Higher Tumor Stage Research Articles

Downregulation of CRTAC1 in Urothelial Carcinoma Promotes Tumor Aggressiveness and Confers Poor Prognosis.

Cartilage acidic protein 1 (CRTAC1) is a glycosylated calcium-binding extracellular matrix protein. The oncological functions of CRTAC1 in urothelial carcinoma (UC) of the urinary bladder (UB) and upper urinary tract (UT) have not yet been elucidated. Based on the published UBUC transcriptome data, we re-evaluated the differential expression profile of calcium ion binding-related genes (GO:0005509), and we found that CRTAC1 was the most significantly downregulated gene in UBUC progression. Therefore, we analyzed the prognostic value and biological significance of CRTAC1 expression in UC. We used immunohistochemistry to determine the CRTAC1 expression levels in 340 patients with UTUC and 295 patients with UBUC. The CRTAC1 expression was compared with the clinicopathological characteristics, and the prognostic impact of CRTAC1 on metastasis-free survival (MFS) and disease-specific survival (DSS) was evaluated. To study the biological functions of CRTAC1, the proliferation, migration, invasion, and tube formation abilities of UC-derived cells were evaluated. A low CRTAC1 expression significantly correlated with high tumor stage, high histological grade, perineural invasion, vascular invasion, nodal metastasis, and high mitotic rate (all p < 0.01). Moreover, the CRTAC1 immunoexpression status was an independent prognostic factor for MFS and DSS in UBUC and UTUC patients (all p < 0.001) in the multivariate analysis. The exogenous expression of CRTAC1 suppressed the cell proliferation, invasion, and angiogenesis, and downregulated the matrix metallopeptidase 2 (MMP2) level in BFTC909 and T24 cells. CRTAC1 may participate in progression of UC and serve as a prognostic marker for metastasis. Low CRTAC1 expression was significantly associated with aggressive UC characteristics and worse clinical outcomes. The inclusion of CRTAC1 immunoexpression in the standard pathological variables may optimize the risk stratification of patients.

Effect of Intraoperative Dexmedetomidine Use on Postoperative Delirium in the Elderly After Laryngectomy: A Randomized Controlled Clinical Trial.

To examine whether intraoperative dexmedetomidine reduces postoperative delirium (POD) in elderly patients who underwent a laryngectomy. Patients were randomly assigned to receive dexmedetomidine or a saline placebo infused during surgery. The study period was July 2020 to January 2022. Participants were elderly individuals (≥65 years) who underwent a laryngectomy. Immediately after induction of anesthesia, a 0.5 μg.kg-1 bolus of study solution was administered for 10 min, followed by a maintenance infusion of 0.2 μg.kg-1.hr-1 until the end of surgery. Patients were assessed daily for POD (primary outcome). Plasma inflammatory factors were measured at baseline, on the first postoperative day, and on the third postoperative day. In total, 304 male patients were randomized; 299 patients [median (interquartile range) age, 69.0 (67.0-73.0) years] completed in-hospital delirium assessments. There was no difference in the incidence of POD between the dexmedetomidine and control groups (21.3% [32 of 150] vs 24.2% [36 of 149], P=0.560). However, dexmedetomidine reduced POD in patients with laryngeal cancer and a higher tumor stage (21.6% vs 38.5%; OR, 0.441; 95% CI, 0.209-0.979; P=0.039). Dexmedetomidine reduced levels of C-reactive protein (CRP) (P=0.0056) and interleukin 6 (IL-6) (P<0.001) on the first and third postoperative days, respectively. More patients had intraoperative hypotension in the dexmedetomidine group (29.3% [44 of 150] vs 17.4% [26 of 149], P=0.015). Intraoperative dexmedetomidine administration did not prevent POD in patients with laryngeal cancer. Dexmedetomidine reduced serum CRP and IL-6 levels postoperatively but caused a higher occurrence of intraoperative hypotension in elderly patients after a laryngectomy.

Risk and prognostic factors in patients with colon cancer with liver metastasis.

