Background
Neoadjuvant therapy and vascular resection may offer patients with locally advanced pancreatic cancer potential cure.
Methods
We reviewed medical records of patients with ductal ...adenocarcinoma who underwent pancreaticoduodenectomy (PD) from 1992 through 2011. We identified patients who received neoadjuvant therapy (NA+) or required vascular resection (VR+) for locally advanced disease and compared outcomes to those who did not.
Results
Of the 643 patients who were initially explored, 506 (143 NA+ and 363 NA− patients) ultimately underwent PD. There were no significant differences in R0 resection or morbidity. Mortality was higher in the NA+ versus NA− group (7.0 vs 3.0 %,
p
= 0.04). More NA+ patients underwent PD VR+ (
p
< 0.001). Among VR+ patients, neoadjuvant therapy resulted in significantly lower R1 resection. Among resected patients, survival of NA+ patients was significantly longer than both NA− patients (27.3 vs 19.7 months,
p
< 0.05) and patients abandoned because of locally advanced disease. Age, tumor grade, lymph node ratio, and R1 resection were independent predictors of poor survival.
Conclusions
Neoadjuvant therapy and vascular resection offer patients with locally advanced pancreatic cancer the chance for cure with acceptable morbidity and mortality. These patients have improved survival over patients deemed locally inoperable by traditional criteria.
Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine that triggers dendritic cell-mediated T helper (Th)2 inflammatory responses through a receptor consisting of a heterodimer ...of the IL-7 receptor alpha (IL-7Rα) chain and the TSLP receptor (TSLPR), which resembles the cytokine receptor common gamma chain. Dendritic cells activated by TSLP prime development of CD4⁺ T cells into Th2 cells contributing to the pathogenesis of allergic inflammation. We hypothesized that allergen exposure induces expression of TSLP and results in recruitment of TSLPR bearing cells in the cutaneous allergen-induced late-phase reaction (LPR) in atopic subjects. Skin biopsies were obtained from atopic subjects (n = 9) at various times after cutaneous allergen challenge. In situ hybridization and immunohistochemistry were used to determine TSLP mRNA expression and to measure infiltration of TSLPR⁺ DC in skin LPR. RT-PCR and flow cytometry were employed to analyse TSLPR expression on isolated blood DC. Allergen-induced skin TSLP expression occurred as early as 1 h after allergen challenge, whereas TSLPR⁺ and CD11c⁺ cells infiltrated relatively late (24-48 h). The majority of TSLPR⁺ cells were DC co-expressing blood DC antigen-1 (BDCA-1) or BDCA-2. Freshly isolated blood DC expressed both TSLPR and IL-7Rα chains. Maturation and stimulation with TSLP or polyriboinosinic-polyribocytidylic acid in vitro upregulated the expression of both TSLPR and IL-7Rα chains in DC but not in chemoattractant receptor-homologous molecule expressed on Th2 cells⁺ CD4⁺ T cells. The data suggest that TSLP plays a role in augmenting, through DC recruitment and activation, the development of Th2-type T cells in allergic inflammation.
The design and conduct of pediatric sedation studies in critically ill patients have historically been challenging due to the complexity of the pediatric intensive care unit (PICU) environment and ...the difficulty of establishing equipoise. Clinical trials, for instance, represent 1 important means of advancing our knowledge in this field, but there is a paucity of such studies in the literature. Accounting for ground-level factors in planning for each trial phase (eg, enrollment, intervention, assessment, and follow-up) and the presence of broader system limitations is of key importance. In addition, there is a need for early planning, coordination, and obtaining buy-in from individual study sites and staff to ensure success, particularly for multicenter studies. This review synthesizes the current state of pediatric sedation research and the myriad of challenges in designing and conducting successful trials in this particular area. The review poses consideration for future research directions, including novel study designs, and discusses electroencephalography monitoring and neurodevelopmental outcomes of PICU survivors.
