Donor variation in stored platelets: Higher metabolic rates of platelets are associated with mean platelet volume, activation and donor health.

BACKGROUND: Platelets (PLTs) differ in glycolytic activity, resulting in rapid acidification of 'poor' storing PLT concentrates (PCs) in plasma, or depletion of glucose when stored in PLT additive solution (PAS). We aimed to understand why PLT glycolysis rates vary between donors and how this affects storage performance. STUDY DESIGN AND METHODS: Buffy coats from donors <45, 45-70 and >70 years were selected and single-donor PCs in plasma or PAS-E were prepared. PCs were stored for 8 days at 22 ± 2°C and sampled regularly for analysis. Mitochondrial activity was analyzed with an Oroboros oxygraph. Age groups, or subgroups divided into quartiles based on glucose consumption, were analyzed with ANOVA. RESULTS: In each comparison, PCs of the different groups were not different in volume and cellular composition. PLTs with the highest glucose consumption had a higher initial mean platelet volume (MPV) and developed higher CD62P expression and Annexin A5 binding during storage. Higher glycolytic activity in these PLTs was not a compensation for lower mitochondrial ATP production, because mitochondrial ATP-linked respiration of fresh PLTs correlated positively with MPV (R2  = 0.71). Donors of high glucose-consuming PLTs had more health-related issues. Storage properties of PCs from donors over 70 were not significantly different compared to PCs from donors younger than 45 years. CONCLUSIONS: High glucose-consuming PCs developing higher activation levels, not only displayed enhanced mitochondrial activity but were also found to contain larger PLTs, as determined by MPV. Storage performance of PLTs was found to be associated with donor health, but not with donor age.

Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era.

BACKGROUND: Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy. METHODS: Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified. RESULTS: Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8-19.6) with antitumour therapy and 2.5 months (1.8-3.5) in untreated patients. OS1 was 12.8 months (10.7-15.2) and OS2 6.2 months (5.4-8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients. CONCLUSION: Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients.

Loss of skeletal muscle index and survival in patients with metastatic colorectal cancer: Secondary analysis of the phase 3 CAIRO3 trial.

BACKGROUND: Low skeletal muscle index (SMI) in metastatic colorectal cancer (mCRC) patients is associated with poor outcomes. The prognostic impact of SMI changes during consecutive palliative systemic treatments is unknown. METHODS: This is a retrospective analysis of the phase 3 CAIRO3 study. The CAIRO3 study randomized 557 patients between maintenance capecitabine + bevacizumab (CAP-B) or observation, after six cycles capecitabine + oxaliplatin + bevacizumab (CAPOX-B). Upon first disease progression (PD1), CAPOX-B was reintroduced until second progression (PD2). SMI was assessed by computed tomography (CT) (total 1355 scans). SMI and body mass index (BMI) changes were analyzed for three time-periods; p1: during initial CAPOX-B, p2: randomization to PD1, and p3: PD1 to PD2. The association between absolute and change in SMI and BMI (both per 1 standard deviation) during p1-p3, with PD1, PD2, and survival was studied by Cox regression models. RESULTS: This analysis included 450 of the 557 patients randomized in the CAIRO3 study. Mean SMI decreased during p1: mean -0.6 SMI units [95% CI -1.07;-0.26] and p3: -2.2 units [-2.7;-1.8], whereas during p2, SMI increased + 1.2 units [0.8-1.6]. BMI changes did not reflect changes in SMI. SMI loss during p2 and p3 was significantly associated with shorter survival (HR 1.19 [1.09-1.35]; 1.54 [1.31-1.79], respectively). Sarcopenia at PD1 was significantly associated with early PD2 (HR 1.40 [1.10-1.70]). BMI loss independent of SMI loss was only associated with shorter overall survival during p3 (HR 1.35 [1.14-1.63]). CONCLUSIONS: In mCRC patients, SMI loss during palliative systemic treatment was related with early disease progression and reduced survival. BMI did not reflect changes in SMI and could not identify patients at risk of poor outcome during early treatment lines.

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma.

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.

Prognostic factors for the feasibility of chemotherapy and the Geriatric Prognostic Index (GPI) as risk profile for mortality before chemotherapy in the elderly.

