Site-specific therapy guided by a 90-gene expression assay versus empirical chemotherapy in patients with cancer of unknown primary (Fudan CUP-001): a randomised controlled trial.

BACKGROUND: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP. METHODS: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600). FINDINGS: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed. INTERPRETATION: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients. FUNDING: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Nab-paclitaxel plus S-1 versus nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer: a multicenter, randomized, phase II study.

BACKGROUND: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). METHODS: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. CONCLUSION: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308).

1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.

BACKGROUND: Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells. METHOD: We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo. RESULT: PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model. CONCLUSION: Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.

Parcellating the human brain using resting-state dynamic functional connectivity.

Brain cartography has expanded substantially over the past decade. In this regard, resting-state functional connectivity (FC) plays a key role in identifying the locations of putative functional borders. However, scant attention has been paid to the dynamic nature of functional interactions in the human brain. Indeed, FC is typically assumed to be stationary across time, which may obscure potential or subtle functional boundaries, particularly in regions with high flexibility and adaptability. In this study, we developed a dynamic FC (dFC)-based parcellation framework, established a new functional human brain atlas termed D-BFA (DFC-based Brain Functional Atlas), and verified its neurophysiological plausibility by stereo-EEG data. As the first dFC-based whole-brain atlas, the proposed D-BFA delineates finer functional boundaries that cannot be captured by static FC, and is further supported by good correspondence with cytoarchitectonic areas and task activation maps. Moreover, the D-BFA reveals the spatial distribution of dynamic variability across the brain and generates more homogenous parcels compared with most alternative parcellations. Our results demonstrate the superiority and practicability of dFC in brain parcellation, providing a new template to exploit brain topographic organization from a dynamic perspective. The D-BFA will be publicly available for download at https://github.com/sliderplm/D-BFA-618.

Effect of Phase Clustering Bias on Phase-Amplitude Coupling for Emotional EEG.

BACKGROUND: Emotions are thought to be related to distinct patterns of neural oscillations, but the interactions among multi-frequency neural oscillations during different emotional states lack full exploration. Phase-amplitude coupling is a promising tool for understanding the complexity of the neurophysiological system, thereby playing a crucial role in revealing the physiological mechanisms underlying emotional electroencephalogram (EEG). However, the non-sinusoidal characteristics of EEG lead to the non-uniform distribution of phase angles, which could potentially affect the analysis of phase-amplitude coupling. Removing phase clustering bias (PCB) can uniform the distribution of phase angles, but the effect of this approach is unknown on emotional EEG phase-amplitude coupling. This study aims to explore the effect of PCB on cross-frequency phase-amplitude coupling for emotional EEG. METHODS: The technique of removing PCB was implemented on a publicly accessible emotional EEG dataset to calculate debiased phase-amplitude coupling. Statistical analysis and classification were conducted to compare the difference in emotional EEG phase-amplitude coupling prior to and post the removal of PCB. RESULTS: Emotional EEG phase-amplitude coupling values are overestimated due to PCB. Removing PCB enhances the difference in coupling strength between fear and happy emotions in the frontal lobe. Comparable emotion recognition performance was achieved with fewer features after removing PCB. CONCLUSIONS: These findings suggest that removing PCB enhances the difference in emotional EEG phase-amplitude coupling patterns and generates features that contain more emotional information. Removing PCB may be advantageous for analyzing emotional EEG phase-amplitude coupling and recognizing human emotions.

Fusion of Multi-domain EEG Signatures Improves Emotion Recognition.

BACKGROUND: Affective computing has gained increasing attention in the area of the human-computer interface where electroencephalography (EEG)-based emotion recognition occupies an important position. Nevertheless, the diversity of emotions and the complexity of EEG signals result in unexplored relationships between emotion and multichannel EEG signal frequency, as well as spatial and temporal information. METHODS: Audio-video stimulus materials were used that elicited four types of emotions (sad, fearful, happy, neutral) in 32 male and female subjects (age 21-42 years) while collecting EEG signals. We developed a multidimensional analysis framework using a fusion of phase-locking value (PLV), microstates, and power spectral densities (PSDs) of EEG features to improve emotion recognition. RESULTS: An increasing trend of PSDs was observed as emotional valence increased, and connections in the prefrontal, temporal, and occipital lobes in high-frequency bands showed more differentiation between emotions. Transition probability between microstates was likely related to emotional valence. The average cross-subject classification accuracy of features fused by Discriminant Correlation Analysis achieved 64.69%, higher than that of single mode and direct-concatenated features, with an increase of more than 7%. CONCLUSIONS: Different types of EEG features have complementary properties in emotion recognition, and combining EEG data from three types of features in a correlated way, improves the performance of emotion classification.

