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PURPOSE: When deliberating palliative cancer treatment, insight into patients' attitudes toward striving for quality of life (QL) and length of life (LL) may facilitate goal-concordant care. We investigated the (1) attitudes of patients with advanced cancer toward striving for QL and/or LL and whether these change over time, and (2) characteristics associated with these attitudes (over time). METHODS: We performed a secondary analysis of a randomized controlled trial on improving shared decision making (SDM), without differentiation between intervention arms. Patients (n = 173) with advanced cancer, a median life expectancy of < 12 months without anticancer treatment, and a median survival benefit of < 6 months from systemic therapy were included in seven Dutch hospitals. We used audio-recorded consultations and surveys at baseline (T0), shortly after the consultation (T2), at 3 and 6 months (T3 and T4). Primary outcomes were patients' attitudes toward striving for QL and LL (Quality Quantity Questionnaire; T2, T3, and T4). RESULTS: Overall, patients' attitudes toward striving for QL became less positive over 6 months ( P < .01); attitudes toward striving for LL did not change on group level. Studying individual patients, 76% showed changes in their attitudes toward striving for QL and/or LL at some point during the study, which occurred in various directions. More helplessness/hopelessness ( P < .001), less fighting spirit ( P < .05), less state anxiety ( P < .001), and more observed SDM ( P < .05) related to more positive attitudes toward striving for QL. Lower education, less helplessness/hopelessness, more fighting spirit, and more state anxiety ( P < .001) related to more positive attitudes toward striving for LL. CONCLUSION: Oncologists may explore patients' attitudes toward striving for QL and LL repeatedly and address patients' coping style and emotions during SDM to facilitate goal-concordant care throughout the last phase of life.

Background Palliative systematic treatment offers uncertain and often limited benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). This trial examined the independent and combined effect of an oncologist training and a patient communication aid on SDM. Methods In this multicenter randomized controlled trial with four parallel arms (2016–2018), oncologists (n = 31) were randomized to receive SDM communication skills training or not. The training consisted of a reader, two group sessions, a booster session, and a consultation room tool (10 hours). Patients (n = 194) with advanced cancer were randomized to receive a patient communication aid or not. The aid consisted of education on SDM, a question prompt list, and a value clarification exercise. The primary outcome was observed SDM as rated by blinded observers from audio‐recorded consultations. Secondary outcomes included patient‐reported SDM, patient and oncologist satisfaction, patients’ decisional conflict, patient quality of life 3 months after consultation, consultation duration, and the decision made. Results The oncologist training had a large positive effect on observed SDM (Cohen's d = 1.12) and on patient‐reported SDM (d = 0.73). The patient communication aid did not improve SDM. The combination of interventions did not add to the effect of training oncologists only. The interventions affected neither patient nor oncologist satisfaction with the consultation nor patients’ decisional conflict, quality of life, consultation duration, or the decision made. Conclusion Training medical oncologists in SDM about palliative systemic treatment improves both observed and patient‐reported SDM. A patient communication aid does not. The incorporation of skills training in (continuing) educational programs for medical oncologists is likely to stimulate the widely advocated uptake of shared decision making in clinical practice. Trial registration. Netherlands Trial Registry NTR 5489. Implications for Practice Treatment for advanced cancer offers uncertain and often small benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). SDM is increasingly advocated for ethical reasons and for its beneficial effect on patient outcomes. Few initiatives to stimulate SDM are evaluated in robust designs. This randomized controlled trial shows that training medical oncologists improves both observed and patient‐reported SDM in clinical encounters (n = 194). A preconsultation communication aid for patients did not add to the effect of training oncologists. SDM training effectively changes oncologists’ practice and should be implemented in (continuing) educational programs., Decisions about treatment for advanced cancer require shared decision making, involving both physician and patient. This trial examined the independent and combined effect of oncologist training and a patient communication aid on shared decision making about palliative chemotherapy.

Background Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. This study examines the effect of shared decision-making (SDM) training for medical oncologists on observed SDM in standardized patient assessments. Materials and Methods A randomized controlled trial comparing training with standard practice was conducted. Medical oncologists and oncologists-in-training (n = 31) participated in a video-recorded, standardized patient assessment at baseline (T0) and after 4 months (T1, after training). The training was based on a four-stage SDM model and consisted of a reader, two group sessions (3.5 hours each), a booster session (1.5 hours), and a consultation card. The primary outcome was observed SDM as assessed with the Observing Patient Involvement scale (OPTION12) coded by observers blinded for arm. Secondary outcomes were observed SDM per stage, communication skills, and oncologists’ satisfaction with communication. Results The training had a significant and large effect on observed SDM in the simulated consultations (Cohen's f = 0.62) and improved observed SDM behavior in all four SDM stages (f = 0.39–0.72). The training improved oncologists’ information provision skills (f = 0.77), skills related to anticipating/responding to emotions (f = 0.42), and their satisfaction with the consultation (f = 0.53). Conclusion Training medical oncologists in SDM about palliative systemic treatment improves their performance in simulated consultations. The next step is to examine the effect of such training on SDM in clinical practice and on patient outcomes. Implications for Practice Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. Hence, applying the premises of shared decision-making (SDM) is recommended. SDM is increasingly advocated based on the ethical imperative to provide patient-centered care and the increasing evidence for beneficial patient outcomes. Few studies examined the effectiveness of SDM training in robust designs. This randomized controlled trial demonstrated that SDM training (10 hours) improves oncologists’ performance in consultations with standardized patients. The next step is to examine the effect of training on oncologists’ performance and patient outcomes in clinical practice.

