Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.

Deletion of the Plasmodium falciparum exported protein PTP7 leads to Maurer's clefts vesiculation, host cell remodeling defects, and loss of surface presentation of EMP1.

Presentation of the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (EMP1), at knob-like protrusions on the surface of infected red blood cells, underpins the parasite's pathogenicity. Here we describe a protein PF3D7_0301700 (PTP7), that functions at the nexus between the intermediate trafficking organelle, the Maurer's cleft, and the infected red blood cell surface. Genetic disruption of PTP7 leads to accumulation of vesicles at the Maurer's clefts, grossly aberrant knob morphology, and failure to deliver EMP1 to the red blood cell surface. We show that an expanded low complexity sequence in the C-terminal region of PTP7, identified only in the Laverania clade of Plasmodium, is critical for efficient virulence protein trafficking.

Disparities in Surgical Treatment of Resectable Pancreatic Adenocarcinoma at Minority Serving Hospitals.

INTRODUCTION: Minority serving hospitals (MSH) are those serving a disproportionally high number of minority patients. Previous research has demonstrated that treatment at MSH is associated with worse outcomes. We hypothesize that patients treated at MSH are less likely to undergo surgical resection of pancreatic adenocarcinoma compared to patients treated at non-MSH. METHODS: Patients with resectable pancreatic cancer were identified using the National Cancer Database. Institutions treating Black and Hispanic patients in the top decile were categorized as an MSH. Factors associated with the primary outcome of definitive surgical resection were evaluated using multivariable logistic regression. Univariate and multivariable survival analysis was performed. RESULTS: Of the 75,513 patients included in this study, 7.2% were treated at MSH. Patients treated at MSH were younger, more likely to be uninsured, and higher stage compared to those treated at non-MSH (P < 0.001). Patients treated at MSH underwent surgical resection at lower rates (MSH 40% versus non-MSH 44.5%, P < 0.001). On multivariable logistic regression, treatment at MSH was associated with decreased likelihood of undergoing definitive surgery (odds ratio 0.91, P = 0.006). Of those who underwent surgical resection, multivariable survival analysis revealed that treatment at an MSH was associated with increased morality (hazard ratio 1.12, P < 0.001). CONCLUSIONS: Patients with resectable pancreatic adenocarcinoma treated at MSH are less likely to undergo surgical resection compared to those treated at non-MSH. Targeted interventions are needed to address the unique barriers facing MSH facilities in providing care to patients with pancreatic adenocarcinoma.

Comparison of epidural infusion versus intrathecal morphine block as part of enhanced recovery after open pancreatoduodenectomy.

BACKGROUND AND OBJECTIVES: The accepted approach to pain management following open pancreatoduodenectomy (PD) remains controversial, with the most recent enhanced recovery after surgery (ERAS) protocols recommending epidural anesthesia (EA). Few studies have investigated intrathecal (IT) morphine, combined with transversus abdominis plane (TAP) blocks. We aim to compare the different approaches to pain management for open PD. METHODS: Patients who underwent open PD at our institution from 2020 to 2022 were included in the study. Patient characteristics, pain management, and postoperative outcomes between EA, IT morphine with TAP blocks, and TAP blocks only were compared using univariate analysis. RESULTS: Fifty patients were included in the study (58% male, median age 66 years [interquartile range, IQR: 58-73]). Most patients received IT morphine (N = 24, 48%) or EA (N = 18, 36%). The TAP block-only group required higher doses of postoperative narcotics while hospitalized (p = 0.004) and at discharge (p = 0.017). The IT morphine patients had a shorter median time to Foley removal (p = 0.007). Postoperative pain scores, non-opioid administration, postoperative bolus requirements, postoperative outcomes, and length of stay were similar between pain modalities. CONCLUSIONS: IT morphine and EA showed comparable efficacy with superior results compared to TAP blocks alone. Integration of IT morphine into PD ERAS protocols should be considered.