First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations.

BACKGROUND: HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations. METHODS: This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5-18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D. RESULTS: Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months. CONCLUSIONS: The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov number: NCT03973151.

Comprehensive analysis of cancer of unknown primary and recommendation of a histological and immunohistochemical diagnostic strategy from China.

BACKGROUND: Previous studies on cancer of unknown primary (CUP) mainly focus on treatment and prognosis in western populations and lacked clinical evaluation of different IHC markers, so this study aimed to evaluate characteristics of CUP and recommend a diagnostic strategy from a single center in China. METHODS AND RESULTS: Data of 625 patients with CUP were retrospectively collected and reviewed. The patients ranged in age from 20 to 91 years, with a female-to-male ratio of 1.3:1. The predominant histological type was poor or undifferentiated adenocarcinomas (308; 49.3%). The results of Canhelp-Origin molecular testing for the identification of the tissue of origin in 262 of 369 patients (71.0%) were considered predictable (similarity score > 45), with the most common predicted primary tumor site being the breast (57, 21.8%). Unpredictable molecular results correlated with more aggressive clinical parameters and poor survival. Thee positivity rates of several targeted antibodies (GATA3, GCDFP15, TTF1, Napsin A, and PAX8), based on the clinically predicted site, were lower than those reported for the corresponding primary tumors. Nonetheless, TRPS1 and INSM1 were reliable markers of predicted breast carcinoma (75.0%) and neuroendocrine tumors (83.3%), respectively. P16 expression, as well as HPV and EBER testing contributed significantly to the diagnosis of squamous cell carcinomas. Survival analysis revealed that older ages (> 57), ≥ 3 metastatic sites, non-squamous cell carcinomas, bone/liver/lung metastases, unpredictable molecular results, and palliative treatment correlated with poor overall survival. CONCLUSIONS: We recommend a CUP diagnostic strategy involving the use of targeted antibody panels as per histological findings that is potentially applicable in clinical practice. The markers TRPS1, INSM1, and P16 expression, as well as HPV and EBER testing are particularly valuable in this aspect. Molecular testing is also predictive of survival rates.

Safety and efficacy of Pucotenlimab (HX008) - a humanized immunoglobulin G4 monoclonal antibody in patients with locally advanced or metastatic melanoma: a single-arm, multicenter, phase II study.

BACKGROUND: Pucotenlimab is a novel recombinant humanized anti-PD-1 (Programmed death-1) monoclonal antibody, which belongs to the human IgG4/kappa subtype, and can selectively block the binding of PD-1 with its ligands PD-L1 and PD-L2. METHODS: In this phase 2 trial, patients with locally advanced or metastatic melanoma who had failed conventional treatment (chemotherapy, targeted therapy, interferon, IL-2, et al.) were recruited. The patients were administrated with Pucotenlimab of 3 mg/kg every 3 weeks until disease progression, intolerable toxicity, or treatment discontinuation for any other reasons. The primary endpoint was the overall response rate (ORR). The secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: One-hundred and nineteen patients were enrolled and followed up for 19.32 (ranging from 15.901 to 24.608) months by the cutoff date of July 30th, 2021. The ORR was 20.17% (24/119, 95% CI, 13.370%-28.506%) based on both independent review committee (IRC) and the investigator's assessment per RECIST v1.1. The median PFS were 2.89 (95% CI, 2.037-4.074) months and 2.46 (95% CI, 2.004-4.008) months based on IRC and investigator's assessment, respectively, per RECIST v1.1. The median OS was 16.59 (95% CI, 13.963-26.973) months. Treatment-related adverse events (TRAEs) occurred in 77.3% (92/119) of the patients. The incidence of Grade ≥ 3 TRAEs was 15.1% (18/119). In addition, none of the patients died because of TRAEs. As for biomarker analysis, Eotaxin (CCL11) and MCP-1 (CCL2) were related to treatment response, while TNF-α and VEGF were related to treatment failure. CONCLUSIONS: Pucotenlimab as a ≥ 2nd line therapy showed promising efficacy and tolerable toxicity for patients with locally advanced or metastatic melanoma. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04749485 (registered retrospectively on 11/02/2021).

