Development of a patient decision aid for discharge planning of hospitalized patients with stroke.

BACKGROUND: Patient involvement in discharge planning of patients with stroke can be accomplished by providing personalized outcome information and promoting shared decision-making. The aim of this study was to develop a patient decision aid (PtDA) for discharge planning of hospitalized patients with stroke. METHODS: A convergent mixed methods design was used, starting with needs assessments among patients with stroke and health care professionals (HCPs). Results of these assessments were used to develop the PtDA with integrated outcome information in several co-creation sessions. Subsequently, acceptability and usability were tested to optimize the PtDA. Development was guided by the International Patient Decision Aids Standards (IPDAS) criteria. RESULTS: In total, 74 patients and 111 HCPs participated in this study. A three-component PtDA was developed, consisting of: 1) a printed consultation sheet to introduce the options for discharge destinations, containing information that can be specified for each individual patient; 2) an online information and deliberation tool to support patient education and clarification of patient values, containing an integrated "patients-like-me" model with outcome information about discharge destinations; 3) a summary sheet to support actual decision-making during consultation, containing the patient's values and preferences concerning discharge planning. In the acceptability test, all qualifying and certifying IPDAS criteria were fulfilled. The usability test showed that patients and HCPs highly appreciated the PtDA with integrated outcome information. CONCLUSIONS: The developed PtDA was found acceptable and usable by patients and HCPs and is currently under investigation in a clinical trial to determine its effectiveness.

Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells.

Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC secretome had a significant chemoattractive effect on SH-SY5Y cells as shown by a transwell assay. To evaluate neural maturation, SH-SY5Y cells were first induced toward neuronal cells, after which they were exposed to the hDPSC secretome. In addition, SH-SY5Y cells subjected to the hDPSC secretome showed increased neuritogenesis compared with nonexposed cells. Maturated cells were shown to increase immune reactivity for neuronal markers compared with controls. Ultrastructurally, retinoic acid (RA) signaling and subsequent exposure to the hDPSC secretome induced a gradual rise in metabolic activity and neuronal features such as multivesicular bodies and cytoskeletal elements associated with cellular communication. In addition, electrophysiological recordings of differentiating cells demonstrated a transition toward a neuronal electrophysiological profile based on the maximum tetrodotoxin (TTX)-sensitive, Na+ current. Moreover, conditioned medium (CM)-hDPSC-maturated SH-SY5Y cells developed distinct features including, Cd2+-sensitive currents, which suggests that CM-hDPSC-maturated SH-SY5Y acquired voltage-gated Ca2+ channels. The results reported in this study demonstrate the potential of hDPSCs to support differentiation and recruitment of cells with neuronal precursor characteristics in a paracrine manner. Moreover, this in vitro experimental design showed that the widely used SH-SY5Y cell line can improve and simplify the preclinical in vitro research on the molecular mechanisms of stem cell-mediated neuronal regeneration.

Pro-angiogenic impact of dental stem cells in vitro and in vivo.

Within the field of dental tissue engineering, the establishment of adequate tissue vascularization is one of the most important burdens to overcome. As vascular access within the tooth is restricted by the apical foramen, it is of major importance to implement effective vascularization strategies in order to recreate viable components of teeth and periodontal tissues. However, while the current regenerative approaches focus on the use of dental stem cells (DSCs), little is known about these cells and their ability to promote angiogenesis. Therefore, the present study aimed to elucidate the paracrine angiogenic properties of postnatal DSCs, in particular dental pulp stem cells (DPSCs), stem cells from the apical papilla (SCAPs) and dental follicle precursor cells (FSCs). An antibody array, together with RT-PCR and ELISA, pointed out the differential expression of pro-angiogenic as well as anti-angiogenic factors by cultured DSCs and human gingival fibroblasts (HGF-1). Despite the secretion of proliferation-promoting factors, DSCs caused no notable increase in the proliferation of human microvascular endothelial cells (HMEC-1). With regard to other aspects of the angiogenic cascade, DPSCs, SCAPs and HGF-1 significantly promoted endothelial migration in a transwell migration assay. DPSCs also had a pronounced effect on endothelial tubulogenesis, as was shown by an in vitro Matrigel™ assay. In the last part of this study, a chorioallantoic membrane assay demonstrated a sustained pro-angiogenic impact of DPSCs and SCAPs in an in vivo setting. Collectively, these data indicate a predominant pro-angiogenic influence of DPSCs and SCAPS in vitro and in vivo in comparison to FSCs, suggesting that both stem cell populations could potentially promote the vascularization of regenerated dental tissues.

