Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.     

Biotherapy for xenografted human central nervous system leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19)- pokeweed antiviral protein immunotoxin

The study of central nervous system (CNS) leukemia has been hampered by the lack of a suitable animal model. We report that severe combined immunodeficiency (SCID) mice invariably develop rapidly progressive fatal CNS leukemia within 3 weeks after intravenous injection of NALM-6 pre-B acute lymphoblastic leukemia (ALL) cells. Colonization of the dura mater and subarachnoid space, usually of the distal spinal cord with occasional extension into the Virchow-Robin spaces of blood vessels subjacent to the meninges, followed involvement of bone marrow in the skull, vertebrae, and, occasionally, the appendicular skeleton. Occult CNS leukemia was detectable by polymerase chain reaction amplification of human DNA as early as 8 days postinoculation of leukemia cells. We used this in vivo model of human CNS leukemia to examine the therapeutic efficacy and toxicity of intrathecally administered B43 (anti-CD19)-pokeweed antiviral protein (PAP), an anti- B-lineage ALL immunotoxin directed against the pan-B-cell antigen CD19/Bp95. Intrathecal therapy with B43 (anti-CD19)-PAP immunotoxin at nontoxic dose levels significantly improved survival of SCID mice and was superior to intrathecal methotrexate therapy.     

TSC1-mTOR-PLK轴以阶段特异性方式调节从施旺细胞增殖到髓鞘形成的内稳态开关

恰如其分的外周髓鞘形成取决于雪旺细胞增殖与分化进程间的平衡。丝氨酸/苏氨酸激酶(mTOR)整合多种环境因素,是细胞生长、代谢、发挥作用的中枢调节者。本文报道了一种mTOR的负性调节剂——结节性硬化复合体(TSC1),通过控制细胞增殖和髓鞘稳态,建立了雪旺细胞谱系进展和髓鞘形成的阶段依赖性程序。小鼠雪旺细胞祖细胞中TSC1的解离导致mTOR信号通路激活,继而导致雪旺细胞过量增殖,分化受阻,髓鞘形成减少。转录组分析显示,TSC1突变体中的mTOR活化使得polo样激酶(PLK)依赖性通路和细胞周期调节剂上调。弱化mTOR或者对PLK进行药理抑制部分挽救了因TSC1缺失导致的外周神经发育过程中的髓鞘形成减少。相较之下,成年小鼠成熟雪旺细胞中TSC1缺失可导致髓鞘的过度增殖和过度生长。本文的发现提示了TSC1-mTOR-PLK信号轴在控制雪旺细胞的发育过程中,从增殖到分化和髓鞘内稳态中起到的阶段特异性功能。     

Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein- 1 alpha

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha with improved solution properties. We show here that it mobilizes stem cells into the peripheral blood. We investigated the mobilizing effects of BB-10010 on the numbers of circulating 8-day spleen colony-forming units (CFU-S8), CFU-S12, and progenitors with marrow repopulating ability (MRA). A single subcutaneous dose of BB-10010 caused a twofold increase in circulating numbers of CFU-S8, CFU-S12, and MRA 30 minutes after dosing. We also investigated the effects of granulocyte colony-stimulating factor (G- CSF) and the combination of G-CSF with BB-10010 on progenitor mobilization. Two days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA progenitors by 25.7-, 19.8-, and 27.7-fold. A single administration of BB-10010 after 2 days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA even further to 38-, 33-, and 100- fold. Splenectomy resulted in increased circulating progenitor numbers but did not change the pattern of mobilization. Two days of treatment with G-CSF then increased circulating CFU-S8, CFU-S12, and MRA by 64-, 69-, and 32-fold. A single BB-10010 administration after G-CSF treatment further increased them to 85-, 117-, and 140-fold, respectively, compared with control. We conclude that BB-10010 causes a rapid increase in the number of circulating hematopoietic progenitors and further enhances the numbers induced by pretreatment with G-CSF. BB- 10010 preferentially mobilized the more primitive progenitors with marrow repopulating activity, releasing four times the number achieved with G-CSF alone. Translated into a clinical setting, this improvement in progenitor cell mobilization may enhance the efficiency of harvest and the quality of grafts for peripheral blood stem cell transplantation.     

