Prognostic significance of lymphatic vessel invasion diagnosed by D2-40 in Chinese invasive breast cancers.

Lymphatic vessel invasion (LVI) is promising in determining prognosis and treatment strategies, but the application of LVI as a histopathological criterion in breast cancer patients especially those of different subgroups is controversial. This research aims to evaluate the prognostic value of LVI assessed by D2-40 not only in patients with early invasive breast cancer but also in lymph node-negative, lymph node-positive, luminal A-like, luminal B-like, HER2-enriched, and triple-negative subgroups.The study cohort included 255 patients with a median follow-up of 101 months. Immunohistochemical staining for D2-40 was performed to identify LVI.LVI was present in 64 (25.1%), 15 (12.1%), 49 (37.4%), 19 (20.9%), 23 (27.7%), 13 (31.7%), and 9 (22.5%), respectively, in the whole cohort, lymph node-negative, lymph node-positive, luminal A-like, luminal B-like, HER2-enriched, and triple-negative patients. LVI was associated with large tumor size (P = .04), high histological grade (P = .004), involved lymph node (P < .001), and high expression of Ki-67 (P = .003). No significant difference was found among patients with different subtypes and LVI status. The presence of LVI was significantly associated with adverse disease-free survival in the whole cohort (P < .001), lymph node-negative (P < .001), lymph node-positive (P < .001), luminal A-like (P < .001), and luminal B-like patients (P < .001) in both of the univariate and multivariate survival analysis.This study indicated that the presence of LVI stained by D2-40 provided independent prognostic information not only in the whole cohort but also in the subgroup of patients with lymph node-negative, lymph node-positive, luminal A-like, and luminal B-like diseases, which may make a case for routine clinical assessment of LVI using D2-40.

Primary or metastatic hepatic carcinoma? A breast cancer patient after adjuvant chemotherapy and radiotherapy postoperatively with intrahepatic cholangiocarcinoma and review of the literature.

BACKGROUND: The liver is a common site of metastases, followed by the bone and lung in breast cancer. The symptoms of hepatic metastases are similar to intrahepatic cholangiocarcinoma (ICC). ICC is rare, with an overall incidence rate of 0.95 cases per 100,000 adults. The incidence of ICC for patients with breast cancer is very uncommon. Breast cancer patient with ICC is easily misdiagnosed as hepatic metastases. CASE PRESENTATION: We report a breast cancer patient postoperatively who was hospitalized because of having continuous irregular fever for 1 month. Antibiotics were given for 1 week without any significant effect. Her admission bloods revealed elevated levels of carcino-embryonic antigen. Magnetic resonance imaging diagnosis showed multiple liver metastases. We believed that the woman had hepatic metastases until biopsy guided by computed tomography. The liver biopsy pathology analysis considered the possibility of primary intrahepatic cholangiocarcinoma. CONCLUSIONS: Breast cancer patient with space-occupying lesions in the liver is easily considered to be progressed hepatic metastases. Image-guided biopsy is the best diagnostic method for breast cancer with liver mass to avoid misdiagnosis and classify the molecular subtypes to make appropriate treatment.

Twist may be associated with invasion and metastasis of hypoxic NSCLC cells.

Hypoxia promotes tumor invasion and metastasis via multiple mechanisms, including epithelial-mesenchymal transition (EMT). Twist, an EMT regulator, has been disclosed to associate with invasion and metastasis as well as poor prognosis of many malignancies. However, it remains undefined whether Twist is involved in invasion and metastasis of hypoxic non-small cell lung cancer (NSCLC). In this study, protein levels of Twist, hypoxia-inducible factor-1α (HIF-1α), and EMT markers (E-cadherin and vimentin) were examined by immunohistochemistry in 76 lung cancer tissues from NSCLC patients. Expression of Twist and its correlation with HIF-1α, E-cadherin, and vimentin were analyzed. Small interfering RNA (siRNA) against Twist was used to knockdown Twist expression in hypoxic NSCLC cells, A549 and NCI-H460. Cellular invasion and protein levels of Twist, E-cadherin, and vimentin were evaluated by matrigel invasion assay and Western blot, respectively. Our results showed that in clinical samples, there was a significant association between Twist expression and differentiation degree, lymph node metastasis, and TNM stage. Correlation analysis demonstrated that expression of Twist was negatively correlated with E-cadherin expression, but positively associated with HIF-1α and vimentin expression. In cultured NSCLC cells, Twist messenger RNA (mRNA) and protein levels were upregulated under hypoxia, while knockdown of Twist suppressed potentiated invasion and expression of mesenchymal marker vimentin induced by hypoxia. Protein level of increased epithelial marker E-cadherin was shown along with Twist downregulation. These findings suggest that Twist promoting hypoxic invasion and metastasis of NSCLC may be associated with altered expression of EMT markers. Inhibition of Twist may be of therapeutic significance.

