Clinicopathologic features and genomic profiling of female axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary.

PURPOSE: Axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary (CUPAx) is a rare disease in women. This retrospective study intended to examine the clinicopathological features of CUPAx and compared CUPAx genetically with axillary lymph node metastases from breast cancer (BCAx), investigating differences in their biological behavior. METHODS: We conducted the clinical and prognostic analysis of 58 CUPAx patients in West China Hospital spanning from 2009 to 2021. Gemonic profiling of 12 CUPAx patients and 16 BCAx patients was conducted by the FoundationOne CDx (F1CDx) platform. Moreover, we also compared the gene mutation spectrum and relevant pathways between the two groups and both TCGA and COSMIC databases. RESULTS: The majority of the 58 CUPAx patients were HR-/HER2- subtype. Most patients received mastectomy combined radiotherapy (50 Gy/25f). CUPAx patients who received mastectomy instead of breast-conserving surgery had a more favorable overall prognosis. Radiotherapy in chest wall/breast and supraclavicular/infraclavicular fossa was the independent prognostic factor (HR = 0.05, 95%CI = 0.00-0.93, P = 0.04). In 28 sequencing samples (CUPAx, n = 12, BCAx, n = 16) and 401 TCGA-BRCA patients, IRS2 only mutated in CUPAx (33.33%) but amplified in BCAx (11.11%) and TCGA-BRCA (1.5%). Pathway analysis revealed that BCAx had more NOTCH pathway mutations than CUPAx. Enrichment analysis showed that CUPAx enriched more in mammary development and PML bodies than BCAx, but less in the positive regulation of kinase activity. CONCLUSIONS: More active treatment methods, like chemotherapy, mastectomy and postoperative radiotherapy, could improve the prognosis of CUPAx. The differential mutation genes of CUPAx and BCAx might be associated with their respective biological behaviors like invasiveness and prognosis.

Targeting PI3Kα increases the efficacy of anti-PD-1 antibody in cervical cancer.

Targeting programmed death 1(PD-1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD-L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP-qPCR/PCR assays were used to determine the transcriptional regulation of PD-L1 by PIK3CA-E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA-seq) and flow cytometry. The efficacy of PI3K inhibitor and anti-PD-1 therapy was assessed in cell-derived xenografts (CDX) and patients-derived xenografts (PDX). PD-L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress-free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD-L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA-E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD-L1 by upregulating the transcription factor IRF1. PI3Kα-specific inhibitor markedly activates immune microenvironment by regulating the PD-1/L1-related pathways and promoting CD8+ T cell differentiation and proliferation in Caski-CDXs with PIK3CA-E545K mutation. PI3Kα inhibitor significantly enhances the anti-tumour efficacy of PD-1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD-1 blockade. The efficacy of PI3Kα inhibitors combined with PD-1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations.

Engineered procyanidin-Fe nanoparticle alleviates intestinal inflammation through scavenging ROS and altering gut microbiome in colitis mice.

Inflammatory bowel disease (IBD) is an idiopathic chronic inflammatory bowel disease characterized by inflammation, intestinal barrier injury, and imbalance of gut microbiota. Excess accumulation of reactive oxygen species (ROS) is closely correlated with the development and reoccurrence of IBD. Previous researches demonstrate that procyanidin, as a natural antioxidant, exhibits strong ability of eliminating ROS, thus showing good therapeutic effects in the inflammation-related diseases. Non-etheless, its poor stability and solubility always limits the therapeutic outcomes. Here, we typically designed an antioxidant coordination polymer nanoparticle using the engineering of procyanidin (Pc) and free iron (Fe), named Pc-Fe nanozyme, for effectively scavenging ROS and further inhibiting inflammation while altering the gut microbiome for the treatment of colitis. Furthermore, in vitro experiments uncover that Pc-Fe nanoparticles exert strong multi biomimic activities, including peroxidase, and glutathione peroxidase, for the scavenging of ROS and protecting cells from oxidative injury. In addition, the colon accumulation of Pc-Fe nanozyme effectively protects the intestinal mucosa from oxidative damage while significantly downregulates pro-inflammatory factors, repairs the intestinal barriers and alternates gut microbiome after orally administrated in sodium dextran sulfate (DSS) induced colitis mice. The results collectively illustrate that the multienzyme mimicking Pc-Fe nanozyme owns high potential for treating IBD through scavenging ROS, inhibiting inflammation, repairing gut barriers and alternating gut microbiome, which further promising its clinical translation on IBD treatment and other ROS induced intestinal diseases.

