Search

Trauma pancreaticoduodenectomy (TP) remains a challenging operation with morbidity and mortality rates as high as 80% and 50%. Many trauma surgeons consider it surgical dogma to avoid performing a TP during the index operation for patients with severe pancreatic or duodenal injuries. However, there is no modern analysis evaluating this belief. Therefore, we hypothesized no difference in risk of mortality between patients with severe pancreatic or duodenal injury undergoing a TP for penetrating trauma to propensity-matched controls undergoing laparotomy without TP. The Trauma Quality Improvement Program (2010-2016) was queried for adults with severe penetrating pancreatic or duodenal injuries undergoing laparotomy. A 1:2 propensity-matching including demographics/comorbidities, injury severity score, vitals on admission, Glasgow Coma Scale and concomitant injuries for laparotomy with or without TP was performed. Risk of mortality was reported using a univariable logistic regression model. Of 2182 patients with severe pancreatic or duodenal injuries undergoing laparotomy, 54 (2.5%) underwent TP and 2128 (97.5%) underwent laparotomy without TP. There were no differences in propensity-matching characteristics. Patients undergoing TP had a similar mortality rate (20.0% vs. 28.7%, p = 0.302) but a longer length of stay (LOS) (27.5 vs. 16.5 days, p = 0.017). The TP group had a similar associated risk of mortality (OR = 0.62, p = 0.302) but higher risk of major complications (OR 3.44, CI 1.35-17.47, p = 0.015). In appropriately selected penetrating trauma patients with severe pancreatic/duodenal injuries, TP is associated with a similar risk of mortality compared to laparotomy without TP. However, TP patients did have an increased associated risk of major complications and longer LOS.

Non-resolving, chronic inflammation (inflammaging) is believed to play an important role in aging and age-related diseases. The goal of this study was to determine if inflammation induced by necroptosis arising from the liver plays a role in chronic liver disease (CLD) and liver cancer in mice fed a western diet (WD). Necroptosis was induced in liver using two knockin (KI) mouse models that overexpress genes involved in necroptosis (Ripk3 or Mlkl) specifically in liver (i.e., hRipk3-KI and hMlkl-KI mice). These mice and control mice (not overexpressing Ripk3 or Mlkl) were fed a WD (high in fat, sucrose, and cholesterol) starting at 2 months of age for 3, 6, and 12 months. Feeding the WD induced necroptosis in the control mice, which was further elevated in the hRipk3-KI and hMlkl-KI mice and was associated with a significant increase in inflammation in the livers of the hRipk3-KI and hMlkl-KI mice compared to control mice fed the WD. Overexpressing Ripk3 or Mlkl significantly increased steatosis and fibrosis compared to control mice fed the WD. Mice fed the WD for 12 months developed liver tumors (hepatocellular adenomas): 28% of the control mice developing tumors compared to 62% of the hRipk3-KI and hMlkl-KI mice. The hRipk3-KI and hMlkl-KI mice showed significantly more and larger tumor nodules. Our study provides the first direct evidence that inflammation induced by necroptosis arising from hepatocytes can lead to the progression of hepatic steatosis to fibrosis in obese mice that eventually results in an increased incidence in hepatocellular adenomas., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The role of neoadjuvant therapy (NAT) in gallbladder cancer (GBC) is not well established. We sought to evaluate the effect of NAT on postoperative outcomes following surgical resection of GBC. We hypothesized that patients receiving NAT would have similar rates of 30-day mortality, readmission, and postoperative complications (e.g. bile leakage and liver failure) compared to those who did not receive NAT., Methods: The 2014-2017 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Procedure-Targeted Hepatectomy database was queried for patients that underwent surgery for GBC. Propensity scores were calculated to match patients in a 1:2 ratio based on age, comorbidities, functional status, and tumor staging., Results: A total of 37 patients undergoing NAT were matched to 74 patients without NAT. There was no difference in any matched characteristics. Compared to the NAT group, the no NAT cohort had similar rates of postoperative bile leakage (NAT 13.5 % vs. no NAT 10.8 %, p  = 0.31), postoperative liver failure (5.4 %, vs. 8.1 %, p  = 0.60), 30-day readmission (10.8 % vs. 10.8 %, p  = 1.00), and 30-day mortality (10.8 % vs. 2.7 %, p  = 0.075). All 30-day complications were similar except for a higher rate of postoperative blood transfusion (NAT 32.4 % vs. no NAT 10.8 %, p  = 0.005)., Conclusion: In patients undergoing surgical resection for GBC, those with and without NAT had similar rates of readmission and 30-day mortality, however NAT was associated with an increased risk for transfusion. Despite use of a large national database, this study may be underpowered to adequately assess the effect of NAT on perioperative GBC outcomes and thus warrants further investigation., Competing Interests: We have no conflicts of interest to disclose., (© 2024 The Authors.)

The recent Hot Topics section focuses on survival rates for patients with cholangiocarcinoma.

To study the impact of necroptosis-induced chronic inflammation on age-related diseases and aging, two knockin mouse models (Ripk3-KI and Mlkl-KI) were generated that overexpress two genes involved in necroptosis (Ripk3 or Mlkl) when crossed to Cre transgenic mice. Crossing Ripk3-KI or Mlkl-KI mice to albumin-Cre transgenic mice produced hepatocyte specific hRipk3-KI or hMlkl-KI mice, which express the two transgenes only in the liver. Ripk3 and Mlkl proteins were overexpressed 10- and fourfold, respectively, in the livers of the hRipk3-KI or hMlkl-KI mice. Treating young (2-month) hRipk3-KI or hMlkl-KI mice with carbon tetrachloride (CCl 4 ), a chemical inducer of oxidative stress, resulted in increased necroptosis (Mlkl-oligomers) and inflammation in the liver compared to control mice receiving CCl 4 . Mlkl-oligomerization also was significantly increased in old (18-month) hRipk3-KI and hMlkl-KI mice compared to old control (Cre negative, Ripk3-KI and Mlkl-KI) mice. The increase in necroptosis was associated with an increase in inflammation, e.g., inflammatory cytokines (TNFα, IL-6) and macrophage markers (F4/80, CD68). Importantly, steatosis (triglycerides) and fibrosis (e.g., picrosirius red staining, hydroxyproline levels, and transcripts for TGFβ, Col1α1, and Col3α1) that increase with age were significantly higher in the livers of the old hRipk3-KI or hMlkl-KI mice compared to old control mice. In addition, markers of cellular senescence were significantly increased in the livers of the old hRipk3-KI and hMlkl-KI mice. Thus, the first mouse models have been developed that allow researchers to study the impact of inducing necroptosis in specific cells/tissues on chronic inflammation in aging and age-related diseases., (© 2023. The Author(s).)

