiology and End Results (SEER) database (2004–2013), 8960 patients undergoing surgical resection for non-metastatic pancreatic adenocarcinoma were identified. Overall survival was estimated using the Kaplan–Meier method and compared using log-rank tests. Concordance indices (c-index) were calculated to evaluate the discriminatory power of both staging systems. The Cox proportional hazards model was used to determine the impact of T and N classification on overall survival. Results The c-index for the AJCC 8th staging system [0.60; 95% confidence interval (CI), 0.59–0.61] was comparable with that for the 7th edition AJCC staging system (0.59; 95% CI, 0.58–0.60). Stratified analyses for each N classification system demonstrated a diminishing impact of T classification on overall survival with increasing nodal involvement. The corresponding c-indices were 0.58 (95% CI, 0.55–0.60) for N 0, 0.53 (95% CI, 0.51–0.55) for N 1, and 0.53 (95% CI, 0.50–0.56) for N 2 classification. Conclusion This is the first large-scale validation of the AJCC 8th edition staging system for pancreatic cancer. The revised system provides discrimination similar to that of the 7th-edition system. However, the 8th-edition system allows for finer stratification of patients with resected tumors according to extent of nodal involvement.

Nanoparticles in polluted air or aerosolized drug nanoparticles predominantly settle in the alveolar lung. Here, we describe a novel, highly effective pathway for the particles to cross the alveolar epithelium and reach the lymph and bloodstream. Amorphous silica nanoparticles, suspended in perfluorocarbon, were instilled into the lungs of mice for intravital microscopy. Particles formed agglomerates that settled on the alveolar wall, half of which were removed from the lung within 30 minutes. TEM histology showed agglomerates in stages of crossing the alveolar epithelium, in large compartments inside the epithelial cells and crossing the basal membrane into the interstitium. This pathway is consistent with published kinetic studies in rats and mice, using a host of (negatively) charged and polar nanoparticles.

Histotripsy is a novel focused ultrasound tumor ablation modality with potent immunostimulatory effects. To measure the spatiotemporal kinetics of local andabscopal responses to histotripsy, C57BL/6 mice bearing bilateral flank B16 melanoma or Hepa1-6 hepatocellular carcinoma tumors were treated with unilateral sham or partial histotripsy. Treated and contralateral untreated (abscopal) tumors were analyzed using multicolor immunofluorescence, digital spatial profiling, RNA sequencing (RNASeq), and flow cytometry. Unilateral histotripsy triggered abscopal tumor growth inhibition. Within the ablation zone, early high mobility group box protein 1 (HMGB1) release and necroptosis were accompanied by immunogenic cell death transcriptional responses in tumor cells and innate immune activation transcriptional responses in infiltrating myeloid and natural killer (NK) cells. Delayed CD8+ T cell intratumoral infiltration was spatiotemporally aligned with cancer cell features of ferroptosis; this effect was enhanced by CTLA-4 blockade and recapitulated when tumor-draining lymph node CD8+ T cells were co-cultured with tumor cells. Inoculation with cell-free tumor fractions generated by histotripsy but not radiation or freeze/thaw conferred partial protection from tumor challenge. We propose that histotripsy may evoke local necroptotic immunogenic cell death, priming systemic adaptive immune responses and abscopal ferroptotic cancer cell death.

Background Pancreaticoduodenectomy (PD) has long been associated with high rates of morbidity and mortality. The objective of this study was to identify preoperative risk factors for serious complications and mortality after PD and to construct a prediction tool to facilitate risk stratification prior to surgery. Materials and Methods Patients who underwent elective PD from 2005 to 2009 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Multivariate logistic regression identified predictors of 30-day serious complications and mortality. A prediction tool was created and validated in a sample of 1254 patients. Results Of 4945 patients who underwent PD, 1342 (27.1%) suffered a serious complication and 127 (2.6%) died within 30 days. The most frequent complications were sepsis (15.3%), surgical site infection (13.1%), and respiratory complications (9.5%). After adjusting for potential confounders, the significant predictors of morbidity included older age, male gender, overweight and obesity, dependent functional status, chronic obstructive pulmonary disease (COPD), steroid use, bleeding disorder, leukocytosis, elevated serum creatinine, and hypoalbuminemia. Significant predictors of 30-day mortality included COPD, hypertension, neoadjuvant radiation therapy, elevated serum creatinine, and hypoalbuminemia. Multivariable models were used to construct a preoperative risk stratification tool. Conclusions Preoperative factors are associated with perioperative outcomes after PD. The prediction tool estimates the probability of early morbidity and mortality for patients undergoing PD. The tool may be used to provide information for patient counseling during the informed consent process and to identify high-risk patients for the purpose of tailoring perioperative care.

Clinically, histotripsy utilizes a fixed, non-optimized dose (defined by the number of histotripsy pulses) to non-invasively ablate liver tumors. This study investigates the impact of histotripsy doses on tumor cellular damage, immune response, and treatment outcomes. Single orthotopic rat HCC liver tumors were established in immunocompetent rats by injecting McA-RH7777 cells into the liver and were classified as intermediate-stage or late-stage. Tumors were treated with doses 20, 50, 100 and 200 pulses per location (ppl) at 20 Hz, 50 Hz, 100 Hz and 200 Hz pulse repetition frequency (PRF) respectively using 1–2 cycle length histotripsy pulses delivered via a 1 MHz custom histotripsy transducer with an estimated peak negative pressure > 30 MPa. Cellular damage and immune response were evaluated in late-stage tumors. Local tumor control, metastasis inhibition, and survival were evaluated and compared across tumor stages. Abscopal response was evaluated by generating multicentric tumors in separate liver lobes but treating only one tumor. As the dose increased from 20 to 200 ppl, histologic cellular disruption increased from sparse-treatment to overtreatment. Dose 100 ppl (intermediate dose resulting in complete treatment) had the greatest infiltration of CD3 + T-cells and NK-cells, highest TUNEL+ area, lowest Ki67 index, and the highest percentage of animals with complete regression in late-stage tumors. Overtreatment dose (200 ppl) did not have the best treatment outcomes for any tumor stage. Dose 100 ppl also demonstrated improved abscopal response in distant untreated tumor. Histotripsy dose impacts histological tumor damage, immune infiltration, local tumor progression, metastasis inhibition, abscopal response, and survival. An intermediate dose had the best outcomes, but overtreatment resulted in worse outcomes, highlighting the need for histotripsy dose optimization.

Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45 hi CD11b + Ly6C + inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4 + T cells and CD8 + T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4 + T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients. IMPORTANCE Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Here, we reveal that CM disease progression in mice is accompanied by inflammatory monocytes infiltration at the periphery of the infected foci that overlap locally perturbed neuronal function and death. Importantly, we identified that CCR2 signaling is a critical pathway driving neuroinflammation, especially inflammatory monocyte recruitment, as well as CNS pathology and mortality in CM mice. Our results imply that targeting the CCR2 pathway may be beneficial as a therapy complementary to antifungal drug treatment, helping to reduce CNS damage and mortality in CM patients.

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8 T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8 T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint , a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.