Search

Objective This study was performed to evaluate the prognostic meaning of volumetric and semi-quantitative parameters measured using [18F]FDG PET/CT and somatostatin receptor (SSTR) imaging in patients with typical lung carcinoid (TC), and their relationship with proliferative index (Ki67). Methods We retrospectively reviewed 67 patients (38–94 years old, mean: 69.7) with diagnosis of TC who underwent [18F]FDG PET/CT and/or SSTR scintigraphy/SPECT with [111In]DTPA-Octreotide plus contrast-enhanced CT (CECT) at staging evaluation. All patients had Ki67 measured and a follow-up (FU) of at least 1 year. SSTR density (SSTRd) was calculated as the percentage difference of tumor/non-tumor ratio at 4 and 24 h post-injection. At PET/CT, metabolic activity was measured using SUVmax and SUVratio; volumetric parameters included MTV and TLG of the primary tumor, measured using the threshold SUV41%. ROC analysis, discriminant analysis and Kaplan–Meier curves (KM) were performed. Results 11 patients died during FU. Disease stage (localized versus advanced), SUVratio, SUVmax, Ki67, MTV and TLG were significantly higher in non-survivors than in survivors. ROC curves resulted statistically significant for Ki67, SUVratio, SUVmax, MTV and TLG. On multivariate analysis, stage of disease and TLG were significant independent predictors of overall survival (OS). In KM curves, the combination of disease stage and TLG identified four groups with significantly different outcomes (p In patients with advanced and localized disease, SSTRd proved to be the best imaging prognostic factor for progression and for disease-free survival (DFS), respectively. In localized disease, SSTRd 31.5% identified two subgroups of patients with significant different DFS distribution and in advanced disease, a high cutoff value (58.5%) was a significant predictor of adverse prognosis. Conclusion Volumetric and semi-quantitative parameters measured using [18F]FDG PET/CT and SSTR imaging combined with Ki67 may provide a reference for prognosis evaluation of patients with TC, to better stratify risk groups with the goal of developing individualized therapeutic strategies.

Purpose Triple-negative breast cancer (TNBC) is an aggressive disease lacking specific biomarkers to guide treatment decisions. We evaluated the combined prognostic impact of clinical features and novel biomarkers of cell cycle-progression in age-dependent subgroups of TNBC patients. Methods One hundred forty seven TNBC patients with complete clinical data and up to 18 year follow-up were collected from Turku University Hospital, Finland. Eight biomarkers for cell division were immunohistochemically detected to evaluate their clinical applicability in relation to patient and tumor characteristics. Results Age at diagnosis was the decisive factor predicting disease-specific mortality in TNBC (p = 0.002). The established prognostic features, nodal status and Ki-67, predicted survival only when combined with age. The outcome and prognostic features differed significantly between age groups, middle-aged patients showing the most favorable outcome. Among young patients, only lack of basal differentiation predicted disease outcome, indicating 4.5-fold mortality risk (p = 0.03). Among patients aged > 57, the established prognostic features predicted disease outcome with up to 3.0-fold mortality risk for tumor size ≥ 2 cm (p = 0.001). Concerning cell proliferation, Ki-67 alone was a significant prognosticator among patients aged > 57 years (p = 0.009). Among the studied cell cycle-specific biomarkers, only geminin predicted disease outcome, indicating up to 6.2-fold increased risk of mortality for tumor size p = 0.03). Conclusion Traditional clinical features do not provide optimal prognostic characterization for all TNBC patients. Young age should be considered as an additional adverse prognostic feature in therapeutic considerations. Increased proliferation, as evaluated using Ki-67 or geminin immunohistochemistry, showed potential in detecting survival differences in subgroups of TNBC.

For years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton's tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.

Objective Most meningiomas are benign and the indications for surgery are determined by size and symptoms, but some are malignant and have a high recurrence rate. Currently, no preoperative prognostic factors have been established. The purpose of this study was to investigate whether Tumor doubling time (Td) is useful in predicting tumor prognosis. Methods Patients who underwent surgery for newly diagnosed meningioma at our hospital between 2007 and 2021 with preoperative magnetic resonance (MR) imaging evaluation over a period of six months were included in this study. We calculated the Td from the preoperative MR images and examined the correlation between Td and WHO grade, MIB-1 SI and other conditions. Results A total of 269 newly diagnosed meningiomas were operated in the period, of which 62 met inclusion criteria. The median Td was 1082 days (54-8579 days) and MIB-1 SI was 2.45% (0.7–14.6%). Td and MIB-1 SI had a negative correlation (r=-0.319, p = 0.0122). MIB-1 SI was higher in patients with Td = 3 (p = 0.005), and the incidence of high WHO grade (grade2) was higher in patients with Td = 1 (p = 0.014). Conclusions Meningiomas with Td of less than 3 years had significantly higher MIB-1 SI, and tumors with Td of less than 1 year had higher likelihood of malignancy. Therefore, early treatment should be considered for the patients with short Td meningioma even if asymptomatic and further consideration could be given to radical resection at the time of surgery.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Progression of disease within 24 months (POD24) is strongly associated with a poor outcome in patients with follicular lymphoma (FL). Our study aimed to identify the potential risk factors for POD24 in patients with FL. Medline, EMBASE and the Cochrane Library were systematically searched from the earliest record to September 2020. Studies investigating the prognostic factors for POD24 in patients with newly diagnosed grade 1-3a FL were included. Among 10,014 pieces of literature, a total of 90 studies investigating 82 risk factors were included for qualitative analysis. Meta-analyses were performed in 31 studies with 11 factors. Results showed that elevated sIL-2R, β2m and LDH, total metabolic tumour volume 510 cm

Among diverse Pattern Recognition Receptors (PRRs), Toll-like receptor-4 (TLR-4) is a key urothelial trigger for innate immune response impacting urothelial bladder carcinoma (BC). Androgen activation promotes immunotolerance, playing an immunoregulatory role by unknown mechanisms. We explored the castration impact on urothelial TLR-4 modulation in carcinogenesis and immunotherapeutic scenario.Intact (SHAM) versus castrated male Fisher-344 rats were evaluated in 2 scenarios: (A) Carcinogenesis: After randomization to SHAM (n = 5) and Castration (n = 5), carcinogenesis was induced by four intravesical doses of 1.5 mg/kg n-methyl-n-nitrosourea (MNU) every 15 days. (B) Treatment: After ultrasonographic confirmed MNU-induced papillary BC on week 8, rats were randomized to SHAM (n = 5) and Castration (n = 5) and offered 6 weekly intravesical treatment of 10Castration induced higher TLR-4 urothelial expression (p = 0.007) and anticarcinogenic effect with fewer urothelial tumors (60 vs. 80%) and lower urothelial cell proliferation compared to intact animals (p = 0.008). In the intravesical BCG treatment setting, castration has potentialized the BCG activation of TLR-4 (p = 0.007) with no residual in situ carcinoma compared to intact animals, suggesting the potential to amplify the BCG immune response.To our knowledge, this is the first description of TLR-4 urothelial expression hormonal modulation. The described castration-mediated immunomodulation will help to improve the knowledge of urothelial cancer gender diversities and PRRs modulations with treatment implications.

The aberrant mRNA expression of a UPR component Cation transport regulator homolog 1 (CHAC1) has been reported to be associated with poor survival in breast and ovarian cancer patients, however, the expression of CHAC1 at protein levels in malignant breast tissues is underreported. The following study aimed at analyzing CHAC1 protein expression in malignant breast cancer tissues.Evaluation of CHAC1 expression in invasive ductal carcinomas (IDCs) with known ER, PR, and HER2 status was carried out using immunohistochemistry (IHC) with CHAC1 specific antibody. The Human breast cancer tissue microarray (TMA, cat# BR1503f, US Biomax, Inc., Rockville, MD) was used to determine CHAC1 expression. The analysis of CHAC1 IHC was done to determine its expression in terms of molecular subtypes of breast cancer, lymph node status, and proliferation index using Qu-Path software. Survival analysis was studied with a Kaplan-Meier plotter.Immunohistochemical analysis of CHAC1 in breast cancer tissues showed significant up-regulation of CHAC1 as compared to the adjacent normal and benign tissues. Interestingly, CHAC1 immunostaining revealed high expression in tumor tissues with high proliferation and positive lymph node metastasis suggesting that CHAC1 might have an important role to play in breast cancer progression. Furthermore, high CHAC1 expression is associated with poor overall survival (OS) in large breast cancer patient cohorts.As a higher expression of CHAC1 was observed in tissue cores with high Ki67 index and positive lymph node metastasis it may be concluded that enhanced CHAC1 expression correlates with proliferation and metastasis. The further analysis of breast cancer patients' survival data through KM plot indicated that high CHAC1 expression is associated with a bad prognosis hinting that CHAC1 may have a possible prognostic significance in breast cancer.