Rh-endostatin combined with chemotherapy in patients with advanced or recurrent mucosal melanoma: retrospective analysis of real-world data.

BACKGROUND: Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. METHODS: Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators' preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). RESULTS: Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. CONCLUSION: Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

Head-to-head evaluation of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT in recurrent soft tissue sarcoma.

PURPOSE: We aimed to evaluate the value of [68 Ga]Ga-DOTA-FAPI-04 PET/CT for the diagnosis of recurrent soft tissue sarcoma (STS), compared with [18F]FDG PET/CT. METHODS: A total of 45 patients (21 females and 24 males; median age, 46 years; range, 18-71 years) with 13 subtypes of STS underwent [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT examination within 1 week for assessment local relapse or distant metastasis. Positive lesions on PET/CT images were verified by biopsy or 3-month follow-up. Wilcoxon matched-pairs signed-rank test was used to compare the semiquantitative values (SUVmax and TBR) of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 in tumor lesions, and McNemar test was applied to test for differences of both tracers. RESULTS: Among the 45 patients, 282 local relapses and distant metastases were identified. Compared to [18F]FDG, [68 Ga]Ga-DOTA-FAPI-04 PET/CT detected more lesions (275 vs. 186) and outperformed in sensitivity, specificity, PPV, NPV, and accuracy for the diagnosis of recurrent lesions (P < 0.001). [68 Ga]Ga-DOTA-FAPI-04 demonstrated significantly higher values of SUVmax and TBR than [18F]FDG PET/CT in liposarcoma (P = 0.011 and P < 0.001, respectively), malignant solitary fibrous tumor (MSFT) (P < 0.001 and P < 0.001, respectively), and interdigitating dendritic cell sarcoma (IDCS) (P < 0.001and P < 0.001, respectively). While mean SUVmax and TBR presented favorable uptake of [18F]FDG over [68 Ga]Ga-DOTA-FAPI-04 in undifferentiated pleomorphic sarcoma (UPS) (P = 0.003 and P < 0.001, respectively) and rhabdomyosarcoma (RMS) (P < 0.001 and P < 0.001, respectively). CONCLUSION: [68 Ga]Ga-DOTA-FAPI-04 PET/CT is a promising new imaging modality for recurrent surveillance of STS, and compares favorably with [18F]FDG for identifying recurrent lesions of liposarcoma, MSFT, and IDCS.

Construction and investigation of ß3GNT2-associated regulatory network in esophageal carcinoma.

BACKGROUND: Glycosyltransferases play a crucial role in various cancers. ß1, 3-N-acetylglucosaminyltransferase 2, a polylactosamine synthase, is an important member of the glycosyltransferase family. However, the biological function and regulatory mechanism of ß3GNT2 in esophageal carcinoma (ESCA) is still poorly understood. METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used for gene expression and prognosis analysis. Quantitative real-time PCR, Western blot, and immunohistochemistry were performed to detect the expression of ß3GNT2 in ESCA cell lines and tissues. In vitro assays and xenograft tumor models were utilized to evaluate the impact of ß3GNT2 on ESCA progression. The downstream effectors and upstream regulators of ß3GNT2 were predicted by online software and verified by functional experiments. RESULTS: We found that ß3GNT2 was highly expressed in ESCA tissues and positively correlated with poor prognosis in ESCA patients. ß3GNT2 expression was closely associated with the tumor size, TNM stage, and overall survival of ESCA patients. Functionally, ß3GNT2 promoted ESCA cell growth, migration, and invasion in vitro, as well as tumorigenesis in vivo. Mechanistically, ß3GNT2 knockdown decreased the expression of the polylactosamine on EGFR. Knockdown of ß3GNT2 also inhibited the JAK/STAT signaling pathway. Meanwhile, the JAK/STAT inhibitor could partly reverse the biological effects caused by ß3GNT2 overexpression. Moreover, ß3GNT2 expression was positively regulated by CREB1 and negatively regulated by miR-133b. Both CREB1 and miR-133b was involved in the ß3GNT2-mediated ESCA progression. CONCLUSIONS: Our study, for the first time, reveals the importance of ß3GNT2 in ESCA progression and offers a potential therapeutic target for ESCA.

