A combination of local inflammation and central memory T cells potentiates immunotherapy in the skin

Adoptive T cell therapy uses the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. In this study, we use a murine model of immunotherapy to optimize cell-mediated immunity in the skin. We show that in vitro - derived central but not effector memory-like T cells bring about rapid regression of skin-expressing cognate Ag as a transgene in keratinocytes. Local inflammation induced by the TLR7 receptor agonist imiquimod subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model. Local CCL4, a chemokine liberated by TLR7 agonism, similarly enhances central memory T cell function. In this model, IL-2 facilitates the development in vivo of effector function from central memory but not effector memory T cells. In a model of T cell tolerogenesis, we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity, which is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer. Thus, adoptive T cell therapy efficacy can be enhanced if CD8+ T cells with a central memory T cell phenotype are transferred, and IL-2 is present with contemporaneous local inflammation. Copyright © 2012 by The American Association of Immunologists, Inc.

Approaches for improving the safety and efficacy of adenoviral gene therapy

Cancer is a devastating disease with poor prognosis and no curative treatment, when widely metastatic. Conventional therapies, such as chemotherapy and radiotherapy, have efficacy but are not curative and systemic toxicity can be considerable. Almost all cancers are caused due to changes in the genetic material of the transformed cells. Cancer gene therapy has emerged as a new treatment option, and past decades brought new insights in developing new therapeutic drugs for curing cancer. Oncolytic viruses constitute a novel therapeutic approach given their capacity to replicate in and kill specifically tumor cells as well as reaching tumor distant metastasis. Adenoviral gene therapy has been suggested to cause liver toxicity. This study shows that new developed adenoviruses, in particular Ad5/19p-HIT, can be redirected towards kidney while adenovirus uptake by liver is minimal. Moreover, low liver transduction resulted in a favorable tumor to liver ratio of virus load. Further, we established a new immunocompetent animal model Syrian hamsters. Wild type adenovirus 5 was found to replicate in Hap-T1 hamster tumors and normal tissues. There are no antiviral drugs available to inhibit adenovirus replication. In our study, chlorpromazine and cidofovir efficiently abrogated virus replication in vitro and showed significant reduction in vivo in tumors and liver. Once safety concerns were addressed together with the new given antiviral treatment options, we further improved oncolytic adenoviruses for better tumor penetration, local amplification and host system modulation. Further, we created Ad5/3-9HIF-Δ24-VEGFR-1-Ig, oncolytic adenovirus for improved infectivity and antiangiogenic effect for treatment of renal cancer. This virus exhibited increased anti-tumor effect and specific replication in kidney cancer cells. The key player for good efficacy of oncolytic virotherapy is the host immune response. Thus, we engineered a triple targeted adenovirus Ad5/3-hTERT-E1A-hCD40L, which would lead to tumor elimination due to tumor-specific oncolysis and apoptosis together with an anti-tumor immune response prompted by the immunomodulatory molecule. In conclusion, the results presented in this thesis constitute advances in our understanding of oncolytic virotherapy by successful tumor targeting, antiviral treatment options as a safety switch in case of replication associated side-effects, and modulation of the host immune system towards tumor elimination.  

How Much Does It Cost to Provide Antiretroviral Therapy for HIV/AIDS in Africa?

Background: Many African countries are rapidly expanding HIV/AIDS treatment programs. Empirical information on the cost of delivering antiretroviral therapy (ART) for HIV/AIDS is needed for program planning and budgeting. Methods: We searched published and gray sources for estimates of the cost of providing ART in service delivery (non-research) settings in sub-Saharan Africa. Estimates were included if they were based on primary local data for input prices. Results: 17 eligible cost estimates were found. Of these, 10 were from South Africa. The cost per patient per year ranged from $396 to $2,761. It averaged approximately $850/patient/year in countries outside South Africa and $1,700/patient/year in South Africa. The most recent estimates for South Africa averaged $1,200/patient/year. Specific cost items included in the average cost per patient per year varied, making comparison across studies problematic. All estimates included the cost of antiretroviral drugs and laboratory tests, but many excluded the cost of inpatient care, treatment of opportunistic infections, and/or clinic infrastructure. Antiretroviral drugs comprised an average of one third of the cost of treatment in South Africa and one half to three quarters of the cost in other countries. Conclusions: There is very little empirical information available about the cost of providing antiretroviral therapy in non-research settings in Africa. Methods for estimating costs are inconsistent, and many estimates combine data drawn from disparate sources. Cost analysis should become a routine part of operational research on the treatment rollout in Africa.

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.

Progress in intra-articular therapy.

Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.

A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir.

