Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression

Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification. © 1999 Cancer Research Campaig

Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort

Background Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. Methods This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Results Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Conclusions Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population

Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial.

BACKGROUND: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question. METHODS/DESIGN: The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0-24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %. DISCUSSION: Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (registration number: NCT01408914 ) on 2 August 2011

The Extra Domain A of Fibronectin Increases VEGF-C Expression in Colorectal Carcinoma Involving the PI3K/AKT Signaling Pathway

The extra domain A (EDA)-containing fibronectin (EDA-FN), an alternatively spliced form of the extracellular matrix protein fibronectin, is predominantly expressed in various malignancies but not in normal tissues. In the present study, we investigated the potential pro-lymphangiogenesis effects of extra domain A (EDA)-mediated vascular endothelial growth factor-C (VEGF-C) secretion in colorectal carcinoma (CRC). We detected the expressions of EDA and VEGF-C in 52 human colorectal tumor tissues and their surrounding mucosae by immunohistochemical analysis, and further tested the correlation between the expressions of these two proteins in aforementioned CRC tissues. Both EDA and VEGF-C were abundantly expressed in the specimens of human CRC tissues. And VEGF-C was associated with increased expression of EDA in human CRC according to linear regression analysis. Besides, EDA expression was significantly correlated with lymph node metastasis, tumor differentiation and clinical stage by clinicopathological analysis of tissue microarrays containing tumor tissues of 115 CRC patients. Then, human CRC cell SW480 was transfected with lentivectors to elicit expression of shRNA against EDA (shRNA-EDA), and SW620 was transfected with a lentiviral vector to overexpress EDA (pGC-FU-EDA), respectively. We confirmed that VEGF-C was upregulated in EDA-overexpressed cells, and downregulated in shRNA-EDA cells. Moreover, a PI3K-dependent signaling pathway was found to be involved in EDA-mediated VEGF-C secretion. The in vivo result demonstrated that EDA could promote tumor growth and tumor-induced lymphangiogenesis in mouse xenograft models. Our findings provide evidence that EDA could play a role in tumor-induced lymphangiogenesis via upregulating autocrine secretion of VEGF-C in colorectal cancer, which is associated with the PI3K/Akt-dependent pathway

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours

The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the nontarget topoisomerase. The initial etoposide dose was 15 mg m−2 b.i.d. days (D)1–5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m−2 day−1 with a dose escalation of 0.1, then at 0.05 mg m−2 day−1. Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22–78) years, received a median 8 (2–19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia. There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m−2 b.i.d. D1–5 and 1.8 mg m−2 96 h (total dose) infusional topotecan D8–11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity

The genetic basis and evolution of red blood cell sickling in deer

Crescent-shaped red blood cells, the hallmark of sickle-cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without obvious pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown. Here, we determine the sequences of human β-globin orthologues in 15 deer species and use protein structural modelling to identify a sickling mechanism distinct from the human disease, coordinated by a derived valine (E22V) that is unique to sickling deer. Evidence for long-term maintenance of a trans-species sickling/non-sickling polymorphism suggests that sickling in deer is adaptive. Our results have implications for understanding the ecological regimes and molecular architectures that have promoted convergent evolution of sickling erythrocytes across vertebrates

Emerging Use of Early Health Technology Assessment in Medical Product Development: A Scoping Review of the Literature

Early health technology assessment is increasingly being used to support health economic evidence development during early stages of clinical research. Such early models can be used to inform research and development about the design and management of new medical technologies to mitigate the risks, perceived by industry and the public sector, associated with market access and reimbursement. Over the past 25 years it has been suggested that health economic evaluation in the early stages may benefit the development and diffusion of medical products. Early health technology assessment has been suggested in the context of iterative economic evaluation alongside phase I and II clinical research to inform clinical trial design, market access, and pricing. In addition, performing early health technology assessment was also proposed at an even earlier stage for managing technology portfolios. This scoping review suggests a generally accepted definition of early health technology assessment to be “all methods used to inform industry and other stakeholders about the potential value of new medical products in development, including methods to quantify and manage uncertainty”. The present review also aimed to identify recent published empirical studies employing an early-stage assessment of a medical product. With most included studies carried out to support a market launch, the dominant methodology was early health economic modeling. Further methodological development is required, in particular, by combining systems engineering and health economics to manage uncertainty in medical product portfolios