Sublobectomy and lymph node sampling are adequate for patients with invasive lung adenocarcinoma presenting as pure ground glass nodules.

PURPOSE: In this study, we aimed to investigate the prognosis of invasive lung adenocarcinoma that manifests as pure ground glass nodules (pGGNs) and confirm the effectiveness of sublobectomy and lymph node sampling in patients with pGGN-featured invasive adenocarcinoma (IAC). MATERIALS AND METHODS: We retrospectively enrolled 139 patients with pGGN-featured IAC, who underwent complete resection in two medical institutions between January 2011 and May 2022. Stratification analysis was conducted to ensure balanced baseline characteristics among the patients. The 5-year overall survival (OS) and disease-free survival (DFS) rates were compared between the groups using Kaplan-Meier survival curves and log-rank test. RESULTS: The 5-year OS and DFS rates for patients with IAC presenting as pGGNs after surgery were 96.5% and 100%, respectively. No lymph node metastasis or recurrence was observed in any of the enrolled patients. There was no statistically significant difference in the 5-year OS between patients who underwent lobectomy or sublobectomy, along with lymph node resection or sampling. CONCLUSION: IAC presented as pGGNs exhibited low-grade malignancy and had a relatively good prognosis. Therefore, these patients may be treated with sublobectomy and lymph node sampling.

A Novel Radiopathological Grading System to Tailor Recurrence Risk for Pathologic Stage IA Lung Adenocarcinoma.

To validate the efficiency of pathologic grading system in pathologic stage IA lung adenocarcinoma (LUAD), and explore whether integrating preoperative radiological features would enhance the performance of recurrence discrimination. We retrospectively collected 510 patients with resected stage IA LUAD between January 2012 and December 2019 from Guangdong Provincial People's Hospital (GDPH). Pathologic grade classification of each case was based on the International Association for the Study of Lung Cancer (IASLC) pathologic staging system. Kaplan-Meier curves was used to assess the power of recurrence stratification. Concordance index (C-Index) and receiver operating characteristic curves (ROC) were used for evaluating the clinical utility of different grading systems for recurrence discrimination. Patients of lower IASLC grade showed improved recurrence-free survival (RFS) (P < 0.0001) where numerically difference was found between grade II and grade III (P = 0.119). By integrating the IASLC grading system and radiological feature, we found the RFS rate decreased as the novel radiopathological (RP) grading system increased (P < 0.0001). The difference of RFS curves between any 2 groups as per the RP grading system was statisticallysignificant (RP grade I vs RP grade II, p = 0.007; RP grade I vs RP grade III, P < 0.0001; RP grade II vs RP grade III, P = 0.0003). Compared with the IASLC grading system, the RP grading system remarkably improved recurrence survival discrimination (C-index: 0.822; area under the curve, 0.845). Integrating imaging features into pathologic grading system enhanced the efficiency of recurrence discrimination for resected stage IA LUAD and might help conduct subsequent management.

Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-ß signaling pathway.

BACKGROUND: Exosomes from cancer cells or immune cells, carrying bio-macromolecules or microRNAs (miRNAs), participate in tumor pathogenesis and progression by modulating microenvironment. Our study aims to investigate the role of these microRNA-501-3p (miR-501-3p) containing exosomes derived from tumor-associated macrophage (TAM) in the progression of pancreatic ductal adenocarcinoma (PDAC). METHODS: Firstly, the function of TAM recruitment in PDAC tissues was assessed, followed by identification of the effects of M2 macrophage-derived exosomes on PDAC cell activities and tumor formation and metastasis in mice. In silico analysis was conducted to predict differentially expressed genes and regulatory miRNAs related to PDAC treated with macrophages, which determined miR-501-3p and TGFBR3 for subsequent experiments. Next, gain- and loss-of-function experiments were performed to examine their role in PDAC progression with the involvement of the TGF-ß signaling pathway. RESULTS: TAM recruitment in PDAC tissues was associated with metastasis. Highly expressed miR-501-3p was observed in PDAC tissues and TAM-derived exosomes. Both M2 macrophage-derived exosomes and miR-501-3p promoted PDAC cell migration and invasion, as well as tumor formation and metastasis in nude mice. MiR-501-3p was verified to target TGFBR3. PDAC cells presented with down-regulated TGFBR3, which was further decreased in response to M2 macrophage treatment. TGF-ß signaling pathway activation was implicated in the promotion of miR-501-3p in PDAC development. The suppression of macrophage-derived exosomal miR-501-3p resulted in the inhibition of tumor formation and metastasis in vivo. CONCLUSION: M2 macrophage-derived exosomal miR-501-3p inhibits tumor suppressor TGFBR3 gene and facilitates the development of PDAC by activating the TGF-ß signaling pathway, which provides novel targets for the molecular treatment of PDAC.

