PD-1 blockade plus COX inhibitors in dMMR metastatic colorectal cancer: Clinical, genomic, and immunologic analyses from the PCOX trial.

BACKGROUND: Approximately 20% of patients with DNA mismatch repair deficiency (dMMR) metastatic colorectal cancer do not respond to anti-programmed death-1 (PD-1) ligand therapy, and baseline biomarkers of response are lacking. METHODS: We conducted a phase 2 study to evaluate the efficacy of cyclooxygenase (COX) inhibitors in combination with anti-PD-1 therapy in patients with dMMR metastatic colorectal cancer. The primary endpoint was objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate, duration of response, and safety. FINDINGS: A total of 30 patients were enrolled, and the objective response rate was 73.3%, meeting the predefined endpoint of 68%. The median PFS and median OS were not reached at a median follow-up period of 50.8 months. Disease control was achieved in 28 patients (93.3%). The median duration of response was not reached. The combination was well tolerated. Multiomics analysis revealed that the antigen processing and presentation pathway was positively associated with treatment response and PFS. Higher TAPBP expression was predictive of better PFS (log-rank p = 0.003), and this prognostic significance was confirmed in an immunotherapy validation cohort. CONCLUSIONS: Thus, COX inhibitors combined with PD-1 blockade may be effective and safe treatment options for patients with dMMR metastatic colorectal cancer, and TAPBP may serve as a biomarker for immune checkpoint inhibitor therapy (this study was registered at ClinicalTrials.gov: NCT03638297). FUNDING: Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).

Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy.

BACKGROUND: PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. METHODS: Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. RESULTS: We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. CONCLUSION: This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors.

Biomarkers of Pathologic Complete Response to Neoadjuvant Immunotherapy in Mismatch Repair-Deficient Colorectal Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking. EXPERIMENTAL DESIGN: Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response. RESULTS: The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while HLA-DQA1 and HLA-DQB1 were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8+ T-cell density was associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2, P = 0.013 Wilcoxon test). Further integrated analysis showed that CD8+ T cells with low PD-1 expression (PD-1lo CD8+ T cells) expressing high levels of TRGC2, CD160, and KLRB1 and low levels of proliferated and exhausted genes were significantly associated with pCR response. CONCLUSIONS: Immune-associated transcriptomic features, particularly CD8+ T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.

Capecitabine maintenance therapy in metastatic colorectal cancer patients with no evidence of disease: CAMCO trial.

Background: In patients with metastatic colorectal cancer (mCRC) exhibiting no evidence of disease (NED), this study assessed the efficacy and safety of capecitabine maintenance therapy. Methods: The single-arm, phase II CAMCO trial enrolled mCRC-NED patients after first-line treatment, administering oral capecitabine maintenance for 1 year. Results: A total of 93 patients were enrolled. The primary end point, 3-year disease-free survival, yielded a rate of 51.6% (95% CI: 41.3-62.0%). Secondary end points included a 3-year overall survival rate of 83.9% (95% CI: 76.3-91.5%). Grade 3 adverse events (AE) were observed in seven patients (7.5%). Predominantly grade 1 and 2, the most common AE was hand-foot syndrome. Conclusion: In mCRC-NED patients, capecitabine maintenance demonstrated a manageable 3-year disease-free survival rate of 51.6%, accompanied by manageable AEs. Clinical Trial Registration: NCT01880658 (ClinicalTrials.gov).

Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer.

Immune checkpoint inhibitor (ICI) therapy can induce complete responses in mismatch repair-deficient and microsatellite instability-high (d-MMR/MSI-H) colorectal cancers (CRCs). However, the underlying mechanism for pathological complete response (pCR) to immunotherapy has not been completely understood. We utilize single-cell RNA sequencing (scRNA-seq) to investigate the dynamics of immune and stromal cells in 19 patients with d-MMR/MSI-H CRC who received neoadjuvant PD-1 blockade. We found that in tumors with pCR, there is a concerted decrease in CD8+ Trm-mitotic, CD4+ Tregs, proinflammatory IL1B+ Mono and CCL2+ Fibroblast following treatment, while the proportions of CD8+ Tem, CD4+ Th, CD20+ B, and HLA-DRA+ Endothelial cells increase. Proinflammatory features in the tumor microenvironment mediate the persistence of residual tumors by modulating CD8+ T cells and other response-associated immune cell populations. Our study provides valuable resources and biological insights into the mechanism of successful ICI therapy and potential targets for improving treatment efficacy.

