Undifferentiated Cancer Research Articles

Molecular subtypes and genomic landscape of undifferentiated and dedifferentiated endometrial cancer

Molecular subtypes and genomic landscape of undifferentiated and dedifferentiated endometrial cancer

Human epidermal growth factor receptor 2(Her2)-targeted pH-responsive MR/NIRF bimodal imaging-mediated nano-delivery system for the diagnosis and treatment of undifferentiated thyroid cancer.

Undifferentiated thyroid cancer (ATC) is highly malignant and does not respond well to sorafenib (SRF) treatment owing to the lack of specificity of SRF targeting. Drug delivery nanosystems can improve the efficiencies of drug in treating various cancer types. However, many conventional drug delivery nanosystems lack targeting and exhibit unresponsive drug release. Therefore, we developed a pH-responsive nano-targeted drug delivery systems using human serum albumin (HSA) as a carrier to generate manganese dioxide (MnO2)@HSA nanoparticles (NPs), then encapsulated SRF and the fluorescent dye indocyanine green (ICG) and finally modifyed the targeting antibody pertuzumab in the outer layer of the nano complexes, resulting in SRF/ICG/MnO2@HSA-pertuzumab (HISMP) NPs. This system targets human epidermal growth factor receptor 2 on the cell membrane surface of thyroid cancer cells and is designed to accumulate at tumor sites. Then, pH-responsive release of divalent manganese ions, ICG, and SRF enables magnetic resonance/fluorescence (MR/NIRF) dual-modality imaging and precise drug delivery for diagnostic and therapeutic integration. Various characterization analyses including transmission electron microscopy, Fourier infrared spectroscopy, and particle size analysis confirm that we successfully synthesized HISMP NPs with a diameter of 150.709nm. The results of CCK8 cytotoxicity and apoptosis assays show that HISMP NPs exhibited high cytotoxicity and induce apoptosis in thyroid cancer cells. In vivo MR/NIRF imaging experiments confirmed that the HISMP NPs specifically aggregated at tumor sites and have good in vivo MR/NIRF imaging ability and effective anti-tumor activity. The nano-delivery system is expected to provide a theoretical foundation for the efficient ATC diagnosis and therapy.

6897 The Role of Neutrophil Heterogeneity on T-cell Immunity in Advanced Thyroid Cancer Patients

Abstract Disclosure: Y. Kang: None. S. Lee: None. J. Yoon: None. D. Kang: None. J. Lee: None. Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I-II), and healthy controls (n=10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1+ immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T cell related pathways, such as T cell receptor signaling pathway and T cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer. Presentation: 6/3/2024

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial.

To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer. The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA-mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs. Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Case of Fatal Type B Lactic Acidosis in Primary Undifferentiated Ovarian Cancer

Case of Fatal Type B Lactic Acidosis in Primary Undifferentiated Ovarian Cancer

Evaluation of Risk Factors Associated with Recurrence and Death in Patients with Thyroid Cancer From 2008 to 2023 in the West of Iran.

Thyroid carcinoma (TC) is a global clinical concern, and its incidence has progressively increased worldwide. Early detection of TC and subsequently decreased age at the diagnosis seem to result from extensive employment of imaging modalities, biopsy techniques, and improvements in the healthcare system. Study Design: A retrospective cohort study. Overall, 400 patients diagnosed with TC following thyroidectomy in the Endocrinology Clinic, who were followed for fifteen years, were investigated in this study. The checklist included patients' demographic characteristics, clinical information, and response to treatment, recurrence, and death. There were 19.25% men and 80.75% women. The mean age was 41.005±15.58 years. The risk of death and recurrence was significantly higher in men, patients>65 years, smokers, patients with a family history of TC, undifferentiated cancer, multifocality, and stages III and IV (P<0.001). Each additional year of life was associated with a 21% increase in the risk of death (P<0.001). Smoking was associated with a 4.36-fold increase in the risk of death (P=0.05). For each additional year of life, the probability of recurrence increased by 3% (P=0.009). Men were 4.73 times more likely to recur (P<0.001) than women. To employ the proper therapeutic intervention and perform meticulous postoperative surveillance, it is crucial to consider the predictive influence of pertinent elements. Diagnosing TC in its early stages is essential for the healthcare system because of the increased incidence, younger age at diagnosis, and overall favorable prognosis of TC.

