Biochemotherapy of advanced metastatic renal-cell carcinoma: results of the combination of interleukin-2, alpha-interferon, 5-fluorouracil,vinblastine, and 13-cis-retinoic acid

Summary We conducted a phase I/II clinical trial evaluating the sequential outpatient combination of S.C. recombinant human interleukin-2 (rIL-2; given at 10 MIU/m² b.i.d. on days 3–5 of weeks 1 and 4 and at 5 MIU/m² on days 1, 3, and 5 of weeks 2 and 3), s.c. recombinant human alpha-interferon (rIFN-; given at 6 MIU/m² on day 1 of weeks 1 and 4 and on days 1, 3, and 5 of weeks 2 and 3 and at 9 MIU/m² on days 1, 3, and 5 of weeks 5–8), i.v. bolus 5-fluorouracil (5-FU; given at 1,000 mg/m² once weekly during weeks 5–8), and i.v. bolus vinblastine (given at 6 mg/m² once weekly during weeks 5 and 8) in conjunction with p.o. 13-cis-retinoic acid (13-C-RA; given at 35 mg/m² daily during weeks 1–8). Therapy was always given in the outpatient setting. Grade 3 constitutional symptoms (malaise, chills, fevers, anorexia) were observed in 4%–8% of treatment cycles and required a 50% reduction in the doses of rIL-2 and rIFN-. None of the patients experienced major 5-FU-related toxicities such as severe diarrhea and/or stomatitis; up to 20% of patients developed vinblastine-associated peripheral polyneuropathy, which was reversible after the cessation of therapy. 13-cis-Retinoic acid produced no significant side effect; no toxic death occurred. Among 24 patients with progressive metastatic disease, there were 4 complete remissions (lung, lymph nodes) and 6 partial remissions (lung, pleura, liver, lymph nodes, and peritoneal carcinosis), for an overall objective response rate of 42% (95% confidence interval, 22%–63%). An additional 13 patients achieved disease stabilization (54%). The median time to response was 3–4 months (range, up to 6 months); all responses are continuous. In summary, although the potential synergy of biochemotherapy plus 13-cis-retinoic acid requires further preclinical investigation, the current outpatient combination regimen (rIL-2, rIFN-a, 5-FU, vinblastine, and 13-C-RA) proved to be both safe and highly effective in patients with advanced metastatic renal-cell carcinoma. A current multiinstitutional prospectively randomized trial is comparing biochemotherapy with and without concomitant 13-C-RA against rIFN- plus vinblastine.     

Antigen-recognition sites of micromanipulated T cells in patients with acquired aplastic anemia

OBJECTIVE: Acquired aplastic anemia (AA) is a rare disorder characterized by pancytopenia and hypocellular bone marrow. Though experimental and clinical data suggest that AA represents a T cell-mediated disease, neither the immune response nor the nature of inciting antigen(s) have been characterized so far. The identification of a restricted T cell repertoire by PCR techniques in total lymphocyte populations supports an antigen-driven T cell response. In order to investigate the clonal composition, we analyzed the gene rearrangements of the T cell receptor (TCR) variable beta chain (Vbeta) at the single-cell level. PATIENTS AND METHODS: CD3(+) T lymphocytes were micromanipulated from peripheral blood and bone marrow samples of 8 AA patients and healthy controls. Subsequently amplified VDJ gene segments of the TCRVbeta chain were analyzed for functional rearrangements. More than 500 functionally rearranged TCR loci were studied for Vbeta/Jbeta gene segment usage and molecular composition of the complementary-determining region 3 (CDR3). RESULTS: In comparison to healthy controls, the Vbeta sequences confirmed a highly restricted T cell repertoire in AA patients at the single-cell level. Both in bone marrow and peripheral blood a predominance of Vbeta13 and Jbeta2S7 was observed. Furthermore, individual clonal T-cell expansion was identified in the majority of patients. However, deduced CDR3 amino acid sequences revealed a high variability without common motifs among the 8 patients. CONCLUSION: Individual clonal T-cell expansion with high diversity of the antigen-binding sites among the analyzed patients argues for the predominance of private inciting epitopes in AA.     

Dissociation as a Mediator of the Relationship Between Childhood Trauma and Nonsuicidal Self-Injury in Females: A Path Analytic Approach

New theoretical models of nonsuicidal self-injury (NSSI) postulate that symptoms subsequent to childhood maltreatment rather than childhood maltreatment itself may lead to engagement in NSSI. However, little is known concerning which specific syndromes serve as underlying mechanisms. In this study we sought to examine the mediating effects of dissociative, posttraumatic, and depressive symptoms, 3 often comorbid syndromes following childhood trauma. In addition, we aimed to assess differences between women with and without NSSI. A sample of 87 female inpatients with a history of childhood abuse and neglect was divided into 2 subgroups (NSSI: n = 42, no NSSI: n = 45). The assessment included measures of NSSI characteristics; adverse childhood experiences; and posttraumatic, dissociative, and depressive symptoms. The NSSI group reported significantly more cases of childhood maltreatment and higher levels of current dissociative, posttraumatic, and depressive symptoms than patients without NSSI. The results of a path analysis showed that only dissociation mediated the relationship between a history of child maltreatment and NSSI when all 3 psychopathological variables were included in the model. The findings point toward a strong and rather specific association between dissociative experiences and NSSI and therefore have important implications for clinical practice.     

