Adjuvant Bestatin immunotherapy in patients with transitional cell carcinoma of the bladder

Summary The first clinical results of an ongoing, prospective trial to determine the value of adjuvant Bestatin immunotherapy in the management of bladder cancer are presented. Patients with nonmetastatic transitional cell carcinoma of the bladder, scheduled for fulldose local radiation therapy (64 Gy), were randomly allocated to adjuvant oral Bestatin treatment (30 mg daily for at least 1 year), starting at completion of irradiation, or no Bestatin. The longest follow-up period of the 151 evaluable patients is 6 years. The results have shown that the disease-free survival of the patients taking Bestatin is significantly improved compared to the controls (p=0.04). However, the overall survival of the patients was not affected by the Bestatin treatment. The beneficial effect of Bestatin seemed to be more marked among men than women. Furthermore, statistical analyses of the patient material according to T tumor categories suggested that compared to the controls, patients with less advanced disease (T1 and T2) benefitted more from Bestatin treatment than those with more advanced tumors (T3 and T4). The results of this ongoing trial thus show that patients with bladder cancer benefit from adjuvant Bestatin treatment in terms of disease-free survival.     

Interleukin 12: still a promising candidate for tumor immunotherapy?

Interleukin 12 (IL-12) seemed to represent the ideal candidate for tumor immunotherapy, due to its ability to activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities. However, despite encouraging results in animal models, very modest antitumor effects of IL-12 in early clinical trials, often accompanied by unacceptable levels of adverse events, markedly dampened  hopes of the successful use of this cytokine in cancer patients. Recently, several clinical studies have been initiated in which IL-12 is applied as an adjuvant in cancer vaccines, in gene therapy including locoregional injections of IL-12 plasmid and in the form of tumor-targeting immunocytokines (IL-12 fused to monoclonal antibodies). The near future will show whether this renewed interest in the use of IL-12 in oncology will result in meaningful therapeutic effects in a select group of cancer patients.     

Effects of hyperthermia on heat shock protein expression, alkaline phosphatase activity and proliferation in human osteosarcoma cells

Hyperthermia can be used as a possible adjuvant therapy in treatment of cancer patients. In this study, the direct effect of hyperthermia on osteosarcoma derived cell lines HOS85, MG-63 and SaOS-2 was investigated. Heat shock at 42 degrees C inhibited proliferation significantly in all three cell lines tested. Furthermore a sub-lethal heat shock (42 degrees C, 1 h) decreases alkaline phosphatase activity, the absolute marker for osteoblast-like cells, in all of the three cell lines. Hsp70 was expressed constitutively and was found to be upregulated in a time-dependent manner; by up to 150% in Western blot analysis. The results of this study indicate that heat shock has an inhibitory effect on human osteosarcoma cells. These data suggest that hyperthermia has an anti-tumour effect on cancers of the bone and might, therefore, become an adjuvant treatment option.     

新辅助化疗联合人工膝关节置换治疗膝关节附近骨肉瘤

目的:评价新辅助化疗联合人工膝关节置换治疗膝关节附近骨肉瘤的临床疗效。方法:38例膝关节附近骨肉瘤采用新辅助化疗和人工膝关节置换,所有病例均进行肿瘤细胞坏死率、5年内肿瘤局部复发率、5年生存率和膝关节功能评估。结果:38例患者新辅助化疗后肿瘤细胞坏死率平均95.8%;随访6-9年,38例患者中5年内肿瘤局部复发12例(31.6%),5年后生存31例(81.6%),膝关节功能优良率92.1%。结论:新辅助化疗联合人工膝关节置换治疗膝关节附近骨肉瘤可有效提高骨肉瘤5年生存率,保存患肢功能,是骨肉瘤保肢治疗的一种较好的方法。     

Evolution of adjuvant chemotherapy of breast cancer from Bonadonna to the taxanes