Effect of isolation methodology on stem cell properties and multilineage differentiation potential of human dental pulp stem cells.

Dental pulp stem cells (DPSCs) are an attractive alternative mesenchymal stem cell (MSC) source because of their isolation simplicity compared with the more invasive methods associated with harvesting other MSC sources. However, the isolation method to be favored for obtaining DPSC cultures remains under discussion. This study compares the stem cell properties and multilineage differentiation potential of DPSCs obtained by the two most widely adapted isolation procedures. DPSCs were isolated either by enzymatic digestion of the pulp tissue (DPSC-EZ) or by the explant method (DPSC-OG), while keeping the culture media constant throughout all experiments and in both isolation methods. Assessment of the stem cell properties of DPSC-EZ and DPSC-OG showed no significant differences between the two groups with regard to proliferation rate and colony formation. Phenotype analysis indicated that DPSC-EZ and DPSC-OG were positive for CD29, CD44, CD90, CD105, CD117 and CD146 expression without any significant differences. The multilineage differentiation potential of both stem cell types was confirmed by using standard immuno(histo/cyto)chemical staining together with an in-depth ultrastructural analysis by means of transmission electron microscopy. Our results indicate that both DPSC-EZ and DPSC-OG could be successfully differentiated into adipogenic, chrondrogenic and osteogenic cell types, although the adipogenic differentiation of both stem cell populations was incomplete. The data suggest that both the enzymatic digestion and outgrowth method can be applied to obtain a suitable autologous DPSC resource for tissue replacement therapies of both bone and cartilage.

Magnetic resonance imaging of human dental pulp stem cells in vitro and in vivo.

Recent advances in stem cell research have shown the promising nature of mesenchymal stem cells as plausible candidates for cell-based regenerative medicine. Many studies reported the use of human dental pulp stem cells (hDPSCs), which possess self-renewal capacity, high proliferation potential, and the ability to undergo multilineage differentiation. Together with this therapeutic approach, development of effective, noninvasive and nontoxic imaging techniques for visualizing and tracking the cells in vivo is crucial for the evaluation and improvement of stem cell therapy. Magnetic resonance imaging (MRI) is one of the most powerful diagnostic imaging techniques currently available for in vivo diagnosis and has been proposed as the most attractive modality for monitoring stem cell migration. The aim of this study was to investigate the labeling efficiency of hDPSCs using superparamagnetic iron oxide (SPIO) particles in order to allow visualization using in vitro and in vivo MRI without influencing cellular metabolism. MRI and transmission electron microscopy (TEM) showed optimal uptake with low SPIO concentrations of 15 µg/ml in combination with 0.75 µg/ml poly-L-lysine (PLL) resulting in more than 13 pg iron/cell and an in vitro detection limit of 50 labeled cells/µl. Very low SPIO concentrations in the culture medium resulted in extremely high labeling efficiency not reported before. For these conditions, tetrazolium salt assays showed no adverse effects on cell viability. Furthermore, in vivo MRI was performed to detect labeled hDPSCs transplanted into the brain of Rag 2-γ C immune-deficient mice. Transplanted cells did not show any signs of tumorgenecity or teratoma formation during the studied time course. We have reported on a labeling and imaging strategy to visualize human dental pulp stem cells in vivo using MRI. These data provide a solid base to allow cell tracking in future regenerative studies in the brain longitudinally.

Retreatment with dose-dense weekly cisplatin after previous cisplatin chemotherapy is not complicated by significant neuro-toxicity.