Prediction of post-hepatectomy liver failure by preoperative gadoxetate disodium-enhanced magnetic resonance imaging.

BACKGROUND: Approximately 15% of patients experience post-hepatectomy liver failure after major hepatectomy. Poor hepatocyte uptake of gadoxetate disodium, a magnetic resonance imaging contrast agent, may be a predictor of post-hepatectomy liver failure. METHODS: A retrospective cohort study of patients undergoing major hepatectomy (≥3 segments) with a preoperative gadoxetate disodium-enhanced magnetic resonance imaging was conducted. The liver signal intensity (standardized to the spleen) and the functional liver remnant was calculated to determine if this can predict post-hepatectomy liver failure after major hepatectomy. RESULTS: In 134 patients, low signal intensity of the remnant liver standardized by signal intensity of the spleen in post-contrast images was associated with post-hepatectomy liver failure in multiple logistic regression analysis (Odds Ratio 0.112; 95% CI 0.023-0.551). In a subgroup of 33 patients with lower quartile of functional liver remnant, area under the curve analysis demonstrated a diagnostic accuracy of functional liver remnant to predict post-hepatectomy liver failure of 0.857 with a cut-off value for functional liver remnant of 1.4985 with 80.0% sensitivity and 89.3% specificity. CONCLUSION: Functional liver remnant determined by gadoxetate disodium-enhanced magnetic resonance imaging is a predictor of post-hepatectomy liver failure which may help identify patients for resection, reducing morbidity and mortality.

Nanobodies against Pfs230 block Plasmodium falciparum transmission.

Transmission blocking interventions can stop malaria parasite transmission from mosquito to human by inhibiting parasite infection in mosquitos. One of the most advanced candidates for a malaria transmission blocking vaccine is Pfs230. Pfs230 is the largest member of the 6-cysteine protein family with 14 consecutive 6-cysteine domains and is expressed on the surface of gametocytes and gametes. Here, we present the crystal structure of the first two 6-cysteine domains of Pfs230. We identified high affinity Pfs230-specific nanobodies that recognized gametocytes and bind to distinct sites on Pfs230, which were isolated from immunized alpacas. Using two non-overlapping Pfs230 nanobodies, we show that these nanobodies significantly blocked P. falciparum transmission and reduced the formation of exflagellation centers. Crystal structures of the transmission blocking nanobodies with the first 6-cysteine domain of Pfs230 confirm that they bind to different epitopes. In addition, these nanobodies bind to Pfs230 in the absence of the prodomain, in contrast with the binding of known Pfs230 transmission blocking antibodies. These results provide additional structural insight into Pfs230 domains and elucidate a mechanism of action of transmission blocking Pfs230 nanobodies.

Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial.

Importance: Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood. Objective: To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics. Design, Setting, and Participants: Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment. Intervention: The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care). Main Outcomes and Measures: The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program. Results: The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32). Conclusions and Relevance: In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03269994.

The Durability of EUS-Guided Chemoablation of Mucinous Pancreatic Cysts: A Long-Term Follow-Up of the CHARM trial.

Pancreatic cancer has known precursor lesions with potential to develop into malignancy over time. At least 20% of pancreatic cancer evolves from mucinous cystic neoplasms and intraductal papillary mucinous neoplasms, which are often discovered incidentally.1,2 Current guidelines for the management of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms include long-term surveillance, which is expensive and nontherapeutic, or surgical resection, which is associated with major risk and may not be an option for patients with significant concomitant illness.3.

Frontoparietal and Default Mode Network Contributions to Self-Referential Processing in Social Anxiety Disorder.

