Clinicopathological Risk Research Articles

Establishment of a Novel Risk Stratification System Integrating Clinical and Pathological Parameters for Prognostication and Clinical Decision‐Making in Early‐Stage Cervical Cancer

ABSTRACTBackgroundHighly heterogeneity and inconsistency in terms of prognosis are widely identified for early‐stage cervical cancer (esCC). Herein, we aim to investigate for an intuitional risk stratification model for better prognostication and decision‐making in combination with clinical and pathological variables.MethodsWe enrolled 2071 CC patients with preoperative biopsy‐confirmed and clinically diagnosed with FIGO stage IA‐IIA who received radical hysterectomy from 2013 to 2018. Patients were randomly assigned to the training set (n = 1450) and internal validation set (n = 621), in a ratio of 7:3. We used recursive partitioning analysis (RPA) to develop a risk stratification model and assessed the ability of discrimination and calibration of the RPA‐derived model. The performances of the model were compared with the conventional FIGO 2018 and 9th edition T or N stage classifications.ResultsRPA divided patients into four risk groups with distinct survival: 5‐year OS for RPA I to IV were 98%, 95%, 85.5%, and 64.2%, respectively, in training cohort; and 99.5%, 93.2%, 85%, and 68.3% in internal validation cohort (log‐rank p < 0.001). Calibration curves confirmed that the RPA‐predicted survivals were in good agreement with the actual survivals. The RPA model outperformed the existing staging systems, with highest AUC for OS (training: 0.778 vs. 0.6–0.717; internal validation: 0.772 vs. 0.595–0.704; all p < 0.05), and C‐index for OS (training: 0.768 vs. 0.598–0.707; internal validation: 0.741 vs. 0.583–0.676; all p < 0.05). Importantly, there were associations between RPA groups and the efficacy of treatment regimens. No obvious discrepancy was observed among different treatment modalities in RPA I (p = 0.922), whereas significant survival improvements were identified in patients who received adjuvant chemoradiotherapy in RPA II–IV (p value were 0.028, 0.036, and 0.024, respectively).ConclusionWe presented a validated novel clinicopathological risk stratification signature for robust prognostication of esCC, which may be used for streamlining treatment strategies.

Society of Surgical Oncology Consensus Statement: Assessing the Evidence for and Utility of Gene Expression Profiling of Primary Cutaneous Melanoma.

Gene expression profiling (GEP) of primary cutaneous melanoma aims to offer prognostic and predictive information to guide clinical care. Despite limited evidence of clinical utility, these tests are increasingly incorporated into clinical care. A panel of melanoma experts from the Society of Surgical Oncology convened to develop recommendations regarding the use of GEP to guide management of patients with melanoma. The use of currently available GEP tests were evaluated in three clinical scenarios: (1) the utility in patient selection for sentinel lymph node biopsy; (2) the utility to guide surveillance; and (3) the utility to inform adjuvant therapy. As a basis for these recommendations, the panel performed a systematic review of the literature, including articles published from January 2012 until August 2023. After review of 137 articles,50met the inclusion criteria. These articles included evidence related to three available GEP tests: 31-GEP, CP-GEP, and 11-GEP. The consensus recommendations were finalized using a modified Delphi process. The panel found that current evidence often fails to account for known clinicopathologic risk factors and lacks high-level data. The panel recognizes that thestudy of GEP tests is still evolving. The integration of GEP into routine clinical practice for predicting sentinel lymph node status and patient prognosis in melanoma is therefore not currently recommended. At present, GEP should be considered primarily an investigational tool, ideally used in the context of clinical trials or specialized research settings.