The most common site of metastasis in patients with colon cancer is the liver. This study aimed to identify patients with colon cancer at high risk of developing liver metastasis and to explore their prognosis. The clinical characteristics, treatment methods and survival outcomes of patients diagnosed with colon cancer from 2010 to 2015 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Patients were divided into two groups according to the presence of liver metastasis, and multivariate logistic and Cox regression models were used to identify risk and prognostic factors. A total of 60,018 patients with colon cancer were selected from the SEER database. The incidence of liver metastasis was 9.2%. African American ethnicity, poor differentiation, higher tumor stage, higher lymph node ratio, and lung metastases were common factors associated with both liver metastasis risk and prognosis. Metastasectomy might improve survival among patients with colon cancer with resectable liver metastasis lesions and no other organ involvement.

Impact of Age, Race, and Gender on the Association Between Marital Status and Treatment Outcomes in Oral Tongue Squamous Cell Carcinomas.

Background: The objective of this study is to assess whether the impact of marital status on oral tongue squamous cell carcinomas (OTSCC) prognosis varied by gender, age, and race. Methods: We examined the clinicopathological variables using chi-squared tests, and we evaluated the association between survival and different variables using the methods of Kaplan-Meier. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. Results: A total of 5282 patients were analyzed. The rate of being married was higher among Asian or Caucasian, and this rate decreased with higher tumor stage. While both married male and female survivors benefit from their marital status, we found a differential in OS based on gender, with females benefiting more than males (male P = .038; female P = .009, respectively). Patients who were divorced/separated/widowed (male HR = 1.275, 95% CI: 1.085-1.499; female HR = 1.313, 95% CI: 1.083-1.593) and never married (male HR = 1.164, 95% CI: 0.983-1.378; female HR = 1.224, 95% CI: 0.958-1.565) had increased hazard of OS compared with married/partnered patients (male P = .038; female P = .009). Subgroups analysis shows that the effect of marital status was significantly associated with treatment outcome only in Caucasian patients aged 50 years or older who harbored non-metastatic disease and received surgery (P < .001). Conclusion: While there are survival benefits for married patients with OTSCC, married/partnered females may benefit more than males. Age, race, and gender could affect the correlation between marital status and survival.

Dynamic Optical Coherence Tomography of Blood Vessels in Cutaneous Melanoma-Correlation with Histology, Immunohistochemistry and Dermoscopy.

Dermoscopy adds important information to the assessment of cutaneous melanoma, but the risk of progression is predicted by histologic parameters and therefore requires surgery and histopathologic preparation. Neo-vascularization is crucial for tumor progression and worsens prognosis. The aim of this study was the in vivo evaluation of blood vessel patterns in melanoma with dynamic optical coherence tomography (D-OCT) and the correlation with dermoscopic and histologic malignancy parameters for the risk assessment of melanoma. In D-OCT vessel patterns, shape, distribution and presence/type of branching of 49 melanomas were evaluated in vivo at three depths and correlated with the same patterns in dermoscopy and with histologic parameters after excision. In D-OCT, blood vessel density and atypical shapes (coils and serpiginous vessels) increased with higher tumor stage. The histologic parameters ulceration and Hmb45- and Ki67-positivity increased, whereas regression, inflammation and PD-L1-positivity decreased with risk. CD31, VEGF and Podoplanin correlated with D-OCT vasculature findings. B-RAF mutation status had no influence. Due to pigment overlay and the summation effect, the vessel evaluation in dermoscopy and D-OCT did not correlate well. In summary, atypical vessel patterns in melanoma correlate with histologic parameters for risk for metastases. Tumor vasculature can be noninvasively assessed using D-OCT before surgery.

Differential Protein Expression Patterns of HOXA13 and HOXB13 Are Associated with Bladder Cancer Progression.

Bladder cancer is a common urological cancer and has the highest recurrence rate of any cancer. The aim of our study was to profile and characterize the protein expression of homeobox A13 (HOXA13) and homeobox B13 (HOXB13) genes in Malaysian bladder cancer patients. The protein expression of HOXA13 and HOXB13 in formalin-fixed paraffin-embedded (FFPE) bladder cancer tissues was determined by immunohistochemistry (IHC) analysis. The association between HOXA13/HOXB13 protein expression and demographic/clinicopathological characteristics of the bladder cancer patients was determined by chi-square analysis. Approximately 63.6% of the bladder cancer tissues harbored high HOXA13 expression. High HOXA13 expression was significantly associated with non-muscle invasive bladder cancer, lower tumor grade, higher number of lymph node metastases, and recurrence risk. In contrast, low HOXB13 expression (including those with negative expression) was observed in 71.6% of the bladder cancer tissues analyzed. Low HOXB13 expression was significantly associated with muscle-invasive bladder cancer, higher tumor stage, tumor grade, and metastatic risk. Both HOXA13 and HOXB13 protein expression were found to be associated with bladder tumorigenesis. The putative oncogenic and tumor suppressive roles of HOXA13 and HOXB13, respectively, suggest their potential utility as biomarkers in bladder cancer.