We generated a genetically heterogenous rat model by a 4-way cross strategy using 4 inbred strains (Brown Norway [BN], Fischer 344 [F344], Lewis [LEW], and Wistar Kyoto [KY]) to provide investigators with a highly genetically diverse rat model from commercially available inbred rats. We made reciprocal crosses between males and females from the 2 F1 hybrids to generate genetically heterogeneous rats with mitochondrial genomes from either the BN (OKC-HETB, a.k.a "B" genotype) or WKY (OKC-HETW a.k.a "W" genotype) parental strains. These two mitochondrial genomes differ at 94 nucleotides, more akin to human mitochondrial genome diversity than that available in classical laboratory mouse strains. Body weights of the B and W genotypes were similar. However, mitochondrial genotype antagonistically affected grip strength and treadmill endurance in females only. In addition, mitochondrial genotype significantly affected multiple responses to a high-fat diet (HFD) and treatment with 17α-estradiol. Contrary to findings in mice in which males only are affected by 17α-estradiol supplementation, female rats fed a HFD beneficially responded to 17α-estradiol treatment as evidenced by declines in body mass, adiposity, and liver mass. Male rats, by contrast, differed in a mitochondrial genotype-specific manner, with only B males responding to 17α-estradiol treatment. Mitochondrial genotype and sex differences were also observed in features of brain-specific antioxidant response to a HFD and 17α-estradiol as shown by hippocampal levels of Sod2 acetylation, JNK, and FoxO3a. These results emphasize the importance of mitochondrial genotype in assessing responses to putative interventions in aging processes., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

The objective of this study was to create a nanofiber-based skin graft with an antimicrobial bandage that could accelerate the healing of an open wound while minimizing infection. To this end, we prepared a bi-layer construct where the top layer acts as bandage, and the bottom layer acts as a dermal equivalent graft. A collagen (CG) gel was combined without and with an electrospun polycaprolactone (PCL) membrane to prepare CG and CG-PCL dermal equivalent constructs. The antibacterial properties of PCL with and without an antibacterial agent (MgO nanoparticles) against Staphylococcus aureus (ATCC 6538) was also examined. Human dermal fibroblasts were cultured in each construct to make the dermal equivalent grafts. After culturing, keratinocytes were plated on top of the tissues to allow growth of an epidermis. Rheological and durability tests were conducted on in vitro dermal and skin equivalent cultures, and we found that PCL significantly affects CG-PCL graft biological and mechanical strength (rheology and durability). PCL presence in the dermal equivalent allowed sufficient tension generation to activate fibroblasts and myofibroblasts in the presence of transforming growth factor-beta. During culture of the skin equivalents, optical coherence tomography (OCT) showed layers corresponding to dermal and epidermal compartments in the presence or absence of PCL; this was confirmed after fixed specimens were histologically sectioned and stained. MgO added to PCL showed antibacterial activity against S. aureus. In vivo animal studies using a rat skin model showed that a polycaprolactone nanofiber bandage containing a type I collagen skin graft has potential for wound healing applications.

Delayed gastric emptying (DGE) is common in patients undergoing pancreaticoduodenectomy (PD). The effect of DGE on mortality is less clear. We sought to identify predictors of mortality in patients undergoing PD for pancreatic adenocarcinoma hypothesizing DGE to independently increase risk of 30-day mortality. The ACS-NSQIP targeted pancreatectomy database (2014-2017) was queried for patients with pancreatic adenocarcinoma undergoing PD. A multivariable logistic regression analysis was performed. Separate sensitivity analyses were performed adjusting for postoperative pancreatic fistula (POPF) grades A-C. Out of 8011 patients undergoing PD, 1246 had DGE (15.6%). About 8.5% of patients with DGE had no oral intake by postoperative day-14. The DGE group had a longer median operative duration (373 vs. 362 min, p = 0.019), and a longer hospital length of stay (16.5 vs. 8 days, p < 0.001). After adjusting for age, gender, comorbidities, preoperative chemotherapy, preoperative radiation, open versus laparoscopic approach, vascular resection, deep surgical space infection (DSSI), postoperative percutaneous drain placement, and development of a POPF, DGE was associated with an increased risk for 30-day mortality (OR 3.25, 2.16-4.88, p < 0.001). On sub-analysis, grades A and B POPF were not associated with risk of mortality while grade C POPF was associated with increased risk of mortality (OR 5.64, 2.24-14.17, p < 0.001). The rate of DGE in patients undergoing PD in this large database was over 15%. DGE is associated with greater than three times the increased associated risk of mortality, even when controlling for POPF, DSSI, and other known predictors of mortality., (© 2022. The Author(s).)

Background: Routine intra-operative abdominal drain placement (IADP) is not beneficial for uncomplicated cholecystectomies though outcomes in gallbladder cancer surgery is unclear. This retrospective study hypothesized that patients with IADP (+IADP) for gallbladder cancer surgery have a higher risk of post-operative infectious complications (PIC) compared with patients without IADP (-IADP). Patients and Methods: The 2014-2017 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for +IADP and -IADP patients who had gallbladder cancer surgery. Post-operative infectious complications were defined as septic shock, organ/space infection (OSI), or percutaneous drainage. Multivariable analyses were performed to analyze the associated risk of PIC. Results: Of 385 patients, 237 (61.6%) were +IADP. The +IADP patients had higher rates of post-operative bile leak, OSI, re-admission, and increased length of stay (p < 0.05). The +IADP patients were not associated with increased risk of PIC (p > 0.05). Bile leak (odds ratio [OR], 10.61; p < 0.001), peri-operative blood transfusion (OR, 3.77; p = 0.003), biliary reconstruction (OR, 2.88; p = 0.018), and pre-operative biliary stent placement (OR, 3.02; p = 0.018) were the strongest associated risk factors of PIC. Patients with drains in place at or longer than 30 days post-operatively had an increased associated risk compared with patients who did not (OR, 6.88; 95% confidence interval [CI], 2.16-21.86; p < 0.001). Conclusions: More than 60% of gallbladder cancer surgeries included IADP and was not associated with an increased risk of PIC. Intra-operative abdominal drain placement was not associated with an increased risk of PIC, unless drains were left in place for 30 days or longer. Increased risk of PIC was associated with bile leak, peri-operative blood transfusion, pre-operative biliary stent placement, and biliary reconstruction.

Introduction: There is early evidence that indocyanine green (ICG) fluorescence imaging has the ability to detect metastatic and primary malignancies in the liver that are too small to be identified by other methods. However, the rate of false positives and false negatives remains unknown., Materials and Methods: This is a single institution prospective single-arm study. Patients with suspected hepatic or pancreatic malignancies were intravenously injected with ICG one to three days prior to their scheduled surgical therapy. At the beginning of the procedure, the liver was assessed with fluorescence imaging and all identified lesions were biopsied and evaluated., Results: Twenty-three patients were enrolled from April 2015 through February 2016. Fifteen patients with confirmed malignancy had adequate fluorescence imaging evaluation of the liver; 10 with pancreatic primary malignancies and five with hepatic primaries. Fluorescence imaging was the only modality that identified nine concerning hepatic lesions, all of which were benign on pathology examination. Out of 11 malignant hepatic masses, six were visible on fluorescence imaging. Out of nine benign hepatic lesions, five were visible. No side effects or complications of the fluorescence imaging were encountered. The sensitivity for ICG fluorescence was 45.5%, the specificity 21.2%, the positive predictive value 25%, and the negative predictive value 40%., Conclusion: Intraoperative hepatic assessment with ICG fluorescence imaging to identify malignancy in the liver is feasible and safe. However, in this study the significant number of false positives limit the utility of the technique. Our preliminary data do not support its routine use for detection of malignancies in the liver.