LncRNA MAGI2-AS3 inhibits hepatocellular carcinoma cell proliferation and migration by targeting the miR-374b-5p/SMG1 signaling pathway.

Long noncoding RNAs (lncRNAs) have been proven to play critical roles in cancer progression. Recently, lncRNA MAGI2-AS3 has been revealed to be a tumor suppressor and inhibit cell growth by targeting the Fas/FasL signalling pathway in breast cancer. However, the role and underlying mechanism of MAGI2-AS3 in hepatocellular carcinoma (HCC) remain largely unknown. In the current study, we found that MAGI2-AS3 expression is downregulated in HCC tissues and closely associated with some clinical characteristics (tumor size, lymph node metastasis, and TNM stage) and poor overall survival. Overexpression of MAGI2-AS3 inhibits HCC cell proliferation and migration in vitro, while impedes tumor growth in vivo accordantly. In addition, our data suggest that MAGI2-AS3 could function as an endogenous sponge of miR-374b-5p by directly binding to it and suppressing its expression. Furthermore, miR-374b-5p upregulation could restore the inhibitory effect of MAGI2-AS3 on HCC cells processes. Moreover, suppressor with morphogenetic effect on genitalia family member 1 (SMG1) is positively regulated by MAGI2-AS3 via absorbing miR-374b-5p in HCC cells. More important, SMG1 knockdown reverses the suppressive function of MAGI2-AS3 in HCC cell processes. Taken together, we reveal a functional MAGI2-AS3/miR-374b-5p/SMG1 axis that suppresses HCC progression, potently suggesting a new road for HCC treatment.

Diffuse large B cell lymphoma associated with chronic inflammation arising within atrial myxoma: aggressive histological features but indolent clinical behaviour.

AIMS: Primary cardiac lymphoma (PCL) is a rare neoplasm. PCL is fatal, unless it is diagnosed and treated early. Recently, a small number of cases of diffuse large B cell lymphoma (DLBCL) arising within atrial myxoma have been reported in immunocompetent patients and showed aggressive histological features but an indolent clinical behaviour. METHODS AND RESULTS: We present four unusual cases of Epstein-Barr virus (EBV)-positive DLBCL arising within atrial myxoma with detailed clinical, histological, immunophenotypical and genotypical features in immunocompetent patients, and review the literature for 11 similar cases. All the patients appeared to have morphological features of DLBCL, B lineage immunophenotype, high proliferative index and latency type III of EBV infection. They achieved complete tumour resection without chemotherapy or radiotherapy after surgery and were healthy at 3- and 7-month and 7- and 10-year follow-ups, respectively. CONCLUSIONS: We suggest that this lymphoma should be regarded as a unique DLBCL associated with chronic inflammation (DLBCL-CI) because of an indolent clinical behaviour to avoid excessive or unnecessary treatments. In addition, early accurate diagnosis and complete resection of this tumour are crucial for optimal patient outcome.

Intravascular NK/T-cell lymphoma: a series of four cases.

Intravascular natural killer/T-cell lymphoma (IVNKTL) is a rare disorder and is reported gradually increased recently. We presented four cases including two extremely rare cases of primary lung IVNKTL with detailed clinicopathological features, therapy and prognosis, and reviewed the literature for 25 similar cases. H&E, Immunohistochemical staining and in situ hybridization (ISH) were used in the study. The medium-sized lymphoid cells were characterized by the selective growth within the kumina of vessels, particularly capillaries. The endothelial cells in the vessels exhibited positive CD34 staining. The lymphoid cells were positive for NK/T-cell markers, and cytotoxic proteins, and negative for B-cell markers. ISH demonstrated that the lymphoid cells expressed EBER. All the patients died of the disease a few months later. To conclude, the overall survival of patients with IVNKTL is very poor and the 1-year survival rate is only 31%. Patients with B symptoms and multiple organs involvement may be associated with the poor clinical prognosis. We deduce that the traditional chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is inadequate for the treatment of IVNKTL. Early accurate diagnosis by biopsy for this lymphoma may be crucial for the patients' medical prognosis due to the fatal disease course.

