Distant Metastasis-free Survival In Patients Research Articles

Frequent Amplification and Overexpression of PSMA in Basallike Breast Cancer from Analysis of The Cancer Genome Atlas.

Prostate-specific membrane antigen (PSMA) is frequently overexpressed in nonprostate malignancies. This preclinical study investigated the molecular basis of the application of PMSA-targeting radiopharmaceuticals in breast cancer subtypes. Methods: The somatic copy number status and the transcriptomic and protein expressions of FOLH1 (gene name of PSMA) were analyzed across breast cancer subtypes in 998 patients from The Cancer Genome Atlas dataset. Results: FOLH1 was frequently amplified in basallike breast cancer (BLBC) (32%) compared with luminal and human epidermal growth factor receptor 2-positive subtypes (16% and 17%, respectively; P < 0.01). FOLH1 expression was higher in BLBC (P < 0.001) and was negatively correlated with estrogen-receptor and progesterone-receptor expressions. Consistently, the PSMA protein level was higher in BLBC (P < 0.05). Interestingly, FOLH1 expression was associated with relapse-free and distant metastasis-free survival in patients with BLBC. Conclusion: The BLBC subtype exhibited frequent amplification and overexpression of PSMA, supporting the exploration of PSMA-targeting radiopharmaceuticals in this aggressive breast cancer subtype.

Neutrophil-to-lymphocyte ratio and monocyte-to-eosinophil ratio as prognostic indicators for advanced nasopharyngeal carcinoma.

To determine the predictive value of the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-eosinophil ratio (NER), lymphocyte-to-eosinophil ratio (LER), monocyte-to-eosinophil ratio (MER), systemic inflammatory response index (SIRI), and ratio of inflammatory cells before and after treatment for predicting survival in advanced nasopharyngeal carcinoma (NPC) and to provide a reference for treatment. A retrospective review of 70 patients was performed. Serological indexes were obtained by drawing blood before and after systemic therapy. The cutoff values of these indexes were determined by receiver operating characteristic (ROC) curves. The prognostic value of the indexes for overall survival (OS) and distant metastasis free survival (DMFS) was evaluated. Survival analysis showed that a smaller pretreatment LMR value was associated with poor OS; larger pretreatment NER, LER, MER, and SIRI values were associated with poor OS; a smaller posttreatment LMR value was associated with poor OS; larger posttreatment NLR, NER, MER, and SIRI values were associated with poor OS; a smaller pretreatment LMR value was associated with poor DMFS; larger pretreatment NLR, NER, LER, and MER values were associated with poor DMFS; and larger posttreatment NLR, NER, LER, and MER values were associated with poor DMFS. Furthermore, a larger neutrophil after treatment-to-neutrophil before treatment ratio was associated with poor OS and DMFS. Logistic regression analysis showed that pretreatment MER and posttreatment NLR were independent predictors of OS in patients with advanced NPC; moreover, pretreatment and posttreatment MER and NLR were independent prognostic factors for DMFS in patients with advanced NPC. The NLR, NER and MER can be used to predict survival in advanced NPC patients. Eosinophils might be one of the factors for the good prognosis of NPC patients. In addition, an increased number of neutrophils after treatment may indicate a favorable prognosis.

Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score

BackgroundPartial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes.MethodsA retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW).ResultsA total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046–0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021–0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011–0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016–0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified.ConclusionsOur findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan.Trial registrationThis study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).