This study has investigated the effects of herpes simplex thymidine kinase gene (HSV-tk) transfer followed by ganciclovir treatment as adjuvant gene therapy to surgical resection in patients with recurrent glioblastoma multiforme (GBM). The study was open and single-arm, and aimed at assessing the feasibility and safety of the technique and indications of antitumor activity. In 48 patients a suspension of retroviral vector-producing cells (VPCs) was administered by intracerebral injection immediately after tumor resection. Intravenous ganciclovir was infused daily 14 to 27 days after surgery. Patients were monitored for adverse events and for life by regular biosafety assaying. Tumor changes were monitored by magnetic resonance imaging (MRI). Reflux during injection was a frequent occurrence but serious adverse events during the treatment period (days 1-27) were few and of a nature not unexpected in this population. One patient experienced transient neurological disorders associated with postganciclovir MRI enhancement. There was no evidence of replication-competent retrovirus in peripheral blood leukocytes or in tissue samples of reresection or autopsy. Vector DNA was shown in the leukocytes of some patients but not in autopsy gonadal samples. The median survival time was 8.6 months, and the 12-month survival rate was 13 of 48 (27%). On MRI studies, tumor recurrence was absent in seven patients for at least 6 months and for at least 12 months in two patients, one of whom remains recurrence free at more than 24 months. Treatment-characteristic images of injection tracks and intracavity hemoglobin were apparent. In conclusion, the gene therapy is feasible and appears to be satisfactorily safe as an adjuvant to the surgical resection of recurrent GBM, but any benefit appears to be marginal. Investigation of the precise effectiveness of this gene therapy requires prospective, controlled studies.

Clinical and immunohistochemical assessment of vulval intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patch-type system loaded with 5-aminolevulinic acid

Background: The work in this study appraised photodynamic treatment (PDT) as a treatment method for vulval intraepithelial neoplasia (VIN) using a novel bioadhesive patch to deliver aminolevulinic acid. An analysis of changes in expression of apoptotic and cell cycle proteins (p53, p21, Mdm2, Blc-2, Bax, Ki-67) in response to PDT was evaluated. Methods: PDT was performed using non-laser light, either as a one or two-cycle treatment, with clinical and pathological assessment following after 6 weeks. Twenty-three patients with 25 VIN lesions underwent 49 cycles of PDT Patches were designed to conform to uneven vulval skin and contained 38 mg cm(-2) aminolevulinic acid. Assessment was carried out at 6 weeks post-treatment. Patient-based treatment assessment, along with clinical and pathological changes, were monitored. Immunohistochemical staining was used to elucidate a possible biomolecular basis for induced cellular changes. Results: Most patients (52%) reported a symptomatic response, with normal pathology restored in 38% of lesions. The patch was easy to apply and remove, causing minimal discomfort. Fluorescence inspection confirmed protoporphyrin accumulation. Pain during implementation of PDT was problematic, necessitating some form of local analgesia. Changes in expression of cell cycle and apoptotic-related proteins suggested involvement of apoptotic pathways. Down regulation of p21 and inverse changes in Bcl-2 and Bax were key findings. Conclusion: Treatment of VIN lesions using a novel bioadhesive patch induced changes in cell cycle and apoptotic proteins in response to PDT with possible utilisation of apoptotic pathways. The efficacy of PDT in treating VIN could be improved by a better understanding of these apoptotic mechanisms, the influence of factors, such as HPV status, and of the need for effective pain management.

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

BACKGROUND:
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
METHODS:
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
FINDINGS:
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
INTERPRETATION:
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.

Local recurrence in patients with large and locally advanced breast cancer treated with primary chemotherapy

Background: Primary chemotherapy is being given in the treatment of large and locally advanced breast cancers, but a major concern is local relapse after therapy. This paper has examined patients treated with primary chemotherapy and surgery (either breast-conserving surgery or mastectomy) and has examined the role of factors which may indicate those patients who are subsequently more likely to experience local recurrence of,disease.

Methods: A consecutive series of 173 women, with data available for 166 of these, presenting with large and locally advanced breast cancer (T2 >4 cm, T3, T4, or N2) were treated with primary chemotherapy comprising cyclophosphamide, vincristine, doxorubicin, and prednisolone and then surgery (either conservation or mastectomy with axillary surgery) followed by radiotherapy were examined.

Results: The clinical response rate of these patients was 75% (21% complete and 54% partial), with a complete pathological response rate of 15%. A total of 10 patients (6%) experienced local disease relapse, and the median time to relapse was 14 months (ranging from 3 to 40). The median survival in this group was 27 months (ranging from 13 to 78). In patients having breast conservation surgery, local recurrence occurred in 2%, and in those undergoing mastectomy 7% experience local relapse of disease. Factors predicting patients most likely to experience local recurrence were poor clinical response and residual axillary nodal disease after chemotherapy.

Conclusions: Excellent local control of disease can be achieved in patients with large and locally advanced breast cancers using a combination of primary chemotherapy, surgery and radiotherapy. However, the presence of residual tumor in the axillary lymph nodes after chemotherapy is a predictor of local recurrence and patients with a better clinical response were also less likely to experience local disease recurrence. The size and degree of pathological response did not predict patients most likely to experience recurrence of disease. (C) 2003 Excerpta Medica, Inc. All rights reserved.

