Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone

Commonly used in vivo models of prostate cancer metastasis include syngeneic rodent cancers and xenografts of human cancer in immunodeficient mice. However, the occurrence of osseous metastases in these models is rare, and in xenograft models, species-specific factors may limit the ability of human cells to metastasize to rodent bones. We have modified the severe combined immunodeficient (SCID)-human model to test the ability of circulating human prostate cancer cells to home to macroscopic fragments of human bone and other organs previously implanted into SCID mice. We have also compared the growth of human prostate cancer cells in various human and mouse tissue microenvironments in vivo. Macroscopic fragments of human fetal bone, lung, or intestine (16-22 weeks gestation) or mouse bone were implanted s.c. into male CB.17 SCID mice. Four weeks later, human prostate cancer cells were injected either i.v. via the tail vein (circulating cell colonization assay) or directly into the implanted tissue fragments transdermally (end organ growth assay). Tumor growth was followed for 6 weeks by palpation and magnetic resonance imaging. After 6 weeks, tumors were enumerated in implanted human and mouse organ fragments and native mouse tissue. Tumors were characterized by histology, immunohistochemistry, and chromosomal analysis. After i.v. injection, circulating PC3 cells successfully colonized implanted human bone fragments in 5 of 19 mice. Tumors were easily followed by palpation and imaging and had an average volume of 258 mm3 at autopsy. Histological examination revealed osteolysis and a strong desmoplastic stromal response, which indicated intense stromal-epithelial interaction. Bone tumors were subcultured, and chromosomal analysis demonstrated that the tumors were derived from the parental prostate cancer cell line. Microscopic tumor colonies were also found in a few mouse lungs after i.v. injection of PC3, DU145, and LNCaP cells, however the volume of the lung nodules was less than 1 mm3 in all of the cases. No colonization of human lung or intestine implants, the mouse skeleton, or other mouse organs was detected, demonstrating a species- and tissue-specific colonization of human bone by PC3 cells. Direct injection of 10(4) prostate cancer cells into human bone implants resulted in large tumors in 75-100% of mice. PC3 and DU145 bone tumors were primarily osteolytic, whereas LNCaP bone tumors were both osteoblastic and osteolytic. PC3 and LNCaP bone tumors showed a desmoplastic stromal response, which indicated intense stromal-epithelial interaction. All three of the cell lines formed tumors in implanted human lung tissue; however, the tumors were all < or = 10 mm3 in volume and showed minimal stromal involvement. No tumors formed after either s.c. injection or injection of cells into implanted mouse bone demonstrating both species- and tissue-specific enhancement of growth of human prostate cancer cells by human bone. The severe combined immunodeficient-human model provides a useful system to study species-specific mechanisms involved in the homing of human prostate cancer cells to human bone and the growth of human prostate cancer cells in human bone.     

Hematopoietic stem cell transplantation in mantle cell lymphoma.

BACKGROUND: Patients with mantle cell lymphoma (MCL) have in general, lower response rates and overall survival (OS) than those with other B-cell non-Hodgkin's lymphomas. The role of hematopoietic stem cell transplantation (HSCT) in MCL is unclear. Hence we decided to study the clinical course of patients who received autologous and allogeneic HSCT for MCL. METHODS: Ninety-seven patients, (80 patients-autologous; 17 patients-allogeneic) who received a HSCT for mantle cell lymphoma were included in the study. RESULTS: The complete response rates at day 100 between the two groups were similar (73% vs. 62%). Day-100 mortality was higher in the allogeneic HSCT group (19% vs. 0%) (P < 0.01). The estimated 5-year relapse rates, 5-year event-free survival (EFS) and 5-year OS among the allogeneic HSCT patients were 21%, 44% and 49%, respectively, similar to 56%, 39% and 47% in the autologous group. Ten patients received HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + high-dose methotrexate and cytarabine) +/- rituximab prior to transplant. There have been no relapses or deaths amongst these patients at a median follow-up of 16 months. CONCLUSIONS: Patients treated with allogeneic HSCT had a lower relapse rate, but similar EFS and OS to autologous HSCT. Treatment of MCL with HyperCVAD +/- rituximab followed by HSCT seems promising.     

Bortezomib in mantle cell lymphoma

Mantle cell lymphoma (MCL) represents 6% of non-Hodgkin lymphomas, but is one of the most active fields of clinical investigation. Unfortunately, there is still no standard or curative therapy in MCL. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyperfractionated cyclophosphamide, vincristine, adriamycin/doxorubicin and dexamethasone/rituximab. Most patients still relapse and a multitude of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and the first US FDA-approved drug for MCL), mTOR inhibitors, Bcl-2 inhibitors, antiangiogenesis agents and histone deacetylase inhibitors among others. An obvious effort is needed to enroll patients on clinical trials, the design of which might benefit from pharmacogenomics and a better understanding of MCL biology and its diversity.     