A PET/CT radiomics model for predicting distant metastasis in early-stage non–small cell lung cancer patients treated with stereotactic body radiotherapy: a multicentric study

ObjectivesStereotactic body radiotherapy (SBRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are unfit for surgery. Some patients may experience distant metastasis. This study aimed to develop and validate a radiomics model for predicting distant metastasis in patients with early-stage NSCLC treated with SBRT.MethodsPatients at five institutions were enrolled in this study. Radiomics features were extracted based on the PET/CT images. After feature selection in the training set (from Tianjin), CT-based and PET-based radiomics signatures were built. Models based on CT and PET signatures were built and validated using external datasets (from Zhejiang, Zhengzhou, Shandong, and Shanghai). An integrated model that included CT and PET radiomic signatures was developed. The performance of the proposed model was evaluated in terms of its discrimination, calibration, and clinical utility. Multivariate logistic regression was used to calculate the probability of distant metastases. The cutoff value was obtained using the receiver operator characteristic curve (ROC), and the patients were divided into high- and low-risk groups. Kaplan-Meier analysis was used to evaluate the distant metastasis-free survival (DMFS) of different risk groups.ResultsIn total, 228 patients were enrolled. The median follow-up time was 31.4 (2.0-111.4) months. The model based on CT radiomics signatures had an area under the curve (AUC) of 0.819 in the training set (n = 139) and 0.786 in the external dataset (n = 89). The PET radiomics model had an AUC of 0.763 for the training set and 0.804 for the external dataset. The model combining CT and PET radiomics had an AUC of 0.835 for the training set and 0.819 for the external dataset. The combined model showed a moderate calibration and a positive net benefit. When the probability of distant metastasis was greater than 0.19, the patient was considered to be at high risk. The DMFS of patients with high- and low-risk was significantly stratified (P < 0.001).ConclusionsThe proposed PET/CT radiomics model can be used to predict distant metastasis in patients with early-stage NSCLC treated with SBRT and provide a reference for clinical decision-making.Plain language summaryIn this study, the model was established by combining CT and PET radiomics signatures in a moderate-quantity training cohort of early-stage NSCLC patients treated with SBRT and was successfully validated in independent cohorts. Physicians could use this easy-to-use model to assess the risk of distant metastasis after SBRT. Identifying subgroups of patients with different risk factors for distant metastasis is useful for guiding personalized treatment approaches.

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation.

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan-Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p=.048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p=.19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p=.008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p=.009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Optimal Cisplatin Cycles in Locally Advanced Cervical Carcinoma Patients Treated with Concurrent Chemoradiotherapy

To analyze the effect of cisplatin cycles on the clinical outcomes of patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT). This study included 749 patients with LACC treated with CCRT between January 2011 and December 2015. A receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off of cisplatin cycles in predicting clinical outcomes. Clinicopathological features of the patients were compared using the Chi-square test. Prognosis was assessed using log-rank tests and Cox proportional hazard models. Toxicities were compared among different cisplatin cycle groups. Based on the ROC curve, the optimal cut-off of the cisplatin cycles was 4.5 (sensitivity, 64.3%; specificity, 54.3%). The 3-year overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival for patients with low-cycles (cisplatin cycles < 5) and high-cycles (≥ 5) were 81.5% and 89.0% (P < 0.001), 73.4% and 80.1% (P = 0.024), 83.0% and 90.8% (P = 0.005), and 84.9% and 86.8% (P = 0.271), respectively. In multivariate analysis, cisplatin cycles were an independent prognostic factor for overall survival. In the subgroup analysis of high-cycle patients, patients who received over five cisplatin cycles had similar overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival to patients treated with five cycles. Acute and late toxicities were not different between the two groups. Cisplatin cycles were associated with overall, disease-free, and loco-regional relapse-free survival in LACC patients who received CCRT. Five cycles appeared to be the optimal number of cisplatin cycles during CCRT.

Optimal cisplatin cycles in locally advanced cervical carcinoma patients treated with concurrent chemoradiotherapy.

