Higher Clinical Stage Research Articles

Disulfidptosis-related prognostic signature correlates with immunotherapy response in colorectal cancer

Disulfidptosis (DSP), a form of cell death caused by disulphide stress, plays an important role in tumour progression. However, the mechanisms by which DSP regulates the tumour microenvironment remain unclear. Thus, we analysed the transcriptome profiles and clinical data, which were obtained from the TCGA database, of 540 patients with colorectal cancer. Compared with the patients with low DSP expression, those with high DSP expression exhibited significantly better survival outcomes; lower stromal and ESTIMATE scores; significantly higher numbers of CD4+ T cells, M2 macrophages, dendritic cells, and neutrophils; higher expression of immune checkpoint-related genes; and lower Tregs and HLA-DQB2 levels. A prognostic signature established based on DSP-related genes demonstrated an increase in risk score with a higher clinical stage. Risk scores negatively correlated with dendritic cells, eosinophils, and CD4+ T cells and significantly positively correlated with Treg cells. Patients with higher risk scores experienced significantly worse survival outcomes and immunotherapy non-response. Our nomogram model, combining clinicopathological features and risk scores, exhibited robust prognostic and predictive power. In conclusion, DSP-related genes actively participated in regulating the tumour microenvironment. Thus, they can serve as biomarkers to provide targeted treatment for colorectal cancer.

The role of obesity in treatment planning for early-stage cervical cancer

ObjectivesOptimal management of obese patients with early-stage cervical cancer is debated despite evidence of non-inferior survival in obese patients undergoing radical hysterectomy with pelvic lymphadenectomy (RH) compared to primary radiation with or without radiosensitizing chemotherapy (RT). Objectives included describing patient factors affecting disposition to RH versus RT; comparing RH outcomes for obese (BMI >30 mg/m2) and non-obese patients; and comparing differences in recurrence free survival (RFS) and overall survival (OS). MethodsThis was a single institution cohort study of all cervical cancer patients who underwent RH or were candidates for RH based on clinical stage. Demographic, clinicopathologic and treatment outcomes were collected and analyzed. ResultsRT patients (n = 39, 15%) had a higher BMI (p = 0.004), older age (p < 0.001), more life-limiting comorbidities (LLC) (p < 0.001), larger tumor size (p = 0.001), and higher clinical stage (p = 0.013) compared to RH patients (n = 221, 85%). On multivariable survival analysis there was no difference in OS based on treatment modality; significant predictors of worse OS were larger tumor size, higher number of LLC and recurrence. Among the RH group, obese patients had a longer operative time (p = 0.01) and more LLC (p = 0.02); there were no differences in demographic or clinicopathologic characteristics, operative outcomes, RFS or OS compared to non-obese patients. ConclusionIn this cohort of RH-eligible cervical cancer patients, BMI was independently associated with disposition to RT. Studies demonstrate that RH is feasible and safe in obese patients with no difference in RFS or OS when compared to non-obese patients. Thus, the decision for disposition to RT should not be based on obesity alone.

Advanced Pediatric-Type Follicular Lymphoma, Consequences of a Late Presentation in a Resource-Poor Setting: Case Report and Literature Review

AbstractPediatric-type follicular lymphoma (PFL) is a rare, nonaggressive, slow-growing (indolent), non-Hodgkin lymphoma that is typically seen in males as a localized disease with excellent outcomes. It is largely different from follicular lymphoma (FL). Few published studies on PFL are case series in developed nations. We report on a patient with advanced PFL, a 14-year-old female with 5-year history of neck swellings, abdominal distension for a month, and pericardial effusion, among others. The swellings waxed and waned; and involved all the peripheral lymph nodes. Tuberculosis (TB) GeneXpert and human immunodeficiency virus (HIV) screening were negative. She received anti-TB drugs prior to presentation in our hospital where nodal histopathology showed effaced architecture with diffuse follicles and abundant blastoid cells as well as negative CD5 and BCL2, and positive CD10 and CD20. Diagnosis of PFL (stage 3) was made. She completed six courses of cyclophosphamide, doxorubicin, vincristine, and prednisolone and is well 9 months after therapy. The PFL usually presents with stage 1 or 2 disease unlike in the index female case that was also complicated by effusion and ascites due to late presentation. It responded to chemotherapy and has not reoccurred; in contrast to classic FL and reactive follicular hyperplasia (RFH) which should be differentiated from PFL. Although RFH can be caused by TB or HIV, they are not causes of malignant lymphadenopathy. Physicians should be aware of PFL which may present in high clinical stages, but still retain its good prognosis, for the purposes of counseling.