Increased expression of developmentally silenced fetal globin (HBG) reduces the clinical severity of β-hemoglobinopathies. Benserazide has a relatively benign safety profile having been approved for 50 years in Europe and Canada for Parkinson's disease treatment. Benserazide was shown to activate HBG gene transcription in a high throughput screen, and subsequent studies confirmed fetal hemoglobin (HbF) induction in erythroid progenitors from hemoglobinopathy patients, transgenic mice containing the entire human β-globin gene (β-YAC) and anemic baboons. The goal of this study is to evaluate efficacies and plasma exposure profiles of benserazide racemate and its enantiomers to select the chemical form for clinical development. Intermittent treatment with all forms of benserazide in β-YAC mice significantly increased proportions of red blood cells expressing HbF and HbF protein per cell with similar pharmacokinetic profiles and with no cytopenia. These data contribute to the regulatory justification for development of the benserazide racemate. Additionally, dose ranges and frequencies required for HbF induction using racemic benserazide were explored. Orally administered escalating doses of benserazide in an anemic baboon induced γ-globin mRNA up to 13-fold and establish an intermittent dose regimen for clinical studies as a therapeutic candidate for potential treatment of β-hemoglobinopathies., (Published by Elsevier Inc.)

Aging of the immune system is characterized by the loss of naïve T-cells, increased inflammation, and immune function impairment. Chronic infection with cytomegalovirus is thought to play a role in age-related changes in immunity. Therefore, to assess the effect of pathogens such as cytomegalovirus on the immune system, we determined lymphocyte populations and inflammatory markers over a 3-y period in captive, middle-age baboons, with various exposure to pathogens and shedding pressure. Groups included SPF (i.e., pathogen-negative; n = 14); large-group, conventionally housed (CONV LG; pathogen- positive; n = 14), and small-group, conventionally housed (CONV SM; pathogen-positive; n = 7). All baboon groups showed a decrease in CD45RA+ CD28+ (i.e., naive) cells over time during middle age, but the rate of decline appeared faster in CONV LG baboons than in the other groups. In addition, the reduction in CD45RA+ CD28+ cells in the CONV LG baboons coincided with higher IgG levels against baboon cytomegalovirus, increased serum cortisol concentration, and a greater inflammatory phenotype. The results of this project support a role for cytomegalovirus infection in immune system alterations in middle-aged baboons.

Chronic liver injury is a risk factor for cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms that regulate the decision between normal injury repair and neoplastic initiation are unclear. Doublecortin-like kinase 1 (DCLK1), a tumor stem cell marker, is induced during cirrhosis and HCC. Here, we demonstrate that DCLK1-overexpressing primary human hepatocytes formed spheroids in suspension cultures. Spheroids derived from DCLK1-overexpressing hepatoma cells showed high level expression of active β-catenin, α-fetoprotein, and SOX9, suggesting that DCLK1 overexpression induces clonogenicity and dedifferentiated phenotypes in hepatoma cells. DCLK1 overexpression in hepatoma cells also increased phosphorylation of GSK-3β at Ser 9 . This was associated with an induction of a 48-kDa active β-catenin with a preserved hypophosphorylated N-terminus that interacted with nuclear TCF-4 resulting in luciferase reporter activity and cyclin D1 expression. DCLK1 downregulation inhibited 48-kDa β-catenin expression. The proteasome inhibitor bortezomib did not block the 48-kDa β-catenin, instead, caused a threefold accumulation, suggesting a proteasome-independent mechanism. Liver tissues from patients with cirrhosis and HCC revealed epithelial co-staining of DCLK1 and active β-catenin, and cleaved E-cadherin. Repopulated DCLK1-overexpressing primary human hepatocytes in humanized FRG mouse livers demonstrated active β-catenin. In conclusion, DCLK1 regulates oncogenic signaling and clonogenicity of hepatocytes by a novel non-canonical/atypical β-catenin-dependent mechanism.

Recent advances in systems biology have shifted vaccine development from a largely trial-and-error approach to an approach that promote rational design through the search for immune signatures and predictive correlates of protection. These advances will doubtlessly accelerate the development of a vaccine for schistosomiasis, a neglected tropical disease that currently affects over 250 million people. For over 15 years and with contributions of over 120 people, we have endeavored to test and optimize Sm-p80-based vaccines in the non-human primate model of schistosomiasis. Using RNA-sequencing on eight different Sm-p80-based vaccine strategies, we sought to elucidate immune signatures correlated with experimental protective efficacy. Furthermore, we aimed to explore the role of antibodies through in vivo passive transfer of IgG obtained from immunized baboons and in vitro killing of schistosomula using Sm-p80-specific antibodies. We report that passive transfer of IgG from Sm-p80-immunized baboons led to significant worm burden reduction, egg reduction in liver, and reduced egg hatching percentages from tissues in mice compared to controls. In addition, we observed that sera from Sm-p80-immunized baboons were able to kill a significant percent of schistosomula and that this effect was complement-dependent. While we did not find a universal signature of immunity, the large datasets generated by this study will serve as a substantial resource for further efforts to develop vaccine or therapeutics for schistosomiasis., (Copyright © 2020 Zhang, Le, Ahmad, Molehin, Siddiqui, Torben, Karmakar, Rojo, Sennoune, Lazarus, Khatoon, Freeborn, Sudduth, Rezk, Carey, Wolf, Papin, Damian, Gray, Marks, Carter and Siddiqui.)

Background: Schistosomiasis continues to inflict significant morbidity and mortality in the tropical and subtropical regions of the world. The disease endemicity overlaps with the transmission of other parasitic diseases. Despite the ubiquity of polyparasitism in tropical regions, particularly in rural communities, little is known about the impact of multiple helminth infections on disease progression. In this pilot study, we describe the influence of chronic Trichuris trichiura infection on Schistosoma mansoni egg-induced hepatopathology in infected baboons., Methods: Baboons with or without underlying whipworm infection were challenged with S. mansoni cercariae to establish schistosomiasis. Adult S. mansoni worms were recovered by perfusion and enumerated, hepatic granulomas were quantified via light microscopy, and transcriptional profiling of tissues were completed using RNA sequencing technologies., Results: Co-infection with both S. mansoni and T. trichiura resulted in higher female schistosome worm burden and significantly larger liver granuloma sizes. Systems biology analyses of peripheral blood mononuclear cells (PBMC) revealed pathways associated with increased liver damage in co-infected baboons., Conclusions: Underlying chronic whipworm infection intensified schistosome egg-induced liver pathology in infected baboons. RNA-Seq analysis provided insight into pathways associated with increased liver damage, corroborating histological findings.