Prospective study to assess treatment response and predict patient prognosis by a blood-based multi-omics assay in lymphoma patients.

116 Background: Lymphoma represents a diverse group of cancer that arises from clonal proliferation of lymphocytes. Clinical existing imaging and biomarkers do not reliably predict treatment response across diverse lymphoma subtypes and treatment regimens. Only rare data show circulating tumor DNA (ctDNA) testing may perform as a good predictive biomarker for assessment of therapeutic response. We conducted a prospective study to assess treatment response and predict patient prognosis via our multi-omics assay (SeekInClarity) in lymphoma patients. Methods: SeekInClarity assay utilized common 7 protein tumor markers (PTMs) and cancer genomic hallmarks: copy number aberration (CNA) and fragment size (FS), which were analyzed by shallow whole genome sequencing, to calculate the molecular tumor burden (MTB) score. 8ml peripheral blood samples were collected from patients before and after every 2 cycles of treatment respectively, meanwhile, samples from a part of patients after 1 cycle of treatment were also collected. Results: Before treatment, 95 out of 133 patients (71.4%) were succeeded in detecting cancer signals with higher MTB scores (defined as baseline+). The proportion of patients with baseline+ was higher in patients with higher tumor stages. After 2 cycles of treatment, 39 out of 112 patients had a higher MTB score (defined as MRD+). The proportion of patients with progression in MRD+ group was significantly higher than that in MRD- group (p&lt;0.001). Meanwhile, MRD+ patients had a worse PFS than MRD- patients (p &lt;0.0001, HR: 26.4, 95% CI:8.7~80.3), regardless of tumor stages, lymphoma subtypes and treatment regimens. Among baseline+ patients, after 2 cycles of treatment the patients with MTB score decrease had a better PFS than that with MTB score increase (P&lt;0.001, HR: 7.5 95% CI:0.7~76.7). Among the baseline- group, patients who remained negative after treatment had extremely well PFS (100% PFS). As for the patients after 1 cycle of treatment, MTB value has a good concordance with that after 2 cycles of treatment which demonstrated a lead time in monitoring treatment response. 54 patients with longitudinal monitoring samples, 9(16.7%) patients were always MRD- during the treatment, who had the best PFS (100% PFS), regardless of baseline status. 11 out of 54 patients with always MRD+ had the worst PFS (p &lt; 0.05). Conclusions: This study demonstrates the clinical utility of multidimensional blood-based SeekInClarity assay in pan-cancer/pan-indication treatment response assessment and patient prognosis. After treatment, the dynamic change of MTB score and MRD status were independently associated with patient’s PFS, which indicated both could be used as biomarkers to predict the effectiveness of treatment. Compared with clinical image evaluation after 2 cycles of treatment, SeekInClarity test after 1 cycle of treatment is sufficient to assess treatment response.

Mutational profile of primary clear cell renal cell carcinoma predicts recurrence and potential candidacy for adjuvant immune checkpoint inhibition

Background: The risk of recurrence after nephrectomy for primary clear cell renal cell carcinoma (ccRCC) is estimated in daily practice solely based on clinical criteria. The aim of this study was to assess the prognostic relevance of common somatic mutations with respect to tumor aggressiveness and outcomes of ccRCC patients after definitive treatment. Methods: Primary tumors from 37 patients with ccRCC who underwent radical nephrectomy were analyzed for presence of somatic mutations using a 15-gene targeted next-generation sequencing (NGS) panel. Associations to histopathologic characteristics and outcomes were investigated in the study cohort (n=37) and validated in The Cancer Genome Atlas (TCGA) ccRCC cohort (n=451). Results: VHL was the most frequently mutated gene (51%), followed by PBRM1 (27%), BAP1 (13%), SETD2 (13%), KDM5C (5%), ATM (5%), MTOR (5%), and PTEN (3%). One-third of patients did not have any somatic mutations within the 15-gene panel. The vast majority of tumors harboring no mutations at all or VHL-only mutations (51%) were more frequently of smaller size (pT1-2) and earlier stage (I/II), whereas presence of any other gene mutations in various combinations with or without VHL was enriched in larger (pT3) and higher stage tumors (III) (p=0.02). No recurrences were noted in patients with unmutated tumors or VHL-only mutations as opposed to three relapses in patients with non-VHL somatic mutations (p=0.06). Presence of somatic mutations in PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, or PTEN genes in 451 TCGA ccRCC patients was associated with a significantly shorter disease-free survival (DFS) compared to those with unaltered tumors (q=0.01). Conclusions: Preliminary findings from this ongoing study support the prognostic value of non-VHL mutations including PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, and PTEN in primary ccRCC tumors as surrogates of earlier recurrence and potential selection for adjuvant immune checkpoint inhibition.

