BACKGROUND: Breast cancer (BC) is the most common cancer in women and accounts for approximately 15% of all cancer deaths among women globally. The underlying mechanism of BC patients with small tumor size and developing distant metastasis (DM) remains elusive in clinical practices.
METHODS: We integrated the gene expression of BCs from ten RNAseq datasets from Gene Expression Omnibus (GEO) database to create a genetic prediction model for distant metastasis-free survival (DMFS) in BC patients with small tumor sizes (≤ 2 cm) using weighted gene co-expression network (WGCNA) analysis and LASSO cox regression.
RESULTS: ABHD11, DDX39A, G3BP2, GOLM1, IL1R1, MMP11, PIK3R1, SNRPB2, and VAV3 were hub metastatic genes identified by WGCNA and used to create a risk score using multivariable Cox regression. At the cut-point value of the median risk score, the high-risk score (≥ median risk score) group had a higher risk of DM than the low-risk score group in the training cohort [hazard ratio (HR) 4.51, p < 0.0001] and in the validation cohort (HR 5.48, p = 0.003). The nomogram prediction model of 3-, 5-, and 7-year DMFS shows good prediction results with C-indices of 0.72-0.76. The enriched pathways were immune regulation and cell-cell signaling. EGFR serves as the hub gene for the protein-protein interaction network of PIK3R1, IL1R1, MMP11, GOLM1, and VAV3.
CONCLUSIONS: Prognostic gene signature was predictive of DMFS for BCs with small tumor sizes. The protein-protein interaction network of PIK3R1, IL1R1, MMP11, GOLM1, and VAV3 connected by EGFR merits further experiments for elucidating the underlying mechanisms.

Studies show that inflammation induced by cancer is a key factor in carcinogenesis. Here, we sought to assess the relationship between patients with locally advanced rectal cancer (LARC) and the lymphocyte to neutrophil granulocyte ratio (LGR) prior to neoadjuvant chemoradiotherapy (nCRT) and distant metastasis-free survival (DMFS). Using a receiver operating characteristic (ROC) analysis of 326 LARC patients who underwent total mesorectal excision (TME) surgery and neoadjuvant chemoradiotherapy, we were able to determine the ideal LGR cutoff value. We used the Kaplan-Meier method and univariate and multivariate Cox regression to study the clinical characteristics of LARC patients in comparison between the low LGR group and the high LGR group. DMFS analysis was one of the primary clinical variables examined. We discovered that the low LGR group of LARC patients had a longer DMFS than the high LGR group. The median duration of follow-up for LARC patients was 89.4 months, with a significantly lower DMFS observed in the high LGR group compared to the low LGR group. Multivariate Cox regression analysis revealed that LARC patients with low LGR levels, early ypTNM stages, and BRAF wild had longer DMFS. LGR prior to nCRT was a critical prognostic indicator that contributed extra predictive value beyond conventional clinicopathological characteristics to predict the outcome of LARC patients receiving neoadjuvant chemoradiotherapy followed by TME surgery.

UNASSIGNED: HER2-positive breast carcinomas (BCs) generally behave more aggressively and show higher cytological and histological grade than HER2-negative BCs. However, the clinical properties of HER2-positive early BCs have not been studied extensively. Hence, the therapeutic significance of neoadjuvant chemotherapy (NAC) for this BC remains debatable.
UNASSIGNED: We retrospectively examined the clinicopathological features of 94 HER2-positive early BCs who perioperatively received anti-HER2 drugs, without undergoing NAC prior to surgery.
UNASSIGNED: The patients\' five year-disease free survival (DFS) and overall survival (OS) rates were 95.6% and 100%, respectively. Univariate analysis demonstrated significant differences in distant metastasis-free survival (DMFS) between clinical and pathological tumor stages (T stages). Pathological T1 stage and clinical T1 stage tumors showed significantly higher DMSF than pT2-3 and cT2-3 (p=0.0002 and 0.0294). Multivariate analysis disclosed no significant differences in DFS, OS, and DMFS with respect to preoperative clinical tumor stage, patient age, type of surgery, postoperative therapy, and pathological factors. Recurrences occurred in nine patients: four (4.3%) and five (5.3%) patients showed local and distant recurrences, respectively. One patient with cT2 BC died of disease. Interestingly, four of the five BCs with distant recurrence pathologically demonstrated lymph vessel invasion. The prognoses of patients with HER2-positive stage cT1/2N0M0 BC were highly favorable.
UNASSIGNED: The indications for NAC in small, localized, and node-negative HER2-positive BC should be carefully assessed based on the presence of a larger tumor size, postoperative pathological evaluation of tumor size, and lymph vessel invasion.