Objectives: Although traumatic injuries to the superior mesenteric vein (SMV), portal vein (PV), and hepatic vein (HV) are rare, their impact is significant. Small single center reports estimate mortality rates ranging from 29% to 100%. Our aim is to elucidate the incidence and outcomes associated with each injury due to unique anatomic positioning and varied tolerance of ligation. We hypothesize that SMV injury is associated with a lower risk of mortality compared to HV and PV injury in adult trauma patients., Methods: The Trauma Quality Improvement Program database (2010-2016) was queried for patients with injury to either the SMV, PV, or HV. A multivariable logistic regression model was used for analysis., Results: From 1,403,466 patients, 966 (0.07%) had a single major hepatoportal venous injury with 460 (47.6%) involving the SMV, 281 (29.1%) involving the PV, and 225 (23.3%) involving the HV. There was no difference in the percentage of patients undergoing repair or ligation between SMV, PV, and HV injuries ( P > .05). Compared to those with PV and HV injuries, patients with SMV injury had a higher rate of concurrent bowel resection (38.5% vs 12.1% vs 7.6%, P < .001) and lower mortality (33.3% vs 45.9% vs 49.3%, P < .01). After controlling for covariates, traumatic SMV injury increased the risk of mortality (odds ratio [OR] 1.59, confidence interval [CI] = 1.00-2.54, P = .05) in adult trauma patients; however, this was less than PV injury (OR = 2.77, CI = 1.56-4.93, P = .001) and HV injury (OR = 2.70, CI = 1.46-4.99, P = .002)., Conclusion: Traumatic SMV injury had a lower rate of mortality compared to injuries of the HV and PV. SMV injury increased the risk of mortality by 60% in adult trauma patients, whereas PV and HV injuries nearly tripled the risk of mortality.

Background/purpose: Perioperative blood transfusion is common after pancreaticoduodenectomy (PD) and may predispose patients to infectious complications. The purpose of this study is to examine the association between perioperative blood transfusion and the development of post-surgical infection after PD., Methods: Patients who underwent PD from 2014 to 2015 were identified in the NSQIP pancreas-specific database. Logistic regression analysis was used to compute adjusted odds ratios (aOR) to identify an independent association between perioperative red blood cell transfusion (within 72 h of surgery) and the development of post-operative infection after 72 h., Results: A total of 6869 patients underwent PD during this time period. Of these, 1372 (20.0%) patients received a perioperative blood transfusion. Patients receiving transfusion had a higher rate of post-operative infection (34.7% vs 26.5%, p < 0.001). After adjusting for significant covariates, perioperative transfusion was independently associated the subsequent development of any post-operative infection (aOR 1.41 [1.23-1.62], p < 0.001), including pneumonia (aOR 2.01 [1.48-2.74], p < 0.001), sepsis (aOR 1.62 [1.29-2.04], p < 0.001), and septic shock (aOR 1.92 [1.38-2.68], p < 0.001)., Conclusion: There is a strong independent association between perioperative blood transfusion and the development of subsequent post-operative infection following PD., (Copyright © 2019. Published by Elsevier Ltd.)

Pertussis is a severe respiratory disease caused by Bordetella pertussis The classic symptoms of pertussis include paroxysmal coughing with an inspiratory whoop, posttussive vomiting, cyanosis, and persistent coryzal symptoms. Infants under 2 months of age experience more severe disease, with most deaths occurring in this age group. Most of what is known about the pathology of pertussis in humans is from the evaluation of fatal human infant cases. The baboon model of pertussis provides the opportunity to evaluate the histopathology of severe but nonfatal pertussis. The baboon model recapitulates the characteristic clinical signs of pertussis observed in humans, including leukocytosis, paroxysmal coughing, mucus production, heavy colonization of the airway, and transmission of the bacteria between hosts. As in humans, baboons demonstrate age-related differences in clinical presentation, with younger animals experiencing more severe disease. We examined the histopathology of 5- to 6-week-old baboons, with the findings being similar to those reported for fatal human infant cases. In juvenile baboons, we found that the disease is highly inflammatory and concentrated to the lungs with signs of disease that would typically be diagnosed as acute respiratory distress syndrome (ARDS) and bronchopneumonia. In contrast, no significant pathology was observed in the trachea. Histopathological changes in the trachea were limited to cellular infiltrates and mucus production. Immunohistostaining revealed that the bacteria were localized to the surface of the ciliated epithelium in the conducting airways. Our observations provide important insights into the pathology of pertussis in typical, severe but nonfatal pertussis cases in a very relevant animal model., (Copyright © 2018 American Society for Microbiology.)

Schistosomiasis is of public health importance to an estimated one billion people in 79 countries. A vaccine is urgently needed. Here, we report the results of four independent, double-blind studies of an Sm-p80-based vaccine in baboons. The vaccine exhibited potent prophylactic efficacy against transmission of Schistosoma mansoni infection and was associated with significantly less egg-induced pathology, compared with unvaccinated control animals. Specifically, the vaccine resulted in a 93.45% reduction of pathology-producing female worms and significantly resolved the major clinical manifestations of hepatic/intestinal schistosomiasis by reducing the tissue egg-load by 89.95%. A 35-fold decrease in fecal egg excretion in vaccinated animals, combined with an 81.51% reduction in hatching of eggs into the snail-infective stage (miracidia), demonstrates the parasite transmission-blocking potential of the vaccine. Substantially higher Sm-p80 expression in female worms and Sm-p80-specific antibodies in vaccinated baboons appear to play an important role in vaccine-mediated protection. Preliminary analyses of RNA sequencing revealed distinct molecular signatures of vaccine-induced effects in baboon immune effector cells. This study provides comprehensive evidence for the effectiveness of an Sm-p80-based vaccine for schistosomiasis., (© 2018 New York Academy of Sciences.)

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus with devastating outcomes seen recently in the Americas due to the association of maternal ZIKV infection with fetal microcephaly and other fetal malformations not previously associated with flavivirus infections. Here, we have developed the olive baboon ( Papio anubis ) as a nonhuman primate (NHP) translational model for the study of ZIKV pathogenesis and associated disease outcomes to contrast and compare with humans and other major NHPs, such as macaques. Following subcutaneous inoculation of adult male and nonpregnant female baboons, viremia was detected at 3 and 4 days postinfection (dpi) with the concordant presentation of a visible rash and conjunctivitis, similar to human ZIKV infection. Furthermore, virus was detected in the mucosa and cerebrospinal fluid. A robust ZIKV-specific IgM and IgG antibody response was also observed in all the animals. These data show striking similarity between humans and the olive baboon following infection with ZIKV, suggesting our model is a suitable translational NHP model to study ZIKV pathogenesis and potential therapeutics. IMPORTANCE ZIKV was first identified in 1947 in a sentinel rhesus monkey in Uganda and subsequently spread to Southeast Asia. Until 2007, only a small number of cases were reported, and ZIKV infection was relatively minor until the South Pacific and Brazilian outbreaks, where more severe outcomes were reported. Here, we present the baboon as a nonhuman primate model for contrast and comparison with other published animal models of ZIKV, such as the mouse and macaque species. Baboons breed year round and are not currently a primary nonhuman primate species used in biomedical research, making them more readily available for studies other than human immunodeficiency virus studies, which many macaque species are designated for. This, taken together with the similarities baboons have with humans, such as immunology, reproduction, genetics, and size, makes the baboon an attractive NHP model for ZIKV studies in comparison to other nonhuman primates., (Copyright © 2018 American Society for Microbiology.)

