Primary Subtype Research Articles

Pleomorphic sarcoma of the chest wall: A case report

Primary pleomorphic liposarcoma of the chest wall is a rare entity. Most of the reported cases of the chest wall liposarcomas are low grade, well differentiated with mediastinal extension. Majority of these develop from a subcutaneous lipoma. Complete surgical resection is the preferred treatment modality. The benefit of adjuvant radiotherapy or chemoradiotherapy for these tumors is a subject of debate. We report, an unusual case of high grade primary pleomorphic subtype of liposarcoma in a 50-year-old male presenting with a painful swelling in the anterior thoracic wall extending into the pleura but without any mediastinal involvement or distant metastasis.

Primary Intraosseous Rhabdomyosarcoma: Rare Subtype Involving Mandible with Unique Translocation

<h3>Introduction</h3> A rare subtype of spindled and epithelioid rhabdomyosarcoma (RMS) with unique gene rearrange- ments (FUS-TFCP2 or EWSR1-TFCP2) was first described in 2018 (J Pathol 245:29–40). These aggressive tumors occur in a wide age range with a female predilection and develop almost exclusively within a variety of bone sites, in par- ticular, the craniofacial bones. Majority of affected individuals died of disease within 15 months. FUS-TFCP2 is the predominant translocation associated with this RMS subtype. This case report describes a rare mandibular sarcoma in a child with a complex, oncologic, medical history. <h3>Clinical Presentation and Pathology Findings</h3> 15-year-old female experienced acute lymphoblastic leukemia at 11 months of age, with oncologic resolution. At age 7, anthracycline-induced cardiomyopathy was diagnosed, ne- cessitating heart transplantation at age 9. Subsequently, EBV-associated diffuse large cell lymphoma involving the retropharynx was diagnosed at age 10, with successful oncologic management. At age 15, a left mandibular en- largement was noted. Fine needle core biopsy identified a spindled and epithelioid sarcoma, diffusely positive for nuclear MyoD1 with rare cytoplasmic desmin and rare nuclear myogenin. ALK and S100 immunostaining were positive in a certain tumor cell population. The diagnosis of spindled and epithelioid RMS was made. Conventional cytogenetics demonstrated a complex hyperdiploid tumor (78XXX with numerous derivative aberrations). Next- generation sequencing identified a FUS-TFCP2 translocation, which appears to be tumor-defining with this primary intrabony RMS subtype. Oncologic sarcoma management was performed with a marginal response to chemother- apy and low-dose radiation therapy. Left mandible resection was performed with negative bone and soft tissue margins (3.5cm tumor size). <h3>Conclusion</h3> Primary intraosseous RMS is a rare and aggressive subtype, which has tumor-defining translocations and expresses MyoD1 to a greater extent than Desmin or Myogenin. Of interest, is the overexpression of ALK, which may provide a target for ALK inhibitors.

Stratification From Heterogeneity of the Cell-Death Signal Enables Prognosis Prediction and Immune Microenvironment Characterization in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the primary subtype of esophageal cancer (EC) characterized by a high incidence rate and extremely poor prognosis worldwide. Previous studies suggested that the specific cell death signal was linked to different immune subtypes in multiple cancers, while a comprehensive investigation on ESCC is to be performed yet. In the current study, we dissected different cell death signals in ESCC tumors and then integrated that functional information to stratify ESCC patients into different immunogenic cell death (ICD) subtypes. By systematically analyzing the transcriptomes of 857 patients and proteomic profile of 124 patients, we found that the signals of necroptosis, pyroptosis, and ferroptosis are positively associated with activated immunity in ESCC. We identified two ICD pattern terms, namely, ICD-high and ICD-low subtypes that positively correlated to both progression-free survival and overall survival. In addition, cell fraction deconvolution analysis revealed that more infiltrated leukocytes were enriched in ICD-high types, especially antigen-presenting cells, such as dendritic cells and macrophages. With the XGBoost algorithm, we further developed a 14-gene signature which can simplify the subtyping for allocating new samples, by which we validated the prognosis value of the signature and proved that the ICD score scheme could serve as a promising biomarker for stratifying patients with immunotherapy in several immune checkpoint blockade treatment cohorts. Collectively, we successfully constructed the ICD scheme, which enables predicting of the prognosis or immunotherapy efficacy in ESCC patients and uncovered the critical interplay between cell death signals and immune status in ESCC.