To analyze the effect of cisplatin cycles on the clinical outcomes of patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT). This study included 749 patients with LACC treated with CCRT between January 2011 and December 2015. A receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off of cisplatin cycles in predicting clinical outcomes. Clinicopathological features of the patients were compared using the Chi-square test. Prognosis was assessed using log-rank tests and Cox proportional hazard models. Toxicities were compared among different cisplatin cycle groups. Based on the ROC curve, the optimal cut-off of the cisplatin cycles was 4.5 (sensitivity, 64.3%; specificity, 54.3%). The 3-year overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival for patients with low-cycles (cisplatin cycles < 5) and high-cycles (≥ 5) were 81.5% and 89.0% (P < 0.001), 73.4% and 80.1% (P = 0.024), 83.0% and 90.8% (P = 0.005), and 84.9% and 86.8% (P = 0.271), respectively. In multivariate analysis, cisplatin cycles were an independent prognostic factor for overall survival. In the subgroup analysis of high-cycle patients, patients who received over five cisplatin cycles had similar overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival to patients treated with five cycles. Acute and late toxicities were not different between the two groups. Cisplatin cycles were associated with overall, disease-free, and loco-regional relapse-free survival in LACC patients who received CCRT. Five cycles appeared to be the optimal number of cisplatin cycles during CCRT.

CircMAN1A2 contributes to nasopharyngeal carcinoma progression via enhancing the ubiquitination of ATMIN through miR-135a-3p/UBR5 axis.

Recently, the dysregulation of circRNAs has been increasingly implicated in the pathogenesis of nasopharyngeal carcinoma (NPC). Among these circRNAs, circMAN1A2 has been highlighted for the up-regulated expression in NPC, whereas the underlying mechanisms have not been clearly established. Thus, the aim of this study was to delineate the tumor-supporting role of circMAN1A2 in the oncogenesis and metastases of NPC. We validated through qRT-PCR that circMAN1A2 was highly expressed in NPC tissues and NPC cells. Survival analysis through Kaplan-Meier method showed that the overall survival, disease-free survival, and distant metastasis-free survival of patients was negatively correlated with the expression of circMAN1A2. Then, gain- and loss-of function assays demonstrated that circMAN1A2 knockdown could impede the proliferation, migration, invasion, and EMT in NPC cells. Further, we conducted dual luciferase reporter gene, RIP, and RNA pull down assays, unveiling that circMAN1A2 functioned as a sponge of miR-135a-3p, and miR-135a-3p targeted UBR5. Additionally, UBR5 interacted with ATMIN to foster the ubiquitination of ATMIN, thereby expediting the malignant behaviors of NPC cells as well as the lung and inguinal lymph node metastases of NPC tumors in vivo. Together, our study uncovered the tumor-initiating and pro-metastatic role of circMAN1A2-miR-135a-3p-UBR5-ATMIN axis in NPC regulation that may be a potential therapeutic target for human NPC.

Effects of lymphopenia on survival in proton therapy with chemotherapy for non-small cell lung cancer.

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose-volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5-20 and lung V5-50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P= 0.042), 26.1% vs 5.6% (P= 0.022) and 39.1% vs 5.6% (P< 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P= 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy.

Aspirin Use Is Associated With Improved Outcomes in Inflammatory Breast Cancer Patients.

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer and has a high propensity for distant metastases. Our previous data suggested that aspirin (acetylsalicylic acid, ASA) use may be associated with reduced risk of distant metastases in aggressive breast cancer; however, there are no reported studies on the potential benefit of ASA use in patients with IBC. Data from patients with non-metastatic IBC treated between 2000-2017 at two institutions, were reviewed. Overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were performed using Kaplan-Meier analysis. Univariate and multivariable logistic regression models were used to identify significant associated factors. Of 59 patients meeting the criteria for analysis and available for review, 14 ASA users were identified. ASA users demonstrated increased OS (p = 0.03) and DMFS (p = 0.02), with 5-year OS and DMFS of 92% (p = 0.01) and 85% (p = 0.01) compared to 51% and 43%, respectively, for non-ASA users. In univariate analysis, pT stage, pN stage, and ASA use were significantly correlated (p < 0.05) with OS and DFS. On multivariable analysis, ASA use (hazard ratio [HR], 0.11; 95% confidence interval [CI], 0.01-0.8) and lymph node stage (HR, 5.9; 95% CI, 1.4-25.9) remained significant for OS and DFS ASA use (HR, 0.13; 95% CI, 0.03-0.56) and lymph node stage (HR, 5.6; 95% CI, 1.9-16.4). ASA use during remission was associated with significantly improved OS and DMFS in patients with IBC. These results suggest that ASA may provide survival benefits to patients with IBC. Prospective clinical trials of ASA use in patients with high-risk IBC in remission should be considered.