Identification of immune cell infiltration landscape for predicting prognosis of colorectal cancer.

Background: The tumor microenvironment plays an essential role in the therapeutic response to immunotherapy. It is necessary to identify immune cell infiltration (ICI) subtypes for evaluating prognosis and therapeutic benefits. This study aimed to evaluate the ICI score as an effective prognostic biomarker for immune response. Methods: The cell-type identification by estimating relative subsets of RNA transcripts and the estimation of stromal and immune cells in malignant tumors using expression methods were used to analyse ICI landscapes in 161 colorectal cancer (CRC) samples with patients' clinical and prognostic data, RNA sequencing data, and whole-exome sequencing data from the Sixth Affiliated Hospital, Sun Yat-sen University (Guangzhou, China). Statistical analysis and data processing were conducted to calculate ICI scores, and to analyse the prognosis of CRC patients with different ICI scores and other features. A similar analysis with RNA sequencing and clinical data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) database was conducted to confirm the correctness of the findings. Results: The high-ICI score group with a better prognosis (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.03-4.64; log-rank test, P = 0.036) was characterized by the increased tumor mutational burden and interleukin-17 (IL-17) signaling pathway. Significant differences in the prognosis and the expression levels of immune checkpoints and chemokine marker genes were found between the two ICI score groups. For COAD samples from TCGA, the results also showed a significant difference in patients' prognosis between the two ICI score groups (HR, 1.72; 95% CI, 1.00-2.96; log-rank test, P = 0.047). Conclusions: Tumor heterogeneity induced differences in identifying ICI subtypes of CRC patients. The ICI score may serve as an effective biomarker for predicting prognosis, help identify new therapeutic markers for CRC, and develop novel effective immune checkpoint blockade therapies.

Plantamajoside Alleviates Substantia Nigra Damage in Parkinson's Disease Mice by Inhibiting HDAC2/MAPK Signaling and Reducing Microglia Polarization.

Parkinson's disease (PD) is a common neurodegenerative disorder caused by dopaminergic neuron progressive degeneration. Inhibition of microglial activation may contribute to the treatment and prevention of PD. Plantamajoside (PMS) is a natural compound extracted from plantain seeds. It has a wide range of biological activities, including anti-inflammatory, antioxidative, as well as antitumor effects. However, its possible effects on PD are still unclear. In this study, lipopolysaccharide (LPS) was first injected into the right midbrain substantia nigra (SN) of male C57BL/6 mice to establish the PD mouse model. We found that PMS improved LPS-induced behavioral dysfunction in PD mice. PMS attenuated LPS-induced SN injury in PD mice. PMS could suppress LPS-induced microglial overactivation in PD mice. In addition, MS inhibited LPS-induced activation of the HDAC2/MAPK pathway in PD mice and BV-2 cells. It further revealed that PMS alleviated microglia polarization by inhibiting HDAC2. The limitation of this study was the lack of experiments for investigating the further molecular mechanism and in vivo animal validation, which needs to be further confirmed in the future. Collectively, our data suggested that PMS could serve as a promising drug for PD.

Neoadjuvant Modified FOLFOXIRI With Selective Radiotherapy in Locally Advanced Rectal Cancer: Long-term Outcomes of Phase II Study and Propensity-Score-Matched Comparison With Chemoradiotherapy.

