The role of vascular invasion and lymphatic invasion in predicting recurrent thoracic oesophageal squamous cell carcinoma

Background Numerous studies have addressed lymphovascular invasion (LVI) in patients with thoracic oesophageal squamous cell carcinoma (ESCC); however, little is known about the individual roles of lymphatic invasion (LI) and vascular invasion (VI). We aimed to analyse the prognostic significance of LI and VI in patients with thoracic ESCC from a single centre. Methods This retrospective study included 396 patients with thoracic ESCC who underwent oesophagectomy and lymphadenectomy in our hospital. The relationship between LI, VI and the other clinical features was analysed, and disease-free survival (DFS) was calculated. Survival analysis was performed by univariate and multivariate statistics. Results Briefly, VI and LI were present in 25.8% (102 of 396) and 23.7% (94 of 396) of ESCC patients, respectively, with 9.15% patients presenting both LI and VI; the remaining patients did not present LI or VI. We found that LI was significantly associated with pN stage (P<0.001) and pTNM stage (P<0.001), and similar results were found in VI. Moreover, survival analysis showed that pT stage (P<0.001), pN stage (P=0.001), pTNM stage (p<0.001), VI (P=0.001) and LI (P<0.001) were associated with DFS in ESCC. Furthermore, multivariate analysis suggested that pT stage (RR=1.4, P =0.032), pN stage (RR=1.9, P<0.001) and LI (RR=1.5, P=0.008) were independent predictive factors for DFS. Finally, relapse was observed in 110 patients (lymph node metastasis, 78 and distant, 32) and 147 patients with cancer-related deaths. Subanalysis showed that LI-positive patients had higher lymph node metastasis, although there was no significant difference (32.1% vs. 15.6%, P=0.100). Conclusions LI and VI were common in ESCC; they were all survival predictors for patients with ESCC, and LI was independent. Patients with positive LI were more likely to suffer lymph node metastasis.

Clinicopathological Features Combined With Immune Infiltration Could Well Distinguish Outcomes in Stage II and Stage III Colorectal Cancer: A Retrospective Study

BackgroundThe Immunoscore predicts prognosis in patients with colorectal cancer (CRC). However, a few studies have incorporated the Immunoscore into the construction of comprehensive prognostic models in CRC, especially stage II CRC. We aimed to construct and validate multidimensional models integrating clinicopathological characteristics and the Immunoscore to predict the prognosis of patients with stage II–III CRC.MethodsPatients (n = 254) diagnosed with stage II–III CRC from 2009 to 2016 were used to generate Cox models for predicting disease-free survival (DFS) and overall survival (OS). The variables included basic clinical indicators, blood inflammatory markers, preoperative tumor biomarkers, mismatch repair status, and the Immunoscore (CD3+ and CD8+ T-cell densities). Univariate and multivariate Cox proportional regressions were used to construct the prognostic models for DFS and OS. We validated the predictive accuracy and ability of the prognostic models in our cohort of 254 patients.ResultsWe constructed two predictive prognostic models with C-index values of 0.6941 for DFS and 0.7138 for OS in patients with stage II–III CRC. The Immunoscore was the most informative predictor of DFS (11.92%), followed by pN stage, carcinoembryonic antigen (CEA), and vascular infiltration. For OS, the Immunoscore was the most informative predictor (8.59%), followed by pN stage, age, CA125, and CEA. Based on the prognostic models, nomograms were developed to predict the 3- and 5-year DFS and OS rates. Patients were divided into three risk groups (low, intermediate, and high) according to the risk scores obtained from the nomogram, and significant differences were observed in the recurrence and survival of the different risk groups (p &lt; 0.0001). Calibration curve and time-dependent receiver operating characteristic (ROC) analysis showed good accuracy of our models. Furthermore, the decision curve analysis indicated that our nomograms had better net benefit than pathological TNM (pTNM) stage within a wide threshold probability. Especially, we developed a website based on our prognostic models to predict the risks of recurrence and death of patients with stage II–III CRC.ConclusionsMultidimensional models including the clinicopathological characteristics and the Immunoscore were constructed and validated, with good accuracy and convenience, to evaluate the risks of recurrence and death of stage II–III CRC patients.