Abstract Objective To evaluate the efficacy and toxicity of erlotinib in the management of squamous cell carcinoma (SCC) of the vulva. Methods Patients with vulvar lesions amenable to surgery or ...chemoradiation (cohort 1) or those with metastatic measurable disease (cohort 2) received erlotinib 150 mg daily. Patients were monitored for toxicity. Responses were determined by digital photography or RECIST 1.1. Cohort 1 underwent pre and post treatment biopsies. EGFR immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and mutational analysis were performed. Results 41 patients were enrolled: 17 in cohort 1 and 24 in cohort 2. Notable grade 3 or 4 toxicities included allergic reaction (1), diarrhea/electrolyte abnormalities (3), ischemic colitis (1), and renal failure (3) and electrolyte abnormalities (n = 2). Mean number of cycles for cohort 2 was 3.3. Overall clinical benefit rate was 67.5% with 11 (27.5%) partial responses (PR), 16 (40.0%) stable disease (SD), and 7 (17.5%) progressive disease. Responses were of short duration. All pre and post treatment biopsies exhibited 2–3 + EGFR staining. 5 of 14 patients (35%) were found to have EGFR amplification (n = 3) or high polysomy/trisomy (n = 2). These five patients had either a PR (n = 3) or SD (n = 2). Gain of function mutations were not been identified. Conclusions This is the first reported controlled trial evaluating erlotinib for the management of vulvar carcinoma. Toxicities were acceptable given the lack of treatment options for these patients. Given the observed clinical benefits erlotinib may represent one of the most active agents available to treat vulvar SCC.
We modeled the clinical course of a cohort of diffuse large B-cell lymphoma (DLBCL) patients with no prior cardiovascular diseases (CVDs) using a multistate modeling framework.
Data on 2600 patients ...with DLBCL diagnosed between 2000 and 2018 and had received chemotherapy with or without radiotherapy were obtained from a population-wide electronic health database of Hong Kong. We used the Markov illness-death model to quantify the impact of doxorubicin and various risk factors (therapeutic exposure, demographic, comorbidities, cardiovascular risk factors, and lifestyle factors which included smoking) on the clinical course of DLBCL (transitions into incident CVD, lymphoma death, and other causes of death).
A total of 613 (23.6%) and 230 (8.8%) of 2600 subjects died of lymphoma and developed incident CVD, respectively. Median follow-up was 7.0 years (interquartile range 3.8-10.8 years). Older ages hazard ratio (HR) for >75 versus ≤60 years 1.88; 95% confidence interval (CI) 1.25-2.82 and HR for 61-75 versus ≤60 years 1.60; 95% CI 1.12-2.30, hypertension (HR 4.92; 95% CI 2.61-9.26), diabetes (HR 1.43; 95% CI 1.09-1.87), and baseline use of aspirin (HR 5.30; 95% CI 3.93-7.16) were associated with an increased risk of incident CVD. In a subgroup of anticipated higher-risk patients (aged 61-75 years, smoked, had diabetes, and received doxorubicin), we found that they remained on average 7.9 (95% CI 7.2-8.8) years in the DLBCL state and 0.1 (95% CI 0.0-0.4) years in the CVD state, if they could be followed up for 10 years. The brief time in the CVD state is consistent with the high chance of death in patients who developed CVD. Other causes of death have overtaken DLBCL-related death after about 5 years.
In this Asian population-based cohort, we found that incident CVDs can occur soon after DLBCL treatment and continued to occur throughout survivorship. Clinicians are advised to balance the risks and benefits of treatment choices to minimize the risk of CVD.
•This is one of the largest studies describing life history path of DLBCL patients in Asia.•Incident CVDs can develop soon after DLBCL treatment and continued to occur throughout survivorship.•This prognostic model can be useful in individualized prognostic estimations for the survivorship outcome.•We advise careful counseling and follow-up throughout lymphoma survivorship.