GRAP2 is a prognostic biomarker and correlated with immune infiltration in lung adenocarcinoma.

BACKGROUND: GRAP2 is an adaptor protein involved in leukocyte signal activation; however, the prognostic value of GRAP2 and its correlation with immune infiltration in lung adenocarcinoma (LUAD) are unclear. METHODS: Original data were downloaded from the TCGA database and Gene Expression Omnibus (GEO) database. GRAP2 expression was analyzed with the TCGA and TIMER databases. We evaluated the influence of GRAP2 on clinical prognosis using the Kaplan-Meier plotter, GEO, and GEPIA database. The TIMER and TISIDB databases were used to investigate correlations between GRAP2 expression and cancer immune characteristics. Finally, we confirmed the expression of GRAP2 in LUAD by immunohistochemistry staining. RESULTS: The transcription levels of GRAP2 were significantly lower in several human cancer types, including LUAD, than in adjacent normal tissues. Immunohistochemistry staining confirmed that LUAD tumor tissues had lower GRAP2 protein expression levels than adjacent normal tissues. GRAP2 downregulation was associated with poorer overall survival, pathologic stage, T stage, N stage, and primary therapy outcome in LUAD. Mechanistically, we found a hub gene set that included a total of 91 genes coexpressed with GRAP2, which were closely related to the immune response in LUAD. The expression levels of GRAP2 were positively correlated with the infiltration levels of multiple immune cells and the cumulative survival time of a few immune cells. GRAP2 expression was found to be positively correlated with that of multiple immune markers, chemokines, chemokine receptors, and MHC molecules in LUAD. CONCLUSIONS: GRAP2 can be used as a biomarker for assessing prognosis and immune infiltration levels in LUAD.

Individualized model for predicting COVID-19 deterioration in patients with cancer: A multicenter retrospective study.

The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID-19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID-19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C-index and time-dependent area under the receiver operating characteristic curve (t-AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C-reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d-dimer) were significantly associated with symptomatic deterioration. The C-index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t-AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low-risk (total points ≤ 9.98) and high-risk (total points > 9.98) group. The Kaplan-Meier deterioration-free survival of COVID-19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID-19 in patients with cancer.

Association between recent oncologic treatment and mortality among patients with carcinoma who are hospitalized with COVID-19: A multicenter study.

BACKGROUND: To the authors' knowledge, little is known regarding the association between recent oncologic treatment and mortality in patients with cancer who are infected with coronavirus disease 2019 (COVID-19). The objective of the current study was to determine whether recent oncologic treatment is associated with a higher risk of death among patients with carcinoma who are hospitalized with COVID-19. METHODS: Data regarding 248 consecutive patients with carcinoma who were hospitalized with COVID-19 were collected retrospectively from 33 hospitals in Hubei Province, China, from January 1, 2020, to March 25, 2020. The follow-up cutoff date was July 22, 2020. Univariable and multivariable logistic regression analyses were performed to identify variables associated with a higher risk of death. RESULTS: Of the 248 patients enrolled, the median age was 63 years and 128 patients (52%) were male. On admission, 147 patients (59%) did not undergo recent oncologic treatment, whereas 32 patients (13%), 25 patients (10%), 12 patients (5%), and 10 patients (4%), respectively, underwent chemotherapy, surgery, targeted therapy, and radiotherapy. At the time of last follow-up, 51 patients (21%) were critically ill during hospitalization, 40 of whom had died. Compared with patients without receipt of recent oncologic treatment, the mortality rate of patients who recently received oncologic treatment was significantly higher (24.8% vs 10.2%; hazard ratio, 2.010 [95% CI, 1.079-3.747; P = .027]). After controlling for confounders, recent receipt of chemotherapy (odds ratio [OR], 7.495; 95% CI, 1.398-34.187 [P = .015]), surgery (OR, 8.239; 95% CI, 1.637-41.955 [P = .012]), and radiotherapy (OR, 15.213; 95% CI, 2.091-110.691 [P = .007]) were identified as independently associated with a higher risk of death. CONCLUSIONS: The results of the current study demonstrated a possible association between recent receipt of oncologic treatment and a higher risk of death among patients with carcinoma who are hospitalized with COVID-19.

