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Operationalization guidance is needed to support health technology assessment (HTA) bodies considering implementing lifecycle HTA (LC-HTA) approaches. The 2022 Health Technology Assessment International (HTAi) Global Policy Forum (GPF) established a Task Force to develop a position paper on LC-HTA. In its first paper, the Task Force established a definition and framework for LC-HTA in order to tailor it to specific decision problems. This second paper focused on the provision of practical operational guidance to implement LC-HTA. Detailed descriptions of the three LC-HTA operational steps are provided (defining the decision problem, sequencing of HTA activities, and developing optimization criteria) and accompanied by worked examples and an operationalization checklist with 20 different questions for HTA bodies to consider when developing an LC-HTA approach. The questions were designed to be applicable across different types of HTA and scenarios, and require adaptation to local jurisdictions, remits, and context.

Abstract Background: Breast tumors in BRCA1 mutation carriers likely arise from luminal progenitor (LP) cells, previously shown to exhibit aberrant growth properties. Oophorectomy, and possibly tamoxifen, reduce breast cancer risk in BRCA1 carriers, potentially via inhibition of paracrine mediated signaling to stem/progenitor cells. RANKL is a major paracrine effector of progesterone's mitogenic action in mammary epithelium via its receptor RANK, and has a role in ovarian hormone-dependent activation of stem cells. Here we assessed RANK and RANKL expression in breast tumors and normal breast epithelial subtypes from women with mutations of BRCA1 (mBRCA1) or BRCA2 (mBRCA2). Methods: RANK and RANKL expression in breast cancer or normal breast tissue samples with mBRCA1, mBRCA2 or wildtype (WT) BRCA1/2 were analyzed in formalin fixed paraffin embedded (FFPE) sections by IHC. kConFab and The Royal Melbourne Hospital Tissue Bank provided the samples used in this analysis; these samples were obtained with relevant IRB approval. RANK expression on normal breast epithelial cells was measured by flow cytometry. Antibodies against human RANK (N-1H8, N-2B10; Amgen) and RANKL (M366; Amgen) were used in both assays. Incidence of IHC staining was scored as a positive IHC signal of any intensity. The overall expression was generated using the H scoring method which is calculated as the staining intensity of the tumor (0-3) multiplied by the percentage of positively staining cells. Results: Breast tumors from women with mBRCA1 had a higher incidence of RANK expression (68/162; 42%) compared with mBRCA2 (17/113; 15%) or WT (34/314; 11%) and higher overall H score (21.3) compared with mBRCA2 (8.0) or WT (3.4); RANKL expression did not vary greatly between groups: mBRCA1 (13/135; 10%), mBRCA2 (5/114; 4%), WT (23/212; 11%). In normal breast tissue, LP (Lin−EpCAM+CD49f+) and basal/stem cells (Lin−EpCAM−CD49fhi) expressed RANK on their surface. Similar expression patterns were seen in these epithelial subtypes from each BRCA1/2 genotype. Stromal cells (Lin−EpCAM−CD49f−) had minimal RANK expression. Conclusions: RANK expression intensity and incidence scores are both enriched approximately 4-fold in breast tumors from BRCA1 carriers compared with other genotypes. Also, RANK is normally expressed in breast LP cells as well as the basal/stem cell containing population. Ongoing studies will assess functional regulation of LP or mammary stem cell activity by RANKL and determine if the RANKL/RANK signaling pathway affects the aberrant growth characteristics of these cells from BRCA1 mutation carriers. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-03-02.

Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed. Two cohorts of eight patients fulfilling strict eligibility criteria for severe active RA (age median 40 years, range 24-60 years; median disease duration 10.5 years, range 2-18 years) received filgrastim (r-Hu-methionyl granulocyte(G)-CSF) at 5 and 10 microg/kg/day, randomised in a 5:3 ratio with placebo. Patients were unblinded on the fifth day of treatment and those randomised to filgrastim underwent cell harvesting (leukapheresis) daily until 2 x 10(6)/kg CD34+ cells (haemopoietic stem and progenitor cells) were obtained. Patients were assessed by clinical and laboratory parameters before, during and after filgrastim administration. RA flare was defined as an increase of 30% or more in two of the following parameters: tender joint count, swollen joint count or pain score. Efficacy was assessed by quantitation of CD34+ cells and CFU-GM. One patient in the 5 microg/kg/day group and two patients in the 10 microg/kg/day group fulfilled criteria for RA flare, although this did not preclude successful stem cell collection. Median changes in swollen and tender joint counts were not supportive of filgrastim consistently causing exacerbation of disease, but administration of filgrastim at 10 microg/kg/day was associated with rises in median C-reactive protein and median rheumatoid factor compared with placebo. Other adverse events were well recognised for filgrastim and included bone pain (80%) and increases in alkaline phosphatase (four-fold) and lactate dehydrogenase (two-fold). With respect to efficacy, filgrastim at 10 microg/kg/day was more efficient with all patients (n = 5) achieving target CD34+ cell counts with a single leukapheresis (median = 2.8, range = 2.3-4.8 x 10(6)/kg, median CFU-GM = 22.1, range = 4.2-102.9 x 10(4)/kg), whereas 1-3 leukaphereses were necessary to achieve the target yield using 5 microg/kg/day. We conclude that filgrastim may be administered to patients with severe active RA for effective stem cell mobilisation. Flare of RA occurs in a minority of patients and is more likely with 10 than 5 microg/kg/day. However, on balance, 10 microg/kg/day remains the dose of choice in view of more efficient CD34+ cell mobilisation.

To assess the safety and to analyse the cost-effectiveness of home treatment, including cytotoxic chemotherapy, for cancer patients. A restrospective overview of a home oncology nursing service over its first five years (1989-1994), and a detailed cost analysis over 12 months, firstly, by comparing direct costs of chemotherapy administration at home or in the hospital's day treatment ward and, secondly, by assessing the marginal cost of treating home care program patients in the hospital versus the total cost of the home care program. Patients of the Haematology/Oncology Unit of a metropolitan teaching hospital treated either at home by an experienced oncology nurse, or in the hospital day care ward. Patients were offered treatments, including chemotherapy, at home rather than in hospital. Safety, assessed by the rate of major complications (i.e., requiring any patient to be admitted to hospital), and cost-effectiveness, assessed by comparing expenditure in the home and hospital settings. Over five years, there were 5444 home visits to 424 patients, including 1688 chemotherapy administrations to 179 patients. Only two of the 424 patients decided against continuing in the home program once it had begun. There were no major complications. The average cost of home chemotherapy administration (excluding drugs) was $49.91, compared with $116.00 in hospital. The cost of treating patients at home was $5.09 per patient more than the "marginal cost" of treating these patients in the hospital. Home anticancer chemotherapy is a safe and economically realistic alternative to traditional in-hospital treatment. Efforts should be made to overcome budgetary and administrative barriers to more widespread adoption of this model of care.

Journal Article BOOK REVIEWS Get access 2nd Review of Principles of Cancer Biotherapy GEORGE MORSTYN, Ph.D., F.R.A.C.P. GEORGE MORSTYN, Ph.D., F.R.A.C.P. Department of Scientific Affairs Amgen Australia Pty. Ltd.79083 High St., Ste. 17 Kew Victoria 3101, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 19, 7 October 1992, Page 1529, https://doi.org/10.1093/jnci/84.19.1529 Published: 07 October 1992