Rare Recurrent EWSR1-PLAGL1 Rearranged Intracranial Tumor With Biphasic Epithelioid Differentiation: One Case Report With Literature Review.

EWSR1-rearranged tumors encompass a rare and heterogeneous group of entities with features of the central nervous system (CNS) mesenchymal and primary glial/neuronal tumors. EWSR1-PLAGL1 gene fusion is a particularly rare form of rearrangement. We presented a recurrent intracranial EWSR1-PLAGL1 rearranged tumor and reviewed the relevant literature. In this case, histopathology and immunohistochemistry (IHC) were evaluated for both the primary and relapsed tumors. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were performed for the relapsed tumor. We compared the morphology, IHC results and molecular features with the previously reported EWSR1-PLAGL1 rearranged CNS tumors. Our case exhibited a unique feature with a variable biphasic pattern of epithelioid differentiation, which differed from the two reported groups. The primary and relapsed tumors both expressed cytokeratin of the focal area with epithelioid differentiation. The recurrent tumor showed an increased proliferation index (average Ki-67 index of 15%) compared with the primary tumor (average Ki-67 index of 5%). NGS showed that TERT promoter mutation was the only molecular change besides EWSR1-PLAGL1 fusion. Our study provides further insight into intracranial tumors with EWSR1-PLAGL1 fusion, representing a distinct CNS tumor with no-reported histological and immunohistochemical features. Future studies, particularly for the biphasic differentiation and the role of TERT promoter mutation were needed to clarify this unusual chromosomal rearrangement in the CNS tumor.

miR-638 Serves as a Biomarker of 5-Fluorouracil Sensitivity to Neoadjuvant Chemotherapy in Breast Cancer.

PURPOSE: Neoadjuvant chemotherapy (NAC) is widely used to treat breast cancer (BC). The prediction and evaluation of chemotherapy responses remains a significant challenge. METHODS: MicroRNAs (miRNAs) play a crucial role in cancer drug resistance. We used a miRNA microarray and identified that miR-638 is downregulated in chemoresistant cases. However, the exact role of miR-638 and the underlying mechanisms of chemoresistance remain unclear. Using real-time quantitative reverse transcription polymerase chain reaction, we found significant downregulation of miR-638 in chemoresistant patients compared with chemosensitive patients. To explore the function of miR-638, we overexpressed and inhibited miR-638 expression in MDA-MB-231 and MCF-7 cells by transfecting them with miR-638 mimics and miR-638 inhibitor, respectively. Cell proliferation and apoptosis were measured using MTS and flow cytometry, respectively. A minimal patient-derived xenograft (MiniPDX™) model was established to evaluate the chemosensitivity to different drugs. RESULTS: The results showed that cell proliferation decreased and cell apoptosis increased in cells transfected with the miR-638 mimic, and cell proliferation and apoptosis were reversed with transfection of miR-638 inhibitor compared with the control group. Among patients who received 5-fluorouracil (5-FU), miR-638 expression levels were lower in the chemoresistant group than in the chemosensitive group. The MiniPDX™ model showed that MDA-MB-231 cells overexpressing miR-638 were more susceptible to 5-FU treatment in vivo. CONCLUSION: We provided evidence of acquired resistance to 5-FU caused by miR-638 deficiency. Alterations in miR-638 may be used with 5-FU chemotherapy during NAC for BC.

Endogenous HCN Channels Modulate the Firing Activity of Globus Pallidus Neurons in Parkinsonian Animals.

The globus pallidus occupies a critical position in the indirect pathway of the basal ganglia motor control system. Hyperpolarization-activated cyclic-nucleotide gated (HCN) channels play an important role in the modulation of neuronal excitability. In vivo extracellular single unit recording, behavioral test and immunohistochemistry were performed to explore the possible modulation of endogenous HCN channels in the globus pallidus under parkinsonian states. In MPTP parkinsonian mice, micro-pressure application of the selective HCN channel antagonist, ZD7288, decreased the firing rate in 10 out of the 28 pallidal neurons, while increased the firing rate in another 15 out of the 28 neurons. In 6-OHDA parkinsonian rats, ZD7288 also bidirectionally regulated the spontaneous firing activity of the globus pallidus neurons. The proportion of pallidal neurons with ZD7288-induced slowing of firing rate tended to reduce in both parkinsonian animals. Morphological studies revealed a weaker staining of HCN channels in the globus pallidus under parkinsonian state. Finally, behavioral study demonstrated that intrapallidal microinjection of ZD7288 alleviated locomotor deficits in MPTP parkinsonian mice. These results suggest that endogenous HCN channels modulate the activities of pallidal neurons under parkinsonian states.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate firing of globus pallidus neurons in vivo.

