RON and MET Co-overexpression Are Significant Pathological Characteristics of Poor Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Triple-Negative Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment. @*Materials and Methods@#We analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model. @*Results@#Patients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. In vivo, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060. @*Conclusion@#RON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.

Comparison of bone marrow biopsy and smear efficacy in patients with multiple myeloma / 中国实验血液学杂志

This study was aimed to explore the significance of the bone marrow biopsy for the diagnosis of multiple myeloma. Bone marrow smears and bone marrow biopsy originated from 279 cases of multiple myeloma were detected and compared in term of bone marrow hyperplasia, bone marrow plasma cell infiltration, proliferation mode, pathological changes in the bone marrow stroma and myelofibrosis. The results indicated that the levels of proliferation in bone marrow biopsy was significantly higher than that in bone marrow smears. Plasma cell proliferation mode in bone marrow biopsy was not completely consistent with the proportion of plasma cells in bone marrow smears. The myelofibrosis level displayed influence on the consistency of the proliferation between bone marrow smears and biopsies. It is concluded that as compared with bone marrow smears the bone marrow biopsy can more accurately reflect the levels of bone marrow hyperplasia and bone marrow plasma cell infiltration, proliferation mode and so on. Bone marrow biopsy is valuable for multiple myeloma diagnosis.

Correlation between clinical outcome of 115 patients with idiopathic thrombocytopenic purpura and megakaryocyte counts in bone marrow biopsy / 中国实验血液学杂志

The aim of study was to explore the influence of the number of megakaryocytes in bone marrow smear and trephine biopsy on clinical outcome of idiopathic thrombocytopenic purpura (ITP). The clinical outcome of 115 patients with ITP was compared by different clinical subtype, number of blood platelet, number of megakaryocyte in bone marrow smear and trephine biopsy. The results showed that: (1) the clinical outcome of acute ITP was better than that of chronic ITP, the short clinical outcome of acute ITP and chronic ITP were 86.6% vs 60.4% respectively (p < 0.01), the long clinical outcome of them were 82.5% vs 68.9% respectively (p < 0.05); (2) different number of blood platelet at occurrence of diseases had no obviously influence on clinical outcome of patients with ITP; (3) all cases were subgrouped according to number of megakaryocyte in bone marrow smear, the number of megakaryocyte in bone marrow smear less than 7/4.5 cm(2) was defined as group I, the number of megakaryocyte between 7/4.5 cm(2) to 35/4.5 cm(2) was defined as group II, and the number of megakaryocyte in bone marrow smear greater than 35/4.5 cm(2) was defined as group III. The effective rates of 3 groups in short term treatment were 53.3%, 73.8% and 86.2% respectively, and there were statistical difference between these 3 groups (p < 0.01), the effective rates of these 3 groups in long term treatment were 42.8%, 84.6% and 85.5% respectively, and there was no statistical different between group II and group III (p > 0.05), but both had statistical difference, as compared with group I (p < 0.01). (4) all cases were subgrouped by the number of megakaryocyte in trephine biopsy on time of disease occurrence, the number of megakaryocyte in bone marrow smear less than 8/mm(2) was defined as group I, the number of megakaryocyte between 8/mm(2) to 15/mm(2) was defined as group II, the number of megakaryocyte greater than 15/mm(2) was defined as group III. The effective rate of these 3 groups in short term treatment were 53.8%, 85.0% and 90.3% respectively, group II and III had no statistical difference each other (p > 0.05), but both groups had statistical difference as compared with group I (p < 0.01). Effective rate of these 3 groups in long term treatment were 33.3%, 63.1% and 87.9% respectively, and there were statistical difference between them (p < 0.01). (5) the number of blood platelet at time of disease occurrence was not related to number of megakaryocyte in bone marrow smear and in trephine biopsy section(r = 0.31, p > 0.05; r = 0.41, p > 0.05). The number of megakaryocyte in bone marrow smear had positive correlation to that in trephine biopsy slides (r = 0.52, p < 0.01). In case to use single factor Logistic regression, the results showed that number of megakaryocyte in bone marrow smear and trephine biopsy had obvious influence on long term treatment of ITP. It is concluded that the number of megakaryocyte in trephine biopsy can be used as a available supplement method for bone smear, and can forecast the therapeutic effect of patients with ITP.