Glucocorticoid receptor (GR) has been implicated in prostate carcinoma growth and progression. Glucocorticoid receptor beta (GRβ) acts as an inhibitor of GR; however, its function is not well understood. Serum- and glucocorticoid-regulated kinase 1 (SGK1) is a GR-responsive gene that phosphorylates N-myc downstream-regulated gene 1 (NDRG1) and is involved in cancer growth and invasion. However, the expression of GR, GRβ, SGK1, and NDRG1 in prostate cancer and their relationship with clinicopathological and functional significance remain unknown. The association between the status of GR, GRβ, SGK1, and NDRG1 immunoreactivity and clinicopathological variables was analyzed in patients with prostate carcinoma to explore their clinical significance. In prostate carcinoma cases, the relative abundance of GR and NDRG1 immunoreactivity was inversely and significantly associated with the primary tumor stage (pT), while GR immunoreactivity was inversely and significantly associated with the Ki-67 score. The relative expression status of NDRG1 was significantly associated with that of GR. However, no significant correlation was observed between any of the clinicopathological parameters and GRβ and SGK1 expression. Our findings indicate that GR and NDRG1 expression status is correlated with clinicopathological features in patients with prostate cancer.

MicroRNAs are regulatory non-coding RNAs, with their outstanding regulatory mechanism, that make them potential biomarker for disease detection and therapeutics. They play an important role in pathological state, such as cancer by acting as oncogenic microRNAs and tumor suppressor microRNAs. The expression of microRNA-206, microRNA-4477a, microRNA-4795-5p, microR-4796-3p, microRNA-451b, and microRNA-4311 has proven to be deregulated in different cancer studies. However, no comprehensive study has been reported yet regarding their role in glioma patients.The present study is designed to examine the expression profiling of microRNAs, such as microRNA-206, microRNA-4477a, microRNA-4795-5p, microR-4796-3p, microRNA-451b, and microRNA-4311 in glioma patients. Furthermore, the expression deregulation of selected microRNAs was correlated with oxidative stress and proliferation rate in glioma patients.For this purpose, 153 glioma tissue samples and 200 brain tissues from epilepsy patients (taken as controls) were collected in the present study. Expression analysis of selected microRNAs was carried out on collected samples using real-time PCR (qPCR). Oxidative stress and proliferation rate were measured by estimation of 8OXOG level and Ki-67 using the ELISA and IHC.Our results showed significant deregulation of microRNA-206 (p 0.0001), microRNA-4477a (p 0.01), microRNA-4311 (p 0.0001), microRNA-4795-5p (p 0.0001), microRNA-4796-3p (p 0.0001), and microRNA-451b (p 0.0001) in glioma patients compared to controls. However, significant upregulation of 8OXOG level (p 0.0001) and Ki-67 (p 0.0001) was observed in glioma patients compared to controls. Kaplan-Meier analysis showed that deregulated expression of selected microRNAs was associated with significant decrease in survival of glioma patients.Our results demonstrated significant deregulation of selected microRNAs in glioma patients. This deregulated expression was found associated with significant increased risk of glioma and could be further developed as effective prognostic biomarker and therapeutic tool in said disease.

Gastric cancer (GC) is a malignant gastrointestinal tumor that can result in high mortality. Surgery and chemotherapy are often used for the effective treatment of GC. In addition, lymph node metastasis is a significant factor affecting the therapy of GC. Current researches have revealed that gut microbiota has the potential as biomarkers to distinguish healthy people and GC patients. However, the relationship between surgery, chemotherapy, and lymph node metastasis is still unclear.In this study, 16S rRNA sequencing was used to investigate 157 GC fecal samples to identify the role of surgery, chemotherapy, and lymph node metastasis. Immunohistochemical analysis was used to value the expression of Ki67, HER2 in GC patient tissues.There exist some gut microbiotas which can distinguish surgery from non-surgery GC patients, including Enterococcus, Megasphaera, Corynebacterium, Roseburia, and Lachnospira. Differences between lymph node metastasis and chemotherapy in GC patients are not significant. Moreover, we found the abundance of Blautia, Ruminococcus, Oscillospira were related to the expression of Ki67 and the abundance of Prevotella, Lachnospira, Eubacterium, Desulfovibiro were correlated with the expression of HER2.The choice of treatment has a certain impact on the intestinal flora of patients with gastric cancer. Our research shows that surgery has a great effect on the intestinal flora of patients with gastric cancer. However, there were no significant differences in the characteristics of intestinal flora in patients with gastric cancer whether they received chemotherapy or whether they had lymph node metastasis. In addition, the association of gut microbiota with Ki67 and HER2 indicators is expected to provide the possibility of gut microbiota as a tumor prognostic marker.

Intercalated duct lesions (IDLs) are usually asymptomatic. We report a case of IDL, in which a palpable mass formed. The patient was a 45-year-old Japanese male, who noticed a mass in the left parotid region. The nodular lesion was well-circumscribed, but did not have a fibrous capsule or exhibit infiltrative growth. It contained a small cystic space and consisted of basaloid cells arranged in a cribriform pattern and inner ductal cells. It had some solid areas of nest-like proliferation displaying mild cellular atypia. Immunohistochemically, the luminal cells were positive for cytokeratin (CK)7 and epithelial membrane antigen, and the abluminal cells were positive for CK5/6, p63, and DOG1. S-100 protein-positive stromal cells were also seen. The lesion's cells were all positive for SOX10, and the nuclei of some basaloid cells were positive for β-catenin. The Ki-67 labeling index was 3.8%. The ductal cells contained diastase-digestion-resistant, Periodic acid Schiff-positive zymogen granules. Genetically, the lesion harbored a missense mutation in the CTNNB1 gene. We diagnosed the lesion as an IDL. As IDLs are usually small non-neoplastic lesions, symptomatic cases are rare. Based on its common immunohistochemical and genetic features, IDL may be a precursor of basal cell adenoma/adenocarcinoma, such as intercalated duct adenoma.

To investigate the effect of surgery to radiotherapy interval (SRI) on the prognosis of patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma.Retrospective analysis of the relationship between SRI and prognosis of patients with IDH wild-type glioblastoma who received postoperative intensity modulated radiotherapy (IMRT) in our center from July 2013 to July 2019. The patients were divided into SRI ≤ 42 days (regular group) and SRI 42 days (delay group). Kaplan-Meier univariate analysis and Cox proportional hazard model were used to analyze whether SRI was an independent factor influencing the prognosis.A total of 102 IDH wild-type glioblastoma were enrolled. Median follow-up was 35.9 months. The 1-, 2- and 3-year OS of "regular group" were 69.5%, 34.8%, 19.1%, and "delay group" were 69.8%, 26.1% and 13.4% respectively. Multivariate analysis showed that extent of resection (p = 0.041) was an independent prognostic factor for OS. SRI (p = 0.347), gender (p = 0.159), age (p = 0. 921), maximum diameter (p = 0.637) MGMT promoter methylation status (P = 0.630) and ki-67 expression (P = 0.974) had no effect on OS. Univariate analysis (p = 0.483) and multivariate analysis (p = 0.373) also showed that SRI had no effect on OS in glioblastoma who received gross total resection.Appropriate extension in SRI has no negative effect on the OS of IDH wild-type glioblastoma. It is suggested that radiotherapy should be started after a good recovery from surgery. This conclusion needs further confirmed by long-term follow-up of a large sample.

Purpose The autophagy inhibitor chloroquine enhances the effect of targeted therapy using tyrosine kinase inhibitor in liver cancer. We would like to further understand the specific mechanism by which chloroquine inhibits the proliferation of tumor cells. Methods We used a human hepatocarcinoma cell line (HepG2) as cell culture model. In contrast to the control groups (treated only with complete medium), cells in experimental groups were treated either with complete medium + 40 ng/ml Hepatocyte growth factor (HGF), or with complete medium + 60 μM chloroquine or with complete medium + 40 ng/ml HGF + 60 μM chloroquine for 24 h. Cell number and ATP content were investigated using spectrophotometric assays. Cell proliferation and apoptosis were detected by immunohistochemistry. Cell morphological alterations were examined by Giemsa and H&E staining. Cellular lipid content was determined by Oil Red O staining and Triglyceride quantification assay. Autophagy-related proteins (LC3B and p62) and hepatocyte proliferation-related protein (S6K1) were examined using western blot. The autophagic flux of cells was assessed by mRFP-EGFP-LC3 transfection assay. Results We found that chloroquine inhibited the proliferation of HepG2 cells, as evidenced by a decrease in cellular ATP content, Ki-67 and S6K1 protein expression and a reduction in cell number. This finding was associated with an increase in lipid content. As expected, chloroquine inhibited autophagy of HepG2 cells, as evidenced by the accumulation of LC3B-II and the significant upregulation of p62. mRFP-EGFP-LC3 transfection assay showed that indeed chloroquine blocked the autophagic flux in HepG2 cells. Conclusion Chloroquine impaired proliferation of HepG2 cells might be due to intracellular accumulation of lipids and inhibition of energy synthesis.