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.

Malignant testicular tumors in children: overview on 10years of Saudi Cancer Registry.

The aim of this study was to identify epidemiological and histopathological patterns of pediatric testicular tumor (TT) in Saudi population over 10years. Retrospective data extracted from the Saudi Cancer Registry for Saudi children diagnosed with TT from 2008 to 2017. The data collected included patient's factors as age, year of diagnosis, survival status, and tumor factors as basis of diagnosis, origin of the tumor, histopathological group and subtype, and tumor behavior, stage, and laterality. A total of 115 patients with a median age of 14 (IQR 1.5-17) were included. The primary tumor site was a normal descended testis in 98.3% (115). Yolk sac tumor was the most common 28.2% (33), followed by embryonal carcinoma in 27.4% (32) and mixed germ-cell tumors in 23.1% (27). Kaplan-Meier analysis revealed significant association between survival and the stage of the tumor (p = 0.002). However, there was a lack of significant association between survival and age groups, histopathological groups, and histopathological subtypes (p = 0.541, p = 0.609, and p = 0.733, respectively). The overall mortality rate of TT 5.2% with all deaths caused by non-seminomatous germ-cell tumor diagnosed with stage 3. The median age of the patients was 14years. Yolk sac tumors were the most common while testicular choriocarcinomas were the least in incidence. No increase in the incidence of TT was seen and the mortality rate over the 10-year period was 5.2%. Shorter survival was associated with higher tumor stage.

Role of CD93 in Health and Disease.

CD93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp), is a transmembrane glycoprotein encoded by a gene located on 20p11.21 and composed of 652 amino acids. CD93 can be present in two forms: soluble (sCD93) and membrane-bound (CD93). CD93 is mainly expressed on endothelial cells, where it plays a key role in promoting angiogenesis both in physiology and disease, such as age-related macular degeneration and tumor angiogenesis. In fact, CD93 is highly expressed in tumor-associated vessels and its presence correlates with a poor prognosis, poor immunotherapy response, immune cell infiltration and high tumor, node and metastasis (TNM) stage in many cancer types. CD93 is also expressed in hematopoietic stem cells, cytotrophoblast cells, platelets and many immune cells, i.e., monocytes, neutrophils, B cells and natural killer (NK) cells. Accordingly, CD93 is involved in modulating important inflammatory-associated diseases including systemic sclerosis and neuroinflammation. Finally, CD93 plays a role in cardiovascular disease development and progression. In this article, we reviewed the current literature regarding the role of CD93 in modulating angiogenesis, inflammation and tumor growth in order to understand where this glycoprotein could be a potential therapeutic target and could modify the outcome of the abovementioned pathologies.

Exploring the Epidemiology and Survival Trends in Pediatric Major Salivary Gland Malignancies: Insights from the National Cancer Database.

