Multiregion WES of metastatic pancreatic neuroendocrine tumors revealed heterogeneity in genomic alterations, immune microenvironment and evolutionary patterns.

Pancreatic neuroendocrine tumors (PanNETs), though uncommon, have a high likelihood of spreading to other body parts. Previously, the genetic diversity and evolutionary patterns in metastatic PanNETs were not well understood. To investigate this, we performed multiregion sampling whole-exome sequencing (MRS-WES) on samples from 10 patients who had not received prior treatment for metastatic PanNETs. This included 29 primary tumor samples, 31 lymph node metastases, and 15 liver metastases. We used the MSK-MET dataset for survival analysis and validation of our findings. Our research indicates that mutations in the MEN1/DAXX genes might trigger the early stages of PanNET development. We categorized the patients based on the presence (MEN1/DAXXmut, n = 7) or absence (MEN1/DAXXwild, n = 3) of these mutations. Notable differences were observed between the two groups in terms of genetic alterations and clinically relevant mutations, confirmed using the MSK-MET dataset. Notably, patients with mutations in MEN1/DAXX/ATRX genes had a significantly longer median overall survival compared to those without these mutations (median not reached vs. 43.63 months, p = 0.047). Multiplex immunohistochemistry (mIHC) analysis showed a more prominent immunosuppressive environment in metastatic tumors, especially in patients with MEN1/DAXX mutations. These findings imply that MEN1/DAXX mutations lead PanNETs through a unique evolutionary path. The disease's progression pattern indicates that PanNETs can spread early, even before clinical detection, highlighting the importance of identifying biomarkers related to metastasis to guide personalized treatment strategies.

Computed Diffusion-Weighted Images of Rectal Cancer: Image Quality, Restaging, and Treatment Response after Neoadjuvant Therapy.

BACKGROUND: Computed diffusion-weighted images (cDWI) of random b value could be derived from acquired DWI (aDWI) with at least two different b values. However, its comparison between aDWI and cDWI images in locally advanced rectal cancer (LARC) patients after neoadjuvant therapy (NT) is needed. PURPOSE: To compare the cDWI and aDWI in image quality, restaging, and treatment response of LARC after NT. STUDY TYPE: Retrospective. POPULATION: Eighty-seven consecutive patients. FIELD STRENGTH/SEQUENCE: 3.0 T/DWI. ASSESSMENT: All patients underwent two DWI sequences, including conventional acquisition with b = 0 and 1000 s/mm2 (aDWIb1000 ) and another with b = 0 and 700 s/mm2 on a 3.0-T MR scanner. The images of the latter were used to compute the diffusion images with b = 1000 s/mm2 (cDWIb1000 ). Four radiologists with 3, 4, 14, and 25 years of experience evaluated the images to compare the image quality, TN restaging performance, and treatment response between aDWIb1000 and cDWIb1000 . STATISTICAL TESTS: Interclass correlation coefficients, weighted κ coefficient, paired Wilcoxon, and McNemar or Fisher test were used. A significance level of 0.05 was used. RESULTS: The cDWIb1000 images were superior to the aDWIb1000 ones in both subjective and objective image quality. In T restaging, the overall diagnostic accuracy of cDWIb1000 images was higher than that of aDWIb1000 images (57.47% vs. 49.43%, P = 0.289 for the inexperienced radiologist; 77.01% vs. 63.22%, significant for the experienced radiologist), with better sensitivity in determining ypT0-Tis tumors. Additionally, it increased the sensitivity in detecting ypT2 tumors for the inexperienced radiologist and ypT3 tumors for the experienced radiologist. N restaging and treatment response were found to be similar between two sequences for both radiologists. DATA CONCLUSION: Compared to aDWIb1000 images, the computed ones might serve as a wise approach, providing comparable or better image quality, restaging performance, and treatment response assessment for LARC after NT. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Angiotensin-converting enzyme 2 in human plasma and lung tissue.