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multidimensional method to detect frailty in elderly patients. Time saving could be accomplished by identifying those individual items that classify elderly cancer patients at risk for feasibility of chemotherapy and for mortality. MATERIAL AND METHODS: Patients older than 70 years of age were assessed before the first chemotherapy administration. GA consisted of the Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). Predictive individual items for feasibility of chemotherapy and mortality were entered in the multivariable logistic regression and Cox-regression models, and a three-item sum scale was constructed: the Geriatric Prognostic Index (GPI). RESULTS: The 494 patients had a median age of 75 years (range 70-92 years). The majority of the patients had malignancies of the digestive tract (41.7%) followed by hematological tumors (22.3%). Three items of the MNA ('psychological distress or acute disease in the past three months', 'neuropsychological problems' and 'using > 3 prescript drugs') independently predicted for feasibility of chemotherapy. Two items of the MNA and one of the GFI ('declining food intake in past 3 months', 'using > 3 prescript drugs', and 'dependence in shopping') independently predicted for mortality. In comparison with patients without any positive item on the three-item GPI, patients with one, two or three positive items had hazard ratios (HRs) of 1.58, 2.32, and 5.58, respectively (all p < 0.001). CONCLUSIONS: With only three items of the MNA, feasibility of chemotherapy can be predicted. The three-item GPI may help to identify elderly cancer patients at elevated risk for mortality.

Prognostic factors for the feasibility of chemotherapy and the Geriatric Prognostic Index (GPI) as risk profile for mortality before chemotherapy in the elderly.

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multidimensional method to detect frailty in elderly patients. Time saving could be accomplished by identifying those individual items that classify elderly cancer patients at risk for feasibility of chemotherapy and for mortality. MATERIAL AND METHODS: Patients older than 70 years of age were assessed before the first chemotherapy administration. GA consisted of the Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). Predictive individual items for feasibility of chemotherapy and mortality were entered in the multivariable logistic regression and Cox-regression models, and a three-item sum scale was constructed: the Geriatric Prognostic Index (GPI). RESULTS: The 494 patients had a median age of 75 years (range 70-92 years). The majority of the patients had malignancies of the digestive tract (41.7%) followed by hematological tumors (22.3%). Three items of the MNA ('psychological distress or acute disease in the past three months', 'neuropsychological problems' and 'using > 3 prescript drugs') independently predicted for feasibility of chemotherapy. Two items of the MNA and one of the GFI ('declining food intake in past 3 months', 'using > 3 prescript drugs', and 'dependence in shopping') independently predicted for mortality. In comparison with patients without any positive item on the three-item GPI, patients with one, two or three positive items had hazard ratios (HRs) of 1.58, 2.32, and 5.58, respectively (all p < 0.001). CONCLUSIONS: With only three items of the MNA, feasibility of chemotherapy can be predicted. The three-item GPI may help to identify elderly cancer patients at elevated risk for mortality.

Prognostic significance of geriatric assessment in combination with laboratory parameters in elderly patients with aggressive non-Hodgkin lymphoma.

The age-adjusted International Prognostic Index (IPI) is an important prognostic factor for patients with non-Hodgkin lymphoma (NHL). We investigated whether a geriatric assessment (GA) is of additional prognostic value in NHL. In this prospective cohort study of 44 patients aged 70 years or older with NHL receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), a GA was administered before the start of chemotherapy. GA was composed of the Mini Nutritional Assessment (MNA), Groningen Frailty Indicator (GFI), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Mini Mental State Examination (MMSE) and levels of albumin, creatinine, lactate dehydrogenase (LDH) and hemoglobin. Multivariate analyses were performed using logistic regression and the Cox regression model. After adjustment for sex, age, comorbidity and univariate laboratory values with p ≤ 0.1, abnormal MNA and GFI scores and low hemoglobin level were associated with not being able to complete the intended chemotherapy: odds ratio (OR) 8.29 (95% confidence interval [CI]: 1.24-55.6; p = 0.03), 9.17 (95% CI: 1.51-55.8; p = 0.02) and 5.41 (95% CI: 0.99-29.8; p = 0.05), respectively. Adjusted for sex, age, comorbidity, age-adjusted IPI and univariate laboratory values with p ≤ 0.1, frailty by GFI and low hemoglobin were associated with worse survival, with a hazard ratio (HR) of mortality of 2.55 (95% CI: 1.07-6.10; p = 0.04) and 4.90 (95% CI: 1.76-13.7; p = 0.002), respectively. We conclude that (risk of) malnutrition, measured with the MNA, frailty, measured with the GFI, and low hemoglobin level had additional predictive value for early treatment withdrawal, and GFI and hemoglobin were, independent of the age-adjusted IPI, predictive for an increased mortality risk.

Evaluation of lecithinized human recombinant super oxide dismutase as cardioprotectant in anthracycline-treated breast cancer patients.

