George F. Borm

Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer

BACKGROUNDnThe association of isolated tumor cells and micrometastases in regional lymph nodes with the clinical outcome of breast cancer is unclear.nnnMETHODSnWe identified all patients in The Netherlands who underwent a sentinel-node biopsy for breast cancer before 2006 and had breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in the regional lymph nodes. Patients with node-negative disease were randomly selected from the years 2000 and 2001. The primary end point was disease-free survival.nnnRESULTSnWe identified 856 patients with node-negative disease who had not received systemic adjuvant therapy (the node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (the node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (the node-positive, adjuvant-therapy cohort). The median follow-up was 5.1 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95% confidence interval [CI], 1.15 to 1.94); among patients with micrometastases, the adjusted hazard ratio was 1.56 (95% CI, 1.15 to 2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95% CI, 0.45 to 0.73) in the node-positive, adjuvant-therapy cohort, as compared with the node-positive, no-adjuvant-therapy cohort.nnnCONCLUSIONSnIsolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. In patients with isolated tumor cells or micrometastases who received adjuvant therapy, disease-free survival was improved.

Maternal hyperhomocysteinemia: A risk factor for neural-tube defects?

The maternal vitamin status, especially of folate, is involved in the pathogenesis of neural-tube defects (NTDs). Maternal folate administration can prevent these malformations. The precise metabolic mechanism of the beneficial effect of folate is unclear. In this study we focus on homocysteine accumulation, which may derive from abnormalities of metabolism of folate, vitamin B12, and vitamin B6. We studied nonpregnant women, 41 of whom had given birth to infants with NTDs and 50 control women who previously had normal offspring. The determinations included the plasma total homocysteine both in the fasting state and 6 hours after the ingestion of a methionine load. In addition, we measured the fasting blood levels of folate, vitamin B12, and vitamin B6. The mean values for both basal homocysteine and homocysteine following a methionine load were significantly increased in the group of women who previously had infants with NTDs. In nine of these subjects and two controls, the values after methionine ingestion exceeded the mean control by more than 2 standard deviations. Cystathionine synthase levels in skin fibroblasts derived from these methionine-intolerant women were within the normal range. Our findings suggest a disorder in the remethylation of homocysteine to methionine due to an acquired (ie, nutritional) or inherited derangement of folate or vitamin B12 metabolism. Increased homocysteine levels can be normalized by administration of vitamin B6 or folate. Therefore, we suggest that the prevention of NTDs by periconceptional folate administration may effectively correct a mild to moderate hyperhomocysteinemia.

Gender differences in Parkinson's disease

Objective: To investigate gender differences in basic disease characteristics, motor deterioration and nigrostriatal degeneration in Parkinson’s disease (PD). Methods: We studied 253 consecutive PD patients who were not receiving levodopa or dopamine agonists (disease duration ⩽10 years). We investigated the influence of gender and oestrogen status on: (1) age at onset, (2) presenting symptom, (3) severity and progression of motor symptoms (Unified Parkinson’s Disease Rating Scale III (UPDRS-III) scores) and (4) amount and progression of nigrostriatal degeneration ([123I]FP-CIT single photon emission computed tomography measurements). Results: Age at onset was 2.1 years later in women (53.4 years) than in men (51.3 years). In women, age at onset correlated positively with parity, age at menopause and fertile life span. Women more often presented with tremor (67%) than men (48%). Overall, patients presenting with tremor had a 3.6 year higher age at onset and a 38% slower UPDRS-III deterioration. Mean UPDRS-III scores at disease onset were equal for both genders, as was the rate of deterioration. Women had a 16% higher striatal [123I]FP-CIT binding than men at symptom onset and throughout the course of PD. Conclusions: Our results suggest that, in women, the development of symptomatic PD may be delayed by higher physiological striatal dopamine levels, possibly due to the activity of oestrogens. This could explain the epidemiological observations of a lower incidence and higher age at onset in women. Women also presented more often with tremor which, in turn, is associated with milder motor deterioration and striatal degeneration. Taken together, these findings suggest a more benign phenotype in women with PD.

Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss * †

OBJECTIVEnTo establish the prevalence of hyperhomocysteinemia in women with unexplained recurrent early pregnancy loss.nnnDESIGNnIn a patient-control study, the methionine-homocysteine metabolism was investigated by a standardized oral methionine-loading test.nnnSETTINGnGynecologic outpatient department of university hospital.nnnPATIENTSnOne-hundred and two women who had been referred to the hospital because they suffered from at least two consecutive unexplained spontaneous abortions (study group) as well as 41 controls who were recruited by public advertisement were selected.nnnINTERVENTIONSnBlood samples were collected just before and 6 hours after oral methionine administration to determine plasma total homocysteine concentrations.nnnMAIN OUTCOME MEASUREnPlasma total homocysteine concentrations 6 hours after methionine loading. Hyperhomocysteinemia was defined as total homocysteine concentration at 6 hours exceeding the 97.5 percentile level of the controls.nnnRESULTSnHyperhomocysteinemia was diagnosed in 21 women of the study group (21%). In the parous women of the study group, the prevalence of hyperhomocysteinemia was more than two times greater compared with the nulliparous subjects (33% and 14%, respectively).nnnCONCLUSIONnHyperhomocysteinemia is a risk factor in women with unexplained recurrent early pregnancy loss.

The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method

BackgroundThe DerSimonian and Laird approach (DL) is widely used for random effects meta-analysis, but this often results in inappropriate type I error rates. The method described by Hartung, Knapp, Sidik and Jonkman (HKSJ) is known to perform better when trials of similar size are combined. However evidence in realistic situations, where one trial might be much larger than the other trials, is lacking. We aimed to evaluate the relative performance of the DL and HKSJ methods when studies of different sizes are combined and to develop a simple method to convert DL results to HKSJ results.MethodsWe evaluated the performance of the HKSJ versus DL approach in simulated meta-analyses of 2–20 trials with varying sample sizes and between-study heterogeneity, and allowing trials to have various sizes, e.g. 25% of the trials being 10-times larger than the smaller trials. We also compared the number of “positive” (statistically significant at pu2009<u20090.05) findings using empirical data of recent meta-analyses withu2009>u2009= 3 studies of interventions from the Cochrane Database of Systematic Reviews.ResultsThe simulations showed that the HKSJ method consistently resulted in more adequate error rates than the DL method. When the significance level was 5%, the HKSJ error rates at most doubled, whereas for DL they could be over 30%. DL, and, far less so, HKSJ had more inflated error rates when the combined studies had unequal sizes and between-study heterogeneity. The empirical data from 689 meta-analyses showed that 25.1% of the significant findings for the DL method were non-significant with the HKSJ method. DL results can be easily converted into HKSJ results.ConclusionsOur simulations showed that the HKSJ method consistently results in more adequate error rates than the DL method, especially when the number of studies is small, and can easily be applied routinely in meta-analyses. Even with the HKSJ method, extra caution is needed when there areu2009=u2009<5 studies of very unequal sizes.

Breast Cancer Prognosis and Occult Lymph Node Metastases, Isolated Tumor Cells, and Micrometastases

BACKGROUNDnThe prognostic relevance of isolated tumor cells and micrometastases in lymph nodes from patients with breast cancer has become a major issue since the introduction of the sentinel lymph node procedure. We conducted a systematic review of this issue.nnnMETHODSnStudies published from January 1, 1977, until August 11, 2008, were identified by use of MEDLINE, EMBASE, and the Cochrane Library. A total of 58 studies (total number of patients = 297,533) were included and divided into three categories according to the method for pathological assessment of the lymph nodes: cohort studies with single-section pathological examination of axillary lymph nodes (n = 285,638 patients), occult metastases studies with retrospective examination of negative lymph nodes by step sectioning and/or immunohistochemistry (n = 7740 patients), and sentinel lymph node biopsy studies with intensified work-up of the sentinel but not of the nonsentinel lymph nodes (n = 4155 patients). We used random-effects meta-analyses to calculate pooled estimates of the relative risks (RRs) of 5- and 10-year disease recurrence and death and the multivariably corrected pooled hazard ratio (HR) of overall survival of the cohort studies.nnnRESULTSnIn the cohort studies, the presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes was associated with poorer overall survival (pooled HR of death = 1.44, 95% confidence interval [CI] = 1.29 to 1.62). In the occult metastases studies, the presence (vs the absence) of occult metastases was associated with poorer 5-year disease-free survival (pooled RR = 1.55, 95% CI = 1.32 to 1.82) and overall survival (pooled RR = 1.45, 95% CI = 1.11 to 1.88), although these endpoints were not consistently assessed in multivariable analyses. Sentinel lymph node biopsy studies were limited by small patient groups and short follow-up.nnnCONCLUSIONnThe presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes detected on single-section examination was associated with poorer disease-free and overall survival.

