High prevalence of peripheral neuropathy in multiple myeloma patients and the impact of vitamin D levels, a cross-sectional study.

PURPOSE: Peripheral neuropathy (PN) is common in patients with multiple myeloma (MM). We hypothesized that the relationship between hypovitaminosis D and PN described in diabetes mellitus patients may also be present in MM patients. METHODS: To study this potential association, we assessed the incidence of hypovitaminosis D (vitamin D < 75 nmol/L [= 30 ng/mL]) in smouldering and active MM patients in two Dutch hospitals. Furthermore, a validated questionnaire was used to distinguish different PN grades. RESULTS: Of the 120 patients included between January 2017 and August 2018, 84% had an inadequate vitamin D level (median vitamin D level 49.5 nmol/L [IQR 34-65 nmol/L]; mean age: 68 years [SD ± 7.7]; males: 58%). PN was reported by 69% of patients (n = 83); however, of these 83 patients, PN was not documented in the medical records of 52%. An association was found between lower vitamin D levels and higher incidence of PN in the total population (P = 0.035), and in the active MM patients (P = 0.016). CONCLUSION: This multi-centre cohort study showed that PN and hypovitaminosis D are common in MM patients, and addressing low vitamin D levels in the treatment of MM patients might be beneficial in reducing the risk of PN. More attention for PN is warranted, as PN is underreported by clinicians. Further research is needed to fully understand the implications of vitamin D in the development of PN in patients with MM. CLINICAL TRIAL REGISTRATION: Netherland Trial Register NL5835, date of registration July 28, 2016.

Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens.

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

No modification of the beneficial effect of NSAIDs on colorectal cancer by CYP2C9 genotype.

BACKGROUND: CYP2C9 enzymes are involved in non-steroidal anti-inflammatory drug (NSAID) metabolism. Therefore, we investigated whether CYP2C9*2 and *3 variant alleles, encoding for enzymes with lower activity, increased the protective effect of NSAIDs on colorectal cancer. METHODS: Individual and combined associations of NSAIDs and CYP2C9*2 and *3 variant alleles with colorectal cancer were studied in 7757 Caucasian individuals of The Rotterdam Study, a population-based prospective cohort since 1990. Additive and multiplicative effect modification models were used to examine drug-gene interactions. RESULTS: There were 212 incident cases of colorectal cancer during follow-up. A reduced risk of colorectal cancer was observed in individuals who used NSAIDs for more than a year (HR 0.45; 95% CI 0.28 to 0.71), and in carriers of an CYP2C9 variant allele associated with lower enzymatic activity (HR 0.67; 95% CI 0.47 to 0.96). The combination of both determinants was associated with a further risk reduction but without synergy. CONCLUSION: Both NSAID use and CYP2C9*2 and/ or *3 carriage are associated with a reduced risk of colorectal cancer. However, no interaction between the determinants was found, which might indicate independent pathophysiological mechanisms.

Protective effect of NSAIDs on cancer and influence of COX-2 C(-765G) genotype.

PURPOSE: Inhibition of COX-2 enzymes is a frequently suggested mechanism for the beneficial effects of NSAIDs on carcinogenesis. The aim of this study was to explore the role of cumulative NSAID use on four common non-skin related cancers and modification by COX-2 G(-765)C genotype. PATIENTS AND METHODS: 7621 participants of The Rotterdam Study were included. In a mean follow up period of 10 years, 720 colorectal, lung, breast or prostate cancers occurred. Cumulative NSAID use was calculated per NSAID class. Individual associations of NSAID use and COX-2 G(-765)C genotype on cancer risk were explored with Cox' proportional hazard models. Next, the association of NSAIDs and cancer stratified by COX-2 genotype was studied. Finally, the effect of combinations of NSAID use and COX-2 genotype on survival times was investigated. RESULTS: All NSAID classes were associated with a reduced risk of colorectal cancer but not of other cancers. No associations between COX-2 genotype and incident cancer, overall or cancer specific mortality were observed. COX-selective NSAIDs showed modest further risk reduction. Survival times were more than twice as long for carriers of a COX-2 C(-765) allele with colorectal cancer who used NSAIDs in the five years prior to diagnosis than for patients homozygous for the wild type (G(-765)) without NSAID use (p = 0.007). CONCLUSION: Our results confirm the protective effect of NSAID use on colorectal cancer. Individuals diagnosed with colorectal cancer who carry a COX-2 C(-765) allele and are on NSAIDs have an increased survival in comparison to non-users with the wild type (G(-765)).

Estrogen receptor alpha polymorphisms and postmenopausal breast cancer risk.