AIM: Anthracycline-induced cardiotoxicity is (partly) mediated by free radical overload. A randomized study was performed in breast cancer patients to investigate whether free radical scavenger super oxide dismutase (SOD) protects against anthracycline-induced cardiotoxicity as measured by changes in echo, electrocardiography and an array of biomarkers. METHOD AND RESULTS: Eighty female, chemotherapy-naïve breast cancer patients (median age 49, range 24-67 years) scheduled for four or five courses of adjuvant 3 weekly doxorubicin plus cyclophosphamide (AC) chemotherapy, were randomly assigned to receive 80 mg PC-SOD (human recombinant SOD bound to lecithin) or placebo, administered intravenously (i.v.) immediately prior to each AC course. The primary end point was protection against cardiac damage evaluated using echocardiography, QT assessments and a set of biochemical markers for myocardial function, oxidative stress and inflammation. Assessments were performed before and during each course of chemotherapy, and at 1, 4 and 9 months after completion of the chemotherapy regimen. In all patients cardiac effects such as increases in NT-proBNP concentration and prolongation of the QTc interval were noticed. There were no differences between the PC-SOD and placebo-treated patients in systolic or diastolic cardiac function or for any other of the biomarkers used to assess the cardiac effects of anthracyclines. CONCLUSION: PC-SOD at a dose of 80 mg i.v. is not cardioprotective in patients with breast carcinoma treated with anthracyclines.

Frailty and malnutrition predictive of mortality risk in older patients with advanced colorectal cancer receiving chemotherapy.

INTRODUCTION: In general, geriatric assessment (GA) provides the combined information on comorbidity and functional, nutritional and psychosocial status and may be predictive for mortality outcome of cancer patients. The impact of geriatric assessment on the outcome of older patients with colorectal cancer treated with chemotherapy is largely unknown. METHODS: In a prospective study, 143 patients with colorectal cancer who were 70years and older were assessed before chemotherapy by Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). RESULTS: Fifty-four (38%) patients received adjuvant chemotherapy and 89 (62%) patients received palliative chemotherapy. Malnutrition and frailty were prevalent in 39 (27%, assessed by MNA) and 34 (24%, by GFI) patients, respectively; whereas cognitive impairment was prevalent in 19 (13%, by IQCODE) and 11 (8%, by MMSE) patients, respectively. In patients with palliative chemotherapy, poor MNA scores were associated with receiving less than 4cycles of chemotherapy (p=0.008). Poor MNA and GFI scores were associated with increased hazard ratios (HR) for mortality for patients with palliative chemotherapy: HR=2.76 (95% confidence interval [CI]: 1.60-4.77; p<0.001) and HR=2.72 (95% CI: 1.58-4.69; p<0.001), respectively, after adjustment for several clinical parameters. CONCLUSIONS: Malnutrition and frailty were strongly associated with an increased mortality risk in patients who underwent palliative chemotherapy. Furthermore, a poor score on MNA was predictive for less tolerance of chemotherapy. Our findings may help the oncologist in future decision making and advice for elderly patients with colorectal cancer.

Dutch women with a low birth weight have an increased risk of myocardial infarction later in life: a case control study.

BACKGROUND: To investigate whether low birth weight increases the risk of myocardial infarction later in life in women. METHODS: Nationwide population-based case-control study. Patients and controls: 152 patients with a first myocardial infarction before the age of 50 years in the Netherlands. 568 control women who had not had a myocardial infarction stratified for age, calendar year of the index event, and area of residence. RESULTS: Birth weight in the patient group was significantly lower than in control women (3214 vs. 3370 gram, mean difference -156.3 gram (95%CI -9.5 to -303.1). The odds ratio for myocardial infarction, associated with a birth weight lower than 3000 gram (20th percentile in controls) compared to higher than 3000 gram was 1.7 (95%CI 1.1-2.7), while the odds ratio for myocardial infarction for children with a low birth weight (< 2000 g) compared to a birth weight >/= 2000 g was 2.4 (95%CI 1.0 - 5.8). Both figures did not change after adjustment for putative confounders (age, education level, body mass index, waist-hip ratio, hypertension, diabetes, hypercholesterolemia, smoking, and family history of cardiovascular disease). CONCLUSIONS: Low birth weight is associated with an increased risk of myocardial infarction before age of 50 in Dutch women.

Hyperhomocysteinemia and risk for peripheral arterial occlusive disease in young women.

