To the Editor: Lipid transfer protein (LTP)-associated peach allergy has been described as an almost exclusively Mediterranean phenomenon in which peach consumption is at the base of ...sensitization.1,2 In areas with high exposure to mugwort or plane tree pollen, sensitization to pollen-derived LTPs has been implicated as modifying the epitope-recognition spectrum by primary sensitization to pollen LTPs.3-5 Overall, however, unlike birch pollen-induced cross-reactivity to Bet v 1 homologs in fruits, sensitization to LTPs is primarily seen as a fruit consumption-driven process.6 Peach allergy has been frequently reported in China, especially among patients with mugwort allergy in northern China, but the molecular sensitization patterns to individual peach and mugwort allergens have not yet been characterized.
Objectives
Primary tumor tissue is often analyzed to search for predictive biomarkers and DNA-guided personalized therapies, but there is an incomplete understanding of the discrepancies in the ...genomic profiles between primary tumors and metastases, such as liver and lung metastases.
Methods
We performed in-depth targeted next-generation sequencing of 520 key cancer-associated genes for 47 matched primary and metastatic tumor samples which were retrospectively collected.
Results
A total of 699 mutations were detected in the 47 samples. The coincidence rate of primary tumors and metastases was 51.8% (n = 362), and compared to patients with liver metastases, patients with lung metastases had a significantly greater coincidence rate (P = .021). The number of specific mutations for the primary tumors and liver and lung metastases was 186 (26.6%), 122 (17.5%), and 29 (4.1%), respectively. Analysis of a patient with all three occurrences, including a primary tumor, liver metastasis, and lung metastasis, indicated a possible polyclonal seeding mechanism for liver metastases. Remarkably, multiple samples from patients with primary and metastatic tumors supported a mechanism of synchronous parallel dissemination from primary tumors to metastatic tumors that were not mediated through pre-metastatic tumors. We also found that the PI3K-Akt signaling pathway significantly altered lung metastases compared to matched primary tumors (P = .001). In addition, patients with mutations in CTCF, PIK3CA, or TP53 and LRP1B, AURKA, FGFR1, ATRX, DNMT3B, or GNAS had larger primary tumor sizes and metastases, especially patients with both LRP1B and AURKA mutations. Interestingly, CRC patients with TP53-disruptive mutations were more likely to have liver metastases (P = .016).
Conclusion
In this study, we demonstrate significant differences in the genomic landscapes of colorectal cancer patients based on the site of metastasis. Notably, we observe a larger genomic variation between primary tumors and liver metastasis compared to primary tumors and lung metastasis. These findings can be used for tailoring treatments based on the specific metastatic site.
Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA ...vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD).
This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18–59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, and 25 μg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212).
Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one 5% of 20 in the 5 μg group, 13 65% of 20 in the 10 μg group, 17 85% of 20 in the 15 μg group, 19 95% of 20 in the 20 μg group, 16 100% of 16 in the 25 μg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 μg group, three (15%) of 20 in the 10 μg group, six (30%) of 20 in the 15 μg group, seven (35%) of 20 in the 20 μg group, five (31%) of 16 in the 25 μg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 μg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19.
ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale.
National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.
Purpose
Clinical target volumes (CTVs) and organs at risk (OARs) could be autocontoured to save workload. This study aimed to assess a convolutional neural network for automatic and accurate CTV and ...OARs in prostate cancer, while comparing possible treatment plans based on autocontouring CTV to clinical treatment plans.
Methods
Computer tomography (CT) scans of 217 patients with locally advanced prostate cancer treated at our hospital were retrospectively collected and analyzed from January 2013 to January 2019. A deep learning-based method, CUNet, was used to delineate CTV and OARs. A training set of 195 CT scans and a test set of 28 CT scans were randomly chosen from the dataset. The mean Dice similarity coefficient (DSC), 95th percentile Hausdorff distance (95HD), and subjective evaluation were used to evaluate the performance of this strategy. Predetermined evaluation criteria were used to grade treatment plans, and percentage errors for clinical doses to the planned target volume (PTV) and OARs were calculated.