BACKGROUND: Neoadjuvant modified FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) chemotherapy with selective radiotherapy did not compromise pathologic complete response and tumor downstaging in locally advanced rectal cancer. OBJECTIVE: The study aimed to analyze disease-free survival and local recurrence of neoadjuvant chemotherapy with modified FOLFOXIRI (mFOLFOXIRI). DESIGN: This was a prospective single-arm phase II study. A propensity score-adjusted method was implemented to compare outcomes against historical controls of chemoradiotherapy. SETTINGS: The study was conducted at single institutions. PATIENTS: One hundred 6 patients with stage II and III rectal cancers were included. INTERVENTION: All patients received neoadjuvant mFOLFOXIRI chemotherapy before total mesorectal excision. Patients with mesorectal fascia-positive or ycT4a/b after reevaluation with MRI received radiation before surgery. Otherwise, immediate total mesorectal excision would be performed. MAIN OUTCOME AND MEASURES: The primary end point was tumor downstaging (ypStage 0-I) rate, which was reported previously. Disease-free survival and local recurrence rate were the main outcomes for the current study. RESULTS: After a median follow-up of 43.3 months, the 2-year disease-free survival rate was 85.6% and the 3-year disease-free survival rate was 78.9%. The local recurrence rate was 7.8% after surgery. After propensity score matching, 73 patients were available for comparison in each group. The pathologic complete response rate was 23.3% and 13.7% ( p = 0.14), the proportion of ypStage 0-I was 45.2% vs 39.7% ( p = 0.5), the 3-year disease-free survival was 87.6% vs 75.8% (HR = 0.46; 95% CI, 0.22-0.95, p = 0.037). The local recurrence rate in the mFOLFOXIRI group was 5.5% and in the chemoradiotherapy group was 4.1% ( p = 0.70). Patients receiving mFOLFOXIRI had a lower incidence of anastomotic fistula compared with the chemoradiotherapy group (5.5% vs 17.8%, p = 0.02). LIMITATIONS: This was a single-arm, nonrandomized phase II study. CONCLUSIONS: Neoadjuvant mFOLFOXIRI with selective radiotherapy was feasible and safe, and it improved 3-year disease-free survival compared with propensity score-matched historical controls who received chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/B989 .Trial registration: NCT02217020. FOLFOXIRI MODIFICADO NEOADYUVANTE CON RADIOTERAPIA SELECTIVA EN CNCER DE RECTO LOCALMENTE AVANZADO RESULTADOS A LARGO PLAZO DEL ESTUDIO DE FASE II Y COMPARACIN EMPAREJADA POR PUNTUACIN DE PROPENSIN CON QUIMIORRADIOTERAPIA: ANTECEDENTES:La quimioterapia neoadyuvante con FOLFOXIRI modificado (ácido folínico, 5-fluoruracilo, oxaliplatino e irinotecan) con radioterapia selectiva no comprometió la respuesta patológica completa ni la reducción del estadio del tumor en el cáncer de recto localmente avanzado.OBJETIVO:El estudio tuvo como objetivo analizar la sobrevida libre de enfermedad y la recurrencia local de la quimioterapia neoadyuvante con FOLFOXIRI modificado (mFOLFOXIRI).DISEÑO:Este fue un estudio prospectivo de fase II de un solo brazo. Se implementó un método ajustado por puntaje de propensión para comparar los resultados con los controles históricos de quimiorradioterapia.ESCENARIO:El estudio se realizó en instituciones individuales.PACIENTES:Se incluyeron 106 pacientes con cáncer de recto en estadio II y III.INTERVENCIÓN:Todos los pacientes recibieron quimioterapia neoadyuvante con mFOLFOXIRI antes de la escisión total del mesorrecto. Los pacientes con fascia mesorrectal positiva o ycT4a/b después de la reevaluación con MRI recibirían radiación antes de la cirugía. En caso contrario, se realizaría una escisión mesorrectal total inmediata.PRINCIPALES RESULTADOS Y MEDIDAS:El criterio principal de valoración fue la tasa de disminución del estadio del tumor (ypEstadio 0-I), que se informó anteriormente. La sobrevida libre de enfermedad y la tasa de recurrencia local son los principales resultados del estudio actual.RESULTADOS:Después de una mediana de seguimiento de 43,3 meses, las tasas de sobrevida libre de enfermedad a 2 y 3 años fueron del 85,6 % y 78,9 %, respectivamente. La tasa de recidiva local fue del 7,8% tras la cirugía. Después del emparejamiento por puntaje de propensión, 73 pacientes estaban disponibles para la comparación en cada grupo. La tasa de respuesta patológica completa fue de 23,3 % y de 13,7 % (p = 0,14), la proporción de ypEstadio 0-I fue del 45,2 % frente al 39,7 % (p = 0,5), la SLE a los 3 años fue del 87,6 % frente al 75,8 % (HR = 0,46, IC del 95 % 0,22-0,95, p = 0,037) y la tasa de recurrencia local fue del 5,5 % y del 4,1 % (p = 0,70) en el grupo de mFOLFOXIRI frente al grupo de quimiorradioterapia, respectivamente. Los pacientes que recibieron mFOLFOXIRI tuvieron una menor incidencia de fístula anastomótica en comparación con el grupo de quimiorradioterapia (5,5 % frente a 17,8 %, p = 0,02).LIMITACIONES:Este fue un estudio de fase II no aleatorizado de un solo brazo.CONCLUSIONES:El mFOLFOXIRI neoadyuvante con radioterapia selectiva fue factible y seguro, y mejoró la SSE a los 3 años en comparación con los controles históricos emparejados por puntaje de propensión que recibieron quimiorradioterapia. Consulte Video Resumen en http://links.lww.com/DCR/B989 . (Traducción-Dr. Felipe Bellolio ).