Social anxiety disorder (SAD) is characterized by negative self-referential processing, which triggers excessive emotional reactivity. In healthy individuals, positive self-views typically predominate and are supported by regions of the default mode network (DMN) that represent self-related information and regions of the frontoparietal control network (FPCN) that contribute to metacognitive awareness and emotion regulation. The current study used functional magnetic resonance imaging (fMRI) to examine patterns of DMN and FPCN activation during positive and negative self-referential judgments in SAD patients (N = 97) and controls (N = 34). As expected, SAD patients demonstrated a striking difference in self-beliefs compared with non-anxious healthy controls, endorsing fewer positive traits and more negative traits. However, SAD patients and controls demonstrated largely similar patterns of DMN and FPCN recruitment during self-referential judgements. No significant group differences were observed. However, equivalence testing identified numerous regions demonstrating effect sizes that were not small enough to conclude that they were practically equivalent to zero, despite the nonsignificant null hypothesis test. These regions may be key targets to investigate in future studies using larger samples.

Surface area-to-volume ratio, not cellular viscoelasticity, is the major determinant of red blood cell traversal through small channels.

The remarkable deformability of red blood cells (RBCs) depends on the viscoelasticity of the plasma membrane and cell contents and the surface area to volume (SA:V) ratio; however, it remains unclear which of these factors is the key determinant for passage through small capillaries. We used a microfluidic device to examine the traversal of normal, stiffened, swollen, parasitised and immature RBCs. We show that dramatic stiffening of RBCs had no measurable effect on their ability to traverse small channels. By contrast, a moderate decrease in the SA:V ratio had a marked effect on the equivalent cylinder diameter that is traversable by RBCs of similar cellular viscoelasticity. We developed a finite element model that provides a coherent rationale for the experimental observations, based on the nonlinear mechanical behaviour of the RBC membrane skeleton. We conclude that the SA:V ratio should be given more prominence in studies of RBC pathologies.

Predictors of Conversion During Minimally Invasive Gastrectomy for Malignancy.

INTRODUCTION: Implementation of minimally invasive gastrectomy (MIG) for malignancy is increasing. However, risk factors for conversion to open surgery during laparoscopic and robotic gastrectomy are poorly understood. This study aimed to determine the risk factors for, and impact of, conversion during oncologic resection. METHODS: The National Cancer Database (NCDB) was used to identify patients with clinical stage I-III gastric cancer from 2010 to 2017. Chi-squared test and t-test were used to compare the robotic versus laparoscopic groups. Propensity score weighted multivariable logistic regression was used to evaluate factors associated with conversion to open surgery. RESULTS: Of 6990 patients identified, 5702 (81.6%) underwent a laparoscopic resection and 1288 (18.4%) underwent robotic-assisted resection. Conversion rates were 14.7% and 7.8% for laparoscopic and robotic gastrectomy, respectively. The robotic approach was associated with lower likelihood of conversion compared to laparoscopic approach (odds ratio [OR] = 0.470, P < 0.001). Other factors predictive of conversion included tumor size >5 cm compared to <2 cm (OR 1.714, P = 0.010), total gastrectomy compared to partial gastrectomy (OR 2.019, P < 0.001), antrum/pylorus (OR 2.345, P < 0.001), and body (OR 2.152, P < 0.001) tumors compared to cardia tumors. Compared to those treated with laparoscopic and robotic gastrectomy, patients who underwent conversion experienced significantly longer hospital length of stay and higher rates of positive surgical margins. CONCLUSIONS: Laparoscopic gastrectomy was associated with a higher conversion rate compared to robotic gastrectomy. Conversion to open surgery was associated with a significantly longer length of stay and higher rates of positive margins. Identification of risk factors for conversion can aid in appropriate modality selection.

Albumin-bilirubin score is superior to platelet-albumin-bilirubin score and model for end-state liver disease sodium for predicting posthepatectomy liver failure.

