Bone marrow transplantation with T lymphocyte depleted and stem cell enriched bone marrows grafts : experiments in Rhesus monkeys

The major complication after allogeneic bone marrow transplantation is the occurrence of acute GvHD. This complication can be successfully prevented when T lymphocytes are depleted from a bone marrow graft. The beneficial effect of prevention of acute GvHD is counterbalanced by an increased frequency of engraftment failures. In view of this problem several experiments were planned to unravel whether the engraftment failures after T lymphocyte depletion were attributable to the loss of the trophic function of T lymphocytes or were attributable to the loss of the immunosuppressive action of donor Tlymphocytes. When the latter option is valid, more immunosuppression of the recipient would result in sustained engraftment ofT lymphocyte depleted bone marrow grafts. With regard to T lymphocyte depletion, it was attempted to positively select for stem cells and concomitantly negatively select for T lymphocytes. Stem cells are the essential cells in a bone marrow graft since they are responsible for sustained engraftment. A positive selection of these cells would yield an uniform method for preparation of a bone marrow graft rich in stem cells and fully depleted of T lymphocytes. A second approach was to investigate whether depletion of a subpopulation of T lymphocytes (helper/inducer or suppressor/ cytotoxic T lymphocytes) was sufficient to prevent acute GvHD

Evaluation of two strategies to implement physical cancer rehabilitation guidelines for survivors of abdominopelvic cavity tumors:a controlled before-and-after study

PURPOSE: This study evaluates the effectiveness and feasibility of two strategies to implement physical cancer rehabilitation (PCR) guidelines for patients who have survived abdominopelvic cavity malignancies. METHODS: We tested and compared two tailored strategies to implement PCR guidelines for survivors of gastrointestinal, female organ and urogenital organ malignancies, in a clustered controlled before-and-after study. A patient-directed (PD) strategy was tested in five cancer centers, aiming to empower survivors. A multifaceted (MF) strategy was tested in four cancer centers, aiming additionally to influence healthcare professionals and the healthcare organization. Data were collected from existing registration systems, patient questionnaires and professional questionnaires. We measured both implementation- and client outcomes. For insight into the effectiveness we measured indicators related to PCR guidelines: (1) screening with the Distress Thermometer (DT) (=primary outcome measure), (2) information provision concerning physical activity (PA) and physical cancer rehabilitation programs (PCRPs), (3) advice to take part in PA and PCRPs, (4) referral to PCRPs, (5) participation in PCRPs, (6) PA uptake (PAU); and patient reported outcomes (PROs) such as (7) quality of life, (8) fatigue, and (9) empowerment. Furthermore, survivor and center determinants were assessed as possible confounders. Multilevel analyses were performed to compare the scores of the indicators of the PD and MF strategies, as well as the differences between the characteristics of these groups. The use of and experiences with both strategies were measured using questionnaires and Google Analytics to assess feasibility. RESULTS: In total, 1326 survivors participated in the study, 673 in the before- and 653 in the after-measurement. Regarding our primary outcome measure, we found a significant improvement of screening with the DT between the before- and after-measurement for both strategies, respectively from 34.2 to 43.1% (delta=8.9%; odds ratio (OR)=1.6706; p=0.0072) for the PD strategy and from 41.5 to 56.1% (delta=14.6%; OR=1.7098; p=0.0028) for the MF strategy. For both the primary and secondary outcomes, no statistically significant effect of the MF strategy compared to the PD strategy was observed. We found good use of and positive experiences with both strategies. CONCLUSION: Implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT for survivors of abdominopelvic cavity malignancies. Further research is needed to assess the additional effectiveness of strategies that stimulate compliance among healthcare professionals and healthcare organizations. IMPLICATIONS FOR CANCER SURVIVORS: Using implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT and might improve the quality of care of patients who have survived abdominopelvic cavity malignancies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11764-021-01045-3

Study protocol: an evaluation of the effectiveness, experiences and costs of a patient-directed strategy compared with a multi-faceted strategy to implement physical cancer rehabilitation programmes for cancer survivors in a European healthcare system; a controlled before and after study

