Association of Predicted HLA T-Cell Epitope Targets and T-Cell-Mediated Rejection After Kidney Transplantation.

RATIONALE & OBJECTIVE: The relationship between human leukocyte antigen (HLA) molecular mismatches and T-cell-mediated rejection (TCMR) is unknown. We investigated the associations between the different donor HLA-derived T-cell targets and the occurrence of TCMR and borderline histologic changes suggestive of TCMR after kidney transplantation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: All kidney transplant recipients at a single center between 2004 and 2013 with available biopsy data and a DNA sample for high-resolution HLA donor/recipient typing (N = 893). EXPOSURE: Scores calculated by the HLA matching algorithm PIRCHE-II and HLA eplet mismatches. OUTCOME: TCMR, borderline changes suggestive of TCMR, and allograft failure. ANALYTICAL APPROACH: Multivariable cause-specific hazards models were fit to characterize the association between HLA epitopes targets and study outcomes. RESULTS: We found 277 patients developed TCMR, and 134 developed only borderline changes suggestive of TCMR on at least 1 biopsy. In multivariable analyses, only the PIRCHE-II scores for HLA-DRB1 and HLA-DQB1 were independently associated with the occurrence of TCMR and with allograft failure; this was not the case for HLA class I molecules. If restricted to rejection episodes within the first 3 months after transplantation, only the T-cell epitope targets originating from the donor's HLA-DRB1 and HLA-DQB1, but not class I molecules, were associated with the early acute TCMR. Also, the median PIRCHE-II score for HLA class II was statistically different between the patients with TCMR compared to the patients without TCMR (129 [IQR, 60-240] vs 201 [IQR, 96-298], respectively; P < 0.0001). These differences were not observed for class I PIRCHE-II scores. LIMITATIONS: Observational clinical data and residual confounding. CONCLUSIONS: In the absence of HLA-DSA, HLA class II but not class I mismatches are associated with early episodes of acute TCMR and allograft failure. This suggests that current immunosuppressive therapies are largely able to abort the most deleterious HLA class I-directed alloimmune processes; however, alloresponses against HLA-DRB1 and HLA-DQB1 molecular mismatches remain insufficiently suppressed. PLAIN-LANGUAGE SUMMARY: Genetic differences in the human leukocyte antigen (HLA) complex between kidney transplant donors and recipients play a central role in T-cell-mediated rejection (TCMR), which can lead to failure of the transplanted kidney. Evaluating this genetic disparity (mismatch) in the HLA complex at the molecular (epitope) level could contribute to better prediction of the immune response to the donor organ posttransplantation. We investigated the associations of the different donor HLA-derived T-cell epitope targets and scores obtained from virtual crossmatch algorithms with the occurrence of TCMR, borderline TCMR, and graft failure after kidney transplantation after taking into account the influence of donor-specific anti-HLA antibodies. This study illustrates the greater importance of the molecular mismatches in class II molecules compared to class I HLA molecules.

Case Report: An Unusual Course of Angiosarcoma After Lung Transplantation.

A 35-year-old woman underwent bilateral lung transplantation for primary ciliary dyskinesia and developed vascular tumors over a slow time course. Initial presentation of non-specific vascular tumors in the lungs and liver for up to 6 years after transplantation evolved toward bilateral ovarian angiosarcoma. Tumor analysis by haplotyping and human leukocyte antigen typing showed mixed donor chimerism, proving donor origin of the tumoral lesions. In retrospect, the donor became brain dead following neurosurgical complications for a previously biopsy-proven cerebral hemangioma, which is believed to have been a precursor lesion of the vascular malignancy in the recipient. Donor-transmitted tumors should always be suspected in solid organ transplant recipients in case of uncommon disease course or histology, and proper tissue-based diagnosis using sensitive techniques should be pursued.

Autoantibodies and Donor-specific Antibodies are Associated With Graft Dysfunction in Pediatric Liver Transplantation.