Research Protocol: A Randomized Controlled Trial of Functional Family Therapy: An Early Intervention Foundation (EIF) Partnership between Croydon Council and Queen's University Belfast

The paper presents a protocol for ‘A Randomized Controlled Trial of Functional Family Therapy (FFT): An Early Intervention Foundation (EIF) Partnership between Croydon Council and Queen's University Belfast’. The protocol describes a trial that uses FFT as an alternative intervention to current use of the youth justice system and local authority care with the aim of reducing crime/recidivism in young people referred to Croydon Council. The trial will take place over a period of 36 months and will involve up to 154 families. Croydon Council will employ a team of five Functional Family Therapists who will work with families to promote effective outcomes. The Centre for Effective Education at Queen’s University Belfast will act as independent evaluators of outcomes for families and young people. The work is supported from the United Kingdom Economic & Social Research Council/Early Intervention Foundation Grant Number ES/M006921/1.

Long-Term Recurrence of Nonmelanoma Skin Cancer after Topical Methylaminolevulinate Photodynamic Therapy in a Dermato-Oncology Department

BACKGROUND: Most available studies on the efficacy of topical photodynamic therapy focus on short-to medium-term results. Long-term data are scarce. OBJECTIVE: To evaluate the long-term efficacy of photodynamic therapy with topical methylaminolevulinate to treat Bowen's disease and basal cell carcinoma in the clinical practice setting of a dermato-oncology department. METHODS: The study included patients diagnosed with Bowen's disease or basal cell carcinoma, and who received photodynamic therapy from 2004 to 2008. Treatment protocol and clinical follow-up were standardized. The primary endpoint was clinically observed recurrence in a previous photodynamic therapy-treated area. Descriptive and survival analyses were performed. RESULTS: A total of 31 Bowen's disease lesions and 44 superficial basal cell carcinoma were treated, with a median follow-up of 43.5 months. Recurrence was observed in 14 Bowen's disease lesions (53.8%) and in 11 superficial basal cell carcinoma (33.3%). Significantly higher estimates for recurrence rates were found in patients with Bowen's disease (p=0.0036) or those aged under 58 years (p=0.039). The risk of recurrence was higher in patients with Bowen's disease than in those with superficial basal cell carcinoma and younger patients. CONCLUSIONS: Recurrence should be considered when choosing to treat non-melanoma skin cancer with photodynamic therapy. Younger age and Bowen's disease were independent predictors for long-term recurrence, suggesting the need to establish an extended period of follow-up for this subset of patients.

Primary localized rectal/pararectal gastrointestinal stromal tumors: results of surgical and multimodal therapy from the French Sarcoma group.

BACKGROUND: Rectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined. METHODS: We conducted a retrospective analysis of 41 patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers. RESULTS: Of 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (≤5) and tumor size (≤5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse. CONCLUSIONS: Perioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended.

Stereotactic body radiation therapy in stage I inoperable lung cancer: from palliative to curative options.

Surgery has historically been the standard of care for operable stage I non-small cell lung cancer (NSCLC). However, nearly one-quarter of patients with stage I NSCLC will not undergo surgery because of medical comorbidity or other factors. Stereotactic ablative radiotherapy (SABR) is the new standard of care for these patients. SABR offers high local tumour control rates rivalling the historical results of surgery and is generally well tolerated by patients with both peripheral and centrally located tumours. This article reviews the history of SABR for stage I NSCLC, summarises the currently available data on efficacy and toxicity, and describes some of the currently controversial aspects of this treatment.

Adult native septic arthritis: a review of 10 years of experience and lessons for empirical antibiotic therapy.

Objectives To review the epidemiology of native septic arthritis to establish local guidelines for empirical antibiotic therapy as part of an antibiotic stewardship programme. Methods We conducted a 10 year retrospective study based on positive synovial fluid cultures and discharge diagnosis of septic arthritis in adult patients. Microbiology results and medical records were reviewed. Results Between 1999 and 2008, we identified 233 episodes of septic arthritis. The predominant causative pathogens were methicillin-susceptible Staphylococcus aureus (MSSA) and streptococci (respectively, 44.6% and 14.2% of cases). Only 11 cases (4.7%) of methicillin-resistant S. aureus (MRSA) arthritis were diagnosed, among which 5 (45.5%) occurred in known carriers. For large-joint infections, amoxicillin/clavulanate or cefuroxime would have been appropriate in 84.5% of cases. MRSA and Mycobacterium tuberculosis would have been the most frequent pathogens that would not have been covered. In contrast, amoxicillin/clavulanate would have been appropriate for only 75.3% of small-joint infections (82.6% if diabetics are excluded). MRSA and Pseudomonas aeruginosa would have been the main pathogens not covered. Piperacillin/tazobactam would have been appropriate in 93.8% of cases (P < 0.01 versus amoxicillin/clavulanate). This statistically significant advantage is lost after exclusion of diabetics (P = 0.19). Conclusions Amoxicillin/clavulanate or cefuroxime would be adequate for empirical coverage of large-joint septic arthritis in our area. A broad-spectrum antibiotic would be significantly superior for small-joint infections in diabetics. Systematic coverage of MRSA is not justified, but should be considered for known carriers. These recommendations are applicable to our local setting. They might also apply to hospitals sharing the same epidemiology.