Using primary site as a predictor of survival in mantle cell lymphoma

BACKGROUND:

Mantle cell lymphoma (MCL) is a rare B cell lymphoma that varies in clinical behavior with some patients experiencing aggressive disease with short survival, whereas others have indolent behavior. We examined the association between primary disease site and survival in MCL patients to identify subgroups with distinct characteristics.

METHODS:

We analyzed the United States Surveillance, Epidemiology and End Results Program database for MCL cases reported from 2000 through 2009. Kaplan‐Meier curves and Cox proportional hazard models were used to estimate the effect of primary site on survival.

RESULTS:

Among 4477 cases included in our study, 19.6% of patients presented with an extranodal primary site. The most common extranodal primary sites were of the gastrointestinal (GI) tract (7.8%), the head and neck (6.2%), and the hematologic/reticuloendothelial systems (3.6%). Asians/Pacific Islanders were more likely than whites or blacks to have GI tract or head and neck disease (P < .0001 and P = .002, respectively). Advanced disease and B symptoms were less common in those with primary disease of the GI tract or head and neck than in those with primary disease of the lymph nodes (both P < .0001). In a multivariate Cox regression model, patients with primary disease of the GI tract and head and neck had superior survival compared to those with primary disease of the lymph nodes; hazard ratios 0.75 (95% CI = 0.62‐0.90) and 0.68 (95% CI = 0.55‐0.85), respectively.

CONCLUSIONS:

Primary site of disease may be an important prognostic factor for patients with MCL. Further studies elucidating a biological basis for these differences are needed. Cancer 2013. © 2013 American Cancer Society.     

Central nervous system involvement in mantle cell lymphoma.

BACKGROUND: Extranodal involvement, including central nervous system (CNS), is a frequent event in patients with mantle cell lymphoma (MCL). However, the incidence, risk factors, and impact on outcome remain controversial. PATIENTS AND METHODS: Main clinical, biological, and evolutive features of 82 patients (60 males/22 females; median age: 61 years) diagnosed with MCL (blastoid, 26%) in a single institution were analyzed for risk of CNS involvement and prognosis. RESULTS: Most patients had advanced stage and intermediate or high-risk International Prognostic Index (IPI). Eleven patients eventually developed CNS involvement with an actuarial 5-year risk of 26% (95% confidence interval 10% to 42%). In one asymptomatic patient, cerebrospinal fluid infiltration was detected at staging maneuvers (1/62; 1.6%). The remaining 10 patients developed neurological symptoms during the course of the disease (median time from diagnosis, 25 months). Initial variables predicting CNS involvement were blastoid histology, high proliferative index measured by Ki-67 staining, high lactate dehydrogenase (LDH) and intermediate- or high-risk IPI. Histological subtype and serum LDH maintained significance in multivariate analysis. Treatment of CNS infiltration consisted of intrathecal chemotherapy (two cases), and intrathecal chemotherapy plus systemic treatment (seven cases). Median survival after CNS involvement was 4.8 months, patients with this complication having shorter survival than those with no CNS disease. CONCLUSION: This study confirms the high incidence of CNS involvement in MCL patients. Treatments aimed at preventing this complication are warranted.     

套细胞淋巴瘤研究进展

套细胞淋巴瘤是B细胞非霍奇金淋巴瘤的一种特殊类型,以t(11;14)染色体易位和细胞周期蛋白D1阳性(Cyclin D1)过度表达为特征.大多数病人发病时即处于疾病晚期,常伴有结外受侵的侵袭性临床过程.单克隆抗体联合高剂量化疗包括自体干细胞移植(ASCT)使治疗有效率较前提高,新的作用于细胞周期和凋亡通路的药物,如蛋白酶体抑制剂、免疫调节剂、mTOR抑制剂等,也取得了令人鼓舞的疗效.     

Novel agents in mantle cell lymphoma

Introduction: Mantle cell lymphoma (MCL) usually takes an aggressive clinical course and carries a poor prognosis. Recently, progress has been made in the treatment of MCL including the development of a number of novel agents which target intracellular pathways and the extracellular microenvironment. These agents have transformed the landscape of available therapeutic options.

Areas covered: The current literature on the novel agents which currently hold a licence for the treatment of MCL in the context of front-line therapy and in the relapsed/refractory setting is summarized. In addition, targeted therapies showing promise at an earlier stage of development will also be discussed. A literature search was performed using the terms ‘mantle cell lymphoma’, ‘bortezomib’, ‘temsirolimus’, ‘lenalidomide’, ‘ibrutinib’, ‘novel agents’, ‘targeted molecular therapies’ and derivations thereof.

