Spores of Clostridium engineered for clinical efficacy and safety cause regression and cure of tumors in vivo.

Spores of some species of the strictly anaerobic bacteria Clostridium naturally target and partially lyse the hypoxic cores of tumors, which tend to be refractory to conventional therapies. The anti-tumor effect can be augmented by engineering strains to convert a non-toxic prodrug into a cytotoxic drug specifically at the tumor site by expressing a prodrug-converting enzyme (PCE). Safe doses of the favored prodrug CB1954 lead to peak concentrations of 6.3 μM in patient sera, but at these concentration(s) known nitroreductase (NTR) PCEs for this prodrug show low activity. Furthermore, efficacious and safe Clostridium strains that stably express a PCE have not been reported. Here we identify a novel nitroreductase from Neisseria meningitidis, NmeNTR, which is able to activate CB1954 at clinically-achievable serum concentrations. An NmeNTR expression cassette, which does not contain an antibiotic resistance marker, was stably localized to the chromosome of Clostridium sporogenes using a new integration method, and the strain was disabled for safety and containment by making it a uracil auxotroph. The efficacy of Clostridium-Directed Enzyme Prodrug Therapy (CDEPT) using this system was demonstrated in a mouse xenograft model of human colon carcinoma. Substantial tumor suppression was achieved, and several animals were cured. These encouraging data suggest that the novel enzyme and strain engineering approach represent a promising platform for the clinical development of CDEPT

Association between Antifungal Prophylaxis and Rate of Documented Bacteremia in Febrile Neutropenic Cancer Patients

Published data have suggested a correlation between antifungal prophylaxis and bacteremia in febrile neutropenia. This correlation was investigated among 3002 febrile neutropenic patients enrolled in 4 trials during 1986-1994. Globally, 1322 patients (44%) did not receive antifungal prophylaxis; 835 (28%) received poorly absorbable antifungal agents and 845 (28%) received absorbable antifungal agents. The rates of bacteremia for these groups were 20%, 26%, and 27%, respectively (P=.0001). In a multivariate model without including antifungal prophylaxis, factors associated with bacteremia were: age, duration of hospitalization, duration of neutropenia before enrollment, underlying disease, presence of an intravenous catheter, shock, antibacterial prophylaxis, temperature, and granulocyte count at onset of fever. When antifungal prophylaxis was included, the adjustment quality of the model improved slightly (P=.05), with an odds ratio of 1.19 (95% confidence interval [CI], 0.92-1.55) for patients receiving nonabsorbable and 1.42 (95% CI, 1.07-1.88) for those who were receiving absorbable antifungal agents. Antifungal prophylaxis with absorbable agents might have an impact on the rate of documented bacteremia in febrile neutropenia. This effect should be confirmed prospectivel

Epidemiology and Outcome of Fungemia in a Cancer Cohort of the Infectious Diseases Group (IDG) of the European Organization for Research and Treatment of Cancer (EORTC 65031)

In a prospective cohort study of 145 030 admissions of cancer patients from 13 European Organisation for Research and Treatment of Cancer centers fungemia occurred in 0.23%. Candida albicans was the predominant pathogen. Fungemia was associated with substantial mortality. Antifungal prophylaxis and remission of cancer predicted better surviva

Recommended age groups and frequency of mammography screening : a systematic review

Esta revisão teve por objetivo avaliar a força de evidência do atual indicador de desempenho português relativo ao rastreio do Câncer da Mama através da mamografia, de modo a determinar o grupo etário e a periodicidade recomendadas. Foram pesquisados artigos nas principais bases de dados internacionais de literatura médica. Incluímos artigos publicados entre Janeiro de 2006 e Janeiro de 2012 que correspondiam aos objetivos da revisão. Foi utilizada a taxonomia SORT para a classificação dos resultados. Dos 253 artigos encontrados foram selecionados cinco que cumpriam os critérios de inclusão. Estes incluem três revisões sistemáticas (RS), uma meta-análise (MA) e uma norma de orientação clínica (NOC) baseada numa RS. Os artigos selecionados avaliaram a redução da mortalidade por câncer da mama através do rastreio com mamografia. A realização do rastreio mamográfico entre os 50 e os 69 anos é recomendado em todos os artigos que avaliam esta faixa etária. A NOC recomenda o rastreio bienal. Em suma, a mamografia deverá ser realizada entre os 50 e os 69 anos com uma periodicidade bienal. Estes resultados vão ao encontro do atual indicador de desempenho do rastreio do câncer da mama em Portugal.The scope of this review was to assess the strength of evidence for the current Portuguese performance indicator on breast cancer screening with mammography in order to determine the recommended age group and periodicity for screening. A search for articles was conducted in the main international databases of medical literature. Articles published between January 2006 and January 2012 addressing the objectives of this review were included. The SORT taxonomy was used to classify the results. Of the 253 articles, five articles met the inclusion criteria and were selected for review. These included three systematic reviews, one meta-analysis and one clinical guideline based on a systematic review. A reduction in breast cancer mortality with mamography screening was the outcome in all articles selected. Mammography screening between 50 and 69 years was recommended in all articles that assess this age group. The clinical guidelines recommended screening every two years. In conclusion, the current literature recommends mammography for women every two years between the ages of 50 and 69 years. This is consistent with the current performance indicator for breast cancer screening in Portugal