The author summarizes the progress of adjuvant chemotherapy of breast cancer from the classical Bonadonna-type CMF over the anthracyclines to the taxanes. The CMF regimen represented the prototype of combination chemotherapy which significantly improved early and long term results. After 20 years the patients given adjuvant combination chemotherapy with CMF had significantly better rates of relapse-free survival (p<0.001) and overall survival (p=0.03) compared with no chemotherapy. 6 cycles of CMF was the gold standard of adjuvant chemotherapy in breast cancer for decades. The Milan research group decided in the early 1980s to challange this popular CMF combination by introducing doxorubicin within the adjuvant program. Compared with standard CMF, anthracyclin-containing regimens reduced the annual risk of recurrence by 12% and the annual risk of death by 11%, equating to a 3.2% absolute reduction in recurrence and a 2.7% absolute reduction in mortality at 5 years. This small but real difference seen with regimens containing three or more agents (e.g. CEF and CAF, FAC, FEC, etc.), whereas 4 cycles of 2-drug regimens (e.g. AC or EC) appears to be equivalent to 6 cycles of CMF. Among the novel chemotherapeutic drugs introduced in the 1990s the taxanes have emerged as the most powerful compounds in breast cancer. Several large, adjuvant clinical trials are currently ongoing or have recently completed accrual. The available results from innumerable clinical studies are still inconclusive and do not support the routine use of taxanes in the adjuvant setting - with the exception of the BCIRG 001 docetaxel trial, in which significant improvement was documented in disease free survival with 6 x TAC compared with 6 x FAC (82% vs 74%). Studies on the effect of the new trastuzumab (an antibody against the extracellular domain of the HER2) in adjuvant setting was initiated in early 2000. The Herceptin adjuvant trial programme is extensive, involving more than 12,000 patients worldwide. This trials will potentially offer many women with HER2-positive disease the chance of improved survival.     

Long-term results after combined modality treatment for non-metastatic osteosarcoma

Since the introduction of multimodality treatment, the prognosis of patients with high-grade non-metastatic osteosarcoma has significantly improved. A retrospective review was performed to assess the long-term results of this approach in a single centre setting, and to investigate the impact of potential clinical prognostic factors. Between 1985 and 1993, 35 patients with stage II-A and II-B osteosarcoma underwent preoperative chemotherapy (high-dose methotrexate), wide surgery, and adjuvant chemotherapy (cisplatin-doxorubicin/bleomycin-cyclophosphamide-dactinomycin) (modified T-10A protocol). There were 19 males and 16 females. Median patient age was 17 y (range 12–42). Primary tumour sites were the extremities (83%) and axial bones (17%). In spite of an unfavourable grade 3–4 histologic response rate to high-dose methotrexate of 12%, 31 (88%) patients were able to undergo limb-sparing surgery and 28 (80%) were rendered disease free after the planned therapy. Median follow-up was 8 y. The actuarial overall survival and disease-free survival rates were 64% and 49% at 5 y, and 59% and 49% at 10y, respectively. Tumour size and primary site were significant prognostic factors for survival in univariate analyses. In conclusion, long-term survival after combined modality treatment can be achieved in more than 60% of patients with localised osteosarcoma, including non-appendicular lesions. Limb-sparing surgery is a realistic goal for most cases. The prognostic value of tumour necrosis and the efficacy of neoadjuvant chemotherapy should be interpreted according to individual high-dose methotrexate scheduling.     

Tumor-biological factors uPA and PAI-1 as stratification criteria of a multicenter adjuvant chemotherapy trial in node-negative breast cancer

In axillary node-negative primary breast cancer, 70% of the patients will be cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is only needed for those 30% of node-negative patients who will relapse after primary therapy and eventually die of metastases. Traditional histomorphological and clinical factors do not provide sufficient information to allow accurate risk group assessment in order to identify node-negative patients who might benefit from adjuvant systemic therapy. In the last decade various groups have reported a strong and statistically independent prognostic impact of the serine protease uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1) in node-negative breast cancer patients. Based on these data, a prospective multicenter therapy trial in node-negative breast cancer patients was started in Germany in June 1993, supported by the German Research Association (DFG). Axillary node-negative breast cancer patients with high levels of either or both proteolytic factors in the tumor tissue were randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was continued until the end of 1998, by which time 684 patients had been enrolled. Since then, patients have been followed up in order to assess the value of uPA and PAI-1 determination as an adequate selection criterion for adjuvant chemotherapy in node-negative breast cancer patients. This paper reports on the rationale and design of this prospective multicenter clinical trial, which may have an impact on future policies in prognosis-oriented treatment strategies.     