The globus pallidus plays a significant role in motor control under both health and pathological states. Recent studies have revealed that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels occupy a critical position in globus pallidus pacemaking activity. Morphological studies have shown the expression of HCN channels in the globus pallidus. To investigate the in vivo effects of HCN channels in the globus pallidus, extracellular recordings and behavioral tests were performed in the present study. In normal rats, micro-pressure ejection of 0.05mM ZD7288, the selective HCN channel blocker, decreased the frequency of spontaneous firing in 21 out of the 40 pallidal neurons. The average decrease was 50.4±5.4%. Interestingly, in another 18 out of the 40 pallidal neurons, ZD7288 increased the firing rate by 137.1±27.6%. Similar bidirectional modulation on the firing rate was observed by a higher concentration of ZD7288 (0.5mM) as well as another HCN channel blocker, CsCl. Furthermore, activation of HCN channels by 8-Br-cAMP increased the firing rate by 63.0±9.3% in 15 out of the 25 pallidal neurons and decreased the firing rate by 46.9±9.4% in another 8 out of the 25 pallidal neurons. Further experiments revealed that modulation of glutamatergic but not GABAergic transmission may be involved in ZD7288-induced increase in firing rate. Consistent with electrophysiological results, further studies revealed that modulation of HCN channels also had bidirectional effects on behavior. Taken together, the present studies suggest that HCN channels may modulate the activity of pallidal neurons by different pathways in vivo.

Modulation of firing activity by endogenous GABAA receptors in the globus pallidus of MPTP-treated parkinsonian mice.

The globus pallidus in rodents, equivalent to the external segment of the globus pallidus in primates, plays an important role in movement regulation. Previous studies have shown abundant γ-aminobutyric acid (GABA)ergic innervation and GABAA receptors in the globus pallidus. In this study, we investigated the effects of endogenous GABAA receptors on the spontaneous firing activity of pallidal neurons in both normal and MPTP-treated mice using multi-barrel electrodes extracellular recordings in vivo. We found that in normal mice, pressure ejection of 0.1 mmol/L gabazine, a specific GABAA receptor antagonist, increased the spontaneous firing rate of globus pallidus neurons by 27.6 ± 5.6%. Furthermore, in MPTP mice (14 days after MPTP treatment), 0.1 mmol/L gabazine increased the firing rates by 51.0 ± 7.9%, significantly greater than in normal mice. These results suggest that endogenous GABAA receptors modulate the activity of globus pallidus neurons. The present findings may provide a rationale for investigations into the potential role of GABAA receptors in Parkinson's disease.

[Protective effect of dexrazoxane on cardiotoxicity in breast cancer patients who received anthracycline-containing chemotherapy].

OBJECTIVE: To evaluate the cardioprotective effects of dexrazoxane (DEX) on breast cancer patients who received anthracycline-containing chemotherapy. METHODS: A total of 122 breast cancer patients after operation were randomly divided into two groups: The experimental group of 61 cases treated with EPI plus DEX (DEX:EPI = 10:1) as adjuvant chemotherapy regimen, and the control group of 61 cases treated with EPI but without DEX. All patients received four cycles of adjuvant chemotherapy and their changes of specific cardiac functional status and hematology status before and after chemotherapy, as well as non-cardiac toxicity were observed and analyzed. RESULTS: Brain natriuretic peptide (BNP) before chemotherapy and after four cycles of chemotherapy in the control group was (106.78 ± 4.52)×10(-6) µg/ml and (187.19 ± 8.71)×10(-6) µg/ml, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (102.34 ± 8.76)×10(-6) µg/ml and (105.29 ± 7.21)×10(-6) µg/ml, respectively, without a significant difference (P > 0.05). Cardiac troponin T (cTnT) before chemotherapy and after four cycles of chemotherapy in the control group was (12.55 ± 2.73)×10(-3) µg/ml and ( 31.05 ± 7.10 )×10(-3) µg/ml, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (12.70 ± 2.15)×10(-3) µg/ml and (13.65 ± 7.82)×10(-3) µg/ml, respectively, without a significant difference (P > 0.05). The hart rate (HR) before chemotherapy and after four cycles of chemotherapy in the control group, was 75.32 ± 7.14 bpm and 89.60 ± 9.21 bpm, respectively, with a significant difference (P < 0.05). It in the experimental group was 78.60 ± 6.29 bpm and 83.10 ± 7.56 bpm, respectively, without a significant difference (P > 0.05). The left ventricular ejection fraction (LVEF) before chemotherapy and after four cycles of chemotherapy in the control group was (65.23 ± 7.82)% and (55.21 ± 7.23)%, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (64.12 ± 6.25)% and (59.6 ± 4.72)%, respectively, without a significant difference (P > 0.05). The absolute neutrophil count before chemotherapy and after four cycles of chemotherapy in the control group was (3.95 ± 1.36)×10(9)/L and (3.50 ± 1.52)×10(9)/L, respectively, without a significant difference (P > 0.05). It in the experimental group, was (4.96 ± 1.41)×10(9)/L and (3.10 ± 1.26)×10(9)/L, respectively, with a significant difference (P < 0.05). The incidence of grade I-IV bone marrow suppression in the experimental group was 21.3%, 16.4%, 24.6%, and 4.9%, respectively. It in the control group was 16.4%, 11.5%, 9.8%, and 5.5%, respectively, with a significant difference (P < 0.05). CONCLUSIONS: Cardiac toxicity after anthracycline treatment in breast cancer patients may be significantly reduced by DEX, without increase of non-cardiac and and non-hematologic toxicity. DEX combined with anthracycline increases the risk of bone marrow suppression, therefore, peripheral blood picture should be monitored or routine bone marrow support may be needed.