Evaluation of Circulating Tumor DNA and Carcinoembryonic Antigen Levels and Relationship with Clinicopathological Risk Factors and Prognostic Indices in Colorectal Cancer Patients

Objective: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. ctDNA has emerged as a promising biomarker for CRC management, offering real-time insights into tumor burden and genetic mutations. This study investigates the correlation between CEA levels, ctDNA, clinicopathological factors, and treatment outcomes in early and advanced CRC patients. Methods: The study retrospectively analyzed data from CRC patients, including early-stage disease and metastatic disease. ctDNA levels, demographic data, and clinical parameters such as CEA, inflammatory indexes, and tumor characteristics were evaluated to determine correlations with treatment outcomes. Results: The study included 20 patients, with 60% diagnosed at the metastatic stage. The study found no statistically significant correlation between ctDNA levels and disease stage, recurrence, or overall survival. While CEA and ctDNA levels were measured, they did not demonstrate a significant relationship with treatment outcomes. Notably, ctDNA levels were higher in metastatic patients, though this was not statistically significant. Conclusion: Despite its potential, the integration of ctDNA as a routine biomarker in CRC care faces challenges, including variability in measurement techniques and cost-effectiveness. However, ctDNA's ability to guide personalized treatment strategies and monitor disease recurrence holds promise. The study's findings align with previous research, suggesting ctDNA as a poor prognostic indicator, though further research is needed. ctDNA represents a significant advance in CRC management, offering non-invasive, real-time insights into tumor dynamics. Ongoing research is expected to solidify its role in personalized treatment planning, potentially leading to more effective and tailored therapies for CRC patients.

Is early-onset colorectal cancer an evolving pandemic? Real-world data from a tertiary cancer center.

Early onset Colorectal Cancer (EOCRC), defined as those diagnosed under the age of 50, has been increasing rapidly since 1970. UK data on EOCRC are currently limited and better understanding of the condition is needed. A single-center retrospective study of patients with EOCRC treated over 9 years (2013-2021) at a large UK cancer center was performed. Clinicopathological features, risk factors, molecular drivers, treatment, and survival were analyzed. In total, 203 patients were included. A significant increase in cases was reported from 2018-2019 (n = 33) to 2020-2021 (n = 118). Sporadic EOCRC accounted for 70% of cases and left-sided tumors represented 70.9% (n = 144). Median duration of symptoms was 3 months, while 52.7% of the patients had de-novo metastatic disease. Progression-free survival after first-line chemotherapy was 6 months (95% CI, 4.85-7.15) and median overall survival (OS) was 38 months (95% CI, 32.86-43.14). In the advanced setting, left-sided primary tumors were associated with a median OS benefit of 14 months over right-sided primaries (28 vs 14 months, P = .009). Finally, primary tumor resection was associated with median OS benefit of 21 months compared with in situ tumors (38 vs 17 months, P < .001). The incidence of EOCRC is increasing, and survival outcomes remain modest. Raising public awareness and lowering the age for colorectal cancer screening are directions that could improve EOCRC clinical outcomes. There is also a need for large prospective studies to improve the understanding of the nature of EOCRC and the best therapeutic approaches.

Association between pathological T1 colorectal cancer with lymphoid follicular replacement and risk of lymph node metastasis

AbstractBackground and AimEndoscopic resection (ER) is widely performed to treat early colorectal cancer. However, additional surgery for pathological T1 colorectal cancer (pT1CRC) after ER is controversial because of the imprecise prediction of lymph node metastasis (LNM). Recently, several patients of pT1CRC with lymphoid follicular replacement (LFR) without LNM have been reported. This study aimed to investigate the clinicopathological features and risk of LNM in patients with pT1CRC with LFR.MethodsWe retrospectively analyzed patients who underwent ER or surgical resection and were diagnosed with pT1CRC between January 2010 and December 2020. We defined pT1CRC with LFR as the replacement of a part of the lymphoid follicular component within the submucosal area by adenocarcinoma, with no invasion into other submucosal areas.ResultsAmong the 600 eligible patients, the incidence rate of pT1CRC with LFR was 6.7% (40/600). Patients with pT1CRC with LFR represented 14.3% (37/258) of the endoscopically treated patients and 0.9% (3/342) of the surgically treated patients. For patients with pT1CRC with LFR, 80.0% (32/40) had flat and depressed lesions, and 35.0% (14/40) had submucosal invasion depth ≥1000 μm. Patients with pT1CRC with LFR had negative lymphovascular invasion, differentiated type, and budding grade 1. In the median follow‐up of 61 months, patients with pT1CRC with LFR had no LNM.ConclusionsThe presence of LFR in pT1CRC may be associated with a low risk of LNM. In patients with pT1CRC with LFR, follow‐up without additional surgery is possible even if the submucosal invasion depth is ≥1000 μm.