Treatment strategies and indications for interventional management of pseudoaneurysms / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Pseudoaneurysms (PAs) are common vascular abnormalities predominantly arising from a disruption in the integrity of the arterial wall. The potential complications of PAs are usually unpredictable and carry high rates of morbidity and mortality. This paper presents our experience with various treatment strategies for PAs.</p><p><b>METHODS</b>Fifty-four patients with 55 PAs were diagnosed by non-invasive imaging examination. The etiology of PAs included trauma (33/55), infection (5/55), iatrogenic (6/55), and idiopathic (11/55). Different procedures including ultrasound (US)-guided compression, endovascular treatment, and surgery were performed depending on the location of PAs, size of the sac and neck, and characteristics of the donor artery. The methods of endovascular treatment included embolization of parent artery, the PA sac, or implantation of a stent-graft. Follow-up was performed using US or CT and ranged from 1 day to 24 months (average 16.7 months).</p><p><b>RESULTS</b>In all 54 patients, 3 patients with superficial PAs were treated by US-guided compression, while 44 patients with 45 PAs located in the head and neck (n = 20), viscera (n = 10) or extremities (n = 15) were treated by endovascular treatment. Nine patients with PAs located in the head and neck (n = 2) or extremities (n = 7) were treated by surgery. Among them, one patient underwent endovascular treatment combined with surgery and 1 was treated by surgery after unsuccessful US-guided compression. In the 3 patients treated with US-guided compression, 2 were successfully treated while the remaining patient required additional surgery. Primary technical success of endovascular management was 97.7% (43/44) and the cure rate was 95.5% (42/44). In the surgery group, 4 patients recovered well, 1 patient was cured by endovascular treatment combined with surgery, 2 cases underwent amputation, 1 patient died of multi-organ failure and 1 patient was paralysed.</p><p><b>CONCLUSIONS</b>Minimally invasive interventional techniques are established treatment methods for PA with favorable success rates and minimal morbidity. The therapeutic options should be tailored to the location, size and rupture risk of PA, condition of the donor artery and existing comorbidity.</p>

Out-of-the-bag intraocular lens dislocation: outcomes of posterior chamber intraocular lens exchange, risk factors, and prevention / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Dislocation of posterior chamber intraocular lens is one of the most common complications of intraocular lens implantation. Lens exchange is an effective solution to this unsatisfactory status. This study was conducted to analyze the possible predisposing factors for out-of-the-bag posterior chamber intraocular lens dislocation and to study the outcomes of lens exchange surgery.</p><p><b>METHODS</b>Thirty-six consecutive patients (36 eyes) with out-of-the-bag intraocular lens dislocation who underwent posterior chamber intraocular lens exchange in Zhongshan Ophthalmic Center of Sun Yat-sen University (Guangdong, China) from January 2003 to October 2009 were included. A 6-month follow-up was completed. The causes for out-of-the-bag intraocular lens dislocation and visual outcomes of posterior chamber intraocular lens exchange were analyzed. The out-of-the-bag intraocular lens dislocation was diagnosed on the basis of the findings from slit-lamp microscope and B-ultrasound. The dislocated intraocular lens was explanted. Reimplantation of a new posterior chamber intraocular lens was performed in each case using standardized surgical procedures.</p><p><b>RESULTS</b>In this study, a total of thirty-six consecutive patients (36 eyes) with out-of-the-bag intraocular lens dislocation underwent posterior chamber intraocular lens exchange surgery. Causes for out-of-the-bag intraocular lens dislocation included posterior capsule rupture during the initial cataract extraction procedure (23 eyes, 63.8%), trauma (5 eyes, 13.9%),neodymium-doped yttrium aluminium garnet (Nd:YAG) laser-induced dislocation (2 eyes, 5.6%), the status after vitrectomy (2 eyes, 5.6%) and unidentifiable etiology (4 eyes, 11.1%). Symptoms of these patients mainly included decrease in visual acuity (17 cases, 47.2%), blurred vision (16 cases, 44.4%), glare (1 case, 2.8%), diplopia (1 case, 2.8%), and halo (1 case, 2.8%). Intraocular lens dislocation into the posterior vitreous cavity (29 eyes, 80.5%), anterior chamber (1 eye, 2.8%) and anterior vitreous cavity (6 eyes, 16.7%) was found in this series. The foldable intraocular lenses (acrylic or silicone) were explanted from 27 eyes (75%) and rigid intraocular lenses (poly methyl methacrylate, PMMA) from 9 eyes (25%). The most common explanted intraocular lens material was single-piece acrylic (13 pieces, 36.1%), followed by 3-piece acrylic (9 pieces, 25%), single-piece PMMA (9 pieces, 25%), and 3-piece silicone (5 pieces, 13.9%). Uncorrected visual acuity postoperatively improved in 29 eyes (81%), unchanged in 4 eyes (11%), and worsened in 3 eyes (8%) in comparison to that before exchange operation (P = 0.006). Best corrected visual acuity tended to improve, but the improvement was not significant (P = 0.206). Complications related to lens exchange surgery were mainly intraocular lens redislocation (1 eye), retinal detachment (1 eye), vitreous hemorrhage (1 eye), and cystoid macular edema (1 eye).</p><p><b>CONCLUSIONS</b>Out-of-the-bag intraocular lens dislocation was mainly caused by posterior capsule rupture during the initial cataract extraction procedure and the foldable lens was the most common dislocated intraocular lens. In most cases, posterior chamber intraocular lens exchange surgery could provide satisfied final visual outcomes.</p>