OBJECTIVE: Few studies to date have examined the relationship between hyperhomocysteinemia and peripheral arterial occlusive disease (PAOD) in young women. In this study we assessed hyperhomocysteinemia as a risk factor for PAOD in young women. In addition, we evaluated the effect of joint exposure to hyperhomocysteinemia and traditional risk factors. METHODS: Two hundred twenty women, ages 18 to 49 years, with PAOD and 629 healthy women (control group) from a population-based case-control study filled out the same structured questionnaire and donated venous blood samples for determination of plasma homocysteine levels. Hyperhomocysteinemia was defined as nonfasting total plasma homocysteine level above the 90th percentile of the control range. RESULTS: Young women with hyperhomocysteinemia had a 2.5-fold (95% confidence interval [CI], 1.7-3.9) increased risk for PAOD. When presence of hyperhomocysteinemia was combined with presence of a traditional risk factor, relative risk strongly increased in smokers (odds ratio [OR], 18.9; 95% CI, 8.3-42.9) and in women with hypertension (OR, 10.3; 95% CI, 5.4-19.8), hypercholesterolemia (OR, 8.5; 95% CI, 4.2-17.1), and diabetes (OR, 8.9; 95% CI, 1.7-46.9). CONCLUSIONS: Hyperhomocysteinemia is a risk factor for PAOD in young women. There is a strong synergistic effect between hyperhomocysteinemia and all traditional vascular risk factors. Our findings may have implications for risk management in these young women.

Prothrombotic coagulation defects and cardiovascular risk factors in young women with acute myocardial infarction.

We investigated the effect of prothrombotic coagulation defects in combination with smoking and other conventional risk factors on the risk of myocardial infarction in young women. In 217 women with a first myocardial infarction before the age of 50 years and 763 healthy control women from a population-based case-control study, factor V Leiden and prothrombin 20210A status were determined. Data on major cardiovascular risk factors and oral contraceptive use were combined with the presence or absence of these prothrombotic mutations, and compared between patients and controls. The overall odds ratio for myocardial infarction in the presence of a coagulation defect was 1.1 [95% confidence interval (CI) 0.6-1.9]. The combination of a prothrombotic mutation and current smoking increased the risk of myocardial infarction 12-fold (95% CI 5.7-27) compared with non-smokers without a coagulation defect. Among women who smoked cigarettes, factor V Leiden presence versus absence increased the risk of myocardial infarction by 2.0 (95% CI 0.9-4.6), and prothrombin 20210A presence versus absence had an odds ratio of 1.0 (95% CI 0.3-3.5). We conclude that factor V Leiden and prothrombin 20210A do not add substantially to the overall risk of myocardial infarction in young women. However, in women who smoke, the presence of factor V Leiden increased the risk of myocardial infarction twofold.

Functional health and well-being of relatively young women with peripheral arterial disease is decreased but stable after diagnosis.

OBJECTIVE: This study was undertaken to investigate the extent to which health-related quality of life (HQOL) is reduced in young women with peripheral arterial disease (PAD) compared with age-matched and gender-matched control subjects. Moreover, potential determinants of HQOL in young women with PAD were studied, ie, traditional cardiovascular risk factors, location of stenosis and time since diagnosis. METHODS: This was a population-based case-control study. Subjects were 208 young (<50 years) women with PAD diagnosed at angiography and 471 population-based age-matched and gender-matched control subjects. All participants completed the RAND-36 questionnaire, which produces a HQOL profile. The questionnaire contains 36 items that assess 8 domains of HQOL. Each domain is given a mean score ranging from 0 to 100, with higher scores indicative of better quality of life. RESULTS: PAD had a deleterious effect on HQOL in young women. Ability to deal with the physical requirements of daily life was affected, and physical capabilities limited activity to a considerable extent. Mean differences observed for 2 domains, ie, Physical functioning and Role-physical, were -25.1 (95% confidence interval [CI], -28.8,-21.4) and -22.5 (95% CI, -28.9,-16.0). Within the group of young women with PAD, HQOL did not depend on age, smoking, hypercholesterolemia, or education. However, women with hyperglycemia, hypertension, or increased body mass index scored lower on 1 or more domains of RAND-36. Location of stenosis was also related to HQOL; patients with more proximal stenosis scored slightly higher on the domain Physical functioning, compared with women with more distal stenosis. Time (0-10 years) between diagnosis (1990-1999) and when RAND-36 was filled out (2000) is related to score on the Mental health domain; score increases over time. Scores on the other 7 domains of HQOL showed no significant relation to duration of disease. CONCLUSION: Quality of life in young women with PAD was statistically significant diminished for all domains of RAND-36 in comparison with HQOL in healthy age-matched control subjects. HQOL of patients with recently diagnosed PAD is comparable to that of patients in whom the diagnosis was made several years previously. Effective therapy might stabilize, albeit not improve, quality of life in this specific patient population.