Comparative Study of Pulmonary Combined Large-Cell Neuroendocrine Carcinoma and Combined Small-Cell Carcinoma in Surgically Resected High-Grade Neuroendocrine Tumors of the Lung

ObjectivesPulmonary large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC (C-SCLC), few studies have compared their clinical features and prognosis.Materials and MethodsWe compared the clinical features, mutation status of driver genes (EGFR, ALK, ROS1, KRAS, and BRAF), and prognosis between C-LCNEC and C-SCLC. Univariate and multivariate Cox regression analyses were applied for survival analysis.ResultsWe included a total of 116 patients with C-LCNEC and 76 patients with C-SCLC in the present study. There were significant differences in distribution of smoking history, tumor location, pT stage, pN stage, pTNM stage, visceral pleural invasion (VPI), and combined components between C-LCNEC and C-SCLC (P&lt;0.05 for all). C-SCLC was more advanced at diagnosis as compared to C-LCNEC. The incidence of EGFR mutations in C-LCNEC patients was higher than C-SCLC patients (25.7 vs. 5%, P=0.004). We found that tumor size, pN stage, peripheral CEA level, and adjuvant chemotherapy were independently prognostic factors for DFS and OS in C-LCNEC patients, while peripheral NSE level, pT stage, pN stage, VPI and adjuvant chemotherapy were independently associated with DFS and OS for C-SCLC patients (P&lt;0.05 for all). Propensity score matching with adjustment for the confounders confirmed a more favorable DFS (P=0.032) and OS (P=0.019) in patients with C-LCNEC in comparison with C-SCLC patients upon survival analysis.ConclusionsThe mutation landscape of driver genes seemed to act in different way between C-SCLC and C-LCNEC, likely by which result in clinical phenotype difference as well as better outcome in C-LCNEC.

Exploration of the Cytoplasmic Function of Abnormally Fertilized Embryos via Novel Pronuclear-Stage Cytoplasmic Transfer

In regular IVF, a portion of oocytes exhibit abnormal numbers of pronuclei (PN) that is considered as abnormal fertilization, and they are routinely discarded. However, it is known that abnormal ploidy still does not completely abandon embryo development and implantation. To explore the potential of cytoplasm from those abnormally fertilized oocytes, we developed a novel technique for the transfer of large cytoplasm between pronuclear-stage mouse embryos, and assessed its impact. A large volume of cytoplast could be efficiently transferred in the PN stage using a novel two-step method of pronuclear-stage cytoplasmic transfer (PNCT). PNCT revealed the difference in the cytoplasmic function among abnormally fertilized embryos where the cytoplasm of 3PN was developmentally more competent than 1PN, and the supplementing of fresh 3PN cytoplasm restored the impaired developmental potential of postovulatory “aged” oocytes. PNCT-derived embryos harbored significantly higher mitochondrial DNA copies, ATP content, oxygen consumption rate, and total cells. The difference in cytoplasmic function between 3PN and 1PN mouse oocytes probably attributed to the proper activation via sperm and may impact subsequent epigenetic events. These results imply that PNCT may serve as a potential alternative treatment to whole egg donation for patients with age-related recurrent IVF failure.

Prognostic Significance of Signet-Ring Cell Components in Patients With Gastric Carcinoma of Different Stages

Background: Gastric carcinoma (GC), which contains signet ring cell (SRC) components are frequently observed in postoperative pathological assessment. This study aims to study the prognostic significance of SRC components in GC patients.Methods: From 2003 to 2017, surgically resected primary GC patients were retrospectively reviewed. All enrolled patients were divided into three groups according to the proportion of SRC. The overall survival (OS) and disease-free survival (DFS) of GC patients with different tumor stages were analyzed.Results: Patients with SRC or mixed-SRC were more associated with female, younger age, middle or lower third of the stomach, larger tumor, higher pN stage, and more lymphovascular invasion. For GC patients in stage I, multivariate survival analysis showed that age &gt;60, SRC components &gt;50%, and pT stage were independent prognostic factors for OS (all p &lt; 0.05). The 5-year OS of patients with SRC were higher than that of patients with pure adenocarcinoma (p = 0.021). For GC patients in stage II/III, multivariate survival analysis showed that age &gt;60, SRC proportion, surgical types, Borrmann's type, pT stage, pN stage, and lymphovascular invasion were independent prognostic factors for OS (all p &lt; 0.05). The 5-year OS/DFS of patients with SRC were lower than that of patients with pure adenocarcinoma (p &lt; 0.001).Conclusions: SRC seemed to be a favorable prognostic factor in GC patients in stage I. However, for GC patients in stage II/III, the SRC components were associated with poor prognosis, independent of other clinicopathological factors.

