Clinicopathological Features Research Articles

Undifferentiated uterine sarcoma : experience of a single center

ObjectivesTo investigate the clinicopathological characteristics and prognosis of patients with undifferentiated uterine sarcomas (UUS).Methods29 patients with UUS who were treated at our institution between 2001 and 2020 were analyzed.ResultsThe median age at diagnosis was 52 years (range: 26–70 years). The FIGO 2009 distribution by stage was as follows: stage I, 17 patients (58.6%); stage II, 5 patients (17.2%); stage III, 4 patients (13.8%); and stage IV, 3 patients (10.3%). For 28 patients who underwent surgical treatment, 27 patients (96.4%) underwent total/sub-radical/radical hysterectomy combined bilateral salpingo-oophorectomy, 17 (58.6%) pelvic lymphadenectomy, 7 (24.1%) para-aortic lymphadenectomy and 8 (28.6%) patients underwent omentectomy, as part of the initial surgical treatment. The median follow-up was 23.4 months (range: 4.5–200.2 months). 18 patients (62.1%) died during follow up, and 13 patients (72.2%, 13/18) died within 2 years after diagnosis. Median progression-free survival (mPFS) and overall survival (mOS) for the entire cohort were 15.5 and 27.4 months, respectively. 2-year and 5-year PFS were 40.3% and 26.9%. 2-year and 5-year OS were 54.0% and 36.5%. Stage-specific median PFS and OS were as follows: stage I-II—17.7 and 35.5 months, stage III-IV—6.0 and 6.7 months. Patients with recurrent UUS who underwent cytoreduction surgery associated with an improved overall survival (mOS: 52.9 vs. 17.9 months), but the difference was not statistically significant (P = 0.081).ConclusionsUUS are a rare group of tumors with an aggressive behavior and poor outcomes. A majority rapidly develops distant metastases despite surgical resection.

Clinicopathologic Features of Breast Tumors in Germline TP53 Variant-Associated Li-Fraumeni Syndrome.

We present one of the largest cohorts of TP53-pathogenic germline variants (PGVs) associated with patients with Li-Fraumeni syndrome (n = 82) with breast tumors (19 to 76y; median age: 35). Most had missense variants (77%), followed by large gene rearrangements (LGRs; 12%), truncating (6%), and splice-site (5%) variants. Twenty-one unique germline missense variants were found, with hotspots at codons 175, 181, 245, 248, 273, 334, and 337. Of 100 total breast tumors, 63% were invasive (mostly ductal), 30% pure ductal carcinoma in situ, 4% fibroepithelial lesions, and 3% with unknown histology. Unlike BRCA-associated tumors, approximately half of the breast cancers exhibited HER2-positivity, of which ~50% showed estrogen receptor coexpression. Pathology slides were available for review for 61 tumors (44 patients), and no significant correlation between the type of TP53 PGVs and histologic features was noted. High p53 immunohistochemistry expression (>50%) was seen in 67% of tumors tested (mostly missense variant). Null pattern (<1% cells) was seen in 2 (LGR and splicing variants carriers). Surprisingly, 2 tumors from patients with an LGR and 1 tumor from a patient with a truncating variant showed p53 overexpression (>50%). The subset of patients with the Brazilian p.R337H variant presented at a higher age than those with non-p.R337H variant (46 vs 35y) though statistically insignificant (P = 0.071) due to an imbalance in the sample size, and were uniquely negative for HER2-overexpressing tumors. To conclude, breast cancer in carriers of TP53 PGVs has some unique clinicopathological features that suggest differential mechanisms of tumor formation. p53 immunohistochemistry cannot be used as a surrogate marker to identify germline TP53-mutated breast cancers.

Dysregulation of the p53 pathway provides a therapeutic target in aggressive pediatric sarcomas with stem-like traits.