Results
The mean DSC and 95HD values of the defined CTVs were (0.84 ± 0.05) and (5.04 ± 2.15) mm, respectively. The average delineation time was < 15 s for each patient's CT scan. The overall positive rates for clinicians A and B were 53.15% versus 46.85%, and 54.05% versus 45.95%, respectively (P > .05) when CTV outlines from CUNet were blindly chosen and compared with the ground truth (GT). Furthermore, 8 test patients were randomly chosen to design the predicted plan based on the autocontouring CTVs and OARs, demonstrating acceptable agreement with the clinical plan: average absolute dose differences in mean value of D2, D50, D98, Dmax, and Dmean for PTV were within 0.74%, and average absolute volume differences in mean value of V45 and V50 for OARs were within 3.4%.
Conclusion
Our results revealed that the CTVs and OARs for prostate cancer defined by CUNet were close to the GT. CUNet could halve the time spent by radiation oncologists in contouring, demonstrating the potential of the novel autocontouring method.
Pancreatic cancer has the highest mortality rate of all major cancers, with a 5-year survival rate of about 10%. Early warning signs and symptoms of pancreatic cancer are vague or nonexistent, and ...most patients are diagnosed in Stage IV, when surgery is not an option for about 80%–85% of patients. For patients with inoperable pancreatic cancer, current conventional treatment modalities such as chemotherapy and radiotherapy (RT) have suboptimal efficacy. Tumor progression is closely associated with the tumor microenvironment, which includes peripheral blood vessels, bone marrow-derived inflammatory cells, fibroblasts, immune cells, signaling molecules, and extracellular matrix. Tumor cells affect the microenvironment by releasing extracellular signaling molecules, inducing peripheral immune tolerance, and promoting tumor angiogenesis. In turn, the immune cells of the tumor affect the survival and proliferation of cancer cells. Myeloid-derived suppressor cells are key cellular components in the tumor microenvironment and exert immunosuppressive functions by producing cytokines, recognizing other immune cells, and promoting tumor growth and metastasis. Myeloid-derived suppressor cells are the main regulator of the tumor immune response and a key target for tumor treatments. Since the combination of RT and immunotherapy is the main strategy for the treatment of pancreatic cancer, it is very important to understand the immune mechanisms which lead to MDSCs generation and the failure of current therapies in order to develop new target-based therapies. This review summarizes the research advances on the role of Myeloid-derived suppressor cells in the progression of pancreatic cancer and its treatment application in recent years.
Objective:
Colorectal cancer is one of the most important malignant cancer in the world with high incidence and mortality. Some studies have found that the expression of low serum L1 cell adhesion ...molecule is associated with poor prognosis in some malignancies. It is suggested that L1 cell adhesion molecule is a candidate serum marker for certain tumors. However, the relationship between serum L1 cell adhesion molecule and colorectal cancer, especially about the diagnostic value, is rarely reported. Therefore, this study aimed to evaluate the diagnostic potential of serum L1 cell adhesion molecule in patients with colorectal cancer.
Methods:
Enzyme-linked immunosorbent assay was carried out to detect L1 cell adhesion molecule level in sera of 229 patients with colorectal cancer and 145 normal controls. Receiver operating characteristic curves were employed to calculate the accuracy of diagnosis.
Results:
The levels of serum L1 cell adhesion molecule in the colorectal cancer group were significantly lower than that in normal controls (P < .05). In the normal group, the area under the receiver operating characteristic curve (area under the curve) of all colorectal cancer was 0.781 (95% confidence interval: 0.734-0.828) and early-stage colorectal cancer was 0.764 (95% confidence interval: 0.705-0.823). With optimized cutoff of 17.760 ng/mL, L1 cell adhesion molecule showed certain diagnostic value with specificity of 90.3% and sensitivities of 43.2% and 36.2% in colorectal cancer and early-stage colorectal cancer, respectively. Clinical data analysis showed that the levels of L1 cell adhesion molecule were significantly correlated with gender (P < .05) and early and late stages (P < .05). Furthermore, when compared with carcinoembryonic antigen, serum L1 cell adhesion molecule had significantly improved diagnostic accuracy for both colorectal cancer and early-stage colorectal cancer.
Conclusions:
Our study demonstrated that serum L1 cell adhesion molecule might be served as a potential biomarker for the diagnosis of colorectal cancer.