Immunoprognostic analysis of indoleamine 2,3-dioxygenase 1 in patients with cervical cancer.

The incidence of cervical cancer is increasing. Immunotherapies show better patient outcomes than monotherapies; however, the mainstay treatment for cervical cancer remains surgery and chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) acts on multiple tryptophan substrates, exhibiting antitumor, immunomodulatory, and antioxidant activities. Despite the association of elevated IDO1 expression with unfavorable outcomes in various cancers, its precise function in cervical cancer remains ambiguous. Here, we explored the prognostic significance of IDO1 in cervical carcinoma. Gene expression datasets were obtained from The Cancer Genome Atlas. Gene Expression Omnibus datasets were used for differential expression and functional correlation analyses. Using Human Protein Atlas alongside Tumor-Immune System Interaction Database, we assessed the association of IDO1 with survival rates. Given the link between cervical cancer prognosis and immune invasion, CIBERSORT was used to assess the connection between immune cells and IDO1, while the percentage of tumor-penetrating immune cells based on IDO1 expression in cervical cancer patients was analyzed using Tumor-Immune System Interaction Database. Incorporating a clinicopathological characteristic-based risk score model with IDO1 risk score, we devised a nomogram to predict cervical cancer patient survival. The effects of IDO1 in immune regulation and its prognostic significance were validated using data from patients with cervical cancer obtained from The Cancer Imaging Archive database. Compared with that in normal cervical tissues, IDO1 expression was significantly upregulated in cervical cancer tissues and significantly correlated with cervical cancer progression and prognosis. IDO1 expression showed a positive association with monocyte and macrophage abundance, while exhibiting a negative correlation with that of endothelial cells and eosinophils. Cox regression analyses highlighted IDO1 as the core immune gene implicated in cervical cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed an association of IDO1 with the metabolic pathways of tryptophan, phenylalanine, and tyrosine. Univariate and multivariate analyses revealed that elevated IDO1 expression correlates markedly with cervical cancer outcomes, suggesting it as a promising therapeutic target. The Cancer Imaging Archive data analysis revealed that the impact of anti-PD1 and CTLA4 therapy is more pronounced in cervical cancer patients exhibiting elevated IDO1 expression. IDO1 is a potential target for immunotherapy for cervical cancer.

Risk factors for unclear margin in cold snare polypectomy for colorectal polyp.

Cold snare polypectomy (CSP) is a common, simple, and safe procedure; however, it has a high rate of unclear margins. We analyzed the risk factors for unclear margins of colorectal polyp. We retrospectively investigated colorectal polyps treated with CSP between July 2021 and July 2022, excluding those that could not be retrieved or pathologically nonneoplastic and hyperplastic polyps without margin evaluation. The clinicopathological features and risk factors for unclear margins were analyzed. Furthermore, the polyps were divided into two groups: those resected by experts and those resected by trainees. A 1 : 1 propensity score matching was performed. After matching, the risk factors for unclear margins in each group were analyzed as secondary outcomes. We analyzed 237 patients with 572 polyps; the margins were negative in 58.6% (negative group) and unclear in 41.4% (unclear group). The unclear margin was significantly higher at straddling folds (P = 0.0001), flexure points (P = 0.005), and in the procedures performed by trainees (P < 0.0001). Altogether, 198 propensity score matched pairs were explored for secondary outcomes. There were no significant differences in risk factors for unclear margins in the expert group, while in the trainee group, the unclear margin was significantly higher at the straddling folds (P = 0.0004) and flexure points (P = 0.005). We demonstrated that straddling folds, flexure points, and procedures performed by the trainees were significant risk factors for unclear margins, and we hypothesized that the rate of unclear margins will reduce as the trainees accumulate experience at difficult sites.