Functional Parcellation of Human Brain Precuneus Using Density-Based Clustering.

The human precuneus is involved in many high-level cognitive functions, which strongly suggests the existence of biologically meaningful subdivisions. However, the functional parcellation of the precuneus needs much to be investigated. In this study, we developed an eigen clustering (EIC) approach for the parcellation using precuneus-cortical functional connectivity from fMRI data of the Human Connectome Project. The EIC approach is robust to noise and can automatically determine the cluster number. It is consistently demonstrated that the human precuneus can be subdivided into six symmetrical and connected parcels. The anterior and posterior precuneus participate in sensorimotor and visual functions, respectively. The central precuneus with four subregions indicates a media role in the interaction of the default mode, dorsal attention, and frontoparietal control networks. The EIC-based functional parcellation is free of the spatial distance constraint and is more functionally coherent than parcellation using typical clustering algorithms. The precuneus subregions had high accordance with cortical morphology and revealed good functional segregation and integration characteristics in functional task-evoked activations. This study may shed new light on the human precuneus function at a delicate level and offer an alternative scheme for human brain parcellation.

Curcumin potentiates laryngeal squamous carcinoma radiosensitivity via NF-ΚB inhibition by suppressing IKKγ expression.

Context: Curcumin has shown efficacy in promoting radiosensitivity combined with radiotherapy. However, the role and mechanism of curcumin on radiosensitivity in laryngeal squamous cell cancer (LSCC) is largely unknown.Objective: The aim of our study is to explore the role of IKKγ-NF-κB signaling in curcumin enhancing LSCC cell radiosensitivity in vitro.Materials and methods: Curcumin and X-ray were used to induce cell DNA damage and apoptosis, or inhibit cell clone formation. IKKγ siRNA and plasmid were used to change IKKγ expression. The CCK8 assay was used to detect cell viability. Clone formation ability was analyzed using a clonogenic assay, cell apoptosis was examined using flow cytometry, an immunofluorescence assay was used to detect DNA damage, while mRNA and protein levels were assayed using real time PCR and western blotting, respectively.Results: Curcumin significantly enhanced irradiation-induced DNA damage and apoptosis, while weakening clone-forming abilities of LSCC cell line Hep2 and Hep2-max. Compared to Hep2 cells, Hep2-max cells are more sensitive to curcumin post-irradiation. Curcumin suppressed irradiation-induced NF-κB activation by suppressing IKKγ expression, but not IKKα and IKKß. Overexpression of IKKγ decreased irradiation-induced DNA damage and apoptosis, while promoting clone-forming abilities of Hep2 and Hep2-max cells. IKKγ overexpression further increased expression of NF-κB downstream genes, Bcl-XL, Bcl-2, and cyclin D1. Conversely, IKKγ silencing enhanced irradiation-induced DNA damage and apoptosis, but promoted clone formation in Hep2 and Hep2-max cells. Additionally, IKKγ silencing inhibited expression of Bcl-XL, Bcl-2, and cyclin D1.Conclusions: Curcumin enhances LSCC radiosensitivity via NF-ΚB inhibition by suppressing IKKγ expression.

Sentinel node theory helps tracking of primary lesions of cancers of unknown primary.