PURPOSE: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. METHODS: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb-July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. RESULTS: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32-81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7-8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months' treatment duration; median of 4 mm [IQR - 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month's duration of BrET. DISCUSSION: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.

Barrett’s esophagus progresses to high-grade dysplasia or cancer along the well-established metaplasia-dysplasia-adenocarcinoma sequence. The aim of this study was to evaluate the value of p53, Ki67, and toll-like receptor 5 (TLR5) in prediction of malignant progression of Barrett’s metaplasia and low-grade dysplasia. This was a retrospective matched case–control study based on Northern and Central Finland population. Patients diagnosed with esophageal high-grade dysplasia or adenocarcinoma were included. From these patients, all previous endoscopy samples were obtained along with original diagnostic HE-slides and clinical data. Age- and sex-matched patients with non-progressing Barrett’s metaplasia and low-grade dysplasia confirmed with follow-up endoscopies were used as controls. Two gastrointestinal pathologist re-reviewed all original HE-slides, and newly made sections to confirm representative tissue material blinded from clinical data. p53, Ki67, and TLR5 were immunohistochemically stained. Final cohort included 45 patients with progressive Barrett’s metaplasia (n = 21) or low-grade dysplasia (n = 24), and 92 patients with non-progressive Barrett’s metaplasia (n = 52) or low-grade dysplasia (n = 40). In Barrett’s metaplasia, aberrant p53 expression was observed in 6% of samples in progressors and 0% in non-progressors. In low-grade dysplasia, aberrant p53 was seen in 56% of samples in progressors and 17% in non-progressors (Odd’s ratio 6.7, 95% CI 1.8–24.6). Ki67 or TLR5 showed no association with disease progression. In this matched case–control study, p53 expression associated with a high risk of malignant progression in Barrett’s low-grade dysplasia. Routine staining of p53 is indicated in expert confirmed low-grade dysplasia.

BACKGROUND. Neoadjuvant chemotherapy (NAC) is standard for most triple-negative and human epidermal growth factor receptor 2 (HER2)+ breast cancers, and frequently downstages node-positive (cN+) disease, permitting omission of axillary dissection. In estrogen receptor (ER)+/HER2− disease, response rates are lower. Whether Ki67 is associated with axillary downstaging in ER+/HER2− disease is unknown. METHODS. With institutional review board approval, we queried our institutional database to identify all patients with primary ER+/HER2− biopsy-proven cN+ breast cancer treated with NAC followed by surgery from January 2012 to December 2021. Nodal pathologic complete response (pCR) rates were evaluated by pretreatment Ki67 and patient age. RESULTS. 315 patients (median age 50 years) were included. Nodal pCR rate was 24.8% (78/315) and was higher in patients aged < 50 years than ≥ 50 years (31.8% versus 17.7%, p = 0.004). Ki67 was available on 236 patients (74.9%). Median Ki67 was 29.0% (range 1–98%) and did not differ by age category (p = 0.23). Patients with nodal pCR had higher Ki67 (median 40.3% versus 25.0%, p < 0.001). Nodal pCR rates were 28.4% (Ki67 ≥ 20%) versus 8.1% (Ki67 < 20%) (p < 0.001). On multivariable analysis, Ki67 and age category were predictive of nodal pCR. Combining these two parameters together, nodal pCR rates in age < 50 years were 35.8% when Ki67 ≥ 20% versus 14.3% with Ki67 < 20% (p = 0.02). In contrast, for age ≥ 50 years, nodal pCR was 21.0% for Ki67 ≥ 20% versus 2.6% with Ki67 < 20% (p = 0.008). CONCLUSIONS. In ER+/HER2− breast cancer, nodal downstaging with NAC is associated with age (< 50 years) and Ki67 (≥ 20%). Age and Ki67 should be considered for NAC decision-making and can identify patients with high rates of nodal downstaging (36%) who would benefit from NAC to enable axillary preservation.

This study aimed to evaluate if paradoxical sleep deprivation induces some tissue changes in the parotid gland of rats.A total of 24 male Wistar rats were distributed into the following groups, as follows: Group 1-Control (CTRL; n = 8); Group 2-Sleep deprivation (PS; n = 8): the animals were submitted to Paradoxical Sleep deprivation for 96 h and Group 3-Recovery (R; n = 8): the animals were submitted to sleep loss for 96 h, followed by a period of 96 h without any intervention. The following parameters were evaluated: microscopic analysis, immunohistochemistry for Caspase-3, Ki-67, and COX-2 and gene expression of cytochrome C, TNF-α, and Interleukins 6, 10.The results pointed out acinar atrophy, and the presence of cytoplasmic vacuoles in the parenchyma of the experimental groups. In the same groups, there was differential expression of interleukins 6, 10 and TNF-α. Apoptosis was also increased by means of cleaved caspase 3 expression. The cellular proliferation (ki-67 expression) was increased the R group.Taken together, sleep deprivation induces tissue degeneration, inflammatory process, as well as activate apoptosis in the parotid gland of rats.

Diabetic wound management is a serious health care challenge due to higher rates of relapse, expensive treatment approaches, and poor healing outcomes. Among cell-based therapies, use of platelet-rich plasma (PRP) has been shown to be effective for diabetic wounds, but its poor shelf-life limits its clinical use. Here, we demonstrate a simple but effective polymer system to increase the shelf-life of PRP by developing a polyelectrolyte complex with dropwise addition of chitosan solution containing PRP by simple mixing at room temperature. Thus, prepared chitosan-fucoidan (CF) carrier complex encapsulated more than 95% of the loaded PRP. The resulting CF/PRP colloids were spherical in shape and ensured extended PRP release up to 72 h at 37 °C. Routine characterization (FT-IR, XRD, SEM) showed the material properties. The biological assays showed that CF complexes were biocompatible while CF/PRP enhanced the proliferation of fibroblasts and keratinocytes via higher Ki67 expression and fibroblast migration. Further investigations using a diabetic mouse model demonstrated significantly higher wound contraction and histopathological observations showed increased fibroblast migration, and collagen and cytokeratin deposition in treatment groups. The results are suggestive of the efficacy of CF/PRP as a cost-effective topical formulation for the sustained delivery of growth factors in treating chronic diabetic wounds.

To investigate the diagnostic performance of the minimal apparent diffusion coefficient (ADCPre-operative magnetic resonance imaging data and postoperative Ki-67 proliferation index data of 42 patients with primary neuroendocrine tumor of the pancreas from November 2014 to March 2021 were included in this retrospective study. According to the Ki-67 proliferation index value, Pan-NETs were divided into a high-expression group (Ki-67 ≥ 10%, n = 17) and low-expression group (Ki-67 10%, n = 25), and mean ADC (ADCThe ADCThe ADC

To build and validate a radiomics nomogram integrated with the radiomics signature and subjective CT characteristics to predict the Ki-67 expression level of gastrointestinal stromal tumors (GISTs). Moreover, the purpose was to compare the performance of pathological Ki-67 expression level with predicted Ki-67 expression level in estimating the prognosis of GISTs patients.According to pathological results, patients were classified into high-Ki-67 labeling index group (Ki-67 LI ≥ 5%) and low-Ki-67 LI group (Ki-67 LI 5%). Radiomics features extracted from contrast-enhanced CT(CECT) images were selected and classified to build a radiomics signature. A combined model was built by incorporating radiomics signature and determinant subjective CT characteristics using multivariate logistic regression analysis. The diagnostic performance of the radiomics signature, subjective CT model and combined model were explored by receiver operating characteristic (ROC) curve analysis and Delong test. The model with best diagnostic performance was then set up for the prediction nomogram. Recurrence-free survival (RFS) rates were compared utilizing Kaplan-Meier curve.The generated combined model yielded the best diagnostic performance with area under the curve (AUC) values of 0.738 [95% confidence interval (CI): 0.669-0.807] and 0.772 (95% CI 0.683-0.860) in the training set and testing set respectively. The nomogram based on the combined model demonstrated good calibration in the training set and testing set (both P 0.05). Patients of high-Ki-67 LI group predicted by our nomogram had a poorer RFS than patients of low-Ki-67 LI group (P 0.0001).This radiomics nomogram based on CECT had a satisfactory performance in predicting both the Ki-67 expression level and prognosis noninvasively in patients with GISTs, which may serve as an effective imaging tool that can assist in guiding personalized clinical treatment.