OBJECTIVES: Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. METHODS: We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. RESULTS: AAb were detected in 27 (43.3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (P = 0,032) and deceased donor LT (P = 0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (P < 0,001), and an association was found with the presence of nonspecific histologic alterations (P = 0,032) in the absence of de novo autoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (P < 0,001), ALT (P < 0,001), AST (P < 0,001), γ-GT (P = 0,001), IgG (P = 0,011) and lower albumin (P = 0,029). Fourteen out of 50 (28%) patients were DSA-positive, mostly anti-HLA class II. DSA positivity was associated with T-cell-mediated rejection (P = 0,019), higher total (P = 0,033), and direct (P = 0,012) bilirubin and γ-GT (P < 0,001). CONCLUSIONS: The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the causal relationships between AAb and DSA development and outcome parameters post pediatric LT.

The role of HLA-DP mismatches and donor specific HLA-DP antibodies in kidney transplantation: a case series.

BACKGROUND: The impact of HLA-DP mismatches on renal allograft outcome is still poorly understood and is suggested to be less than that of the other HLA loci. The common association of HLA-DP donor-specific antibodies (DSA) with other DSA obviates the evaluation of the actual effect of HLA-DP DSA. METHODS: From a large multicenter data collection, we retrospectively evaluated the significance of HLA-DP DSA on transplant outcome and the immunogenicity of HLA-DP eplet mismatches with respect to the induction of HLA-DP DSA. Furthermore, we evaluated the association between the MFI of HLA-DP antibodies detected in Luminex assays and the outcome of flowcytometric/complement-dependent cytotoxicity (CDC) crossmatches. RESULTS: In patients with isolated pretransplant HLA-DP antibodies (N = 13), 6 experienced antibody-mediated rejection (AMR) and 3 patients lost their graft. In HLAMatchmaker analysis of HLA-DP mismatches (N = 72), HLA-DP DSA developed after cessation of immunosuppression in all cases with 84DEAV (N = 14), in 86% of cases with 85GPM (N = 6/7), in 50% of cases with 56E (N = 6/12) and in 40% of cases with 56A mismatch (N = 2/5). Correlation analysis between isolated HLA-DP DSA MFI and crossmatches (N = 90) showed negative crossmatch results with HLA-DP DSA MFI <2000 (N = 14). Below an MFI of 10,000 CDC crossmatches were also negative (N = 33). Above these MFI values both positive (N = 35) and negative (N = 16) crossmatch results were generated. CONCLUSIONS: Isolated HLA-DP DSA are rare, yet constitute a significant risk for AMR. We identified high-risk eplet mismatches that can lead to HLA-DP DSA formation. We therefore recommend HLA-DP typing to perform HLA-DP DSA analysis before transplantation. HLA-DP DSA with high MFI were not always correlated with positive crossmatch results.

HLA Class II Genotype Does Not Affect the Myelin Responsiveness of Multiple Sclerosis Patients.

BACKGROUND: When aiming to restore myelin tolerance using antigen-specific treatment approaches in MS, the wide variety of myelin-derived antigens towards which immune responses are targeted in multiple sclerosis (MS) patients needs to be taken into account. Uncertainty remains as to whether the myelin reactivity pattern of a specific MS patient can be predicted based upon the human leukocyte antigen (HLA) class II haplotype of the patient. METHODS: In this study, we analyzed the reactivity towards myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP) and proteolipid protein (PLP) peptides using direct interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT). Next, the HLA class II haplotype profile was determined by next-generation sequencing. In doing so, we aimed to evaluate the possible association between the precursor frequency of myelin-reactive T cells and the HLA haplotype. RESULTS: Reactivity towards any of the analyzed peptides could be demonstrated in 65.0% (13/20) of MS patients and in 60.0% (6/10) of healthy controls. At least one of the MS risk alleles HLA-DRB1*15:01, HLA-DQA1*01:02 and HLA-DQB1*06:02 was found in 70.0% (14/20) of patients and in 20.0% (2/10) of healthy controls. No difference in the presence of a myelin-specific response, nor in the frequency of myelin peptide-reactive precursor cells could be detected among carriers and non-carriers of these risk alleles. CONCLUSION: No association between HLA haplotype and myelin reactivity profile was present in our study population. This complicates the development of antigen-specific treatment approaches and implies the need for multi-epitope targeting in an HLA-unrestricted manner to fully address the wide variation in myelin responses and HLA profiles in a heterogeneous group of MS patients.

Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study.

BACKGROUND: In kidney transplantation, evaluating mismatches of HLA eplets-small patches of surface-exposed amino acids of the HLA molecule-instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. METHODS: To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. RESULTS: De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell- or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. CONCLUSIONS: Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA1 and DQB1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.

Assessing the Complex Causes of Kidney Allograft Loss.

BACKGROUND: Although graft loss is a primary endpoint in many studies in kidney transplantation and a broad spectrum of risk factors has been identified, the eventual causes of graft failure in individual cases remain ill studied. METHODS: We performed a single-center cohort study in 1000 renal allograft recipients, transplanted between March 2004 and February 2013. RESULTS: In total, 365 graft losses (36.5%) were identified, of which 211 (57.8%) were due to recipient death with a functioning graft and 154 (42.2%) to graft failure defined as return to dialysis or retransplantation. The main causes of recipient death were malignancy, infections, and cardiovascular disease. The main causes of graft failure were distinct for early failures, where structural issues and primary nonfunction prevailed, compared to later failures with a shift towards chronic injury. In contrast to the main focus of current research efforts, pure alloimmune causes accounted for only 17.5% of graft failures and only 7.4% of overall graft losses, although 72.7% of cases with chronic injury as presumed reason for graft failure had prior rejection episodes, potentially suggesting that alloimmune phenomena contributed to the chronic injury. CONCLUSIONS: In conclusion, this study provides better insight in the eventual causes of graft failure, and their relative contribution, highlighting the weight of nonimmune causes. Future efforts aimed to improve outcome after kidney transplantation should align with the relative weight and expected impact of targeting these causes.

HLA Class II Antibodies at the Time of Kidney Transplantation and Cardiovascular Outcome: A Retrospective Cohort Study.

BACKGROUND: The negative role of HLA class II donor-specific antibody on graft outcome is well recognized. However, the potentially negative cardiovascular effects of preformed HLA class II antibodies and donor HLA in kidney transplant recipients (KTRs) remain unestablished. METHODS: We conducted a single-center, retrospective cohort study including 1115 KTRs (2003-2016) with up to 4449 person-years of follow-up after transplantation and a median follow-up time of 5.1 years (interquartile range, 2.7-7.6). We evaluated the unadjusted and multivariable-adjusted association between pretransplant HLA class I and II antibodies, as well as HLA-DR1 donor/recipient genotype and the primary (major adverse cardiac and cerebrovascular event [MACCE] or all-cause mortality) and secondary (MACCE or cardiovascular mortality) outcome. RESULTS: In a multivariate Cox proportional hazard model, HLA class II antibodies before transplantation were associated with increased adjusted hazard ratio (aHR) for MACCE or all-cause mortality (aHR, 1.71 [1.13-2.60]; P = 0.012) even after adjustment for time-varying covariate graft loss (aHR, 1.68 [1.08-2.62]; P = 0.022) and biopsy-proven acute rejection (aHR, 1.71 [1.13-2.60]; P = 0.012). HLA class II antibodies were also associated with increased aHR for the secondary outcome, MACCE, or cardiovascular mortality (aHR, 1.92 [1.12-3.30]; P = 0.018). We investigated the effect of donor and recipient HLA-DR1 on these outcome parameters and demonstrated that KTRs with HLA-DR1 positive donors had an increased aHR for MACCE with all-cause (aHR, 1.45 [1.09-1.94]; P = 0.012) and cardiovascular mortality (aHR, 1.49 [1.00-2.22]; P = 0.05). CONCLUSIONS: Prior sensitization against HLA class II antigens is associated with unfavorable long-term cardiovascular outcome in KTRs independent of graft loss or rejection. Recipients of an HLA-DR1 donor also have an impaired cardiovascular outcome.

