siRNA-mediated down-regulation of survivin inhibits bladder cancer cell growth

Survivin is recognized as a general target in cancer therapy because of its selective overexpression in the majority of tumors. In bladder cancer (BCa), its expression correlates with tumor grade, recurrence risk and survival. In this study, we compared the therapeutic efficiency of two survivin specific small interfering RNA (siRNA) constructs, SVV284 and SVV094, to inhibit the growth of five human BCa cell lines (EJ28, 5637, J82, RT112, RT4). In a period between 24 to 72 h after siRNA SVV284 transfection, EJ28 and 5637 showed a significant reduction (up to 47%) of viability. For both cell lines cell cycle analysis and quantitation of apoptosis revealed both a specific G2/M arrest and an induction of apoptosis, as well as the occurrence of multinucleated cells. The cell lines EJ28, 5637 and J82 exhibited a prolonged duplication time up to 1.4-fold at 72 h after treatment. Furthermore, in these three cell lines the mRNA and protein expression quantified by real time RT-PCR and ELISA was reduced by at least 50% and up to 99%, respectively. However, RT112 and RT4 cells did not show an effective down-regulation of survivin expression. In comparison to siRNA SVV284, the treatment with siRNA SVV094 exhibited less inhibitory effects on cell growth and survivin expression in all BCa cell lines tested. In summary, the results suggest that the anti-survivin siRNA treatment might represent a suitable therapeutic approach to selectively inhibit growth of BCa cells in addition to commonly applied therapy schemes.     

Understanding the breast cancer experience of women: a qualitative study of African American, Asian American, Latina and Caucasian cancer survivors

Breast cancer is the most common form of cancer in American women across most ethnic groups. Although the psychosocial impact of breast cancer is being studied, there is little information on women from diverse ethnic and socioeconomic backgrounds. We conducted a qualitative study with breast cancer survivors (BCS) of various ethnicities. A total of 102 BCS participated in focus group interviews (24 African Americans, 34 Asians, 26 Latinas and 18 Caucasians); 20 health professionals participated in key informant interviews. Important ethnic differences in type of treatment were noted, Asians and Latinas were more likely to receive mastectomies and African American BCS were least likely to receive adjuvant therapies, including radiation and chemotherapy. These BCS enjoyed a fairly good overall health-related quality of life (HRQOL) with some persistent concerns. The prevailing concerns among all women included overall health, moderate physical concerns, cancer recurrence or metastases, psychosocial concerns related to worry about children and burdening the family, and body image and sexual health concerns. Additional challenges included: lack of knowledge about breast cancer; medical care issues such as insurance, cost and amount of time spent with physician; cultural sensitivity of providers, language barriers, cultural factors related to beliefs about illness, gender role and family obligations (e.g. self-sacrifice). These BCS, particularly the women of color, voiced that their spiritual beliefs and practices are central to their coping. This study accomplishes two goals; it adds to the sparse literature concerning the psychosocial sequelae of breast cancer among women of color, and it increases our knowledge of specific cultural influences (e.g. dietary practices, coping) and socio-ecological factors on HRQOL. More importantly, the study addressed areas that have not been studied before, specifically, an in-depth study on BCS QOL comparing multiple ethnic groups in the US. The results of this investigation will provide preliminary information to survivors and health-care providers about the impact of culture and socio-ecological contexts on survivorship. Among women of all major ethnic groups, breast cancer is the most common form of cancer and the second leading cause of cancer death (American Cancer Society (ACS), 2002). In 2002, over 203,000 women in the United States will be diagnosed with breast cancer (ACS, 2002). Ethnic disparities exist for cancer stage, diagnosis, survival, morbidity and mortality. In general, ethnic minority women are diagnosed with more advanced disease and experience greater morbidity and mortality (Haynes & Smedley, 1999; Miller et al., 1996; Ries et al., 2000; Shinagawa, 2000). In general, increases in survival rates have prompted greater interest in the quality of life (QOL) of breast cancer survivors (BCS) over the past two decades. Additionally, the QOL of cancer survivors from diverse ethnic, cultural and socioeconomic backgrounds is an emerging priority area for studies on survivorship research and clinical care (Haynes and Smedley, 1999; National Cancer Institute (NCI), 2002; President's Cancer Panel, 2000).     

Effects of ethnicity on treatment attendance,stimulant response/dose,and 14-month outcome in ADHD

From the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder--a randomized clinical trial of 579 children ages 7-9 years receiving 14 months of medication management, behavioral treatment, combination, or community care--the authors matched each African American and Latino participant with randomly selected Caucasian participants of same sex, treatment group, and site. Although Caucasian children were significantly less symptomatic than African American and Latino children on some ratings, response to treatment did not differ significantly by ethnicity after controlling for public assistance. Ethnic minority families cooperated with and benefited significantly from combination (multimodal) treatment (d = 0.36, compared with medication). This incremental gain withstood statistical control for mother's education, single-parent status, and public assistance. Treatment for lower socioeconomic status minority children, especially if comorbid, should combine medication and behavioral treatment.     

