SOME PHYSICAL AND RADIOBIOLOGICAL PROPERTIES OF IMMUNOLOGICALLY REACTIVE MOUSE SPLEEN CELLS

Three classes of immunologically reactive cells, differing only slightly in size from each other, are required for the production of hemolysin-forming cells in culture. The three classes of cells can be detected in the normal mouse spleen by the combined use of rosette formation, velocity sedimentation, and irradiation. One class of cells (peak sedimentation velocity, 3.2 mm per hr) forms rosettes. The capacity of these cells to participate in immune responses to foreign erythrocytes is inhibited by relatively low doses of irradiation. These cells may be the immediate precursors of hemolysin-forming cells. A second class of cells (peak sedimentation velocity, 3.6 mm per hr) facilitates the production of hemolysin-forming cells by small numbers of normal spleen cells. Their facilitative activity is resistant to a relatively large dose of radiation. They do not form rosettes. The requirement of a third class of cells was deduced from the results of mixing experiments. Neither rosette-forming cells nor spleen cells largely depleted of rosette-forming cells could give rise to hemolysin-forming cells when cultured either alone or in the presence of large numbers of heavily irradiated cells. However, when rosette-forming cells, cells depleted of rosette-forming cells, and heavily irradiated cells were mixed together, hemolysin-forming cells were produced. The peak responses were found in fractions sedimenting at 4 mm per hr. Thus, it is suggested that these fractions contain a third class of cells. This class of cells does not form rosettes, but its function is inhibited by relatively low doses of radiation

RESTRICTION OF THE CAPACITY TO RESPOND TO TWO ANTIGENS BY SINGLE PRECURSORS OF ANTIBODY-PRODUCING CELLS IN CULTURE

Experiments were designed to determine whether or not precursors of antibody-producing cells are restricted in the number of antigens to which they can respond. An in vitro culture system was used, in which the successful production of hemolysin PFC was dependent on the presence of a large number of heavily irradiated spleen cells which did not themselves give rise to PFC, but which supported the production of PFC by a small number of normal spleen cells. All spleen cells were obtained from unimmunized CBA mice. The cells were mixed with either sheep or chicken erythrocytes, or both, cultured for 4 days and analyzed for hemolysin PFC. By reducing the number of unirradiated spleen cells to limiting dilution it was shown that normal spleen cell suspensions contain approximately three times as many precursors capable of responding to chicken erythrocytes as to sheep erythrocytes. In cultures containing both antigens, the number of precursors responding to one antigen was not affected by the presence of the other antigen. In addition, some cultures were positive for PFC-producing hemolysin against chicken erythrocytes, but not against sheep erythrocytes, and vice versa. This pattern of response was independent of the concentration of antigen in the cultures. Thus, the antigen-sensitive precursors for these non-cross-reacting antigens responded independently of each other, indicating that each precursor was restricted in its capacity to respond to more than one antigen prior to stimulation

Evaluating Health-Related Quality of Life in Cancer Clinical Trials: The National Cancer Institute of Canada Clinical Trials Group Experience

AbstractIntroductionThe National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) Quality of Life (QOL) Committee was initiated in 1986.PurposeThe purpose of this review is to describe the evolution of the Committee's work and to highlight key developments such as the formulation of a policy regarding health-related quality-of-life (HRQOL) assessment, the provision of guidelines to ensure completion of HRQOL data within the protocol requirements, the rationale behind the choice of HRQOL instruments, the timing of assessments and the development of data analytic methods. These developments are illustrated with examples from CTG studies.RecommendationsThere is a lack of concordance between conventional toxicity data and HRQOL data and comparative studies designed to elucidate these differences are to be encouraged. Also, more studies are required to compare different analytic strategies and to determine how much missing data is acceptable, particularly in oncology studies where attrition is inevitable

The effects of energy density and heat treatment on the microstructure and mechanical properties of laser additive manufactured Haynes 282

The nickel-based superalloy Haynes 282 is a promising candidate material among the existing batch of aerospace alloys for manufacture via laser powder bed fusion (LPBF). LPBF Haynes 282 has a strong preference for epitaxial grain growth in the (0 0 1) orientation, promoting inhomogeneous grain morphologies and anisotropic mechanical behaviour. In this paper, LPBF Haynes 282 specimens have been extracted from perpendicular and parallel orientations in respect to the primary vertical build direction and studied in their original as-built form and when exposed to a solution and age heat treatment. The effect of alternative energy densities is also considered in the different conditions. Results show that the numerous processing variables discussed in this research have a direct influence on the morphology of the final grain structure. Although a strongly anisotropic microstructure was present in the as-built material in both respective orientations, this behaviour was eradicated following the solution and aging heat treatment through recrystallisation, and the alleviation of local texture and misorientation to help produce a more uniform equiaxed grain morphology. The subsequent mechanical behaviour has been assessed through hardness, tensile and creep stress rupture testing, and results have corroborated the microstructural findings to confirm a more isotropic material was successfully achieved

3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.

BACKGROUND: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment. METHODS: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing. FINDINGS: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1-78·2) for the 3 month group and 77·1% (75·6-78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909-1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group). INTERPRETATION: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care. FUNDING: Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK

Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer

Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19).status: publishe

Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician’s choice: Results from the randomised phase III BEACON trial

Background: Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician’s choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL. Patients and methods: HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m2 every 3 weeks (q3wk)) or single-agent TPC (n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (≥5 points) in HRQoL scores were compared. Results: Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of −9.4 and −10.8 points, respectively. Conclusion: There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression. Study number: NCT01492101