Intragraft donor-specific anti-HLA antibodies in phenotypes of chronic lung allograft dysfunction.

INTRODUCTION: Circulating anti-human leukocyte antigen (HLA) serum donor-specific antibodies (sDSAs) increase the risk of chronic lung allograft dysfunction (CLAD) and mortality. Discrepancies between serological and pathological/clinical findings are common. Therefore, we aimed to assess the presence of tissue-bound graft DSAs (gDSAs) in CLAD explant tissue compared with sDSAs. METHODS: Tissue cores, obtained from explant lungs of unused donors (n=10) and patients with bronchiolitis obliterans syndrome (BOS; n=18) and restrictive allograft syndrome (RAS; n=18), were scanned with micro-computed tomography before elution of antibodies. Total IgG levels were measured via ELISA. Anti-HLA class I and II IgG gDSAs were identified using Luminex single antigen beads and compared with DSAs found in serum samples. RESULTS: Overall, mean fluorescence intensity was higher in RAS eluates compared with BOS and controls (p<0.0001). In BOS, two patients were sDSA+/gDSA+ and two patients were sDSA-/gDSA+. In RAS, four patients were sDSA+/gDSA+, one patient was sDSA+/gDSA- and five patients were sDSA-/gDSA+. Serum and graft results combined, DSAs were more prevalent in RAS compared with BOS (56% versus 22%; p=0.04). There was spatial variability in gDSA detection in one BOS patient and three RAS patients, who were all sDSA-. Total graft IgG levels were higher in RAS than BOS (p<0.0001) and in gDSA+ versus gDSA- (p=0.0008), but not in sDSA+ versus sDSA- (p=0.33). In RAS, total IgG levels correlated with fibrosis (r= -0.39; p=0.02). CONCLUSIONS: This study underlines the potential of gDSA assessment as complementary information to sDSA findings. The relevance and applications of gDSAs need further investigation.

Occurrence of Diabetic Nephropathy After Renal Transplantation Despite Intensive Glycemic Control: An Observational Cohort Study.

OBJECTIVE: The kinetics and risk factors of diabetic nephropathy after kidney transplantation remain unclear. This study investigated the posttransplant occurrence of diabetic nephropathy and the contribution of posttransplant glycemic control. RESEARCH DESIGN AND METHODS: We performed a single-center prospective cohort study of 953 renal allograft recipients and 3,458 protocol-specified renal allograft biopsy specimens up to 5 years after transplantation. The effects of pretransplant diabetes and glycemic control (glycated hemoglobin levels) on the posttransplant histology were studied. RESULTS: Before transplantation, diabetes was present in 164 (17.2%) renal allograft recipients, primarily type 2 (n = 146 [89.0%]). Despite intensive glycemic control (glycated hemoglobin 7.00 ± 1.34% [53 ± 14.6 mmol/mol], 6.90 ± 1.22% [52 ± 13.3 mmol/mol], and 7.10 ± 1.13% [54 ± 12.4 mmol/mol], at 1, 2, and 5 years after transplantation), mesangial matrix expansion reached a cumulative incidence of 47.7% by 5 years in the pretransplant diabetes group versus 27.1% in patients without diabetes, corresponding to a hazard ratio of 1.55 (95% CI 1.07-2.26; P = 0.005). Mesangial matrix expansion was not specific for diabetic nephropathy and associated independently with increasing age. Pretransplant diabetes was associated with posttransplant proteinuria but not with estimated glomerular filtration rate, graft failure, or any other structural changes of the glomerular, vascular, or tubulointerstitial renal compartments. The occurrence of diabetic nephropathy was independent of posttransplant glycated hemoglobin levels. CONCLUSIONS: Mesangial matrix expansion, an early indicator of diabetic nephropathy, can occur rapidly in patients with diabetes before transplantation, despite intensive glycemic control. Prevention of diabetic nephropathy requires more than pursuing low levels of glycated hemoglobin.

Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: Clinical presentation and implications for outcome.