Change in emotion-regulation strategy for women with metastatic breast cancer following supportive-expressive group therapy

Four relatively independent emotion-regulation constructs (suppression of negative affect, restraint, repression, and emotional self-efficacy) were tested as outcomes in a randomized trial of supportive-expressive group therapy for women with metastatic breast cancer. Results indicate that report of suppression of negative affect decreased and restraint of aggressive, inconsiderate, impulsive, and irresponsible behavior increased in the treatment group as compared with controls over 1 year in the group. Groups did not differ over time on repression or emotional self-efficacy. This study provides evidence that emotion-focused therapy can help women with advanced breast cancer to become more expressive without becoming more hostile. Even though these aspects of emotion-regulation appear trait-like within the control group, significant change was observed with treatment.     

Which functional diagnostic tools do German coloproctologists favour?

AIM: We tried to evaluate the role of anorectal functional diagnostic tools according to the judgement of German coloproctologists. METHOD: Questionnaires concerning accuracy of different diagnostic tests were sent to 585 physicians specialized in coloproctology. RESULTS: 261 (44.6 %) completed forms were returned. An analysis of the answers revealed that endorectal sonography is widely (73 %) regarded as useful and reliable diagnostic tool. Though manometry is still frequently used, only 50.5 % of the coloproctologists made their decision concerning the further treatment depending on the results of this method. Other radiologic methods as defecography and colon transit time are still regularly performed, though video-defecography is not accepted by most coloproctologists. Neurological investigations as pudendal nerve terminal latency, surface-EMG and needle-EMG are exclusively applied in specialized departments. DISCUSSION: Regarding the variety of diagnostic tools and its different appraisal a consensus should be defined. The usefulness of neurological examination techniques needs to be clarified before their performance can be recommended for a wide-spread routine work up.     

Arthroscopic knee surgery does not modify hyperalgesic responses to heat injury

BACKGROUND: Experimental studies suggest that surgical injury may up- or down-regulate nociceptive function. Therefore, the aim of this clinical study was to evaluate the effect of elective arthroscopically assisted knee surgery on nociceptive responses to a heat injury. METHODS: Seventeen patients scheduled to undergo repair of the anterior cruciate ligament and 16 healthy controls were studied. The first burn injury was induced 6 days before surgery, and the second burn was induced 1 day after surgery with a contact thermode (12.5 cm2, 47 degrees C for 7 min) placed on the medial aspect of the calf contralateral to the surgical side. Ibuprofen and acetaminophen were given for 2 days before the first burn injury and again from the time of surgery. In the controls, the two burn injuries were separated by 7 days. Sensory variables included cumulated pain score during induction of the burn (visual analog scale), secondary hyperalgesia area, and mechanical and thermal pain perception and pain thresholds assessed before and 1 h after the burn injury. RESULTS: The heat injuries induced significant increases in pain perception (P < 0.001) and decreases in pain thresholds (P < 0.02). Baseline heat pain thresholds were higher during the second burn injury in patients (P < 0.001) and controls (P < 0.01). However, there were no significant differences in pain to heat injury (P > 0.8), secondary hyperalgesia areas (P > 0.1), mechanical and thermal pain perception (P > 0.1), or mechanical and thermal pain thresholds (P > 0.08) in the burn area before surgery compared to after surgery. CONCLUSION: Arthroscopic knee surgery did not modify nociceptive responses to a contralaterally applied experimental burn injury.     

Comparison of consumption effects of brief interventions for hazardous drinking elderly

We sought to determine if Brief Interventions [BIs, Motivational Enhancement (ME), and Brief Advice (BA)] reduced alcohol consumption among hazardous alcohol drinking elderly (65 years or older) and whether the elderly responded similarly to younger populations. In 12 primary care offices from October 1995 to December 1997, we screened 13,438 patients of whom 2702 were elderly (180 were hazardous drinkers). Forty-five elderly enrollees were randomized to receive ME (n = 18), BA (n = 12), and Standard Care (SC, n = 12). At baseline, the elderly drank more alcohol and abstained fewer days than the younger cohort (p < 0.05). During the year, the elderly in ME, BA, and SC intervention arms increased the number of days abstained, decreased the number of drinks per day, and reduced the number of total days per month drinking. There were trends toward decreases in the alcohol consumption measures in the ME and BA treatment arms compared to SC. The elderly's response to all interventions was similar to that of the younger cohort. This study suggests that hazardous alcohol consumption in the elderly is common and that BIs reduce alcohol consumption in the elderly similar to younger populations.     

