B. L. F. van Eck-Smit

Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: arrest of bone loss?

Objective: To explore the effects of anti-tumour necrosis factor (TNF)α antibody therapy on bone mineral density (BMD) of the lumbar spine and femur neck in patients with rheumatoid arthritis (RA). Methods: A total of 50 patients with active RA (DAS28⩾3.2) who started adalimumab (40 mg subcutaneously/2 weeks) were included in an open label prospective study. All patients used stable methotrexate and were allowed to use prednisone (⩽10 mg/day). The BMD of the lumbar spine and femur neck was measured before and 1 year after start of treatment. Results: Disease activity at baseline (28-joint Disease Activity Score (DAS28)) and disease duration were inversely correlated with femoral neck BMD and lumbar spine BMD (p<0.05). Mean BMD of lumbar spine and femur neck remained unchanged after 1 year of adalimumab therapy (+0.3% and +0.3%, respectively). Of interest, a beneficial effect of prednisone on change in femur neck BMD was observed with a relative increase with prednisone use (+2.5%) compared to no concomitant prednisone use (−0.7%), (pu200a=u200a0.015). Conclusion: In contrast to the progressive bone loss observed after conventional disease-modifying antirheumatic drug therapy, TNF blockade may result in an arrest of general bone loss. Consistent with previous observations, the data also suggest that the net effect of low-dose corticosteroids on BMD in RA may be beneficial, possibly resulting from their anti-inflammatory effects.

Effects of psychotherapy on regional cerebral blood flow during trauma imagery in patients with post-traumatic stress disorder: a randomized clinical trial

BACKGROUNDnFunctional brain-imaging studies in post-traumatic stress disorder (PTSD) have suggested functional alterations in temporal and prefrontal cortical regions. Effects of psychotherapy on these brain regions have not yet been examined.nnnMETHODnTwenty civilian PTSD out-patients and 15 traumatized control subjects were assessed at baseline using psychometric ratings. Cerebral blood flow was measured using trauma script-driven imagery during 99mtechnetium hexamethyl-propylene-amine-oxime single-photon emission computed tomography scanning. All 20 out-patients were randomly assigned to treatment or wait-list conditions. Treatment was brief eclectic psychotherapy (BEP) in 16 weekly individual sessions.nnnRESULTSnAt baseline, greater activation was found in the right insula and right superior/middle frontal gyrus in the PTSD group than in the control group. PTSD patients treated with BEP significantly improved on all PTSD symptom clusters compared to those on the waiting list. After effective psychotherapy, lower activation was measured in the right middle frontal gyrus, compared to the PTSD patients on the waiting list. Treatment effects on PTSD symptoms correlated positively with activation in the left superior temporal gyrus, and superior/middle frontal gyrus.nnnCONCLUSIONSnBEP induced clinical recovery in PTSD patients, and appeared to modulate the functioning of specific PTSD-related sites in the prefrontal cortical regions.

Monocyte migration to the synovium in rheumatoid arthritis patients treated with adalimumab

Objectives The mechanism of action of treatment with tumour necrosis factor (TNF) blockers in rheumatoid arthritis (RA) is still not completely understood. The aim of this study was to test if adalimumab treatment could affect the influx of monocytes into the synovium. Methods A novel technique was used to analyse the migration of labelled autologous monocytes before and 14 days after initiation of adalimumab treatment using scintigraphy. CD14 monocytes were isolated from patients with RA, using a positive selection procedure with magnetic-activated cell sorting, and labelled with technetium-99m-hexamethylpropylene-amino-oxime. Scintigraphic scans were made 1, 2 and 3 h after re-infusion. Results As early as 14 days after the start of treatment with adalimumab a significant decrease in disease activity score evaluated in 28 joints was shown. There was no significant decrease in the influx of monocytes into the joint at this time. Conclusions This study indicates that adalimumab treatment does not reduce the influx of monocytes into the synovium early after initiation of treatment. As previous studies showed a rapid decrease in macrophage infiltration after TNF-antibody therapy, which could not be explained by increased cell death, this points to an important role for enhanced efflux of inflammatory cells from the synovium.

Long-term prognostic value of CFVR and FFR versus perfusion scintigraphy in patients with multivessel disease

ObjectiveIn this multicentre study, we investigated the long-term prognostic value of intracoronary derived haemodynamic parameters compared with the results of myocardial perfusion scintigraphy (MPS).MethodsPatients (n=191) who were referred for angioplasty of a severe lesion in the presence of an intermediate lesion in another coronary artery were included. MPS was performed to determine the presence of reversible perfusion defects in the area of the intermediate lesion. Coronary flow velocity reserve (CFVR), and additionally fractional flow reserve (FFR; n=129), were determined distal to the intermediate lesion; CFVR ≥2.0 and FFR ≥0.75 were considered negative.ResultsIn total 67 events occurred in 49 patients (3 deaths, 9 MI, 9 CABG, 46 PTCA) during a mean of 793 days follow-up. Event-free survival was 63% for MPS, 79% for CFVR, and 79% for FFR if a negative test result was obtained. The relative risk was 1.2 (not significant) for MPS, 2.2 (p=0.001) for CFVR, and 2.4 (p=0.004) for FFR. ConclusionSelective evaluation of an intermediate lesion using CFVR or FFR allows more adequate risk stratification in patients with multivessel disease than MPS. A CFVR <2.0 or a FFR <0.75 was associated with a significant increase of the occurrence of cardiac events during long-term follow-up, predominantly associated with revascularisation. (Neth Heart J 2007;15:369-74.)

Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma - A systematic review

BACKGROUNDnTreatment of differentiated thyroid carcinoma (DTC) often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. As DTC has favorable outcome and the incidence is increasing, concerns have been raised about the possible adverse effects of I-131 therapy. We systematically reviewed the literature to examine the risk of intermediate and long-term adverse effects of I-131 therapy in DTC patients.nnnMETHODSnMultiple electronic databases were searched up to November 2014 for English-language, controlled studies that reported on the risk of salivary gland dysfunction, lacrimal gland dysfunction, gonadal dysfunction, female reproductive outcomes or second primary malignancies (SPM) after I-131 exposure. The certainty of the evidence found was assessed using GRADE.nnnRESULTSnIn total, 37 articles met all inclusion criteria, no studies reporting on adverse effects after I-131 treatment focused solely on children. After exposure to I-131 for DTC, patients experienced significantly more frequently salivary gland dysfunction (prevalence range: 16-54%, moderate-level evidence), lacrimal gland dysfunction (prevalence: 11%, low-level evidence), transient male gonadal dysfunction (prevalence: 35-100%, high-level evidence), transient female gonadal dysfunction (prevalence: 28%, low-level evidence) and SPM (prevalence: 2.7-8.7%, moderate-level evidence) compared to unexposed patients. I-131 therapy seems to have no deleterious effects on female reproductive outcomes (very-low level evidence). The prevalence and severity of adverse effects were correlated to increasing cumulative I-131 activity.nnnCONCLUSIONnTreatment with I-131 for DTC may have significant adverse effects, which seem to be dose dependent. These adverse effects of treatment must be balanced when choosing for I-131 therapy in patients with DTC.

Long-term follow-up of the thyroid gland after treatment with 131I-Metaiodobenzylguanidine in children with neuroblastoma: Importance of continuous surveillance

Thyroid dysfunction has been reported in up to 52% of patients 1.4 years after treatment with 131I‐Metaiodobenzylguanidine (MIBG) in children with neuroblastoma (NBL), despite the use of potassium‐iodide (KI). Our aim was to investigate if the incidence and severity of thyroid damage increases in time.

Is outcome of differentiated thyroid carcinoma influenced by tumor stage at diagnosis

BACKGROUNDnThere is no international consensus on surveillance strategies for differentiated thyroid carcinoma (DTC) after radiotherapy for childhood cancer. Ultrasonography could allow for early detection of DTC, however, its value is yet unclear since the prognosis of DTC is excellent. We addressed the evidence for the question: is outcome of DTC influenced by tumor stage at diagnosis?.nnnMETHODSnA multidisciplinary working group answered the sub-questions: is recurrence or mortality influenced by DTC stage at diagnosis? Does detection of DTC at an early stage contribute to a decline in adverse events of treatment? The literature was systematically reviewed, and conclusions were drawn based on the level of evidence (A: high, B: moderate to low, C: very low).nnnRESULTSnIn children, level C evidence was found that detection of DTC at an early stage is associated with lower recurrence and mortality rates. No evidence was found that it influences morbidity rates. In adults, clear evidence was found that less advanced staged DTC is a favorable prognostic factor for recurrence (level B) and mortality (level A). Additionally, it was found that more extensive surgery increases the risk to develop transient hypoparathyroidism (level A) and that higher doses of radioiodine increases the risk to develop second primary malignancies (level B).nnnCONCLUSIONnIdentification of DTC at an early stage is beneficial for children (very low level evidence) and adults (moderate to high level evidence), even considering that the overall outcome is excellent. These results are an important cornerstone for the development of guidelines for childhood cancer survivors at risk for DTC.

Primary Ovarian Insufficiency in Children After Treatment With 131I-Metaiodobenzylguanidine for Neuroblastoma: Report of the First Two Cases