Pediatric sarcomas are bone and soft tissue tumors that often exhibit high metastatic potential and refractory stem-like phenotypes, resulting in poor outcomes. Aggressive sarcomas frequently harbor a disrupted p53 pathway. However, whether pediatric sarcoma stemness is associated with abrogated p53 function and might be attenuated via p53 reactivation remains unclear. We utilized a unique panel of pediatric sarcoma models and tumor tissue cohorts to investigate the correlation between the expression of stemness-related transcription factors, p53 pathway dysregulations, tumorigenicity in vivo, and clinicopathological features. TP53 mutation status was assessed by next-generation sequencing. Major findings were validated via shRNA-mediated silencing and functional assays. The p53 pathway-targeting drugs were used to explore the effects and selectivity of p53 reactivation against sarcoma cells with stem-like traits. We found that highly tumorigenic stem-like sarcoma cells exhibit dysregulated p53, making them vulnerable to drugs that restore wild-type p53 activity. Immunohistochemistry of mouse xenografts and human tumor tissues revealed that p53 dysregulations, together with enhanced expression of the stemness-related transcription factors SOX2 or KLF4, are crucial features in pediatric osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma development. p53 dysregulation appears to be an important step for sarcoma cells to acquire a fully stem-like phenotype, and p53-positive pediatric sarcomas exhibit a high frequency of early metastasis. Importantly, reactivating p53 signaling via MDM2/MDMX inhibition selectively induces apoptosis in aggressive, stem-like Ewing's sarcoma cells while sparing healthy fibroblasts. Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.

Esophageal submucosal gland duct adenoma: An unrecognised esophageal counterpart of minor salivary gland tumours with frequent BRAF V600E mutations.

Esophageal submucosal gland duct adenoma is an extremely rare benign tumour, with only a few reported cases. We conducted the largest single-centre clinical study of esophageal submucosal gland duct adenoma, examining its molecular mechanisms and clinicopathological features. Between 2018 and 2023, seven cases of esophageal submucosal gland duct adenoma were identified at a tertiary medical centre; two were female and five were male, aged between 51 and 75 years (mean = 63.8 years). Comprehensive evaluations of clinicopathological, immunohistochemical and molecular characteristics were conducted. Histologically, tumours showed papillotubular and cystic patterns lined with double layers of cells arranged in ducts, papillary folds and microcysts. The inner luminal tall columnar cells had eosinophilic cytoplasm and did not show mucin production and the basal cells showed myoepithelial differentiation. Immunohistochemically, inner luminal layer cells were positive for CK7, CK19 and CK5/6 and outer basal layer cells were positive for SMA and P40. Both layers were negative for CK20, CDX2, MUC5AC, MUC6, MUC2, GCDFP15 and Alcian blue-periodic acid-Schiff (AB-PAS). Genomic analyses revealed the presence of BRAF V600E mutations in five of seven tumours (71.43%). This study delineates a distinct subtype of benign adenoma arising from the esophageal submucosal gland duct, characterised by multiple lobulated cystic proliferation of benign epithelial layers within the submucosa. BRAF V600E mutations were present, similar to in sialadenoma papilliferum. We determined the genetic mutation present in esophageal submucosal gland duct adenoma, providing further evidence that it is an esophageal counterpart of minor salivary gland tumours.

Clinicopathological characteristics of Japanese patients with breast cancer and MET exon 14 skipping alterations.

In non-small cell lung cancer, alterations in mesenchymal-epithelial transition (MET) have been recognized as novel therapeutic targets. In particular, the MET exon 14 skipping mutation (METex14s) is a rare oncogenic driver. Targeted therapy with MET tyrosine kinase inhibitors has recently been approved for this mutation. However, c-MET expression and METex14s frequency and their clinicopathological effects in Japanese patients with breast cancer (BC) remain unknown. Tissue microarray-based immunohistochemistry (IHC) was performed to measure c-MET expression in 930 patients with BC (808 with invasive and 122 with noninvasive BC). Reverse transcription polymerase chain reaction was performed to analyse METex14s in patients exhibiting c-MET expression. Clinicopathological characteristics, including patient prognosis based on c-MET expression and METex14s, were elucidated. IHC staining revealed c-MET expression in 91/930 (9.7%) patients. Notably, IHC expression was frequently observed in apocrine carcinomas (11/26 cases). Among the c-MET IHC-positive cases, METex14s frequency was 25.9% (14/54 cases) in invasive BC and 54.1% (20/37 cases) in noninvasive BC. Furthermore, 4/11 informative noninvasive and invasive BC cases with apocrine differentiation carried METex14s. The nuclear grade was significantly higher in the METex14s-positive group among invasive BC with c-met IHC expression. Furthermore, patients' age and negative rate for PgR IHC was significantly lower in the METex14s-positive group among noninvasive BC. Regarding the factors associated with patient outcomes, both c-MET IHC staining and METex14s expression did not affect survival, regardless of the hormone receptor status. High c-MET expression and METex14s are common in apocrine carcinoma.