Grade 3, type 3 gastric neuroendocrine tumor (g-NET) shows specific features of clinical interest and the therapeutic management of the lesion is not yet completely standardized. We present the unusual case of a 34-year-old male patient with a diminutive (less than 0.5 cm), well-differentiated, G3, type 3g-NET with extremely high Ki-67 index (higher than 80%). The lesion was subsequently removed en bloc via endoscopic submucosal dissection. Regarding the proliferation rate, Ki-67 index values usually range from 21 to 50%, and less commonly above 55%, in G3 NET. To our knowledge, this lesion represents a small size with the highest Ki-67 index diagnosed with G3 g-NET. However, as g-NET might recur even after a long duration, we recommend a long-term follow-up, such as 10 years after complete resection in patients to evaluate the endoscopic resection approach.

To evaluate the glioma grade, Ki-67 expression, and IDH-1 mutation status using mean apparent propagator (MAP) MRI.Forty enrolled glioma patients underwent structural and diffusion MRI. The diffusion metric values including fractional anisotropy (FA), mean diffusivity (MD), mean squared displacement (MSD), q-space inverse variance (QIV), return-to-origin probability (RTOP), return-to-axis probability (RTAP), and return-to-plane probability (RTPP) in tumor parenchyma (TP) and contralateral normal-appearing white matter (NAWM) were calculated. The TP/NAWM ratios of diffusion metric values were correlated with tumor grades, Ki-67, and IDH-1 mutation statuses, and the diagnostic performance was assessed.QIV were significantly higher, whereas RTAP and RTOP were significantly lower in low-grade gliomas (LGGs) than those in high-grade gliomas (HGGs); QIV and MD were significantly higher, whereas RTAP and RTOP were significantly lower in lower-grade gliomas (grade II and III) than those in grade IV gliomas (p 0.05 for all). RTAP performed best in grading gliomas. MSD, QIV, and MD were significantly higher, whereas RTAP, RTOP, RTPP, and FA were significantly lower in the IDH-1 mutant gliomas than those in the IDH-1 wild-type ones both for all gliomas and lower-grade gliomas (p 0.05 for all). RTAP performed best in all gliomas, while QIV performed best in lower-grade gliomas. Additionally, RTAP, RTOP, and FA correlated positively, whereas MSD, QIV, and MD correlated negatively with Ki-67 (p 0.05 for all).MAP-MRI is a potent approach in evaluating the microstructural changes in gliomas with different grades, cellular proliferation, and IDH-1 mutation statuses.• MAP-MRI, a newly developed diffusion technique, accurately reveals microstructure-related features in the complex white matter by recovering important microstructural tissue parameters. • MAP-MRI is a potent approach in evaluating the glioma grade, IDH-1 mutation status, and Ki-67 expression. • Compared with DTI, MAP-MRI seems to demonstrate higher diagnostic performance.

To explore the value of an apparent diffusion coefficient (ADC) histogram in predicting the Ki-67 proliferation index in pituitary macroadenomas.This retrospective study analyzed the pathological and imaging data of 102 patients with pathologically confirmed pituitary macroadenoma. Immunohistochemistry staining was used to assess Ki-67 expression in tumor tissue samples, and a high Ki-67 labeling index was defined as 3%. The ADC images of the maximum slice of tumors were selected and the region of interest (ROI) of each slice was delineated using the MaZda software (version 4.7, Technical University of Lodz, Institute of Electronics, Łódź, Poland) and analyzed by ADC histogram. Histogram characteristic parameters were compared between the high Ki-67 group (n = 42) and the low Ki-67 group (n = 60). The important parameters were further analyzed by receiver operating characteristic (ROC).The mean value, and the 1st, 10th, 50th, 90th, and 99th percentiles were found to be negatively correlated with Ki-67 expression (all P 0.05), with correlation coefficients of -0.292, -0.352, -0.344, -0.289, -0.253 and -0.267, respectively. The mean ADC and the 1st, 10th, 50th, 90th, and 99th quantiles extracted from the histogram were significantly lower in the high Ki-67 group than in the low Ki-67 group (all P 0.05). The area under the ROC curve was 0.699-0.720; however, there were no significant between-group differences in variance, skewness and kurtosis (all P 0.05).An ADC histogram can be a reliable tool to predict the Ki-67 proliferation status in patients with pituitary macroadenomas.

Purpose This study aimed to identify the association between Ki-67 level and the prognosis of patients with breast cancer, regardless of the timing of Ki-67 testing (using preoperative biopsy vs. postoperative specimen). Methods A total of 4177 patients underwent surgery between January 2008 and December 2016. Immunohistochemical Ki-67 levels, using either preoperative (1673) or postoperative (2831) specimens, were divided into four groups using cutoff points of 10%, 15%, and 20%. Results Groups with higher-Ki-67 levels, in both the pre- and postoperative periods, showed significantly larger tumor size, higher grade, more frequent hormone receptor-negativity and human epidermal growth factor receptor 2 overexpression, and active adjuvant treatments than groups with lower-Ki-67 levels. High-Ki-67 levels were also significantly associated with poor survival, irrespective of the timing of specimen examination. Conclusion Despite the problems associated with Ki-67, Ki-67 level is an important independent prognostic factor, regardless of the timing of Ki-67 testing, i.e., preoperative or postoperative testing.

To compare region of interest (ROI)-apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) measurements and Ki-67 proliferation index before and after neoadjuvant chemotherapy (NACT) for breast cancer. 55 women were enrolled in this prospective single-center study, with a final population of 47 women (49 cases of invasive breast cancer). ROI-ADC measurements were obtained on MRI before and after NACT and were compared to histological findings, including the Ki-67 index in the whole study population and in subgroups of “pathologic complete response” (pCR) and non-pCR. Nineteen percent of women experienced pCR. There was a significant inverse correlation between Ki-67 index and ROI-ADC before NACT (r = − 0.443, p = 0.001) and after NACT (r = − 0.614, p –3 mm2/s before NACT to 1.533 × 10–3 mm2/s after NACT (p Clinical trial registration number: clinicaltrial.gov NCT02798484, date: 14/06/2016.

To investigate in vitro the impact of fibroblast growth factor 1 (FGF1) in comparison to ascorbic acid (AscA) on human periodontal ligament fibroblast (HPdLF) growth, their osteogenic differentiation, and modulation of their inflammatory reaction to mechanical stress.The influence of different concentrations of FGF1 (12.5-200 ng/mL) on growth and proliferation of HPdLF cells was analyzed over 20 days by counting cell numbers and the percentage of Ki67-positive cells. Quantitative expression analysis of genes encoding the osteogenic markers alkaline phosphatase (ALPL), Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osteopontin (OSP), as well as the fibroblast markers vimentin (VIM) and fibroblast-specific protein 1 (FSP1), was performed after 2 and 20 days of cultivation. Metabolic activity was determined by MTT assay. For comparison with AscA, 50 ng/mL FGF1 was used for stimulation for 2 and 20 days. Cell number, percentage of Ki67-positive cells, and expression of osteoblast- and fibroblast-specific genes were examined. Alkaline phosphatase activity was visualized by NBT/BCIP and calcium deposits were stained with alizarin red. Cytokine (IL‑6, IL‑8, COX2/PGE2) expression and secretion were analyzed by qPCR and ELISA in 6 h mechanically compressed HPdLF cultured for 2 days with FGF1 or ascorbic acid.Higher concentrations of FGF1 promoted cell proliferation upon short-term stimulation, whereas prolonged treatment induced the expression of osteogenic markers even with low concentrations. AscA promotes cell growth more markedly than FGF1 in short-term cultures, whereas FGF1 induced osteogenic cell fate more strongly in long-term culture. Both factors induced an increased inflammatory response of HPdLF to mechanical compression.Our data suggest that FGF1 promotes an osteogenic phenotype of HPdLF and limits inflammatory response to mechanical forces compared to AscA.ZIELSETZUNG: In-vitro-Evaluation des Einflusses von Fibroblastenwachstumsfaktor 1 (FGF1) im Vergleich zu Ascorbinsäure (AscA) auf das Wachstum, das osteogene Differenzierungspotenzial und die inflammatorische Stressreaktion humaner Parodontalligamentfibroblasten (HPdLF).Der Einfluss von verschiedenen Konzentrationen von FGF1 (12,5–200 ng/ml) auf das Wachstum und die Proliferation von HPdLF-Zellen wurde über 20 Tage anhand von Zellzahlen und dem Anteil an Ki67-positiven Zellen analysiert. Die quantitative Expressionsanalyse von Genen, welche für die osteogenen Marker alkalische Phosphatase (ALPL), „runt-related transcription factor 2“ (RUNX2), Osteocalcin (OCN) und Osteopontin (OSP) sowie für die Fibroblastenmarker Vimentin (VIM) und „fibroblast-specific protein 1“ (FSP1) kodieren, wurde nach 2 und 20 Tagen Kultivierung durchgeführt. Die metabolische Aktivität wurde mittels MTT-Assay bestimmt. Für den Vergleich mit AscA wurde 50 ng/ml FGF1 zur Stimulation für 2 und 20 Tage verwendet. Die Zellzahl, der Anteil Ki67-positiver Zellen und die Expression von osteoblasten- und fibroblastenspezifischen Genen wurden untersucht. Die Aktivität der alkalischen Phosphatase wurde mittels NBT/BCIP visualisiert und Kalziumablagerungen mit Alizarin-Rot angefärbt. Die Expression und die Sezernierung von Zytokinen (IL‑6, IL‑8, COX2/PGE2) wurden mittels qPCR und ELISA in 6 h mechanisch komprimierten HPdLF analysiert, die 2 Tage mit FGF1 oder Ascorbinsäure kultiviert wurden.Höhere Konzentrationen von FGF1 förderten die Zellproliferation bei Kurzzeitstimulation, während bei längerer Behandlung auch mit niedrigen Konzentrationen die Expression osteogener Marker induziert wurde. AscA förderte das Zellwachstum in Kurzzeitkulturen deutlicher als FGF1, wohingegen FGF1 den osteogenen Phänotyp bei Langzeitkultivierung stärker hervorrief. Beide Faktoren induzierten eine erhöhte inflammatorische Reaktion von HPdLF auf mechanische Kompression.Unsere Daten deuten darauf hin, dass FGF1 den osteogenen Phänotyp von HPdLF bei Langzeitkultivierung fördert und die immunologische Stressreaktion auf mechanische Kräfte im Vergleich zu AscA mindert.