In this cohort study (n = 935 transplantations), we investigated the phenotype and risk of graft failure in patients with histological criteria for antibody-mediated rejection (ABMR) in the absence of circulating donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA), and compared this to patients with definite ABMR and HLA-DSA-positivity. The histological picture did not differ between HLA-DSA-positive (n = 85) and HLA-DSA-negative (n = 123) cases of ABMR histology, apart from increased complement split product 4d (C4d) deposition in the peritubular capillaries in HLA-DSA-positive cases. Histology of ABMR without HLA-DSA was more transient than DSA-positive ABMR, and patients with ABMR histology without HLA-DSA had graft survival superior to that of HLA-DSA-positive patients, independent of concomitant T cell-mediated rejection (38.2%) or borderline changes (17.9%). Multivariate analysis showed that the risk of graft failure was not higher in patients with histological picture of ABMR (ABMRh ) in the absence of HLA-DSA, compared to patients without ABMRh . Despite an association between C4d deposition and HLA-DSA-positivity, using C4d deposition as alternative for the DSA criterion in the diagnosis of ABMR, as proposed in Banff 2017, did not contribute to the prognosis of graft function and graft failure. We concluded that biopsies with ABMRh but without detectable HLA-DSA represent a distinct, often transient phenotype with superior allograft survival.

The clinical significance of epitope mismatch load in kidney transplantation: A multicentre study.

Since the advent of kidney transplantation a key strategy for maximising graft survival by avoiding allorecognition has been to minimise HLA mismatching between donor and recipient. As HLA antibodies are now recognised as being specific for epitopes and donor-recipient HLA mismatch at the amino acid level can now be determined, HLA epitope mismatch load could be a better predictor for dnDSA development than classical HLA antigen mismatch calculation. This hypothesis has been investigated by other studies and the aim of our multicentre study was to confirm this observation in our population. Two algorithms, HLAMatchmaker and PIRCHE-II, were used to determine the HLA epitope mismatch load between donor and recipient. We have shown a significant association between the number of HLA epitope mismatches and the development of dnDSA and we have confirmed the earlier observations.

Epitope analysis of DQ6-reactive antibodies in sera from a DQ6-positive transplant candidate sensitized during pregnancy.

This case report describes DQ6-reactive serum antibody reactivity in a patient who types as DQ6. DNA typing showed DQB1*06:09 on the antibody producer and serum reactivity with DQB1*06:01, *06:02 and *06:03 but not with *06:04 and *06:09. HLAMatchmaker serum analysis showed antibody reactivity with a new antibody-verified 85VA eplet on DQB but additional reactivity with DQB1*02:01 could not be readily interpreted. After applying the nonself-self algorithm of HLA immunogenicity we have identified a new DQB epitope structurally described as 140A2+130R+135D and shared by DQB1*02:01 and DQB1*05:01 and DQB1*06:02 of the immunizer.

Geriatric screening tools are of limited value to predict decline in functional status and quality of life: results of a cohort study.

BACKGROUND: Geriatric screening tools are increasingly implemented in daily practice, especially in the oncology setting, but also in primary care in some countries such as the Netherlands. Nonetheless, validation of these tools regarding their ability to predict relevant outcomes is lacking. In this study we evaluate if geriatric screening tools predict decline in functional status and quality of life after one year, in a population of older cancer patients and an older primary care population without cancer with a life expectancy of at least six months. METHODS: Older cancer patients and a general older primary care population without a history of cancer (≥ 70 years) were included in an on-going prospective cohort study. Data were collected at baseline and after one-year follow-up. Functional decline was based on the Katz Index and Lawton IADL-scale and was defined as deterioration on one or more domains. Decline in quality of life was measured using the global health related subscale of the EORTC QLQ-C30, and was defined as a decline ≥ 10 points. The selected geriatric screening tools were the abbreviated Comprehensive Geriatric Assessment, Groningen Frailty Indicator, Vulnerable Elders Survey-13, and G8. We calculated sensitivity, specificity, predictive values, and odds ratios to assess if normal versus abnormal scores predict functional decline and decline in quality of life. RESULTS: One-year follow-up data were available for 134 older cancer patients and 220 persons without cancer. Abnormal scores of all screening tools were significantly associated with functional decline. However, this was only true for older persons without cancer, and only in univariate analyses. For functional decline, sensitivity ranged from 54% to 71% and specificity from 33% to 66%. For decline in quality of life, sensitivity ranged from 40% to 67% and specificity from 37% to 54%. CONCLUSION: In older persons with a relatively good prognosis, geriatric screening tools are of limited use in identifying persons at risk for decline in functional status or quality of life after one year. Hence, a geriatric screening tool cannot be relied on in isolation, but they do provide very valuable information and may prompt physicians to also consider different aspects of functioning.