Knockdown of Med19 suppresses proliferation and enhances chemo-sensitivity to cisplatin in non-small cell lung cancer cells.

Mediator 19 (Med19) is a component of the mediator complex which is a coactivator for DNA-binding factors that activate transcription via RNA polymerase II. Accumulating evidence has shown that Med19 plays important roles in cancer cell proliferation and tumorigenesis. The involvement of Med19 in sensitivity to the chemotherapeutic agent cisplatin was here investigated. We employed RNA interference to reduce Med19 expression in human non-small cell lung cancer (NSCLC) cell lines and analyzed their phenotypic changes. The results showed that after Med19 siRNA transfection, expression of Med19 mRNA and protein was dramatically reduced (p<0.05). Meanwhile, impaired growth potential, arrested cell cycle at G0/G1 phase and enhanced sensitivity to cisplatin were exhibited. Apoptosis and caspase-3 activity were increased when cells were exposed to Med19 siRNA and/or cisplatin. The present findings suggest that Med19 facilitates tumorigenic properties of NSCLC cells and knockdown of Med19 may be a rational therapeutic tool for lung cancer cisplatin sensitization.

Effect of celecoxib on inhibiting tumor repopulation during radiotherapy in human FaDu squamous cell carcinoma.

AIM OF THE STUDY: FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrated accelerated tumor repopulation during fractionated irradiation with pathological validation in a xenograft model system. Previous studies showed that the selective cyclooxygenase (COX)-2 inhibitor celecoxib can enhance the tumor response to radiotherapy. So we aimed to explore the effect of celecoxib in inducing apoptosis and inhibiting repopulation of FaDu tumors in nude mice during fractionated radiotherapy. MATERIAL AND METHODS: FaDu-hSCC was transplanted into the right hind leg of BALB/C nude mice. Mice were treated with celecoxib and/or fractionated irradiation. Celecoxib (100 mg/kg/day) was administered by daily gavage. Irradiation was delivered with 12 to 18 fractions of 3.0 Gy daily or every second day based on Petersen's repopulation model. At different time points, tumors were excised for immunohistochemistry staining. RESULTS: Significant tumor repopulation occurred after about 18 days of radiotherapy. On average, Ki-67 and bromodeoxyuridine (BrdUrd) labeling indices (LI) decreased with daily irradiation (both p < 0.05) and increased with every-second-day irradiation (both p > 0.05), suggesting accelerated repopulation. Ki-67 LI decreased in celecoxib concurrent with radiotherapy for 12 fractions in 24 days and 18 fractions in 36 days compared with irradiated alone (p = 0.004 and 0.042, respectively). BrdUrd LI values were lower in the concurrent groups than irradiated alone (p = 0.001 and 0.006, respectively). Epithelial growth factor receptor (EGFR) expression score decreased in the concurrent groups than irradiated alone (p = 0.037 and 0.031, respectively). Caspase-3 expression scores were higher in the concurrent groups than irradiated alone (p = 0.05 and 0.006, respectively). CONCLUSIONS: Celecoxib concurrent radiotherapy could inhibit tumor repopulation and increase tumor apoptosis during the treatment in FaDu squamous cell carcinoma.

Clinical features and outcome of patients with HIV-negative multicentric Castleman's disease treated with combination chemotherapy: a report on 10 patients.