Background Multiple clinical trials demonstrate consistent but modest benefit of adjuvant extended endocrine therapy (EET) in HR + breast cancer patients. Predictive biomarkers to identify patients that benefit from EET are critical to balance modest reductions in risk against potential side effects of EET. This study compares the performance of the Breast Cancer Index, BCI (HOXB13/IL17BR, H/I), with expression of estrogen (ER), progesterone (PR), and androgen receptors (AR), and Ki67, for prediction of EET benefit. Methods Node-positive (N+) patients from the Trans-aTTom study with available tissue specimen and BCI results (N = 789) were included. Expression of ER, PR, AR, and Ki67 was assessed by quantitative immunohistochemistry. BCI (H/I) gene expression analysis was conducted by quantitative RT-PCR. Statistical significance of the treatment by biomarker interaction was evaluated by likelihood ratio tests based on multivariate Cox proportional models, adjusting for age, tumor size, grade, and HER2 status. Pearson’s correlation coefficients were calculated to evaluate correlations between BCI (H/I) versus ER, PR, AR, Ki67 and AR/ER ratio. Results EET benefit, measured by the difference in risk of recurrence between patients treated with tamoxifen for 10 versus 5 years, is significantly associated with increasing values of BCI (H/I) (interaction P = 0.01). In contrast, expression of ER (P = 0.83), PR (P = 0.66), AR (P = 0.78), Ki67 (P = 0.87) and AR/ER ratio (P = 0.84) exhibited no significant relationship with EET benefit. BCI (H/I) showed a very weak negative correlation with ER (r = − 0.18), PR (r = − 0.25), and AR (r = − 0.14) expression, but no correlation with either Ki67 (r = 0.04) or AR/ER ratio (r = 0.02). Conclusion These findings are consistent with the growing body of evidence that BCI (H/I) is significantly predictive of response to EET and outcome. Results from this direct comparison demonstrate that expression of ER, PR, AR, Ki67 or AR/ER ratio are not predictive of benefit from EET. BCI (H/I) is the only clinically validated biomarker that predicts EET benefit.

Although ependymomas (EPNs) have similar histopathology, they are heterogeneous tumors with diverse immunophenotypes, genetics, epigenetics, and different clinical behavior according to anatomical locations. We reclassified 141 primary EPNs from a single institute with immunohistochemistry (IHC) and next-generation sequencing (NGS). Supratentorial (ST), posterior fossa (PF), and spinal (SP) EPNs comprised 12%, 41%, and 47% of our cohort, respectively. Fusion genes were found only in ST-EPNs except for one SP-EPN with ZFTA-YAP1 fusion, NF2 gene alterations were found in SP-EPNs, but no driver gene was present in PF-EPNs. Surrogate IHC markers revealed high concordance rates between L1CAM and ZFTA-fusion and H3K27me3 loss or EZHIP overexpression was used for PFA-EPNs. The 7% cut-off of Ki-67 was sufficient to classify EPNs into two-tiered grades at all anatomical locations. Multivariate analysis also delineated that a Ki-67 index was the only independent prognostic factor in both overall and progression-free survivals. The gain of chromosome 1q and CDKN2A/2B deletion were associated with poor outcomes, such as multiple recurrences or extracranial metastases. In this study, we propose a cost-effective schematic diagnostic flow of EPNs by the anatomical location, three biomarkers (L1CAM, H3K27me3, and EZHIP), and a cut-off of a 7% Ki-67 labeling index. Supplementary Information The online version contains supplementary material available at 10.1007/s10014-021-00417-y.

Introduction Meningiomas are the most common benign intracranial neoplasms. CNS invasion in meningiomas has been integrated into the 2016 WHO classification of CNS tumors as a stand-alone criterion for atypia. Since then, its prognostic impact has been debated based on contradictory results from retrospective analyses. The aim of the study was to elucidate whether histopathological evidence of CNS invasion is associated with increased proliferative potential. Methods We have conducted a quantified measurement of the proliferation marker Ki67 and analyzed its association with CNS invasion determined by histology together with other established prognostic markers of progression. Routine, immunohistochemical staining for Ki67 were digitalized and automatic quantification was done using Image J software. Results Overall, 1718 meningiomas were assessed. Histopathological CNS invasion was seen in 108 cases (6.7%). Uni- and multivariate analysis revealed a significantly higher Ki67 proliferation rate in meningiomas with CNS invasion (p Conclusions Meningiomas with histopathological CNS invasion show a higher proliferative activity.

Lower grade gliomas with 1p/19q codeletion are often responsive to chemotherapy, and several of these have been treated using upfront chemotherapy and subsequent resection following tumor volume decrease. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in 1p/19-codeleted gliomas. Fourteen 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin–eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry for Ki-67/MIB-1, CD68 as a pan-macrophage/monocyte marker, CD163 as a presumed marker of M2 polarity, and nestin and CD133 as markers of GSCs. The most frequent histological findings following chemotherapy included a sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 index decreased and the number of CD68 + cells increased after chemotherapy. The increasing rate of CD68 + cells in the post-/pre-chemotherapy specimens was inversely correlated with patient prognosis but not tumor response. The number of CD163 + cells, M2/M1 + M2 ratio, and the ratio of GSCs to total tumor cells increased after chemotherapy, and those in the post-chemotherapy specimens were negatively correlated with patient prognosis. There was a correlation between the M2/M1 + M2 ratio and the ratio of GSCs in both pre- and post-chemotherapy specimens. GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in 1p/19q-codeleted gliomas.

Long noncoding RNAs have recently emerged as significant contributors to cancers, including breast cancer (BC). One class of long noncoding RNAs called transcribed ultraconserved regions (T-UCRs) is highly conserved in many species and closely related to diverse physiological and pathological processes. However, the function of T-UCRs in BC remains largely unclear. In this study, we identified uc.51, a T-UCR that is overexpressed in both BC tissues and cell lines and is correlated with larger tumor size. Loss- and gain-of-function assays were performed in vitro and demonstrated that uc.51 promotes the proliferation, migration, and invasion of BC cells. Mechanistically, non-POU domain-containing octamer-binding protein (NONO) was found to physically interact with uc.51 by RNA pulldown followed by mass spectrometry. This interaction was further verified by RNA immunoprecipitation. Moreover, uc.51 positively regulated the expression of NONO, maintained its stability through the ubiquitin-proteasome system, and activated the phosphorylation of CREB. Rescue experiments demonstrated that NONO overexpression compensated for the attenuated influence on BC progression resulting from downregulation of uc.51, indicating that NONO functions downstream of uc.51. In vivo functional experiments also revealed a positive correlation between uc.51 expression and tumor size. Ki-67 and NONO levels in the lv-uc.51-shRNA group were decreased compared with those in the lv-con-shRNA group, according to the immunohistochemical staining results, and a decreased incidence of distant metastasis was observed in the lv-uc.51-shRNA group in the xenograft model. Collectively, our results reveal a substantial role for the uc.51-NONO axis in BC progression and indicate that the uc.51-NONO axis has potential to be a therapeutic target for BC.

