Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

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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.     

Favorable toxicity profile of raltitrexed in elderly patients treated for colorectal cancer: a case series

BACKGROUND: Age-related physiological changes may lead to an increased toxicity of chemotherapy in the elderly, thus making tumor treatment difficult in this increasing subset of patients. OBJECTIVE: Since many trials claimed a favorable therapeutic index with raltitrexed, the aim of our preliminary study was to evaluate the anticancer activity and the toxic profile of this drug in the elderly. METHODS: Thirteen elderly patients with colorectal cancer, aged 75-90 years, were enrolled in a monochemotherapy treatment with raltitrexed. Due to their advanced age, the drug was administered with a 33% reduction of the dose. RESULTS: One partial response, four disease stabilizations, and two disease progressions were observed in 7 patients with advanced colorectal cancer. The patients with response or disease stabilisation had a satisfactory time to progression. Four out of 6 patients treated in the adjuvant setting for Dukes' C colorectal cancer remain disease free at observation periods of 15+ to 29+ months. Toxicity was virtually absent in all patients. CONCLUSIONS: The activity of monochemotherapy with raltitrexed appears to be appealing, above all because it is observed in the absence of toxicity. Though recent reports suggest some concern about severe complications of treatment with raltitrexed, administration of reduced doses of this drug seems to be a putative therapy for those patients who, because of their age, are highly susceptible to the adverse effects of chemotherapy.     

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。     

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.     

Total abdominal colectomy and ileorectal anastomosis for inflammatory bowel disease

PURPOSE: This retrospective study assesses the results of total colectomy and ileorectostomy for inflammatory bowel disease. METHODS: Between January 1974 and December 1990, 90 patients underwent total colectomy and ileorectal anastomosis for chronic ulcerative colitis (n=48) or Crohn's colitis (n=42) at the Mayo Clinic. Patients' records were reviewed retrospectively. Long-term results were assessed by chart reviews and postal questionnaires. Conversion to a permanent ileostomy, with or without proctectomy, was considered a failure of the procedure. The Kaplan-Meier method was used to estimate survivorship free of failure. The log-rank test was used to compare survivorship curves. Ninety-five percent confidence intervals were calculated at selected time points.P values<0.05 were considered to be statistically significant. RESULTS: The main indication for surgery was refractory chronic disease. There were no immediate postoperative deaths. The anastomotic leakage rate was 4.4 percent, and small-bowel obstruction occurred in 15.6 percent. At the time of follow-up (mean, 6.5±4.8 years), 46 patients (58.9 percent) had recurrence or exacerbation of the disease. This was the most common indication for subsequent proctectomy/permanent ileostomy in the follow-up period. There were 8 failures in 48 patients with ulcerative colitis (16.7 percent) and 11 failures in 42 patients with Crohn's disease (26.2 percent), although this difference was not statistically significant. Cumulative probability of having a functioning ileorectal anastomosis at five years was 84.2 percent (95 percent confidence interval, 71–95.9 percent) for ulcerative colitis and 73.8 percent (95 percent confidence interval, 58.6–88.6 percent) for Crohn's disease. In the latter group, females showed a significantly lower cumulative probability of having a functioning ileorectal anastomosis (females, 634 percent; males, 92.3 percent;P =0.04). Crohn's patients 36 years of age or younger also showed a lower probability of success (patients 36 years, 57 percent; patients >36 years, 93.8 percent;P =0.03). In the group with chronic ulcerative colitis, younger patients also seemed to require additional surgery more frequently; however, this difference was not statistically significant. Previous duration of symptoms, with mild or moderate disease in a distensible rectum, had no effect on results in either disease group. Functional results were acceptable in 63.6 and 87.5 percent of patients with Crohn's and ulcerative colitis, respectively. Eighty-four percent of ulcerative colitis patients and 91 percent of Crohn's disease patients reported an improvement in their quality of life, and overall, more than 90 percent considered their health status to be better than before surgery. One patient with ulcerative colitis developed carcinoma of the rectal stump 11.5 years after the colectomy and ileorectal anastomosis (cumulative probability of remaining free of cancer, 85.7 percent at 12 years; 95 percent confidence interval, 57.7–100 percent). CONCLUSIONS: These results demonstrate that, in selected patients with a relatively spared rectum and without severe perineal disease, total colectomy and ileorectal anastomosis still remains a viable option to total proctocolectomy with extensive Crohn's colitis. In addition, ileorectal anastomosis, as a sphincter-saving procedure, continues to have a place in the surgical treatment of chronic ulcerative colitis for high-risk or older patients who are not good candidates for ileal pouch-anal anastomosis, when the latter procedure cannot be done because of technical reasons and in the presence of advanced carcinoma concomitant with colitis, when life expectancy is limited.     

The risk of advanced heart block in surgical patients with right bundle branch block and left axis deviation

The risk of advanced atrioventricular block during anesthesia was studied prosepctively in 44 patients with right bundle branch block and left axis deviation who underwent a total of 52 operations over a 14 month period. All patients had continuous electrocardiographic monitoring throughout anesthesia induction, operation, and surgical recovery. Of the 52 operative procedures, 24 were done under general anesthesia, 11 under spinal, and 17 under local. The preoperative cardiac rhythms were atrial fibrillation in two patients, atrial tachycardia with block in one patient, atrial flutter in one patient, and sinus rhythm in the remaining patients. Temporary pacemakers were inserted preoperatively in six patients, usually because of PR interval prolongation on the preoperative electrocardiogram. There was only one episode of transient complete heart block in 51 of the 52 operative procedures. In two of the six patients with temporary pacemakers, significant pacer-related ventricular irritability occurred. This study indicates that temporary pacemaker insertion is rarely required in patients with chronic right bundle branch block and left axis deviation who require noncardiac surgery.     

Screening for Anti-Human T-Lymphotropic Virus Antibody in Blood Donors and Polytransfused Patients in Apulia (Italy)

A stringent procedure for the diagnosis of human T-lymphotropic virus (HTLV) infection was applied to 1,732 volunteer blood donors, 401 patients with various hematological disorders and 78 individuals at high risk for HIV infection. It consisted of a viral lysate-based screening assay (Abbott Laboratories, North Chicago, Ill., USA), and two confirmatory assays (Western blot and radioimmunoprecipitation assay). A confirmed positive sample had to react with at least two different HTLV gene products. Evidence of HTLV infection was not found in either blood donors or patients with hematological disorders. In fact, HTLV infection was only observed in 10 intravenous drug abusers or their sexual partners. Contrary to previous reports that claimed HTLV seroprevalences of between 0.3 and 8% in blood donors from Apulia (Italy), our data suggest that infection with this virus is principally restricted to intravenous drug abusers.