A Novel Clinical Nomogram for Predicting Lymph Node Metastasis in Ovarian Cancer: A SEER Analysis and External Validation in a Tertiary Center

Introduction The aim of the study is to investigate the risk factors for developing lymph node metastases (LNM) in cases diagnosed as a presumed early-stage ovarian carcinoma (OC). Methodology Information of patients who had been diagnosed as OC in 2018 was obtained from the SEER database. We enrolled 104 OC patients in General Hospital of Northern Theatre Command for external validation. A logistic regression was conducted to determine the independent predictors for LNM, which were used for establishing a nomogram. In order to evaluate the reliability of nomogram, we applied a receiver operating characteristic curve (ROC) analysis, calibration curves and plotted decision curves. Results We found that age(≥70, OR=0.544, p=0.022), histology type (Mucinous carcinoma, OR=0.390, p=0.001; Endometrioid carcinoma, OR=7.946, p=0.053; Others, OR=2.400, p=0.040), histology grade (Grade II, OR=2.423, p=0.028; Grade III, OR=1.982, p=0.152; Grade IV, OR=1.594, p=0.063) and preoperative serum CA125 level (positive, OR=2.236, p=0.001) were all significant predictors of LNM. The AUC of the model training cohort, internal validation cohort, and external validation cohort were 0.78, 0.79 and 0.76 respectively. The calibration curves showed that the predicted outcome fitted well to the observed outcome in the training cohort (p=0.825) internal validation cohort (p=0.503), and external validation cohort (p=0.108). The decision curves showed the nomogram had more benefits than the All or None scheme if the threshold probability is >50% and <100% in training cohort and internal validation cohort, >30% and <90% in the external validation cohort. Conclusion The multivariate logistic regression showed that age, histology type, histology grade and preoperative serum CA125 level were all significant predictors of LNM. The nomogram established using the above variables had great performance for clinical applying.

The Potential of Differentiation-Related Gene-1 (DRG1) as a Biomarker for Metastasis of Estrogen Receptor-Positive Breast Cancer

Introduction: Breast cancer is major burden worldwide and the majority of breast cancers express estrogen receptors (ER) suggesting a high dependence on estrogen hormone. Age is among the major determinants of breast cancer development, however, although Western Kenya is one of the areas with high breast cancer cases, age distribution of ER-positive breast cancer in the sub-region remains largely undocumented. Differentiation-related gene-1 (DRG1) is a metastasis suppressor and thus a potential biomarker for predicting level of metastasis but its potential application in assessing extent of metastasis of ER positive breast cancer has not been fully explored. This study therefore investigated the age distribution and the potential of expression of DRG1 in assessing metastasis of ER positive breast cancer. Materials and Methods: Breast cancer tumour blocks archived in safe cabins in the histology laboratory section, Moi Teaching and Referral hospital, Eldoret, Kenya were used. Clinico-pathological parameters such as histology grade, tumor size, which are associated with metastatic cancer, were assessed using the archived clinico-pathological reports and/or histological analysis of the tumour blocks. Expression of DRG1 and Ki-67 proteins were determined using immunohistochemistry. Results: ER positive breast cancer was predominant among women aged 40 and 50 years. No association was observed between immunohistochemical expression of DRG1 and parameters such as histology grade, tumor size or expression of Ki-67 protein expressed DRG1 (p > 0.05). Conclusion: The findings suggest that expression of DRG1 protein is not associated with parameters that indicate breast cancer metastasis. Thus, DRG1 expression is not a potential biomarker candidate for ER positive breast cancer metastasis. However, since the small sample size was used, further research using larger prospective study is necessary to support the present findings.

Upregulated hsa_circRNA_100269 inhibits the growth and metastasis of gastric cancer through inactivating PI3K/Akt axis