BACKGROUND: Twenty percent of women referred to colposcopy have a type 3 transformation zone—where colposcopic assessment for high-grade dysplasia (CIN2+) is not possible. This study examines the effectiveness of HPV biomarkers and genotyping in combination with techniques that sample an endocervical TZ. METHODS: A prospective diagnostic accuracy study. Women booked for large-loop excision (LLETZ) with squamous dyskaryosis, high-risk HPV and a TZ3 were recruited. Immediately prior to LLETZ samples were collected for p16/Ki-67 dual-stained cytology, HPV genotyping and H&E, p16- and Ki-67-stained endocervical curettings. RESULTS: In women with low-grade screening (n = 64), 35.9% had CIN2+; dual-stained cytology had the greatest effect on the PPV of routine screening (76.1% vs 35.9%) and perfectly predicted the absence of CIN2+. In women with a high-grade screening result (n = 37); 75.6% had CIN2+ and dual-stained curettings improved the PPV (96.5 vs 75.6%). CONCLUSIONS: With high-grade screening and a TZ3, LLETZ appears safest as three quarters have CIN2+ . Women with low-grade screening and a TZ3 have a twofold increased risk of CIN2+ when compared to women where the TZ is visible. The use of dual-stained cytology may help identify those women who can be safely offered surveillance and those who require treatment.

We report two pituitary neuroendocrine tumors (PitNETs) with very high Ki67 labeling indices, many mitoses and TP53 mutation (nearly all tumor cell nuclei were positive for p53). One of the tumors had bone and liver metastases. One was a corticotroph cell tumor; the other was a lactotroph tumor. The classification of these tumors is the subject of this discussion. Traditionally, pituitary carcinomas are only diagnosed by demonstration of metastases according to the 2017 WHO classification. In contrast, neuroendocrine neoplasms of the gastrointestinal tract and pancreas are classified as either well differentiated NETs that are graded as G1, G2, and G3 based on proliferation as determined by Ki67 indices of ≤ 3, 3–20 and > 20%, and/or 20 mitoses per 10 high-power field respectively, or as neuroendocrine carcinomas (NECs) that are poorly differentiated neoplasms with mitoses > 20/HPF and/or a Ki67 index > 20%. With the reclassificiation of PitNETs, in our opinion, the adequate term for the well-differentiated corticotroph tumor that we report is a PitNET G3, whereas the undifferentiated prolactin tumor should be classified as PitNEC. This report expands the spectrum of pituitary neuroendocrine neoplasms.

Background Gastrointestinal neuroendocrine tumor (GI-NET) is a group of neoplasia consisting of amine and acid producing cells with different hormonal profiles. Although the entire GIS accounts for about 2% of tumors, recent research reveals that the incidence rate has increased. Given the increasing incidence in GI-NETs, more and more extensive research is needed on this subject. In this regard, the demographic and clinicopathological features of the patients diagnosed with GI-NET and their relationship with survival were investigated in the present study. Methods Thirty-four patients diagnosed with GI-NETs between January 2009 and December 2019 at the Department of Gastroenterology, Inonu University Faculty of Medicine were analyzed retrospectively. Gender, age, tumor localization, metastasis status, tumor number, tumor diameter, tumor grade, Ki-67 index, and the relationships of these factors with overall survival were examined. Results Of the patients, 61.8% included in the study were male and 38.2% were female. The average age of the patients was 60.74 years. The most common tumor location was in the stomach (26.5%) and liver (26.5%). Apart from this, 17.6% of NETs were seen in the pancreas, 11.8% in the colon, 8.8% in the rectum, 5.9% in the small intestine, and 2.9% in the appendix. No significant relationship was observed between tumor location and gender (p = .326) and age (p = .641). The tumor diameter ranged from 0.2 cm to 13.91 cm, but the average tumor diameter was 3.84 cm. Solitary tumor was found in 51.5% of cases and multiple tumors in 48.5% of cases. The most common grade was Grade 1 with 41.2% of occurrence. The average of Ki-67 index was 18.36%. There was metastasis in 52.9% of cases. The rate of medical treatment was 48.5%. The median overall survival time of the patients was 23.1 months. In addition, 1-year overall survival was 74.9%, 2-year overall survival was 44.6%, and 5-year overall survival was 35.7%. A statistically significant difference was found between tumor grade and the presence of metastasis, and the overall survival (p = .003 and p = .005). Conclusions The tumor grade and the presence of metastasis in gastrointestinal neuroendocrine tumors were found to be the most important prognostic factors affecting overall survival.

Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II–III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)−0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3–41.3). RCB-0/I is 55.7% (95% CI, 44.7–66.1). ORR is 87.4%, (95% CI, 78.1–93.2) and bpCR is 35.4% (95% CI, 25.8–46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P

Background Squamous cell carcinoma of the external auditory canal (EACSCC) is an uncommon tumor and responsible for no more than 0.2% of all the head and neck malignancies. Although there is remarkable research evidence exhibiting that high-risk human papillomavirus (HPV) accounts for considerable head and neck malignancies, its role in the pathogenesis of EACSCC is yet to be determined. Methods We evaluated 16 patients with EACSCC treated at our department. We employed PCR to assay for high-risk subtypes of HPV. Two pathologists reviewed the histopathological staining via hematoxylin and eosin along with immunohistochemical staining of p16INK4a and Ki‑67. Results Detection of HPV DNA was done via PCR in 3 (18.75%) patients, and 8 (50%) positive (+) cases were determined via p16INK4a immunostaining. Besides, 3 (37.5%) individuals were HPV positive as per p16INK4a PCR results. In addition, all of the p16INK4a-positive specimens were diagnosed as moderately differentiated carcinomas. Conclusions Expression of Ki-67 was related to HPV status. This is the first report implicating high-risk HPV in squamous cell carcinoma of the external auditory canal. However, p16INK4a immunostaining is a suspectable approach for diagnosing HPV for EACSCC. In addition, HPV might enhance an elevated proliferation rate in EACSCC, illustrated via expression of Ki-67. Graphical Abstract

The world health organization (WHO) called for coordinated global action in 2018 to eliminate cervical cancer, ensuring that every woman is screened and treated for precancerous lesions (World Health Organization. Cervical cancer: an NCD we can overcome. Geneva, 2018. http://www.who.int/director-general/speeches/detail/cervical-cancer-an-ncd-we-can-overcome.tegy). Cytology-based screening has been for decades the conventional method of screening. Ancillary techniques have been added like immunocytochemistry with P16/Ki67 and L1-Capsid, but these methods require maintenance of complex infrastructure and highly trained personnel as well as relatively short screening intervals. HPV-based screening method to detect high-risk groups is a faster and automated method, which does not need morphologically highly qualified personal with high social costs. In the study, we have focused on the distribution of cervical lesions in the age groups with concordance of detection HPV high-risk subtypes (HPV-HR) and on the safety of the screening method. In the Institute for Pathology and Cytology-Schuettorf-Leer-Germany 146.800 samples of women from the age of and above 35 years were analyzed between the beginnings of 2020 until the beginning of 2021. 63.710 cases under 35 years old were analyzed. The samples were processed for both conventional cytological techniques and for molecular detection and subtyping of HPV-HR according to the advice and measurements of BD-manufacture. In this study, we have studied the histopathological results (Table 2) after colposcopy according to the age subgroups. The histopathological results were subdivided into no dysplasia, cervical intraepithelial neoplasia I (CIN I), cervical intraepithelial neoplasia II (CIN II), cervical intraepithelial neoplasia III (CIN III), squamous cell carcinoma (Sq.c.c), adenocarcinoma in situ (AIS), endometrial carcinoma, endocervical adenocarcinoma and cases without biopsy during the colposcopy (COB). We have used the muenchener classification III (Table 3) as a subgrading system for the cytological specimens. The frequency of detecting HPV56/59/66 is higher as detecting HPV-16 and HPV18 in age groups under 35 years old, 41–50 years old and 51–60 years old. HPV16 is detected higher in age groups 35–40 years old and above 60 years. The incidence of high squamous intraepithelial lesions (CIN II and III) is 0.92% in age group 35–40 years, 0.54% in age under 35 years, 0.59% in age group 41–50 years old, 0.35% in age group 51–60 years old and 0.15% in age group above 60 years old. There is no significance (p value = 0.4060). Low grade cervical lesions (CIN I) were 0.13% ( 60Y s), which was statistically significant (p value = 0.04,0.60). Without dysplasia 0.19% ( 60 Ys). There is no significance between occurrence of cervical dysplasia and without dysplasia despite of detection of HPV-HR subtypes (p value = 0.1754). The only use of HPV-subtyping is not a secure method and a protective way for women. There are worldwide many HPV-positive cases, which have been psychologically impaired with higher costs, although they have no cervical epithelial changes during the HPV-infection. There are many HPV-negative cases, in some studies up to 13% of cases, which develop cervical cancer. We have the opinion and are convinced that the screening should be both morphologically via cytological examination and may be with adding immunocytochemistry to detect the really dysplastic cervical lesions. HPV-subtyping may be added every three years to detect the concomitant subtype.