Molecular and clinicopathological features of granzyme B-negative extranodal NK/T-cell lymphoma

Extranodal NK/T-cell lymphoma (ENKTL) generally expresses cytotoxic molecules, including granzyme B (GZMB), T-cell-restricted intracellular antigen-1 (TIA-1), and perforin; however, the expression of these molecules varies across cases. We performed gene expression profiling and identified unique biological and clinicopathological features of GZMB-negative ENKTL. We reviewed the clinicopathological characteristics of 71 ENKTL samples. Gene expression profiling on nine ENKTLs using multiplexed, direct, and digital mRNA quantification divided ENKTLs into Groups A (n = 7) and B (n = 2) through hierarchical clustering and t-distributed stochastic neighbor embedding. Group B was characterized by downregulation of genes associated with IL6-JAK-STAT3 signaling and inflammatory responses. GZMB mRNA expression was significantly downregulated in Group B. GZMB protein expression was evaluated with immunohistochemistry in all 71 ENKTLs, and expression data of Tyr705-phosphorylated STAT3 (pSTAT3) and MYC from our previous study was utilized. T-cell receptor gamma (TRG) gene rearrangement in the selected samples was also assessed using PCR. GZMB expression was higher in pSTAT3-positive (p = 0.028) and MYC-positive (p = 0.014) ENKTLs. Eighteen percent (13/71) of all ENKTLs were negative for GZMB (defined by positivity <10 %); patients with GZMB-negative ENKTLs were often in a higher clinical stage (p = 0.016). We observed no other correlations with clinical parameters or TRG rearrangement and no significant association between GZMB expression and survival. In conclusion, GZMB expression is highly heterogeneous in ENKTLs and is associated with the activation of the JAK-STAT3 pathway and higher MYC expression. GZMB-negative ENKTLs correlate with an advanced clinical stage, suggesting the potential utility of GZMB immunohistochemistry as a biomarker of ENKTL.

Alteration of Cadherin 3 Expression and DNA Methylation in Association with Aggressive Renal Cell Carcinoma.

Cadherins (calcium-dependent adhesion proteins) are important in cellular adhesion and may play a role in the development and progression of renal cell carcinoma (RCC). This study investigated changes in cadherin 3 (CDH3; P-cadherin) mRNA expression, DNA methylation, and protein expression in RCC and compared the results with the histopathological and clinical characteristics of patients. The possible contribution of CDH3 to tumor cell invasiveness was tested in a functional assay using siRNA-based suppression of CDH3 expression and subsequent real-time impedance analysis using a Matrigel invasion model. Our analyses revealed a tumor-specific loss of CDH3 mRNA expression, CDH3 DNA hypermethylation, and loss of distal tubular and collecting duct CDH3 protein expression in RCC. A relatively higher methylation level in tumors was associated with a loss of cell differentiation and higher clinical stage. siRNA-induced suppression of CDH3 expression modulated the invasion characteristics of tumor cells in the impedance-based real-time cellular analysis. Our results indicate that loss of CDH3 expression is common in RCC and may contribute to the pathogenesis of a subset of RCC. Further studies to reveal the mechanisms of loss of expression and its effects on the invasive behavior of renal tumor cells are required.

Lack of association between XRCC1 SNPs and acute radiation‑induced injury or prognosis in patients with nasopharyngeal carcinoma.