Pregnancy and fetal outcomes of chronic hepatitis C mothers with viremia in China.

BACKGROUND: Data that assess maternal and infant outcomes in hepatitis C virus (HCV)-infected mothers are limited. AIM: To investigate the frequency of complications and the associated risk factors. METHODS: We performed a cohort study to compare pregnancy and fetal outcomes of HCV-viremic mothers with those of healthy mothers. Risk factors were analyzed with logistic regression. RESULTS: Among 112 consecutive HCV antibody-positive mothers screened, we enrolled 79 viremic mothers. We randomly selected 115 healthy mothers from the birth registry as the control. Compared to healthy mothers, HCV mothers had a significantly higher frequency of anemia [2.6% (3/115) vs 19.0% (15/79), P < 0.001] during pregnancy, medical conditions that required caesarian section [27.8% (32/115) vs 48.1% (38/79), P = 0.004], and nuchal cords [9.6% (11/115) vs 34.2% (27/79), P < 0.001]. In addition, the mean neonatal weight in the HCV group was significantly lower (3278.3 ± 462.0 vs 3105.1 ± 459.4 gms; P = 0.006), and the mean head circumference was smaller (33.3 ± 0.6 vs 33.1 ± 0.7 cm; P = 0.03). In a multivariate model, HCV-infected mothers were more likely to suffer anemia [adjusted odds ratio (OR): 18.1, 95% confidence interval (CI): 4.3-76.6], require caesarian sections (adjusted OR: 2.6, 95%CI: 1.4-4.9), and have nuchal cords (adjusted OR: 5.6, 95%CI: 2.4-13.0). Their neonates were also more likely to have smaller head circumferences (adjusted OR: 2.1, 95%CI: 1.1-4.3) and lower birth weights than the average (≤ 3250 gms) with an adjusted OR of 2.2 (95%CI: 1.2-4.0). The vertical transmission rate was 1% in HCV-infected mothers. CONCLUSION: Maternal HCV infections may associate with pregnancy and obstetric complications. We demonstrated a previously unreported association between maternal HCV viremia and a smaller neonatal head circumference, suggesting fetal growth restriction.

Peripheral blood lymphocytes subtypes as new predictors for neoadjuvant therapy efficacy in breast cancer.

BACKGROUND: Host immunity plays an important role in tumor development and treatment. Tumor-infiltrating lymphocytes (TILs) have been proven to predict the efficacy of neoadjuvant therapy (NAT) in breast cancer (BC) patients, but their application is limited due to various reasons. This study aims to explore the relationship between peripheral blood lymphocytes (PBLs) subsets distribution and the efficacy of NAT. METHODS: Between December 2017 and March 2021, a total of 116 BC patients appropriate for NAT in Sun Yat-Sen University cancer center were enrolled, pre-NAC baseline blood samples were taken for further flow cytometry analysis to quantitatively evaluate the PBLs subsets distribution, and corresponding clinical information including pathological complete response (pCR) rate of NAT response were recorded. RESULTS: Baseline CD3+ T cells(OR 1.11, 1.03-1.21, p = 0.011), CD8+ T cells (OR 1.09, 1.02-1.18, p = 0.015), and NK cells (OR 0.91, 0.83-0.98, p = 0.028) in PBLs subgroup distribution were independent predictors of pCR in BC patients receiving NAT, in which CD8+ T cells had the highest predictive ability (AUC = 0.76). Compared with some previous prediction indicators, its prediction ability has been improved to some extent. CONCLUSION: Peripheral baseline CD3+ T cells, CD8+ T cells, and NK cells were independent predictors of pCR in BC patients receiving NAT, in which CD8+ T cells had the highest predictive ability. Therefore, it can provide newly non-invasive, relatively accurate and easily accessible predictors for corresponding patients, and help clinicians better understand tumor immunity.