Integrative Analysis of Genetic and Epigenetic Alterations in the CBX7 Gene Reveals Its Tumor-Suppressive Function by Regulating the Cell Cycle in Human Breast Cancer

CBX7 is a member of the chromobox gene family, which plays an important role in epigenetic transcriptional regulation. In this study, we found that compared to normal mammary tissues, mRNA levels of CBX7 are consistently significantly downregulated in breast cancers (BCs) across different datasets. Integrative multiomics analysis revealed the genetic and epigenetic mechanisms for the loss of CBX7 expression in BCs. Lower expression levels of CBX7 are significantly associated with shorter overall, disease-free, and distant metastasis-free survival of patients with BC. These prognostic impacts of CBX7 are independent of estrogen receptor status and PAM50 molecular subtypes. Coexpression analysis identified 207 genes consistently coexpressed with CBX7 (157 negatively and 50 positively). Gene Ontology, KEGG, and Reactome enrichment analysis revealed that cell cycle‑, DNA replication‑, and mitosis-related pathways are significantly overrepresented within the set of CBX7 negatively coexpressed genes, suggesting that CBX7 functions as a suppressor of the cell cycle. Moreover, transcription factor enrichment analysis detected the E2F family of transcription factors significantly associated with CBX7 negatively coexpressed genes, consistent with E2F function regulating the cell cycle. Furthermore, we found that loss of CBX7 expression significantly increases genomic instability and tumor mutation burden. Our findings indicate that CBX7 acts as a tumor suppressor in BC through its potential role in the negative regulation of cell proliferation and the maintenance of genome integrity.

Postoperative Radiotherapy Involving Tumor Bed with or without Elective Nodal Irradiation in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma: A Multi-Center, Prospective Randomized Phase II Trial

<h3>Purpose/Objective(s)</h3> Postoperative radiotherapy (PORT) is necessary in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) who have not received neoadjuvant chemoradiotherapy (NCRT). However, the optimal clinical target volume has under hot debate for decades. This clinical trial aims to estimate the optimal radiation volume of PORT for patients with LA-ESCC. <h3>Materials/Methods</h3> Patients confirmed LA-ESCC (pT3-4N0-3M0) after esophagectomy without NCRT were randomly assigned to either large-field irradiation (LFI, primary lesion and lymph node tumor bed plus elective nodal irradiation) arm or small-field irradiation (SFI, primary lesion and lymph node tumor bed alone) arm with a ratio of 1:1, stratified by T stage and number of lymph node metastasis (LN<3 vs LN≥3). The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS), adverse events and first failure patterns. The log-rank test was used to estimate the survival differences. The Chi-square test was used to compare adverse events and failure patterns between groups. <h3>Results</h3> In the intention-to-treat analysis, a total of 401 patients with LA-ESCC were randomly assigned to the LFI arm (n=210) and the SFI arm (n=191). With a median follow-up of 38.9 months, the DFS and OS rates of the whole population at 1-year and 3-year were 72.9% and 51.8%, 88.4% and 61.7%, respectively, which were close to patients who received NCRT. Patients in the two irradiation arms had similar DFS (LFI vs SFI, 46.6 vs 48.1 months; HR=0.92, 95% CI, 0.68-1.25; p=0.60). The difference of OS between the two arms did not reach significant (NR vs 73.5 months, HR=0.82, 95% CI, 0.59-1.14; p=0.26). The locoregional recurrence-free survival (HR=0.57, 95% CI 0.35-0.92; p=0.022) and the failure patterns (p=0.021) between two arms were significantly different. Locoregional failure occurred in 12.9% and 20.4% of patients in the LFI arm and SFI arm, respectively; The differences of distant diseases and distant metastasis-free survival of patients between the two arms had no significance. The most frequent toxicity was grade 2 esophagitis (LFI vs SFI, 22.9% vs 16.8%). Grade 3 acute adverse events occurred in 6.7% and 2.6% of patients in the LFI and SFI arms, respectively. No toxicity of grade 4 or 5 was recorded in this study. <h3>Conclusion</h3> Both postoperative irradiation fields are alternatives for LA-ESCC patients without NCRT with the promising survival outcomes comparable to CROSS study. Patients in the LFI arm achieved better locoregional control with a safety profile consistent with the SFI arm.