To investigate the clinicopathological, therapeutic, and survival data on pediatric major salivary gland cancers. National Cancer Database (NCDB) query from 2004 to 2018. In total, 967 cases of individuals under the age of 21 were identified. Most cancers affected the parotid gland (86%). Mucoepidermoid carcinoma (41.3%) and acinic cell adenocarcinoma (33.6%) were the most common. Tumors occurred more often from age 11 to 21, and females were more affected. Histology varied by age, gender, and race. In the 0-5 age group, mucoepidermoid carcinoma and myoepithelial carcinoma/sarcoma/rhabdomyosarcoma were the most common pathologies. In patients over 5 years old, mucoepidermoid carcinoma was the most frequent tumor in boys, while acinic cell adenocarcinoma was more common in girls. African American patients had a higher incidence of mucoepidermoid carcinoma, while White patients in the 0-5 age group had a higher incidence of myoepithelial carcinoma/sarcoma/rhabdomyosarcoma tumors. Low-grade tumors were commonly diagnosed at stage I, but the 0-5 age group had a high frequency of stage IV tumors. The overall 5-year survival rate was 94.9%, with 90% for the 0-5 years age group and 96% for the 11-15 years age group. Negative margins were associated with higher 5-year survival rates in high-stage tumors (93%) compared to positive margins (80%). Submandibular malignancies had worse 5-year survival rates across all age groups. Major salivary gland malignancies in pediatric patients exhibit variations in histopathologic characteristics by age, gender, and race. Negative margins impact 5-year survival rates, especially in high-stage tumors.

Advanced age is an independent prognostic factor of disease progression in high-risk prostate cancer: results in 180 patients treated with robot-assisted radical prostatectomy and extended pelvic lymph node dissection in a tertiary referral center

ObjectivesThis study aimed to assess more clinical and pathological factors associated with prostate cancer (PCa) progression in high-risk PCa patients treated primarily with robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection (ePLND) in a tertiary referral center.Materials and methodsIn a period ranging from January 2013 to October 2020, RARP and ePLND were performed on 180 high-risk patients at Azienda Ospedaliera Universitaria Integrata of Verona (Italy). PCa progression was defined as biochemical recurrence/persistence and/or local recurrence and/or distant metastases. Statistical methods evaluated study endpoints, including Cox’s proportional hazards, Kaplan-Meyer survival curves, and binomial logistic regression models.ResultsThe median age of included patients was 66.5 [62–71] years. Disease progression occurred in 55 patients (30.6%), who were more likely to have advanced age, palpable tumors, and unfavorable pathologic features, including high tumor grade, stage, and pelvic lymph node invasion (PLNI). On multivariate analysis, PCa progression was predicted by advanced age (≥ 70 years) (HR = 2.183; 95% CI = 1.089–4377, p = 0.028), palpable tumors (HR = 3.113; 95% CI = 1.499–6.465), p = 0.002), and PLNI (HR = 2.945; 95% CI = 1.441–6.018, p = 0.003), which were associated with clinical standard factors defining high-risk PCa. Age had a negative prognostic impact on elderly patients, who were less likely to have palpable tumors but more likely to have high-grade tumors.ConclusionsHigh-risk PCa progression was independently predicted by advanced age, palpable tumors, and PLNI, which is associated with standard clinical prognostic factors. Consequently, with increasing age, the prognosis is worse in elderly patients, who represent an unfavorable age group that needs extensive counseling for appropriate and personalized management decisions.

The conundrum of metaplastic breast cancer: a single Egyptian institution retrospective 10-year experience (2011–2020)

BackgroundMetaplastic breast cancer (MetBC) still represents a conundrum owing to its peculiar histogenesis and molecular drivers that render it extremely resistant to standard chemotherapy with ultimate dismal survival.AimDescribe the Egyptian National Cancer Institute’s (NCI-E) experience with MetBC regarding its clinicopathologic features, treatment, and survival outcomes.Patients and methodsBetween 2011 and 2020, all MetBC patients presented to NCI-E were retrospectively evaluated. Original clinicopathologic data, therapeutic modalities, pathologic response to neoadjuvant chemotherapy (NACT), recurrence, and date of last follow-up/death were obtained from archived charts.ResultsA cohort of 135 females, the median age was 52 years, and median follow-up period was 40 months (range: 2.6–130.8). Two-thirds were triple negative (TN). Squamous carcinoma was prevalent in 74.8% followed by carcinoma with osseous/chondroid differentiation, spindle cell, and low-grade adenosquamous carcinoma encountered in 13.3, 7.4, and 4.5%, respectively. Modified radical mastectomy was done in 59.3%, and positive nodes (pN+) were depicted in 37.7%. Median Ki-67 was 45% (range: 10–88); grade III and lymphovascular invasion (LVI) were observed in 83.7 and 43.7%, respectively. Stage II was the most common (49%), whereas initial stage IV was encountered in 8.1%. Anthracyclines/taxane combinations were rampant in adjuvant/neoadjuvant settings. The latter was employed in 41 patients, with only 3 cases (7.3%) achieving pathologic complete response (pCR), while moderate/significant residual tumor burden was found in 83%. The 5-year DFS and OS were 56.4 and 57.6%, respectively. Spindle cell carcinoma showed the worst survival parameters in univariate analysis. On the multivariate level, higher tumor stage (pT3 & 4), Ki-67 ≥ 45%, and TN subtype were independent variables for worse DFS and OS; age ≥ 52 years and the presence of LVI were independent features for worse DFS, whereas pN+ was an independent parameter for worse OS.ConclusionsThis study further solidifies the dreadful response of MetBC to conventional chemotherapy regimens employed in common non-metaplastic pathologies. A radical shift in treatment standards tailored to combat the molecular landscape of this distinctive tumor is urgently needed. Immunotherapy and molecularly targeted agents demonstrated promising results in phase I and II trials with hopeful sooner implementation in phase III studies.