IMP3 Predicts Invasion and Prognosis in Human Lung Adenocarcinoma.

PURPOSE: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with several aggressive and advanced cancers. Whether IMP3 can predict invasion, and prognosis in patients with human lung adenocarcinoma (LAC) remains unclear. METHODS: Ninety-five LAC and 75 non-tumor lung tissue samples were included in a tissue microarray. IMP3 expression was assessed by immunohistochemical examination. Correlation between IMP3 expression levels, clinicopathological characteristics, and overall prognosis was evaluated. In a separate in vitro study, RNA interference method was applied for knockdown of IMP3 gene in human LAC cell lines. Invasive potential of LAC cells was then evaluated by transwell migration assay. RESULTS: IMP3 immunoreactivity was observed in 39 out of 95 (41.1 %) LAC patients, but not in non-tumor lung tissues. IMP3 expression levels were closely associated with histological grade (P = 0.037), TNM stage (P = 0.034), and lymph node metastasis (P = 0.011). Patients presenting with positive IMP3 expression (P = 0.000), an advanced TNM stage (P = 0.000), and lymph node metastasis (P = 0.001) had a worse overall survival, compared to those lacking these characteristics. Both IMP3 expression (hazard ratio [HR], 2.310; 95 % confidence interval [CI] 1.192-4.476; P = 0.013) and TNM stage (HR 2.338; 95 % CI 1.393-3.925; P = 0.001) were independent predictors of poor prognosis. The invasive potential of LAC cells was significantly inhibited by IMP3 knockdown. CONCLUSION: IMP3 appears to play an important role in tumor invasion in patients with LAC and may serve as a useful prognostic biomarker in these patients.

SEPTIN2 and STATHMIN Regulate CD99-Mediated Cellular Differentiation in Hodgkin's Lymphoma.

Hodgkin's lymphoma (HL) is a lymphoid neoplasm characterized by Hodgkin's and Reed-Sternberg (H/RS) cells, which is regulated by CD99. We previously reported that CD99 downregulation led to the transformation of murine B lymphoma cells (A20) into cells with an H/RS phenotype, while CD99 upregulation induced differentiation of classical Hodgkin's lymphoma (cHL) cells (L428) into terminal B-cells. However, the molecular mechanism remains unclear. In this study, using fluorescence two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), we have analyzed the alteration of protein expression following CD99 upregulation in L428 cells as well as downregulation of mouse CD99 antigen-like 2 (mCD99L2) in A20 cells. Bioinformatics analysis showed that SEPTIN2 and STATHMIN, which are cytoskeleton proteins, were significantly differentially expressed, and chosen for further validation and functional analysis. Differential expression of SEPTIN2 was found in both models and was inversely correlated with CD99 expression. STATHMIN was identified in the A20 cell line model and its expression was positively correlated with that of CD99. Importantly, silencing of SEPTIN2 with siRNA substantially altered the cellular cytoskeleton in L428 cells. The downregulation of STATHMIN by siRNA promoted the differentiation of H/RS cells toward terminal B-cells. These results suggest that SEPTIN2-mediated cytoskeletal rearrangement and STATHMIN-mediated differentiation may contribute to changes in cell morphology and differentiation of H/RS cells with CD99 upregulation in HL.

A fine decision tree consisted of CK5/6, IMP3 and TTF1 for cytological diagnosis among reactive mesothelial cells, metastatic adenocarcinoma of lung and non-lung origin in pleural effusion.