PURPOSE: We investigated plasma angiotensin-converting enzyme 2 (ACE2) concentration in a population sample and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue in patients who underwent lung surgery. MATERIALS AND METHODS: The study participants were recruited from a residential area in the suburb of Shanghai for the plasma ACE2 concentration study (n = 503) and the lung tissue samples were randomly selected from the storage in Ruijin Hospital (80 men and 78 age-matched women). RESULTS: In analyses adjusted for covariables, men had a significantly higher plasma ACE2 concentration (1.21 vs. 0.98 ng/mL, p = 0.027) and the mean intensity of ACE2 in the lung tissue (55.1 vs. 53.9 a.u., p = 0.037) than women. With age increasing, plasma ACE2 concentration decreased (p = 0.001), while the mean intensity of ACE2 in the lung tissue tended to increase (p = 0.087). Plasma ACE2 concentration was higher in hypertension than normotension, especially treated hypertension (1.23 vs. 0.98 ng/mL, p = 0.029 vs. normotension), with no significant difference between users of RAS inhibitors and other classes of antihypertensive drugs (p = 0.64). There was no significance of the mean intensity of ACE2 in the lung tissue between patients taking and those not taking RAS inhibitors (p = 0.14). Neither plasma ACE2 concentration nor the mean intensity of ACE2 in the lung tissue differed between normoglycemia and diabetes (p ≥ 0.20). CONCLUSION: ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics of patients.Plain language summary What is the context? • The primary physiological function of ACE2 is the degradation of angiotensin I and II to angiotensin 1-9 and 1-7, respectively. • ACE2 was found to behave as a mediator of the severe acute respiratory syndrome coronavirus (SARS) infection. • There is little research on ACE2 in humans, especially in the lung tissue. • In the present report, we investigated plasma ACE2 concentration and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue respectively in two study populations. What is new? • Our study investigated both circulating and tissue ACE2 in human subjects. The main findings were: • In men as well as women, plasma ACE2 concentration was higher in younger than older participants, whereas the mean intensity of ACE2 in the lung tissue increase with age increasing. • Compared with normotension, hypertensive patients had higher plasma ACE2 concentration but similar mean intensity of ACE2 in the lung tissue. • Neither plasma ACE2 concentration nor lung tissue ACE2 expression significantly differed between users of RAS inhibitors and other classes of antihypertensive drugs. What is the impact? • ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics, such as sex, age, and treated and untreated hypertension. • A major implication is that plasma ACE2 concentration might not be an appropriate surrogate for the ACE2 expression in the lung tissue, and hence not a good predictor of SARS-COV-2 infection or fatality.

GATA3 aids in distinguishing fumarate hydratase-deficient renal cell carcinoma from papillary renal cell carcinoma.

GATA3 has been reported to be positive in clear cell papillary renal cell carcinoma and papillary renal neoplasm with reverse polarity. However, its features in high-grade RCC remain unclear. Despite the emergence of novel renal entities, FH-deficient RCC remains one of the most aggressive renal neoplasms. The diagnosis is mainly based on the loss of FH at the protein level. Previous studies have shown that inclusion-like nuclei, multiple architectural patterns, FH loss, and 2SC positivity can differentiate FH-deficient RCC from other RCC. In some FH-deficient RCC cases, FH is normally expressed and is difficult to diagnose. This study included 11 FH-deficient RCC, and GATA3 showed different expression in seven cases. However, 147 papillary renal cell carcinomas were included, and GATA3 expression was negative. A comparison of clinicopathological aspects between 11 FH-deficient RCC and 30 high-grade PRCC showed statistical significance in age, size, multiple architectural patterns, inclusion-like nuclei, and prognosis. However, PRCC exhibited similar characteristics. CK7, GATA3, and FH profiles were also statistically significant. Different chromosomal alterations were found in FH-deficient RCC, and chromosomal alterations were not different between FH-deficient RCC and PRCC. GATA3 was positive in 33 % (7/21) of collecting duct carcinomas and negative in other high-grade renal neoplasms. GATA3 is negative in PRCC, but can be positive in FH-deficient RCC and collecting duct carcinoma. GATA3 expression may indicate a worse outcome in high-grade RCC with papillary architecture. We recommend GATA3 IHC for the differential diagnosis and prognostic assessment of high-grade RCC with papillary architecture.

Papillary renal neoplasm with reverse polarity with a favorable prognosis should be separated from papillary renal cell carcinoma.