Posterior cortical atrophy: Primary occipital variant.

Posterior cortical atrophy (PCA) is one of the atypical Alzheimer's disease variants, characterized by predominant visuospatial and visuoperceptual deficits, with established dorsal and ventral subtypes. A third primary occipital (caudal) variant has been suggested. We aimed to determine its demographics, clinical manifestations, and biomarker findings. Fifty-two PCA patients were investigated. Patients underwent neuropsychological assessment, magnetic resonance imaging, and fluorodeoxyglucose (FDG)-, amyloid-, and tau-positron emission tomography (tau-PET) scans. Normalized regional FDG-PET values were represented as z-scores relative to a control population. Patients were divided into "primary occipital" and "other PCA" subgroups according to FDG-PET-defined criteria, with primary occipital defined as patients in which the z-scores for occipital subregions were at least one standard deviation lower (SD) (i.e., more abnormal) than the z-scores in all other brain regions. Global amyloid-PET, temporo-parietal FDG-PET, and temporal tau-PET regions-of-interest (ROIs) were calculated. Nine patients were classified as primary occipital; they were older (p=0.034) and had more years of education (p=0.007) than other PCA patients. The primary occipital group performed worse on the Ishihara test for color perception (p<0.001), while other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p=0.005). Overall neuropsychiatric symptom burden was lower in the primary occipital group (p<0.001). The FDG-PET meta-ROI was higher in the primary occipital subtype (p=0.006), but no differences were observed in amyloid- and tau-PET. Our findings suggest that primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia, and less hypometabolism in temporo-parietal meta-ROI compared to established phenotypes.

The Extent of Necrosis in Brain Metastases May Predict Subtypes of Primary Cancer and Overall Survival in Patients Receiving Craniotomy.

Simple SummaryKnowledge regarding the character of necrosis in brain metastases from different primary cancer subtypes, as well as its impact on patient survival post-craniotomy, remains unknown. We performed a retrospective analysis on 145 BMs and found that lung cancers presented with a generally larger area of necrosis. Further, moderately abundant necrosis to tumor ratio appeared to confer better overall survival versus highly abundant, or even sparse necrosis. Findings of this study indicate that necrosis to tumor ratio in brain metastasis may predict subtypes of primary cancer and have potential as a biomarker for disease prognostication.Although necrosis is common in brain metastasis (BM), its biological and clinical significances remain unknown. We evaluated necrosis extent differences by primary cancer subtype and correlated BM necrosis to overall survival post-craniotomy. We analyzed 145 BMs of patients receiving craniotomy. Necrosis to tumor ratio (NTR) was measured. Patients were divided into two groups by NTR: BMs with sparse necrosis and with abundant necrosis. Clinical features were compared. To investigate factor relevance for BM necrosis, multivariate logistic regression, random forests, and gradient boosting machine analyses were performed. Kaplan–Meier analysis and log-rank tests were performed to evaluate the effect of BM necrosis on overall survival. Lung cancer was a more common origin for BMs with abundant necrosis (42/72, 58.33%) versus sparse necrosis (23/73, 31.51%, p < 0.01). Primary cancer subtype and tumor volume were the most relevant factors for BM necrosis (p < 0.01). BMs harboring moderately abundant necrosis showed longer survival, versus sparse or highly abundant necrosis (p = 0.04). Lung cancer BM may carry larger necrosis than BMs from other cancers. Further, moderately abundant necrosis in BM may predict a good prognosis post-craniotomy.