The pathogenesis of GC involves the complex networking of multiple signaling pathways; however, the detailed mechanisms of tumorigenesis of GC remains largely unknown. Therefore, it is necessary to explore novel diagnostic/prognostic biomarkers for GC. In this study, the levels of hsa_circRNA_100269 in gastric cancer (GC) samples and cells were examined, and its effects on the biological functions of GC cells were elucidated. The levels of hsa_circRNA_100269 in specimens/cell lines were examined using RT-qPCR. Cell models with hsa_circRNA_100269 overexpression or knockdown were generated using lentiviral vectors. Cell viability was determined by MTT assay; cell migratory/invasive activity was evaluated using wound healing/Transwell assay. Cell cycle arrest and apoptosis were assessed by flow cytometry; expression of associated markers involved in cell apoptosis, EMT and the PI3K/Akt signaling were determined by RT-qPCR/immunoblotting. In vivo study was also performed using hsa_circRNA_100269 knockout mice. Our findings revealed downregulation of hsa_circRNA_100269 in GC tissues compared to non-cancerous control. Additionally, the levels of PI3K were remarkably elevated in GC tissues, where hsa_circRNA_100269 and PI3K was negatively correlated. Moreover, the expression of hsa_circRNA_100269 was associated with histology grade and occurrence of metastasis in GC patients. In addition, hsa_circRNA_100269 was downregulated in GC cells compared to normal gastric epithelial cells. Overexpressed hsa_circRNA_100269 notably inhibited the proliferation, migration, invasion and EMT of GC cells, whereas cell cycle arrest at G0/G1 phase was promoted and cell apoptosis was enhanced. Moreover, the PI3K/Akt signaling was involved in hsa_circRNA_100269-regulated GC cell proliferation, migration, invasion, EMT and apoptosis. Knockdown of hsa_circRNA_100269 also remarkably induced tumor growth in mouse model. In summary, our findings indicated that the levels of hsa_circRNA_100269 were reduced in GC. Furthermore, hsa_circRNA_100269 could suppress the development of GC by inactivating the PI3K/Akt pathway. More importantly, hsa_circRNA_100269/PI3K/Akt axis may be a novel therapeutic candidate for GC treatment.

Impact of breast surgery on survival of patients with stage IV breast cancer: a SEER population-based propensity score matching analysis

Background Breast surgery for stage IV breast cancer remains controversial. The aim of this study was to investigate the impact of breast surgery on survival of stage IV breast cancer patients based on the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. Methods In total, 13,034 patients were selected and divided into surgery and non-surgery groups. Univariate and multivariable analyses were conducted to determine factors related to survival. Propensity score matching method was utilized to achieve balanced covariates across different groups. One-to-one (1:1) PSM was conducted to construct a matched sample consisting of pairs of surgery and non-surgery subjects. Breast cancer-specific survival (BCSS) and overall survival (OS) of the two groups were assessed by Kaplan–Meier plots and Cox proportional hazard regression models. Stratified analysis according to different variables was also performed. Results Patients treated with breast surgery were more likely to be younger, smaller tumor size, more advanced nodal status, higher histology grade and higher proportion of bone-only metastasis. Those who received chemotherapy and radiotherapy also tended to be treated with surgery. After adjustment for potential confounders, breast surgery group exhibited a better survival both in BCSS (HR = 0.557, 95% CI [0.523–0.594], p < 0.001) and OS (HR = 0.571, 95% CI [0.537–0.607], p < 0.001). After propensity score matching, the surgery and non-surgery group consisted of 2,269 patients respectively. The median survival time was 43 months for the surgery group and 27 months for the non-surgery group. Kaplan–Meier curves indicated that breast surgery could clearly improve both the BCSS and OS for patients with stage IV breast cancer. On multivariate analysis, surgery group was associated with a better survival compared with the non-surgery group (BCSS: HR = 0.542, 95% CI [0.499–0.589], p < 0.001; OS: HR = 0.555, 95% CI [0.512–0.601], p < 0.001). Furthermore, this survival advantage persisted in all subgroups irrespective of age, race, tumor size, nodal status, histology grade, molecular subtype, chemotherapy status, radiotherapy status or status of distant metastasis. Conclusion Our study provided additional evidence that patients with stage IV breast cancer could benefit from breast surgery and it might play a more important role in multimodality therapy.

No evidence for increased prevalence of colorectal carcinoma in 399 Dutch patients with Birt-Hogg-Dubé syndrome

Background Previously, it has been suggested that colorectal polyps and carcinomas might be associated with Birt-Hogg-Dubé syndrome. We aimed to compare the occurrence of colorectal neoplasms between Dutch patients with Birt-Hogg-Dubé syndrome and their relatives without Birt-Hogg-Dubé syndrome. Methods In all, 399 patients with a pathogenic FLCN mutation and 382 relatives without the familial FLCN mutation were included. Anonymous data on colon and rectum pathology was provided by PALGA: the Dutch Pathology Registry. Results No significant difference in the percentage of individuals with a history of colorectal carcinoma was found between the two groups (3.6% vs 2.6%, p = 0.54). There was also no significant difference between the age at diagnosis, diameter, differentiation and location of the colorectal carcinomas. Significantly more individuals with Birt-Hogg-Dubé syndrome underwent removal of colorectal polyps (12.2% vs 6.3%, p = 0.005). However, there was no significant difference between the number of polyps per person, the histology, grade of dysplasia and location of the polyps. Conclusion Our data do not provide evidence for an increased risk for colorectal carcinoma in Birt-Hogg-Dubé syndrome, arguing against the need for colorectal surveillance. The difference in polyps might be due to a bias caused by a higher number of colonoscopies in patients with Birt-Hogg-Dubé syndrome.