BACKGROUND: Risk stratification for patients undergoing hepatectomy can be attempted using established models. This study compares the platelet-albumin-bilirubin (PALBI) score with albumin-bilirubin (ALBI) and model for end-stage liver disease sodium (MELD-Na) for predicting posthepatectomy liver failure (PHLF) and 30-day mortality. METHODS: The 2014-2018 NSQIP database was queried for patients who underwent elective hepatectomy. Multivariable logistic regressions assessed associations of posthepatectomy outcomes with patient and clinical characteristics. Predictive accuracy of the grading systems was evaluated using receiver operator characteristic (ROC) curves and calculating area under the curve (AUC). RESULTS: Severe PHLF (Grade B/C) and mortality were present in 2.58% (N = 369) and 1.2% (N = 171) of patients who underwent hepatectomy (N = 13 925), respectively. ALBI Grade 2/3 had a stronger association with severe PHLF (odds ratio [OR] = 1.62, p < 0.01) and mortality (OR = 2.06, p < 0.005) than PALBI Grade 2/3 (OR = 1.14, p = 0.43 for PHLF and OR = 2.01, p < 0.005 for mortality) or MELD-Na ≥10 (OR = 1.29, p = 0.25 for PHLF and OR = 1.84, p < 0.03). ALBI had a higher AUC (0.671) than PALBI (0.625) and MELD-Na (0.627) for predicting severe PHLF. ALBI had a higher AUC (0.695) than PALBI (0.642) for predicting 30-day mortality. CONCLUSIONS: ALBI was a more accurate predictor of severe PHLF and 30-day mortality than MELD-Na and PALBI for patients who underwent hepatectomy.

Is preoperative biliary stenting associated with increased rate of postoperative complications for patients undergoing pancreatoduodenectomy? A review of national surgical quality improvement program data.

BACKGROUND: Jaundice in the setting of periampullary neoplasms is often treated with biliary stenting. Level 1 data demonstrated an increase in perioperative complications after pancreaticoduodenectomy in patients undergoing stent placement. However, the impact of this data on practice patterns in the US remains unknown. METHODS: The National Surgical Quality Improvement Program (NSQIP) Pancreatectomy Targeted Participant Use Data File was used to identify patients from 2014 to 2017 undergoing pancreatoduodenectomy. Chi-square test and multivariable logistic regression were used to compare outcomes between those with biliary stent and those without. RESULTS: Of the 5524 patients, 3321 (60.1%) had biliary stent placement. The stent group was older, had a higher ASA class, and had preoperative weight loss compared to the group without biliary stenting (all p < 0.05). When adjusting for demographic and operative characteristics, the non-stent group had lower associated overall complications and postoperative infections. There was no significant difference in mortality and pancreatic fistula rate between groups. CONCLUSION: Preoperative biliary stenting is still common prior to pancreaticoduodenectomy. With a trend toward increased utilization of neoadjuvant chemotherapy, stenting will likely remain a common practice. Recognition of increased rates of complications associated with stent placement allows for appropriate risk-benefit analysis.

Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine.

BACKGROUND: There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. METHODS: The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression). RESULTS: None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo. CONCLUSIONS: This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).

The knob protein KAHRP assembles into a ring-shaped structure that underpins virulence complex assembly.

Plasmodium falciparum mediates adhesion of infected red blood cells (RBCs) to blood vessel walls by assembling a multi-protein complex at the RBC surface. This virulence-mediating structure, called the knob, acts as a scaffold for the presentation of the major virulence antigen, P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1). In this work we developed correlative STochastic Optical Reconstruction Microscopy-Scanning Electron Microscopy (STORM-SEM) to spatially and temporally map the delivery of the knob-associated histidine-rich protein (KAHRP) and PfEMP1 to the RBC membrane skeleton. We show that KAHRP is delivered as individual modules that assemble in situ, giving a ring-shaped fluorescence profile around a dimpled disk that can be visualized by SEM. Electron tomography of negatively-stained membranes reveals a previously observed spiral scaffold underpinning the assembled knobs. Truncation of the C-terminal region of KAHRP leads to loss of the ring structures, disruption of the raised disks and aberrant formation of the spiral scaffold, pointing to a critical role for KAHRP in assembling the physical knob structure. We show that host cell actin remodeling plays an important role in assembly of the virulence complex, with cytochalasin D blocking knob assembly. Additionally, PfEMP1 appears to be delivered to the RBC membrane, then inserted laterally into knob structures.