The purpose of this study was to establish a novel mouse model of adenomyosis suitable for longitudinal and quantitative analyses and perinatal outcome studies. Using a 30 G needle, the entire uterine wall of one horn was mechanically punctured at a frequency of 100 times/1 cm (adenomyosis horn). The other horn was left unpunctured (control horn). Balb/c mice were sacrificed on day 14 (D14) or day 65 (D65) (n = 3 each). The uterus was fixed, paraffin-embedded, sliced, and stained. Lesions were detected and counted, and their volumes were measured. Cell proliferation and fibrosis were assessed by Ki67 and Masson’s Trichrome staining, respectively. Blood vessels were detected using CD31 immunostaining. Some of the mice (n = 4), were mated and the date of delivery, litter size, number of implantations, and number and volume of postpartum lesions were measured. The number of lesions per horn did not differ between D14 and D65. The volume of the entire lesion was significantly greater on D65 than on D14 (p

Background: Orthokeratinized odontogenic cyst (OOC) is a rare developmental odontogenic cyst of the jaw. It was originally believed to be a variant of odontogenic keratocyst (OKC) but is now considered to be a distinct entity. OOC usually presents as a single lesion and recurs infrequently. On the other hand, OKC often presents with multiple lesions and displays locally aggressive behavior and a high recurrence rate associated with the protein patched homolog 1 (PTCH1) gene mutation. Multiple OOC cases are extremely rare and seem to be aggressive, but their pathogenesis is not fully understood. This study aimed to determine the clinical, pathological, and genetic characteristics of multiple OCC. Methods: Three cases of multiple OOC were evaluated for clinical and histological findings, and immunohistochemical expression of Ki-67 and Bcl-2. Furthermore, PTCH1 mutations were analyzed by next-generation sequencing using a custom panel to cover the entire exon of PTCH1. Results: The three cases of multiple OOC included two men and one woman with a mean age of 25.3 years old (range, 18–38 years old). Each case had two or three OOCs (total of seven OOCs), all of which were simultaneously detected. Of the seven OOCs that manifested as multiple jaw cysts, seven (100%) occurred in the posterior regions, four (57.1%) occurred in the mandible, and four (57.1%) were associated with an impacted tooth. Histological examination revealed cysts lined by orthokeratinized stratified squamous epithelium. Immunohistochemistry showed a low Ki-67 labeling index and no Bcl-2 expression in the seven OOCs. No pathogenic PTCH1 mutations were detected in any of the seven OOCs. None of the patients had any other symptoms or signs of recurrence at the last follow-up (6–60 months). Conclusion: Multiple OOCs appeared to occur more often in younger patients than solitary OOC. Both multiple and solitary OOCs may be related diseases within the entity of odontogenic cysts. Multiple OOCs are clinicopathologically and genetically distinct from OKC.

Neuroendocrine neoplasm (NEN) is a common gastrointestinal (GI) tract tumor divided into the neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) according to mitosis and Ki-67 index. However, the objective discordance between interobserver may cause unsuitable diagnosis and misleading treatment. Nowadays, aberrant glycosylation of glycoconjugates inducing further populations of elongated complex oligosaccharide covalent attached to glycoconjugates anchored in the cell membrane by neo-synthesis of cancer-associated alteration of carbohydrate determinants were observed during cancer development. This study aimed to demonstrate the wax physisorption kinetics coupled with Fourier transform infrared (WPK-FTIR) imaging between NET and NEC in the rectum, colon, and stomach by utilizing two wax reagents (beeswax and paraplast) as glycan adsorbents for physical binding glycans of glycoconjugates based on dipole-induced dipole interaction. Results showed greater physisorption with beeswax than that of paraplast, suggesting highly populated elongated glycans of glycoconjugates adhering onto the tumor surfaces of NETs than that of adjacent benign mucosa in the rectum and colon. Besides, the WPK results of gastric NEN tissue sections showed a higher infrared absorbance ratio of beeswax-remnant to paraplast-remnant remains onto the tissue sections referring to a higher population of elongated glycans in gastric NET as compared with that of gastric NEC. Based on our findings, different anatomical locations could share similar phenomena with minor variance. In conclusion, WPK-FTIR imaging may have the potential to be employed as an alternative diagnostic method in GI NENs in the future.

Background We aimed to evaluate the correlation between the pathological changes and multi-parameter MRI characteristics of liver regeneration (LR) in a standard partial hepatectomy (PH) rat model. Methods Seventy Sprague–Dawley rats were randomly divided into two groups: MR scan group (n = 14) and pathologic analysis (PA) group (n = 56). All 14 rats in the MR group underwent liver T1 mapping, T2 mapping, and diffusion kurtosis imaging before and the 1st, 2nd, 3rd, 5th, 7th, 14th, and 21st day after 70% hepatectomy. Seven rats in the PA group were euthanized at each time point to determine Ki-67 indices, hepatocyte size (HTS), steatosis grade, and inflammation score. Results Liver T1 and T2 values increased to maximum on day 2 (P P P P P P P Conclusions PH induced liver changes that can be observed on MRI. The MRI parameters correlate with the LR activity and allow monitoring of LR process.

Background The data in the real-world setting on breast pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for hormone receptor–positive, human epidermal growth factor receptor-2-negative (HR+, HER2−) breast cancer (BC) is limited. The present study aims to screen for some predictors and investigate the prognostic significance of breast pCR after NAC in HR+, HER2− BC in China. Methods This was a multicenter, retrospective study. In this study, three hundred eighty-four HR+, HER2− BC patients who received NAC were enrolled between 2010 and 2016 from Shanghai Jiaotong University Breast Cancer Database (SJTU-BCDB). These patients were dichotomized according to the presence of breast pCR after NAC. Logistic analysis was used to screen for predictors associated with breast pCR. Kaplan-Meier (K-M) curve and a propensity score matching (PSM) analysis were performed to compare the disease-free survival (DFS) between the two groups. Cox regression was used to analyze the prognostic significance of breast pCR on DFS in HR+, HER2− BC. A nomogram model was established to predict the probability of DFS at 1, 3, and 5 years after NAC. Results Fifty-seven patients (14.8%) achieved breast pCR. Univariate analysis showed that tumor size, estrogen receptor (ER), progesterone receptor (PR), and Ki67 were associated with breast pCR. Further, multivariate analysis showed that tumor size, PR, and Ki67 remained statistically significant. K-M curves showed a statistical difference between the breast pCR and non-pCR groups before PSM (p = 0.047), and a more significant difference was shown after PSM (p = 0.033). Cox regression after PSM suggested that breast pCR, adjuvant ET, clinical T stage, and Ki67 status were the significant predictive factors for DFS in HR+, HER2− BC patients. The adjusted hazards ratio (aHR) for breast pCR was 0.228 (95% CI, 0.070~0.739; p = 0.014), for adjuvant endocrine therapy was 0.217 (95% CI, 0.059~0.801; p = 0.022), for Ki67 was 1.027 (95% CI, 1.003~1.052; p = 0.027), for cT stages 2 and 3 compared with 1, the values were 1.331 (95% CI, 0.170~10.389), and 4.699 (95% CI, 0.537~41.142), respectively (p = 0.043). A nomogram was built based on these significant predictors, providing an integrated probability of DFS at 1, 3, and 5 years. The values of area under the receiver operating characteristic (ROC) curve (AUC) were 0.967, 0.991, and 0.787, at 1 year, 3 years, and 5 years, respectively, demonstrating the ability of the nomogram to predict the DFS. Conclusions This real-world study demonstrates that tumor size, PR, and Ki67 were independent predictive factors for breast pCR in HR+, HER2− BC. Breast pCR after NAC was an independent predictor for DFS in HR+, HER2− patients, regardless of a change in nodes. Furthermore, the nomogram built in our study could predict the probability of individualized DFS in HR+, HER2− BC patients.