BACKGROUND: Antibodies produced against the D antigen make use of IGHV genes restricted to the IGHV3 superfamily. These findings are based on the IGHV gene analysis in anti-D–producing B cells from hyperimmunized donors, however, and therefore the restriction might be due to the hyperimmunization. In this study the IGHV gene usage of anti-Rh–producing B cells in a woman who was immunized in the last trimester of her pregnancy was analyzed. STUDY DESIGN AND METHODS: Serologic analysis was performed by absorption and elution. Antibody-dependent cellular cytotoxicity (ADCC) of the different anti-Rh was determined. A phage display library was constructed from 2.2 × 106 isolated B cells and pannings were performed with red cells of the r′r, R1R1, and R2R2 phenotype. RESULTS: A plasma sample of the immunized person showed high levels of both anti-D and anti-G and low levels of anti-C. Anti-D and anti-G contributed equally strong to the ADCC whereas anti-C did not. Eighteen anti-D–, 5 anti-G–, and 1 anti-C–specific phage clones were found, of which 16, 2, and 1 used the IGHV3s genes, respectively. CONCLUSION: For the first time a restriction to the IGHV3s genes in anti-D in a naturally immunized pregnant woman is shown. Moreover, the use of IGHV3s genes appears to be present in anti-C and anti-G as well. Therefore, it is concluded that restricted IGHV3s gene usage in anti-D is not due to hyperimmunization but due to characteristics of the Rh antigens and the intrinsic binding capacities of IGHV3s genes, supporting the common Rh footprint hypothesis.

Summary Healthy volunteers are hyperimmunized with RhD-positive red cells in order to obtain plasma containing high titres of anti-D immunoglobulin, which is used for the prevention of haemolytic disease of the fetus and newborn. We analysed the anti-D immune response in a donor who had been hyperimmunized for 7 years and who showed declining anti-D titres despite re-immunization. A phage display library representing the complete immunorepertoire and a second library representing the IGHV3 superspecies family genes (IGHV3s) repertoire in the donor were constructed and analysed. A clonal Ig-gene rearrangement was quantified in the peripheral blood by limiting dilution polymerase chain reaction (PCR) All RhD-binding phages from both libraries, except one, had heavy chains with IGH–VDJ rearrangements of the same clonal origin, but with different patterns of somatic mutations and joined with different light chains. Limiting dilution PCR performed on mRNA and genomic DNA showed a frequency of 1 clonal B cell in 2000 IgG1/3-positive B cells. We show the presence of clonally related RhD-specific B cells in a hyperimmunized anti-D donor who had declining anti-D titres and who was unresponsive to re-immunization. Furthermore, we found a high frequency of clonal B cells. These results contribute to the understanding of the immune response against RhD in hyperimmunized anti-D donors.

The Ig-genes of the heavy chains in anti-D-specific hybridomas and Fab/scFv-fragments selected from phage-display libraries are restricted to a group of closely related genes (IGHV3s genes). We analyzed the Ig-gene repertoire in anti-D-specific B cells of two hyperimmunized donors using a completely different method. Single B cells were cultured for 10 days in an EL4.B5 culture system. mRNA from anti-D-producing B cells was reverse transcribed into cDNA. Heavy- and light-chain gene rearrangements were amplified by PCR reactions, sequenced and cloned into a pNUT-vector system, thereby allowing the production of complete IgG and IgM. Eleven anti-D-specific B-cell clones were isolated and analyzed. Eight of these clones (including IgM-producing clones) had IGHV3s genes. We demonstrated that functional anti-D-specific IgM (4 clones) and IgG (2 clones) was produced. Using a new method, we analyzed the IGHV gene repertoire of anti-D-specific B cells of hyperimmunized donors and showed that it is indeed restricted. Moreover, we found a high frequency (1:100 and 1:500) of anti-D-specific B cells in the peripheral B cells of hyperimmunized donors. We suggest that this approach could be applied for the selection of human mAbs from immunized donors and for the analysis of Ig-gene repertoires at the single-B cell level. &COPY; 2005 Elsevier B.V. All rights reserved