Tumor calcification is associated with better survival in metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy.

Aims: The purpose was to investigate the correlation between calcification and outcome in metastatic colorectal cancer (mCRC) patients who received bevacizumab plus chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy. Results: Among all enrolled patients (n = 159), 31 had tumor calcification. The median overall survival and progression-free survival were significantly better in patients with tumor calcification than in those without calcification. A higher objective overall response rate was also observed in the tumor calcification group. On multivariate analysis, tumor calcification was independently associated with overall survival and progression-free survival. Conclusions: Tumor calcification was independently associated with improved survival in mCRC patients treated with bevacizumab plus chemotherapy.

Colorectal cancer is one of the most commonly diagnosed malignancies globally and nearly half of these patients develop metastatic colorectal cancer (mCRC). The current standard treatment for mCRC includes 5-fluorouracil-based chemotherapy with or without bevacizumab. Nevertheless, a predictive biomarker of efficacy for bevacizumab has not yet been firmly established. This retrospective study aimed to investigate the correlation between tumor calcification and prognosis in mCRC patients who received bevacizumab plus chemotherapy as the first-line treatment. The authors found that tumor calcification was independently associated with improved survival in mCRC patients treated with bevacizumab plus chemotherapy.

Immune-Related Pneumonitis Was Decreased by Addition of Chemotherapy with PD-1/L1 Inhibitors: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials (RCTs).

PURPOSE: Immune-related pneumonitis (IRP) has attracted extensive attention, owing to its increased mortality rate. Conventional chemotherapy (C) has been considered as an immunosuppressive agent and may thus reduce IRP's risk when used in combination with PD-1/L1 inhibitors. This study aimed to assess the risk of IRP with PD-1/L1 inhibitors plus chemotherapy (I+C) versus PD-1/L1 inhibitors alone (I) in solid cancer treatment. METHOD: Multiple databases were searched for RCTs before January 2021. This NMA was performed among I+C, I, and C to investigate IRP's risk. Subgroup analysis was carried out on the basis of different PD-1/L1 inhibitors and cancer types. RESULTS: Thirty-one RCTs (19,624 patients) were included. The I+C group exhibited a lower risk of IRP in any grade (RR, 0.60; 95% CI, 0.38-0.95) and in grade 3-5 (RR, 0.44; 95% CI, 0.21-0.92) as opposed to the I group. The risk of any grade IRP with PD-1 plus chemotherapy was lower than that with PD-1 monotherapy (RR, 0.50; 95% CI, 0.28-0.89), although grade 3-5 IRP was similar. There was no statistically meaningful difference in the risk of any grade IRP between PD-L1 plus chemotherapy and PD-L1 inhibitors monotherapy (RR, 0.95; 95% CI, 0.43-2.09) or grade 3-5 IRP (RR, 0.71;95% CI, 0.24-2.07). In addition, compared with the I group, the I+C group was correlated with a decreased risk in IRP regardless of cancer type, while a substantial difference was only observed in NSCLC patients for grade 3-5 IRP (RR, 0.39; 95% CI, 0.15-0.98). CONCLUSION: In comparison to PD-1/L1 inhibitor treatment alone, combining chemotherapy with PD-1/L1 inhibitors might reduce the risk of IRP in the general population. Furthermore, PD-1 inhibitors in combination with chemotherapy were correlated with a decreased risk of IRP compared to PD-1 inhibitor treatment alone. In contrast to the I group, the I+C group exhibited a lower risk of IRP, especially for NSCLC patients.

Anterior wall adenocarcinoma of bladder with similar clinicopathological and prognostic characteristics as common bladder carcinomas should not be treated as or classified into urachal adenocarcinomas.