Histogenetic insights and genetic landscape of fibromatosis-like undifferentiated gastric carcinoma: a focused study

BackgroundThe aim of this study was to elucidate the histogenesis and genetic underpinnings of fibromatosis-like undifferentiated gastric carcinoma (FLUGC), a rare pathological entity.MethodThrough a detailed analysis of seven cases, including histopathological evaluation, CTNNB1 gene mutation screening, human epidermal growth factor receptor 2 (HER2) protein level quantification, and HER2 gene amplification assessment to identify the pathological and molecular characteristics of FLUGC.ResultsOf the seven patients in this study, five were male and two were female (age: 39–73 years). Four patients presented with lesions in the gastric antrum and three had lesions in the lateral curvature of the stomach. Histopathologically, over 90% of the tumor consisted of aggressive fibromatosis-like tissue, including proliferating spindle fibroblasts and myofibroblasts and varying amounts of collagenous fibrous tissues. Undifferentiated cancer cells, accounting for less than 10%, were dispersed among the aggressive fibromatosis-like tissues. These cells were characterized by their small size and were relatively sparse without glandular ducts or nested mass-like structures. Immunophenotyping results showed positive expression of CKpan, CDX2, villin, and p53 in undifferentiated cancer cells; positive expression of vimentin in aggressive fibromatosis-like tissue; positive cytoplasmic expression of β-catenin; and focal cytoplasmic positive expression of smooth muscle actin (SMA). Genetic analysis did not reveal any mutations in the CTNNB1 gene test, nor was there amplification in the HER2 gene fluorescence in situ hybridization (FISH) test. Additionally, the Epstein-Barr encoding region (EBER) of in situ hybridization was negative; and the mismatch repair (MMR) protein was positive. Programmed cell death-1 (PD-1) was < 1–5%; programmed cell death ligand 1 (PD-L1): TPS = 1–4%, CPS = 3–8.ConclusionThe study highlights the significance of CTNNB1, HER2, EBER, and MMR as pivotal genetic markers in FLUGC, underscoring their relevance for diagnosis and clinical management. The rarity and distinct pathological features of FLUGC emphasize the importance of accurate diagnosis to prevent underdiagnosis or misdiagnosis and to raise awareness within the medical community.

Laparoscopic total gastrectomy for multiple type І gastric neuroendocrine tumours: a case report

Background. The gastric neuroendocrine tumours (G-NETs), arising from neuroendocrine cells within the stomach. Type I lesions are associated with chronic atrophic gastritis (CAG). Multiple G-NETs are rare. Purpose – of our report is to describe a rare case of multiple Type-I G-NETs. Material and methods. During routine gastroscopy in a 44-year-old female with history of CAG and anaemia, multiple (15–20) polyps of size 2–9 mm were found. Multiple biopsies were obtained. Histopathological examination with haematoxylin and eosin staining described these lesions as undifferentiated cancer. Repeated gastroscopy was done. The three biggest polyps (5–9 mm) were removed by snare polypectomy. Repeated histopathological examination was specific for G-NET. The neoplasm presented Ki-67 proliferation index of &lt; 3%; Cytokeratin 18, Chromogranin A, Synaptophysin, INSM1 were positive in neoplasm cells. Laparoscopic total gastrectomy was done. The operative time was 255 min, and the blood loss was 50 ml. Histopathological examination of a surgical specimen revealed multiple, Grade 1 G-NET (fig. 1–3). All lesions are limited to the mucosa and submucosa of the stomach, the longest size of the largest tumour lesion is 5 mm, what corresponds to pT1(m). No signs of lymphovascular or perineural invasion were found (L0 V0 Pn0). 18 regional lymph nodes were examined, no metastases were detected (0/18, pN0). Edges of resections of the esophagus and duodenum without signs of tumour growth (R0). Outside of tumours, there were signs of chronic inflammation of the stomach mucosa, with intestinal metaplasia and mixed glandular atrophy, there are also foci of nodular hyperplasia of neuroendocrine cells. Conclusion. We reported a rare case of multiple type-I G-NETs (pT1N0M0) with pernicious anaemia due to autoimmune CAG. Laparoscopic total gastrectomy is a method of choice in treatment of such patients.