BACKGROUNDnPrimary ovarian insufficiency (POI) is a noted late effect in childhood cancer survivors treated with alkylating agents or after radiation to a field that includes the ovaries. Gonadal failure in children with neuroblastoma (NBL) who were exposed to 131I- metaiodobenzylguanidine (MIBG) has only been reported in those who were also treated with chemotherapy. In these cases, the cause of gonadal failure was assumed to be the cytotoxic therapy. Here, we present the first two cases of POI after 131I-MIBG treatment only for NBL, indicating that 131I-MIBG treatment may have a causative role.nnnPATIENTSnDuring follow-up after treatment for NBL in childhood, elevated gonadotropins were found in a 12-year-old girl and an 11-year-old girl (FSH values, 105 and 161 U/L, respectively), indicating POI. The first patient had been diagnosed at the age of 17 months with sacrally located (intraspinal) NBL. Treatment consisted of five courses of 131I-MIBG and local resection. The second patient had been diagnosed at the age of 8 months with an abdominal (intraspinal) NBL. She had been treated with acute (neuro) surgery for decompression of her intraspinal tumor causing neurological symptoms, followed by two courses of 131I-MIBG therapy. Both girls had normal karyotypes (46, XX). No other cause for the ovarian failure was found. Estrogen suppletion was started, and patients and parents were counseled regarding fertility options.nnnCONCLUSIONnThese two cases suggest that exposure to 131I-MIBG may damage the female gonads. Clinicians caring for childhood cancer survivors should be aware of the risk of POI after 131I-MIBG treatment. Prospective studies are warranted to confirm our observations.

Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma

PurposeTreatment with 131I-MIBG is associated with significant thyroid damage. This study was undertaken to investigate the long-term efficacy of current thyroid prophylaxis, to explore the relationship between thyroid dysfunction and thyroid volume after exposure to 131I-MIBG and to evaluate the possible negative effects of 131I− on the parathyroid glands.MethodsOf 81 long-term surviving patients with neuroblastoma treated with 131I-MIBG during the period 1999–2012, 24 were finally evaluated. Patients received thyroxine (T4), methimazole and potassium iodide as thyroid protection. In all patients (para)thyroid function was evaluated and ultrasound investigation of the (para)thyroid gland(s) was performed. Thyroid dysfunction was defined as a plasma thyrotropin concentration >5.0xa0mU/L (thyrotropin elevation, TE) or as the use of T4 at the time of follow-up. Hyperparathyroidism was defined as a serum calcium concentration above the age-related reference range in combination with an inappropriately high parathyroid hormone level.ResultsAt a median follow-up of 9.0xa0years after 131I-MIBG treatment, thyroid disorders were seen in 12 patients (50xa0%; 9 with TE, 5 with a thyroid nodule and 1 patient was subsequently diagnosed with differentiated thyroid carcinoma). No significant risk factors for the occurrence of thyroid damage could be identified. In 14 of 21 patients (67xa0%) in whom thyroid volume could be determined, the volume was considered small (<−2SD) for age and gender. Patients treated with T4 at the time of follow-up had significantly smaller thyroid volumes for age than patients without T4 treatment (pu2009=u20090.014). None of the patients was diagnosed with hyperparathyroidism.ConclusionThyroid protection during treatment with 131I-MIBG needs attention and must be further improved, as thyroid disorders are still frequently seen despite current thyroid prophylaxis. Reduced thyroid volume in neuroblastoma survivors may be related to previous 131I-MIBG therapy or current T4 treatment. No deleterious effects of 131I-MIBG on the parathyroid glands could be found.

No significant effects of single intravenous, single oral and subchronic oral administration of acetylcholinesterase inhibitors on striatal [123I]FP-CIT binding in rats

Purpose[123I]FP-CIT SPECT is a valuable diagnostic tool to discriminate Lewy body dementia from Alzheimer’s dementia. To date, however, it is uncertain whether the frequently used acetylcholinesterase inhibitors (AChEIs) by demented patients, have an effect on [123I]FP-CIT binding to dopamine transporters (DATs). Earlier animal studies showed a decline of DAT availability after acute intravenous injection of AChEIs. The aim of this study was to investigate effects of single intravenous, single oral and subchronic oral administration of AChEIs on DAT availability in the rat brain as measured by [123I]FP-CIT.MethodsBiodistribution studies were performed in Wistar rats (nu2009=u20095–16 per group). Before [123I]FP-CIT injection, rats were injected intravenously with a single dose of the AChEI rivastigmine (2.5xa0mg/kg body weight) or donepezil (0.5xa0mg/kg), the DAT-blocker methylphenidate (10xa0mg/kg) or saline. A second group was orally treated with a single dose of rivastigmine or donepezil (2.5xa0mg/kg), methylphenidate (10xa0mg/kg) or saline before injection of [123I]FP-CIT. Studies were also performed in rats that were orally treated during 14 consecutive days with either rivastigmine (1xa0mg/kg daily), donepezil (1.5xa0mg/kg daily), methylphenidate (2.5xa0mg/kg) or saline. Brain parts were assayed in a gamma counter, and specific striatum/cerebellum ratios were calculated for the [123I]FP-CIT binding to DATs.ResultsNo significant effects of either single intravenous, single oral or subchronic oral administration of AChEIs on striatal FP-CIT binding could be detected. Single pretreatment with methylphenidate resulted in an expected significantly lower striatal FP-CIT binding.ConclusionWe conclude that in rats, single intravenous and single or subchronic oral administration of the tested AChEIs does not lead to an important alteration of [123I]FP-CIT binding to striatal DATs. Therefore, it is unlikely that these drugs will induce large effects on the interpretation of [123I]FP-CIT SPECT scans in routine clinical studies.