Background: Bordetella pertussis is a human pathogen responsible for serious respiratory illness. The disease is most severe in infants too young to be vaccinated with most hospitalizations and deaths occurring within this age group. The Advisory Committee on Immunization Practices recommended immunization of pregnant women to protect infants from birth until their first vaccination at 6-8 weeks of age. We previously demonstrated that maternal vaccination with licensed acellular pertussis vaccines protected newborn baboons from disease. We hypothesized that protection was due to toxin-neutralizing, maternal anti-pertussis toxin antibodies and predicted that maternal vaccination with a pertussis toxoid (PTx)-only vaccine would protect newborns from disease., Methods: Infant baboons born to unvaccinated mothers or mothers vaccinated with a PTx-only vaccine were challenged with B. pertussis at 5 weeks of age and followed for infection and signs of disease., Results: Although all challenged infants were heavily colonized, the infant baboons born to mothers vaccinated with PTx-only vaccine were free from clinical disease following exposure to B. pertussis. In contrast, disease was observed in infants born to unvaccinated mothers., Conclusions: Our results demonstrated that maternal vaccination with a PTx-only vaccine is sufficient to protect newborn baboons from disease following exposure to pertussis.

Background: In various types of pulmonary research, pulmonary function testing (PFT) is performed to quantify the severity of lung disease. Induction of apnea and positive pressure ventilation are required for accurate PFT measurements in non-cooperative subjects. We compared two methods of apnea induction in infant olive baboons (Papio anubis)., Methods: Pulmonary function testing results were compared during apnea induced by hyperventilation (CO 2 washout) vs. intravenous propofol (1 dose 10 mg/kg). PFT was evaluated using a hot-wire pneumotachometer incorporated within an Avea ventilator in nine 1-month-old baboons., Results: Propofol induced apnea faster and more reliably. In both groups, PFT values passed the statistical equivalence test and were not significantly different (Student's t-test). There was a trend toward less data variability after propofol administration., Conclusions: Intravenous propofol was non-inferior to CO 2 washout for apnea induction in infant olive baboons. Propofol induced apnea faster and more reliably and yielded less variable PFT results., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Several commercial Giardia immunoassays were evaluated in baboons for sensitivity and specificity as well as ease of use in a large specific pathogen-free (SPF) colony. An additional objective was to identify the assemblage(s) of Giardia duodenalis present in this baboon colony. A direct immunofluorescent antibody test (IFAT) was used as the reference test. Tests evaluated were a patient-side rapid test for dogs and cats, a human rapid test, and a well-plate ELISA designed for use with humans. Test sensitivities and specificities were compared using the McNemar paired t-test and were further evaluated for agreement using an unweighted Cohen kappa statistic. When compared to the IFAT reference, both human tests were more sensitive than the veterinary test. Based on PCR and sequencing of the G. duodenalis small-subunit ribosomal RNA and glutamate dehydrogenase loci, assemblage AI was present in this baboon colony. We found that 10 of the 110 (9%) baboons in this SPF colony were infected with a zoonotic strain of G. duodenalis.

Introduction: A novel 3-dimensional (3D) guidance system was developed to aid accurate needle placement during ablation., Methods: Five novices and 5 experienced hepatobiliary surgeons were recruited. Using an agar block with analog tumor, participants targeted under 4 conditions: in-line with the ultrasound plane using ultrasound, in-line using 3D guidance, 45° off-axis using ultrasound, and off-axis using 3D guidance. Time to target the tumor, number of withdrawals, and the National Aeronautics and Space Administration Task Load Index were collected. Initial and final parameters for each of the conditions were compared using a within-subjects paired t test., Results: A significant reduction was seen in the number of required withdrawals in all situations when using the 3D guidance (0.75 vs 3.65 in-line and 0.25 vs 3.6 for off-axis). Mental workload was significantly lower when using 3D guidance compared with ultrasound both for novices (29.85 vs 41.03) and experts (31.98 vs 44.57), P < .001 for both. The only difference in targeting time between first and last attempt was in the novice group during off-axis targeting using 3D guidance (115 vs 32.6 seconds, P = .03)., Conclusion: Though 3D guidance appeared to decrease time to target, this was not statistically significant likely as a result of lack of power in our trial. Three-dimensional guidance did reduce the number of required withdrawals, potentially decreasing complications, as well as mental workload after proficiency was achieved. Furthermore, novices without experience in ultrasound were able to learn targeting with the 3D guidance system at a faster pace than targeting with ultrasound alone.

Objectives: Literature addressing the significance of lymph node positivity in the management of nonfunctional pancreatic neuroendocrine tumors (PNETs) is conflicting., Methods: The National Cancer Data Base was queried for patients who underwent surgical resection of nonfunctional PNETs between 1998 and 2011. Clinical data and overall survival were analyzed using χ and Cox proportional hazards regression. Multiple imputation was used as a comparative analysis because of the high number of patients missing data on tumor grade., Results: Two thousand seven hundred thirty-five patients were identified. The overall incidence of lymph node metastasis was 51%. In the subset of patients with grade 1 tumors less than 1 cm, 24% had positive lymph nodes. Overall median survival for patients with negative lymph nodes was 11 years compared with 8 years for lymph node-positive patients (P < 0.001). On multivariate survival analysis, tumor grade, distant metastases, regional lymph node involvement, positive surgical margins, male sex, and older age were predictive of decreased overall survival., Conclusions: Lymph node positivity was associated with decreased overall survival. The incidence of lymph node involvement in resected low-grade tumors less than 1 cm is higher than previously reported. Patients selected for resection of PNETs should be offered lymphadenectomy for staging.

Introduction: Current literature addressing the treatment of solid pseudopapillary neoplasms (SPNs) of the pancreas is limited, particularly for patients with distant metastases. We aimed to define predictive indicators of survival in a large series of patients and assess the outcome of patients with distant metastases., Methods: The National Cancer Database was queried for patients diagnosed with SPNs of the pancreas between 1998 and 2011. Single predictor univariate analyses were performed on variables including demographics, tumor characteristics, and surgery outcomes, and multivariate Cox proportional hazards survival analysis was then completed with backward elimination., Results: Overall, 340 patients were identified: 82% were female, median age was 39 years, and 84% had no comorbidities. Patients undergoing any type of surgical resection experienced long-term survival (85% 8-year survival). Patients undergoing surgical resection (n = 296) had superior survival (hazard ratio [HR] 21 for no surgery, p < 0.0001), as did patients treated at academic centers and those with private insurance (HR 3.9, p = 0.009; HR 4.9, p = 0.007). Sex, age, tumor size, presence of lymph node metastases, positive surgical margins, and presence of distant metastases were not significant predictors of survival in multivariate analysis. Of 24 patients with distant metastases, seven were treated surgically and experienced long-term survival similar to that of patients without metastases treated surgically (HR 2, p = 0.48)., Conclusion: SPNs of the pancreas are rare neoplasms with excellent overall survival; however, in a low number of patients they metastasize. Of the few patients with metastatic disease selected for resection, most experienced long-term survival.