Expert commentary: In addition to improvements in immunochemotherapy, a succession of new molecular targets and corresponding drugs has revolutionised MCL therapy. The discovery of a novel agent which disrupts external signalling pathways through inhibition of Bruton’s tyrosine kinase has been a particularly exciting breakthrough. The best way to sequence and combine these agents with existing regimens and how to overcome the problem of drug resistance represent new challenges in this rapidly developing field.     

Radiotherapy in mantle cell lymphoma: A literature review

Mantle cell lymphoma (MCL) is a B-cell malignancy, comprising between 3% and 10% of all adult-onset non-Hodgkin lymphomas. MCL is considered incurable with current treatment modalities and most patients require multiple lines of treatment during their lifetime. MCL is very sensitive to radiotherapy (RT), even when delivered in low doses. In limited-stage MCL, RT can enable the de-escalation of systemic therapy. RT monotherapy is a valid option for frail patients. In advanced-stage disease, RT is very potent mode of palliation, even in heavily pretreated and chemo-resistant patients. Furthermore, it can provide a respite during which systemic treatment is unnecessary. In general, RT has a favorable toxicity profile and can be repeated as necessary for local relapse or distant disease. This effective, safe, and relatively inexpensive modality of therapy has been underutilized for patients with MCL. In this review, we will outline the use of RT for limited and advanced-stage disease and its potential application in combination with novel drugs.     

Therapeutic options in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive lymphoma requiring intensive chemotherapy ± autologous stem cell transplantation (SCT) to achieve optimal rates of progression-free survival. Here we review the treatment options for patients with newly-diagnosed or relapsed MCL and discuss recent advances in management, including the role of autologous and allogeneic SCT.     

Clinical characteristics and outcomes of primary versus secondary gastrointestinal mantle cell lymphoma

Primary gastrointestinal (GI) mantle cell lymphoma (MCL) is rare and the optimal management is unknown. We reviewed 800 newly diagnosed MCL cases and found 22 primary (2.8%) and 79 (9.9%) secondary GI MCL cases. Age, sex, and performance status were similar between primary and secondary cases. Secondary cases had more elevations in lactate dehydrogenase (28% vs 0%, P = 0.03) and a trend for a higher MCL international prognostic index (P = 0.07). Observation or local therapy was more common for primary GI MCL (29% vs 8%, P < 0.01), and autologous stem-cell transplant was more common for secondary GI MCL (35% vs 14%, P < 0.05). The median follow-up was 85 months. Primary and secondary GI MCL had similar 5-year progression-free survival (PFS) (30% vs 28%, P = 0.59) and overall survival (OS) (65% vs 66%, P = 0.83). The extent of GI involvement in primary GI MCL affected treatment selection but not outcome, with a 5-year PFS of 43% vs 14% vs 31% (P = 0.48) and OS of 57% vs 71% vs 69% (P = 0.54) in cases with single lesion vs multiple lesions in 1 organ vs multiple lesions in ≥2 organs. Less aggressive frontline treatment for primary GI MCL is reasonable. It is unknown whether more aggressive treatment can result in improved outcomes.Subject terms: B-cell lymphoma, B-cell lymphoma     

原发中枢神经淋巴瘤小鼠模型的建立

目的:建立小鼠淋巴瘤的原位脑肿瘤模型。方法:鼠源性B淋巴瘤细胞株A20,调整浓度到1×108 mL-1。在立体定向仪下将A20淋巴瘤细胞0.5μL植入BALB/c小鼠大脑中,每日观察,隔2d称体质量。3周后处死,制作石蜡切片做免疫组化及病理分析。结果:免疫组化及病理显示成功种植淋巴瘤,种植后小鼠体质量变化情况及存活时间恒定有规律。该方法建立的脑淋巴瘤动物模型在组织病理学上接近人脑淋巴瘤,且颅内生长稳定,成功率为80%。未见颅外转移病灶,实验周期短,重复性较好。结论:植入小鼠同源的B系淋巴瘤细胞株A20,可在小鼠大脑中形成原位肿瘤,其形态及恶性程度符合脑淋巴瘤模型的要求,生长特性及病理特征与人脑淋巴瘤相似,可作为临床淋巴瘤基础研究的理想模型。     

套细胞淋巴瘤治疗进展

套细胞淋巴瘤仍然是不能治愈的疾病.常规化疗可以取得很高的缓解率,但缓解期较短.加入利妥昔单抗可以提高缓解率,但尚未证实可以延长无进展生存期和总生存期.在第一次缓解期行自体造血干细胞移植可以延长疾病无进展生存期.一些新药的出现,如硼替佐米、替西罗莫司,为治疗套细胞淋巴瘤带来新的希望.     

The severe combined immunodeficient (SCID) mouse as a model for human myeloid leukemias.