The response to radiation therapy (RT) is closely associated with DNA damage repair. X-ray repair cross-complementing group-1 (XRCC1) is a key gene in the DNA damage repair pathway, and SNPs in this gene alter the expression and activity of its effector protein, which may in turn affect sensitivity to RT. Therefore, the course of tumor treatment and local control rate can be influenced. In the present study, a group of 158 patients with nasopharyngeal carcinoma (NPC) who received intensity-modulated RT at Fujian Cancer Hospital (Fuzhou, China) between July 2012 and October 2013 were included in retrospective chart review and followed up. Plasma was collected before treatment for genotype analysis of the three SNPs of XRCC1, namely Arg194Trp, Arg280His and Arg399Gln. Acute radiation-induced injuries sustained during treatment was graded according to the Radiation Therapy Oncology Group scoring criteria. Post-treatment follow-up was performed until August 2020. In the 158 cases of NPC, no statistically significant association was observed between the three SNPs of the XRCC1 gene and the severity of acute radiation-induced injury or prognosis. However, the AA genotype of XRCC1-Arg399Gln tended to be associated with worse progression-free survival (PFS) compared with the GA + GG genotype, although this was not significant (P=0.069). In addition, multivariate logistic analysis showed that nodal stage was significantly associated with the occurrence of acute severe radiation-induced oral mucositis (P=0.018), and there was also a trend towards an association between nodal stage and the incidence of acute severe radiation-induced pharyngitis; however, this was not statistically significant (P=0.061). Furthermore, multivariate Cox regression analysis showed that older age, distant metastasis and higher clinical stage were independent risk factors for PFS in patients with NPC. In conclusion, relying solely on the aforementioned SNPs of the XRCC1 gene may not provide a robust enough basis to predict the response to RT or prognosis in patients with NPC.

Investigating the prognostic role of lncRNAs associated with disulfidptosis-related genes in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered programmed cell death process, is linked to the actin cytoskeleton, which plays a vital role in maintaining cell shape and survival. The role of disulfidptosis is poorly depicted in the clear cell histologic variant of RCC (ccRCC). Three sets of ccRCC cohorts, ICGC_RECA-EU (n =91), GSE76207 (n =32) and TCGA-KIRC (n =607), were included in our study, the batch effect of which was removed using the "combat" function. Correlation was calculated using the "rcorr" function of the "Hmisc" package for Pearson analysis, which was visualized using the "pheatmap" package. Principal component analysis was performed by the "vegan" package, visualized using the "scatterplot3d" package. Long non-coding RNAs (lncRNAs) associated with disulfidptosis were screened out using least absolute shrinkage and selection operator (LASSO) and COX analysis. Tumor mutation, immune landscaping and immunotherapy prediction were performed for further characterization of two risk groups. A total of 1822 disulfidptosis-related lncRNAs was selected, among which 308 lncRNAs were found to be significantly associated with the clinical outcome of ccRCC patients. We retained 11 disulfidptosis-related lncRNAs, namely, AP000439.3, RP11-417E7.1, RP11-119D9.1, LINC01510, SNHG3, AC156455.1, RP11-291B21.2, EMX2OS, AC093850.2, HAGLR and RP11-389C8.2, through LASSO and COX analysis for prognosis model construction, which displayed satisfactory accuracy (area under the curve, AUC, values all above 0.6 in multiple cohorts) in stratification of ccRCC prognosis. A nomogram model was constructed by integrating clinical factors with risk score, which further enhanced the prediction efficacy (AUC values all above 0.7 in multiple cohorts). We found that patients of male gender, higher clinical stages and advanced pathological T stage were inclined to have higher risk score values. Dactinomycin_1911, Vinblastine_1004, Daporinad_1248 and Vinorelbine_2048 were identified as promising candidate drugs for treating ccRCC patients of higher risk score value. Moreover, patients of higher risk value were prone to be resistant to immunotherapy. We developed a prognosis predicting model based on 11 selected disulfidptosis-related lncRNAs, the efficacy of which was verified in different cohorts. Furthermore, we delineated an intricate portrait of tumor mutation, immune topography and pharmacosensitivity evaluations within disparate risk stratifications.

Axillary management in breast cancer after neoadjuvant chemotherapy in the modern era: A national cancer database analysis

