Non-POEMS osteosclerotic multiple myeloma: Clinical characteristics and differential diagnosis.

Osteosclerosis in multiple myeloma (MM) is typically associated with rare POEMS syndrome, characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M), and skin changes (S). However, osteosclerosis in multiple myeloma (MM) without POEMS syndrome, defined as non-POEMS Osteosclerotic MM, is exceedingly rare. We report a 70-year-old man with rib pain, remarkably high bone mineral density and diffuse osteosclerosis. The diagnosis of non-POEMS osteosclerotic MM was confirmed by biopsy and aspiration of bone marrow through surgery. A literature review spanning from 1990 identified 12 cases of similar non-POEMS osteosclerotic MM, including 5 males and 7 females with a mean age of 59.7 ± 10.6 years. The non-POEMS osteosclerotic MM can be divided into two subtypes, the osteosclerotic lesion subtype and the diffuse osteosclerosis subtype. Absence of polyneuropathy and organomegaly are the main factors that differentiate non-POEMS osteosclerotic MM from POEMS. A hyperactive osteoblastic process might be the etiology of diffuse osteosclerosis. Further research is needed to understand its etiology and pathophysiology.

KDF1 Promoted Proliferation, Migration and Invasion of Lung Adenocarcinoma Cells through Activating STAT3 and AKT Pathway.

KDF1 has been reported to be correlated with carcinogenesis. However, its role and mechanism are far from clear. To explore the possible role and underlying mechanism of KDF1 in lung adenocarcinoma (LUAD), we investigated KDF1 expression in LUAD tissues and the influence of KDF1 in the phenotype of LUAD cells (A549 and PC-9) as well as the underlying mechanism. Compared to non-tumor lung epithelial cells, KDF1 was upregulated in the cancer cells of the majority of LUAD patients, and its expression was correlated with tumor size. Patients with enhanced KDF1 in cancer cells (compared with paired adjacent non-neoplastic lung epithelial cells) had shorter overall survival than patients with no increased KDF1 in cancer cells. Knockdown of KDF1 inhibited the migration, proliferation and invasion of LUAD cells in vitro. And overexpression of KDF1 increased the growth of the subcutaneous tumors in mice. In terms of molecular mechanisms, overexpression of KDF1 induced the expression of AKT, p-AKT and p-STAT3. In KDF1-overexpressing A549 cells, inhibition of the STAT3 pathway decreased the level of AKT and p-AKT, whereas inhibition of the AKT pathway had no effect on the activation of STAT3. Inhibition of STAT3 or AKT pathways reversed the promoting effects of KDF1 overexpression on the LUAD cell phenotype and STAT3 inhibition appeared to have a better effect. Finally, in the cancer cells of LUAD tumor samples, the KDF1 level was observed to correlate positively with the level of p-STAT3. All these findings suggest that KDF1, which activates STAT3 and the downstream AKT pathway in LUAD, acts as a tumor-promoting factor and may represent a therapeutic target.

An inflammation-related signature could predict the prognosis of patients with kidney renal clear cell carcinoma.

Background: Kidney renal clear cell carcinoma (KIRC) is an inflammation-related carcinoma, and inflammation has been recognized as an important factor in inducing carcinogenesis. To further explore the role of inflammation in KIRC, we developed an inflammation-related signature and verified its correlation with the tumor micro-environment. Methods: After the differential inflammation-related prognostic genes were screened by Lasso regression, the inflammation-related signature (IRS) was constructed based on the risk score of multivariate Cox regression. Then, the prognostic value of the IRS was evaluated by Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis and multivariate Cox regression. Gene set variation analysis (GSVA) was applied to screen out enriched signaling pathways. Infiltrated immune cells, tumor mutational burden (TMB) and immune checkpoints were explored by CIBERSORTx and maftool. Results: Four genes (TIMP1, PLAUR, CCL22, and IL15RA) were used to construct the IRS in patients with KIRC. Kaplan-Meier analysis and multivariate Cox regression identified that the IRS could independently predict the prognosis of patients with KIRC in the training and validation groups. The diagnostic value of the nomogram increased from 0.811 to 0.845 after adding the IRS to the multiparameter ROC analysis. The GSVA results indicated that IRS was closely related to primary immunodeficiency and antigen processing and presentation. The immune checkpoint LAG3 was highly expressed in patients with high-risk score (p < 0.05), while CD274 (PD-L1) and HAVCR2 were highly expressed in patients with low-risk score (p < 0.001). There was a significant positive correlation between the high-risk score group and CD8+ T, activated CD4+ memory T, gamma and delta regulatory T and M0 macrophage cells, while the low-risk score group was negatively associated with B memory, plasma, resting CD4+ memory T, activated NK, M1 macrophages and resting mast cells. Conclusion: We found that the IRS might serve as a biomarker to predict the survival of KIRC. Moreover, patients with high or low-risk score might be sensitive to immune drugs at different immune checkpoints.