B cell memory to T cell–dependent (TD) Ags are considered to largely reside in class-switched CD27+ cells. However, we previously observed that anti-RhD (D) Igs cloned from two donors, hyperimmunized with D+ erythrocytes, were predominantly of the IgM isotype. We therefore analyzed in this study the phenotype and frequency of D- and tetanus toxoid–specific B cells by culturing B cells in limiting dilution upon irradiated CD40L-expressing EL4.B5 cells and testing the culture supernatant. Most Ag-specific B cells for both TD Ags were found to reside in the IgM-expressing B cells, including CD27− B cells, in both hyperimmunized donors and nonhyperimmunized volunteers. Only shortly after immunization a sharp increase in Ag-specific CD27+IgG+ B cells was observed. Next, B cells were enriched with D+ erythrocyte ghosts and sorted as single cells. Sequencing of IGHV, IGLV, IGKV, and BCL6 genes from these D-specific B cell clones demonstrated that both CD27−IgM+ and CD27+IgM+ B cells harbored somatic mutations, documenting their Ag-selected nature. Furthermore, sequencing revealed a clonal relationship between the CD27−IgM+, CD27+IgM+, and CD27+IgG+ B cell subsets. These data strongly support the recently described multiple layers of memory B cells to TD Ags in mice, where IgM+ B cells represent a memory reservoir which can re-enter the germinal center and ensure replenishment of class-switched memory CD27+ B cells from Ag-experienced precursors.

ObjectivesThe mechanism of action of treatment with tumour necrosis factor (TNF) blockers in rheumatoid arthritis (RA) is still not completely understood. The aim of this study was to test if adalimumab treatment could affect the influx of monocytes into the synovium.MethodsA novel technique was used to analyse the migration of labelled autologous monocytes before and 14 days after initiation of adalimumab treatment using scintigraphy. CD14 monocytes were isolated from patients with RA, using a positive selection procedure with magnetic-activated cell sorting, and labelled with technetium-99m-hexamethylpropylene-amino-oxime. Scintigraphic scans were made 1, 2 and 3 h after re-infusion.ResultsAs early as 14 days after the start of treatment with adalimumab a significant decrease in disease activity score evaluated in 28 joints was shown. There was no significant decrease in the influx of monocytes into the joint at this time.ConclusionsThis study indicates that adalimumab treatment does not reduce the influx of monocytes into the synovium early after initiation of treatment. As previous studies showed a rapid decrease in macrophage infiltration after TNF-antibody therapy, which could not be explained by increased cell death, this points to an important role for enhanced efflux of inflammatory cells from the synovium.

Rheumatoid arthritis (RA) involves the accumulation of monocyte-derived macrophages in the affected synovial tissue. This process of cell migration could be portrayed scintigraphically to monitor noninvasively the effects of therapy on the progress of the disease. For this purpose, labeling of purified autologous monocytes with Tc-99m-hexamethylpropyleneamine oxime (Tc-99m-HMPAO) at very high specific radioactivity has recently been developed. The aim of this study was to assess the biodistribution and radiation dosimetry of Tc-99m-HMPAO-labeled monocytes in adult patients with RA. Methods: In 8 patients with RA, monocytes were isolated from 100 mL of blood and labeled with Tc-99m-HMPAO to a yield of 10 Bq/cell. Multiple whole-body scans were performed up to 20 h after reinjection of an average of 200 MBq of Tc-99m-HMPAO-labeled monocytes. Urine and blood samples were collected. The fraction of administered activity in 7 source organs was quantified from the attenuation-corrected geometric mean counts in conjugate views. Radiation-absorbed doses were estimated with OLINDA/EXM software. Results: Autologous monocytes labeled with Tc-99m-HMPAO at high intracellular yields showed in vivo kinetics comparable with labeled leukocytes, with initial trapping in the lungs followed by distribution into the liver, spleen, and bone marrow. The radiation-absorbed estimates for 99mTc-HMPAO-labeled monocytes were comparable with those for 99mTc-HMPAO-labeled mixed white blood cells, with an effective dose of 0.011 mSv/MBq. Conclusion: 99mTc-HMPAO-labeled monocytes have biodistribution and radiation dosimetry similar to those of Tc-99m-HMPAO- labeled mixed white blood cells and might therefore be used for in vivo monitoring of immunomodulating therapy in patients with RA

Rheumatoid arthritis of joints involves the accumulation of monocyte-derived macrophages in the affected synovial tissue. This process of cell migration can be portrayed scintigraphically in order to monitor noninvasive effects of therapy on the progress of the disease. Scintigraphic detection of inflammation by means of technetium 99m-hexamethylpropylene amine oxime (99mTc-HMPAO)-labeled leukocytes provides a classic example. Present state-of-the-art methods in cell biology allow the isolation of cells like lymphocytes or monocytes, which are less abundant than main blood constituents but, instead, harbor particular functions like specific homing properties. To facilitate scintigraphic imaging of the cell functions involved, the relatively small population of cells must be labeled to radioactive yields as high as possible. We demonstrate that autologous monocytes isolated from 100 ml of peripheral blood can be radiolabeled to a yield of 10 (instead of 1) Bq per cell, allowing scintigraphic analysis of rheumatoid arthritis up to 20 h post injection of patients. The method is based on the instantaneous distribution of lipophilic 99mTc-HMPAO between the hydrophobic inside of cells and the hydrophilic (aqueous) surrounding of cells, followed by decomposition of the radiopharmaceutical into compounds that are unable to cross the cellular membrane. The procedure provides a method of choice for cell-mediated scintigraphy at low availability of cells with the correct homing properties.