[Correlation of Her-2 overexpression with endocrine status and response to tamoxifen treatment in patients with breast cancer].

OBJECTIVE: To investigate the correlation of Her-2 overexpression with endocrine status and response to tamoxifen treatment in patients with breast cancer. METHODS: Immunohistochemistry was used to measure the expression of estrogen receptor (ER), progesterone receptor (PR), Her-2, p53, proliferating cell nuclear antigen (PCNA) in 4773 consecutive in-hospitalized patients with primary breast cancer confirmed by pathological examination of the resected specimens, all females, aged 50 (15 - 92), and were followed up for 42 months on average. 1090 if then received tamoxifen (TAM), an anti-estrogen agent, post-operationally. The correlation of Her-2 overexpression with other factors was analyzed. RESULTS: (1) The Her-2 overexpression rate was 26.6%. Her-2 overexpression was significantly negatively correlated with expressions of ER and PR (both P < 0.01). (2) The general 3-year disease-free survival (DFS) rate of those treated with TAM was 92.7%; and the 3-year GFS rate of the subgroup of the TAM-treated patients with Her-1 overexpression was 91.2%, significantly lower than that of those without Her-2 overexpression (93.4%, P = 0.004). (3) The 3-year DFS rate premenopausal patients with Her-2 overexpression was 91.8%, not significantly different from that of those without Her-2 overexpression (92.6%, P > 0.05), however, the 3-year DFS rate of the postmenopausal patients with Her-2 overexpression was 90.4%, significantly lower than that of those without Her-2 overexpression (92.6%, P = 0.010). (4) The 3-year DFS rate of the axillary lymph node-positive patients with Her-2 overexpression was 89.1%, significantly lower than that without Her-2 overexpression (92.3%, P = 0.037). (5) In the premenopausal patients there was no significant difference in the 3-year DFS rate between the lymph node-negative patients with and without Her-2 overexpression (P > 0.05). However, in the postmenopausal lymph node positive patients the 3-year DFS rate of those with Her-2 overexpression was 88.7%, significantly lower than that of those without Her-2 overexpression (92.2%, P = 0.0069). CONCLUSION: ER and PR are independent factors of Her-2 expression. Her-2 overexpression signifies resistance to TAM treatment. The response to TAM is not influenced by the Her-2 expression and axillary lymph node metastasis status in the premenopausal patients, and is not influenced by the Her-2 expression level in the postmenopausal patients.

[Comparison of tolerance and toxicity of CEF-100 regimen versus CEF-60 regimen as adjuvant therapy for breast cancer].

OBJECTIVE: To evaluate tolerance and toxicity of high-dose epirubicin regimen CEF-100 as adjuvant therapy for breast cancer. METHODS: From March 2005 to October 2006, 98 patients with stage I - III a breast cancer were randomly assigned to receive postoperative chemotherapy with CEF-100 regimen (epirubicin 100 mg/m2, dl per 21 days for 6 cycles, n =48) or CEF-60 regimen (epirubicin 60 mg/m2, dl per 21 days for 6 cycles, n = 50). Blood routine test were done every cycle, liver and kindey function were examined and adverse effects were recorded after every cycle. RESULTS: No difference of average leucocyte or neutrophil count (P >0.05) was observed in every cycle. Adverse effects of digestive tract and damage of liver function in CEF-100 group were more severe than that in CEF-60 group (P <0.05), but all adverse effects could be relieved by treatment. No severe non-hematological toxicity and cardiac toxicity in both groups were observed (P <0.05). There was no death caused by chemotherapy. CONCLUSION: Our data shows that high dose epirubicin-containing CEF regimen is safe and tolerable for postoperative chemotherapy of breast cancer patient, and the adverse effects could be relieved by marrow support and liver-protection therapy. Further observation and longer follow-up is still needed in order to evaluate the efficacy of this high dose regimen.