Robotic salvage radical hysterectomy for locally recurrent cervical cancer: A comparison with open surgery in a single-surgeon series.

To compare the surgical and oncologic outcomes between patients with locally recurrent cervical cancer undergoing robotic-assisted salvage radical hysterectomy (RH) and those undergoing conventional open salvage RH, performed by a single surgeon. This retrospective comparative observational study utilized data obtained from consecutive patients with locally recurrent cervical cancer, developed after definitive radiotherapy. These patients either underwent robot-assisted RH (robotic group) or conventional open RH (open group). Clinicopathological characteristics, surgical outcomes, and oncological outcomes were compared between the two groups. The operative time was slightly longer in the robotic group; however, this difference was not statistically significant. Estimated blood loss was significantly lower in the robotic group (median; 0 mL [robotic group] vs. 700 mL [open group]: p < 0.01). The incidence of intraoperative and early and late complications did not statistically differ between the two groups. The mean follow-up was 29.0 and 17.1 months in the open and robotic groups, respectively. Disease recurrence rates were similar between the two groups (40% [robotic group] vs. 44.4% [open group]). Kaplan-Meier survival analysis for progression-free survival and overall survival did not show statistically significant differences between the two groups. Robot-assisted salvage RH in women with locally recurrent cervical cancer showed perioperative and oncological outcomes comparable to those of the open procedure. Although our results suggest that the robot-assisted approach is as good as or better than the open approach, further investigation is required to establish a more robust conclusion.

Adenocarcinoma of the rete testis: clinicopathological study of 18 cases with emphasis on MET amplification and a review of the literature.

Knowledge regarding adenocarcinoma of the rete testis (ACRT) is extremely limited due to its scarcity. This study enrolled 18 patients with ACRT from multiple institutions. Clinicopathological and immunohistochemical features were investigated, together with a comprehensive review of 95 previously reported cases. One case was assessed using next-generation sequencing (NGS). The median age of the patient cohort was 54 years (range = 20-69 years), with the majority presenting with a testicular mass (13 of 18); predominantly right-sided (11 of 18). Six patients died within the second year following diagnosis. The morphology of ACRT spans a wide spectrum, including newly identified mucinous carcinoid-like features, with mucous cells floating in mucus and signet-ring cells. Notably, transition from a benign to a malignant rete epithelium was noted in 38.9% of cases (seven of 18). Immunohistochemically, tumour cells most frequently showed strong positivity for CK7 (12 of 16) and CK20 (10 of 17), with occasionally positivity for calretinin (three of 16), WT-1 (two of 17) and PAX-8 (two of 15). According to NGS in a single case, MET was amplified, leading to the patient benefiting from mesenchymal-epidermal transition factor (MET) inhibitors. Furthermore, MET amplification was assessed in 13 cases using fluorescence in-situ hybridisation and detected in two cases (15.4%). No significant correlation between MET amplification and mesenchymal-epidermal transition factor (MET) levels was observed in the cases studied. Primary ACRT is a rare malignant tumour which poses a diagnostic challenge, and is associated with poor prognosis. Cases of ACRT with MET amplification might represent promising candidates for the treatment with MET inhibitors.

Surgical treatment of pancreatic metastases: More appropriate surgical methods based on a clinicopathologic study of 43 patients.

There is no established surgical method for metastatic lesion to the pancreas. In the case of relatively small lesion, we often hesitate to select which surgical method, that is, wedge/partial resection or Whipple/distal pancreatectomy. Moreover, it is debatable whether lymph node dissection is necessary or not. We investigated clinicopathological characteristics in order to resolve the above problems. Forty-three patients underwent pancreatic resection formetastatic tumors in Cancer Institute of the Japanese Foundation for Cancer Research, whose specimens were investigated clinicopathologically. Primary tumors included renal cell carcinoma(RCC), colorectal carcinoma (CRC), and miscellaneous malignancy (MM) in 23, 9, and 11 cases, respectively. Plural metastases in a resected specimen or mpd, i.e., tumor extension into the main pancreatic duct (MPD) was observed in eleven (26%, 11/43) or 9 (21%, 9/43) patients, respectively. Five of 9 mpd cases had more over 2cm intraductal tumor extention from the main metastatic lesion. Lymph node metastasis surrounding the main metastasis was observed in 11 patients (5 CRCs, 5 MMs, and 1 RCC), with a metastatic rate to lymph node of 56% (5/9), 45% (5/11), and 4% (1/23) for CRCs, MMs, and RCCs, respectively. 1) Wedge or partial resection of the pancreas for metastatic tumor should not be easily chosen, because of positive resection margin due to mpd and/or leaving another metastatic lesion. 2) Lymph node dissection is not strictly necessary for the surgical removal of pancreatic metastasis from RCC, whereas this is highly recommended for patients with metastasis from CRC or MM.