Generation of “Virtual” Control Groups for Single Arm Prostate Cancer Adjuvant Trials

It is difficult to construct a control group for trials of adjuvant therapy (Rx) of prostate cancer after radical prostatectomy (RP) due to ethical issues and patient acceptance. We utilized 8 curve-fitting models to estimate the time to 60%, 65%, … 95% chance of progression free survival (PFS) based on the data derived from Kattan post-RP nomogram. The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx to develop 8 subsets of cases (reference case sets) whose observed PFS times were most accurately predicted by each model. To prepare a virtual control group for a single-arm adjuvant Rx trial, we first select the optimal model for the trial cases based on the minimum weighted Euclidean distance between the trial case set and the reference case set in terms of clinical features, and then compare the virtual PFS times calculated by the optimum model with the observed PFSs of the trial cases by the logrank test. The method was validated using an independent dataset of 155 post-RP patients without adjuvant Rx. We then applied the method to patients on a Phase II trial of adjuvant chemo-hormonal Rx post RP, which indicated that the adjuvant Rx is highly effective in prolonging PFS after RP in patients at high risk for prostate cancer recurrence. The method can accurately generate control groups for single-arm, post-RP adjuvant Rx trials for prostate cancer, facilitating development of new therapeutic strategies.     

Enhancement of intravesical delivery with Syn3 potentiates interferon-α2b gene therapy for superficial bladder cancer

Intravesical administration of interferon alpha-2b protein (IFN) has been successfully used in the treatment of patients with superficial bladder tumors. Local dosing of IFN minimizes well-known systemic side effects of the drug, but exposure to bladder tumors is limited by the duration of instillation and transient concentrations achieved in the urothelium. Intravesical delivery of the gene encoding interferon results in an alternative strategy for IFN-based therapy of the disease, enabling sustained exposure of IFN protein that results from production by tumor and non-tumor cells in the urothelium. Efficient gene delivery and expression of IFN has been achieved using a recombinant adenovirus gene delivery system (rAd-IFN) in conjunction with the novel small molecule excipient Syn3. Studies with rAd-IFN/Syn3 in animal models result in urine concentrations of IFN that persisted for weeks and correlated with potent anti-tumor effects. The objective of this review is to communicate the rationale and preclinical findings that support ongoing clinical investigation of intravesical rAd-IFN/Syn3 in superficial bladder cancer.     

Enhancement of intravesical delivery with Syn3 potentiates interferon-alpha2b gene therapy for superficial bladder cancer

Intravesical administration of interferon alpha-2b protein (IFN) has been successfully used in the treatment of patients with superficial bladder tumors. Local dosing of IFN minimizes well-known systemic side effects of the drug, but exposure to bladder tumors is limited by the duration of instillation and transient concentrations achieved in the urothelium. Intravesical delivery of the gene encoding interferon results in an alternative strategy for IFN-based therapy of the disease, enabling sustained exposure of IFN protein that results from production by tumor and non-tumor cells in the urothelium. Efficient gene delivery and expression of IFN has been achieved using a recombinant adenovirus gene delivery system (rAd-IFN) in conjunction with the novel small molecule excipient Syn3. Studies with rAd-IFN/Syn3 in animal models result in urine concentrations of IFN that persisted for weeks and correlated with potent anti-tumor effects. The objective of this review is to communicate the rationale and preclinical findings that support ongoing clinical investigation of intravesical rAd-IFN/Syn3 in superficial bladder cancer.     

Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]

Background

The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question.

Design

GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage.

Conclusion

372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients.

Trial Registration

Current Controlled Trials ISRCTN45122933     

Cost effectiveness of day and inpatient psychiatric treatment: results of a randomised controlled trial.