Background: Fistula Risk Score (FRS) is a previously developed tool to assess the risk of clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD)., Methods: Prospectively collected databases from 4 university affiliated and non-affiliated HPB centers in United States and Canada were used. The influence of individual baseline characteristics, FRS and FRS group on CR-POPF was assessed in univariate and multivariate analyses. FRS calculator performance was assessed using a C-statistic., Results: 444 patients were identified. Pathology, soft pancreas texture and pancreatic duct size were associated with CR-POPF rates (p < 0.001 for each); EBL was not (p = 0.067). The negligible risk group consisted of 50 (11.3%) patients, low risk of 118 (26.6%), moderate 234 (52.7%) and high risk group of 42 (9.5%) patients. The overall rate of CR-POPF was 20%. Of the patients in the negligible risk group, 2% developed CR-POPF, 13.6% of the low risk, 23.1% moderate and 42.9% in the high risk group (p < 0.001). Overall C-statistic was 0.719., Conclusion: FRS is robust and able to stratify the risk of developing CR-POPF following PD in diverse North American academic and non-academic institutions. The FRS should be used in research and to guide clinical management of patients post PD in these institutions., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

The baboon model of Bordetella pertussis infection is the newest and most clinically accurate model of the human disease to date. However, among the 15 experimentally infected baboons in this study, a subset of baboons did not exhibit the expected high bacterial colonization levels or increase in white blood cell count. Moreover, cultures of nasopharyngeal wash samples from several baboons suggested B. bronchiseptica coinfection. Analysis of serum antibodies recognizing filamentous hemagglutinin, pertussis toxin and B. pertussis lipo-oligosaccharide indicated that several baboons had likely been previously exposed to Bordetella species and that prior exposure correlated with partial protection from B. pertussis infection. Notably, all animals with a baseline Fha titer of 5 IU/ml or below exhibited symptoms typical of the model, suggesting this value can be used as inclusion criteria for animals prior to study enrollment. While B. pertussis infection is endemic to human populations and B. bronchiseptica is common in wild small mammals, this study illustrates that baboons can readily harbor both organisms. Awareness of Bordetella species that share antigens capable of generating protective immune responses and tracking of prior exposure to those species is required for successful use of the baboon model of pertussis.

In this study, we evaluated the efficacy of combined treatment with ivermectin and fenbendazole (IVM-FBZ) for treating captive olive baboons (Papio anubis) infected with Strongyloides fülleborni and Trichuris trichiura, 2 common nematode parasites of these NHP. Infected baboons were treated for a total of 9 wk with ivermectin (400 μg/kg IM twice weekly) and fenbendazole (50 mg/kg PO once daily for 3 d; 3 rounds of treatment, 21 d apart). Five baboons naturally infected with both S. fülleborni and T. trichiura (n = 4) or S. fülleborni alone (n = 1) received the combination therapy; an additional baboon infected with both parasites served as a nontreated control. The efficacy of IVM-FBZ was measured as the reduction in fecal egg counts of S. fülleborni and T. trichiura as determined by quantitative fecal flotation examination after treatment of baboons with IVM-FBZ. All baboons treated with IVM-FBZ stopped shedding S. fülleborni and T. trichiura eggs by 8 d after treatment and remained negative for at least 161 d. The nontreated control baboon shed S. fülleborni and T. trichiura eggs throughout the study period. Our results indicate that the IVM-FBZ regimen was efficacious for treating olive baboons infected with S. fülleborni and T. trichiura.

Background: Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy., Methods: To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma., Results: We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation., Conclusion: Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells., Trial Registration: ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.

Background: In metastatic testicular cancer patients treated with bleomycin, etoposide, and cisplatin (BEP) chemotherapy, bleomycin-induced pneumonitis is a well-known and potentially fatal side effect. We sought to determine the prevalence of lesions as signs of bleomycin-induced pulmonary changes on restaging computed tomography (CT) scans after treatment and to ascertain whether fibrosis markers were predictive of these changes., Patients and Methods: This prospective nonrandomized cohort study included metastatic testicular cancer patients, 18-50 years of age, treated with BEP chemotherapy. Restaging CT scans were examined for lesions as signs of bleomycin-induced pulmonary changes by two independent radiologists and graded as minor, moderate, or severe. Plasma samples were collected before, during, and after treatment and were quantified for transforming growth factor-β1 (TGF-β1), growth differentiation factor-15 (GDF-15), and high-sensitivity C-reactive protein (hs-CRP)., Results: In total, 66 patients were included: forty-five (68%) showed signs of bleomycin-induced pulmonary changes on the restaging CT scan, 37 of which were classified as minor and 8 as moderate. No differences in TGF-β1, GDF-15, or hs-CRP plasma levels were found between these groups., Conclusion: Bleomycin-induced pulmonary changes are common on restaging CT scans after BEP chemotherapy for metastatic testicular cancer. Changes in TGF-β1, GDF-15, and hs-CRP plasma levels do not differ between patients with and without radiological lesions as signs of bleomycin-induced pulmonary changes and are therefore not helpful as predictive biomarkers., Implications for Practice: Bleomycin-induced pneumonitis (BIP) is a well-known and potentially fatal side effect in metastatic testicular cancer patients treated with bleomycin, etoposide, and cisplatin chemotherapy. Currently, the decision to discontinue bleomycin administration is made during treatment and is based on clinical signs. An upfront or early marker or biomarker that identifies patients likely to develop BIP would be preferable. This study found that bleomycin-induced pulmonary changes are common on restaging computed tomography scans and mostly resolve. No correlation was seen between these changes and fibrosis or inflammation markers (transforming growth factor-β1, growth differentiation factor-15, and high-sensitivity C-reactive protein)., (©AlphaMed Press.)