The Significance of INHBE Expression in the Cancer Cells of Clear-Cell Renal Cell Carcinoma.

BACKGROUND: Activins and inhibins are structurally related dimeric glycoprotein hormones belonging to the transforming growth factor-ß superfamily but whether they are also involved in malignancy is far from clear. No study has reported the expression of INHBE in kidney cancer. The purpose of this study was to examine the expressions of INHBE in the tumor tissue of patients with clear-cell renal cell carcinoma (ccRCC) and to explore the pathologic significance. METHODS: The INHBE mRNA expression in the tumor tissue of ccRCC patients was analyzed by using RNA sequencing data from the TCGA database. To examine the expression of inhibin ßE protein, 241 ccRCC patients were recruited and immunohistochemistry was performed on the tumor tissue of these patients along with 39 normal renal samples. The association between the inhibin ßE expression level and patient's clinicopathological indices was evaluated. RESULTS: In the normal renal tissue, inhibin ßE was found to be expressed mainly by renal tubular epithelial cells. In the tumor tissue, inhibin ßE was expressed mainly in cancer cells. The expressions of INHBE mRNA and protein in the tumor tissue of ccRCC patients increased significantly compared with those in normal renal samples. There was a significant correlation between the level of inhibin ßE in the tumor tissue and tumor grade. Patients with a lower inhibin ßE expression in the tumor tissue were found to have a longer overall survival and disease-specific survival. CONCLUSIONS: INHBE might be involved in the pathogenesis of ccRCC and function as a tumor promoter.

KDF1, a Novel Tumor Suppressor in Clear Cell Renal Cell Carcinoma.

KDF1 has been identified as a key regulator of epidermal proliferation and differentiation, but it is unknown whether KDF1 is involved in the pathogenesis of malignancy. No study has reported the expression and function of KDF1 in renal cancer. To explore the pathologic significance of KDF1 in clear cell renal cell carcinoma (ccRCC), the expression level of KDF1 protein in the tumor tissue of ccRCC patients was examined by immunohistochemistry and Western blot while the expression level of KDF1 mRNA was analyzed by using the data from TCGA database. In vitro cell experiments and allogeneic tumor transplantation tests were performed to determine the effects of altered KDF1 expression on the phenotype of ccRCC cells. Both the KDF1 mRNA and protein were found to be decreasingly expressed in the tumor tissue of ccRCC patients when compared with the adjacent non-tumor control tissue. The expression level of KDF1 in the tumor tissue was found to correlate negatively with the tumor grade. Patients with higher KDF1 in the tumor tissue were found to have longer overall survival and disease-specific survival time. KDF1 was shown to be an independent factor influencing the disease-specific survival of the ccRCC patients. Overexpression of KDF1 was found to inhibit the proliferation, migration and invasion of ccRCC cells, which could be reversed by decreasing the expression of KDF1 again. ccRCC cells with KDF1 overexpression were found to produce smaller transgrafted tumors. These results support the idea that KDF1 is involved in ccRCC and may function as a tumor suppressor.

Metallothionein 1M suppresses tumorigenesis in hepatocellular carcinoma.

Members of the metallothionein (MT) family are involved in metal detoxifcation and in the protection of cells against certain electrophilic carcinogens. In present study, it was found that MT1M was downregulated in more than 77.1% (91/118) of hepatocellular carcinoma (HCC) tissues compared with adjacent non-tumor tissues. Furthermore, overexpression of MT1M inhibited cell viability, colony formation, cell migration and invasion in HCC cell lines and tumor cell growth in xenograft nude mice, and activated cell apoptosis in HCC cell lines. In addition, immunohistochemistry analysis showed MT1M was negative or weak staining in tumor tissues but moderate or strong staining in adjacent non-tumor tissues. The sensitivity and specificity of MT1M for HCC diagnosis were 76.27% and 89.83%, respectively. In conclusion, MT1M was identified as a potential tumor marker for HCC and may serve as a useful therapeutic agent for HCC gene therapy.