Abstract 048: Changes In Bile Acid Metabolism, Circulating MicroRNA-34a, And Improvements In Lipid Profiles In Response To Weight-loss Diets: The Pounds Lost Trial

Background: Bile acids are synthesized from cholesterol in the liver and play pivotal roles in nutrient absorption and metabolic regulation. Altered bile acid metabolism is related to dyslipidemia, and microRNA-34a (miR-34a) may play a pivotal role in the treatment of lipid homeostasis by regulating the bile acid biosynthesis. Hypothesis: We investigated whether weight-loss diet-induced changes in primary and secondary bile acids were associated with the improvements in lipid profiles. We also tested the role of circulating miR-34a in the altered bile acid metabolism in adults with overweight and obesity. Methods: A total of 520 participants of a weight-loss dietary intervention (the POUNDS Lost trial) with data on bile acids and miR-34a were included in the present analysis. Circulating levels of miR-34a and bile acid subtypes (primary and secondary unconjugated bile acids and their taurine-/glycine-conjugates) were measured at baseline and 6 months after the intervention. Outcome measurements were improvements in lipids (triglycerides and cholesterol) in response to the interventions. Results: At baseline, higher levels of primary bile acids (chenodeoxycholate (CDCA), glycocholate (GCA), taurocholate (TCA), and glycochenodeoxycholate (GCDCA) were associated with elevated levels of triglycerides ( P FDR &lt;0.05). Greater decreases in the primary bile acid subtypes (CDCA, GCA, TCA, GCDCA, and taurochenodeoxycholate [TCDCA]) in response to the interventions were significantly associated with larger reductions of triglycerides at 6 months ( P FDR &lt;0.05 for all). Decreases in secondary bile acids (deoxycholate and its conjugated forms) also showed significant associations with decreases in triglycerides. Similarly, reductions of total cholesterol at 6 months were associated with decreases in the primary (such as GCA, GCDCA, TCDCA) and secondary bile acid subtypes. We found that greater levels of miR-34a at baseline were related to higher levels of triglycerides at baseline (p=0.038) and higher levels of primary bile acids (such as CA, CDCA, GCA, and TCA [PFDR &lt;0.05 for all]) but not with the secondary bile acids at baseline. Further, weight-loss diet-induced changes in miR-34a were positively correlated with changes in the primary bile acid subtypes (CDCA, GCA, and GCDCA). Conclusions: Changes in the specific primary and secondary bile acid subtypes were related to the improvements in lipid profiles in response to weight-loss diet interventions. Circulating miR-34a might in part contribute to the alterations in the primary bile acid subtypes in obese adults.

The Accuracy of Simple and Adjusted Aldosterone Indices for Assessing Selectivity and Lateralization of Adrenal Vein Sampling in the Diagnosis of Primary Aldosteronism Subtypes.

ObjectiveThis study aimed to evaluate the reliability of simple and corrected aldosterone indices for assessing the selectivity and lateralization of adrenal vein sampling (AVS) in patients with primary aldosteronism.MethodsData of all consecutive patients with primary aldosteronism who underwent AVS for subtype diagnosis, followed at two Italian referral centers, were analyzed retrospectively.ResultsAVS achieved bilateral selectivity in 112/144 patients. Unilateral disease was diagnosed in 60 cases (53.6%) and idiopathic hyperaldosteronism in 52 individuals (46.4%). The aldosterone index (aldosterone ratio between an adrenal vein and the inferior vena cava) showed a high accuracy in predicting selectivity, compared to a cortisol selectivity index of 1.1, and a moderate accuracy, compared to cortisol cut-offs of 2 and 3. The simple aldosterone index showed a moderate accuracy in predicting ipsi/contralateral aldosterone hypersecretion, while lesion side- and hypokalemia-corrected aldosterone index revealed a significant improvement in predicting ipsi/contralateral disease. Moreover, the comparative aldosterone index (aldosterone ratio in the dominant vs the non-dominant adrenal vein) revealed a high accuracy in predicting unilateral primary aldosteronism. For an immediate clinical application of our results, the adjusted cut-offs were calculated, according to the Youden’s criterion and to a pre-established specificity of 90%, for all possible combinations of lesion side at imaging and presence/absence of hypokalemia.ConclusionsThis study demonstrated the diagnostic accuracy of simple and clinical-/imaging-corrected aldosterone indices for adrenal vein sampling in subtype diagnosis of primary aldosteronism and suggests the potential application of these tools to select patients for adrenalectomy when standard indices cannot be performed.