ROR2 promotes epithelial-mesenchymal transition by hyperactivating ERK in melanoma.

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a protein with important functions during embryogenesis that is dysregulated in human cancer. An intriguing feature of this receptor is that it plays opposite roles in different tumor types either promoting or inhibiting tumor progression. Understanding the complex role of this receptor requires a more profound exploration of both the altered biological and molecular mechanisms. Here, we describe that ROR2 promotes Epithelial-Mesenchymal Transition (EMT) by inducing cadherin switch and the upregulation of the transcription factors ZEB1, Twist, Slug, Snail, and HIF1A, together with a mesenchymal phenotype and increased migration. We show that ROR2 activates both p38 and ERK mitogen-activated protein kinase pathways independently of Wnt5a. Further, we demonstrated that the upregulation of EMT-related proteins depends on the hyperactivation of the ERK pathway far above the typical high constitutive activity observed in melanoma. In addition, ROR2 also promoted ERK phosphorylation, EMT, invasion, and necrosis in xenotransplanted mice. ROR2 also associates with EMT in tumor samples from melanoma patients where analysis of large cohorts revealed that increased ROR2 levels are linked to EMT signatures. This important role of ROR2 translates into melanoma patient' s prognosis since elevated ROR2 levels reduced overall survival and distant metastasis-free survival of patients with lymph node metastasis. In sum, these results demonstrate that ROR2 contributes to melanoma progression by inducing EMT and necrosis and can be an attractive therapeutic target for melanoma.

Prophylactic lymphaticovenous bypass performed during complete lymphadenectomy is oncologically safe.

9557 Background: Lymphaticovenous anastomosis (LVA) is a physiologic surgery indicated for secondary lymphedema of the extremities, particularly for disease refractory to conservative management. Immediate lymphatic reconstruction (ILR) is prophylactic LVA concurrently performed with CLND. After the transected lymphatics are mapped through a dye injection, they are anastomosed to a nearby venous outflow tract. Though prophylactic LVA is increasingly being performed, its risk on cancer recurrence and distant metastasis is currently unknown. The purpose of this study was to compare the distant-metastasis free survival (DMFS) and relapse-free survival (RFS) times in melanoma patients who underwent prophylactic LVA during CLND versus those who underwent conventional CLND for grossly metastatic disease. Our study is the first prospective evaluation of the impact of prophylactic LVA on DMFS in patients undergoing CLND. Methods: This was a prospective study of patients with cutaneous melanoma who underwent CLND with concurrent LVA (LVA group) or CLND alone (comparison group) between 2012 and 2021. Patients were excluded if they had non-melanoma skin cancers, stage IV cancers before CLND, microscopic lymphatic disease only or follow-up time of less than 12 months who did not die from melanoma-related causes. The comparison group consisted of all consecutive patients that underwent CLND alone and met inclusion criteria. To reduce surgical technique variability, all cases were performed by a single, high-volume surgeon at a tertiary care center. Results: A total of 46 melanoma patients underwent prophylactic LVA during this time period. Twenty-three of these patients met all inclusion criteria and were included in the LVA group. Twenty-two consecutive patients that underwent CLND alone were included in the comparison group. All patients underwent either axillary or inguinal CLND. Average number of lymph nodes removed during CLND were 18.20 ± 9.61 and 17.04 ± 9.97 for the LVA and comparison groups, respectively (p = 0.69). Size of largest metastatic tumor in lymph nodes was 45.91 ± 35.03 mm and 44.54 ± 23.32 mm, respectively (p = 0.99). Average time to first recurrence diagnoses was 6.75 ± 3.54 months vs 8.28 ± 5.66 months. For distant metastases only, the average time to first recurrence diagnoses was 6.16 ± 3.79 months and 9.39 ± 6.19 months, respectively (p = 0.25). There was no significant difference in recurrence type between the two groups (p = 0.66). There were no differences in DMFS and RFS times between the LVA and comparison groups. Conclusions: Prophylactic LVA performed for grossly metastatic melanoma does not negatively impact DMFS nor RFS. Considering the extremely aggressive nature of melanoma, our finding is potentially applicable to other cancers that are amenable to CLND and LVA.