Dermatofibrosarcoma Protuberans: An Updated Review of the Literature.

Dermatofibrosarcoma protuberans (DFSP) is a rare proliferative condition representing skin sarcomas which is known to locally recur yet very rarely metastasizes. Its genetic background is a reciprocal translocation t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion. Complete resection is the primary treatment. The aim of this review is to outline the pathogenesis, diagnosis, and management of DFSP. A clear-cut distinction between low-to-moderate-grade DFSP with excellent prognosis and high-grade fibrosarcomatous DFSP with a much worse prognosis is underlined. Malignant transformation within DFSP (or high histologic grade), older age, being female, large primary tumor size (≥10 cm), narrow surgical margins of excision (<3 cm), surgical margin positivity for tumor cells, short time to recurrence, numerous recurrences, tumor that was recently rapidly enlarging, and presence of pain in the tumor have all been proposed as clinicopathological risk factors for recurrence and metastasis. A tendency for local growth and local relapses of well- and moderately differentiated DFSPs is an argument for their surgical excision, possibly combined with reconstructive surgery, even in patients of advanced age. Another main point of this review is that cases of DFSP with fibrosarcomatous transformation are a challenge and require careful medical attention. Both anatomopathological evaluation of the presence of lymphovascular space invasion and sentinel lymph node biopsy at DFSP surgery merit further study.

Clinicopathological risk factors of oral second primary tumours

BackgroundOral second primary tumours (SPTs) have a poor prognosis due to late-stage diagnosis. This study evaluates the demographic and clinicopathological risk predictors of SPTs. MethodsPatients with oral squamous cell carcinoma, carcinoma in situ, or severe dysplasia were accrued into the Oral Cancer Prediction Longitudinal study within one year post-curative treatment. Data on demographics, risk habits, and primary tumour characteristics were collected. Clinical follow-up included assessing the presence of second oral premalignant lesions (SOPLs), clinicopathological features, and the results from toluidine blue staining and fluorescence visualization. ResultsAmong 296 patients, 23 (8 %) developed SPTs. Older age at primary cancer diagnosis (P = 0.008) and a history of chewing tobacco or betel nut (P = 0.043) increased the risk of SPTs. Patients with primary tumours located at low-risk sites had an increased risk of SPTs (P = 0.004), which often presented at high-risk sites. The presence of SOPLs (P < 0.001), and multiple lesions (P = 0.017) significantly increased the risk of SPTs. Positive toluidine blue staining indicated a trend toward higher risk of SPTs, whereas fluorescence visualization did not. The median time to SPT diagnosis was 3.25 years post-treatment. ConclusionsIdentifying second or multiple oral premalignant lesions is critical for predicting the risk of SPTs regardless of their clinical or histological characteristics. Routine biopsy of these lesions should be prioritized to ensure timely diagnosis. Incorporating these risk predictors into clinical follow-up can enhance early cancer detection and improve patient outcomes.

495P Clinicopathological risk factors for prognosis and therapeutic response of primary central nervous system lymphoma in China: A single-center retrospective analysis of 118 cases

495P Clinicopathological risk factors for prognosis and therapeutic response of primary central nervous system lymphoma in China: A single-center retrospective analysis of 118 cases

Prognostic factors in post-prostatectomy salvage radiotherapy setting with and without hormonotherapy: An individual patient data analysis of randomized trials from ICECaP database