How Does Smoking Change the Clinicopathological Characteristics of Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma? One Medical Center Experience

Introduction: Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCCs) are 2 distinct cancers, with HPV-positivity conferring a better prognosis. Smoking status is a complicating factor for both patient populations. There have been scattered literature that have reported on incomplete information regarding the profiles of their patient population. Details including age and sex distributions, TNM staging, histology grading, recurrence time and types, death rates, and the direct causes of deaths have been reported incompletely in the literature. Here, based on the experience at our university medical centers, we explored all the details of the important clinical profiles of HPV-negative OPSCC, HPV-positive OPSCC in smokers and nonsmokers. Objective: In this article, we compare detailed clinical profiles of HPV-negative OPSCC and HPV-positive OPSCC in both smokers and nonsmokers. The clinical profiles we elucidated here include patients’ age and sex distribution, general health conditions, histology grading, TNM staging, perineural invasion (PNI), and lymphovascular invasion (LVI), extracapsular extension (ECE), recurrence rate and types, death rate, and direct causes. Specifically, we divided HPV-positive OPSCC into smokers and nonsmokers and compared the different clinical profiles between these groups to give a better idea of the complicating role of smoking in the development of HPV-positive OPSCC. Method: All patients with OPSCC at a tertiary care publicly funded county hospital and a tertiary care university hospital from June 2009-July 2015 were retrospectively reviewed. The attending physicians were the same at both hospitals. The primary outcome measure was posttreatment 2-year follow-up status (locoregional recurrence, distant recurrence, death rate). Other measures included HPV status based on p16 staining, smoking history, age, sex, comorbidities, tumor size, nodal and distant metastasis information, LVI, PNI, ECE, and tumor histology grade. Results: A total of 202 patients with OPSCC were identified. They were categorized into 3 groups: HPV-negative OPSCC group (HPV−), HPV-positive smoker group (HPV+SMK+), and HPV-positive nonsmoker group (HPV+SMK−). Patients of HPV− group are older (61.1 ± 11.6 years) than the other groups on average. The HPV− group has the highest percentage of women (22.7%). The HPV− patients with OPSCC have more comorbidities than the HPV+SMK+ group and the HPV+SMK− group, although there is no statistical difference. Grade 2 tumor is the most common histology grade for HPV− patients with OPSCC, whereas grade 3 is the most common grade for HPV+SMK+ and HPV+SMK− groups. Both PNI and LVI are positive at around 40% for all groups without any significant difference, but ECE is very common for HPV− OPSCC, at 86.7%, which is significantly higher than that of the HPV+SMK+ and HPV+SMK− groups. There was no difference of bilateral neck metastases noticed among different groups. For T staging and N staging, although HPV+SMK− and HPV+SMK+ patients have relatively lower T stages and higher N stages, there is no significant difference. HPV+SMK− group has highest TNM stages. All death rates and recurrence rates increase with time, but the death rate of HPV− group is about 4 times higher than that of the HPV+SMK+ group and 6 times higher than that of the HPV+SMK+ group. The major recurrence type of HPV− OPSCC and HPV+SMK+ is locoregional, and the major recurrence type of HPV+SMK+ is distant metastasis. Conclusions: Our data confirmed that HPV+ OPSCC normally presents with more advanced stage, however, it has better prognosis. In comparison, HPV− OPSCC presents at an earlier stage, but the prognosis is worse. Based on their clinical profiles, we noted that HPV-positive OPSCC cells are more “mobile”; they metastasize sooner and further. However, HPV-negative OPSCC cells are more locally infiltrative, leading to more locoregional recurrence. The HPV-positive patients usually are younger and healthier at diagnosis. Although HPV-positive OPSCC tend to be histologically higher grades, there was no statistical difference noticed. Metastatic and recurrent patterns are very different between HPV-positive and HPV-negative patients, but the death rate of HPV-negative patients is way higher, and it is mainly due to locoregional recurrences, which is the major recurrence type for HPV-negative patients. Of our note, smoking is a complicating factor for HPV-positive OPSCC, and it makes the death rate, recurrence rate, histology grade, and TNM staging shift toward HPV-negative OPSCC. How smoking makes HPV-positive OPSCC behave more like OPSCC-negative OPSCC deserves more translational research for further elucidation.