Ultrasound is a critical non-invasive test for preoperative diagnosis of ovarian cancer. Deep learning is making advances in image-recognition tasks; therefore, we aimed to develop a deep ...convolutional neural network (DCNN) model that automates evaluation of ultrasound images and to facilitate a more accurate diagnosis of ovarian cancer than existing methods.
In this retrospective, multicentre, diagnostic study, we collected pelvic ultrasound images from ten hospitals across China between September 2003, and May 2019. We included consecutive adult patients (aged ≥18 years) with adnexal lesions in ultrasonography and healthy controls and excluded duplicated cases and patients without adnexa or pathological diagnosis. For DCNN model development, patients were assigned to the training dataset (34 488 images of 3755 patients with ovarian cancer, 541 442 images of 101 777 controls). For model validation, patients were assigned to the internal validation dataset (3031 images of 266 patients with ovarian cancer, 5385 images of 602 with benign adnexal lesions), external validation datasets 1 (486 images of 67 with ovarian cancer, 933 images of 268 with benign adnexal lesions), and 2 (1253 images of 166 with ovarian cancer, 5257 images of 723 benign adnexal lesions). Using these datasets, we assessed the diagnostic value of DCNN, compared DCNN with 35 radiologists, and explored whether DCNN could augment the diagnostic accuracy of six radiologists. Pathological diagnosis was the reference standard.
For DCNN to detect ovarian cancer, AUC was 0·911 (95% CI 0·886–0·936) in the internal dataset, 0·870 (95% CI 0·822–0·918) in external validation dataset 1, and 0·831 (95% CI 0·793–0·869) in external validation dataset 2. The DCNN model was more accurate than radiologists at detecting ovarian cancer in the internal dataset (88·8% vs 85·7%) and external validation dataset 1 (86·9% vs 81·1%). Accuracy and sensitivity of diagnosis increased more after DCNN-assisted diagnosis than assessment by radiologists alone (87·6% 85·0–90·2 vs 78·3% 72·1–84·5, p<0·0001; 82·7% 78·5–86·9 vs 70·4% 59·1–81·7, p<0·0001). The average accuracy of DCNN-assisted evaluations for six radiologists reached 0·876 and were significantly augmented when they were DCNN-assisted (p<0·05).
The performance of DCNN-enabled ultrasound exceeded the average diagnostic level of radiologists matched the level of expert ultrasound image readers, and augmented radiologists’ accuracy. However, these observations warrant further investigations in prospective studies or randomised clinical trials.
National Key Basic Research Program of China, National Sci-Tech Support Projects, and National Natural Science Foundation of China.
Summary Background The current influenza pandemic calls for a safe and effective vaccine. We assessed the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine ...produced by ten Chinese manufacturers. Methods In this multicentre, double-blind, randomised trial, 12 691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratified by age and randomly assigned by a random number table to receive one of several vaccine formulations or placebo. The study assessed eight formulations: split-virion formulation containing 7·5 μg, 15 μg, or 30 μg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5 μg or 10 μg haemagglutinin per dose, with adjuvant. All formulations were produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34). We analysed the safety (adverse events), immunogenicity (geometric mean titre GMT of haemagglutination inhibition antibody), and seroprotection (GMT ≥1:40) of the formulations. Analysis was by per protocol. Two sites registered their trial with ClinicalTrials.gov , numbers NCT00956111 and NCT00975572 . The other eight studies were registered with the State Food and Drug Administration of China. Findings 12 691 participants received the first dose on day 0, and 12 348 participants received the second dose on day 21. The seroprotection rate 21 days after the first dose of vaccine ranged from 69·5% (95% CI 65·9–72·8) for the 7·5 μg adjuvant split-virion formulation to 92·8% (91·9–93·6) for the 30 μg non-adjuvant split-virion formulation. The seroprotection rate was 86·5% (796 of 920; 84·1–88·7) in recipients of one dose of the 7·5 μg non-adjuvant split-virion vaccine compared with 9·8% (140 of 1432; 8·3–11·4) in recipients of placebo (p<0·0001). One dose of the 7·5 μg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children (aged 3 years to <12 years; 76·7%, 70·7–82·0), 211 of 218 adolescents (12 years to <18 years; 96·8%, 93·5–98·7), 289 of 323 adults (18–60 years; 89·5%, 85·6–92·6), and 118 of 147 adults older than 60 years (80·3%, 72·9–86·4), meeting the European Union's licensure criteria for seroprotection in all age-groups. In children, a second dose of the 7·5 μg formulation increased the seroprotection rate to 97·7% (215 of 220, 94·8–99·3). Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse effects occurred in 69 (0·6%, 0·5–0·8) recipients of vaccine compared with one recipient (0·1%, 0–0·2) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0·22%; 0·14–0·33) recipients of vaccine after the first dose and four (0·04%; 0·01–0·09) recipients of vaccine after the second dose compared with no recipients of placebo after either dose. Interpretation One dose of non-adjuvant split-virion vaccine containing 7·5 μg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older. In children (aged <12 years), two 7·5 μg doses might be needed. Funding Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical.