In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease

The B-lymphocyte/accessory-cell activation antigen B7 (BB1) has been shown in vitro to stimulate T-lymphocyte proliferation and cytokine production via CD28 present on the latter cells. In this study, benign lymphoid tissues, lymphomas, and extralymphoid inflammatory sites were examined immunohistochemically using anti-B7 and other relevant monoclonal antibodies. B7 was expressed by benign transformed germinal center B cells, as it was by B cells of follicular lymphomas. B7 was also expressed by a subpopulation (a mean of 31% to 65%) of macrophages and dendritic cells in a variety of lymphoid tissues. It was present in abundance on all macrophages constituting sarcoid granulomas in lymph nodes. In extralymphoid inflammation, 17% to 35% of macrophages expressed B7 only weakly. Cases of Hodgkin's disease showed expression of B7 by the majority of Reed-Sternberg cells or malignant mononuclear variants, a phenomenon that potentially contributes to the lymphocytic accumulation that is a feature of this condition. CD28+ T cells were seen in all areas where T cells were present. B7+ and CD28+ cells colocalized in, for example, lymphoid follicles, lymph node paracortex, sarcoid granulomas, and Hodgkin's disease tissue, indicating a potential for cellular interaction via these molecules at these sites.     

Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease

INTRODUCTION: We sought to examine the relationship between C-reactive protein (CRP) and clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease (IBD). METHODS: All IBD patients at our institution between January 2002 and August 2003 who had a CRP, colonoscopy, and either small bowel follow-through (SBFT) or CT enterography (CTE) performed within 14 days were identified. Clinical activity was assessed retrospectively through review of the medical record. Logistic regression was used in Crohn's disease (CD) patients to estimate the odds ratio (OR) with 95% confidence intervals for an elevated CRP. Associations were assessed using Fisher exact test in ulcerative colitis (UC) patients due to small sample size. RESULTS: One-hundred four CD patients (46% males) and 43 UC and indeterminate colitis patients (44% males) were identified. In CD patients, moderate-severe clinical activity (OR, 4.5; 95% CI, 1.1-18.3), active disease at colonoscopy (OR, 3.5; 95% CI, 1.4-8.9), and histologically severe inflammation (OR, 10.6; 95% CI; 1.1-104) were all significantly associated with CRP elevation. Abnormal small bowel radiographic imaging was not significantly associated with CRP elevation. In UC patients, CRP elevation was significantly associated with severe clinical activity, elevation in sedimentation rate, anemia, hypoalbuminemia, and active disease at ileocolonoscopy, but not with histologic inflammation. CONCLUSIONS: CRP elevation in IBD patients is associated with clinical disease activity, endoscopic inflammation, severely active histologic inflammation (in CD patients), and several other biomarkers of inflammation, but not with radiographic activity.     

Sequential histologic evaluations in collagenous colitis

To evaluate the histologic manifestations of collagenous colitis and correlate histologic changes with disease behavior, 14 patients who had undergone sequential evaluations during 33±6 months of follow-up were studied. Two hundred twelve tissue specimens from all anatomic regions of the colon (mean, 15±3 samples per patient) were interpretated independently under code by two pathologists. Eight patients (57%) had histologic resolution after 14±4 months of empiric therapy and in only one of these (12%) did symptoms persist. Four patients (29%) had sequential histologic examinations from the same anatomic region that varied from classical collagenous colitis to ilflamed mucosa without a thickened collagen band to normal mucosa. Eight patients (57%) had varying histologic findings from different anatomic regions during the same examination that ranged from classical collagenous colitis to increased inflammation with resolution of the collagen band to normal mucosa. Normal mucosa was found mainly in specimens from the rectosigmoid, and proctosigmoidoscopic examinations alone would have missed the diagnosis of collagenous colitis in 40% of cases. Pathologic interpretations were concordant in 171 of 212 instances (81%). We conclude that histologic resolution of collagenous colitis can occur and it is associated with loss of symptoms. The histologic features of collagenous colitis are distinctive, but they may be patchy and inconsistently sampled. Rectosigmoid biopsies underestimate the diagnosis.Data analysis was performed in part using the CLINFO Data Analysis System.Presented in part at the annual meeting of the American College of Gastroenterology, October 16, 1991, Boston, Massachusetts.