UNASSIGNED: This study aimed to assess the prognostic and predictive value of a circulating hematological signature (CHS) and to develop a CHS-based nomogram for predicting prognosis and guiding individualized chemotherapy in non-metastatic nasopharyngeal carcinoma (NPC) patients.
UNASSIGNED: NPC patients were recruited between January 2014 and December 2017 at the Jiangxi Cancer Hospital. The CHS was constructed based on a series of hematological indicators. The nomogram was developed by CHS and clinical factors.
UNASSIGNED: A total of 779 patients were included. Three biomarkers were selected by least absolute shrinkage and selection operator regression, including prognostic nutritional index, albumin-to-fibrinogen ratio, and prealbumin-to-fibrinogen ratio, were used to construct the CHS. The patients in the low-CHS group had better 5-year DMFS and OS than those in the high-CHS group in the training (DMFS: 85.0% vs 56.6%, p<0.001; OS: 90.3% vs 65.4%, p<0.001) and validation cohorts (DMFS: 92.3% vs 43.6%, p<0.001; OS: 92.1% vs 65.5%, p<0.001). The nomogram_CHS showed better performance than clinical stage in predicting distant metastasis (concordance index: 0.728 vs 0.646). In the low-TRS (total risk scores) group, the patients received RT alone, CCRT and IC plus CCRT had similar 5-year DMFS and OS (p>0.05). In the middle-TRS group, the patients received RT alone had worse 5-year DMFS (58.7% vs 80.8% vs 90.8%, p=0.002) and OS (75.0% vs 94.1% vs 95.0%, p=0.001) than those received CCRT or IC plus CCRT. In the high-TRS group, the patients received RT alone and CCRT had worse 5-year DMFS (18.6% vs 31.3% vs 81.5%, p<0.001) and OS (26.9% vs 53.2% vs 88.8%, p<0.001) than those received IC plus CCRT.
UNASSIGNED: The developed nomogram_CHS had satisfactory prognostic accuracy in NPC patients and may individualize risk estimation to facilitate the identification of suitable IC candidates.

BACKGROUND: umor cells, immune cells and stromal cells jointly modify tumor development and progression. We aim to explore the potential effects of tumor purity on the immune microenvironment, genetic landscape and prognosis in prostate cancer (PCa).
METHODS: Tumor purity of prostate cancer patients was extracted from The cancer genome atlas (TCGA). Immune cellular proportions were calculated by the CIBERSORT. To identify critical modules related to tumor purity, we used weighted gene co-expression network analysis (WGCNA). Using STRING and Cytoscape, protein-protein interaction (PPI) networks were constructed and analyzed. A Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Disease Ontology (DO), and Gene Set Enrichment Analysis (GSEA) enrichment analysis of identified modules was conducted. To identify the expression of key genes at protein levels, we used the Human Protein Atlas (HPA) platform.
RESULTS: A model of tumor purity score (TPS) was constructed in the gene expression omnibus series (GSE) 116,918 cohort. TCGA cohort served as a validation set and was employed to validate the TPS. TPS model, as an independent prognostic factor of distant metastasis-free survival (DMFS) in PCa. Patients had higher tumor purity and better prognosis in the low-TPS group. Tumor purity was related to the infiltration of mast cells and macrophage cells positively, whereas related to the infiltration of dendritic cells, T cells and B cells negatively in PCa. The nomogram based on TPS, Age, Gleason score and T stage had a good predictive value and could evaluate the prognosis of PCa metastasis. GO and KEGG enrichment analyses showed that hub genes mainly participate in T cell activation and T-helper lymphocytes (TH) differentiation. Hub genes were mainly enriched in primary immunodeficiency disease, according to DO analysis. SLAMF8 was identified as the most critical gene by Cytoscape and HPA analysis.
CONCLUSIONS: Dynamic changes in the immune microenvironment associated with tumor purity could correlate with a poor DMFS of low-purity PCa. The TPS can predict the DMFS of PCa. In addition, prostate cancer metastases may be related to immunosuppression caused by a disorder of the immune microenvironment.