BackgroundAxillary management for node-positive breast cancer continues to evolve. Data further supporting targeted axillary dissection after neoadjuvant chemotherapy was published in 2016 and may have induced changes in practice. MethodsPatients included in the National Cancer Database from 2014 to 2017 with clinical T1 to T4 and node-positive disease who underwent neoadjuvant chemotherapy before surgical axillary management were evaluated. Patients were divided into the following 3 groups: selective axillary dissection, minimal axillary dissection, and maximal axillary dissection, according to surgical axillary management and pathological node status. ResultsPatients who underwent selective axillary dissection were younger (52.4 years ± 12.4, P < .0001) compared to maximal axillary dissection (55.1 ± 12.7) and minimal axillary dissection (54.6 ± 12.7). Patients with higher clinical stage more frequently underwent maximal axillary dissection, and those with lower tumor grade more frequently underwent minimal axillary dissection (P < .0001). Community cancer programs were more likely to perform maximal axillary dissection compared to all other types of programs and had the slowest rate of adoption of selective axillary dissection. Integrated Network Cancer Programs had the lowest proportion of maximal axillary dissection performed and the highest proportion of selective axillary dissection. Uninsured patients were more likely to receive maximal axillary dissection, and those with private insurance were more likely to undergo selective axillary dissection (P < .0001). Selective axillary dissection rates increased from 29.8% of procedures in 2016 to 41.5% in 2017, and MaxAD rates decreased from 62.4% in 2016 to 47.9% in 2017. ConclusionUtilization of selective axillary dissection has increased since 2016; however, discrepancies in surgical axillary management after neoadjuvant chemotherapy still exist.

Identification of pyroptosis-related lncRNA subtype and signature predicts the prognosis in bladder cancer.

Pyroptosis is a new type of programmed cell death involved in all stages of tumorigenesis. Herein, a comprehensive study was conducted to evaluate the prognostic significance of pyroptosis-related lncRNAs in bladder cancer. Consensus clustering analysis was performed to identify the subclusters of bladder cancer. The prognostic pyroptosis-related lncRNA signature was constructed using LASSO Cox regression analysis. Consensus clustering identified 2 clusters of bladder cancer. Interestingly, significant differences in the ESTIMAE score, immune cell infiltration and immune checkpoint expression were obtained between the 2 clusters. A signature consisting of 11 pyroptosis-related lncRNAs was established and it had a good performance in predicting the overall survival rate of bladder cancer, with an AUC of 0.713. Moreover, pyroptosis-related lncRNA signature acted as a risk factor in bladder cancer. Bladder cancer patients with high-risk score had a higher tumor grade and higher clinical stage. A significant correlation was obtained between the risk score and immune cell infiltration. The expression of most checkpoints was higher in bladder cancer patients with high-risk score. A novel pyroptosis-related lncRNA signature was identified with prognostic value for bladder cancer patients. Pyroptosis-related lncRNAs have a potential role in cancer immunology and may serve as prognostic or therapeutic targets in bladder cancer.

Predictors and benefits of multiagent chemotherapy for pancreatic adenocarcinoma: Timing matters.

Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS). The National Cancer Databasewas queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model. A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%;odds ratio [OR]: 0.59;p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18;95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95%CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001). Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.

Thermally boosted interstitial high-dose-rate brachytherapy in high-risk early-stage breast cancer conserving therapy - large cohort long-term results.

Early-stage high-risk breast cancer (BC) is standardly treated with breast-conserving therapy (BCT), combined with systemic therapy and radiotherapy (RT) ± tumor bed boost, e.g., with interstitial high-dose-rate brachytherapy (HDR-BT). To improve local recurrence rate (LRR), BT radiosensitization (thermal boost, TB) with interstitial microwave hyperthermia (MWHT) may be an option. The paper aims to report a retrospective single-institutional study on 5- and 10-year local control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS), overall survival (OS), cosmetic outcome (CO), and late toxicity (fibrosis, fat necrosis) after thermally enhanced HDR-BT boost to the BC tumor bed. In 2006-2018, 557 early-stage (I-IIIA) high-risk BC patients were treated with BCT. If indicated, they were administered systemic therapy, then referred for 40.0-50.0 Gy whole breast irradiation (WBI) and 10 Gy interstitial HDR-BT boost (group A). Eligible patients had a single MWHT session preceding BT (group B). Based on present risk factors (RF), medium-risk (1-2 RF) and high-risk subgroups (≥ 3 RF) were formed. Patients were standardly checked, and control mammography (MMG) was performed yearly. Breast cosmesis (Harvard scale) and fibrosis were recorded. LC, DMFS, DFS, and OS were statistically analyzed. Out of 557 patients aged 57 years (26-84), 364 (63.4%) had interstitial HDR-BT boost (group A), and 193 (34.6%) were preheated with MWHT (group B). Patients in group B had a higher clinical stage and had more RFs. The median follow-up was 65.9. Estimated 5-year and 10-year LC resulted in 98.5% and 97.5%, respectively. There was no difference in LC, DMFS, DFS, and OS between groups A and B and between extracted high-risk subgroups A and B. Five- and ten-year OS probability was 95.4% and 88.0%, respectively, with no difference between groups A and B. Harvard criteria-based CO assessment revealed good/excellent cosmesis in 74.9-79.1%. Tumor bed hardening was present in 40.1-42.2%. Asymptomatic fat necrosis-related macrocalcifications were detected in 15.6%, more frequently in group B (p = 0.016). Thermally boosted or not, HDR-BT was locally highly effective as part of combined treatment. Five- and ten-year LC, DMFS, DFS, and OS were high and equally distributed between the groups, although TB was prescribed in more advanced one with more RFs. TB did not influence CO and fibrosis. TB added to late toxicity regarding asymptomatic fat necrosis detected on MMG.