Small intestinal metastasis from primary breast cancer: a case report and review of literature

Small intestinal metastasis from primary breast cancer remains a rare clinical occurrence. Despite extensive research into its clinicopathological features and treatment options, the specific pathogenesis and optimal management strategies remain incompletely understood. This case report presents a patient with breast cancer that metastasized to the small intestine. The primary breast tumor was diagnosed as classic invasive lobular carcinoma. Subsequent surgical intervention successfully addressed the intestinal obstruction and confirmed the metastatic origin of the small intestinal tumor. Interestingly, the metastatic lesions exhibited features suggestive of pleomorphic lobular carcinoma. A PET-CT scan was performed to evaluate the distant metastasis status of this patient. Notably, hormonal receptor status shifted from positive to negative, while HER2 expression changed from negative to low between the primary tumor and metastatic lesions. The presence of an undiagnosed pleomorphic component in the primary tumor might explain the disease’s progressive nature. In this case, systemic treatment with trastuzumab deruxtecan yielded favorable therapeutic outcomes. Overall, our findings suggest that re-evaluation of receptor status in breast cancer metastases is crucial for tailoring treatment strategies. Furthermore, a combination of palliative resection of small intestinal metastases and targeted therapy for HER2-low breast cancer may potentially improve survival.

Minimally invasive surgery versus open surgery in advanced stage endometrial cancer.

Staging surgery in early stage endometrial cancer has been shown to be feasible and safe with minimally invasive surgery (MIS) in many previous studies. However, there is limited literature on MIS's safety in advanced stages. This study aims to identify factors associated with survival in stage III endometrial cancer and investigate survival differences based on surgical approach. Patients with stage III endometrial cancer who underwent staging surgery from March 2002 to March 2023 were included in this study. Various clinicopathological features, disease-free survival (DFS), and overall survival (OS) were evaluated. Among the 79 patients included in this study, 20 patients underwent MIS (25.3%) and 59 patients underwent open surgery (74.7%). The open surgery group had a higher prevalence of aggressive histology, a higher median pretreatment CA-125 level, and a greater number of harvested lymph nodes compared to the MIS group. Five-year OS and DFS was higher in the open surgery group than in the MIS group (DFS: 67.9% vs. 59.9%, p = 0.046; OS: 74.3 vs. 50.6%, p = 0.008). In multivariate analysis, younger than 55 years old (OR, 2.778; 95% CI, 1.078-7.156; p = 0.034), and open surgery (OR, 3.671; 95% CI, 1.581-8.522; p = 0.002) was related to improved OS. Open staging surgery showed better survival outcomes when compared to MIS in stage III endometrial cancer patients in our study. For patients who are older than 55 years old and have aggressive histology in endometrial biopsy, considering open surgery may help improve their prognosis, even if preoperative MRI suggests early-stage endometrial cancer.

Clinicopathological Characteristics of Extranodal Marginal Zone Lymphoma of the Mucosa Associated Lymphoid Tissue (MALT-Lymphoma) of the Intestine: A Single Center Analysis.

Extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT-lymphoma) is an indolent B-cell lymphoma with a distinct affinity for mucosal structures. Most commonly arising in the stomach, only roughly 2% of MALT-lymphomas occur in the colon or the intestine. In view of this, we have retrospectively assessed all patients with MALT-lymphoma involving the intestine for clinicopathological characteristics. Data of all patients with MALT-lymphoma and intestinal involvement (i.e. both primary and secondary), treated and followed at the Medical University of Vienna between 1999 and 2021 were retrospectively collected from hospital records and analyzed. Differences in baseline and therapy characteristics, as well as survival between primary and secondary, and between intestinal and gastric MALT-lymphoma (as the most common subgroup of patients) were investigated. In total, 42 patients were identified; 24/484 (5%) were classified as primary and 18 (3.7%) as secondary intestinal MALT-lymphomas. The most common primary intestinal location was the colon (10/24) and the most frequent primary site in the 18 cases with secondary intestinal MALT-lymphomas was the stomach (14/18). A total of 28/42 (66.7%) patients presented with LUGANO stage I, 7/42 (16.7%) with stage II/IIE and 7/42 (16.7%) with stage IV disease. Translocation t (11; 18) (q21; q21) was positive in 47% of patients with secondary and 25% of primary intestinal MALT-lymphomas. Median OS in for intestinal MALT-lymphoma was 301months (95% CI n.a.) with 89.1% alive at 5years and 77.2% alive at 10years. Median PFS in the entire cohort was 50.4months (95% CI 38.4-62.4months), with an overall response rate and disease control rate of 73% and 97.3%, respectively. No difference in OS and PFS between primary and secondary intestinal, as well as between intestinal and gastric MALT-lymphoma was detected. Our data suggest that dissemination within the GI tract does not seem to be an adverse prognostic feature and highlights the preferred use of the Lugano staging system in such patients, which also summarizes multiple lesions within the GI-tract as Stage I.

Comprehensive review of mitochondrial nephropathy-a renal phenotype in mitochondrial disease: causative genes, clinical and pathological features, diagnosis, prognosis, and treatment.

Mitochondrial nephropathy is a genetic renal disease characterized by oxidative phosphorylation abnormalities in the mitochondrial respiratory chain in kidney cells, caused by pathogenic gene variants located on mitochondrial or nuclear DNA. Recent advancements in genetic diagnostic techniques and their widespread adoption have led to the identification of various genes associated with mitochondrial nephropathy. This review investigates the causative genes and clinicopathological features of mitochondrial nephropathy, including the various phenotypes and associated complications, and suggests potential pathogenic mechanisms. Furthermore, the diagnostic methods of the disease are explained with particular emphasis on characteristic pathological findings and genetic analysis. We also analyze the available long-term observational prognostic data. Although there is currently no evidence-based treatment for mitochondrial nephropathy, an overview of the existing treatment options is discussed, including future expectations. The choice of renal replacement therapy in cases with progression to end-stage renal disease has also been discussed. Overall, this review highlights the importance of raising awareness about mitochondrial nephropathy and establishing appropriate diagnostic systems to facilitate rapid and effective treatment.

Prognostic and Molecular Characterization of Metastatic Transverse Colon Cancer: Insights From a Single-Center Retrospective Study.

Metastatic transverse colon cancer (TCC) represents a unique subset of colorectal cancer with features of both right and left colon tumors due to its distinct embryologic origin. This study retrospectively analyzes the clinical, pathological, and molecular factors influencing survival outcomes in TCC patients treated at a single center. For this study, we reviewed the files of 372 metastatic patients and analyzed the data of 71 patients with a diagnosis of TCC in detail. The remaining patients were patients with right or left colon tumors and we compared the overall survival (OS), molecular mutations (KRAS, NRAS, BRAF, MSI status), and clinicopathological features of our patients with transverse colon tumors with these patients. The median OS for TCC patients was 19.7 months, with metastasectomy and Eastern Cooperative Oncology Group (ECOG) performance status emerging as significant prognostic factors. Molecular analyses revealed KRAS mutations in 49% and BRAF mutations in 13% of TCC cases, aligning TCC closer to right-sided tumors in certain molecular characteristics. However, histopathologic diversity, including mucinous histology in 20% of TCC cases, indicated a need to consider TCC as a distinct entity. These findings underscore the complex biological nature of TCC and the necessity for tailored therapeutic approaches, especially as survival rates remain suboptimal. Further multicenter, prospective studies are recommended to establish refined treatment strategies for TCC patients.