Expression and prognostic role of MEKK3 and pERK in patients with renal clear cell carcinoma.

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is an important serine/threonine protein kinase and a member of the MAPK family. MEKK3 can effectively activate the MEK/ERK signaling pathway and promote an autocrine growth loop critical for tumor genesis, cell proliferation, terminal differentiation, apoptosis and survival. To explore the relationship between MEKK3 and cell apoptosis, clinicopathology and prognosis, we characterize the expression of MEKK3, pERK and FoxP3 in the renal clear cell carcinoma (RCCC). Protein expression was detected by tissue microarray and immunochemistry in 46 cases of RCCC and 28 control cases. Expression levels of CD3+ ,CD3+CD4+,CD3+CD8+,CD4+CD25+, CD4+CD25+ FoxP3+ were assessed by flow cytometry and analyzed for their association with pathological factors, correlation and prognosis in RCCC. Expression of MEKK3, pERK and FoxP3 was significantly up-regulated in RCCC as compared to control levels (p<0.01), associated with pathological grade (p<0.05)and clinical stage (p<0.05). CD4+CD25+ Foxp3+ Treg cells were also significantly increased in RCCC patients (p<0.05). Cox multivariate regression analysis showed that MEKK3, pERK expression and patholigical stage were independent prognostic factors in patients with RCCC (p<0.05). MEKK3 can be used as an important marker of early diagnosis and prognostic evaluation in RCCC. It may be associated with imbalance of anti-tumor immunity and overexpression of pERK. Expression of MEKK3 and pERK are significantly increased in RCCC, with protein expression and clinical stage acting as independent prognostic factors.

MEKK3 and survivin expression in cervical cancer: association with clinicopathological factors and prognosis.

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is an important protein kinase and a member of the MAPK family, which regulates cellular responses to environmental stress and serves as key integration points along the signal transduction cascade that not only link diverse extracellular stimuli to subsequent signaling molecules but also amplify the initiating signals to ultimately activate effector molecules and induce cell proliferation, differentiation and survival. To explore the relationship between MEKK3 and cell apoptosis, clinicopathology and prognosis, we characterize the expression of MEKK3 and survivin in cervical cancer. MEKK3 and survivin expression was measured by RT-PCR and Western blotting of fresh surgical resections from 30 cases of cervical cancer and 25 cases of chronic cervicitis. Protein expression was detected by tissue microarray and immunochemistry (En Vision) in 107 cases of cervical cancer, 86 cases of cervical intraepithelial neoplasia (CIN), and 35 cases of chronic cervicitis. Expression patterns were analyzed for their association with clinicopathological factors and prognosis in cervical cancer. Expression of MEKK3 and survivin mRNA was significantly higher in cervical cancer than in the controls (p<0.05). MEKK3 and survivin expression differed significantly between cervical carcinoma, CIN, and cervicitis (p<0.05) and correlated with clinical stage, infiltration depth, and lymph node metastasis (p<0.05). MEKK3 expression was positively correlated with survivin (p<0.05). Kaplan-Meier survival analysis showed that MEKK3 and survivin expression, lymph node metastasis, depth of invasion, and FIGO stage reduce cumulative survival. Cox multivariate regression analysis showed that MEKK3, survivin, and clinical staging are independent prognostic factors in cervical cancer (p<0.05). Expression of MEKK3 and survivin are significantly increased in cervical cancer, their overexpression participating in the occurrence and development of cervical cancer, with protein expression and clinical staging acting as independent prognostic factors for patients with cervical cancer.

Expression and function analysis of mitotic checkpoint genes identifies TTK as a potential therapeutic target for human hepatocellular carcinoma.