Background The need for physical cancer rehabilitation programmes (PCRPs), addressing adverse effects from cancer, is growing. Implementing these programmes into daily practice is still a challenge. Since barriers for successful implementation often arise at different levels in healthcare, multi-faceted strategies focusing on multiple levels are likely more effective than single-faceted strategies. Nevertheless, most studies implementing PCRPs used strategies directed at patients only. The aim of this study is to develop and identify the most effective strategy to implement PCRPs into daily care. We want to assess the added value of a multi-faceted strategy compared with a single-faceted patient-directed strategy. Methods/design We will conduct a clustered controlled before and after study (CBA) in the Netherlands that compares two strategies to implement PCRPs. The patient-directed (PD) strategy (five hospitals) will focus on change at the patient level. The multi-faceted (MF) strategy (five hospitals) will focus on change at the patient, professional and organizational levels. Eligibility criteria are as follows: (A) patients: adults; preferably (history of) cancer in the gastro-intestinal, reproductive and/or urological system; successful primary treatment; and without recurrence/metastases. (B) Healthcare professionals: involved in cancer care. A stepwise approach will be followed: Step 1: Analysis of the current implementation of PCRPs and the examination of barriers and facilitators for implementation, via a qualitative study with patients (four focus groups n = 10–12) and their healthcare workers (four focus groups n = 10–12 and individual interviews n = 30–40) and collecting data on adherence to quality indicators (n = 500 patients, 50 per hospital). Step 2: Selection and development of interventions to create a PD and MF strategy during expert roundtable discussions, using the knowledge gained in step 1 and a literature search of the effect of strategies for implementing PCRPs. Step 3: Test and compare both strategies with a clustered CBA (effectiveness, process evaluation and costs), by data extraction from existing registration systems, questionnaires and interviews. For the effectiveness and cost-effectiveness, n = 500 patients, 50 per hospital. For the process evaluation, n = 50 patients, 5 per hospital, and n = 40 healthcare professionals, 4 per hospital. Main outcome measures: % screened patients, % referrals to PCRPs, incremental costs and incremental cost-effectiveness ratios (ICERs)

Preclinical exploration of combining plasmacytoid and myeloid dendritic cell vaccination with BRAF inhibition

Contains fulltext : 171226.pdf (publisher's version ) (Open Access)Background: Melanoma is the most lethal type of skin cancer and its incidence is progressively increasing. The introductions of immunotherapy and targeted therapies have tremendously improved the treatment of melanoma. Selective inhibition of BRAF by vemurafenib results in objective clinical responses in around 50 % of patients suffering from BRAFV600 mutated melanoma. However, drug resistance often results in hampering long-term tumor control. Alternatively, immunotherapy by vaccination with natural dendritic cells (nDCs) demonstrated long-term tumor control in a proportion of patients. We postulate that the rapid tumor debulking by vemurafenib can synergize the long-term tumor control of nDC vaccination to result in an effective treatment modality in a large proportion of patients. Here, we investigated the feasibility of this combination by analyzing the effect of vemurafenib on the functionality of nDCs. Methods: Plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were isolated from PBMCs obtained from buffy coats from healthy volunteers or vemurafenib-treated melanoma patients. Maturation of pDCs, mDCs and immature mono-cyte-derived DCs was induced by R848 in the presence or absence of vemurafenib and analyzed by FACS. Cytokine production and T cell proliferation induced by mature DCs were analyzed. Results: Vemurafenib inhibited maturation and cytokine production of highly purified nDCs of healthy volunteers resulting in diminished allogeneic T cell proliferation. This deleterious effect of vemurafenib on nDC functionality was absent when total PBMCs were exposed to vemurafenib. In patients receiving vemurafenib, nDC functionality and T cell allostimulatory capacity were unaffected. Conclusion: Although vemurafenib inhibited the functionality of purified nDC of healthy volunteers, this effect was not observed when nDCs were matured in the complete PBMC fraction. This might have been caused by increased vemurafenib uptake in absence of other cell types. In accordance, nDCs isolated from patients on active vemurafenib treatment showed no negative effects. In conclusion, our results pave the way for a combinatorial treatment strategy and, we propose that combining vemurafenib with nDC vaccination represent a powerful opportunity that deserves more investigation in the clinic

Symptomatic Skeletal Events and the Use of Bone Health Agents in a Real-World Treated Metastatic Castration Resistant Prostate Cancer Population:Results From the CAPRI-Study in the Netherlands