Investigating the role of KARS in lung adenocarcinoma via single-cell RNA sequencing

ObjectiveLung Adenocarcinoma (LUAD) is one of the leading causes to cancer-related deaths worldwide and exhibited extensive molecular diversity in its cellular components. In summary, this study examined the expression and function of KARS in various LUAD cell populations using single-cell RNA sequencing (scRNA-seq) to identify its prognostic value as well as potential implications for therapy.MethodsAll datasets related to this study were analyzed in previous published studies, which was downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression(GTEx) project and Gene Expression Omnibus (GEO). We subsequently sought to analyze the association between either clinically tumorigenic or low survival-grade KARS expression, respectively with varied clinicopathological features and all patients OS. Verification of KARS expression was performed by in vitro RT-PCR.ResultsOur investigation found that KARS expression was markedly elevated in LUAD tissue samples compared to normal controls. Genomic analysis indicated a robust association between increased copy number of the KARS gene and its overexpression. The upregulation of KARS was also correlated with distinct genetic mutations and a higher mutational load in LUAD. The heightened activity of KARS was implicated in LUAD progression. Furthermore, our research indicated a significant interplay between KARS's role in LUAD and the tumor's immune microenvironment, along with various dimensions of the tumor immunology landscape. Comprehensive assessments of immune cell populations within the tumor microenvironment uncovered a pronounced link between heightened immune responses and the presence of specific immune cell types. KARS expression in A549 cell line was higher than in the 16HBE cell line.ConclusionUtilizing single-cell omics technologies, this research offers a detailed perspective on the role of KARS in LUAD, highlighting its potential as a prognostic biomarker and a candidate for tailored therapeutic intervention. Future research should probe possible therapeutic strategies that could target KARS in a pathologically relevant manner.

TAp73 and ΔTAp73 isoforms show cell-type specific distributions and alterations in cancer

TP73 is a member of the TP53 gene family and produces N- and C-terminal protein isoforms through alternative promoters, alternative translation initiation and alternative splicing. Most notably, p73 protein isoforms may either contain a p53-like transactivation domain (TAp73 isoforms) or lack this domain (ΔTAp73 isoforms) and these variants have opposing or independent functions. To date, there is a lack of well-characterised isoform-specific p73 antibodies. Here, we produced polyclonal and monoclonal antibodies to N-terminal p73 variants and the C-terminal p73α isoform, the most common variant in human tissues. These reagents show that TAp73 is a marker of multiciliated epithelial cells, while ΔTAp73 is a marker of non-proliferative basal/reserve cells in squamous epithelium. We were unable to detect ΔNp73 variant proteins, in keeping with recent data that this is a minor form in human tissues. Most cervical squamous cell carcinomas (79%) express p73α, and the distribution of staining in basal cells correlated with lower tumour grade. TAp73 was found in 17% of these tumours, with a random distribution and no association with clinicopathological features. These data indicate roles for ΔTAp73 in maintaining a non-proliferative state of undifferentiated squamous epithelial cells and for TAp73 in the production of differentiated multiciliated cells.

PCDHGA10 as a potential prognostic biomarker and correlated with immune infiltration in gastric cancer

BackgroundGastric cancer (GC) is one of the most common malignant tumors and is associated with poor prognosis. To improve the prognosis of GC patients, an effective immune-related prognostic biomarker is urgent. Here, we aim to explore the correlation between the expression of procalcitonin gamma subfamily A, 10 (PCDHGA10) and clinicopathological characteristics, especially its relation with tumor-infiltrating immune cells (TILs) in GC.MethodsThe differential mRNA expression of PCDHGA10 between GC tissues and normal gastric mucosa and prognostic potential were assessed from The Cancer Genome Atlas (TCGA). Then, based on tissue microarrays (TMAs) with multiplex immunohistochemistry (mIHC) from GC patients, we statistically assess the correlation between PCDHGA10 protein expression and the clinical profiles and prognosis of the patients. Additionally, with IHC and mIHC, we applied the machine-learning algorithms to evaluate the localization and expression levels of TILs and immune checkpoints in the tumor microenvironment. We analyzed the relationship between PCDHGA10 protein expression and TILs and immune checkpoints.ResultsThrough the database and TMA analysis, the expression of PCDHGA10 was significantly higher in GC tissues compared with normal tissues. High PCDHGA10 expression independently predicted poor prognosis in GC. Additionally, elevated PCDHGA10 expression was positively associated with the number of CD8+ T cells, CD68+ macrophages, Foxp3+ T cells, and CD4+ T cells in GC tissues and the stromal region. Besides, the expression of PCDHGA10 was positively correlated with immune checkpoints, including CTLA-4, LAG3, and PD-L1.ConclusionsPCDHGA10 might be a potential prognostic marker and an immunological therapeutic target for GC.