PURPOSE: To discuss whether the dome or anterior wall of bladder adenocarcinoma (BAC) should be classified into urachal carcinoma (UrC) and the relationship of primary tumor location (PTL) as well as treatment with survival. METHODS: Surveillance, Epidemiology, and End Results 18 database was examined for eligible patients from 1975 to 2016. Patients were classified into adenocarcinoma originating from the urachus (UAC), the dome (D-BAC), the anterior wall (A-BAC), and the other sites adenocarcinoma of the bladder (O-BAC). The clinicopathological features, treatment, and survival were compared among the groups. RESULTS: Comparable clinicopathologic features were obtained between UAC and D-BAC, which were different from those of A-BAC and O-BAC; otherwise, the latter two had similar clinicopathologic features. Univariable and multivariable Cox regression analyses indicated that PTL was an independent predictor for survival. O-BAC conferred the worst prognosis then followed by A-BAC, D-BAC, and UAC. For non-metastatic UAC or D-BAC, partial cystectomy (with an en bloc resection of the urachus and umbilicus) is optimal for survival. However, the worse survival of non-metastatic D-BAC (compared with UAC) suggested different modalities, maybe more intensive surgery approaches, should be considered for D-BAC. CONCLUSION: This study illustrates that PTL of UAC and BAC was an independent predictor for survival. A-BAC had comparable characters and prognosis with O-BAC and should not be classified into and treated as UrC. For non-metastatic disease, non-metastatic D-BAC may need more intensive modality.

First-line therapy of bevacizumab plus chemotherapy versus cetuximab plus chemotherapy for metastatic colorectal cancer patients with mucinous adenocarcinoma or mucinous component.

BACKGROUND: To compare the efficacy of first-line bevacizumab plus chemotherapy with cetuximab plus chemotherapy based on the stratification of metastatic colorectal cancer (mCRC) patients with mucinous adenocarcinoma (MA) or mucinous component (MC). METHODS: A retrospective study involving all mCRC patients receiving first-line bevacizumab-based or cetuximab-based chemotherapy at our hospital from September 2013 to January 2020 was conducted. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group on the basis of the conventional pathological classification of MA or MC. RESULTS: A total of 620 patients with mCRC were included in our study, consisting of 141 (22.7%) patients with MA/MC and 479 (77.3%) patients with non-mucinous adenocarcinoma (NMA). In the MA/MC cohort, patients who were treated with bevacizumab-based chemotherapy were associated with significantly better OS than those treated with cetuximab-base chemotherapy (30.0 vs. 26.3 months, p = 0.002), irrespective of tumor sites. The efficacy of bevacizumab-based chemotherapy was higher in nearly all subgroups as shown in the subgroup analysis. In the NMA cohort, median OS was better in the cetuximab plus chemotherapy group than that in the bevacizumab plus chemotherapy group (32.2 vs. 27.0 months, p = 0.005) for left-side mCRC patients, whereas OS was significantly longer in the bevacizumab plus chemotherapy group for right-side mCRC patients (26.0 vs. 20.9 months, p = 0.013). CONCLUSION: Conventional pathological classification (e.g. MA/MC) should be considered when tailoring the individualized optimal treatment for mCRC. Bevacizumab plus chemotherapy as first-line therapy may be the optimal option for patients with MA/MC.

Thyroid function abnormality induced by PD-1 inhibitors have a positive impact on survival in patients with non-small cell lung cancer.

BACKGROUND: Thyroid function abnormality (TFA) is a common immune-related adverse event (irAEs), but the association between it and the efficacy of programmed cell death protein 1 (PD-1) inhibitor in advanced non-small cell lung cancer (NSCLC) is finitely understood. MATERIALS AND METHODS: We conducted a single center, retrospective study of advanced NSCLC patients who were treated with PD-1 inhibitors between 10 October 2016 and 1 April 2020. TFA was characterized as new onset subclinical hypothyroidism, overt hypothyroidism, subclinical hyperthyroidism and overt hyperthyroidism. Frequency of development of TFA-irAEs, and its relationship with overall survival (OS) and progression free survival (PFS) were evaluated. RESULTS: In our study, 191 patients were treated with PD-1 inhibitors. Among them, forty patients (20.9%) developed TFA, of whom 10 (5.2%) presented with subclinical hypothyroidism, 15 (7.9%) with overt hypothyroidism, 6 (3.1%) with subclinical hyperthyroidism and 9 (4.7%) with overt hyperthyroidism. Survival analysis showed that the OS (16.8 months vs. 11.1 months, p < 0.001) and PFS (10.4 months vs. 5.5 months, p < 0.001) were significantly longer in patients with TFA-irAEs than in those without TFA-irAEs. In subgroup analysis of hypothyroidism and hyperthyroidism groups, similar trends were also obtained for both OS and PFS. After adjusting for potential confounding variables, patients with TFA-irAEs had a lower mortality risk (HR 0.334, 95%CI 0.196-0.571) than those without TFA-irAEs. CONCLUSIONS: TFA-irAEs is associated with enhanced PD-1 inhibitor efficacy in advanced NSCLC patients and it may be a biomarker for antitumor immune response.