To investigate the clinical characteristics and outcome of patients with HIV-negative multicentric Castleman's disease (MCD) treated exclusively with combination chemotherapy, and review literature to improve the diagnosis and management of this disease. A retrospective study was performed on the medical records of 10 patients with HIV-negative MCD treated exclusively with combination chemotherapy at one medical institution from May 2004 to April 2012. And relevant clinical, pathological, radiographic, and laboratory data were examined in order to evaluate treatment responses, with symptom onsets and survival period serving as the endpoints of the assessment. All patients have multifocal lymphadenopathy, and the associated system symptoms are found in 80 % of the cases. All patients were treated with lymphoma-based chemotherapy alone. The duration of follow-up ranged from 5 to 77 months for nine patients. Four patients were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone: One was alive with no evidence of disease, and three were alive with disease. Three patients received cyclophosphamide, vincristine, and prednisone (COP) alone: One remained alive with disease, and two experienced recurrences and passed away. Two had only minimal response to COP and were switched to CHOP, and they were still alive with disease. MCD is a more progressive clinical entity, and long-term follow-up is necessary. CHOP chemotherapy may be an effective treatment option for patients with MCD, whereas when to start chemotherapy, how many cycles of chemotherapy required, and the role of combined radiotherapy remain to be further studied.

Lysyl oxidase may play a critical role in hypoxia-induced NSCLC cells invasion and migration.

Lysyl oxidase (LOX), a copper-dependent amine oxidase known to function both intracellularly and extracellularly, is implicated in promoting tumor progression and hypoxic metastasis in certain malignancies. Nonsmall cell lung cancer (NSCLC) is a highly aggressive cancer with poor prognosis worldwide. However, the role and molecular mechanism by which LOX involving in hypoxic NSCLC invasion and migration are poorly understood. This study explores the effect of LOX on invasion and migration of NSCLC cells under hypoxic conditions. Small interfering RNA (siRNA) targeting LOX was used to silence LOX expression of hypoxic NSCLC cells, SPCA1 and A549. Cellular invasive and migratory potentials were determined by matrigel invasion and migration assays. Expression of LOX, Src, Src activation (Tyr418 phosphorylation of Src), and Snail were evaluated by real-time PCR and western blot, respectively. The results showed that LOX mRNA and protein expression were upregulated under hypoxic conditions in NSCLC cells. Knockdown of LOX led to inhibition of hypoxia-induced invasion and migration. Phosphorylated Src (Tyr418) and Snail proteins were decreased along with LOX downregulation. Our data provide molecular evidences that LOX is mechanistically linked to increased invasion and migration of hypoxic NSCLC cells, and may serve as an antimetastasis target of human NSCLC.

[Effects of lysyl oxidase down-regulation on invasion, migration and E-cadherin protein expression of hypoxic lung cancer cells].

OBJECTIVE: To observe the effects of lysyl oxidase (LOX) down-regulation on invasion, migration and epithelial-mesenchymal transition phenotype molecule E-cadherin protein expression, induced by hypoxia in lung cancer NCI-H460 cells. METHODS: Small interfering RNA against human LOX gene (LOX siRNA) was used to transfect lung cancer cells under normoxia (19%O2). After a 24 h incubation, the cells were plated for 24 h in hypoxic incubator (0.5%O2). Real-time polymerase chain reaction (PCR) was performed to detect the LOX mRNA expression. The protein levels of LOX and E-cadherin were determined by Western blot. And invasion and migration capacities were detected by transwell chamber. RESULTS: Compared with NCI-H460 cells under normoxia (set to 1), hypoxia increased to the levels of LOX mRNA and protein expression up to 26.04 ± 1.78 and 5.57 ± 1.27 respectively (both P < 0.05). Compared with control siRNA group (set to 1), LOX mRNA and protein expression after LOX siRNA transfection were 0.24 ± 0.03 and 0.29 ± 0.03 respectively, cellular invasive and migratory capacities were 0.57 ± 0.03 and 0.49 ± 0.02 respectively, the protein expression of E-cadherin was 2.17 ± 0.21 (all P < 0.05). CONCLUSION: LOX down-regulation reduces invasion and migration potentials of hypoxic human lung cancer cell and potentiates the protein expression of E-cadherin.

[The study of the relationship between microlymphatic vessel density and lymph metastasis in hepatocellular carcinoma].

Not Abstract.