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly documented renal entity with an easily recognizable morphology, distinct immunohistochemical profiles, and frequent KRAS mutations. The latest practice guidelines regard PRNRP as a subtype of papillary renal cell carcinoma due to the documented chromosomal alterations of 7, 17, and Y. This study included 20 patients with PRNRP and 30 patients with PRCC. Statistically significant differences were observed in size, WHO/ISUP grade, macrophages in the papillae, reverse polarity, CK7, basolateral positivity for Claudin7, GATA3 expression, KRAS mutation, and chromosomal alterations. No adverse events such as perinephric invasion, lymphovascular invasion, sarcomatoid of rhabdoid differentiation, metastasis, or recurrence were found in PRNRP. However, PRCC can cause these adverse events. Basolateral positivity for Claudin7 together with GATA3 expression indicated distal tubule derivation of PRNRP. KRAS mutations were detected in 89% (16/18) of PRNRP. No KRAS mutations were detected in PRCC. Six patients with PRNRP had one chromosomal alteration and the other 12 had no chromosomal alterations. However, only four patients with PRCC showed no chromosomal alterations. Eighteen patients had two or three chromosomal alterations. PRCC can metastasize, recur, and even cause death, whereas PRNRP has a favorable prognosis. We recommend that PRNRP should be separated from PRCC and partial nephrectomy is more suitable for PRNRP.

Exposure patterns, chemical structural signatures, and health risks of pesticides in breast milk: A multicenter study in China.

China is the world's largest pesticide user. These chemicals are bioaccumulative in the human body, and eventually could be transferred from the mother to the fetus/infant via placental and breastfeeding transport, which might pose developmental deficiency risks. In this study, human biomonitoring of legacy pesticides was conducted in three Chinese cities using 60 breast milk samples. The patterns, chemical structural signatures, and the estimated daily intake of pesticides were assessed. The median concentration of HCB (57.8 ng g-1 lw, Interquartile range: 28.5-76.9 ng g-1 lw) was the highest among all pesticides, whereas the HCHs, DDXs, TCVP, and heptachlor were also detected. A significantly different pattern of pesticides was found among three sampling cities: the Mianyang cases were mostly DDXs oriented while the Wuhan and Hangzhou cases were under HCB, HCHs, TCVP, and heptachlor influences. Maternal age and pre-pregnancy BMI were found to be the influencing factors for the pesticides in the breast milk, and dietary preferences were an important factor in the exposure scenario. Chemical structural signatures indicated that for HCHs and DDXs the exposure was mostly historical, while the lindane and dicofol exposure may exist among the volunteering mothers. The EF for chiral pesticides did not deviate significantly from the racemic value. The risk from breastfeeding was negligible according to the Chinese and UN standard, while some cases from Hangzhou and Wuhan exceeded the Canadian restrictions. Thus, the adverse health effects of chemical exposure by dietary intake for infants need to be closely monitored in future studies.

Comprehensive economic evaluation of enhanced recovery after surgery in hepatectomy.

BACKGROUND: Enhanced recovery after surgery (ERAS) is attracting extensive attention and being widely applied to reduce postoperative stress and accelerate recovery. However, the economic benefits of ERAS are less clarified at the social level. We aimed to assess the economic impact of ERAS in hepatectomy from the perspectives of patients, hospitals and society, as well as identify the approach to create the economic benefits of ERAS. METHODS: By combining the literature and national statistical data, the cost-effectiveness framework was clarified, and parameter values were determined. Cost-effectiveness analysis, cost-benefit analysis and cost-minimisation analysis were used to compare ERAS and conventional treatment from the perspectives of patients, hospitals and society. The capital flow diagram was used to analyse the change between them. RESULTS: ERAS significantly reduced the economic burden of disease on patients ($8935.02 vs $10,470.02). The hospital received an incremental benefit in ERAS (the incremental benefit cost ratio value is 1.09), and the total social cost was reduced ($5958.67 vs $6725.80). Capital flow diagram analysis demonstrated that the average daily cost per capita in the ERAS group increased ($669.51 vs $589.98), whereas the benefits depended on the reduction of hospital stay and productivity loss. CONCLUSION: The mechanism by which ERAS works is to reduce the average length of stay, thereby reducing the economic burden and productivity loss on patients and promoting the hospital bed turnover rate. Therefore, ERAS should further focus on accelerating the rehabilitation process, and more economic support (such as subsidies) should be given to hospitals to carry out ERAS.