Plasmodium-specific antibodies block in vivo parasite growth without clearing infected red blood cells.

Plasmodium parasites invade and multiply inside red blood cells (RBC). Through a cycle of maturation, asexual replication, rupture and release of multiple infective merozoites, parasitised RBC (pRBC) can reach very high numbers in vivo, a process that correlates with disease severity in humans and experimental animals. Thus, controlling pRBC numbers can prevent or ameliorate malaria. In endemic regions, circulating parasite-specific antibodies associate with immunity to high parasitemia. Although in vitro assays reveal that protective antibodies could control pRBC via multiple mechanisms, in vivo assessment of antibody function remains challenging. Here, we employed two mouse models of antibody-mediated immunity to malaria, P. yoelii 17XNL and P. chabaudi chabaudi AS infection, to study infection-induced, parasite-specific antibody function in vivo. By tracking a single generation of pRBC, we tested the hypothesis that parasite-specific antibodies accelerate pRBC clearance. Though strongly protective against homologous re-challenge, parasite-specific IgG did not alter the rate of pRBC clearance, even in the presence of ongoing, systemic inflammation. Instead, antibodies prevented parasites progressing from one generation of RBC to the next. In vivo depletion studies using clodronate liposomes or cobra venom factor, suggested that optimal antibody function required splenic macrophages and dendritic cells, but not complement C3/C5-mediated killing. Finally, parasite-specific IgG bound poorly to the surface of pRBC, yet strongly to structures likely exposed by the rupture of mature schizonts. Thus, in our models of humoral immunity to malaria, infection-induced antibodies did not accelerate pRBC clearance, and instead co-operated with splenic phagocytes to block subsequent generations of pRBC.

Undertreatment of Pancreatic Cancer: Role of Surgical Pathology.

BACKGROUND: Current guidelines recommend treatment of early-stage pancreatic cancer with surgical resection and chemotherapy. Undertreatment can occur after resection when patients fail to receive adjuvant chemotherapy. Final pathologic results have the potential to bias providers to omit adjuvant chemotherapy, however, the association of surgical pathology and adjuvant chemotherapy is unknown. METHODS: Data from the National Cancer Database identified patients who underwent surgery for stage I or II pancreatic cancer. Chi-square tests and logistic regression were used to determine differences between patients receiving surgery followed by chemotherapy and those who had resection alone. Survival analysis of subgroups with favorable pathology (node-negative disease, tumor size ≤ 2 cm, well-differentiated histology) was performed by the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Of the 22,131 patients included in this study, 28% were considered undertreated (surgery alone). Favorable pathologic traits of negative lymph nodes, tumor 2 cm in size or smaller, and well-differentiated histology were associated with a 15-35% lower probability that adjuvant chemotherapy would be given than less favorable pathologic results (p < 0.001). Multivariable survival analysis showed significantly lower odds of mortality for patients who received resection and chemotherapy than for those who were undertreated among two subgroups: patients with node-negative disease (hazard ratio [HR] 0.774) and those with a tumor 2 cm in size or smaller (HR 0.771). CONCLUSION: The patients who had early-stage pancreatic cancer with favorable pathology after pancreatectomy were less likely than those with unfavorable pathology to receive adjuvant chemotherapy. This omission had significant survival consequences for subgroups with node-negative disease and tumors 2 cm in size or smaller. Recognition of patients with favorable pathology as an undertreated group is required for efforts to be directed toward encouraging guideline-concordant care and to combat undertreatment of pancreatic cancer.

Adjuvant Chemotherapy After Neoadjuvant Chemotherapy for Pancreatic Cancer is Associated with Improved Survival for Patients with Low-Risk Pathology.