Abstract P5-06-01: Spatiotemporal gene expression analysis to identify novel tumor-neural crosstalk in TNBC brain metastases

Abstract Brain metastasis (BrM) occurs in 25-40% of TNBC metastatic patients while one-year survival remains a single digit. In contrast to other primary subtypes, TNBC usually spreads to the brain rapidly at early stages or even before the diagnosis of primary cancer. The shorter development time of BrM in TNBC and shorter survival time after BrM diagnosis may indicate a certain innate ability of TNBC cells in adapting to the brain. Recent seminal findings and our studies identified enriched and diverse expressions of neurotransmitters receptors, transporters, and key synthesis enzymes in brain metastatic TNBC cells. Since neurotransmitters, gliotransmitters, neurotrophic factors, and neural cytokines, called neuroactive substances (NSs), are the most abundant and key intercellular communication signals in the brain, we hypothesize that tumor cells leverage NSs to assimilate into the neural circuitry via communicating with various types of neural cells, including astrocytes, microglia/macrophages, oligodendrocytes and so on, to reinforce tumor-neural crosstalk in the development of BrM. By performing spatial transcriptomics experiments on mouse brain tissue sections bearing TNBC metastatic tumors, we found that brain regions, tumor lesions at different locations, and even tumor-surrounding areas were well separated into different clusters based on the spatial gene expressions and further predicted several novel paracrine and autocrine signalings between/within tumors and tumor-surrounding neural niches under different conditions, including tumor locations, tumor sizes, tumor center vs. edges, and stages of tumor development using the Cell-Cell Communication Explorer (CCCExplorer), a computational modeling tool for multi-cellular crosstalk and intracellular signaling developed by our lab. We conducted functional experiments to demonstrate that cell type-specific depletion of the secreted NSs deactivated the activities of corresponding receptor and downstream signaling using a cellular co-culture BrM system. The presented study indicates that the characterization and identification of spatiotemporal tumor-neural crosstalk in the BrM metastatic niche would open up a new vista for discovering novel therapeutics targets for devastating metastatic brain tumor. Citation Format: Hong Zhao, Xin Wang, Jianting Sheng, Shan Xu, Dongbing Gao, Stephen Wong. Spatiotemporal gene expression analysis to identify novel tumor-neural crosstalk in TNBC brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-01.

Epidemiological analysis of lung and mediastinal neuroendocrine neoplasms in Japan based on the national database

BackgroundNeuroendocrine neoplasms (NENs) are rare and can originate from any body part. However, there are only few epidemiological studies, especially on lung and mediastinal NENs. This study investigated the epidemiological trends and differences between lung and mediastinal NENs in Japan. MethodsPatients with lung and mediastinal NENs were identified in a national hospital-based cancer registry between 2009 and 2015 in Japan. NENs were subclassified into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs were further subdivided into large neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). We examined the patient characteristics: sex, age, histology, year of diagnosis, diagnostic opportunity, and initial treatment. ResultsWe identified 48,433 patients with 47,888 lung (98.9%) and 545 mediastinal (1.1%) NENs. The commonest subtype of lung NENs was SCCs (87%), followed by LCNECs (10%) and NETs (3%). In the mediastinum, SCCs were also the commonest (48%), followed by NETs (38%) and LCNECs (14%). The number of lung NEN annually increased; however, that of mediastinal NENs did not change over time. The mean age of patients with lung NETs was lower than that of patients with lung LCNECs and SCCs (NETs, 62 ± 14 years; LCNECs, 70 ± 9 years; SCCs, 71 ± 9 years; p < .001). The lung and mediastinal NENs were mainly detected based on symptoms, except for lung NETs. Surgical intervention, including multimodal therapy, was performed for 89.3% of lung NETs (surgery alone: 83.6%), while only 15.6% of lung NECs were treated with surgery. For the mediastinum, 75.9% of NETs were treated with surgery, with 27.1% of cases treated with surgery plus multimodal therapy. Surgery was performed more frequently for mediastinal NECs (37%) than for lung NECs (15.6%). ConclusionsThis study highlights differences in trends of lung and mediastinal NENs. This study’s findings support the importance of epidemiological evaluations based on the primary sites and histological subtypes.

Jejunal volvulus within an inguinal hernia sac like as an extremely rare cause of acute mechanical gastrointestinal obstruction in adults: First literature report.