Procurement of bone allograft must be performed by trained personnel. Improper handling and lack of knowledge during bone procurement will lead to contamination hence jeopardizing quality of the ...procured bones and expose bone recipients to risks of infection in post-operative phase. Bone procurement workshop is the fundamental training programme to enhance skill among personnel who has been or will be involved in bone procurement. This study evaluated the effectiveness of the workshop contents including teaching materials by assessing the knowledge on bone procurement among the participants before and after the workshop.
Bone procurement workshop was held for 2 days for doctors and paramedics. The knowledge on bone procurement was evaluated in pre- and post-assessments by answering self administration questionnaire before and after the workshop, respectively.
A total of 50 participants comprised of doctors and paramedics attended the workshop however only 15 (55.6%) doctors and 12 (44.4%) paramedics completed the assessments. Overall, the mean total score for the post-assessment (61.4%) was significantly higher (p < 0.05) than that of the pre-assessment score (32.2%). The mean values of correct responses for the post-assessment was significantly higher (p < 0.05) than that of the pre-assessment in all five topics given during the workshop. The correct responses for the pre- and the post- assessments in the respective group of the doctors and paramedics were also statistically significant (p < 0.05). In the pre-assessment, the doctors had the highest score in Surgical Approach & Reconstruction (50%) while the paramedics had the highest score in Donor Screening & Selection Criteria (33.3%). In the post-assessment, the doctors had the highest score in Donor Screening & Selection Criteria (70%) while the paramedics in Packaging & Transportation (65.8%).
The assessment managed to show that the workshop contents and teaching materials were effective in improving the cognitive knowledge of the personnel who would get involved in bone procurement under the National Donation Programme.
Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for ...psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10
), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10
). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10
), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10
) and LMO7 (13q22.2, P=7.3x10
), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10
). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10
-9.8 × 10
). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.
The Clinical Genome Resource (ClinGen) Actionability Working Group (AWG) developed a semiquantitative scoring metric to rate clinical actionability of genetic disorders and associated genes in four ...domains: (1) severity of the outcome, (2) likelihood of the outcome, (3) effectiveness of the intervention to prevent/minimize the outcome, and (4) nature of the intervention with respect to burden, risk, tolerability, and acceptability to the patient. This study aimed to assess whether nature of the intervention scores assigned by AWG experts reflected lay perceptions of intervention burden, risk, tolerability, and acceptability given the subjectivity of this domain.
In July 2017, a general population sample of 1344 adults completed the study. Each participant was asked to read 1 of 24 plain language medical intervention synopses and answer questions related to its burden, risk, tolerability, and acceptability. We conducted three multilevel mixed model analyses predicting the perceived burden, perceived risk, and perceived overall nature of the intervention.
As AWG nature of the intervention scores increased, lay perceptions of intervention burden and risk decreased, and perceptions of tolerability and acceptability increased.
The findings show alignment between the ClinGen actionability scoring metric and lay perceptions of the nature of the intervention.
Summary Background Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective ...against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. Methods After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Donéguébougou and surrounding villages in Mali. We recruited 18–35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 105 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov , number NCT01988636. Findings Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three 7% people in the vaccine group vs four 9% in the placebo group) followed by fatigue (one 2% person in the placebo group), fever (one 2% person in the placebo group), and myalgia (one 2% person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313–0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528–0·918) by proportional analysis (p=0·006). Interpretation PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season. Funding US National Institutes of Health Intramural Research Program, Sanaria.
Thermally grown oxide scales that form beneath ZrO
2 top coats play an important role in determining the performance of thermal barrier coatings. Numerous factors, including the composition of both ...the alloy substrate and the bond coat, affect adhesion of the
α-Al
2O
3 scale. Three areas of focus in the formation of an `ideal', adherent scale encompass: (1) migration of Al and other elements in the metal substrate, (2) segregation of elements to the metal–scale interface and the scale grain boundaries, and (3) generation of stresses in the scale. Examples of the effects of reactive elements, Pt, indigenous S, and reaction temperature on scale adhesion are discussed.
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