OBJECTIVE: To compare direct and indirect costs of day and inpatient treatment of acute psychiatric illness. DESIGN: Randomised controlled trial with outcome and costs assessed over 12 months after the date of admission. SETTING: Teaching hospital in an inner city area. SUBJECTS: 179 patients with acute psychiatric illness referred for admission who were suitable for random allocation to day hospital or inpatient treatment. 77 (43%) patients had schizophrenia. INTERVENTIONS: Routine inpatient or day hospital treatment. MAIN OUTCOME MEASURES: Direct and indirect costs over 12 months, clinical symptoms, social functioning, and burden on relatives over the follow up period. RESULTS: Clinical and social outcomes were similar at 12 months, except that inpatients improved significantly faster than day patients and burden on relatives was significantly less in the day hospital group at one year. Median direct costs to the hospital were 1923 pounds (95% confidence interval 750 pounds to 3174 pounds) per patient less for day hospital treatment than inpatient treatment. Indirect costs were greater for day patients; when these were included, overall day hospital treatment was 2165 pounds cheaper than inpatient treatment (95% confidence interval of median difference 737 pounds to 3593 pounds). Including costs to informants when appropriate meant that day hospital treatment was 1994 pounds per patient cheaper (95% confidence interval 600 pounds to 3543 pounds). CONCLUSIONS: Day patient treatment is cheaper for the 30-40% of potential admissions that can be treated in this way. Carers of day hospital patients may bear additional costs. Carers of all patients with acute psychiatric illness are often themselves severely distressed at the time of admission, but day hospital treatment leads to less burden on carers in the long term.     

The Clinical Effectiveness of Patient Initiated Clinics for Patients with Chronic or Recurrent Conditions Managed in Secondary Care: A Systematic Review

Background

Missed or inappropriate hospital appointments cost the UK National Health Service millions of pounds each year and delay treatment for other patients. Innovative methods of appointment scheduling that are more flexible to patient needs, may improve service quality and preserve resources.

Methods

A systematic review of the evidence for the clinical effectiveness of patient initiated clinics in managing long term care for people with chronic or recurrent conditions in secondary care. Seven databases were searched including MEDLINE, Embase and PsycINFO (using the OVID interface), the Cochrane Library of Systematic Reviews and CENTRAL, Science Citation Index Expanded, Social Sciences Citation Index, and Conference Proceedings Citation Index (via the Web of Science interface) from inception to June 2013. Studies comparing patient initiated clinics with traditional consultant-led clinics in secondary care for people with long term chronic or recurrent diseases were included. Included studies had to provide data on clinical or resource use outcomes. Data were extracted and checked by two reviewers using a piloted, standardised data extraction form.

Results

Eight studies (n = 1927 individuals) were included. All were conducted in the UK. There were few significant differences in clinical outcomes between the intervention and control groups. In some instances, using the patient initiated clinics model was associated with savings in time and resource use. The risk of harm from using the patient initiated clinic model of organising outpatient care is low. Studies with longer follow-up periods are needed to assess the long term costs and the ongoing risk of potential harms.

Conclusions

The UK policy context is ripe for evidence-based, patient-centred services to be implemented, especially where the use of health care resources can be optimised without reducing the quality of care. Implementation of patient initiated clinics should remain cautious, with importance placed on ongoing evaluation of long term outcomes and costs.     

Long-term follow-up of patients with myocarditis and idiopathic dilated cardiomyopathy after immunomodulatory therapy

Abstract The randomized clinical trial with interferon-α (IFN) or thymic hormones versus conventional therapy was conducted in patients with myocarditis and idiopathic dilated cardiomyopathy (IDC). We enrolled 180 patients to receive IFN (3–5 million units per day) for 3 months, thymomodulin (10 mg three times per week) for 2 months, or conventional therapy alone. Patients were followed-up for 7 years after the end of treatment. Left ventricular function, exercise tolerance and survival rate were significantly better at long-term follow-up in patients treated with IFN or thymomodulin, than in conventionally treated patients. These results implicate that immune modulating therapy might represent important contribution in the treatment of myocarditis and IDC.     

Adjuvant liver perfusion in colorectal cancer: initial results of a clinical trial.

Fifty consecutive patients with colorectal cancer but no evidence of secondary deposits in the liver were included in an ongoing controlled clinical trial of adjuvant liver perfusion aimed at reducing the incidence of hepatic metastases. All patients had their primary tumour resected in the standard way. Twenty-six of the patients served as controls, and 24 received fluorouracil, 1 g daily, as a continuous infusion into the portal venous system during the first seven days after operation. The patients were matched for age, sex, and site and stage of the disease. The immediate postoperative mortality and morbidity did not differ significantly between the two groups. During the follow-up period (mean duration 15.5 months), however, six deaths occurred in the control group and only one in the perfusion group. At necropsy four of the controls had multiple liver metastases. Two of the surviving controls developed evidence of liver metastases, and two had a local recurrence. No patient in the perfusion group developed evidence of hepatic metastases. These initial results suggest that adjuvant portal venous perfusion with fluorouracil may reduce the incidence of liver metastases in colorectal cancer.     