Prognostic Value of Dual-Time-Point [18F]FDG PET/CT for Predicting Distant Metastasis after Treatment in Patients with Non-Small Cell Lung Cancer

This study aimed to evaluate the prognostic significance of 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake in the bone marrow (BM) and primary tumors on dual-time-point (DTP) PET/CT for predicting progression-free survival (PFS) and distant metastasis-free survival (DMFS) in patients with non-small cell lung cancer (NSCLC). We retrospectively analyzed DTP [18F]FDG PET/CT images from 211 patients with NSCLC. The maximum standardized uptake value (SUV) of primary lung cancer and mean [18F]FDG uptake of the BM (BM SUV) were measured from early and delayed PET/CT images, and the percent changes in these parameters (∆maximum SUV and ∆BM SUV) were calculated. On multivariate survival analysis, the maximum SUV and BM SUV on both early and delayed PET/CT scans were significantly associated with PFS, while the ∆maximum SUV and ∆BM SUV failed to show statistical significance. For DMFS, the ∆maximum SUV and ∆BM SUV were independent predictors along with the TNM stage. Distant progression was observed only in 1.3% of patients with low ∆maximum SUV and ∆BM SUV, whereas 28.2% of patients with high ∆maximum SUV and ∆BM SUV experienced distant progression. The ∆maximum SUV and ∆BM SUV on DTP [18F]FDG PET/CT were significant independent predictors for DMFS in patients with NSCLC.

Nomogram for distant metastasis-free survival in patients with locoregionally advanced nasopharyngeal carcinoma.

To develop and validate anomogram to predict distant metastasis-free survival of patients with locoregionally advanced nasopharyngeal carcinoma. We collected the total clinical data of 820nasopharyngeal carcinoma (NPC) patients, of whom 482formed the training cohort from one hospital and 328made up the validation cohort from another hospital. By analyzing the prognosis of all patients after intensity-modulated radiotherapy by univariate and multivariate Cox regression models, anomogram related to DMFS was created in the training cohort. The discriminatory and calibration power of the nomogram was successively assessed in the training and validation cohorts by the C‑index and calibration curve. The predictive ability for 3‑year DMFS was compared between the nomogram and TNM stage using ROC curves. Patients were divided into different risk groups based on scores calculated from the nomogram. Age, lymph node gross tumor volume (GTVnd), and gross tumor volume of the nasopharynx (GTVnx) were the factors included in the nomogram. The C‑index of the nomogram was 0.721 in the training cohort and 0.750 in the validation cohort. The calibration curves were satisfactory. Patients in the high-risk group were more likely to develop metastases. Anomogram incorporating age, GTVnd, and GTVnx showed good performance for predicting DMFS in patients with locoregionally advanced NPC.