mFOLFOXIRI versus mFOLFOX6 as neoadjuvant chemotherapy in locally advanced rectal cancer: A Propensity Score Matching Analysis.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC). However, CRT failed to impact metastatic recurrence and the risk of side effects on bowel and genitourinary remained a concern. Neoadjuvant chemotherapy alone with mFOLFOX6 or FOLFOXIRI had been investigated in LARC. Here, we tried to compare the efficacy of mFOLFOXIRI with mFOLFOX6 as neoadjuvant chemotherapy in LARC. PATIENTS AND METHODS: Between January 2014 and December 2019, patients with LARC receiving neoadjuvant chemotherapy with mFOLFOXIRI or mFOLFOX6 were retrospective analyzed, including data from a prospective trial (NCT02217020). All patients underwent total mesorectal excision (TME). The propensity-score matching was preformed to adjust baseline potential confounders and to estimate differences in outcomes between patients receiving mFOLFOXIRI and mFOLFOX6. Survival analysis was done using Kaplan-Meier analysis and Cox proportional regression analysis. RESULTS: The median follow-up time was 31.1 months. After propensity score matching, 156 patients were available for comparison in each group. The pathological complete response (pCR) rate was 17.9% vs. 5.1% (P< .001), the incidence rate of anastomotic fistula was 3.2% vs. 9% (P = .03), the 3 year disease-free survival (DFS) rate was 75% vs. 66.7% (P = .047) and the distant metastasis rate was 16.4% versus 26.6% (P = .013) for mFOLFOXIRI and mFOLFOX6 group, respectively. Patients receiving mFOLFOXIRI had higher incidence of grade III and/or IV nausea and/or vomiting (7.6% vs. 2.5%, P = .04). CONCLUSIONS: Neoadjuvant mFOLFOXIRI regimens improved pCR rate and survival outcome, reduced the rate of distant metastasis and anastomotic fistula when comparing with propensity-score matched controls of mFOLFOX6 neoadjuvant chemotherapy. MICROABSTRACT: This trial assessed the short-term and long-term effects of neoadjuvant chemotherapy with mFOLFOXIRI and mFOLFOX6 in patients with locally advanced rectal cancer. Comparing with propensity-score matched historical control of chemoradiotherapy, neoadjuvant mFOLFOXIRI chemotherapy was well tolerated and led to higher rates of 3 year disease-free survival in patients with locally advanced rectal cancer.

Nomogram to Predict Tumor-Infiltrating Lymphocytes in Breast Cancer Patients.

Background: Tumor-infiltrating lymphocytes (TILs) play important roles in the prediction of prognosis and neoadjuvant therapy (NAT) efficacy in breast cancer (BRCA) patients, in this study, we identified clinicopathological factors related to BRCA TILs, then to construct and validate nomogram to predict high density of TILs. Methods: A total of 826 patients diagnosed with BRCA in Sun Yat-Sen University cancer center were enrolled in nomogram cohort. TILs were assessed using hematoxylin-eosin (H&E) staining by two pathologists. Complete clinical data were collected for analysis. Then the enrolled patients were split into a training set and validation set at a ratio of 8:2. and the backward multivariate binary logistic regression model was used to establish nomogram for predicting BRCA TILs, which were further evaluated and validated using the C-index, receiver operating characteristic (ROC) curves and calibration curves. Then another independent NAT cohort of 106 patients was established for verifying this nomogram in NAT efficacy prediction. Results: TILs were significantly correlated with body mass index (BMI), tumor differentiation, ER, PR, HER2 expression, Ki67, blood biochemical indicators including total bilirubin (TBIL), indirect bilirubin (IBIL), total protein (TP), Globulin (GLOB), inorganic phosphorus (IP), calcium (Ca). In which ER expression level [OR = 0.987, 95%CI (0.982-0.992), p < 0.001], IP [OR = 4.462, 95%CI (1.171∼17.289), p = 0.029], IBIL [OR = 0.906, 95%CI (0.845-0.966), p = 0.004] and TP [OR = 1.053, 95%CI (1.010-1.098, p = 0.016)] were independent predictors of TILs. Then nomogram was established, for which calibration curves (C-index = 0.759) and ROC curve (AUC = 0.759, 95%CI 0.717-0.801) in training sets, calibration curves (C-index = 0.708) and ROC curve (AUC = 0.708, 95%CI 0.617-0.800) in validation sets demonstrated great evaluation efficiency. Besides, independent NAT cohort verified this nomogram can distinguish patients with greater NAT efficacy (p = 0.041). Conclusion: The finds of clinicopathological factors associated with TILs could help clinicians to understand the tumor immunity of BRCA and improve treatment system for patients, and the established nomogram with high evaluation efficiency may be used as a complement tool for distinguishing patients with better NAT efficacy.