Echocardiographic monitoring during induction of general anesthesia with a miniaturized esophageal probe

Standard transesophageal echocardiography (TEE) does not allow cardiac monitoring during the induction of anesthesia because standard probes would limit the oropharyngeal space and impair mask ventilation and tracheal intubation. We hypothesized that a prototype, miniaturized TEE probe could be safely introduced transnasally in awake patients and that mask ventilation and orotracheal intubation could be performed while continuously monitoring left ventricular (LV) function during the induction of anesthesia. Forty-five patients were studied prospectively. The transnasal TEE probe was introduced through one of the nares and advanced until a transverse plane image of the LV at the level of the papillary muscles was seen. Anesthesia was induced, and the patients were ventilated with a mask that had previously been threaded over the TEE probe via a central perforation. Probe insertion was successful in 12 patients under local anesthesia alone and in an additional 31 patients with a combination of local anesthesia and mild sedation. In two cases, probe placement was unsuccessful. Overall, hemodynamic variables did not change significantly during insertion. No case of significant mucosal bleeding was seen. In one patient, regurgitation of gastric contents occurred without affecting the perioperative outcome. The two-dimensional echocardiogram image quality of the LV during the induction of anesthesia was good or acceptable in 95% of patients. We conclude that transnasal TEE can effectively be used for cardiac monitoring during the induction of general anesthesia. IMPLICATIONS: This study demonstrates that it is feasible and generally safe to introduce a miniaturized transesophageal echocardiography probe transnasally in awake cardiac risk patients to monitor cardiac performance during the induction of general anesthesia.     

Carboxymethyl benzylamide dextran inhibits angiogenesis and growth of VEGF-overexpressing human epidermoid carcinoma xenograft in nude mice

Vascular endothelial growth factor (VEGF) expression is elevated in a wide variety of solid tumours. Inhibition of VEGF activities is able to reduce angiogenesis and tumour growth. We have recently shown in vitro that carboxymethyl dextran benzylamide (CMDB7) prevents the binding of VEGF(165) to its cell surface receptors and thus inhibits VEGF activities on endothelial cells. In the present study, we explored the effects of CMDB7 on highly aggressive human epidermoid carcinoma A431 cells known to overexpress epidermal growth factor receptors (EGFRs) and produce a high amount of VEGF and a minor quantity of bFGF. In vitro, CMDB7 blocked the mitogenic activity of A431-conditioned medium on endothelial cells. Concerning A431 cells, CMDB7 inhibited their proliferation and the VEGF(165) binding to them. In vivo, administration of CMDB7 (10 mg kg(-1)) three times per week for 2 weeks inhibited the growth of A431 xenografts in nude mice by 73% as compared to the control group. Immunostaining of endothelial cells with mouse-specific GSL-1 lectin in tumour sections revealed that CMDB7 also inhibited the density of intratumour endothelial cells by 66%. These findings demonstrate that CMDB7 has an efficient antiangiogenic and antitumour action in vivo even when tumour cells produce a high level of VEGF and EGFRs.     

Current status and future of relapsed primary central nervous system lymphoma (PCNSL)

The treatment of primary central nervous system lymphoma (PCNSL) has centered around high-dose methotrexate and radiotherapy (RT). Methotrexate administered intra-arterially (IA) with blood-brain barrier disruption (BBBD) and without RT, has been a highly effective treatment with a 5 year survival of 42% without cognitive loss. The purpose of this analysis is to determine responses for patients with relapsed PCNSL treated with second line IA carboplatin-based chemotherapy with BBBD. Between February 1991 and April 2000, 37 relapsed PCNSL patients, most who failed front line therapy with methotrexate based chemotherapy, were treated at Oregon Health & Science University (OHSU) and Hadassah Hebrew University Hospital (HHUH) with IA carboplatin-based chemotherapy with BBBD. Nine patients had prior RT. The mean age was 57.5 years, and all but 1 patient were treated within 8 months after relapse. The median time for survival from first IA carboplatin/BBBD treatment was 6.8 months;however, 7 out of 37 patients survived > or = 27 months. Nine patients had radiographic complete response (CR), 4 patients had radiographic partial response (PR), 12 had stable disease (SD), 10 had progressive disease (PD), and 2 were non-evaluable. The median time to failure for patients with CR and PR was 9.1 months. One long-term survivor is alive at 91.0 months from first carboplatin/BBBD treatment. In conclusion, we show that relapsed PCNSL has shown sensitivity to second line IA carboplatin-based chemotherapy with BBBD. We have developed a new protocol using i.v. rituximab prior to BBBD with IA carboplatin, i.v. cyclophosphamide and i.v. etoposide phosphate. The long-term program goal is to consolidate dose-intensive chemotherapy with monoclonal antibody directed radiation. Because patients with recurrent PCNSL commonly continue to relapse even after obtaining a complete response to enhanced chemotherapy treatment, patients w ho complete or fail the above carboplatin/BBBD treatment regimen will be offered consolidation with radioimmunotherapy using zevalin (Ibritumomab tiuxetan), IDEC-2B8 conjugated with yttrium-90 (90Y).