Prognostic value of the long noncoding RNA AFAP1-AS1 in cancers*

Abstract Objective This meta-analysis explored whether the expression of actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) is related to the prognosis and clinicopathological features of patients with cancer. Methods PubMed, EMBASE, and Cochrane Library were systematically searched. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the prognostic value based on overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Odds ratios (ORs) with 95% CIs were used to determine the relationships between AFAP1-AS1 and clinicopathological features, such as large tumor size (LTS), high tumor stage (HTS), poor histological grade (PHG), lymph node metastasis (LNM), and distant metastasis (DM). Results Thirty-five eligible articles and 3433 cases were analyzed. High AFAP1-AS1 expression, compared to low AFAP1-AS1 expression, correlated with significantly shorter OS (HR = 2.15, 95% CI = 1.97-2.34, P &lt; 0.001), DFS (HR = 1.37, 95% CI = 1.19-1.57, P &lt; 0.001), and PFS (HR = 1.97, 95% CI = 1.56-2.50, P &lt; 0.001) in patients with cancer. In various cancers, elevated AFAP1-AS1 expression was significantly associated with LTS (OR = 2.76, 95% CI = 2.16-3.53, P &lt; 0.001), HTS (OR = 2.23, 95% CI = 1.83-2.71, P &lt; 0.001), and PHG (OR = 1.39, 95% CI = 1.08-1.79, P = 0.01) but not LNM (OR = 1.59, 95% CI = 0.88-2.85, P = 0.12) or DM (OR = 1.81, 95% CI = 0.90-3.66, P = 0.10). Conclusion High AFAP1-AS1 expression was associated with prognostic and clinicopathological features, suggesting that AFAP1-AS1 is a prognostic biomarker for human cancers.

Elucidating the genomic and transcriptomic landscape of L858R vs ex19del EGFR-mutated NSCLC.