The Trends of Psychological Status of People Entering from High-Risk Areas of COVID-19 Coronavirus During the Quarantine in Dedicated Hotels: A Longitudinal Survey Study from Guangzhou, China.

BACKGROUND: The quarantine in dedicated hotels has become an inevitable safety measure due to the frequent cross-border travel since the outbreak of COVID-19. The aim of the present study was to explore the trends in the psychological status of individuals entering from high-risk areas of COVID-19 coronavirus while quarantining in dedicated hotels. METHODS: A total of 591 individuals who isolated in dedicated hotels were recruited between March and June 2020. Participants self-reported mental symptoms [Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS)] every three days during the quarantine. A mixed-effects linear regression model was used to assess the trends. RESULTS: Participants reporting anxiety and depression symptoms at least one time during quarantine accounted for 4.5% and 18.4%, respectively. Their psychological status was alleviated during some first 9 days, and then it slightly deteriorated, which was suggested by SAS and SDS scores that were negatively correlated with the days of quarantine (T) (adjusted coefficient [ß] -0.81, 95% CI -1.00 to -0.62; and ß -0.75, 95% CI -0.97 to -0.53, respectively), and were positively correlated with the square of T (ß 0.04, 95% CI 0.02 to 0.06; and ß 0.04, 95% CI 0.02 to 0.06, respectively). The unemployed and 18~30-year-old participants were prone to greater levels of psychological distress. No significant difference in the trend of mental health was found among different subgroups. CONCLUSION: The mental health of the people entering Guangzhou from high-risk areas of COVID-19 coronavirus resulted positive during the early period of quarantine in dedicated hotels, after which it deteriorated. The psychological status of individuals should be closely monitored at the beginning and after more than 9 days of quarantine, especially for individuals who are unemployed and 18~30-year-old ones.

Downregulation of FEM1C enhances metastasis and proliferation in colorectal cancer.

BACKGROUND: Feminization-1 (FEM-1) is considered a substrate recognition subunit of CUL2-RING E3 ubiquitin ligase complexes, which refers to sex determination by modulating TRA-1 stability in C. elegans. The function of mammalian orthologous gene of FEM-1 remains to be elucidated. METHODS: The expression of FEM1C in colorectal cancer (CRC) cells was interfered by small interference RNA (siRNA) transfection, and Cell counting kit-8 (CCK-8) assay, colony formation assay and transwell assay were performed. In order to estimate the function on metastasis, stable knockdown FEM1C cells were used to established liver and lung metastasis models. In addition, the expression of FEM1C in normal tissues, adenomas and tumor tissues were analyzed, and the relationship between FEM1C expression level and prognosis was analyzed by Kaplan-Meier method. RESULTS: Here, we report that the elimination of FEM1C, one of the members of FEM-1, significantly promoted the migration and invasion of colorectal cancer (CRC) cells in vitro and promoted liver and lung metastases in vivo. It also showed that the removal of FEM1C improved the proliferation ability of CRC cells. In particular, the cell shape changed from epithelial to fibroblast-like morphology. The tight cell monolayer was transformed into a dispersed distribution. Furthermore, it was demonstrated that FEM1C is down-regulated in tissues of CRC compared to normal tissues, and the high expression of FEM1C positively correlates with a good prognosis in patients with CRC. GSEA analysis showed that EMT signatures was enriched in FEM1C knockdown groups. CONCLUSIONS: Down-regulation of FEM1C promotes proliferation and metastasis, and FEM1C may be a tumor suppressor in the development of CRC.