Complex clinical and cytological diagnosis of eye adnexa epithelial tumors

Purpose. Studying clinical and cytological signs of malignant epithelial genesis tumors of eye adnexa. Material and methods. In 2015–2020, 308 patients aged from 23 to 87 (58.0 ± 6.7) years with suspected malignant neoplasms of eyelid skin and conjunctiva were cytologically examined. The material for cytological examination was obtained by scraping (n = 271; 88 %), imprinting (n = 27; 8.8 %), and fine needle aspiration biopsy (n = 10; 3.2 %) if the neoplasm was more than 10 mm thick. Preparations were processed and fixed according to the standard technique using panchromic Pappenheim staining. Results. The cytological analysis confirmed the clinical diagnosis and the epithelial genesis of the malignant neoplasm in 273 (88.7 %) patients. The benign nature of the tumor was confirmed in 17 patients (5.5 %) and the non-tumor nature of the process was confirmed in 11 patients (3.6 %). In the group of malignant tumors, basal cell cancer prevailed, affecting 240 patients (87.9 % of all malignant tumors). 27 patients (9.9% ) had squamous cell cancer, 4 patients had meibomian gland cancer in 4 patients, and 2 patients had undifferentiated cancer. Benign tumors included papillomas (n = 11), while tumor-like lesions included atheromas (n = 3) and granulation polyps (n = 3). Non-tumor lesions involved productive inflammation of the chalazion type (n = 7), or chronic inflammation of a reactive nature (n = 4). 22 patients had histological examination to check the diagnosis, in all cases the histological outcome coincided with the cytological diagnosis. Conclusion. The comprehensive clinical and cytological study allowed us to specify cytomorphological characteristics of epithelial tumors of the eye adnexa: the basal cell cancer and its varieties according to the clinical forms of the tumor, squamous cell cancer and meibomian gland cancer, and papilloma. The complex clinical and cytological method of diagnostics is easily applicable in out-patient conditions, allowing us to specify the diagnosis during the initial visit, which considerably reduces the time required for full patient’s examination.

KLHL14 is a tumor suppressor downregulated in undifferentiated thyroid cancer

KLHL14 is a substrate-binding subunit of Cullin-RING ligase 3 ubiquitin ligase complex, highly enriched in thyroid since early embryonic development, together with its antisense RNA KLHL14-AS. We have previously demonstrated that Klhl14-AS is a competing endogenous RNA regulating several differentiation and survival factors in thyroid cancer, acting as tumor suppressor. Recently, also KLHL14 has been shown to function as tumor suppressor in diffuse large B-cell lymphoma and in malignant mesothelioma. Here we show that KLHL14 expression is strongly reduced in anaplastic thyroid cancer, the less differentiated and most aggressive type of thyroid neoplasia. Such reduction is reproduced in different in vivo and in vitro models of thyroid cancer, being invariably associated with loss of differentiation. When Klhl14 expression is rescued in thyroid transformed cells, it reduces the cell proliferation rate and increase the number of apoptotic cells. On the other side, Klhl14 loss of function in normal thyroid cells affects the expression of several regulatory as well as functional thyroid markers. All these findings suggest that KLHL14 could be considered as a novel tumor suppressor in thyroid cancer, by also revealing its physiological role in the maintenance of a fully differentiated and functional thyroid phenotype.

Long-term outcomes of endoscopic submucosal dissection for undifferentiated type early gastric cancer over 2 cm with R0 resection.

Endoscopic submucosal dissection (ESD) for over 2 cm in size undifferentiated type (UD type) early gastric cancer (EGC) confined to the mucosa is not only challenging, but also long-term outcomes are not well known. To evaluate the long-term outcomes of ESD done for UD type EGCs confined to the mucosa over 2 cm in size and compare the results with those where the lesions were less than 2 cm. 143 patients with UD type EGC confirmed on histology after ESD at a tertiary hospital were reviewed. Cases with synchronous and metachronous lesions and a case with emergency surgery after ESD were excluded. A total of 137 cases were enrolled. 79 cases who underwent R0 resection were divided into 2 cm or less (group A) and over 2 cm (group B) in size. Among 79 patients who underwent R0 resection, the number in group A and B were 51 and 28, respectively. The mean follow-up period (SD) was 79.71 ± 45.42 months. There was a local recurrence in group A (1/51, 2%) and group B (1/28, 3.6%) respectively. This patient in group A underwent surgery while the patient in group B underwent repeated ESD with no further recurrences in both patients. There was no regional lymph node metastasis, distant metastasis, and deaths in both groups. With R0 resection strategy for ESD on lesions over 2 cm, 20.4% (28/137) of patients were able to avoid surgery compared with expanded indication. If R0 resection is achieved by ESD, UD type EGCs over 2 cm also showed good and similar clinical outcomes as compared to lesions less than 2 cm when followed for over 5 years. With R0 resection strategy, several patients can avoid surgery.