The utility of combination with CK5/6, IMP3 and TTF1 to differentiate among reactive mesothelial cells (RMs), metastatic adenocarcinoma of lung (LAC) and non-lung (NLAC) origin was investigated by using immunocytochemistry (ICC) and conventional PCR (C-PCR) in pleural effusion. A total of 108 cell blocks (32 RMs, 51 LAC and 25 NLAC were evaluated by ICC for CK5/6, IMP3 and TTF1 protein expression. In addition, we further performed C-PCR for amplification of CK5/6, IMP3 and TTF1 DNA from 28 specimens (9 MAC and 7 RMs, 6 LAC and 6 NLAC) for molecular diagnosis. CK5/6 staining was observed in the majority of reactive specimens (78.1%) and was rare in adenocarcinoma cells (14.5%), whereas the opposite was true for IMP3 and TTF1. We found a high frequency of TTF1 positivity (76.5%) in LAC, but not in NLAC (4.0%); while there was no significant difference of IMP3 expression in LAC (88.2%) and NLAC (88.0%). The 487 bp DNA fragments of IMP3 was expected to be amplified in 6/9 of adenocarcinoma cases showed negative in ICC; and the 394 bp DNA fragments of CK5/6 was also expected to be amplified in 4/7 of RMs cases showed negative in ICC. Consistent with ICC results, there was significant difference of TTF1 expression in the LAC and NLAC compared with IMP3 expression. The combination with CK5/6, IMP3 and TTF1 immunostaining appears to be useful to improve the accuracy of cytological diagnoses between RMs, metastatic adenocarcinoma of lung and non-lung origin in pleural effusion. In addition, C-PCR may act as a useful supplemental approach for ICC, especially negative cases in ICC for differential cytological diagnosis.

IMP3 expression is associated with poor survival in cervical squamous cell carcinoma.

Insulin-like growth factor II messenger RNA (mRNA)-binding protein 3 (IMP3) is an oncofetal protein that promotes tumor progression and metastasis in a number of malignancies. However, the clinical significance of IMP3 expression in squamous cell carcinoma (SCC) of the uterine cervix is unclear. In this study, the correlation between IMP3 expression and cervical cancer progression and prognosis was assessed by immunohistochemistry. IMP3 expression was observed in a large number of tissue specimens from patients with normal cervical tissues, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, and SCC. IMP3 protein and mRNA expression was also determined in the SiHa and HeLa human cervical cancer cell lines. IMP3 expression was observed in 0 (0%) of 62 CIN I, 0 (0%) of 38 CIN II, and 9 (8.7%) of 104 CIN III specimens. Of the 96 SCC cases, IMP3 expression was detected in 54 cases (56.3%). Significant difference in IMP3 expression existed between all of the groups tested (P < .001). IMP3 protein and mRNA expressions in SiHa and HeLa cell lines were dramatically increased, as compared with normal tissue (P < .001). IMP3 expression was significantly related to age (P < .001), International Federation of Gynecology and Obstetrics stage (P < .001), and lymph node metastasis (P = .001). IMP3 expression was also shown to be an independent prognostic factor in SCC. In conclusion, these findings suggest that IMP3 expression may be a prognostic indicator of SCC.

[Optimization of streptozotocin dosing for establishing tumor-bearing diabetic mouse models].

OBJECTIVE: To determine the optimal dosing of streptozotocin (STZ) for establishing lymphoma-bearing diabetic mouse models. METHODS: A total of 200 healthy male Balb/c mice were randomized into 4 groups (n=50) for intraperitoneal injection of a single dose of vehicle solution (control) or 75, 150, or 200 mg/kg STZ. The changes of body weight and blood glucose were observed regularly, and the success rate of modeling, mortality rate, and survival of the mice were recorded after the injections. The mice with successfully induced diabetes received subcutaneous or tail vein injection of A20 lymphoma cells, and the rate of tumorigenesis, mortality rate, and survival time were observed at 1 month and 3 months after tumor cell injection. RESULTS: Compared with the control group, the mice receiving STZ injection at 150 and 200 mg/kg showed significantly decreased body weight and increased blood glucose (P<0.05), while STZ at 75 mg/kg did not produced such obvious changes. STZ injection at 200 mg/kg resulted in a significantly higher mortality rate and shorter survival time than STZ at 150 mg/kg (P<0.05). In the control group and 150 and 200 mg/kg STZ groups, the rate of tumorigenesis or mortality rate showed no significant differences after subcutaneous injection of A20 lymphoma cells (P>0.05), but differed significantly at 3 months after tail vein injection of the tumor cells (P<0.05). CONCLUSION: Intraperitoneal injection of STZ at 150 mg/kg is associated with a low mortality rate, a high successful modeling rate of diabetes and a long survival time in mice, and is therefore optimal for establishing diabetic mouse models bearing transplanted tumors.