Expression of insulin-like growth factor receptor type I in marrow nucleated cells from hematologic malignancies and its anti-apoptotic effect / 中国实验血液学杂志

To explore the expression of insulin-like growth factor receptor type I (IGF-IR) and its relationship to apoptosis in hematopoietic cells of MDS and AML marrow, bone marrow nucleated cells from 16 patients with myelodysplastic syndrome (MDS) and 16 patients with acute myeloid leukemia (AML) were collected for analysis, respectively. Another 16 normal donors' marrow samples were taken as controls. Immunocytochemical method (APAAP) and TdT-mediated dUTP nick end labeling (TUNEL) fluorescence were used simultaneously on cytospins of nucleated cells from these patients. Then, the ratios of IGF-IR positive cells and apoptosis cells in all nucleated cells were counted separately. The results showed that (1) there was a higher IGF-IR expression rate (56.8 +/- 14.3)% in nucleated cells of MDS marrow than that in normal marrow (40.4 +/- 9.6)% (P < 0.01). Also IGF-IR positive rate in AML marrow (86.8 +/- 13.8)% was significantly higher than that in normal marrow (P < 0.01). Furthermore, IGF-IR had higher expression in AML marrow when compared to MDS marrow (P < 0.01); (2) apoptosis in nucleated cells of MDS marrow (5.4 +/- 3.0)% was significantly higher than that in normal marrow (1.2 +/- 0.9)% (P < 0.01) and AML marrow (0.3 +/- 0.4)% (P < 0.01), while there was less apoptosis in AML marrow than that in normal marrow (P < 0.01); (3) apoptosis occurred mainly in IGF-IR negative cells (9.0 +/- 4.8)% and less in IGF-IR positive cells (1.4 +/- 2.4)% (P < 0.01). IGF-IR expression showed negative correlation with apoptosis (r = -0.852, P < 0.01); (4) IGF-IR of MDS nucleated cells in RAEB/RAEB-t/CMML expressed higher than that in RA/RAS (64.1 +/- 3.2% vs 53.5 +/- 16.2%) subgroup, although no significant difference was found (P > 0.05); and apoptosis in RAEB/RAEB-t/CMML subgroup was lower than that in RA/RAS cases (3.1 +/- 2.1% vs 6.4 +/- 2.8%) (P < 0.05); (5) IGF-IR positive rate in nucleated cells of MDS and AML marrow showed positive correlation with blast rate (r = 0.677; P < 0.01). It is concluded that there is overexpression of IGF-IR in marrow nucleated cells in MDS and AML cases. And it seems that the overexpression of IGF-IR may suggest some malignant proliferation tendency and suppress cell apoptosis through some mechanism in these malignant hematologic ailments. So, anti-IGF-IR will become a new approach for therapy of MDS and AML.

Relationship between macrophages and apoptosis in patients with myelodysplastic syndromes / 中华病理学杂志

<p><b>OBJECTIVE</b>To observe the relationship between macrophage proliferation and cell apoptosis in patients with myelodysplastic syndromes (MDS).</p><p><b>METHODS</b>A double labelling method of immunohistochemistry (alkaline phosphatase anti-alkaline phosphatase, APAAP) and ISEL (DNA in situ end labelling) was used to detect the positive CD68 expression (macrophages) and apoptosis on cold plastic embedded bone marrow biopsy sections in 30 MDS cases. 12 cases of iron deficient diseases (IDA) were used as the control.</p><p><b>RESULTS</b>(1) The number of CD68 positive cells in MDS were higher than that in controls (29.2 +/- 33.0/mm(2) bone marrow tissue vs 21.2 +/- 16.7/mm(2)) (P > 0.05); (2) The number of apoptotic cells in MDS group was much higher than that in the controls (71.5 +/- 70.9/mm(2) vs 37.3 +/- 23.0/mm(2), P < 0.05); (3) The number of CD68 expression (35.5 +/- 37.0/mm(2)) and apoptosis (90.7 +/- 74.6/mm(2)) in less advanced MDS were much higher than that in advanced MDS group (14.6 +/- 11.7/mm(2) and 26.8 +/- 33.1/mm(2), P < 0.05 and < 0.01 respectively); (4) CD68 expression showed an obvious positive correlation to apoptosis in MDS cases (r = 0.83, P < 0.001); (5) CD68 positive cells did not show location correlation to apoptotic cells; (6) CD 68 positive cells in MDS showed simultaneous apoptosis.</p><p><b>CONCLUSIONS</b>Over-apoptosis existed in MDS. Less advanced group has a higher ratio of apoptosis than in advanced group. The correlation between macrophages and apoptosis indicates the participation of TNFalpha in apoptosis-induction during MDS development.</p>