Prognostic Factors Associated with Breast Cancer-Specific Survival from 1995 to 2022: A Systematic Review and Meta-Analysis of 1,386,663 Cases from 30 Countries.

Breast cancer is the fifth-ranked cancer globally. Despite early diagnosis and advances in treatment, breast cancer mortality is increasing. This meta-analysis aims to examine all possible prognostic factors that improve/deteriorate breast cancer-specific survival. MEDLINE, PubMed, ScienceDirect, Ovid, and Google Scholar were systematically searched until September 16, 2023. The retrieved studies from 1995 to 2022 accumulated 1,386,663 cases from 30 countries. A total of 13 out of 22 prognostic factors were significantly associated with breast cancer-specific survival. A random-effects model provided a pooled estimate of the top five poorest prognostic factors, including Stage 4 (HR = 12.12; 95% CI: 5.70, 25.76), followed by Stage 3 (HR = 3.42, 95% CI: 2.51, 4.67), a comorbidity index ≥ 3 (HR = 3.29; 95% CI: 4.52, 7.35), the poor differentiation of cancer cell histology (HR = 2.43; 95% CI: 1.79, 3.30), and undifferentiated cancer cell histology (HR = 2.24; 95% CI: 1.66, 3.01). Other survival-reducing factors include positive nodes, age, race, HER2-receptor positivity, and overweight/obesity. The top five best prognostic factors include different types of mastectomies and breast-conserving therapies (HR = 0.56; 95% CI: 0.44, 0.70), medullary histology (HR = 0.62; 95% CI: 0.53, 0.72), higher education (HR = 0.72; 95% CI: 0.68, 0.77), and a positive estrogen receptor status (HR = 0.78; 95% CI: 0.65, 0.94). Heterogeneity was observed in most studies. Data from developing countries are still scarce.

DsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe

The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA–directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.

Clinicopathological Differences between Right and Left Colorectal Cancer by Sex.

Background: Until now, studies on colorectal cancer (CRC) have focused on clinicopathological characteristics based on location without considering sex differences. However, as men and women have fundamentally different physiological characteristics, research results in the clinical field are limited. We aimed to elucidate the differences in the clinicopathological characteristics between right-sided CRC (RCC) and left-sided CRC (LCC) according to sex. Methods: We classified 1492 South Korean patients with no history of colon surgery between July 2005 and June 2015 based on tumor location and sex. For these patients, differences in the clinical characteristics according to sex were compared using univariate and multivariate analyses. Results: Of the 1269 patients, 951 (74.9%) had LCC, and 318 (25.1%) had RCC, making LCC approximately three times more common than RCC. When sex was not taken into account, patients with RCC had significantly higher rates of anemia and undifferentiated cancers than the rates in those with LCC. Even considering sex, anemia and undifferentiated cancer were more prevalent in RCC than in LCC in both men and women. In contrast, age over 65 years and abnormal white blood cell count differed between RCC and LCC only in women. Conclusions: The clinicopathologic characteristics of CRC vary according to the location and sex. Therefore, sex must be considered as a fundamental characteristic of personalized treatment.

Neutrophil diversity is associated with T-cell immunity and clinical relevance in patients with thyroid cancer

Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I–II), and healthy controls (n = 10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1+ immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T-cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T-cell-related pathways, such as T-cell receptor signaling pathway and T-cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor-infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer.

S100A6 could not promote the differentiation of Calu-6 lung cancer cell line.

Our previous study demonstrated that S100 calcium binding protein A6 (S100A6) impairs tumorigenesis by Calu-6 lung cancer cells, as well as inhibit their growth. However, the role that S100A6 plays in tumor cell differentiation has not been previously explored. This study aimed to confirm the effect of S100A6 on the direction of differentiation in the human lung cancer cell linem Calu-6m based on our previous published research. A S100A6-overexpressing lentiviral vector was successfully constructed in our previous study. Nude mouse tumorigenicity was then applied successfully, and 15 mice were divided into three groups (Calu-6, Calu-6/neo, Calu-6/S100A6). After 5 weeks, we detected lung cancer markers with immunohistochemistry in mice tumor tissues, including the adenocarcinoma markers, TTF-1 and NapsinA, the squamous cell carcinoma markers, P40, CK5/6 and P63, and the small cell lung cancer markers CD56, Syn, CgA, TTF-1, CK, and Ki-67. Differences among the three groups were statistically compared. All the above-mentioned markers were positive in the tumor tissues of all three groups, and there were no significant differences. S100A6 cannot promote differentiation of the undifferentiated human lung cancer cell line, Calu-6, into adenocarcinoma, squamous, or small cell carcinoma cell lines.