BackgroundEarly salvage radiotherapy (SRT) is the standard of care for biochemical recurrence post-prostatectomy but outcomes are heterogeneous. ObjectiveTo develop a risk scoring system based on relevant standard-of-care clinico-pathological prognostic factors for patients treated with SRT with and without hormonal therapy (HT). Design, setting, and participantsThe Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) database included three randomized trials (Individual patients’ data from 1647 subjects) assessing SRT (GETUG-AFU-16; NRG/RTOG-9601, and a subset of EORTC-22911). Outcome measurements and statistical analysisOutcomes were clinical progression (CP). metastasis free-survival (MFS) and overall survival (OS). Clinico-pathological factors, including pathological Gleason Score (GS), PSA at SRT start, margin status, persistent PSA post-RP and time from RP to SRT were evaluated by multivariable models stratified by type of treatment. Results and limitationsOn multivariable analysis PSA ≥ 0.5 ng/mL at SRT start, GS ≥ 8 and negative margin status were the three strongest prognostic factors. Three prognostic groups defined by number of these risk features (high risk: 2 or 3; intermediate risk: 1 and low risk: 0) were strongly associated with OS, MFS and CP outcomes with SRT alone or with HT. This prognostic group definition was also relevant for patients with persistent PSA post RP and for patients treated < 1 year from RP to SRT and with and without HT. ConclusionA risk score for patients receiving SRT with or without HT, using three standard-of-care clinico-pathological risk factors provides refined prognostic information for individual patient counselling. Patient summaryBy using a composite score of pathology grading (Gleason Score), PSA at start of salvage radiation and margin status data, physicians can provide patients with more refined information on the risk of a second relapse after receiving radiation to the prostate bed after a prostatectomy for a rising or persistent PSA, both with and without hormonal therapy.

Development and validation of an MRI and clinicopathological factors prediction model for low anterior resection syndrome in anterior resection of middle and low rectal cancer

ObjectiveTo validate the predictive power of newly developed magnetic resonance (MR) morphological and clinicopathological risk models in predicting low anterior resection syndrome (LARS) 6 months after anterior resection of middle and low rectal cancer (MLRC). MethodsFrom May 2018 to January 2021, 236 patients with MLRC admitted to two hospitals (internal and external validation) were included. MR images, clinicopathological data, and LARS scores (LARSS) were collected. Tumor morphology data included longitudinal involvement length, maximum tumor diameter, proportion of tumor to circumference of the intestinal wall, tumor mesorectal infiltration depth, circumferential margin status, and distance between the tumor and anal margins. Pelvic measurements included anorectal angle, mesenterial volume (MRV), and pelvic volume. Univariate and multivariate logistic regression was used to obtain independent risk factors of LARS after anterior resection Then, the prediction model was constructed, expressed as a nomogram, and its internal and external validity was assessed using receiver operating characteristic curves. ResultsThe uni- and multivariate analysis revealed distance between the tumor and anal margins, MRV, pelvic volume, and body weight as significant independent risk factors for predicting LARS. From the nomogram, the area under the curve (AUC), sensitivity, and specificity were 0.835, 75.0 %, and 80.4 %, respectively. The AUC, sensitivity, and specificity in the external validation group were 0.874, 83.3 %, and 91.7 %, respectively. ConclusionThis study shows that MR imaging and clinicopathology presented by a nomogram can strongly predict LARSS, which can then individually predict LARS 6 months after anterior resection in patients with MLRC and facilitate clinical decision-making. Clinical relevance statementWe believe that our study makes a significant contribution to the literature. This method of predicting postoperative anorectal function by preoperative measurement of MRV provides a new tool for clinicians to study LARS.

Circulating tumor DNA analysis in patients with esophageal cancer treated with neoadjuvant chemoradiotherapy followed by surgery.

69 Background: The aim of this prospectively study is to investigate circulating tumor DNA (ctDNA) as a prognostic marker for survival in locally advanced esophageal squamous cell cancer (ESCC) patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery. Methods: Serial plasma samples were collected from 68 ESCC patients treated with neoadjuvant chemoradiotherapy before surgery. ctDNA was detected before treatment, after neoadjuvant chemoradiotherapy and after surgery by personalized, next-generation sequencing assay. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for recurrence-free survival (RFS) and overall survival (OS). Results: ctDNA was detectable in 89.7%, 17.2%, and 6.9% of pretreatment, post-neoadjuvant chemoradiotherapy and post-surgery plasma samples, respectively. The conversion of ctDNA status from positive at baseline to negative at 4-6 weeks after neoadjuvant chemoradiotherapy was significantly associated with pathological complete response (pCR) ( P = 0.02). Significant worse RFS was related to detectable ctDNA after neoadjuvant chemoradiotherapy ( P = 0.008) or after surgery ( P = 0.001). Detectable ctDNA at baseline ( P = 0.01) and after surgery ( P = 0.008) were associated with worse OS. In multivariate analysis, detectable postoperative ctDNA was significantly associated with RFS ( P = 0.012) and OS ( P = 0.025) after adjusting for other clinicopathological risk factors. Conclusions: ctDNA status is a strong prognostic factor of recurrence in locally advanced ESCC patients. Consequently, ctDNA could potentially improve pre- and post-treatment risk assessment and facilitate individual therapy for ESCC patients.