Establishment and Validation of a Novel MRI Radiomics Feature-Based Prognostic Model to Predict Distant Metastasis in Endemic Nasopharyngeal Carcinoma

PurposeWe aimed to establish a prognostic model based on magnetic resonance imaging (MRI) radiomics features for individual distant metastasis risk prediction in patients with nasopharyngeal carcinoma (NPC).MethodsRegression analysis was applied to select radiomics features from T1-weighted (T1-w), contrast-enhanced T1-weighted (T1C-w), and T2-weighted (T2-w) MRI scans. All prognostic models were established using a primary cohort of 518 patients with NPC. The prognostic ability of the radiomics, clinical (based on clinical factors), and merged prognostic models (integrating clinical factors with radiomics) were identified using a concordance index (C-index). Models were tested using a validation cohort of 260 NPC patients. Distant metastasis-free survival (DMFS) were calculated by using the Kaplan-Meier method and compared by using the log-rank test.ResultsIn the primary cohort, seven radiomics prognostic models showed similar discrimination ability for DMFS to the clinical prognostic model (P=0.070-0.708), while seven merged prognostic models displayed better discrimination ability than the clinical prognostic model or corresponding radiomics prognostic models (all P<0.001). In the validation cohort, the C-indices of seven radiomics prognostic models (0.645-0.722) for DMFS prediction were higher than in the clinical prognostic model (0.552) (P=0.016 or <0.001) or in corresponding merged prognostic models (0.605-0.678) (P=0.297 to 0.857), with T1+T1C prognostic model (based on Radscore combinations of T1 and T1C Radiomics models) showing the highest C-index (0.722). In the decision curve analysis of the validation cohort for all prognostic models, the T1+T1C prognostic model displayed the best performance.ConclusionsRadiomics models, especially the T1+T1C prognostic model, provided better prognostic ability for DMFS in patients with NPC.

Prognostic value of EGFR and p-EGFR in nasopharyngeal carcinoma: A systematic review and meta-analysis.

Purpose:To evaluate the prognostic effect and clinical significance of epidermal growth factor receptor and its phosphorlated form (EGFR/p-EGFR) in nasopharyngeal carcinoma.Methods:A systematic review and meta-analysis was designed. We visited PubMed, Embase, China National Knowledge Infrastructure Database, Database of Chinese sci-tech periodicals, WanFang Database, and China Biology Medicine disc to search for Chinese and English publications of prospective studies and retrospective studies investigating the association of EGFR/p-EGFR and nasopharyngeal carcinoma prognosis from inception to April 2021. The inclusion criteria were that the samples should be pathologically confirmed as nasopharyngeal carcinoma and the expression of EGFR/p-EGFR should be detected via immunohistochemistry; the study should analyze the prognostic significance of EGFR/p-EGFR in nasopharyngeal carcinoma; hazard ratio (HR) and 95% confidence interval (CI) should be reported in the study or could be derived from survival curves; and the outcomes of the study should include overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS).Results:A total of 18 studies evaluating 1451 samples were included. For studies that reported OS as an outcome, EGFR overexpression indicated worse OS of nasopharyngeal carcinoma patients. The heterogeneity between studies was high (I2 = 91%, P < .01), and a random-effect model was used to combine the effect size (HR = 1.71, 95% CI [1.21, 2.41], P < .01). Further sensitivity analysis and prespecified subgroup analysis were performed to detect the source of heterogeneity, and the results showed that the heterogeneity could not be eliminated. Publication bias assessed by funnel plots and Begg test and Egger test was low (Begg test: P = .846 and Egger test: P = .074). p-EGFR was not correlated with the OS of nasopharyngeal carcinoma patients (HR = 1.01, 95% CI [0.88, 1.15], P = .92). For studies that reported DFS, EGFR overexpression was associated with worse DFS in patients with nasopharyngeal carcinoma (HR = 2.53, 95% CI [1.84, 3.47], P < .01). For studies that reported PFS, EGFR overexpression was not correlated with the PFS of nasopharyngeal carcinoma patients (HR = 1.86, 95% CI [0.90, 3.82], P = .09). For studies that reported DMFS, EGFR overexpression was not correlated with the DMFS of nasopharyngeal carcinoma patients, and high heterogeneity between studies was detected (I2 = 97%, P < .01). A random-effect model was used to combine the effect size (HR = 1.80, 95% CI [0.56, 5.76], P = .32). A sensitivity analysis was conducted. Publication bias was detected to be low (Begg test: P = .817 and Egger test: P = .954). There was no correlation between p-EGFR overexpression and DMFS in patients with nasopharyngeal carcinoma (HR = 1.20, 95% CI [0.95, 1.52], P = .12).Conclusion:In nasopharyngeal carcinoma patients, EGFR overexpression could be used as a biomarker that predicts poor OS and DFS, but not a prognostic biomarker for PFS and DMFS. The overexpression of p-EGFR was not shown to be associated with the prognosis of nasopharyngeal carcinoma patients and could not be used as a prognostic biomarker.Ethics and dissemination:This study was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), and reported as stated by the Preferred Reporting Items for Systematic reviews and Meta-Analyses. Neither ethical approval nor informed consent was required since this study was conducted based on previous publications.INPLASY registration number:INPLASY 202150010