Mucinous Adenocarcinoma Predicts Poor Response and Prognosis in Patients With Locally Advanced Rectal Cancer: A Pooled Analysis of Individual Participant Data From 3 Prospective Studies.

PURPOSE: To evaluate the predictive implications and prognosis of mucinous adenocarcinoma (MAC) in locally advanced rectal cancer (LARC) with intensified neoadjuvant treatment. METHODS: Individual patient data of LARC patients from 3 prospective clinical trials was analyzed. Neoadjuvant treatment regimens comprised chemoradiotherapy (CRT) with fluorouracil (5-FU) or mFOLFOX6, neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI. The postoperative pathological result, local recurrence and disease-free survival (DFS) were retrospectively analyzed in patients with MAC and adenocarcinoma (AC) with neoadjuvant treatment. RESULTS: Totally, 743 patients were recruited, with 620 patients eligible for analysis. Fifty-three (8.5%) patients were MAC. The pathological complete response (pCR) rate and tumor downstaging rate (ypStage 0-I) between MAC and AC patients was 7.5% vs. 22.0% (P = .01) and 20.8% vs. 48.7% (P < .001), respectively. Among patients receiving preoperative CRT with 5FU or mFOLFOX6, the pCR rate and tumor downstaging rate between MAC and AC patients was 11.1% vs. 27.3% (P = .03) and 23.7% vs. 52.6% (P = .001), respectively. Regarding neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI, the pCR rate and tumor downstaging rate was 0 vs.13.2% (P = .11) and 11.8% vs. 42.5% (P = .03) between MAC and AC group, respectively. With the median follow-up time of 38.9 months, the 3-year DFS and 3-year locoregional recurrence rate was 58.4% vs. 77.6% (P = .02) and 26.0% vs. 5.7% (P = .001) in the MAC and AC group, respectively. MAC (hazard ratio [HR] 1.85, 95% confidence interval [CI], 1.15-2.98), PNI (HR 3.23, 95% CI, 1.85-5.72) and LVI (HR 2.04, 95% CI, 1.02-4.08) were independent prognosis factors and were associated with worse DFS. CONCLUSIONS: Patients with MAC of the rectum are associated with a lower pCR rate and tumor downstaging rate, higher incidence of local recurrence, and poorer DFS with neoadjuvant treatment.

Selection of Oral Therapeutics in China for the Treatment of Colorectal Cancer.

OPINION STATEMENT: Intravenous administration of fluoropyrimidine-based chemotherapy has been the backbone of treatment in colorectal cancer (CRC) for decades. The availability of oral capecitabine has improved the tolerability and simplified combination schedules. In addition to capecitabine, several other oral drugs have proven efficacy, particularly in palliative treatment lines. Clinical guidelines describe several available third-line treatment options for metastatic CRC (mCRC), but few insights are provided to guide the selection and sequence. In this review, we describe the available evidence and most recent data concerning oral drugs with proven efficacy in CRC, including antiangiogenetic tyrosine kinase inhibitors (VEGFR TKIs), inhibitors blocking EGFR/Raf/MEK/ERK signaling pathway and modified fluoropyrimidine, and share recommendations and insights on selecting third-line oral therapies for mCRC in China. In general, third-line treatment options for mCRC are mainly regorafenib, fruquintinib, and chemo/targeted therapy reintroduction, while FTD/TPI was rarely used in China probably due to poor accessibility. Fruquintinib is preferred in patients with poor performance status (PS), elder age, and severe organ dysfunction, compared to regorafenib. New drugs of clinical trials were more recommended for the patients with BRAF mutant tumor, and those with good previous treatment efficacy tended to be recommended for chemo/targeted therapy reintroduction. The management of mCRC is evolving, and it must be emphasized that the consideration and recommendations presented here reflect current treatment practices in China and thus might change according to new clinical data as well as the availability of new oral drugs.

LncRNA ENSG00000254615 Modulates Proliferation and 5-FU Resistance by Regulating p21 and Cyclin D1 in Colorectal Cancer.