Background: Preoperative risk stratification for postoperative pancreatic fistula in patients undergoing distal pancreatectomy is needed., Methods: Risk factors for postoperative pancreatic fistula in 220 consecutive patients undergoing distal pancreatectomy at 2 major institutions were recorded retrospectively. Gland density was measured on noncontrast computed tomography scans (n = 101), and histologic scoring of fat infiltration and fibrosis was performed by a pathologist (n = 120)., Results: Forty-two patients (21%) developed a clinically significant pancreatic fistula within 90 days of surgery. Fat infiltration was significantly associated with gland density (P = .0013), but density did not predict pancreatic fistula (P = .5). Recursive partitioning resulted in a decision tree that predicted fistula in this cohort with a misclassification rate less than 15% using gland fibrosis (histology), density (HU), margin thickness (cm), and pathologic diagnosis., Conclusions: This multicenter study shows that no single perioperative factor reliably predicts postoperative pancreatic fistula after distal pancreatectomy. A decision tree was constructed for risk stratification., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Routine lymphadenectomy in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) is not routinely performed. We aim to define predictive indicators of survival in patients with positive lymph nodes., Methods: The National Cancer Data Base (NCDB) was queried for patients who underwent major hepatectomy for ICC between 1998 and 2011. Clinical and pathologic data were assessed using uni- and multi-variate analyses. A sub-analysis was performed on the 160 patients with positive lymph nodes., Results: Of 849 patients with lymph node data, 57% had at least one lymph node examined. Median survival for lymph node negative patients was 37 months versus 15 months for lymph node positive patients. In lymph node positive patients, poorer survival was associated with not receiving chemotherapy (HR 1.83, p = 0.003), tumor size > 5 cm (p = 0.029), and older age (p < 0.0001). Lymph node positive patients age less than 45 had a median survival of 27 months., Conclusions: Overall survival in patients with lymph node metastases from ICC is poor. Adjuvant therapy was associated with a longer survival in lymph node positive patients, although prospective data are needed. Routine lymphadenectomy should be strongly considered to provide prognostic information and guidance for adjuvant therapy., (Copyright © 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Total pancreatectomy is infrequently performed for pancreatic cancer. Perceived operative mortality and questionable survival benefit deter many surgeons. Clinical outcomes, described in single-center series, remain largely unknown., Methods: The National Cancer Database was queried for cases of pancreatic ductal adenocarcinoma undergoing total pancreatectomy (1998-2011). Univariate survival analyses were performed for 21 variables: demographic (8), tumor characteristics (5), surgery outcomes (6), and adjuvant therapy (2). The Log-rank test of differences in Kaplan-Meier survival curves was used for categorical variables. Variables with p < 0.05 were included in a multivariate analysis. Cox proportional hazards regression was used to analyze continuous variables and multivariate models., Results: 2582 patients with staging and survival data made up the study population. 30-day mortality was 5.5%. Median overall survival was 15 months, with 1, 3, and 5-year survival rates of 60%, 22%, and 13%, respectively. Age, facility type, tumor size and grade, lymph node positivity, margin positivity, and adjuvant therapy significantly impacted survival in multivariate analysis., Conclusion: Although total pancreatectomy is a reasonable option for selected patients with pancreatic ductal adenocarcinoma, survival of the entire group is limited. Operative mortality is improved from prior reports. Greater survival benefits were seen in younger patients with smaller, node negative tumors resected with negative margins in academic research centers., (Copyright © 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

High-level fetal (γ) globin expression ameliorates clinical severity of the beta (β) hemoglobinopathies, and safe, orally-bioavailable γ-globin inducing agents would benefit many patients. We adapted a LCR-γ-globin promoter-GFP reporter assay to a high-throughput robotic system to evaluate five diverse chemical libraries for this activity. Multiple structurally- and functionally-diverse compounds were identified which activate the γ-globin gene promoter at nanomolar concentrations, including some therapeutics approved for other conditions. Three candidates with established safety profiles were further evaluated in erythroid progenitors, anemic baboons and transgenic mice, with significant induction of γ-globin expression observed in vivo. A lead candidate, Benserazide, emerged which demonstrated > 20-fold induction of γ-globin mRNA expression in anemic baboons and increased F-cell proportions by 3.5-fold in transgenic mice. Benserazide has been used chronically to inhibit amino acid decarboxylase to enhance plasma levels of L-dopa. These studies confirm the utility of high-throughput screening and identify previously unrecognized fetal globin inducing candidates which can be developed expediently for treatment of hemoglobinopathies.

A2E and related toxic molecules are part of lipofuscin found in the retinal pigment epithelial (RPE) cells in eyes affected by Stargardt's disease, age-related macular degeneration (AMD), and other retinal degenerations. A novel therapeutic approach for treating such degenerations involves slowing down the visual cycle, which could reduce the amount of A2E in the RPE. This can be accomplished by inhibiting RPE65, which produces 11-cis-retinol from all-trans-retinyl esters. We recently showed that phenyl-N-tert-butylnitrone (PBN) inhibits RPE65 enzyme activity in RPE cells. In this study we show that like PBN, certain PBN-derivatives (PBNDs) such as 4-F-PBN, 4-CF3-PBN, 3,4-di-F-PBN, and 4-CH3-PBN can inhibit RPE65 and synthesis of 11-cis-retinol in in vitro assays using bovine RPE microsomes. We further demonstrate that systemic (intraperitoneal, IP) administration of these PBNDs protect the rat retina from light damage. Electroretinography (ERG) and histological analysis showed that rats treated with PBNDs retained ~90% of their photoreceptor cells compared to a complete loss of function and 90% loss of photoreceptors in the central retina in rats treated with vehicle/control injections. Topically applied PBN and PBNDs also significantly slowed the rate of the visual cycle in mouse and baboon eyes. One hour dark adaptation resulted in 75-80% recovery of bleachable rhodopsin in control/vehicle treated mice. Eye drops of 5% 4-CH3-PBN were most effective, inhibiting the regeneration of bleachable rhodopsin significantly (60% compared to vehicle control). In addition, a 10% concentration of PBN and 5% concentration of 4-CH3-PBN in baboon eyes inhibited the visual cycle by 60% and by 30%, respectively. We have identified a group of PBN related nitrones that can reach the target tissue (RPE) by systemic and topical application and slow the rate of rhodopsin regeneration and therefore the visual cycle in mouse and baboon eyes. PBNDs can also protect the rat retina from light damage. There is potential in developing these compounds as preventative therapeutics for the treatment of human retinal degenerations in which the accumulation of lipofuscin may be pathogenic.

Despite widespread vaccination, pertussis rates are rising in industrialized countries and remain high worldwide. With no specific therapeutics to treat disease, pertussis continues to cause considerable infant morbidity and mortality. The pertussis toxin is a major contributor to disease, responsible for local and systemic effects including leukocytosis and immunosuppression. We humanized two murine monoclonal antibodies that neutralize pertussis toxin and expressed them as human immunoglobulin G1 molecules with no loss of affinity or in vitro neutralization activity. When administered prophylactically to mice as a binary cocktail, antibody treatment completely mitigated the Bordetella pertussis-induced rise in white blood cell counts and decreased bacterial colonization. When administered therapeutically to baboons, antibody-treated, but not untreated control animals, experienced a blunted rise in white blood cell counts and accelerated bacterial clearance rates. These preliminary findings support further investigation into the use of these antibodies to treat human neonatal pertussis in conjunction with antibiotics and supportive care., Competing Interests: M.K. and A.B. are employed by Synthetic Biologics, which has a financial interest in hu1B7 and hu11E6. J.A.M., A.W.N., E.K.W., and E.A.P. have filed a provisional patent jointly with Synthetic Biologics with the US Patent and Trademark Office for humanized pertussis antibodies. This work was supported in part by funding from Synthetic Biologics., (Copyright © 2015, American Association for the Advancement of Science.)