Comparison of Prognosis Between Breast Conserving Therapy and Mastectomy in Early Breast Cancer: A Propensity Score Matching Analysis

The survival benefit of breast conserving therapy (BCT) over mastectomy has been shown in recent studies. The aim of the present study is to further explore oncologic outcomes between BCT and mastectomy in modern era.Continuous patients diagnosed with stage pT1-2, pN0-1, M0 breast cancer between 2009 and 2015 in one hospital were retrospectively reviewed. Recurrence patterns were evaluated among whole breast irradiation (WBI), mastectomy-alone, WBI with RNI and PMRT. Two separate comparisons of survival outcomes were performed using 1:1 propensity score matching (PSM): WBI versus mastectomy-alone, WBI with RNI versus PMRT (including RNI).2429 patients were enrolled in this analysis. The median follow up was 72 months (range, 54 to 94 months). Compared with those treated with mastectomy, patients who received BCT were younger (P<0.001) and with smaller tumors (P = 0.000). In addition, patients with BCT were more likely to receive RNI (OR, 2.579; P = 0.001). Nonetheless, there were no differences in chemotherapy regimens between patients who received BCT and those who underwent mastectomy (OR, 1.396; P = 0.062). For first recurrence, WBI patients demonstrated the lowest rate of distant metastases (3.1%), followed by mastectomy (4.1%), WBI with RNI (7.6%), PMRT (8.3%) (P = 0.007). Besides, WBI had the lowest rate of lung, liver and brain metastases (P = 0.047). There were no significant differences in terms of locoregional recurrence (P = 0.155) or contralateral breast cancer (P = 0.807) as first recurrence. After PSM, 904 patients (452 in the WBI group and 452 in the mastectomy-alone group) and 188 patients (94 in the WBI with RNI group and 94 in the PMRT group) were included for further analysis, respectively. There was no difference between WBI group and mastectomy-alone group in terms of overall survival (OS), breast cancer specific survival (BCSS), disease free survival (DFS), distant metastasis free survival (DMFS) and regional recurrence free survival (RRFS). No significant difference of local recurrence free survival (LRFS) was found between WBI and mastectomy. In subgroup analysis, patients with grade I/II tumor had a superior DMFS over mastectomy alone (P = 0.005). The 10-year RRFS was significantly higher in patients who underwent WBI with RNI versus PMRT (100% vs 90.3%, P = 0.025). In patients≥40 years and with grade I/II tumor (n = 76), WBI with RNI group had better DFS (P = 0.035) and DMFS (P = 0.035) over PMRT.In the whole cohort, there exist differences in recurrence patterns, while no differences in overall survival between WBI and mastectomy-alone group or WBI with RNI and PMRT group. However, WBI patients did show superior DMFS in patients with grade I/II tumor over mastectomy alone. WBI with RNI group had a higher RRFS rates compared with PMRT. Patients ≥ 40 years and with grade I/II tumor had better DFS and DMFS following WBI with RNI compared with PMRT. BCT is recommended to be therapeutic choice of priority in early breast cancer.