The Impact of Mutations of BRCA1/2 Genes in Patients with Breast Cancer on Treatment Outcomes Following Radiation Therapy (RT)

BRCA1/2 mutations in isolated cancer cells have been shown to enhance radiosensitivity, but it is not known if similar mutations in breast cancer (BC) patients yield improved responses to RT. We analyzed a large, national, previously unexamined dataset to determine if patients with BRCA1/2 mutations receiving RT achieve longer disease-free survival (DFS) and overall survival (OS) than patients with wild-type (WT) BRCA genes. The study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to select patients with Stage 0-III BC. Patients with known BRCA1/2 status were eligible if treated with RT≤ 1 year from diagnosis. Demographic data for patients with mutated and WT BRCA1/2 were compared using ANOVA and Chi-square tests. DFS was calculated from the start of RT until local/ distant recurrence or death and censored after the last clinic visit. Kaplan Meier estimates and multivariable Cox-proportional models (MVA) were used to compare DFS and OS for mutated and WT BRCA1/2 patients, for clinical stage, biomarkers (ER/PR/HER2), and surgery type (lumpectomy vs mastectomy). The study group of 1561 Stage 0-III BC patients included 1482 patients (95%) with WT BRCA and 79 patients (5%) with BRCA1/2 mutations (31 patients with a mutation of BRCA1, 46 patients with a mutation of BRCA2, and 2 patients with both mutations). Patients with BRCA1/2 mutations were younger (median: 51 vs 56, p = 0.004), diagnosed at higher clinical stage (Stage 0: 0% vs 0.2%, I: 31.6% vs 48.5%, II: 48.1% vs 34.0%, III: 20.3 vs 17.4%, p = 0.016), and more often grade 3 (60.8% vs 39.9%, p<0.001) than those with WT BRCA. Mastectomy was performed more often for patients with BRCA1/2 mutations (60.8% vs 31.5%, p<0.001). When BRCA1 and BRCA2 mutations were compared, BRCA1 patients were younger (median: 44 vs 52, p = 0.006), more often ER/PR negative (51.6% vs 13%, p<0.001), and had higher stage tumors (T1: 32.3% vs 47.8%; T2: 38.7% vs 28.3%, p = 0.032). On MVA, comparison of BRCA1/2 mutations vs WT BRCA identified no differences in DFS or OS. In spite of pre-clinical data demonstrating increased radiosensitivity for BRCA1/2-mutated BC cells lines, this large, previously unexamined dataset found BRCA1/2 mutations did not predict an improved OS or DFS for patients who received RT. When compared with WT BRCA patients, patients with BRCA1/2 mutations were found to have tumors of higher grade and clinical stage and to undergo more mastectomies. In a comparison with BRCA2-mutated patients, patients with mutations of BRCA1 were younger, more often ER/PR negative, and more likely to have high-stage tumors. The survival data and the advanced stage of BRCA1/2-mutated tumors suggest that the effect of BRCA1/2 mutations on radiosensitivity in vitro may be nullified by the aggressive behavior of BRCA1/2-mutated tumors in vivo.

High hsa_circ_0081621 expression indicates a poor prognosis of laryngeal squamous cell carcinoma: A bioinformatics analysis and retrospective clinical study.

Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumour of the head and neck with a low 5-year survival rate. There is need to identify novel biomarkers for diagnosis and treatment of LSCC. The present study identified differentially expressed circular RNAs (circRNAs/circs) in LSCC and larynx adjacent non-carcinoma epithelial specimens by analysing the circRNA microarray dataset GSE117001. hsa_circ_0081621 had highest expression among three circRNAs (hsa_circ_0015211, hsa_circ_0023326 and hsa_circ_0081621) in LSCC specimens by reverse transcription-quantitative PCR. The expression levels of hsa_circ_0081621 in 67 LSCC specimens were detected by fluorescence in situ hybridization (FISH). Expression levels of hsa_circ_0081621 were analysed in relation to clinicopathological parameters and prognosis of patients with LSCC. According to FISH results, 59.7% of LSCC specimens exhibited high hsa_circ_0081621 expression. In LSCC specimens, hsa_circ_0081621 high expression was associated with lymph node metastasis and high clinical stage. High expression levels of hsa_circ_0081621 were associated with a poor 5-year overall survival rate in patients with LSCC. In addition, high hsa_circ_0081621 expression was an independent prognostic factor for patients with LSCC. hsa_circ_0081621 may participate in malignant progression of LSCC, and its high expression could be used for prognostic assessment of patients with LSCC.

The multifaceted roles of matrix metalloproteinases in lung cancer.

Though the matrix metalloproteinases (MMPs) are widely investigated in lung cancer (LC), however, almost no review systematically clarify their multi-faced roles in LC. We investigated the expression of MMPs and their effects on survival of patients with LC, the resistance mechanisms of MMPs in anti-tumor therapy, the regulatory networks of MMPs involved, the function of MMPs inducing CSCLs, MMPs-related tumor immunity, and effects of MMP polymorphisms on risk of LC. High expression of MMPs was mainly related to poor survival, high clinical stages and cancer metastasis. Role of MMPs in LC are multi-faced. MMPs are involved in drug resistance, induced CSCLs, participated in tumor immunity. Besides, MMPs polymorphisms may increase risk of LC. MMPs might be promising targets to restore the anti-tumor immune response and enhance the killing function of nature immune cells in LC.

The Diagnostic Performance of Tumor Stage on MRI for Predicting Prostate Cancer-Positive Surgical Margins: A Systematic Review and Meta-Analysis.

Surgical margin status in radical prostatectomy (RP) specimens is an established predictive indicator for determining biochemical prostate cancer recurrence and disease progression. Predicting positive surgical margins (PSMs) is of utmost importance. We sought to perform a meta-analysis evaluating the diagnostic utility of a high clinical tumor stage (≥3) on magnetic resonance imaging (MRI) for predicting PSMs. A systematic search of the PubMed, Embase databases, and Cochrane Library was performed, covering the interval from 1 January 2000 to 31 December 2022, to identify relevant studies. The Quality Assessment of Diagnostic Accuracy Studies 2 method was used to evaluate the studies' quality. A hierarchical summary receiver operating characteristic plot was created depicting sensitivity and specificity data. Analyses of subgroups and meta-regression were used to investigate heterogeneity. This meta-analysis comprised 13 studies with 3924 individuals in total. The pooled sensitivity and specificity values were 0.40 (95% CI, 0.32-0.49) and 0.75 (95% CI, 0.69-0.80), respectively, with an area under the receiver operating characteristic curve of 0.63 (95% CI, 0.59-0.67). The Higgins I2 statistics indicated moderate heterogeneity in sensitivity (I2 = 75.59%) and substantial heterogeneity in specificity (I2 = 86.77%). Area, prevalence of high Gleason scores (≥7), laparoscopic or robot-assisted techniques, field strength, functional technology, endorectal coil usage, and number of radiologists were significant factors responsible for heterogeneity (p ≤ 0.01). T stage on MRI has moderate diagnostic accuracy for predicting PSMs. When determining the treatment modality, clinicians should consider the factors contributing to heterogeneity for this purpose.