Cardiovascular autonomic neuropathy in chronic kidney disease: a study of kidney biopsy cases

BackgroundThe interplay between cardiac and kidney functions is mediated by the autonomic nervous system. Cardiovascular autonomic neuropathy (CAN) is a well-documented dysfunction of this system, with heart rate variability (HRV) serving as the principal diagnostic tool. CAN is recognized as a prognostic marker for adverse kidney outcomes in diabetic kidney disease (DKD). However, the pathogenesis of CAN in patients with nondiabetic chronic kidney disease (CKD) remains underexplored. This study elucidated the prevalence of CAN and its clinicopathologic characteristics in patients with nondiabetic CKD.MethodsThis cross-sectional analysis evaluated 165 nondiabetic CKD patients who underwent kidney biopsy from 2020 to 2023. HRV was quantified using the coefficient of variation of the RR interval (CVRR). CAN was diagnosed based on the CVRR and defined using the CVRR reference value—derived by defining the age and sex-dependent lower normal limits as the 2.5 percentile point of the distribution of the CVRR values in healthy individuals.ResultsThe median patient age was 47.0 (34.0–57.0) years, and 50.9% were male. The median estimated glomerular filtration rate was 65.0 (42.0–85.0) mL/min/1.73m2, and the CVRR was 3.5 (2.4–4.7)% and 16 patients (9.7%) were diagnosed with CAN. CAN was frequently associated with kidney dysfunction, dyslipidemia, and advanced interstitial fibrosis/tubular atrophy (IF/TA). Multivariable analysis revealed that IF/TA was associated with CVRR, independent of established risk factors for CAN (P = 0.045).ConclusionsThe prevalence of CAN diagnosed using the CVRR in this nondiabetic CKD cohort was 9.7%, which is four times higher than that in healthy individuals. Nondiabetic CKD patients with CAN was associated with advanced IF/TA.

Investigation of HOTAIR rs12826786, rs920778 and rs4759314 variants with breast cancer susceptibility and clinicopathological characteristics in a Mexican population

BackgroundBreast cancer (BC) is a multifactorial disease of unknown etiology whose major risk factors are genetic alterations of cell proliferation and migration pathways. HOX transcript antisense RNA gene (HOTAIR) is a long non-coding RNA (lncRNA) related to cell proliferation, progression, invasion, metastasis, and poor survival of multiple cancers, including BC. Controversial results have emerged on the association between breast cancer risk in multiple ethnicities. This study explores the association of rs12826786, rs920778, and rs4759314 variants in the HOTAIR gene in BC patients. MethodsDNA of peripheral blood samples was obtained from 588 women (289 patients and 299 control females). Genotypes were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. The association was calculated using the odds ratio (OR) test. P-values were adjusted by the Bonferroni test (0.016). ResultsThe rs12826786 (C>T), rs920778 (T>C), and rs4759314 (A>G) variants were associated with BC and with TNM stage, histologic type, and histologic molecular subtype (P=0.001). Likewise, the haplotype C-T-G in the HOTAIR gene (rs12826786-rs920778-rs4759314) was significantly related to BC (OR= 5.44, 95%, CI= 2.22-13.32, P= 0.001). ConclusionThe results suggest that rs12826786, rs920778, and rs4759314 variants in HOTAIR significantly influence breast cancer risk. Micro-abstractHOX transcript antisense intergenic RNA (HOTAIR) is a long non-coding RNA strongly correlated with the tumor grade and prognosis of various carcinomas, including breast cancer (BC). In this study, we analyzed the association of the rs12826786, rs920778, and rs4759314 variants in the HOTAIR gene and observed an increased susceptibility to BC and clinicopathological characteristics in a Mexican population.