Adjuvant treatment with polyadenylic-polyuridylic acid in operable breast cancer: updated results of a randomised trial.

The results of a randomised trial of polyadenylic-polyuridylic acid given as adjuvant treatment for operable breast cancer were reviewed after a mean follow up period of 87 months. Of the 300 patients included in the original trial, 145 had been allocated to conventional treatment alone and served as controls. At the time of review the overall survival of the group given polyadenylic-polyuridylic acid was significantly improved (p less than 0.05) as compared with that of the controls given conventional treatment alone. Significant benefit (p less than 0.02) was also observed among patients with evidence of disease in lymph nodes, the best results occurring in those with up to three invaded nodes, who showed a significant increase in both overall and relapse free survival. No evidence of toxicity was recorded. These findings confirm the value of polyadenylic-polyuridylic acid as adjuvant treatment for operable breast cancer. Results in an experimental model and in patients receiving the adjuvant suggested a possible role of interferon and natural killer (NK) cells in the mechanism of action.     

影响骨肉瘤治疗预后效果的临床因素的研究进展

骨肉瘤是最常见的骨的原发性恶性肿瘤,常常好发于15-19岁。目前治疗上已经有了很大的进步,其最有效的治疗方案包括新辅助加上局部控制。但不幸的是,其治疗效果仍然非常低。因此在选择不同的治疗方式前需要对患者的预后进行严谨和科学的预测和判断,从而选择最佳的治疗方案。传统意义上影响骨肉瘤治疗预后效果的因素主要包括以下几点:年龄,性别,肿瘤大小,位置,分期和耐药性等。但是这些因素有着太多的测量和衡量方法,在不同的研究中进行统一标准下的比较是很难的。通常来讲,利用转移,耐药性等因素来进行预后的判断尽管能达到较高的准确性,但已经往往处于疾病的后期,对疾病治疗本身的意义不大。因此,需要去寻找新的,能够在早期对于预后进行判断,能够于早期进行准确的诊断从而进行早期治疗的方法。本文从位置,大小,年龄,分期,肿瘤的复发或转移,病理性骨折,手术和化学治疗等方面对骨肉瘤的预后及影响因素进行综述。     

A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire.

BACKGROUND: The development of effective adjuvant therapies for the treatment of high-risk melanoma patients is critical for the prevention of metastatic disease and improvement of patient survival. Active specific immunotherapy has been tested as an adjuvant treatment in numerous clinical trials with overall limited, but occasionally promising, success rates. Newcastle disease virus (NDV) oncolysate has been utilized as an adjunctive immunotherapeutic agent in the postsurgical management of these patients. A phase II study initiated in 1975 using adjuvant vaccine therapy composed of allogeneic and autologous human melanoma cells infected with live NDV (NDV oncolysate) in patients with AJCC stage III melanoma following therapeutic lymph node dissection has shown >60% survival rate at 10 years with no adverse effects. Continued long-term analysis of trials with promising early results as well as assessment of immunologic responses generated in these patients may result in improved therapeutic decisions for clinical trials in the future. MATERIALS AND METHODS: We analyzed the 15-year survival of patients treated postsurgically with NDV oncolysate in the phase II study described above. In an attempt to understand the immunological effects of this treatment, we have also carried out a comprehensive analysis of the peripheral blood T cell repertoire in these patients. RESULTS: The overall 15-year survival of this group of patients is 55%. Previous studies have suggested that improved outcome in patients undergoing immunotherapy is correlated with increased numbers of CD8(+)CD57(+) cells. In surviving patients, we observed a striking oligoclonality in the CD8(+) T cell population in peripheral blood, which reflects clonal expansions in the CD8(+)CD57(+) subset. CONCLUSIONS: The data suggest that adjuvant vaccination with NDV oncolysates is associated with prolonged survival of patients with lymph node-positive malignant melanoma and that CD8(+) T cells may be an important component of therapeutic efficacy.