Primary adenosquamous carcinoma (ASC) is a rare liver malignancy with very little data published so far. We describe the clinical characteristics of this tumor and analyze its survival pattern to ...improve the diagnosis and treatment.
This study collected data of 15 patients with primary hepatic ASC in our hospital within 10 years (from 2009 to 2018). We analyzed the clinical characteristics, imaging data, treatment, and survival of ASC in the study. Two of these cases have been reported.
The common clinical symptoms of hepatic ASC are liver pain and jaundice. Laboratory examination showed that carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) increased, but Alpha-FetoProtein (AFP) did not. Primary hepatic ASC is a rare subtype of intrahepatic cholangiocarcinoma (ICC) and meets the requirements of pathological diagnosis: CK20 (-), CK7 (+), CK19 (+), and p63 (+). Of the 15 patients, 11 were treated surgically, of which 3 patients received adjuvant chemotherapy. The prognosis of ASC patients is poor with a median survival time (MST) of 6 months (range: 2 to 15). The duration of MST in surgically treated patients was longer than that of nonsurgical patients (7.0 months
3.0 months). Patients that received adjuvant chemotherapy survived longer (MST: 15 months). Patients with lymph node metastasis had a worse prognosis.
Primary hepatic ASC is a rare malignant tumor with a poor prognosis. Radical surgery may be an effective treatment for prolonging survival. Surgical treatment combined with adjuvant therapy may further improve survival.
IntroductionRadical cystectomy remains the standard treatment for intravesical Bacille Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) because potential ...bladder-preserving therapies are not well established. Combination of radiotherapy with programmed death-1 (PD-1) antibody may offer an optional bladder preservation treatment for high-risk/extremely high risk NMIBC. Hence, the current study aims to investigate the safety and efficacy of short-course radiotherapy (5×5 Gy) and toripalimab (PD-1 antibody) as a novel bladder sparing treatment in this population.Methods and analysisHOPE-04 is an open-label, single-arm, phase II study, designed to evaluate the safety and efficacy of short-course radiotherapy and toripalimab in patients with high-risk/extremely high risk NMIBC. Fifty-five patients with pathological and imaging diagnosed NMIBC with or without BCG treatment will be recruited. Radiotherapy of 5×5 Gy will be given to the whole bladder followed by a focal tumour bed boost and concomitant administration of toripalimab of 240 mg intravenous infusion every 21 days for 12 cycles (about 1 year). The primary endpoints are disease-free survival and safety. The secondary endpoint is overall survival. Additional indicators include implementation rate of salvage surgery and quality of life.Ethics and disseminationThis trial has been approved by the Ethics Committee of West China Hospital, Sichuan University. Trial findings will be disseminated via peer reviewed journals and conference presentations.Trial registration numberChinese Ethics Committee of Registering Clinical Trials (ChiCTR2200059970).
It has been reported that overexpression of the CRLF2 gene is associated with poor outcomes in pediatric B cell acute lymphoblastic leukemia (B-ALL), but the incidence rates, clinical characteristics ...and outcomes of CRLF2 gene overexpression in pediatric T cell ALL (T-ALL) have not been systematically analyzed. In this study, CRLF2 mRNA expression levels and clinical and laboratory parameters in 63 pediatric T-ALL patients were detected at the Children's Hospital of Chongqing Medical University and Children's Hospital of Xianyang between February 2015 and June 2018. The patients were treated according to the modified St. Jude TXV ALL protocol, and early treatment responses (bone marrow smear and MRD level) and prognoses in the enrolled patients were assessed. CRLF2 overexpression was detected in 21/63 (33.33%) patients. Statistical differences were not found for clinical or laboratory parameters (including sex, age, initial WBC count, incidence mediastinal involvement, abnormal karyotype and fusion genes) between patients with high CRLF2 expression and patients with low expression of CRLF2 (P>0.05). One patient died of tumor lysis syndrome and renal failure, and the treatment response was monitored on day 19 (TP1) of remission in 62 patients. One patient quit treatment because of family decisions, and 61 patients underwent treatment response evaluation on day 46 (TP2) of remission. Significant differences were not found between patients with high CRLF2 expression and patients with low CRLF2 expression in terms of the treatment responses at TP1 or TP2 (P>0.05). Following October 2018, 12 patients among the 61 evaluable patients relapsed (relapse rate: 19.67%), 3 patients died from chemotherapy, and the treatment-related mortality (TRM) rate was 4.92%. Secondary tumors occurred in 1 patient. The 3-year prospective EFS rate was 54.1±11.2% and 77.7±6.6% for the 61 evaluable patients and 58 patients without TRM. Patients with low CRLF2 expression had longer EFS durations than patients with high CRLF2 expression (61 evaluable patients: 35.91± 2.38 months vs 23.43± 2.57 months; 58 patients without TRM: 37.86± 2.08 months vs 24.55±2.43 months, P<0.05). CRLF2 expression levels were also monitored in 13 patients at TP1 and TP2, and the MRD level did not vary with the CRLF2 expression level. Our data suggest that clinical features, laboratory findings and treatment responses in the pediatric T-ALL population do not vary based on the overexpression of CRLF2 but that CRLF2 overexpression can contribute to a high risk of relapse in pediatric T-ALL. Thus, CRLF2 expression levels should not be used as biomarkers for monitoring MRD.