5-Fluorouracil (5-FU) resistance is an urgent problem of colorectal cancer (CRC) chemotherapy that needs to be resolved. To investigate 5-FU-associated lncRNAs for CRC might be of great significant. LncRNA ENSG00000254615 was detected by RNA-sequencing. ENSG00000254615 were detected highly expressed in 5-FU-sensitive CRC cells and tissue specimens, and inhibited cell proliferation and attenuated 5-FU resistance in vitro and in vivo. Furthermore, ENSG00000254615 participated in the regulation of p21 and Cyclin D1. Taken together, we proposed that ENSG00000254615 inhibits proliferation and attenuates 5-FU resistance of CRC by regulating p21 and Cyclin D1 expression.

A Self-Adaptive Response Strategy for Dynamic Multiobjective Evolutionary Optimization Based on Objective Space Decomposition.

Dynamic multiobjective optimization deals with simultaneous optimization of multiple conflicting objectives that change over time. Several response strategies for dynamic optimization have been proposed, which do not work well for all types of environmental changes. In this article, we propose a new dynamic multiobjective evolutionary algorithm based on objective space decomposition, in which the maxi-min fitness function is adopted for selection and a self-adaptive response strategy integrating a number of different response strategies is designed to handle unknown environmental changes. The self-adaptive response strategy can adaptively select one of the strategies according to their contributions to the tracking performance in the previous environments. Experimental results indicate that the proposed algorithm is competitive and promising for solving different DMOPs in the presence of unknown environmental changes. Meanwhile, the proposed algorithm is applied to solve the parameter tuning problem of a proportional integral derivative (PID) controller of a dynamic system, obtaining better control effect.

Clinicopathological, molecular features and prognosis of colorectal cancer with mucinous component.

Background: Colorectal cancer (CRC) with mucinous component is associated with distinct characteristics and controversial prognosis. Patients & methods: A total of 1800 CRC patients were retrospectively enrolled and grouped by the mucinous content of the primary tumors. The clinicopathological characteristics and overall survival rate were compared between groups. Results: Mucinous adenocarcinoma (MAC) and adenocarcinoma with mucinous component (AMC) had higher frequencies of DNA mismatch repair protein deficiency, KRAS, BRAF and PIK3CA mutations as compared to those of conventional adenocarcinoma (CAC). MAC had worse prognosis than CAC. However, MAC was not an independent prognostic factor in multivariable analysis. Conclusion: Molecular features of AMC and MAC were similar, which were different from those of CAC. Neither MAC nor AMC were independent prognostic factors for CRC.

Duration of FOLFOX Adjuvant Chemotherapy in High-Risk Stage II and Stage III Colon Cancer With Deficient Mismatch Repair.

BACKGROUND: We evaluated the impact of 3 months of mFOLFOX6 adjuvant chemotherapy or surgery alone in comparison with 6 months of mFOLFOX6 on disease-free survival (DFS) in deficient mismatch repair (dMMR) colon cancer (CC) patients. METHODS: This retrospective study identified a cohort of patients with high-risk stage II and III dMMR CC who underwent curative surgery between May 2011 and July 2019. DFS was compared using the Kaplan-Meier survival methods and Cox proportional hazards models. Propensity-score matching was performed to reduce imbalance in baseline characteristics. RESULTS: A total of 242 dMMR CC patients were identified; 66 patients received 6 months of mFOLFOX6, 87 patients received 3 months of mFOLFOX6, and 89 patients were treated with surgery alone. The 3-year DFS rate was 72.8% in 3-month therapy group and 86.1% in 6-month therapy group, with a hazard ratio (HR) of 2.78 (95CI%, 1.18 to 6.47; P= 0.019). The difference in DFS between surgery alone group and 6-month therapy group was also observed but was nonsignificant (HR= 2.30, 95%CI, 0.99 to 5.38; P=0.054). The benefit of 6-month therapy in DFS compared with 3-month therapy group was pronounced for patients with stage III (HR=2.81, 95%CI, 1.03 to 7.67; P=0.044) but not for high-risk stage II patients. Propensity score matched analysis confirmed a DFS benefit in the 6-month therapy group. CONCLUSION: This study suggested that a 6-month duration of mFOLFOX6 adjuvant chemotherapy in dMMR CC patients may be associated with improved DFS compared with 3-month therapy, particularly in patients with stage III. The observational nature of the study implies caution should be taken in the interpretation of these results.