BACKGROUND: Therapeutic lymphadenectomy (TLND) is still performed in most melanoma patients to treat nodal recurrences after initial negative lymph node biopsy (-SLNB), despite the lack of evidence for survival benefit. We sought to compare melanoma-specific survival (MSS) and distant metastasis-free survival (DMFS) of patients who underwent TLND versus no TLND using our institutional and MSTL-1 databases.
METHODS: We identified 146 patients with nodal recurrence following -SLNB: 132 underwent TLND and 14 did not. DMFS and MSS were evaluated for the cohorts followed by a matched-pair analysis between the cohorts.
RESULTS: No difference was observed in five-year DMFS (p ​= ​0.454) and five-year MSS (p ​= ​0.945) between the two groups. The matched-pair analysis showed similar results (p ​= ​0.329 and p ​= ​0.363 for DMSF and MSS, respectively).
CONCLUSIONS: From this limited retrospective study, TLND for nodal recurrence after a -SLNB does not appear to improve DMFS or MSS in melanoma patients compared to no TLND.

Tissue biomarkers that aid in identifying cutaneous melanoma (CM) patients who will benefit from adjuvant immunotherapy are of crucial interest. Metastatic tumor-draining lymph nodes (mTDLN) are the first encounter site between the metastatic CM cells and an organized immune structure. Therefore, their study may reveal mechanisms that could influence patients´ outcomes.
Twenty-nine stage-III CM patients enrolled in clinical trials to study the vaccine VACCIMEL were included in this retrospective study. After radical mTDLN dissection, patients were treated with VACCIMEL (n=22) or IFNα-2b (n=6), unless rapid progression (n=1). Distant Metastasis-Free Survival (DMFS) was selected as an end-point. Two cohorts of patients were selected: one with a good outcome (GO) (n=17; median DMFS 130.0 months), and another with a bad outcome (BO) (n=12; median DMFS 8.5 months). We analyzed by immunohistochemistry and immunofluorescence the expression of relevant biomarkers to tumor-cell biology and immune cells and structures in mTDLN, both in the tumor and peritumoral areas.
In BO patients, highly replicating Ki-67+ tumor cells, low tumor HLA-I expression and abundant FoxP3+ lymphocytes were found (p=0.037; p=0.056 and p=0.021). In GO patients, the most favorable biomarkers for prolonged DMFS were the abundance of peri- and intra-tumoral CD11c+ cells (p=0.0002 and p=0.001), peri-tumoral DC-LAMP+ dendritic cells (DCs) (p=0.001), and PNAd+ High Endothelial Venules (HEVs) (p=0.004). Most strikingly, we describe in GO patients a peculiar, heterogeneous structure that we named FAPS (Favoring Antigen-Presenting Structure), a triad composed of DC, HEV and CD62L+ naïve lymphocytes, whose postulated role would be to favor tumor antigen (Ag) priming of incoming naïve lymphocytes. We also found in GO patients a preferential tumor infiltration of CD8+ and CD20+ lymphocytes (p=0.004 and p=0.027), as well as peritumoral CD20+ aggregates, with no CD21+ follicular dendritic cells detected (p=0.023). Heterogeneous infiltration with CD64+CD68-CD163-, CD64+CD68+CD163- and CD64+CD68+CD163+ macrophages were observed in both cohorts.
The analysis of mTDLN in GO and BO patients revealed marked differences. This work highlights the importance of analyzing resected mTDLN from CM patients and suggests a correlation between tumor and immune characteristics that may be associated with a spontaneous or vaccine-induced long DMFS. These results should be confirmed in prospective studies.