Correlation between Immune Microenvironment and Clinicopathological Characteristics and Prognosis of Primary Large B-cell Lymphoma of Immune-Privileged Sites

ObjectivesTo explore the correlation between tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor-associated angiogenesis (TAA) in the tumor microenvironment with the clinicopathological characteristics and prognosis of primary large B-cell lymphoma of immune-privileged sites (LBCL-IP).MethodsA total of 46 cases of LBCL-IP from the Department of Pathology, the Third Affiliated Hospital of Xinjiang Medical University, from January 2010 to February 2024, were collected, along with clinical and follow-up data of LBCL-IP patients. Immunohistochemistry and triple immunofluorescence were used to detect related proteins of TAMs, TILs, and TAA, and to analyze the correlation between TAMs, TILs, TAA, and the polarization of TAMs with the clinical and prognostic factors of LBCL-IP patients.ResultsThere are 30 cases (65.2%) showed high expression of CD68 proteins, 32 cases (69.6%) showed high expression of CD163 proteins, 19 cases (41.3%) showed high expression of CD4 proteins, 34 cases (73.9%) showed high expression of CD8 proteins, and 25 cases (54.3%) showed high expression of CD34 proteins. A total of 27 cases (58.7%) showed CD68+CD163+/CD68+CD86+≥1. The chi-square tests showed that high expression of CD163 proteins was positively correlated with elevated LDH and BMG values, and the count of CD68+CD163+/CD68+CD86+≥1 was positively correlated with ECOG scores ≥2, Ann Arbor staging III-IV, and increased BMG value. High expression of CD8 proteins was positively correlated with a Ki-67 proliferation index ≥70%, and high MVD values were positively correlated with Ann Arbor staging III-IV. The Kaplan-Meier estimator analysis showed that LBCL-IP patients with low expression of CD68 proteins, high expression of CD163 proteins, CD68+CD163+/CD68+CD86+≥1, low expression of CD8 proteins, high MVD values, ECOG scores ≥2, Ann Arbor staging III-IV, LDH ≥250U/L, BMG ≥2.2mg/L, and IPI scores ≥2 had shorter survival times. Multivariate Cox regression analysis showed that low expression of CD8 proteins, CD68+CD163+/CD68+CD86+≥1, LDH ≥250U/L, and ECOG scores ≥2 are independent risk factors affecting the survival of LBCL-IP patients.ConclusionM2-polarized TAMs and low infiltration of CD8+ TILs were more strongly correlated with poor clinical pathological indicators and worse prognosis, and MVD values may serve as an aiding means for the diagnosis and prognostic prediction of LBCL-IP disease.

LMAN2 Promotes Breast Cancer Tumorigenesis and Drug Resistance by Interacting With MAPK9 via Activation of the MAPK Pathway

ABSTRACTIntroductionBreast cancer (BC) is the most prevalent malignancy among women worldwide. Lectin, mannose‐binding 2 (LMAN2) is a cargo receptor engaged in the transport and sorting of glycoproteins. Despite its ubiquity, the function and underlying mechanisms of LMAN2 in BC continue to elude understanding.MethodsMultiple databases were employed to examine the expression of LMAN2 in breast cancer. Immunohistochemistry(IHC), qRT‐PCR, and Western blot were performed to quantify LMAN2 expression in BC cell lines and clinical samples. Heat map analysis and Kaplan–Meier analysis were used to analyze the correlation between LMAN2 and clinicopathological features. SiRNAs and overexpression plasmids were transfected into two BC cells to assess the effect of LMAN2 on malignant phenotypes. Coimmunoprecipitation and immunofluorescence were used to screen for potential interacting proteins. Additionally, tumor subcutaneous xenograft mode was constructed to explore tumor chemoresistance.ResultLMAN2 expression was significantly higher in BC compared to that in matched, adjacent normal tissues, and its higher expression level was correlated with worse patient prognosis. In vitro, we found that LMAN2 functions as an oncogene, promoting BC cell proliferation, cell cycle progression, invasion, and chemoresistance while preventing apoptosis. Coimmunoprecipitation and colocalization experiments confirmed the direct binding of LMAN2 to MAPK9 in BC cells. Our investigation of signaling pathways suggested that LMAN2 is involved in the regulation of the MAPK signaling pathway, utilizing this pathway to confer cisplatin resistance. Furthermore, knockdown of LMAN2 improves the sensitivity of drug‐resistant BC cells to cisplatin (DDP) in vivo.ConclusionLMAN2 was a novel diagnostic and prognostic biomarker for BC that promotes chemoresistance via interaction with MAPK9 and activation of the MAPK pathway.