交界性大疱性表皮松解症的分子机制：Co115区域突变降低了ⅩⅦ型胶原的热稳定性

ⅩⅦ型胶原即COL17A1基因突变，与交界性大疱性表皮松解症发病有关。大部分COL17A1突变可产生提前终止密码子（PTC），而只有一些突变引起氨基酸置换或缺失。作者描述2个新的甘氨酸置换，G609D和G612R，和一处剪接位点突变引起3个Gly—X—Y三氨酸缺失。为了研究非PTC突变的分子病理机制，将G609D和G612R及2个先前已知的置换，即G627V和G633，和779。787氨基酸缺失引入重组ⅩⅦ型胶原。突变胶原的热稳定性用提高温度的蛋白酶消化法评估。所有4种氨基酸的置换明显使ⅩⅦ型胶原的外功能区不稳定，其在低于Tm（螺旋解链一半时的温度）16℃～20℃即出现表现。这些结果为二级结构预测所支持，其提示在最大胶原区Co115发生胶原三股螺旋断裂。相比之下，3个全长的Gly-X-Y三聚体——氨基酸779～787缺失，对外功能区的稳定性无整体影响，因为缺失在三聚体结构区域，并且NC15区域也发生了代偿性的改变。     

An overview of adverse events reported by participants in CDC's anthrax vaccine and antimicrobial availability program

PURPOSE: The CDC's Anthrax Vaccine and Antibiotic Availability Program was implemented under an Investigational New Drug (IND) application to provide additional post-exposure prophylaxis for individuals potentially exposed to Bacillus anthracis in the fall of 2001. Participants were provided with two options: (1) 40 additional days of antimicrobial prophylaxis (i.e., ciprofloxacin, doxycycline, or amoxicillin); or (2) 40 additional days of antimicrobial prophylaxis plus three doses of anthrax vaccine adsorbed (AVA). METHODS: Participants were monitored for adverse events (AEs). Participants were asked to complete 2-week AE diaries for 6 weeks post-enrollment, and approximately 2 months after enrollment, active surveillance was conducted through telephone interviews with 1113 (64%) participants. RESULTS: A total of 1727 of approximately 10 000 previously prophylaxed persons enrolled to receive 40 additional days of antibiotics. Of these, 199 opted at enrollment to receive three doses of AVA in addition to the additional 40 days of antibiotic. Overall, 28% of participants reported at least one AE on their diaries. Results varied by surveillance mechanism, the diary data indicated differences in the proportion reporting AEs between participants receiving antibiotic only and participants receiving antibiotic and AVA. However, during the active 2-month telephone follow-up, the rates of AEs reported for both the antibiotic only and antibiotic plus AVA treatment regimens were similar. Additionally, ciprofloxacin and doxycycline had similar AE profiles, with only rigors reported significantly more often among ciprofloxacin recipients. CONCLUSIONS: Overall, the rates of AEs experienced by all participants were acceptable given the seriousness of potential B. anthracis exposure.     

Alcohol treatment research follow-up interviews and drinking behaviors

OBJECTIVE: This study, drawing upon data collected as part of a randomized clinical trial of alcohol treatment matching effects, investigates the relationship between research follow-up assessment interviews and subsequent drinking behaviors. METHOD: Subjects (N = 188; 143 men) participated in a day hospital substance-use disorder treatment program at either a private psychiatric hospital (n = 151) or a community hospital (n = 37) and were classified into one of three research groups: regularly scheduled follow-up interviews, missed scheduled follow-up interviews, and delayed Year-2 follow-up interviews. Complete data relevant to the present study were collected on 157 subjects. RESULTS: Study results provided support for a subject reactivity effect related to the research follow-up interview; that is, those subjects classified within the regularly scheduled follow-up interviews condition had the better drinking outcomes. Furthermore, by the end of the second follow-up year, subjects classified within the delayed Year-2 follow-up interviews condition had the poorest drinking outcomes. CONCLUSIONS: There may be considerable potential for subject reactivity effects, specific to the research assessment interview, to confound study results. Therefore, the interpretation of data from alcohol treatment outcome studies that fail to control for such potential confounding effects must be viewed with caution. Researchers are advised to control for these potentially confounding effects via methodological and/or statistical mechanisms.     

IL-1β and IL-10 have dual effects on enteric glial cell proliferation

Inflammatory bowel disease is typically accompanied by functional and structural changes of the enteric nervous system. In pathological studies, cellular loss and axonal degeneration have been described in the myenteric plexus. However, more recent studies suggest that the proliferation rate of myenteric glial cells is enhanced in animal models of intestinal inflammation. Therefore, we have investigated the effect of different cytokines on the proliferative response of enteric glial cells (EGCs), comparing transformed enteric glial cell lines, primary astrocyte cultures and transformed oligodendrocytes. Cells were incubated in serum-free chemically defined medium in the presence or absence of either interleukin (IL)-1beta or IL-10 at concentrations ranging between 0.1 and 100 ng mL(-1) for 48 h. Subsequently, [3H]thymidine was added to each culture dish for an additional 6 h, and the amount of incorporated [3H] was assessed. IL-1beta significantly and dose-dependently suppressed [3H]-uptake by EGCs. In contrast, IL-10 induced a biphasic response; IL-10 at low concentrations (0.1 ng mL(-1)) caused a significant suppression of [3H]-uptake, whereas high concentrations (5-100 ng mL(-1)) significantly enhanced [3H] uptake. These results indicate that EGC proliferation can be modulated by cytokines. The differential effects of IL-1beta and IL-10 suggest that during intestinal inflammation there may be a regulatory interplay between different classes of cytokines modulating EGC proliferation.