Clinical application of the 21-gene oncotype recurrence score in an older cohort: A single center experience

BackgroundIn early luminal breast cancer, the Oncotype DX® Recurrence Score (RS) prognostic and predictive value with regards to chemotherapy (CHT) application benefit has been broadly validated. In older patients its value has not been deeply addressed. This study aimed to evaluate the benefits of RS testing and to look at differences in treatment allocation for these patients when compared with younger ones. MethodsWe included data from consecutive patients with early luminal HER2-negative breast cancer, treated between 2010 and 2022 at the University Hospital Basel and Cantonal Hospital Baselland, Switzerland. The older cohort included 63 (19%) patients aged ≥70, and the younger cohort 263 (81%) patients aged <70. ResultsOlder breast cancer patients had more co-morbidities (N = 36, 57% vs. N = 92, 35%, p = 0.002) and a higher clinical risk status (N = 49, 78% vs. N = 155, 59%; p = 0.01) when compared to younger patients. Histopathologic characteristics were significantly different between the two cohorts. Although older patients had a higher clinical risk status (78% vs. 59%) (p = 0.01), most of them (74%) received no CHT. Specifically, adjuvant CHT was administered less frequently in older than in younger patients (13% vs. 22%; p = 0.01). Moreover, older patients were less likely to complete CHT (>4 cycles: 78% vs. 97%). ConclusionBreast cancer patients aged ≥70 have higher clinical risk status, more co-morbidities, higher clinical stage (driven by larger tumor size), and more often RS ≥26. However, they receive fewer adjuvant RT and CHT than those aged <70. RS maintains its independent prognostic value in older patients. However, assessing the predictive value of additional CHT benefit remains challenging due to significant differences in CHT administration. Although therapy decision-making in older patients with breast cancer still follows RS-based guidelines, clinical practice indicates an individualized treatment approach.

A novel machine learning-based programmed cell death-related clinical diagnostic and prognostic model associated with immune infiltration in endometrial cancer.

To explore the underlying mechanism of programmed cell death (PCD)-related genes in patients with endometrial cancer (EC) and establish a prognostic model. The RNA sequencing data (RNAseq), single nucleotide variation (SNV) data, and corresponding clinical data were downloaded from TCGA. The prognostic PCD-related genes were screened and subjected to consensus clustering analysis. The two clusters were compared by weighted correlation network analysis (WGCNA), immune infiltration analysis, and other analyses. The least absolute shrinkage and selection operator (LASSO) algorithm was used to construct the PCD-related prognostic model. The biological significance of the PCD-related gene signature was evaluated through various bioinformatics methods. We identified 43 PCD-related genes that were significantly related to prognoses of EC patients, and classified them into two clusters via consistent clustering analysis. Patients in cluster B had higher tumor purity, higher T stage, and worse prognoses compared to those in cluster A. The latter generally showed higher immune infiltration. A prognostic model was constructed using 11 genes (GZMA, ASNS, GLS, PRKAA2, VLDLR, PRDX6, PSAT1, CDKN2A, SIRT3, TNFRSF1A, LRPPRC), and exhibited good diagnostic performance. Patients with high-risk scores were older, and had higher stage and grade tumors, along with worse prognoses. The frequency of mutations in PCD-related genes was correlated with the risk score. LRPPRC, an adverse prognostic gene in EC, was strongly correlated with proliferation-related genes and multiple PCD-related genes. LRPPRC expression was higher in patients with higher clinical staging and in the deceased patients. In addition, a positive correlation was observed between LRPPRC and infiltration of multiple immune cell types. We identified a PCD-related gene signature that can predict the prognosis of EC patients and offer potential targets for therapeutic interventions.

Clinicoradiological parameters predicting operative difficulty in laparoscopic partial nephrectomy for renal tumors.

The number of renal tumors amenable to laparoscopic surgery is rising, both, due early detection by improved imaging techniques and due to progressive improvements in minimal access surgery. Conversion to open surgery, which is a significant event, can be minimized by proper case selection. We assessed the pre-operative factors that can predict the operative difficulty and can help in case selection, thus avoiding complications and reducing the chances of conversion to open. One hundred and sixteen patients (73 males and 43 females) with the mean age of 50.78 ± 14.2 years, meeting the inclusion criteria underwent transperitoneal laparoscopic partial nephrectomy (LPN). Various clinical, anthropometric, radiological, and pathological parameters were recorded. Intraoperative difficulty was assessed and graded on a scale of 1 (easiest) to 4 (most difficult or open conversion) by an independent observer to calculate the difficulty score, which along with the other parameters of operative difficulty, was used to calculate the difficulty scale. Significant parameters on the univariate analysis, were subjected to a multivariate analysis, to find parameters that can predict the operative difficulty. The mean age was 52 ± 14.29 years, mean size was 4 ± 1.04 cm, male:female ratio was 1.6:1, most of the tumors were exophytic (60%) and anteriorly located (62%) and had a mean perinephric fat surface density (PnFSD) of 6446.026 ± 2244 surface density pixel units (SDPU). On the univariate analysis, age >60 years, Eastern Cooperative Oncology Group performance score >1, presence of perinephric fat stranding, increased PnFSD (>10,000 SDPU), large tumor size (>4 cm), hilar/posterior location, endophytic tumors and higher clinical stage were significantly associated with intraoperative difficulty. However, on the multivariate analysis, no single factor could independently predict intraoperative difficulty in LPN for Renal tumors. It is difficult to predict the intra-operative difficulty during LPN. Feasibility of LPN should be based on multiple factors rather than a single factor.