Background Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in particular of non-functioning dNENs. Aim To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome Results 102 (57m/45f) patients were identified with mean age at diagnosis 62 (range 32-87) years. The majority were non-functioning tumours 87/102 and median size was 10mm (range 0.9-130mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 >3% was a predictor of lymph nodes metastases with OR 18.2 (2.54-13)(p < 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56-29.5)( p < 0.05) in the multivariate analysis. Lesions 11 - 20 mm in size had OR 11.1 (1.16-106) compared to lesions Conclusion dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed.

This work combines Raman spectroscopy (RS) with supervised learning methods—group and basis restricted non-negative matrix factorisation (GBR-NMF) and linear discriminant analysis (LDA)—to aid in the prediction of clinical indicators of disease progression in a cohort of 9 patients receiving high dose rate brachytherapy (HDR-BT) as the primary treatment for intermediate risk (D’Amico) prostate adenocarcinoma. The combination of Raman spectroscopy and GBR-NMF-sparseLDA modelling allowed for the prediction of the following clinical information; Gleason score, cancer of the prostate risk assessment (CAPRA) score of pre-treatment biopsies and a Ki67 score of 3.5% in post treatment biopsies. The three clinical indicators of disease progression investigated in this study were predicted using a single set of Raman spectral data acquired from each individual biopsy, obtained pre HDR-BT treatment. This work highlights the potential of RS, combined with supervised learning, as a tool for the prediction of multiple types of clinically relevant information to be acquired simultaneously using pre-treatment biopsies, therefore opening up the potential for avoiding the need for multiple immunohistochemistry (IHC) staining procedures (H&E, Ki67) and blood sample analysis (PSA) to aid in CAPRA scoring.

Retroperitoneal leiomyoma is a very rare disease, with little reported information on its origin. Herein, we report a case of a large retroperitoneal leiomyoma that developed from the pelvic floor. A 44-year-old woman had a large mass protruding outside the body from the right hip. Imaging revealed a large tumor developing from the pelvic floor to the buttocks. It was difficult to identify the place of origin. Upon preoperative biopsy, the patient was diagnosed with retroperitoneal leiomyoma. Tumor removal with abdominoperineal and partial vaginal resection was performed. Based on the histological findings of the surgical specimens, she was diagnosed with a retroperitoneal leiomyoma (gynecologic type) via immunohistochemistry, the tumor cells were positive for αSMA, desmin, estrogen receptor(ER), and progesterone receptor(PgR), but negative for myoglobin, S-100, CD34, and MIB-1.This is a case of a large retroperitoneal leiomyoma that was successfully removed via abdominoperineal and partial vaginal resection.

Ki-67 serves as a prominent cancer marker. We describe how expression of the MKI67 gene coding for Ki-67 is controlled during the cell cycle. MKI67 mRNA and Ki-67 protein are maximally expressed in G2 phase and mitosis. Expression is dependent on two CHR elements and one CDE site in the MKI67 promoter. DREAM transcriptional repressor complexes bind to both CHR sites and downregulate the expression in G0/G1 cells. Upregulation of MKI67 transcription coincides with binding of B-MYB-MuvB and FOXM1-MuvB complexes from S phase into G2/M. Importantly, binding of B-MYB to the two CHR elements correlates with loss of CHR-dependent MKI67 promoter activation in B-MYB-knockdown experiments. In knockout cell models, we find that DREAM/MuvB-dependent transcriptional control cooperates with the RB Retinoblastoma tumor suppressor. Furthermore, the p53 tumor suppressor indirectly downregulates transcription of the MKI67 gene. This repression by p53 requires p21/CDKN1A. These results are consistent with a model in which DREAM, B-MYB-MuvB, and FOXM1-MuvB together with RB cooperate in cell cycle-dependent transcription and in transcriptional repression following p53 activation. In conclusion, we present mechanisms how MKI67 gene expression followed by Ki-67 protein synthesis is controlled during the cell cycle and upon induction of DNA damage, as well as upon p53 activation.

Congenital biliary dilatation (CBD), defined as pancreaticobiliary maljunction (PBM) with biliary dilatation, is a high risk factor for biliary tract cancer (BTC). KRAS and p53 mutations reportedly affect this process, but the mechanisms are unclear, as is the likelihood of BTC later in life in children with CBD. We investigated potential carcinogenetic pathways in children with CBD compared with adults. The subjects of this study were nine children with CBD and 13 adults with PBM (10 dilated, 3 non-dilated) without BTC who underwent extrahepatic bile duct resections, as well as four control patients who underwent pancreaticoduodenectomy for non-biliary cancer. We evaluated expressions of Ki-67, KRAS, p53, histone deacetylase (HDAC) and activation-induced cytidine deaminase (AID) in the biliary tract epithelium immunohistochemically. The Ki-67 labeling index (LI) and expressions of KRAS, p53, HDAC, and AID in the gallbladder epithelium were significantly higher or tended to be higher in both the children with CBD and the adults with PBM than in the controls. BTC may develop later in children with CBD and in adults with PBM, via HDAC and AID expression and through epigenetic and genetic regulation.

Background We studied the magnetic resonance spectroscopy (MRS) associations with clinicopathologic features of estrogen-dependent endometrial cancer (type I EC). Methods Totally 45 patients with type I EC who underwent preoperative multi-voxel MRS at 3.0 T were enrolled. The mean ratio of the Cho peak integral to the unsuppressed water peak integral (Cho/water) of the tumor was calculated. The Cho/water and apparent diffusion coefficient (ADC) of type I EC with and without local invasion, as well as with different levels of Ki-67 staining index (SI) (≤ 40% and > 40%), were compared. Correlation test was used to examine the relationship of Cho/water, as well as mean ADC, with Ki-67 SI, tumor stage, and tumor grade. Results The mean Cho/water of EC with Ki-67 SI ≤ 40% (2.28 ± 0.93) × 10−3 was lower than that with Ki-67 SI > 40% (4.08 ± 1.00) × 10−3 (P −3 and (2.43 ± 1.11) × 10−3, respectively (P = 0.011). There was no significant difference in Cho/water between type I EC with and without cervical invasioin ([2.68 ± 1.00] × 10−3 and [2.77 ± 1.28] × 10−3, P = 0.866). The mean Cho/water of type I EC with and without lymph node metastasis was (4.02 ± 1.90) × 10−3 and (2.60 ± 1.06) × 10−3, respectively (P = 0.014). The Cho/water was positively correlated with the Ki-67 SI (r = 0.701, P P > 0.05). Conclusion MRS is helpful for preoperative assessment of clinicopathological features of type I EC.

Background The role of serum high-density lipoprotein cholesterol (HDL-c) in tumorigenesis are observed in several endocrine-related cancers. However, its role in pancreatic neuroendocrine neoplasms (PNENs) has not been understood. In the current study, the relationship between HDL-c levels and malignant behavior in PNENs was explored. Methods One hundred ninety-seven patients with histopathology confirmed PNENs were included. PNENs were divided into three grades (G1, G2 and G3) as 2017 WHO classification based on ki67 index and mitosis count. The demographic data, clinical information, tumor morphological and pathological features (organs invasion, lymph node metastasis, vascular invasion and perineural invasion), and serum tumor biomarkers were collected. The relationships between HDL-c levels and malignant behaviors in PNENs were analyzed using logistic regression analysis. Models were also developed for the identification of high grade PNENs. Results The levels of serum HDL-c in G2/G3 tumor were significantly lower than that in G1 tumor (P = 0.031). However, no such difference was found between G3 and G1/G2. The proportions of low HDL-c (≤ 0.9 mmol/L) were higher in high-grade PNENs (G2/G3 or G3) than those in low-grade (G1 or G1/G2) (29.0 vs 15.2%, P = 0.032; 37.0 vs 20.5%, P = 0.023). The risk of G2/G3 tumors in patients with high serum HDL-c levels was decreased (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.12–0.99). Similarly, the risk of G3 PNENs increased in patients with low HDL-c levels (OR = 2.51, 95%CI:1.12–5.60). HDL-c level was also associated with a high ki67 index (> 55%) (OR = 0.10, 95%CI: 0.02–0.51) and neuroendocrine carcinoma G3 (OR = 0.21, 95%CI: 0.06–0.80). The area under the curve (AUC) of HDL-c + tumor size + age was 0.85 (95% CI: 0.79–0.91) in identifying G2/G3 PNENs, and HDL-c (> 0.9 mmol/L) + tumor size + age had an AUC of 0.77 (95% CI: 0.70–0.84) in identifying G3 PNENs. HDL-c level was associated with lymph node metastasis (OR = 0.24, 95%CI:0.08–0.99). Conclusion Serum HDL-c levels were significantly associated with malignant behaviors in PNENs, in particular to tumor grade and lymph node metastasis.