Immunohistochemical expression of substance P in breast cancer and its association with prognostic parameters and Ki-67 index

Background The neuropeptide substance P is a potential biomarker and therapeutic target in cancer. The main objectives of this study were to investigate the expression level of substance P in different breast cancer molecular subtypes and identify its association with clinicopathological parameters of patients and with Ki-67 index. Methods A retrospective analysis was performed for a total of 164 paraffin-embedded breast cancer tissue samples [42 Her2/neu-enriched, 40 luminal A, 42 luminal B (triple-positive) and 40 triple negative subtypes]. The tissue microarray slides containing specimens were used to determine the expression of substance p and Ki-67 by immunohistochemical staining. Results The mean age of the cohort was 51.35 years. Twenty two percent of cases had low substance P expression levels (TS ≤ 5), while 78% had high expression levels (TS > 5). A significant association was found between SP expression level and breast cancer molecular subtype (p = 0.002), TNM stage (p = 0.034), pN stage (p = 0.013), axillary lymph node metastasis (p = 0.004), ER and PR statuses (p<0.001) and history of DCIS (p = 0.009). The average percentage of Ki-67 expression was 27.05%. When analyzed as a continuous variable, significant differences were observed between the mean Ki-67 scores and molecular subtype (p = 0.001), grade (p = 0.003), pN stage (p = 0.007), axillary lymph node metastasis (p = 0.001), and ER and PR statuses (p <0.001). Conclusion SP is overexpressed in most of the analyzed tissues and has a negative prognostic value in the breast cancer patients. Besides substance P is a potential therapeutic target in breast cancer.

Prognostic value of subclassification of pT2 stage in patients with gastric cancer.

e16070 Background: The data about prognosis difference of patients with pT2 stage gastric cancer (GC) after radical surgery is diverse. The latest TNM staging system does not define details for the pT2 stage subclassification. The purpose of this study is to investigate the survival difference according to depth of tumor muscularis propria involvement and find biomarker to reinforce the prognostic and therapy-guided ability of TNM staging system. Methods: A total of 380 patients with pT2 GC after radical surgery were retrospectively analyzed, including 185 in sMP (superficial muscularis propria) group and 195 in dMP (deep muscularis propria) group. The log-rank test was used to identify survival outcomes. Independent factors were identified by multivariable Cox proportional hazard model for OS. Results: The overall survival (OS) of patients in sMP group was significantly better than patients in dMP group (P = 0.007). On multivariate analysis, age (＜60 vs ≥60: P = 0.004, HR, 2.075(95%CI: 1.261-3.414)), primary location (P = 0.002, U vs M: 0.985(0.509-1.909); U vs L: 0.400(0.235-0.680)), depth of tumor invasion (sMP vs dMP: P = 0.050, 1.584(1.261-3.414), pN stage (P = 0.000, N0 vs N1: 2.304(1.364-3.890); N0 vs N2: 1.879(0.967-3.652); N0 vs N3: 5.335(2.533-11.237)), expression of p53 (negative vs positive: P = 0.016, 1.793(1.117-2.879)) were independent prognostic factors for the OS. In pN0 stage tumor, the sMP group had a significantly better OS than the dMP group (P = 0.014). When classified as N+, there was no obviously difference of OS between two groups (P = 0.384). When patients were stratified according to the depth of tumor invasion and pN stage, the OS was not significant difference between dMPN0 group and sMPN1-2 group (P = 0.100), the OS of patients with adjuvant chemotherapy were statistically better than those without in dMPN0 group (P = 0.045), but not significance in sMPN1-2 group (P = 0.486). After further grouping according to adjuvant chemotherapy status, in comparison to sMPN1-2 patients, dMPN0 patients with adjuvant chemotherapy had better OS (P = 0.015), but not significance in patients without (P = 0.599). Upon stratification according to the expression of p53, in p53-positive group, greater OS could be observed in patients with sMPN0 than patients with dMPN0 (P = 0.002). Similar OS could be seen between dMPN0 patients with p53-positive and T2N1-2 patients (P = 0.872). Conclusions: For pT2 gastric cancer patients, there were differences in survival outcomes for sMP and dMP invasion. The prognosis of dMPN0 patients were similar to patients with sMPN1-2, and dMPN0 patients who accepted adjuvant chemotherapy had an improved prognosis than those without. Appropriate adjuvant chemotherapy should be considered for patients with dMPN0 stage. In addition, positive expression of p53 could be potential factors to identify the different prognoses for patients with pT2 gastric cancers.