Introduction and importanceSmall bowel volvulus (SBV) represents a rare and life-threatening cause of gastrointestinal obstruction among adults. SBV can be classified as primary and secondary subtypes. Preoperative diagnosis of SBV is a challenge because of the absence of pathognomonic clinical, radiographic and laboratory findings. Surgery represents the correct treatment of SBV.Case presentationA 69-year-old Caucasian male presented to the Emergency Department with a two-day history of abdominal pain, inability to pass gas or stool, nausea, vomiting. Physical examination revealed abdominal distension, generalized abdominal pain without guarding or rebound tenderness, a partially reducible and painless right inguinal hernia. Laboratory tests reported neutrophilic leukocytosis. Abdominal computed tomography revealed massive gastroduodenal dilatation with pneumoperitoneum and small bowel loops in the right inguinal sac. The patient underwent exploratory laparotomy: a jejunal volvulus (JV) located within the right inguinal hernia sac, causing gastrointestinal obstruction, was devolvulated and a right prosthetic inguinal hernia repair was also performed. The patient was discharged on the 10th postoperative day.Clinical discussionSecondary SBV is due to any congenital or acquired lesions and rarely occurs among adults in Western countries. This is the first literature report of a JV located within an inguinal hernia sac causing gastrointestinal obstruction.ConclusionSecondary JV represents an extremely rare abdominal emergency necessitating early diagnosis to prevent the development of intestinal ischemia, bowel necrosis and peritonitis. Diagnosis of JV needs a high index of suspicion and may be facilitated by imaging, often it is made intraoperatively. Surgery represents the appropriate treatment of JV.

Prognostic Utility of CpG Island Hypermethylated Phenotype in Early-Stage Invasive Primary Melanomas

In their article in the Journal of Investigative Dermatology, Conway etal. (2021) show the significance of the CpG island methylator phenotype (CIMP) subclass in early-stage invasive primary melanomas, particularly in the lentigo maligna melanoma histological subtype. CIMP melanomas had reduced melanoma-specific survival compared with intermediate and low methylation subtypes. This study emphasizes the importance of epigenomic changes in early-stage primary tumors that are associated with poor prognosis.

Comparing Clinicopathologic Factors and Survival in Stage III Adenocarcinoma and Squamous Cell Carcinoma of the Lung Following Definitive Chemoradiotherapy

<h3>Purpose/Objective(s)</h3> Non-small cell lung carcinoma (NSCLC) represents a diverse array of malignancies with the primary histologic subtypes of adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Nearly one third of patients diagnosed with NSCLC will present with stage III disease. In patients with unresectable disease, the current standard is definitive chemoradiotherapy (CRT) followed by immunotherapy. Even though the systemic therapeutic landscape has changed based on histological subtype, radiation treatment remains the same for all NSCLC. Also it remains unclear whether certain clinicopathologic factors are associated with either histology or if histology influences survival outcomes following definitive CRT. Therefore, we analyzed the national cancer database (NCDB) to compare overall survival (OS) in Stage III NSCLC patients with ADC and SCC treated with definitive CRT. <h3>Materials/Methods</h3> We queried the NCDB for patients diagnosed with Stage III ADC or SCC of the lung between the years 2004 – 2015 who were treated non-surgically with concurrent CRT to a definitive dose (60-74 Gy). Univariable and multivariable analyses identified characteristics predictive of OS. Survival was calculated using Kaplan Meier method. Multivariable logistic regression was performed to identify clinicopathologic variables associated with each histology. <h3>Results</h3> Ultimately 17,015 Stage III NSCLC patients with either SCC (n=9,406) or ADC (n=7,609) were eligible for analysis. Univariable analysis demonstrated a median OS of 24 months and 20 months (p<0.0001) and 3-year OS rates of 36% and 30% (p<0.0001) in patients diagnosed with ADC and SCC, respectively. Patients with SCC were more likely to be older (OR: 1.14, 95% CI: 1.07-1.23), have higher comorbidity scores (OR: 1.60, 95% CI: 1.43-1.80), left sided tumors (OR: 1.23, 95% CI: 1.14-1.31), and T4 lesions [OR: 2.68, 95% CI: 2.40-2.99, (p<0.0001, for all)]. Patients with SCC were less likely to have N2 (OR: 0.83, 95% CI: 0.72-0.94) or N3 disease (OR: 0.53, 95% CI: 0.46-0.62) and to receive treatment at an academic treatment facility (OR: 0.90, 95% CI: 0.84-0.97). Younger age, lower comorbidity score, higher radiation dose (i.e. ≥ 70 Gy), female sex, lower T stage, lower N stage, and ADC histology were associated with improved OS on multivariable comparison (p<0.01, for all). <h3>Conclusion</h3> Compared to ADC, SCC was associated with higher T stage, lower N stage, older patients with greater comorbidity scores, and left sided tumors. Both median, as well as, 3-year and 5-year OS rates were inferior in patients with SCC compared to ADC. Prospective studies are needed to validate these findings and potentially identify radiotherapeutic strategies that may improve outcomes in this histologic subset.