BACKGROUND: Lymphovascular invasion (LVI) is a crucial predictor of lymph node metastasis (LNM). However, few studies have investigated the LVI positivity rate and its clinical significance in pT1b esophageal squamous cell carcinoma (ESCC) using immunohistochemistry and elastin staining.
METHODS: We collected data from158 patients with pT1b ESCC who had undergone radical esophagectomy. All paraffin blocks of invasive carcinoma from each patient were subjected to HE staining, elastin staining + CK (AE1/AE3) immunohistochemistry (E&IHC), and CD31/D2-40 + CK (AE1/AE3) double immunohistochemistry (D-IHC). The LVI was classified into types, i.e., vascular invasion (VI) and lymphatic vessel invasion (LI), and its location, quantity, and clinical significance were explored.
RESULTS: The positivity rates of VI by E&IHC (E-VI), VI by CD31D-IHC (CD31-VI), and LI by D2-40 D-IHC (D2-40-LI) were significantly higher than those obtained by HE staining (P < 0.001, respectively). CD31-VI and E-VI were independent adverse prognostic factors for recurrence-free survival (RFS), and they were significantly associated with poor distant metastasis-free survival and overall survival in pT1b ESCC. Intratumoral LVI was also crucial in pT1b ESCC, and L2 (the count of D2-40-LI was 5 or more) was the strongest predictor for LNM and RFS in pT1b ESCC.
CONCLUSIONS: E&IHC and D-IHC can dramatically improve the detection rate of LVI in pT1b ESCC, and the classification and grading of LVI can help to improve the prediction of LNM and prognosis.

The use of adjuvant therapy has provided survival benefits in patients with advanced melanoma. This study aimed to explore the recurrence and prognosis of the PD-1 inhibitor, conventional interferon (IFN), or observation (OBS) on resected stage III acral and cutaneous melanoma patients through a retrospective analysis. Patients with resected stage III melanoma at Fudan University Shanghai Cancer Center from 2017 to 2021 were enrolled with all of their clinicopathologic characteristics collected. They were divided into three groups: PD-1 inhibitor, IFN, and OBS. Survival analyses were performed to indicate the significance of different adjuvant therapies. A total of 199 patients were enrolled (PD-1 n = 126; IFN n = 31; and OBS n = 42), with their median follow-up times being 21 months, 24 months, and 49 months, respectively. The PD-1 inhibitor significantly improved relapse-free survival (p = 0.027) and overall survival (p = 0.033) compared with conventional treatment (IFN+OBS). The superiority of the PD-1 inhibitor was witnessed in stage IIIC/D (p = 0.000) acral (p = 0.05) melanoma patients with ulceration (p = 0.011) or lymph node macrometastasis (p = 0.010). The PD-1 inhibitor significantly reduced local recurrence and systemic metastasis compared with conventional therapy (p = 0.002). In conclusion, adjuvant anti-PD-1 immunotherapy can achieve better survival outcomes in acral and cutaneous melanoma patients compared with conventional treatment, without considering adverse events. More clinical benefits were seen in later-stage acral melanoma patients with ulceration or lymph node macrometastasis.

BACKGROUND: We investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced rectal cancer (LARC) and whether modifiable factors in radiotherapy (RT) influenced the NLR.
METHODS: Data of 1386 patients who were treated with neoadjuvant RT and concurrent or sequential chemotherapy for LARC between 2006 and 2019 were evaluated. Most patients (97.8%) were treated with long-course RT (LCRT; 50-50.4 Gy in 25-28 fractions) using three-dimensional conformal radiotherapy (3D-CRT) (n = 851) or helical tomotherapy (n = 504), and 30 patients underwent short-course RT (SCRT; 25 Gy in 5 fractions, followed by XELOX administration for 6 weeks). Absolute neutrophil and lymphocyte counts were obtained at initial diagnosis, before and during the preoperative RT course, and after preoperative concurrent chemoradiotherapy. The primary endpoint was distant metastasis-free survival (DMFS).
RESULTS: The median follow-up time was 61.3 (4.1-173.7) months; the 5-year DMFS was 80.1% and was significantly associated with the NLR after RT but not before. A post-RT NLR ≥ 4 independently correlated with worse DMFS (hazard ratio, 1.42; 95% confidence interval, 1.12-1.80), along with higher ypT and ypN stages. Post-RT NLR (≥ 4) more frequently increased following LCRT (vs. SCRT, odds ratio [OR] 2.77, p = 0.012) or helical tomotherapy (vs. 3D-CRT, OR 1.29, p < 0.001).
CONCLUSIONS: Increased NLR after neoadjuvant RT is associated with increased distant metastasis risk and poor survival outcome in patients with LARC. Moreover, high NLR following RT is directly related to RT fractionation, delivery modality, and tumor characteristics. These results are hypothesis-generating only, and confirmatory studies are required.