8530 Background: Epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is heterogeneous and L858R derive less benefit from osimertinib than ex19del in both the metastatic and adjuvant setting, which remains poorly understood. We sought to examine the genomic and transcriptomic features of L858R vs ex19del. Methods: Consecutive patients with AJCC7 Stage IA-IIIA EGFR-mutated NSCLC diagnosed 1/1/2010 – 31/12/2019 who underwent surgery at National Cancer Centre Singapore were included. Patients who received neoadjuvant therapy were excluded. Fresh frozen tumour and normal samples were subject to whole exome sequencing (WES) at 400X and 100X coverage respectively, with approximately 50 million paired-end reads for RNA-seq per sample. Wilcoxon and Fisher’s exact test were used for association analysis. Results: A total of 203 patients were included. Median age at diagnosis was 66, 66.0% (134/203) were females and 84.2% (171/203) never-smokers. Stage IA comprised 44.3% (90/203), IB 28.6% (58/203), II 15.8% (32/203) and IIIA 11.3% (23/203). Median tumour mutational burden (TMB) was 1.3 mutations/megabase (range 0.3 – 44.3). Ex19del represented 46.3% (94/203) and L858R 41.9% (85/203). Whole genome doubling (WGD) was found in 70.0% (142/203) and was more common in TP53-mutated compared to TP53-wildtype (81.1% vs. 63.6%, p=0.01). TP53 mutations were more common in stage II/IIIA tumours compared with stage IB and IA (50.9% vs 32.8% vs 30.0%, p=0.035). Comparing ex19del and L858R, there was no difference in stage distribution (p=0.337), proportion of TMB≥10 (1.1% vs 5.9%, p=0.103), number of cancer co-driver mutations (p=0.174), TP53 mutations (39.4% vs 32.9%, p=0.437) and WGD (69.1% vs 76.5%, p=0.316). L858R had a higher incidence of smoking mutational signature (median 0.35 vs 0.28, p=0.018) compared to ex19del despite similar smoking history (15.3% vs 12.8%, p=0.67), whereas APOBEC mutational signature was higher in ex19del (median 0.06 vs 0.04, p=0.015). L858R tumors were associated with a higher incidence of co-mutations in RBM10 (21.2% vs 6.38%, p=0.004), RNF213 (10.6% vs 1.06%, p=0.007) and amplification of NTHL1 (15.3% vs 2.13%, p=0.001) and AXIN1 (17.6% vs 3.19%, p=0.002) compared to ex19del. Transcriptomic subtype differed significantly by EGFR mutation with a higher representation of TRU subtype among L858R than ex19del (51.0% vs 35.3%, p=0.010), while GEP score was similar (median 0.189 vs 0.325, p=0.122). Conclusions: L858R have distinct co-mutations and copy number alterations compared to ex19del, in addition to a higher representation of smoking mutational signature and TRU subtype. TP53 co-mutations are more frequently observed in higher stage tumours and are associated with WGD. Our findings highlight the molecular heterogeneity of resected EGFR-mutated NSCLC, which could contribute to the differential outcomes to adjuvant osimertinib between ex19del and L858R.

Comment On: Prospective Phase II Trials Validate the Effect of Neoadjuvant Chemotherapy on Pattern of Recurrence in Pancreatic Adenocarcinoma.

We read with great interest the article by Dr. Chawla et al.1 They investigated the pattern of recurrence from a retrospective cohort of patients treated with neoadjuvant chemotherapy (NAC) followed by chemoradiation and then surgery or surgery first followed by adjuvant chemotherapy and 2 prospective cohorts of patients derived from 2 phase II clinical trials assessing patients treated with NAC in borderline-resectable and locally advanced pancreatic adenocarcinoma (PDAC). They found that the site of recurrence in PDAC is mostly distant metastasis (DM) rather than locoregional, regardless of the use of NAC and margin status. After reading their article, we have some questions that we hope to communicate with the authors. First, the authors consider that the surgical margin distance less than 1 mm of the resection is R1 resection, which can be agreed upon by most surgeons in the resectable or borderline-resectable cohort. However, in the locally advanced cohort, for PDCA with vascular invasion, how did the authors determine the status of the surgical margin because the tumor was removed along the vessels? In theory, for PDCA with vascular invasion, the surgical margin distance is always less than 1 mm. Then, according to the authors’ definition of surgical margin, PDCA with vascular invasion would have no way to achieve an R0 resection. Second, in the locally advanced cohort, the DM rate was only 67%. Patients in the locally advanced cohort had the highest tumor stage but the lowest DM rate compared to other cohorts. Different from the treatment of other cohorts (surgery + adjuvant therapy), losartan is added to the treatment in the locally advanced cohort. Is the decrease in DM associated with the use of losartan? To observe recurrence patterns consistent with the rest of the cohort, we think that treatment in the locally advanced cohort should be substantially consistent with the rest of the cohort. We raise these questions not to challenge Chawla et al.’s1 research but to have a friendly academic exchange with them. And, we acknowledge Chawla et al.1 for their contribution to the discovery of recurrence patterns in PDCA. Meanwhile, we are also very grateful to Annals of Surgery Open for giving us a platform to communicate.

A Fecal MicroRNA Signature by Small RNA Sequencing Accurately Distinguishes Colorectal Cancers: Results From a Multicenter Study