Use of predictive spatial modeling to reveal that primary cancers have distinct central nervous system topography patterns of brain metastasis.

Brain metastasis is the most common intracranial neoplasm. Although anatomical spatial distributions of brain metastasis may vary according to primary cancer subtype, these patterns are not understood and may have major implications for treatment. To test the hypothesis that the spatial distribution of brain metastasis varies according to cancer origin in nonrandom patterns, the authors leveraged spatial 3D coordinate data derived from stereotactic Gamma Knife radiosurgery procedures performed to treat 2106 brain metastases arising from 5 common cancer types (melanoma, lung, breast, renal, and colorectal). Two predictive topographic models (regional brain metastasis echelon model [RBMEM] and brain region susceptibility model [BRSM]) were developed and independently validated. RBMEM assessed the hierarchical distribution of brain metastasis to specific brain regions relative to other primary cancers and showed that distinct regions were relatively susceptible to metastasis, as follows: bilateral temporal/parietal and left frontal lobes were susceptible to lung cancer; right frontal and occipital lobes to melanoma; cerebellum to breast cancer; and brainstem to renal cell carcinoma. BRSM provided probability estimates for each cancer subtype, independent of other subtypes, to metastasize to brain regions, as follows: lung cancer had a propensity to metastasize to bilateral temporal lobes; breast cancer to right cerebellar hemisphere; melanoma to left temporal lobe; renal cell carcinoma to brainstem; and colon cancer to right cerebellar hemisphere. Patient topographic data further revealed that brain metastasis demonstrated distinct spatial patterns when stratified by patient age and tumor volume. These data support the hypothesis that there is a nonuniform spatial distribution of brain metastasis to preferential brain regions that varies according to cancer subtype in patients treated with Gamma Knife radiosurgery. These topographic patterns may be indicative of the abilities of various cancers to adapt to regional neural microenvironments, facilitate colonization, and establish metastasis. Although the brain microenvironment likely modulates selective seeding of metastasis, it remains unknown how the anatomical spatial distribution of brain metastasis varies according to primary cancer subtype and contributes to diagnosis. For the first time, the authors have presented two predictive models to show that brain metastasis, depending on its origin, in fact demonstrates distinct geographic spread within the central nervous system. These findings could be used as a predictive diagnostic tool and could also potentially result in future translational and therapeutic work to disrupt growth of brain metastasis on the basis of anatomical region.

Regulation of IncRNA ZNF667-AS1 in Proliferation and Invasion of Esophageal Squamous Cell Carcinoma Cells via Mediating ceRNA Network.