Tumor lysis syndrome (TLS) often occurs early after induction chemotherapy for acute lymphoblastic leukemia (ALL) and can rapidly progress. This study aimed to construct a machine learning model to ...predict the risk of TLS using clinical indicators at the time of ALL diagnosis.
This observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data were collected from pediatric ALL patients diagnosed between December 2008 and December 2021. Four machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction.
The study included 2,243 pediatric ALL patients, and the occurrence of TLS was 8.87%. A total of 33 indicators with missing values ≤30% were collected, and 12 risk factors were selected through LASSO regression analysis. The CatBoost model with the best performance after feature screening was selected to predict the TLS of ALL patients. The CatBoost model had an AUC of 0.832 and an accuracy of 0.758. The risk factors most associated with TLS were the absence of potassium, phosphorus, aspartate transaminase (AST), white blood cell count (WBC), and urea levels.
We developed the first TLS prediction model for pediatric ALL to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200060616).
https://www.chictr.org.cn/, identifier ChiCTR2200060616.
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between ...metastatic and primary lesions are still unclear.
In this study, whole-exome, RNA-seq, and DNA methylation sequencing were performed on primary-metastatic paired specimens from 19 FH-RCC cases, including 23 primary and 35 matched metastatic lesions. Phylogenetic and clonal evolutionary analyses were used to investigate the evolutionary characteristics of FH-RCC. Transcriptomic analyses, immunohistochemistry, and multiple immunofluorescence experiments were performed to identify the tumor microenvironmental features of metastatic lesions.
Paired primary and metastatic lesions generally showed similar characteristics of tumor mutation burden, tumor neoantigen burden, microsatellite instability score, CNV burden, and genome instability index. Notably, we identified an FH-mutated founding MRCA (the most recent common ancestor) clone that dominated the early evolutionary trajectories in FH-RCC. Although both primary and metastatic lesions manifested high immunogenicity, metastatic lesions exhibited higher enrichment of T effector cells and immune-related chemokines, together with upregulation of PD-L1, TIGIT, and BTLA. In addition, we found that concurrent NF2 mutation may be associated with bone metastasis and upregulation of cell cycle signature in metastatic lesions. Furthermore, although in FH-RCC metastatic lesions in general shared similar CpG island methylator phenotype with primary lesions, we found metastatic lesions displaying hypomethylated chemokine and immune checkpoints related genomic loci.
Overall, our study demonstrated the genomic, epigenomic, and transcriptomic features of metastatic lesions in FH-RCC and revealed their early evolutionary trajectory. These results provided multi-omics evidence portraying the progression of FH-RCC.
Physiological circuits differ across increasing isometric force levels during unilateral contraction. Therefore, we first explored the possibility of predicting the force level based on ...electroencephalogram (EEG) activity recorded during a single trial of unilateral 5% or 40% of maximal isometric voluntary contraction (MVC) in right-hand grip imagination. Nine healthy subjects were involved in this study. The subjects were required to randomly perform 20 trials for each force level while imagining a right-hand grip. We proposed the use of common spatial patterns (CSPs) and coherence between EEG signals as features in a support vector machine for force level prediction. The results showed that the force levels could be predicted through single-trial EEGs while imagining the grip (mean accuracy = 81.4 ± 13.29%). Additionally, we tested the possibility of online control of a ball game using the above paradigm through unilateral grip imagination at different force levels (i.e., 5% of MVC imagination and 40% of MVC imagination for right-hand movement control). Subjects played the ball games effectively by controlling direction with our novel BCI system (n = 9, mean accuracy = 76.67 ± 9.35%). Data analysis validated the use of our BCI system in the online control of a ball game. This information may provide additional commands for the control of robots by users through combinations with other traditional brain–computer interfaces, e.g., different limb imaginations.