Prognostic value of circulating cytokines on overall survival and disease-free survival in cancer patients.

Through their tumor-promoting and/or tumor-suppressive properties, cytokines can influence progression of cancer. We systematically reviewed the current literature on the prognostic value of the circulating cytokines IL-1α/ß, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-ß and IFN-γ to predict overall and disease-free survival in any type of cancer patients. PubMed was systematically searched and based on eligibility assessment using our five criteria of the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) checklist, six unique studies were reviewed. Elevated IL-6 and IL-10 levels seem independently associated with worse prognosis in terms of overall and disease-free survival. The prognostic value of IL-1α/ß, IL-8, IL-12, TNF-α, TGF-ß and IFN-γ could not be demonstrated. The small number of selected studies underlines the need for large well-designed prospective studies, using the REMARK checklist as a guideline, to determine which cytokines have prognostic value on survival in cancer patients.

Study protocol of KLIMOP: a cohort study on the wellbeing of older cancer patients in Belgium and the Netherlands.

BACKGROUND: Cancer is mainly a disease of older patients. In older cancer patients, additional endpoints such as quality of survival and daily functioning might be considered equally relevant as overall or disease free survival. However, these factors have been understudied using prospective designs focussing on older cancer patients. Therefore, this study will focus on the impact of cancer, ageing, and their interaction on the long-term wellbeing of older cancer patients. METHODS/DESIGN: This study is an observational cohort study. We aim to recruit 720 cancer patients above 70 years with a new diagnosis of breast, prostate, lung or gastrointestinal cancer and two control groups: one control group of 720 patients above 70 years without a previous diagnosis of cancer and one control group of 720 cancer patients between 50 - 69 years newly diagnosed with breast, prostate, lung or gastrointestinal cancer. Data collection will take place at inclusion, after six months, after one year and every subsequent year until death or end of the study. Data will be collected through personal interviews (consisting of socio-demographic information, general health information, a comprehensive geriatric assessment, quality of life, health locus of control and a loneliness scale), a handgrip test, assessment of medical records, two buccal swabs and a blood sample from cancer patients (at baseline). As an annex study, caregivers of the participants will be recruited as well. Data collection for caregivers will consist of a self-administered questionnaire examining depression, coping, and burden. DISCUSSION: This extensive data collection will increase insight on how wellbeing of older cancer patients is affected by cancer (diagnosis and treatment), ageing, and their interaction. Results may provide new insights, which might contribute to the improvement of care for older cancer patients.

Rapid parallel synthesis of dipeptide diphenyl phosphonate esters as inhibitors of dipeptidyl peptidases.

In this paper, we present a parallel synthesis of several series of dipeptide diphenyl phosphonates that are known to be irreversible inhibitors of serine proteases. Polymer-assisted solution-phase synthesis (PASP) is used for the rapid and clean coupling between various alpha-aminoalkyl diphenyl phosphonate ester building blocks and commercially available or easily accessible amino acids. These compounds were used for the rapid profiling of dipeptidyl peptidase II (DPP II) and the closely related dipeptidyl peptidase IV (DPP IV). A highly selective DPP II inhibitor was identified, N-cyclopentylglycyl-NHCH(C(6)H(5))PO(OPh)(2) (9.35), that will be useful to discriminate between DPP II and DPP IV in biological systems in order to further elucidate the biological function of DPP II.