Esophageal squamous cell carcinoma (ESCC), classified as a primary histological subtype of esophageal cancer (EC), dominates approximately 90% of the newly diagnosed EC. Long non-coding RNAs (lncRNAs) are frequently related to the course of ESCC. The current study aimed to investigate whether lncRNA zinc finger protein 667-antisense RNA 1 (ZNF667-AS1) modulates the proliferation and invasion of ESCC cells. ESCC tissues and cell lines, para-carcinoma tissues, and human esophageal epithelial cells (HEEpiCs) were collected. lncRNA ZNF667-AS1 expression in the above tissues and cells was detected. The effect of lncRNA ZNF667-AS1 on proliferation and invasion of Eca109 cells was detected using cell counting kit-8, colony formation, and Transwell assays. lncRNA ZNF667-AS1 subcellular localization was determined via the nuclear/cytosol fractionation assay. The binding relationships between miR-18b-5p and lncRNA ZNF667-AS1 and RAS p21 protein activator 1 (RASA1) were verified using dual-luciferase reporter gene experiment and RNA immunoprecipitation experiment. The expressions of miR-18b-5p and RASA1 in the tissues and cells were identified. The roles of miR-18b-5p overexpression or silencing RASA1 in proliferation and invasion of ESCC cells were examined through rescue experiments. lncRNA ZNF667-AS1 was underexpressed in ESCC tissues and cells, and lncRNA ZNF667-AS1 overexpression hampered ESCC cell proliferation and invasiveness. miR-18b-5p targeted RASA1 while lncRNA ZNF667-AS1 promoted RASA1 transcription via binding to miR-18b-5p. Over-expression miR-18b-5p or silencing RASA1 reversed the inhibitory effects of lncRNA ZNF667-AS1 overexpression on ESCC cell proliferation and invasion. lncRNA ZNF667-AS1 overexpression accelerated RASA1 transcription by competitively binding to miR-18b-5p, thus suppressing ESCC cell proliferation and invasion.

The effect of preoperative prognostic nutritional index on outcome in glioblastoma multiforme patients

Background/Aim: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor subtype with a poor prognosis despite various treatments. Some prognostic markers on survival (such as age, Eastern Cooperative Oncology Group Performance Score (ECOG-PS), isocitrated hydrogenase (IDH) status, alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutation status, possibility of extensive surgery) have been defined. Prognostic Nutritional Index (PNI) has been evaluated in various cancers (such as lung, esophagus, and pancreas), and patients with a low PNI score have been associated with a poor prognosis for overall survival (OS). Our study aimed to examine the effectiveness of molecular and demographic characteristics and preoperative PNI score that may affect OS in GBM patients. Methods: In this retrospective cohort study, GBM diagnosed patients who were 18 years old or older, were included in the study. We measured their pretreatment PNI score and performed multivariate Cox regression analyses of OS in GBM patients. Results: A total of 107 patients were included in the study. Median age was 58 (range, 32-83) years. 72 patients (67.3%) were male and 35 patients (32.7%) were female. The mean preoperative PNI level was calculated as 50.5. The median overall-survival (mOS) was 19.7 months and the median time to progression (mTTP) was 8.1 months. There was no statistically significant result on overall survival in the univariate analysis of patients with PNI>50.5 (P=0.121). In multivariate analysis, being 70 years or older (P=0.012), IDH-1 wild and ATRX mutant patients (P=0.016), IDH-1 mutant and ATRX wild patients (P=0.037), and TTP 12 months and older (P<0.001) were considered as independent risk factors on overall survival. Conclusions: In our study, the effect of preoperative PNI score on survival could not be demonstrated. Further studies are needed to elucidate the potential impact of PNI on outcomes in patients with GBM.

A self-supervised contrastive learning approach for whole slide image representation in digital pathology

Image analysis in digital pathology has proven to be one of the most challenging fields in medical imaging for AI-driven classification and search tasks. Due to their gigapixel dimensions, whole slide images (WSIs) are difficult to represent for computational pathology. Self-supervised learning (SSL) has recently demonstrated excellent performance in learning effective representations on pretext objectives, which may improve the generalizations of downstream tasks. Previous self-supervised representation methods rely on patch selection and classification such that the effect of SSL on end-to-end WSI representation is not investigated. In contrast to existing augmentation-based SSL methods, this paper proposes a novel self-supervised learning scheme based on the available primary site information. We also design a fully supervised contrastive learning setup to increase the robustness of the representations for WSI classification and search for both pretext and downstream tasks. We trained and evaluated the model on more than 6000 WSIs from The Cancer Genome Atlas (TCGA) repository provided by the National Cancer Institute. The proposed architecture achieved excellent results on most primary sites and cancer subtypes. We also achieved the best result on validation on a lung cancer classification task.

Analysis of serum HE4 levels in various histologic subtypes of epithelial ovarian cancer and other malignant tumors.