Recent work has demonstrated the ability of lymphoblastic leukemias of pre-B- and T-cell origin to grow in severe combined immunodeficient (SCID) mice with a pattern reminiscent of the human clinical disease. Here, we investigated the possibility of engrafting human myeloid leukemias using both established cell lines and primary patient material. Whereas the two growth factor-independent cell lines K562 and U937 grew aggressively and induced leukemia in these animals, three other myeloid cell lines which require interleukin 3 or granulocyte-macrophage colony-stimulating factor for continuous growth in vitro failed to induce disease. Primary bone marrow and peripheral blood cells from five out of seven patients with different types of myeloid leukemias (undifferentiated, megakaryoblastic, monoblastic and chronic myelogenous leukemia in blast crisis) induced patterns of leukemic infiltration that were distinct for each leukemia subtype. The diagnosis of leukemia in SCID mice was established by microscopic detection of myeloblasts in the bone marrow, peripheral blood and, in some instances, in extramedullary sites, including the central nervous system and gonads. The karyotype and phenotype of the blasts recovered from mouse tissues were identical to those of the original patient cells. Moreover, human specific ALU sequences were amplified from the bone marrow DNA by polymerase chain reaction. Despite their ability to grow in vivo by serial transfers in SCID mice, the leukemic cells recovered from mouse tissues could not be maintained in vitro, even in the presence of recombinant cytokines. Overall, these data indicate that the SCID mouse may represent a useful animal model for human myeloid leukemias and for the development of new pharmacological and molecular approaches to therapy.     

Patterns of survival in mantle cell lymphoma

Background: The term mantle cell lymphoma (MCL) describes asubtype of non-Hodgkin's lymphoma that includes those lymphomaspreviously defined as centrocytic lymphoma, intermediate lymphocyticlymphoma, and mantle zone lymphoma. Since MCL has only recentlybeen recognised as a distinct entity, the clinical literatureis sparse and very little information is available about itstreatment. Patients and methods: We retrospectively attemptedto analyse the clinical features and outcome of 65 patientswith mantle cell lymphoma (MCL) treated from 1979 to 1993 attwo institutions in the same geographic area. Univariate (Log-ranktest) and multivariate (Cox regression) analyses of the majorprognostic factors were performed. Results: At the time of analysisthe median follow-up was 49 months. Median age was 64 yearswith a range of 27–85 years. The male to female ratiowas 2:1. Forty-seven patients (72%) had stage IV at presentationand 20 (31%) had B-symptoms at presentation. The patients usuallypresented with generalised adenopathy (78% of cases) and bonemarrow involvement (58%). Serum LDH were analysed at diagnosisin 61 patients and found to be elevated in 30%. ß2-Microglobulinwas determined at presentation in 42 patients and was higherthan normal in 54% of them. In comparison with the other subtypesof NHLs in our series, MCL appears to have a very poor survivalpattern. The median overall survival was 42 months. The CR ratewas 51% with a median DFS of 44 months. Good performance status,normal LDH, normal ß2-microglobulin, younger age (<65years), and a low prognostic risk according to the InternationalIndex were significantly associated (p <0.05) with a betteroutcome. Conclusions: The characteristics of the patients inthis study appear to be in general agreement with those in mostof the previously reported series except for the somewhat lowerrate of bone marrow infiltration observed in this series. Despitethe limitations of a retrospective analysis and the lack ofrandomization between the treatment options, this study seemsto suggest a survival advantage with anthra-cycline-containingregimens in some patients with MCL. However, this benefit wasevident only for the patients with favourable InternationalIndex prognostic scores (i.e., lowand to low-intermediate-riskdisease) who may already have a better prognosis. Patients withintermediate-high and high-risk disease according to the InternationalIndex have a poor prognosis regardless of the type of therapygiven. non-Hodgkin's lymphoma, mantle-cell lymphoma, prognostic factors, chemotheraphy, anthracycline     

套细胞淋巴瘤治疗进展

套细胞淋巴瘤(MCL)是一种侵袭性的非霍奇金淋巴瘤(NHL),占成年人NHL的6%~8%,常表现为淋巴结、胃肠道、骨髓等受累,虽最初治疗有效,但易复发或耐药.第58届美国血液学会年会关于MCL的研究涵盖了基础研究、临床治疗、新药研究等多个方面,一些新动物模型的建立、信号通路靶点的研究为完善MCL发病机制及新药研究提供了基础;VcR-CVAD、VCR方案及对于年轻、 老年患者治疗新方案的尝试都取得了不错的效果;周期蛋白依赖性激酶(CDK)抑制剂、 磷脂酰肌醇3激酶(PI3K)抑制剂、bcl-2抑制剂等新型药物在初期临床试验中也显示出令人欣喜的结果,IACS-010759等小分子的出现为MCL治疗提供了新方向.