Neural tube defects and elevated homocysteine levels in amniotic fluid

OBJECTIVEnOur purpose was to study maternal blood and amniotic fluid concentrations of homocysteine and relevant vitamins in relation to neural tube defects.nnnSTUDY DESIGNnConcentrations of total homocysteine, folate, and vitamins B12 and B6 were measured in maternal blood and amniotic fluid of 27 women carrying a fetus with a neural tube defect and 31 control women carrying a healthy fetus.nnnRESULTSnThe mean total homocysteine concentration in amniotic fluid of the study group was significantly higher than that of the control group. The mean concentrations of total homocysteine in blood and the vitamins folate, B12, and B6 in, respectively, blood and amniotic fluid were not significantly different between the groups. The mean concentrations of homocysteine and vitamin B6 were significantly lower in amniotic fluid than in blood in both groups, whereas vitamin B12 in amniotic fluid was higher than in blood.nnnCONCLUSIONnThese results support the hypothesis that at least the cause of a subset of neural tube defects could reside in a primary or secondary maternal or fetal derangement of homocysteine metabolism.

Conversion from Cyclosporine to Tacrolimus Improves Quality of Life Indices, Renal Graft Function and Cardiovascular Risk Profile

Long‐term use of cyclosporine after renal transplantation results in nephrotoxicity and an increased cardiovascular risk profile. Tacrolimus may be more favorable in this respect. In this randomized controlled study in 124 renal transplant patients, the effects of conversion from cyclosporine to tacrolimus on renal function, cardiovascular risk factors, and perceived side‐effects were investigated after a follow‐up of 2 years. After conversion from cyclosporine to tacrolimus renal function remained stable, whereas continuation of cyclosporine was accompanied by a rise in serum creatinine from 142 ± 48 μmol/L to 157 ± 62 μmol/L (p < 0.05 comparing both groups). Conversion to tacrolimus resulted in a sustained reduction in systolic and diastolic blood pressure, and a sustained improvement in the serum lipid profile, leading to a reduction in the Framingham risk score from 5.7 ± 4.3 to 4.8 ± 5.3 (p < 0.05). Finally, conversion to tacrolimus resulted in decreased scores for occurrence of and distress due to side‐effects. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant patients is beneficial with respect to renal function, cardiovascular risk profile, and side‐effects. Therefore, for most renal transplant patients tacrolimus will be the drug of choice when long‐term treatment with a calcineurin inhibitor is indicated.

Memory and learning strategies in patients with Parkinson's disease

Parkinsons disease patients (PD) do not differ from control subjects (CS) when they have to execute a problem solving task in which external cues for solving the problem are given. However, when PD have to solve a problem by means of an internally generated strategy, they show a serious decrease in performance. We hypothesised that this distinction may also apply to the way PD and CS organize recall. In order to test our hypothesis the California Verbal Learning Test (CVLT) was administered to 59 PD and 30 CS. The test consists of five learning trials using a 16-word target list, composed of four items from each of four semantic categories. The fact that the word list was built on this implicit organization was not divulged in advance. The sequence in which the words were read is fixed; each subsequent word belongs to a category being different from the category to which the preceding word belongs. The organization in recall according to the semantic categories is considered to be the result of an unprompted, internally generated strategy. Recall according to the sequence in which the words are read by the experimenter, is viewed as an externally offered strategy. The results prove to be in line with our hypothesis: unlike CS who appeared to rely mainly and increasingly on an internally generated semantic organization, PD showed evidence of gradually adhering more to the externally imposed serial sequence.

No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial.

Background The objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimers disease (AD). Methodology/Principal Findings This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinicians Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8±7.6), than in the placebo group (9.3±10.0). This difference (1.5 points; CI −4.5–7.5) was not statistically significant, and neither were any of the secondary outcome measures. Conclusions/Significance The results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD. Trial Registration ClinicalTrials.gov NCT00432081