Dasatinib, a second-line tyrosine kinase inhibitor (TKI), has been widely used in chronic myeloid leukemia (CML) and Philadelphia-positive B-cell acute lymphoblastic leukemia (Ph + B-ALL). Although ...dasatinib has been well tolerated, side effects including hemorrhage are not rare. Cases of bleeding disorders ultimately result in thrombocytopenia, but platelet aggregation dysfunction induced by dasatinib has also been demonstrated in Ph + B-ALL and CML patients. We report three Chinese children with Ph + B-ALL who received a combination treatment of chemotherapy and dasatinib and developed gastrointestinal bleeding several months later. The platelet count and clotting tests were normal, and these patients presented with dasatinib-induced platelet dysfunction. These findings reveal that physicians should be aware of and carefully monitor for side effects, including bleeding disorders.
A split Hopkinson pressure bar equipment was used to perform high strain rate compressive tests on concrete filled steel tubes (CFT) along with benchmark plain concrete cylinders for comparison. This ...paper reports the results of dynamic compressive strength, ultimate strain, residual strength and the secant stiffness. The dynamic increase factor (DIF) of CFT strength upon the increase of strain rate was obtained based on the logarithm linear fitting of the test results. The DIF of the CFT specimens can be relatively well estimated with conservatism using the simple superposition of dynamic uniaxial strength of concrete and steel. The confinement stress and the confinement coefficient under high strain rate loading are also discussed based on assumptions similar to those used for the static loading cases.
Abstract Background and purpose Online adaptive correction in image-guided intensity-modulated radiotherapy appeared to be a promising approach for precision radiation treatment in head and neck ...tumors. This protocol was designed to evaluate the clinical feasibility and effect of online cone beam computed tomography (CBCT) guidance in IMRT of nasopharyngeal cancer (NPC). Methods and materials The Elekta Synergy system, which integrates an X-ray volumetric imager (XVI), was used to deliver radiation treatment for 22 cases of NPC. The acquired CBCT was registered to the planning CT for online and offline analysis. The systematic and random setup errors, as well as planning target volume (PTV) margin, were calculated at different correction threshold levels. The impact of online setup correction on dosimetry was evaluated by simulation of pre-correction errors. Results The correction-of-setup-errors frequencies for 1, 2 and 3 mm thresholds were 41.3–53.9%, 12.7–21.2% and 6.3–10.3%, respectively. Online correction was effective at the 2 mm threshold level for all three axes. The pre-correction systematic errors for the whole group ranged 1.1–1.3 mm, and the random errors were also 1.1–1.3 mm. After online correction, the systematic and random errors ranged 0.4–0.5 mm and 0.7–0.8 mm, respectively, in the three directions. The PTV margins for the pre-correction, pretreatment and post-treatment positions were 3.5–4.2 mm, 1.6–1.8 mm and 2.5–3.2 mm, respectively, in three directions. Analysis of hypothetical dosimetric change due to a translational isocenter shift of 3 mm showed that if no correction was applied, the mean maximum dose to both the brain stem and spinal cord would be increased by 10 Gy, the mean dose to the left and right parotids would be increased by 7.8 and 8.5 Gy, respectively, and the dose to target volumes would be decreased: 4 Gy for 95% GTV and 5.6 Gy for 95% CTV60. Conclusions CBCT-based online correction increased the accuracy of IMRT for NPC and reduced irradiated margins, by decreasing both the systematic and random errors. Online CBCT correction reduces the radiation dose to normal tissue and creates room for further dose escalation of tumors.
Isopeptidase activity of proteases plays critical roles in physiological and pathological processes in living organisms, such as protein stability in cancers and protein activity in infectious ...diseases. However, the kinetics of protease isopeptidase activity has not been explored before due to a lack of methodology. Here, we report the development of novel qFRET-based protease assay for characterizing the isopeptidase kinetics of SENP1. The reversible process of SUMOylation in vivo requires an enzymatic cascade that includes E1, E2, and E3 enzymes and Sentrin/SUMO-specific proteases (SENPs), which can act either as endopeptidases that process the pre-SUMO before its conjugation, or as isopeptidases to deconjugate SUMO from its target substrate. We first produced the isopeptidase substrate of CyPet-SUMO1/YPet-RanGAP1c by SUMOylation reaction in the presence of SUMO E1 and E2 enzymes. Then a qFRET analyses of real-time FRET signal reduction of the conjugated substrate of CyPet-SUMO1/YPet-RanGAP1c to free CyPet-SUMO1 and YPet-RanGAP1c by the SENP1 were able to obtain the kinetic parameters,
,
, and catalytic efficiency (
) of SENP1. This represents a pioneer effort in isopeptidase kinetics determination. Importantly, the general methodology of qFRET-based protease isopeptidase kinetic determination can also be applied to other proteases.
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