BACKGROUND: With limited evidence, the benefit of adjuvant chemotherapy (AT) after completion of neoadjuvant chemotherapy (NT) and surgical resection for patients with pancreatic adenocarcinoma is debated. Guidelines recommend 6 months of AT for patients receiving NT. However, the patient-derived benefit from additional AT remains unknown. METHODS: The National Cancer Database from 2006 to 2015 was used to identify patients undergoing NT. The chi-square test and multivariable logistic regression were used to identify differences between those receiving only NT and those receiving NT and AT. Survival analysis using the Kaplan-Meier method and the Cox proportional hazard ratio model was applied to the entire cohort and to subgroups with differing lymph node ratios (LNRs), tumor sizes, grades, and surgical margin statuses. RESULTS: Of the 3897 patients who received NT, 36.7 % received additional AT. Analysis of the entire cohort showed that associated survival was significantly improved with NT and AT compared with NT alone (hazard ratio [HR], 0.83; p < 0.001). In the subgroup analysis, the survival benefit of additional AT remained significant for those with negative nodal disease, an LNR lower than 0.15, low-grade histology, and negative margin status. Overall survival did not differ between those receiving NT only and those receiving NT and AT in the group with an LNR of 0.15 or higher, high-grade histology, and positive margins. CONCLUSION: This study identified an increasing trend in the use of AT after NT and showed an associated survival benefit for subgroups with low-risk pathologic features. These results suggest that the addition of AT after NT likely beneficial for these subgroups.

Neurocysticercosis and HIV/AIDS co-infection: A scoping review.

OBJECTIVES: Neurocysticercosis (NCC) and human immunodeficiency virus (HIV) have a high disease burden and are prevalent in overlapping low- and middle-income areas. Yet, treatment guidance for people living with HIV/AIDS (PLWH/A) co-infected with NCC is currently lacking. This study aims to scope the available literature on HIV/AIDS and NCC co-infection, focusing on epidemiology, clinical characteristics, diagnostics and treatment outcomes. METHODS: The scoping literature review methodological framework, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. A total of 16,969 records identified through database searching, and 45 additional records from other sources were reduced to 52 included studies after a standardised selection process. RESULTS: Two experimental studies, ten observational studies, 23 case series/case reports and 17 reviews or letters were identified. Observational studies demonstrated similar NCC seroprevalence in PLWH/A and their HIV-negative counterparts. Of 29 PLWH/A and NCC co-infection, 17 (59%) suffered from epileptic seizures, 15 (52%) from headaches and 15 (52%) had focal neurological deficits. Eighteen (62%) had viable vesicular cysts, and six (21%) had calcified cysts. Fifteen (52%) were treated with albendazole, of which 11 (73%) responded well to treatment. Five individuals potentially demonstrated an immune-reconstitution inflammatory syndrome after commencing antiretroviral therapy, although this was in the absence of immunological and neuroimaging confirmation. CONCLUSIONS: There is a paucity of evidence to guide treatment of PLWH/A and NCC co-infection. There is a pressing need for high-quality studies in this patient group to appropriately inform diagnostic and management guidelines for HIV-positive patients with NCC.

Pathologic upstaging in resected pancreatic adenocarcinoma: Risk factors and impact on survival.

BACKGROUND: Clinical and pathologic staging determine treatment of pancreatic cancer. Clinical stage has been shown to underestimate final pathologic stage in pancreatic cancer, resulting in upstaging. METHODS: National Cancer Database was used to identify clinical stage I pancreatic adenocarcinoma. Univariate, multivariable logistic regression, and Cox proportional hazard ratio were used to determine differences between upstaged and stage concordant patients. RESULTS: Upstaging was seen in 80.2% of patients. Factors found to be significantly associated with upstaging included pancreatic head tumors (OR 2.56), high-grade histology (OR 1.74), elevated Ca 19-9 (OR 2.09), and clinical stage T2 (OR 1.99). Upstaging was associated with a 45% increased risk of mortality compared to stage concordant disease (HR 1.44, p < .001). CONCLUSION: A majority of clinical stage I pancreatic cancer is upstaged after resection. Factors including tumor location, grade, Ca 19-9, and tumor size can help identify those at high risk for upstaging.