The mitotic spindle checkpoint (SAC) genes have been considered targets of anticancer therapies. Here, we sought to identify the attractive mitotic spindle checkpoint genes appropriate for human hepatocellular carcinoma (HCC) therapies. Through expression profile analysis of 137 selected mitotic spindle checkpoint genes in the publicly available microarray datasets, we showed that 13 genes were dramatically up-regulated in HCC tissues compared to normal livers and adjacent non-tumor tissues. A role of the 13 genes in proliferation was evaluated by knocking them down via small interfering RNA (siRNA) in HCC cells. As a result, several mitotic spindle checkpoint genes were required for maintaining the proliferation of HCC cells, demonstrated by cell viability assay and soft agar colony formation assay. Then we established sorafenib-resistant sublines of HCC cell lines Huh7 and HepG2. Intriguingly, increased TTK expression was significantly associated with acquired sorafenib-resistance in Huh7, HepG2 cells. More importantly, TTK was observably up-regulated in 46 (86.8%) of 53 HCC specimens. A series of in vitro and in vivo functional experiment assays showed that TTK overexpression promoted cell proliferation, anchor-dependent colony formation and resistance to sorafenib of HCC cells; TTK knockdown restrained cell growth, soft agar colony formation and resistance to sorafenib of HCC cells. Collectively, TTK plays an important role in proliferation and sorafenib resistance and could act as a potential therapeutic target for human hepatocellular carcinoma.

Sarcomatoid thymic carcinoma arising in metaplastic thymoma: a case report.

Metaplastic thymoma is an extremely rare tumor. To date, only 17 cases of metaplastic thymoma have been reported. To the best of the authors' knowledge, this is the second reported case of a sarcomatoid carcinoma arising in metaplastic thymoma; the carcinoma in this case is larger than that in the previous case. A 63-year-old woman with cough and asthenia for 2 weeks was admitted to the hospital. Computed tomography (CT) revealed a giant mass on the right side of the front mediastinum medium. The mediastinal tumor was excised, and additional pathological examinations, immunohistochemical tests, and electron-microscopic tests were performed. The tumor was diagnosed as a sarcomatoid carcinoma arising in metaplastic thymoma. Here, the authors discuss the clinical pathology of the sarcomatoid carcinoma arising in metaplastic thymoma and describe the biological behaviors with respect to the pathological features.

Primary gastric plasmacytoma associated with Helicobacter pylori infection: a report of two cases with different prognosis.

We describe two cases of primary gastric plasmacytoma (GP) associated with Helicobacter pylori infection. Case 1 was that of a 58-year-old man with epigastric pain. H. pylori was eradicated before surgical resection was performed, and after the therapy, the tumor size was reduced. A postoperative pathological examination revealed that the tumor was in early stage and histological grade was grade 1. After 44 months of operation, the patient was in complete remission with no evidence of local relapse or progression to systemic MM. Case 2 was that of a 70-year-old woman with a history of melena. H. pylori eradication was not presented preoperatively. The resected specimen showed the tumor was in advanced stage and histological grade 3. GP eventually progressed to MM and she died of pulmonary infection. In our opinion, GP cannot be eradicated with H. pylori eradication, but disease progression can be effectively controlled to a certain extent. The prognosis of this disease is relatively fair when treated at an early stage. In addition to the treatment, the difference in prognosis could be associated with age, the stage of the tumor, and histological grade.

Survival and prognostic factors analysis in surgically resected gastrointestinal stromal tumor patients.

BACKGROUND/AIMS: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract and predicting the clinical behavior and prognosis of GISTs has still been problem for both pathologists and clinicians. The aim of this study was to investigate the survival and prognostic factors of gastrointestinal stromal tumors after surgery. METHODOLOGY: Hematoxylin and eosin (H&E) stained histopathological slides of tumors from patients with GISTs were reviewed. Immunohistochemical staining was performed to demonstrate CD117, CD34, platelet -derived growth factor receptor (PDGFR-alpha) and Ki-67 protein expression. Clinicopathologic features (age, sex, tumor location and size, cell type, mitotic count, risk category, necrosis, surgical method, expression of CD117, CD34, PDGFR-alpha and Ki-67 protein) were evaluated by univariate and multivariate analyses in 135 patients with resected primary GISTs to identify independent prognostic factors. RESULTS: The overall disease-specific survival of 135 patients was 94.1% at 1 year, 76.3% at 3 years and 65.9% at 5 years. Multivariate analyses indicated that the tumor size, primary location, mitotic count, risk category, necrosis and Ki-67 index were independent significant predictors of survival (p < 0.05). Ki-67 index was strong poor predictors of survival as tumor size and mitotic count. CONCLUSIONS: Fletcher's biological behavior ranking method was a good approach to predict prognosis of GIST patients and had significant clinical value. It's better to combine other factors such as Ki-67 index and tumor primary location et al to predict prognosis accurately. Accurate prognostic prediction could provide evidence for postoperative adjuvant targeted therapy.