CORRECT-MRD I: A clinical validation study to predict recurrence in stage II-III colorectal cancer (CRC) using a bespoke circulating tumor DNA (ctDNA) assay to detect molecular residual disease (MRD).

TPS98 Background: Despite standard of care management with surgery ± adjuvant chemotherapy treatment (ACT), &gt;30% of patients (pts) with resectable CRC recur. The presence of ctDNA in plasma after resection and after ACT, has been shown to be a strong prognostic factor for the risk of recurrence, suggesting that the presence of ctDNA in blood is molecular evidence of residual disease. As such, ctDNA analysis may enable post-surgical risk stratification for ACT decision-making, as well as detection of molecular recurrence during surveillance and subsequent early intervention. The CORRECT-I study aims to validate the association of post-definitive therapy and pre-recurrence follow-up ctDNA positivity with recurrence-free interval (RFI) in pts who have undergone complete surgical resection for stage II or III CRC. Methods: This study is a prospective, observational, multicenter study, which is open in Israel, Italy, Japan, Spain, and the UK. Pts must have pathologically confirmed stage II or III CRC, have undergone complete surgical resection, and have tissue available from the primary resection. Pts may not have started ACT prior to baseline blood draw post-surgery. Pts are asked to provide serial whole blood specimens for ctDNA analysis at a) post-surgical baseline, b) pre-recurrence follow-up visits (max 15 blood draws over max 5 years), and c) clinical recurrence. ctDNA will be analyzed with an NGS-based tumor-informed MRD assay that identifies somatic genomic alterations from DNA derived from the patient’s tumor tissue and detects a selected subset of tumor-specific (bespoke) ctDNA in their blood. The primary objective of this study is to validate the association of post-definitive therapy and serial pre-recurrence follow-up ctDNA positivity with RFI, using a Cox proportional hazards regression analysis. Further objectives include the assessment of sensitivity and specificity of the ctDNA assay, the association between ctDNA at individual timepoints and RFI, ctDNA dynamics and RFI, and the time from ctDNA positivity to clinical recurrence. A multivariable model, including ctDNA, clinicopathological risk features, serial serum CEA assessments, and recurrence risk as determined by the Oncotype Colon Recurrence Score will be fit with RFI as endpoint. The primary analysis will be conducted when ≥30 histologic and/or radiographic confirmed cases of clinical recurrence have been observed. As of April 2, 2024, 158 pts of 400 have been enrolled.

Molecular biomarkers of progression in non-muscle-invasive bladder cancer - beyond conventional risk stratification.

The global incidence of bladder cancer is more than half a million diagnoses each year. Bladder cancer can be categorized into non-muscle-invasive bladder cancer (NMIBC), which accounts for ~75% of diagnoses, and muscle-invasive bladder cancer(MIBC). Up to 45% of patients with NMIBC develop disease progression to MIBC, which is associated with a poor outcome, highlighting a clinical need to identify these patients. Current risk stratification has a prognostic value, but relies solely on clinicopathological parameters that might not fully capture the complexity of disease progression. Molecular research has led to identification of multiple crucial players involved in NMIBC progression. Identified biomarkers of progression are related to cell cycle, MAPK pathways, apoptosis, tumour microenvironment, chromatin stability and DNA-damage response. However, none of these biomarkers has been prospectively validated. Reported gene signatures of progression do not improve NMIBC risk stratification. Molecular subtypes of NMIBC have improved our understanding of NMIBC progression, but these subtypes are currently unsuitable for clinical implementation owing to a lack of prospective validation, limited predictive value as a result of intratumour subtype heterogeneity, technical challenges, costs and turnaround time. Future stepsinclude thedevelopment of consensus molecular NMIBC subtypes that mightimprove conventional clinicopathological risk stratification. Prospective implementation studies of biomarkers and the design ofbiomarker-guided clinical trials are required for the integration of molecular biomarkersinto clinical practice.

Circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers combined with clinicopathological risk has potential to better predict recurrence in stage III breast cancer treated with neoadjuvant chemotherapy: a pilot study.

The potential value of detecting epithelial-mesenchymal transition (EMT) CTCs in early breast cancer, especially during the neoadjuvant therapy period, requires further investigation. We analyzed dynamic CTC phenotype status, to improve recurrence risk stratification for patients with stage III breast cancers. We enrolled 45 patients with stage III breast cancers from 2 clinical trials undergoing neoadjuvant chemotherapy and utilized the CanPatrol CTC enrichment technique pre- and post-chemotherapy to identify CTC phenotypes, including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs, in peripheral blood samples. Kaplan-Meier analyses were conducted to explore the prognostic value of dynamic change of CTC count and the proportion of CTCs with different phenotypes. Then, redefine the risk stratification based on CTC status and clinicopathological risk in combination. Increased proportion of M + CTCs was a high-risk CTC status that was associated with decreased DFS (HR, 3.584; 95% CI, 1.057-12.15). In a combined analysis with clinicopathological risk, patients with high-risk tumors had an elevated risk of recurrence compared to patients with low-risk tumors (HR, 4.482; 95% CI, 1.246-16.12). The recurrence risk could be effectively stratified by newly defined risk stratification criteria, with 5-year DFS of 100.0%, 77.3%, and 50.0%, respectively, for low-risk, mid-risk, and high-risk patients (P = 0.0077). Finally, in the ROC analysis, the redefined risk stratification demonstrated higher predictive significance with an AUC of 0.7727, compared to CTC status alone (AUC of 0.6751) or clinicopathological risk alone (AUC of 0.6858). The proportion of M + CTCs increased after neoadjuvant chemotherapy indicating a higher risk of tumor recurrence. Combining CTC status with clinicopathological risk has potential to redefine the risk stratification of stage III breast cancers and provide improved predictions of relapse.

The impact of estrogen receptor and L1 cell adhesion molecule expression on endometrial cancer outcome correlates with clinicopathological risk group and molecular subgroup

ObjectiveTo assess the risk stratification of clinicopathologically and molecularly classified endometrial cancer based on estrogen receptor (ER) and L1 cell adhesion molecule (L1CAM) expression. MethodsThis was a retrospective study of patients who underwent primary treatment at a single tertiary center. Carcinomas were classified into 5 clinicopathological risk groups, as per European guidelines. Immunohistochemistry and polymerase-ϵ sequencing were conducted for molecular classification and determination of ER and L1CAM expression. ResultsData from 1044 patients were analyzed. The median follow-up was 67.5 months. In univariable analyses, ER expression correlated with improved disease-specific survival (DSS) in the “no specific molecular profile” (NSMP) (P < 0.001) and mismatch repair deficient (MMRd) (P = 0.002) subgroups. Negative L1CAM expression was associated with enhanced DSS in the NSMP subgroup alone (P < 0.001). ER (hazard ratio [HR] 0.18), but not L1CAM, exhibited prognostic significance within NSMP when controlling for parameters available at the time of diagnosis (tumor histotype, grade, age). ER and L1CAM were not independently associated with DSS within NSMP when controlling for parameters available after surgery (clinicopathological risk groups, age, adjuvant therapy). However, in high-risk–advanced-metastatic cases, both ER (HR 0.26) and L1CAM (HR 3.9) independently correlated with DSS. Similarly, within MMRd, ER was associated with improved DSS in high-risk–advanced-metastatic carcinomas (HR 0.42). ConclusionThe prognostic significance of ER and L1CAM varies across clinicopathological risk groups and molecular subgroups of endometrial cancer. Notably, risk assessment for high-risk–advanced-metastatic NSMP and MMRd subtype carcinomas can be refined by ER status.