Low Mannose-Binding Lectin Concentration Is Associated with Severe Infection in Patients with Hematological Cancer Who Are Undergoing Chemotherapy

Background. Mannose-binding lectin (MBL) is a serum lectin involved in innate immune response. Low serum MBL concentration may constitute a risk factor for infection in patients receiving myelosuppressive chemotherapy. Methods. We conducted a prospective, observational study that assessed MBL concentration as a risk factor for infection in patients with hematological malignancy who were hospitalized to undergo at least 1 chemotherapy cycle. MBL deficiency was defined using an algorithm that considered the serum MBL concentration and the MBL genotype. The primary end point was the ratio of duration of febrile neutropenia to the duration of neutropenia. Secondary end points included the incidence of severe infection (e.g., sepsis, pneumonia, bacteremia, and invasive fungal infection). Logistic regression analysis was conducted, and Fisher's exact test was used to analyze binary outcomes, and Kaplan-Meier estimates and log rank tests were used for time-to-event variables. Results. We analyzed 255 patients who received 569 cycles of chemotherapy. The median duration of neutropenia per cycle was 7 days (interquartile range, 0-13 days). Sixty-two patients (24%) were found to have MBL deficiency. Febrile neutropenia occurred at least once in 200 patients. No difference in the primary outcome was seen. The incidence of severe infection was higher among MBL-deficient patients than among non-MBL-deficient patients (1.96 vs. 1.34 cases per 100 days for analysis of all patients [P = .008] and 1.85 vs. 0.94 cases per 100 days excluding patients with acute leukemia [P < .001]). Conclusions. MBL deficiency does not predispose adults with hematological cancer to more-frequent or more-prolonged febrile episodes during myelosuppressive chemotherapy, but MBL-deficient patients have a greater number of severe infections and experience their first severe infection earlier, compared with nondeficient patient

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients

Objectives Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. Methods Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. Results In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of ≤50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. Conclusions Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of ≤35%. Underlying disease-related factors had a major impact on result

Phase I trial combining temozolomide plus lapatinib for the treatment of brain metastases in patients with HER2-positive metastatic breast cancer: the LAPTEM trial

Background Brain metastases (BMs) pose a clinical challenge in breast cancer (BC). Lapatinib or temozolomide showed activity in BM. Our study assessed the combination of both drugs as treatment for patients with HER2-positive BC and BM. Methods Eighteen patients were enrolled, with sixteen of them having recurrent or progressive BM. Any type of previous therapy was allowed, and disease was assessed by gadolinium (Gd)-enhanced magnetic resonance imaging (MRI). The primary end points were the evaluation of the dose-limiting toxicities (DLTs) and the determination of the maximum-tolerated dose (MTD). The secondary end points included objective response rate, clinical benefit and duration of response. Results The lapatinib-temozolomide regimen showed a favorable toxicity profile because the MTD could not be reached. The most common adverse events (AEs) were fatigue, diarrhea and constipation. Disease stabilization was achieved in 10 out of 15 assessable patients. The estimated median survival time for the 16 patients with BM reached 10.94 months (95% CI: 1.09-20.79), whereas the median progression-free survival time was 2.60 months [95% confidence interval (CI): 1.82-3.37]. Conclusions The lapatinib-temozolomide combination is well tolerated. Preliminary evidence of clinical activity was observed in a heavily pretreated population, as indicated by the volumetric reductions occurring in brain lesion

Vancomycin versus Placebo for Treating Persistent Fever in Patients with Neutropenic Cancer Receiving Piperacillin-Tazobactam Monotherapy

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P = .52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P = .75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cance

Risk Assessment in Adult Cancer Patients with Febrile Neutropenia: A Review of Methods and of Risk-adapted Empiric Treatments

Febrile neutropenia is a common complication of antineoplasic chemotherapy. It is a potentially serious event, sometimes lethal. However, it is well recognized that the population of patients with febrile neutropenia is heterogeneous in terms of prognosis. Simplified therapy, for instance oral antibiotic empiric treatment or ambulatory treatment, in comparison to the classical management of intravenously administered empiric antibiotics and in-hospital surveillance, has been the purpose of research for patients predicted at low-risk for serious complications development. However, for such a strategy to be successful an accurate identification of patients at low-risk is required. The objective of the present review is to present the available tools for risk assessment, in adult patients populations and to review the status of our knowledge regarding the efficacy and the safety of risk-adapted therapy

Invasive mechanical ventilation in cancer patients: prior non-invasive ventilation is a poor prognostic factor

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