Objective
To investigate the diagnostic values of D-dimer, plasminogen activator inhibitor-1 (PAI-1), thrombin–antithrombin (TAT), and prothrombin fragment F1 + 2 (F1 + 2) for predicting venous ...thromboembolism (VTE) after total knee arthroplasty (TKA).
Methods
Ultrasonography and CTPA were performed to diagnose VTE in 252 patients who underwent TKAs. Plasma D-dimer, PAI-1, TAT, and F1 + 2 levels were assessed 1–3 days prior to operation (T1), second hour (T2), first (T3), and third day (T4) after the operation. Receiver–operating characteristic curves (ROC) analysis was conducted and pairwise compared to evaluate the diagnostic value of those biomarkers.
Results
Plasma D-dimer levels differed between patients with and without VTE significantly on T4, PAI-1, TAT, and F1 + 2 levels differed on T3 and T4. The areas under ROC of D-dimer, PAI-1, TAT and F1 + 2 levels were 0.645, 0.773, 0.771 and 0.797, respectively. The most feasible cutoff values of D-dimer, PAI-1, TAT and F1 + 2 in predicting VTE after TKA were 2.24 ug/ml, 35.96 ng/ml, 13.36 ng/mg and 11.1 ng/ml, respectively. Pairwise comparison of ROC curves revealed that D-dimer level had the lowest diagnostic accuracy, whereas PAI-1, TAT and F1 + 2 level had similar diagnostic accuracy. There were significant differences in duration of tourniquet time and duration of anesthesia between patients with and without VTE.
Conclusion
After TKA, using 2.24ug/mL as the threshold value of D-dimer is more accurate than using 0.5ug/mL in the monitoring of VTE, PAI-1, TAT and F1 + 2 are more valuable than D-dimer in predicting VTE. Duration of tourniquet and duration of anesthesia are risk factors for the development of VTE.
Case finding for cognitive impairment (CI) is recommended for all persons older than 70 years.
The present study identified additional risk factors of CI so as to operationalize a composite total ...risk score (TRS) for case finding. We then examined the additive effect of the TRS and brief cognitive tests to improve the diagnosis of CI.
The study was conducted in 2 primary health care centers in Singapore. A total of 1082 individuals (≥60 years old) were assessed for sociodemographic risk factors and their informants were administered the AD8; 309 individuals who agreed for further cognitive assessments completed the Mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA), and a neuropsychological battery at a research center. Primary health care medical records were accessed for data on vascular risk factors.
Of the 309 individuals who underwent neuropsychological evaluation, 4 were excluded due to missing medical data; 167 (54.8%) individuals had CI and 138 (45.2%) had No Cognitive Impairment (NCI). The β coefficients were standardized to calculate risk scores. CI was significantly predicted by age >70 years (odds ratio OR 5.99; score = 3), diabetes (OR 3.36; score = 2), stroke (OR 2.70; score = 1), female gender (OR 2.02; score = 1) and individual cognitive complaints (SCC) (OR 1.95; score = 1). The TRS had an optimal cutoff of ≥3 and explained considerable variance in global cognitive composite Z-scores (R(2) = 0.41, P < .001). The MoCA explained substantial variance compared with the MMSE and AD8 (R(2) changes of 0.474, 0.422, and 0.157, P < .001, respectively).
The TRS is a reasonable measure to predict individuals at risk of CI. The addition of the MoCA, in persons with positive TRS scores, is a useful approach to improve the diagnosis of CI for at-risk patients attending primary health care.
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