Role of Clinical–Demographic Data in Survival Rates of Advanced Laryngeal Cancer

Background and Objectives: Laryngeal cancer is one of the most common cancers in the upper aerodigestive tract, and tobacco and alcohol habits are the most relevant risk factors. The role of these risk factors in the incidence of laryngeal carcinomas is well known, yet only a few studies have been conducted on their role as risk factors of prognosis. The aim of the study was to assess the impact of clinical–demographic data on overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) in patients with advanced-stage laryngeal cancer (Stage III–IV) who underwent total laryngectomy. Materials and Methods: This retrospective study was carried out on patients with Stage III–IV laryngeal squamous cell carcinoma treated with total laryngectomy between 2004 and 2014. For each patient, clinical and anamnestic data were collected and collated in a database, including alcohol and smoking habits. Results: Considering the variable age, family history, alcohol, grading, subsite, stage, pT stage, pN stage, and adjuvant therapy, no statistical significance was found for five-year OS. Smoking was the only variable that was statistically significant (p = 0.0043). A relevant difference was noted in the five-year DFS between pN-negative and pN-positive tumors (74.3% vs. 55.26%, respectively; p = 0.056), and a statistically significant difference was found between non- and ≤20 cigarettes/day smokers and heavy smokers (77.78% vs. 53.66%, respectively; p = 0.021). The five-year disease-specific survival rate was 68.83%, and a significant difference was detected for the smoking and pN stage variables. Heavy smokers (43.90% died vs. 16.67% of the non- and ≤20 cigarettes/day smokers; p = 0.0057) and pN-positive (42.1% died vs. 20.51% of the pN-negative patients; p = 0.042) patients had a worse prognosis. Conclusion: Smoking in our study was found to be an important independent risk factor for worse OS and DSS in patients with advanced laryngeal cancer.

RGS12 as a Novel Maternal-Effect Gene Causes Arrest at the Pronuclear Stage of Human Zygote

Background: Early embryonic arrest is one of the major causes of female infertility after in vitro fertilization (IVF), but the causal gene of arrest at the pronuclear (PN) zygote stage is largely unknown. Results: To understand this process, we recruited a family characterized by recurrent PN arrest during IVF cycles and performed whole-exome sequencing. The missense variant c.C1630T (p.R544W) in RGS12 was responsible for a phenotype characterized by paternal transmission. RGS12 controls Ca2+ oscillation, which is required for oocyte activation after fertilization. Single-cell transcriptome profiling of PN-arrest zygotes revealed defective established translation, RNA processing and cell cycle, which explained the failure of complete oocyte activation. Furthermore, we identified proximal genes involved in Ca2+ oscillation–cytostatic factor–anaphase-promoting complex (Ca2+ oscillation–CSF–APC) signaling, including upregulated CaMKII, ORAI1, CDC20, and CDH1 and downregulated EMI1 and BUB3. The findings indicated abnormal spontaneous Ca2+ oscillations leading to oocytes with prolonged low CSF and high APC level, which resulted in defective nuclear envelope breakdown and DNA replication. The changes in levels of critical genes were confirmed by examining other independent PN-arrest zygotes. However, the PN-arrest zygote phenotype was not consistent with that of RGS12-deficient mice, thereby indicating species-specific functions between human and mouse. Conclusion: Our findings expand our knowledge of the genetic determinants of human early embryonic arrest at the PN stage and provide guidance for selecting clinically infertile individuals with PN-arrest zygotes for Ca2+ intervention.