In Vivo Microstructure Imaging in Oropharyngeal Squamous Cell Carcinoma Using the Random Walk With Barriers Model.

Apparent diffusion coefficient is not specifically sensitive to tumor microstructure and therapy-induced cellular changes. To investigate time-dependent diffusion imaging with the short-time-limit random walk with barriers model (STL-RWBM) for quantifying microstructure parameters and early cancer cellular response to therapy. Prospective. Twenty-seven patients (median age of 58 years and 7.4% of females) with p16+/p16- oropharyngeal/oral cavity squamous cell carcinomas (OPSCC/OCSCC) underwent MRI scans before therapy, of which 16 patients had second scans at 2 weeks of the 7-weeks chemoradiation therapy (CRT). 3-T, diffusion sequence with oscillating gradient spine echo (OGSE) and pulse gradient spin echo (PGSE). Diffusion weighted images were acquired using OGSE and PGSE. Effective diffusion times were derived for the STL-RWBM to estimate free diffusion coefficient D0 , volume-to-surface area ratio of cellular membranes V/S, and cell membrane permeability κ. Mean values of these parameters were calculated in tumor volumes. Tumor microstructure parameters were compared with clinical stages of p16+ I-II OPSCC, p16+ III OPSCC, and p16- IV OCSCC by Spearman's rank correlation and with digital pathological analysis of a resected tissue sample. Tumor microstructure parameter responses during CRT in the 16 patients were assessed by paired t-tests. A P-value of <0.05 was considered statistically significant. The derived effective diffusion times affected estimated values of V/S and κ by 40%. The tumor V/S values were significantly correlated with clinical stages (r = 0.47) as an increase from low to high clinical stages. The in vivo estimated cell size agreed with one from pathological analysis of a tissue sample. Early tumor cellular responses showed a significant increase in D0 (14%, P = 0.03) and non-significant increases in κ (56%, P = 0.6) and V/S (10%, P = 0.1). Effective diffusion time estimation might impact microstructure parameter estimation. The tumor V/S was correlated with OPSCC/OCSCC clinical stages. 1 TECHNICAL EFFICACY STAGE: 1.

Dual-targeted and dual-sensitive self-assembled protein nanocarrier delivering hVEGI-192 for triple-negative breast cancer

Breast cancer is a highly prevalent malignancy worldwide among women with an increasing incidence in recent years. Triple-negative breast cancer (TNBC), a specific type of breast cancer, occurs primarily in young women and exhibits large tumor size, high clinical stage, and extremely poor prognosis with a high rate of lymph node, liver, and lung metastases. TNBC is insensitive to endocrine therapy and trastuzumab treatment, and there is an urgent need for effective therapeutics and treatment guidelines. However, investigations into antiangiogenic agents for the treatment of TNBC are ongoing. In this study, we successfully engineered a self-assembled protein nanocarrier TfRBP9-hVEGI-192-ELP fusion protein (TVEFP) to deliver the therapeutic protein, human vascular endothelial growth inhibitor (hVEGI-192). This was found to be effective in inhibiting tumor angiogenesis in vivo. The protein nanocarrier effectively inhibited the progression of TNBC in vivo and showed the behavior of self-assembly, thermoresponsiveness, enzyme stimulation-responsiveness, tumor-targeting, biocompatibility, and biodegradability. Near-infrared imaging studies showed that fluorescent dye-stained TVEFP effectively aggregated at the tumor site. The TVEFP nanocarrier significantly expands the application of the therapeutic protein hVEGI-192 and improves the imaging and biotherapeutic effects in TNBC, chiefly based on anti-angiogenesis effects.