[Create a standard mini-swine model of chronic ischemic myocardium by thoracoscopy].

OBJECTIVE: To create a standard mini-swine model of chronic ischemic myocardium by endoscopy for the research of gene transfer and stem cell. METHODS: Twenty-three male China experimental minipigs were used, aged from 8 to 11 months with a mean of (9.3 +/- 1.8) months and weighed from 20 to 30 kg with a mean of (29.3 +/- 4.3) kg. The myocardial ischemia was established by gradual occlusion of the left circumflex coronary artery (LCX) with an Ameroid constrictor. The Ameroid constrictor was implanted around LCX by endoscopy. Selective coronary angiography, electrocardiogram and Echo-Doppler study were performed perioperatively to evaluate the degree of stenosis. RESULTS: Chronic ischemic myocardial models were successfully generated in 20 of 23 swine by full-endoscopy. Ameroid constrictors were placed at the LCX accurately. Three swine died of anesthetic accident, cardiac arrhythmia at secondary coronary angiography, and pulmonary infection within 6 weeks after operation respectively. Operation time was 25 to 65 min with a mean of (46 +/- 9) min. The blood loss was 30 to 60 ml with a mean of (55 +/- 12) ml. Six weeks later, coronary angiography revealed the total occlusion and partial stenosis (> 85%) of the LCX occurred in 7 and 13 swine respectively. Cardiac systolic and diastolic dysfunction were found in all swine. The ejection fraction value was (65.0 +/- 6.3)% before operation and (41.0 +/- 9.3)% after operation (P = 0.008). The fractional shortening value was (36.2 +/- 4.3)% before operation and (34.2 +/- 2.3)% after operation (P = 0.027). CONCLUSION: The endoscopic surgery is a less invasive way to create a standard mini-swine model of chronic ischemic myocardium with effective results.

[Interdigitating dendritic cell sarcoma/tumor: a study of 3 cases].

OBJECTIVE: To study the pathologic features, diagnosis and differential diagnosis of interdigitating dendritic cell sarcoma (IDCS). METHODS: The clinical findings, morphologic features and immunophenotype of 3 cases of IDCS were investigated. RESULTS: Gross examination showed that IDCS had a greyish-white to greyish-yellow cut surface. The site of occurrence included lung, spleen (with lymph node metastasis) and lymph node. Histologically, the tumor cells were arranged in nests, fascicles and whorls, with intimate admixture of many lymphocytes and plasma cells. They were oval to spindle in shape and contained pale eosinophilic cytoplasm, oval and sometimes grooved nuclei, small distinct nucleoli and ill-defined cell borders. Immunohistochemical study showed that the tumor cells expressed S-100 protein. CONCLUSIONS: IDCS is a rare type of histiocytic and dendritic cell malignancy with distinctive morphologic findings. It needs to be distinguished from follicular dendritic cell sarcoma, inflammatory pseudotumor, Langerhans' cell histiocytosis, malignant melanoma, undifferentiated carcinoma and anaplastic large cell lymphoma. Immunohistochemical staining for S-100 protein is helpful in confirming the diagnosis.

Adrenal myelolipoma within myxoid cortical adenoma associated with Conn's syndrome.

The coexistence of myelolipoma within adrenal cortical adenoma is extremely rare, for both tumors present usually as separate entities. There are only 16 such cases reported worldwide. To the best of our knowledge, the case we reported here is the first one of myxoid adrenal cortical adenoma associated with myelolipoma reported. A 32-year-old Chinese woman with 4-year history of hypertension was presented in our study. Computed tomography (CT) of the abdomen showed a large heterogeneously-enhancing mass (4.5 cm in diameter) in the left suprarenal region. Clinical history and laboratory results suggest a metabolic disorder as Conn's syndrome. The patient underwent a left adrenalectomy, and a histopathological study confirmed the mass to be a myxoid adrenal cortical adenoma containing myelolipoma. The patient was postoperatively well and discharged uneventfully. In the present case report, we also discuss the etiology of simultaneous myelolipoma and adrenal adenoma associated with Conn's syndrome, and the methods of the diagnosis and differential diagnosis.