The Sex and Age-Associated Infiltration of B Cells May Result in the Dimorphic Behaviors Observed in Papillary Thyroid Carcinomas.

Sex and age show a dimorphism role in the pathogenesis, lymph node metastasis, and prognostic outcomes of papillary thyroid carcinoma. This investigation endeavors to elucidate the mechanisms underlying these disparities. The clinicopathological characteristics and risk factors of lymph node metastasis were explored by analyzing the 2261 patients. The gene expression information of 497 samples from The Cancer Genome Atlas Thyroid Cancer database was used to explore the differentially expressed genes in different phenotypes. What's more, the single-cell RNA sequencing data obtained from the Gene Expression Omnibus database was used to explore the gene expression in specific cells. Multivariate logistic regression analysis showed that in male patients, a larger tumor size, extrathyroidal extension, younger age, and the presence of calcification emerged as significant predictors for lymph node metastasis (LNM)(p < 0.05). Conversely, female patients exhibited a different profile, with larger tumor size, extrathyroidal extension, younger age, calcification, and bilateral tumors being identified as key risk factors (p < 0.05). Further stratification by age demonstrated distinct patterns: among the younger cohort, a larger tumor size, extrathyroidal extension, male gender, calcification, multifocality, and the presence of Hashimoto's thyroiditis held statistical significance (p < 0.05). In contrast, the older subgroup was characterized by a larger tumor size, extrathyroidal extension, male gender, calcification, bilateral tumors, and unclear margins as salient indicators of risk (p < 0.05). In the bulk gene analysis, there were two sex-age-related differentially expressed genes with a contrary trend in tissue sources and LNM status: TCL1A and CR2. The analysis of single-cell RNA sequencing showed that the infiltration of TCL1A- and CR2-related B cells varied in different clinical subtypes. Lymph node metastasis of papillary thyroid carcinoma in different sexes and ages may have distinct patterns, and the ages-sex-related B cell infiltration might explain the dimorphism biological behavior.

Proteomic profiling improves prognostic risk stratification of the Sarculator nomogram in soft tissue sarcomas of the extremities and trunk wall.

High-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outcomes remain unknown. We analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define four risk groups. A DNA replication protein signature-Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification. DNA replication and cell cycle proteins were upregulated in high-risk versus very low-risk patients. Evaluation of the functional effects of CRISPR-Cas9 gene knockdown of proteins enriched in high-risk patients using the cancer cell line encyclopaedia database identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e-06), histology (p = 1.4e-05) and risk groups (p = 2.6e-06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy = 0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6). Risk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next-generation nomograms.

Adjuvant Therapy for Endometrial Cancer in the Era of Molecular Classification

ABSTRACT Endometrial cancer primarily undergoes surgical intervention, with adjuvant treatments such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and combined therapy investigated in randomized trials. Treatment decisions hinge on clinicopathological risk factors. Low-risk cases usually require surgery alone, whereas high-intermediate risk often benefit from adjuvant vaginal brachytherapy for enhanced local control with minimal side effects. Recent trials advocate pelvic radiotherapy for high-risk cases, particularly in Stage I–II tumors with risk factors. Chemoradiation proves advantageous for serous cancers and Stage III disease, improving recurrence-free, and overall survival. Molecular studies, notably the Cancer Genome Atlas project, identified four distinct molecular classes, transcending stages, and histological types. These molecular subtypes exhibit a stronger prognostic impact than histopathological characteristics, heralding a shift toward molecular-integrated diagnostics and treatments. Incorporating molecular factors into adjuvant strategies, including targeted therapies, marks a new paradigm in endometrial cancer management, underpinning ongoing research, and clinical trials. This review outlines current adjuvant approaches, underscores the emergence of molecular-integrated risk profiling, and touches on developments in targeted therapy.