Apoptotic characteristics of CD34 positive cells in myelodysplastic syndromes / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the apoptotic situation of CD(34) positive cells in myelodysplastic syndromes (MDS).</p><p><b>METHOD</b>In 36 MDS patients, immunocytochemical technique was used for the detection of the expression of CD(34) antigen and DNA in situ end labelling (ISEL) (fluorescein) for the apoptotic signals. Fourteen cases of iron deficiency anemias (IDA) were used as controls.</p><p><b>RESULTS</b>(1) CD(34) expression in MDS group was much higher than that in controls (49.2 +/- 38.5 vs 10.2 +/- 9.7, P < 0.01), and MDS cases had an obviously higher apoptotic rate than control did (69.1 +/- 28.2 vs 17.8 +/- 11.2, P < 0.01). (2) Expression of CD(34) was higher in transforming group (P < 0.05) than in non-transforming and post-transforming groups. Apoptotic rates in both non-transforming/transforming group were higher than in post-transforming group (P < 0.02 and < 0.05 respectively). (3) No apoptosis was found in CD(34) positive cells in MDS; (4) Both CD(34) positive cells and apoptotic cells formed into small or large clusters but did not co-distributed in a given area.</p><p><b>CONCLUSION</b>There is overexpression of CD(34) antigen on hematopoietic cells in MDS. High CD(34) expression accompanied high apoptosis coexisted in the process of transformation from MDS to AML. Apoptosis-resistance of these CD(34) positive cells suggested that they came from malignant hematopoietic cell clones.</p>

Study about proliferation and apoptosis of megakaryocytes in patients with myelodysplastic syndromes / 中国实验血液学杂志

In order to observe the proliferative and apoptotic situation of megakaryocytes in patients with myelodysplastic syndromes (MDS). CD41 immunoenzyme labeling (alkaline phosphatase anti-alkaline phosphatase APAAP)/DNA in situ end labelling (ISEL) double stained techniques was used onto plastic cold embedded bone marrow sections in 29 MDS patients to analyse the proliferative and apoptostic characterization of megakaryocytic line with 14 cases of iron deficient diseases (IDA) as control. The results showed that the mean CD41 positive cell number in MDS group was (26.23 +/- 8.18) /mm(2) with a count of (15.64 +/- 7.11) /mm(2) in control group (p < 0.05). The small-micro megakaryocytes in MDS is much higher than that in IDA group (P<0.01). There was a positive co-relation between total megakaryocytes and small-micro megakaryocytes count in MDS (r = 0.702, p<0.01). Some megakaryocytes distributed abnormally around trabecula and formed small or large clusters. Apoptotic megakaryocytes in MDS occupied 4.40% and 9.32% of all CD14 positive cells and all apoptotic cells respectively (p > 0.5 comparing with control). Apoptosis in megakargocytic line occurred only in small-micro megakaryocytes and showed positive co-relation to the number of micro-megakaryocytes. Some apoptotic cell with morphologic characters of megakaryocytes expressed no CD41. It is concluded that overproliferation of megakaryocytes exists in MDS. Apoptosis occurring in micro-megakaryocytes may be a kind of physiological response to abnormal megakaryopoicsis in MDS. No obvious increased apoptosis of megakaryocytes in MDS was found perhaps due to lack of surface antigens CD41 in some later stages of apoptotic cell.

Clinical analysis of juvenile ovary granulose cell tumor / 中华妇产科杂志

Objective To explore clinicopathological features and prognosis of juvenile granulosa cell tumor (JGCT).Methods Patients were divided into JGCT group (n=10) and the adult granulosa cell tumor (AGCT) group (n=10).The tumor samples were examined by HE and immunohistochemical methods.Results Age of JGCT group ranged from 7-31 years (average 20.5 years);90% occurred before 30 years old.Diameter of the tumors ranged from 5.5 cm to 15.0 cm,average 9.8 cm.Characteristic features included nodular arrangement,irregular formation of follicles containing muein and luteinization, atypical hyperplasia of ceils and high mitotic activity.Nuclei grooved and Call-Exner bodies were absent or rare.Survival rate was 90% in 5 years.Age of AGCT group ranged from 14-74 years (average 45.1 years);AGCT occurred mostly in over 40 years old.Atypical hyperplasia of cell,mitotic activity and luteinization were absent or rare.Nuclei grooved and eall-Exner bodies were common.Survival rate was 100% in 5 years.Immunohistochemical staining were positive for p53 at 70%,PCNA at 90% in 10 cases of JGCT and p53 at 10%,PCNA at 20% in 10 cases of AGCT(P