Prevalence, Association Relation, and Dynamic Evolution Analysis of Critical Values in Health Checkup in China: A Retrospective Study.

Objective: The critical values in health checkup play a key role in preventing chronic diseases and different types of cancer. This study aimed to analyze the prevalence, association relation, and dynamic evolution of critical values in health checkups at a large physical examination center in China. Methods: Herein, we chose 33,639 samples of physical examiners from January 2017 to December 2019. After strict exclusion processes, combined with the critical values in health checkup reporting data, 4,721 participants with at least one critical value were included. We first defined a critical value list for laboratory test, imaging, cervical cancer screening, electrocardiogram, and health checkup informed on site, and then performed a cross-sectional study to analyze the distribution and significance of critical values of 4,721 participants from different views and the association relation of 628 participants with more than one critical value and a retrospective cohort study to analyze the incidence and dynamic evolution of critical values based on 2,813 participants attending the physical examination from 2017 to 2019. Results: A total of 4,721 participants were included in the retrospective study. The prevalence of 10 critical values from 33,639 participants was over 0.6%. The critical values of obesity, hypertension, Glucose_T, Liver_T, Kidney_T, Lipid_T, Urine_T, and Head_CT were significantly increased in men (P < 0.05), whereas the results were the opposite for the Blood_T and Thyroid_US (P < 0.01). The prevalence trend of critical values increased along with age, where the prevalence of men was higher than that of women under 60 years old (P < 0.01), while the prevalence of women increased by four times and exceeded the prevalence of men above 70 years old. Association relation analysis identified 16 and 6 effective rules for men and women, respectively, where the critical values of Urine_T and Glucose_T played the central roles. Furthermore, a retrospective dynamic evolution analysis found that the incidence of new critical values was about 10%, the incidence of persistent critical values was about 50%, and that most of the effective evolution paths tended to no critical values for men and women. Conclusion: In conclusion, this study provides a new perspective to explore the population health status using the critical value reporting data in a physical examination center, which can assist in decision-making by health management at the population level and in the prevention and treatment of various types of cancer and chronic diseases at the individual level.

Microwave ablation for the treatment of arterial epistaxis: "how I do it".

BACKGROUND: Arterial epistaxis is commonly seen in the rhinology clinic and can have a significant impact on quality of life. Previous studies have explored various therapies to address epistaxis. METHODS: Patients were treated in the outpatient clinic or operating room by microwave ablation (MWA) with a 2450-MHz cooled-shaft antenna to treat an epistaxis bleeding point. RESULTS: Of the 481 patients with arterial epistaxis, bleeding was controlled within 1 to 2 minutes and only 2 patients with recurrent bleeding required re-ablation. The shape of the thermal lesion was elliptical and it was approximately 2 mm in length, 1 mm in width, and 0.5 to 1 mm in penetration depth. Of the 481 patients, 167 (34.7%) complained of minor nasal pain on the same day of ablation. No patients complained of nasal pain or obstruction during the follow-up period. In addition, 139 (28.9%) patients showed a minor increase in rhinorrhea during the first postoperative week. Of the 481 patients, 469 (97.5%) were followed-up at 6 months with no severe MWA-related complications, such as septal perforation, synechiae formation, or orbit and brain complications. CONCLUSION: MWA is a technically feasible alternative method for patients with arterial epistaxis.

Trajectories of Hospitalization Cost Among Patients of End-Stage Lung Cancer: A Retrospective Study in China.

This study was conducted to investigate the trajectory of hospitalization costs, and to assess the determinants related to the membership of the identified trajectories, with the view of recommending future research directions. A retrospective study was performed in urban Yichang, China, where a total of 134 end-stage lung cancer patients were selected. The latent class analysis (LCA) model was used to investigate the heterogeneity in the trajectory of hospitalization cost amongst the different groups that were identified. A multi-nominal logit model was applied to explore the attributes of different classes. Three classes were defined as follows: Class 1 represented the trajectory with minimal cost, which had increased over the last two months. Classes 2 and 3 consisted of patients that incurred high costs, which had declined with the impending death of the patient. Patients in class 3 had a higher average cost than those in Class 2. The level of education, hospitalization, and place of death, were the attributes of membership to the different classes. LCA was useful in quantifying heterogeneity amongst the patients. The results showed the attributes were embedded in hospitalization cost trajectories. These findings are applicable to early identification and intervention in palliative care. Future studies should focus on the validation of the proposed model in clinical settings, as well as to identify the determinants of early discharge or aggressive care.