BACKGROUND: Sentinel lymph node is the first stop of lymphatic spreading of cancer with known primary. The lymph node metastasis pattern of cancer of unknown primary (CUP) is unclear and has been presumed to follow the same pathway. To test this hypothesis, data of all 716 patients clinically diagnosed as CUP in our center were collected. METHODS: Diagnoses of lymph node metastasis were established by 18F-FDG PET-CT and/or biopsy pathology. Three hundred and forty-seven cases meeting the criteria were divided into three groups: pathology-confirmed primary with invasive biopsy or surgery of the suspicious lesion (group A, n = 64), primary still unknown even with invasive biopsy or surgery of the suspicious lesion (group B, n = 204), and others with no suspicious lesion or lesions who had not been sampled due to medical or other reasons (group C, n = 79). We assessed the clinicopathological features between these groups, and the relationship between lymph node metastasis pattern and confirmed primary site. RESULTS: In group A, the primary sites of 61 cases were compatible with sentinel node theory, resulting in a positive predictive value of 95%. No significant differences in age, sex, bone metastasis, or visceral metastasis observed between group A and group B, except that group A had a higher ratio of differentiated carcinoma (94% vs. 77%, P = 0.003). CONCLUSION: To our knowledge, this is the first evidence indicating that the majority of clinical CUP cases follow the sentinel node theory to spread in lymph nodes, which helps tracking the primary, especially for differentiated carcinoma.

DEPDC1B knockdown inhibits the development of malignant melanoma through suppressing cell proliferation and inducing cell apoptosis.

Malignant melanoma (MM) remains the leading cause of skin cancer related death, which has very poor prognosis because of locoregional recurrence and distant metastasis. DEPDC1B (DEP domain-containing protein 1B), has been proved to be associated with some types of malignant tumors. However, the role of DEPDC1B in MM is still unknown. In this study, the expression levels of DEPDC1B in MM tissues were detected by IHC. DEPDC1B knockdown cell lines were constructed, evaluated by Western blot and qRT-PCR, and also used for construction of mice xenograft models. Cell proliferation and apoptosis were investigated by MTT, colony formation assay and flow cytometry, respectively. The results indicated significantly up-regulated expression of DEPDC1B in tumor tissues. Moreover, knockdown of DEPDC1B could inhibit cell proliferation while inducing cell apoptosis. The in vivo study demonstrated the significant suppression of tumor growth by knockdown of DEPDC1B. Finally, the results of antibody array proved the up-regulation of pro-apoptotic proteins and the down-regulation of anti-apoptotic proteins by DEPDC1B knockdown. Therefore, it could be concluded that DEPDC1B was involved in the development and progression of MM, which may act as promotor for MM and could be a potential therapeutic target.

PAG1 promotes the inherent radioresistance of laryngeal cancer cells via activation of STAT3.

Phosphoprotein associated with glycosphingolipid-enriched microdomains 1(PAG1) is a ubiquitous protein that is essential for the development and progression of various malignancies. A previous study in our laboratory confirmed that PAG1 plays an important role in modulating the inherent radioresistance of laryngeal cancer cells, but the underlying mechanisms are still poorly defined. In this study, we found that PAG1 was significantly increased in laryngeal cancer tissues compared to adjacent non-tumor tissues (P < 0.05). The expression of PAG1 was positively correlated with lymph node metastasis (P < 0.05) and TNM stage (P < 0.05). High expression of PAG1 also predicted a poor prognosis in patients with laryngeal cancer. Moreover, gain-of-function and loss-of-function studies showed that PAG1 overexpression was able to promote growth, increase migration and invasion, and enhance inherent radioresistance of laryngeal cancer cells. Mechanistic investigations revealed that the activation of STAT3 was required for PAG1-mediated inherent radioresistance of laryngeal cancer. Inhibition of STAT3 activity with a chemical inhibitor sensitized radioresistant cells to radiation. Importantly, PAG1-integrin ß1 complex was involved in the regulation of STAT3 activation. In addition, downregulation of PAG1 could suppress tumor growth and reverse inherent radioresistance in the nude mouse xenograft model. Taken together, these results suggested that PAG1 conferred inherent radioresistance by activating STAT3, which provided a novel therapeutic strategy for laryngeal cancer.