Fecal tests currently used for colorectal cancer (CRC) screening show limited accuracy in detecting early tumors or precancerous lesions. In this respect, we comprehensively evaluated stool microRNA (miRNA) profiles as biomarkers for noninvasive CRC diagnosis. A total of 1273 small RNA sequencing experiments were performed in multiple biospecimens. In a cross-sectional study, miRNA profiles were investigated in fecal samples from an Italian and a Czech cohort (155 CRCs, 87 adenomas, 96 other intestinal diseases, 141 colonoscopy-negative controls). A predictive miRNA signature for cancer detection was defined by a machine learning strategy and tested in additional fecal samples from 141 CRC patients and 80 healthy volunteers. miRNA profiles were compared with those of 132 tumors/adenomas paired with adjacent mucosa, 210 plasma extracellular vesicle samples, and 185 fecal immunochemical test leftover samples. Twenty-five miRNAs showed altered levels in the stool of CRC patients in both cohorts (adjusted P < .05). A 5-miRNA signature, including miR-149-3p, miR-607-5p, miR-1246, miR-4488, and miR-6777-5p, distinguished patients from control individuals (area under the curve [AUC], 0.86; 95% confidence interval [CI], 0.79-0.94) and was validated in an independent cohort (AUC, 0.96; 95% CI, 0.92-1.00). The signature classified control individuals from patients with low-/high-stage tumors and advanced adenomas (AUC, 0.82; 95% CI, 0.71-0.97). Tissue miRNA profiles mirrored those of stool samples, and fecal profiles of different gastrointestinal diseases highlighted miRNAs specifically dysregulated in CRC. miRNA profiles in fecal immunochemical test leftover samples showed good correlation with those of stool collected in preservative buffer, and their alterations could be detected in adenoma or CRC patients. Our comprehensive fecal miRNome analysis identified a signature accurately discriminating cancer aimed at improving noninvasive diagnosis and screening strategies.

KRAS mutation in primary ovarian serous borderline tumors correlates with tumor recurrence.

Oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway due to KRAS or BRAF gain-of-function mutation is frequently found in ovarian serous borderline tumor (SBT) and their extraovarian implants. We investigated mutational status of KRAS and BRAF of the primary ovarian SBTs that had a high stage presentation in correlation with clinical outcome. Among 39 consecutive primary SBTs with either invasive implants (20 cases) or non-invasive implants (19 cases), KRAS and BRAF mutational analysis was informative in 34 cases. Sixteen cases (47%) harbored a KRAS mutation, while 5 cases (15%) had a BRAF V600E mutation. High-stage disease (IIIC) was seen in 31% (5/16) of patients with a KRAS mutation and 39% (7/18) of patients without a KRAS mutation (p = 0.64). KRAS mutations were present in 9/16 (56%) tumors with invasive implants/LGSC versus 7/18 (39%) tumors with non-invasive implants (p = 0.31). BRAF mutation was seen in 5 cases with non-invasive implants. Tumor recurrence was seen in 31% (5/16) of patients with a KRAS mutation, compared to 6% (1/18) of patients without a KRAS mutation (p = 0.04). A KRAS mutation predicted an adverse disease-free survival (31% survival at 160months) compared to those with wild-type KRAS (94% at 160months; log-rank test, p = 0.037; HR 4.47). In conclusion, KRAS mutation in primary ovarian SBTs is significantly associated with a worse disease-free survival, independent of the high tumor stage or histological subtypes of extraovarian implant. KRAS mutation testing of primary ovarian SBT may servce as a useful biomarker for tumor recurrence.

Surgical management of splenic flexure cancer: is there an optimal technique? A bi-national registry analysis.

Splenic flexure tumours (SFC) are uncommon and present at more advanced disease stages. The optimal surgical technique for SFC remains controversial. We sought to compare the short-term outcomes of a left hemicolectomy (LHC) versus an extended resection (subtotal colectomy, STC) for SFCs. A retrospective analysis using the Binational Colorectal Cancer Audit (BCCA) registry was performed. All patients with SFC who underwent elective or emergency surgery for a SFC between 2010 and 2021 were included. Primary outcomes included short-term inpatient complications. Secondary outcomes included survival outcomes. Six hundred and ninety-nine patients underwent resections for SFCs. A LHC was more common, performed in 64.1%. Patients having a LHC were significantly older, with proportionally more LHCs done laparoscopically. Overall grade III/IV complications were similar between both operations. Prolonged ileus and return to theatre were significantly higher in patients undergoing a STC. On multivariate analysis, anastomotic leak and overall grade III/IV complications were not independently associated with the type of operation. There was no difference in medial survival based on type of operation. Higher tumour stage (Stage III/IV) were independently associated with worse survival. Segmental and extended resections are both oncologically sound procedures for SFCs. Segmental resections are associated with lower rates of prolonged ileus.