Introduction: With technological advances, questions arise regarding how to best fit newer treatment modalities, such as transarterial therapies, into the treatment algorithm for patients with hepatocellular carcinoma (HCC)., Methods: Between 2005 and 2011, 128 patients initially treated with transarterial radioembolization or chemoembolization using drug-eluting beads were identified. The response was graded retrospectively. Toxicity was measured 1, 3, and 6 months after the first and last treatments., Results: Sixty-five patients (53%) were advanced stage. Twenty patients (16%) had an initial complete response, but with additional treatments, this was increased to 46 (36%). Patients with a complete response as their best response to treatment had a median survival [95% confidence interval (CI)] of 5.77 (2.58, upper limit not yet reached) years, significantly longer than those whose best response was a partial response, 1.22 (0.84, 2.06) years and those with stable disease as their best response, 0.34 (0.29, 0.67) years. Repeated treatments did not increase toxicity., Discussion: This retrospective review of patients treated for intermediate and advanced stage HCC revealed a significant survival advantage in patients who achieved a complete response. These data support use of a multi-modality approach to intermediate and advanced stage HCC, combining liver-directed treatments as necessary to achieve a complete response., (© 2015 International Hepato-Pancreato-Biliary Association.)

A wide array of ablation technologies, in addition to the progressive sophistication of imaging technologies and percutaneous, laparoscopic, and open surgical techniques, have allowed us to expand treatment options for patients with liver tumors. In this article, technical considerations of chemical and thermal ablations and their application in hepatic oncology are reviewed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The human immune system undergoes age-related changes that can lead to increased disease susceptibility. Using the baboon as a model for human immune system aging, we examined age-related changes in relative and absolute numbers of T cell subpopulations, cytomegalovirus (CMV) titer and markers of inflammation. In addition, the effect of gender, social status and peer group on lymphocyte subpopulations was determined. Relative and absolute numbers of total lymphocytes (CD3+), T helper cells (CD4+), and cytotoxic T cells (CD8+) increased with age. The proportion of naïve T cells (CD45RA+) decreased, while the total number of cells negative for the co-stimulatory receptor, CD28 (CD28-) increased in an age-dependent manner. Furthermore, CMV titers were negatively correlated with the number of naive CD4+ cells. IL-6 and cortisol concentration were also negatively associated with T cell subpopulations. Additionally, socially dominant baboons exhibited decreases in naïve CD4+ and CD8+ cells (by 65% and 52%, respectively) compared to subordinate animals. These results suggest that factors such as CMV exposure and inflammation may contribute to the age-related decline in immune health and indicate that factors like social status should be considered when studying immunosenescence in animal models.

Background: The United States is experiencing a pertussis resurgence that resulted in a 60-year high of 48 000 cases in 2012. The majority of hospitalizations and deaths occur in infants too young to be vaccinated. Neonatal and maternal vaccination have been proposed to protect newborns until the first vaccination, currently recommended at 2 months of age. These interventions result in elevated anti-Bordetella pertussis titers, but there have been no studies demonstrating that these measures confer protection., Methods: Baboons were vaccinated with acellular pertussis vaccine at 2 days of age or at 2 and 28 days of age. To model maternal vaccination, adult female baboons primed with acellular pertussis vaccine were boosted in the third trimester of pregnancy. Neonatally vaccinated infants, infants born to vaccinated mothers, and naive infants born to unvaccinated mothers were infected with B. pertussis at 5 weeks of age., Results: Naive infant baboons developed severe disease when challenged with B. pertussis at 5 weeks of age. Baboons receiving acellular pertussis vaccine and infants born to mothers vaccinated at the beginning of their third trimester were protected., Conclusions: Our results demonstrate that neonatal vaccination and maternal vaccination confer protection in the baboon model and support further study of these strategies for protection of newborns from pertussis., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The Explorer Minimally Invasive Liver (MIL) system uses imaging to create a 3-dimensional model of the liver. Intraoperatively, the system displays the position of instruments relative to the virtual liver. A prospective clinical study compared it with intraoperative ultrasound (iUS) in laparoscopic liver ablations., Methods: Patients undergoing ablations were accrued from 2 clinical sites. During the procedures, probes were positioned in the standard fashion using iUS. The position was synchronously recorded using the Explorer system. The distances from the probe tip to the tumor boundary and center were measured on the ultrasound image and in the corresponding virtual image captured by the Explorer system., Results: Data were obtained on the placement of 47 ablation probes during 27 procedures. The absolute difference between iUS and the Explorer system for the probe tip to tumor boundary distance was 5.5 ± 5.6 mm, not a statistically significant difference. The absolute difference for probe tip to tumor center distance was 8.6 ± 7.0 mm, not statistically different from 5 mm., Discussion: The initial clinical experience with the Explorer MIL system shows a strong correlation with iUS for the positioning of ablation probes. The Explorer MIL system is a promising tool to provide supplemental guidance information during laparoscopic liver ablation procedures., (© The Author(s) 2013.)

No vaccines are available for human use for any parasitic infections, including the helminthic disease schistosomiasis. Sm-p80, the large subunit of Schistosoma mansoni calpain, is a leading antigen candidate for a schistosomiasis vaccine. Prophylactic and antifecundity efficacies of Sm-p80 have been tested using a variety of vaccine approaches in both rodent and nonhuman primate models. However, the therapeutic efficacy of a Sm-p80-based vaccine had not been determined. In this study, we evaluated the therapeutic efficacy of Sm-p80 by using 2 different strategies and 3 Sm-p80-based vaccine formulations in baboons. Vaccine formulations were able to decrease established adult worms by 10%-36%, reduce retention of eggs in tissues by 10%-57%, and decrease egg excretion in feces by 13%-33%, compared with control formulations. Marked differences were observed in B and T cell immune correlates between vaccinated and control animals. This is the first report of killing of established adult schistosome worms by a vaccine. In addition to distinct prophylactic efficacy of Sm-p80, this study adds to the evidence that Sm-p80 is a potentially important antigen with both substantial prophylactic and therapeutic efficacies. These data reinforce that Sm-p80 should be moved forward along the path toward human clinical trials., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Based on data obtained using vaccine efficacy studies in mice, hamsters, and baboons, the credentials of Sm-p80 as a first tier vaccine candidate for schistosomiasis have been well established. Sm-p80-based vaccine formulation(s) have consistently exhibited potent prophylactic efficacy in reducing adult worm burden following cercarial challenge and induce killing of established adult worms in chronic infection. This vaccine is protective against both intestinal and urinary schistosomiasis. In this study, the longevity of Sm-p80-specific antibody responses was studied in mice and in baboons. Robust antibody titers were detected in mice for up to 60 weeks following vaccination with Sm-p80 recombinant vaccine (Sm-p80 + GLA-SE). In the follow-up experiments to our published studies, Sm-p80-specific IgG was also detected in baboons 5-8 years following the initial vaccination with an Sm-p80 DNA vaccine. In one baboon, transfer of Sm-p80-specific antibody was detected in umbilical cord blood and in the baby. These long-lasting humoral immune response data coupled with the vaccine efficacy data in rodents and nonhuman primates further strengthens the case for Sm-p80 to be moved forward through development leading to human clinical trials.