The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported. The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies. Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group. A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n = 391) of serous, 85%(n = 73) of endometrioid, 45%(n = 42) of mucinous, 86%(n = 51) of mixed tumors, and 69%(n = 36) of clear cell tumors had elevated serum HE4 levels. Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors.

A 'Mini Linguistic State Examination' to classify primary progressive aphasia.

There are few available methods for qualitatively evaluating patients with primary progressive aphasia. Commonly adopted approaches are time-consuming, of limited accuracy or designed to assess different patient populations. This paper introduces a new clinical test—the Mini Linguistic State Examination—which was designed uniquely to enable a clinician to assess and subclassify both classical and mixed presentations of primary progressive aphasia. The adoption of a novel assessment method (error classification) greatly amplifies the clinical information that can be derived from a set of standard linguistic tasks and allows a five-dimensional profile to be defined. Fifty-four patients and 30 matched controls were recruited. Five domains of language competence (motor speech, phonology, semantics, syntax and working memory) were assessed using a sequence of 11 distinct linguistic assays. A random forest classification was used to assess the diagnostic accuracy for predicting primary progressive aphasia subtypes and create a decision tree as a guide to clinical classification. The random forest prediction model was 96% accurate overall (92% for the logopenic variant, 93% for the semantic variant and 98% for the non-fluent variant). The derived decision tree produced a correct classification of 91% of participants whose data were not included in the training set. The Mini Linguistic State Examination is a new cognitive test incorporating a novel and powerful, yet straightforward, approach to scoring. Rigorous assessment of its diagnostic accuracy confirmed excellent matching of primary progressive aphasia syndromes to clinical gold standard diagnoses. Adoption of the Mini Linguistic State Examination by clinicians will have a decisive impact on the consistency and uniformity with which patients can be described clinically. It will also facilitate screening for cohort-based research, including future therapeutic trials, and is suitable for describing, quantifying and monitoring language deficits in other brain disorders.

Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China.

BackgroundImmune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune‐related adverse events (irAEs) remain poorly understood, especially in a real‐world setting.MethodsA multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD‐L1) monotherapy, anticytotoxic T‐lymphocyte antigen‐4 monotherapy, or combination therapy.ResultsIn total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28–87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3–5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0–1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD‐L1 expression (≥1%) and who received first‐line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001).ConclusionsThe incidence rate of irAEs was 26.9% in a real‐world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Different Response to Immunotherapy According to Melanoma Histologic Subtype.

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are the most common melanoma histologic subtypes and are characterized by different biological features. We retrospectively analyzed all consecutive patients with advanced melanoma, treated with anti-PD-1 and/or anti-CTLA-4 at our center, with data available on primary tumor subtype. The primary objective was to assess the association between histologic subtype and patients' outcomes. In addition, we analyzed whole-exome and whole-transcriptome sequencing data of a cohort of advanced melanoma to identify genes and related pathways, characterized by significant differences between NMs and SSMs. Twenty-one patients with NM and 39 with SSM, treated with anti-PD-1(53/60) as monotherapy or combined with anti-CTLA-4 (7/60), were analyzed. All known clinical-pathologic prognostic factors were well balanced between NM and SSM groups, except for the ECOG-PS score. The overall response rate was 52.4% (95% confidence interval, 29.8-74.3) in the NMs group versus 20.5% (9.3-36.5) in the SSMs group (P-value=0.02). The median progression-free survival and overall survival were, respectively, 13.9 and 44.5 months in the NMs group versus only 3.2 and 12 months in SSMs group (progression-free survival P-value=0.032; overall survival P-value=0.002). Multivariable analysis adjusting for the ECOG-PS, confirmed similar results. Whole-exome and whole-transcriptome data of 28 NMs and 21 SSMs were analyzed. No significant differences were observed in terms of both TMB and frequency of mutation in any gene. A total of 266 genes were overexpressed in NMs as compared with SSMs, and enrichment-analysis revealed a significant enrichment (false discovery rate<0.05) of genes belonging to immune-related pathways involved in antigens presentation mechanisms, response to interferon gamma and neutrophil activation. We provided clinical evidences suggesting a relevant association between melanoma histologic subtype and response to immunotherapy.