BACKGROUND: The estrogen receptor alpha (ESR1) is a mediator of estrogen response in the breast. The most studied variants in this gene are the PvuII and XbaI polymorphisms, which have been associated to lower sensitivity to estrogen. We evaluated whether these polymorphisms were associated with breast cancer risk by means of an association study in a population of Caucasian postmenopausal women from the Rotterdam study and a meta-analysis of published data. METHODS: The PvuII and XbaI polymorphisms were genotyped in 3,893 women participants of the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted logistic regression analyses to assess the risk of breast cancer by each of the ESR1 genotypes. Meta-analyses of all publications on these relations were done by retrieving literature from Pubmed and by further checking the reference lists of the articles obtained. RESULTS: There were 38 women with previously diagnosed breast cancer. During follow-up, 152 were additionally diagnosed. The logistic regression analyses showed no difference in risk for postmenopausal breast cancer in carriers of the PvuII or XbaI genotypes neither in overall, incident or prevalent cases. No further evidence of a role of these variants was found in the meta-analysis. CONCLUSIONS: Our results suggest that the ESR1 polymorphisms do not play a role in breast cancer risk in Caucasian postmenopausal women.

Clinical value of gallium-67 SPECT scintigraphy in the diagnostic and therapeutic evaluation of retroperitoneal fibrosis: a prospective study.

BACKGROUND: Gallium-67 (67Ga) scintigraphy may be useful in evaluating patients with retroperitoneal fibrosis (RPF), but a systematic assessment of its value is lacking. OBJECTIVE: Prospective evaluation of the value of 67Ga scintigraphy in assessing active RPF disease and in predicting treatment response. METHODS: Thirty-four patients with nonmalignant RPF treated with tamoxifen underwent 67Ga scintigraphy at baseline and--if baseline gallium scan was positive--at 3 months follow-up. Gallium scans were visually scored according to pathologic 67Ga-uptake compared to normal bone marrow 67Ga-uptake. Results were correlated with other (follow-up) measurements. Value of (follow-up) 67Ga scintigraphy in predicting treatment response was also assessed. RESULTS: Gallium scans were positive in 24 patients (71%). Mass thickness was greater in patients with positive gallium scan compared with patients with negative gallium scan (P = 0.006). Visual gallium score correlated with mass thickness (P = 0.006). Visual gallium score decreased significantly following tamoxifen treatment (P < 0.0001). Decrease in visual gallium score correlated with decreases in C-reactive protein and erythrocyte sedimentation rate (P = 0.019) and with decrease in mass thickness (P < 0.01). Positive predicting value (PPV) of positive baseline gallium scan was 0.71; PPV of negative follow-up gallium scan in patients with initial positive scan was 0.89. 67Ga scintigraphy detected extra-abdominal involvement in one patient and recurrent active disease in two symptomatic patients with normal acute-phase reactants and stable residual mass. CONCLUSION: 67Ga scintigraphy is useful in assessing (recurrent) activity of RPF disease and in evaluating treatment response in patients with initial positive gallium scan.

IGF-1 CA repeat variant and breast cancer risk in postmenopausal women.

IGF-I is an important growth factor for the mammary gland. We evaluated the relationship of the IGF-I CA(n) polymorphism with breast cancer risk in Caucasian postmenopausal women and performed a meta-analysis of published data. The IGF-I CA(n) polymorphism was genotyped in 4091 from the Rotterdam Study. A disease-free survival analysis was performed along with a meta-analysis of all available data on IGF-I CA(n) polymorphism and breast cancer risk. During follow-up 159 women were diagnosed with breast cancer. The disease-free survival analysis adjusted for age at entry, age at menopause, body mass index and waist hip ratio yielded a HR=0.97 (95% CI=0.59-1.58) for CA(19) non-carriers against carriers. The meta-analysis using the random-effects model gave a pooled OR of 1.26 (95% CI=0.95-1.82) for IGF-I CA(19) non-carriers versus CA(19) homozygous carriers. According to these results, the IGF-I CA(19) promoter polymorphism is not likely to predict the risk of breast cancer.

Differential roles of Angiotensinogen and Angiotensin Receptor type 1 polymorphisms in breast cancer risk.

While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1-1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR) = 1.5; 95% CI: 1.1-2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.

Transforming-growth factor beta1 Leu10Pro polymorphism and breast cancer morbidity.

TGF-beta1 has a dual role in carcinogenesis. In this gene, a leucine to proline substitution in codon 10 leads to higher circulating levels of TGF-beta1. This variant has been studied in relationship to the risk for breast cancer yielding contradicting results. We aim to unravel the relationship of this polymorphism and the risk of breast cancer. Women participating in the Rotterdam Study including 143 patients with incident breast cancer were genotyped for this polymorphism. We carried out a logistic regression and a survival analysis using age as the time variable. The logistic regression analysis showed an increased risk of breast cancer for Proline carriers (OR=1.4; 95% confidence interval (CI)=1.1-2.0) versus non-carriers. The survival analysis showed that carriers of the same allele had an increased risk of breast cancer (HR=1.4, 95% CI=1.1-2.0) against non-carriers. Our data suggest that the TGF-beta1 Leu10Pro polymorphism might play a role in breast cancer risk.