Prognostic analysis of 23 cases of undifferentiated thyroid carcinoma

Objective: To investigate the relationship between clinical features, treatment and prognosis of undifferentiated thyroid carcinoma. Methods: The clinical and follow-up data of 23 patients with undifferentiated thyroid carcinoma admitted to Chongqing University Cancer Hospital from March 2012 to September 2019 were retrospectively analyzed. Results: The median survival time of 23 patients with undifferentiated thyroid carcinoma was 15 weeks, 3-month survival time was 56.5%, 6-month survival rate was 39.1%, and 1-year survival rate was 30.4%. Univariate analysis showed that the size of primary tumor lesion, normal albumin, normal platelets, activated partial thrombin time, fibrinogen, thyroglobulin antibody and radiotherapy were the factors influencing the prognosis of undifferentiated thyroid cancer. The analysis of the effect of treatment on the prognosis showed that surgery, radiotherapy and combined treatment can obviously improve the prognosis. Multivariate analysis showed that the independent factors affecting prognosis were the diameter of the primary lesion, whether radiotherapy was given or not, the dose of radiotherapy, and whether radiotherapy was combined with surgery. Conclusion: The malignant degree of undifferentiated thyroid cancer is very high, so R0 or R1 resection of neck lesions plus radiotherapy should be taken as far as possible for patients with surgical opportunity, and the same effect may be achieved for patients who have lost the surgical opportunity. Anticoagulant and antiplatelet therapy may benefit patients.

Efficacy of immune checkpoint inhibitors in SMARCA4-deficient and TP53 mutant undifferentiated lung cancer.

The present study was conducted to characterize the clinicopathologic characteristics, immunohistochemical staining results, and immune checkpoint inhibitors (ICIs) efficacy in patients with SMARCA4-deficient/TP53 mutant lung cancer. Patients diagnosed with advanced or metastatic undifferentiated lung cancer harboring SMARCA4-deficient and TP53 mutations, however, without targetable sensitive mutations were retrieved from the electronic medical record system. Descriptive statistics were used to describe the baseline characteristics and clinical features including age, gender, eastern cooperative oncology group performance status, disease stage, smoking status, chief complaint, site of the primary mass, tumor size, gross type, symptoms, local invasion, and metastatic sizes. Immunological markers and potential drive genes were detected by immunohistochemical staining and next generation sequencing. Efficacy and safety profile of ICIs in included patients was evaluated with progression-free survival and overall survival. Between January 2019 and September 2022, there were 4 patients included within the inclusion criteria in the present study. Biomarkers including CK, CK7, and integrase interactor 1 were detected positive, however, other immunological markers including CK20, CD56, P63, P40, NapsinA, TTF-1, CgA, Syn, BRG1, or PD-L1 were detected negative among them. Results of next generation sequencing panel were failed to discover any targetable sensitive mutations. A total of 4 mutation types of TP53, including p.C141Y, p.S240G, p.E339X (terminator acquired), and p.L130F detected for the patients, respectively. Microsatellite stability status, as well as low tumor mutation burden was identified among all the patients. Median progression-free survival for ICIs as first line treatment and median overall survival were 3.25 months (range from 1.3 to 6.8 months), and 6.0 months (range from 2.7 to 9.6 months), respectively. Our results indicated that advanced lung cancer patients harboring co-occurring SMARCA4-deficient/TP53 mutations might respond to ICIs treatment, though within negative programmed cell death-ligand 1 expression or low tumor mutation burden. However, hyperprogressive disease by ICIs may also happen for such patients. The mutation types of TP53 might play a role during the exposure of ICIs, however, need further identification in basic experiments.

Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

Sex-dependent different clinicopathological characterization of Epstein-Barr virus-associated gastric carcinoma: a large-scale study.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5-16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV-ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan-Meier survival curve. However, this effect was evident only in males. EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females.