The functional verification of EGFR-CAR T-cells targeted to hypopharyngeal squamous cell carcinoma.

BACKGROUND: The aim of this study was to validate the antitumor function of EGFR-chimeric antigen T-cells (CART) targeted to FaDu cells, a hypopharyngeal squamous cell carcinoma cell line, and to provide a preclinical basis for the application of CART cell technology in hypopharyngeal squamous cell carcinoma. METHODS: Detection of cytokine secretions of EGFR-CAR T and CART-controls in the presence of target cells and nontarget cells as an indicator of CART cell activation. Detection of the cytotoxic effects of EGFR-CAR T on specific tumors in the presence of target cells was evaluated by LDH release and CART cell proliferation. RESULTS: The results showed that cytokine secretion increased significantly after EGFR-CAR T-cells were incubated with target cells, and EGFR-CAR T-cells has higher cytotoxic effect on target cells than the CART-control group. The target cell lysis rate was 52.66%. The proliferation of EGFR-CAR T-cells in the presence of target cells was not distinctly observed. CONCLUSION: In this study, we validated the antitumor function of EGFR-CAR T-cells targeted to the FaDu cell line and provided the foundation for application of the CART technique in the treatment of hypopharyngeal carcinoma.

Sulfur Partitioning between Glutathione and Protein Synthesis Determines Plant Growth.

Photoautotrophic organisms must efficiently allocate their resources between stress-response pathways and growth-promoting pathways to be successful in a constantly changing environment. In this study, we addressed the coordination of sulfur flux between the biosynthesis of the reactive oxygen species scavenger glutathione (GSH) and protein translation as one example of a central resource allocation switch. We crossed the Arabidopsis (Arabidopsis thaliana) GSH synthesis-depleted cadmium-sensitive cad2-1 mutant, which lacks glutamate cysteine (Cys) ligase, into the sulfite reductase sir1-1 mutant, which suffers from a significantly decreased flux of sulfur into Cys and, consequently, is retarded in growth. Surprisingly, depletion of GSH synthesis promoted the growth of the sir1-1 cad2-1 double mutant (s1c2) when compared with sir1-1 Determination of GSH levels and in vivo live-cell imaging of the reduction-oxidation-sensitive green fluorescent protein sensor demonstrated significant oxidation of the plastidic GSH redox potential in cad2-1 and s1c2 This oxidized GSH redox potential aligned with significant activation of plastid-localized sulfate reduction and a significantly higher flux of sulfur into proteins. The specific activation of the serine/threonine sensor kinase Target of Rapamycin (TOR) in cad2-1 and s1c2 was the trigger for reallocation of Cys from GSH biosynthesis into protein translation. Activation of TOR in s1c2 enhanced ribosome abundance and partially rescued the decreased meristematic activity observed in sir1-1 mutants. Therefore, we found that the coordination of sulfur flux between GSH biosynthesis and protein translation determines growth via the regulation of TOR.

Sulfur availability regulates plant growth via glucose-TOR signaling.

Growth of eukaryotic cells is regulated by the target of rapamycin (TOR). The strongest activator of TOR in metazoa is amino acid availability. The established transducers of amino acid sensing to TOR in metazoa are absent in plants. Hence, a fundamental question is how amino acid sensing is achieved in photo-autotrophic organisms. Here we demonstrate that the plant Arabidopsis does not sense the sulfur-containing amino acid cysteine itself, but its biosynthetic precursors. We identify the kinase GCN2 as a sensor of the carbon/nitrogen precursor availability, whereas limitation of the sulfur precursor is transduced to TOR by downregulation of glucose metabolism. The downregulated TOR activity caused decreased translation, lowered meristematic activity, and elevated autophagy. Our results uncover a plant-specific adaptation of TOR function. In concert with GCN2, TOR allows photo-autotrophic eukaryotes to coordinate the fluxes of carbon, nitrogen, and sulfur for efficient cysteine biosynthesis under varying external nutrient supply.