Background: Patients with metastatic castration resistant prostate cancer (mCRPC) are at risk of symptomatic skeletal events (SSE). Bone health agents (BHA, ie bisphosphonates and denosumab) and new life-prolonging drugs (LPDs) can delay SSEs. The aim of this study is to investigate the use of BHAs in relation to SSEs in treated real-world mCRPC population. Patients and Methods: We included patients from the CAPRI registry who were treated with at least one LPD and diagnosed with bone metastases prior to the start of first LPD (LPD1). Outcomes were SSEs (external beam radiation therapy (EBRT) to the bone, orthopedic surgery, pathologic fracture or spinal cord compression) and SSE-free survival (SSE-FS) since LPD1. Results: One-thousand nine hundred and twenty-three patients were included with a median follow-up from LPD1 of 16.7 months. Fifty-two percent (n = 996) started BHA prior or within 4 weeks after the start of LPD1 (early BHA). In total, 41% experienced at least one SSE. SSE incidence rate was 0.29 per patient year for patients without BHA and 0.27 for patients with early BHA. Median SSE-FS from LPD1 was 12.9 months. SSE-FS was longer in patients who started BHA early versus patients without BHA (13.2 vs. 11.0 months, P =.001). Conclusion: In a real-world population we observed an undertreatment with BHAs, although patients with early BHA use had lower incidence rates of SSEs and longer SSE-FS. This finding was irrespective of type of SSE and presence of risk factors. In addition to LPD treatment, timely initiation of BHAs is recommended in bone metastatic CRPC-patients with both pain and/or opioid use and prior SSE

Response and survival of metastatic melanoma patients treated with immune checkpoint inhibition for recurrent disease on adjuvant dendritic cell vaccination

Vaccination with autologous dendritic cells (DC) loaded ex vivo with melanoma-associated antigens is currently being tested as an adjuvant treatment modality for resected locoregional metastatic (stage III) melanoma. Based on its mechanism of action, DC vaccination might potentiate the clinical efficacy of concurrent or sequential immune checkpoint inhibition (ICI). The purpose of this study was to determine the efficacy of ICI administered following recurrent disease during, or after, adjuvant DC vaccination. To this end, we retrospectively analyzed clinical responses of 51 melanoma patients with either irresectable stage III or stage IV disease treated with first- or second-line ICI following recurrence on adjuvant DC vaccination. Patients were analyzed according to the form of ICI administered: PD-1 inhibition monotherapy (nivolumab or pembrolizumab), ipilimumab monotherapy or combined treatment with ipilimumab and nivolumab. Treatment with first- or second-line PD-1 inhibition monotherapy after recurrence on adjuvant DC vaccination resulted in a response rate of 52%. In patients treated with ipilimumab monotherapy and ipilimumab-nivolumab response rates were 35% and 75%, respectively. In conclusion, ICI is effective in melanoma patients with recurrent disease on adjuvant DC vaccination

Third-line Life-prolonging Drug Treatment in a Real-world Metastatic Castration-resistant Prostate Cancer Population:Results from the Dutch Castration-resistant Prostate Cancer Registry

Third-line life-prolonging drugs (LPDs) might not be appropriate for all metastatic castration-resistant prostate cancer patients. We developed a prognostic model and identified a high-risk subgroup in which no meaningful benefit from third-line LPDs is derived in clinical practice

Being Transparent About Brilliant Failures:An Attempt to Use Real-World Data in a Disease Model for Patients with Castration-Resistant Prostate Cancer

Background: Real-world disease models spanning multiple treatment lines can provide insight into the (cost) effectiveness of treatment sequences in clinical practice. Objective: Our objective was to explore whether a disease model based solely on real-world data (RWD) could be used to estimate the effectiveness of treatments for patients with castration-resistant prostate cancer (CRPC) that could then be suitably used in a cost-effectiveness analysis. Methods: We developed a patient-level simulation model using patient-level data from the Dutch CAPRI registry as input parameters. Time to event (TTE) and overall survival (OS) were estimated with multivariate regression models, and type of event (i.e., next treatment or death) was estimated with multivariate logistic regression models. To test internal validity, TTE and OS from the simulation model were compared with the observed outcomes in the registry. Results: Although patient characteristics and survival outcomes of the simulated data were comparable to those in the observed data (median OS 20.6 vs. 19.8 months, respectively), the disease model was less accurate in estimating differences between treatments (median OS simulated vs. observed population: 18.6 vs. 17.9 [abiraterone acetate plus prednisone], 24.0 vs. 25.0 [enzalutamide], 20.2 vs. 18.7 [docetaxel], and 20.0 vs. 23.8 months [radium-223]). Conclusions: Overall, the disease model accurately approximated the observed data in the total CRPC population. However, the disease model was unable to predict differences in survival between treatments due to unobserved differences. Therefore, the model is not suitable for cost-effectiveness analysis of CRPC treatment. Using a combination of RWD and data from randomised controlled trials to estimate treatment effectiveness may improve the model

Lutetium-177-PSMA-I&T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial

Background: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177Lu-PSMA-I&T in a randomized multicenter setting. Methods & design: This study compares 177Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. Discussion: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177Lu-PSMA-I&T for patients with oHSPC. Trial registration: Clinicaltrials.gov identifier: NCT04443062