Cisplatin induces a cumulative dose-dependent axonal sensory neuropathy. With a cumulative dose over 600 mg/m2, a significant percentage of patients will develop a moderate or severe neuropathy. We retreated patients with progressive or recurrent ovarian cancer after previous platinum-containing chemotherapy with weekly 50-70 mg/m2 cisplatin for six cycles. This group was prospectively followed for the development of neuropathy. Patients received six weekly cycles of either 50 or 70 mg/m2 cisplatin, combined with oral etoposide. Responding patients continued treatment with daily oral etoposide for nine months. Neurological toxicity was assessed with a sensory sum score, the sensory neuropathy common toxicity criteria (CTC) and quantitated sensory analysis of the vibration perception threshold (VPT). Neurological assessment was scheduled at baseline, after three cycles, at the end of cisplatin chemotherapy and at 3 monthly intervals until 1 year after the discontinuation of chemotherapy. The first evaluation carried out in the interval of 1-4 months after the end of weekly cisplatin therapy was taken as the principle evaluation for neurotoxicity because during this time interval the nadir of cisplatin neurotoxicity is to be expected. Of 89 patients evaluated for neurological toxicity, 80 patients were fully evaluable. Forty-nine had received prior cisplatin (median cumulative dosage 450 mg/m2); the others had received prior treatment with carboplatin. Cisplatin pretreated patients had slightly higher neuropathy scores at the start of weekly cisplatin. Almost all cisplatin pretreated patients received six cycles of cisplatin, 29 at 50 mg/m2 and 20 at 70 mg/m2 per cycle. Despite treatment up to an overall cumulative dose of 750-900 mg/m2 cisplatin, only 1 patient discontinued treatment due to neurotoxicity. One other patient developed a grade 3 neuropathy during follow-up. Only a marginal increase of neuropathic signs and symptoms were observed in all the other patients. In multiple regression analysis, the increase in VPT or the sensory sum score was not related to prior treatment (cisplatin or carboplatin). Patients with mild signs of neuropathy after prior treatment with cisplatin to a cumulative dose level of 400-450 mg/m2 can be retreated with weekly cisplatin to a cumulative dose of 420 mg/m2 (overall cumulative dose up to 800-900 mg/m2) with only a minimal risk of significant neurotoxicity.

Intramedullary enterogenous cyst presenting with spastic paraparesis during two consecutive pregnancies: a case report.

A 35 year old woman presented with two episodes of spastic paraparesis, occurring in the third trimester of two consecutive pregnancies. The neurological symptoms seemed to be caused by an intramedullary cyst in the thoracic spinal cord. The cyst was subtotally removed and histopathologically diagnosed as enterogenous cyst. Other congenital abnormalities were absent. The peculiar timing of the clinical manifestation of an intramedullary cyst has not been described before. An unequivocal explanation for this phenomenon is missing, but several factors related to pregnancy that may play a part are discussed.

Corticosteroid co-medication does not reduce the incidence and severity of neurotoxicity induced by docetaxel.

Docetaxel is a new antimicrotubule agent that induces a predominantly sensory neuropathy that is mild in most patients. This prospective study was performed to determine if corticosteroid co-medication reduces the incidence and severity of docetaxel-induced neuropathy. Two groups of patients treated with docetaxel in subsequent cohorts were prospectively analyzed for neurotoxicity. Group A consisted of 38 patients with a variety of solid tumors, who were treated in studies before corticosteroid co-medication was recommended, while 49 female patients in group B with metastatic breast cancer were treated after co-medication with corticosteroids was introduced as a routine. Neuropathy was evaluated by a clinical sum-score for symptoms and signs, and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to NCI Common Toxicity Criteria. In 42% of patients of group A and in 65% of patients of group B a mainly mild neuropathy was documented. There was no statistically significant difference in neurotoxicity between group A and B. The cumulative dose of docetaxel showed a significant correlation with post-treatment scores of VPT, sensory sum-score, grade of paresthesias, and grade of neurosensory and neuromotor toxicity. Corticosteroid co-medication does not reduce the development of docetaxel-related neuropathy.

Lhermitte's sign following chemotherapy with docetaxel.

Specific causes for Lhermitte's sign (LS) in cancer patients are spinal cord compression, radiation therapy to the spinal cord, and cisplatin chemotherapy. We observed a transient LS in five of 87 patients treated with more than two cycles of 100 mg/m2 docetaxel (Taxotere). LS developed either concurrently or after the onset of docetaxel-induced sensory neuropathy, and disappeared after the discontinuation or dose reduction of chemotherapy.

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.

PURPOSE: This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects. MATERIALS AND METHODS: Patients who were not pretreated with taxanes or cisplatin derivatives and who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of docetaxel given as a 1-hour infusion followed by cisplatin as a 3-hour infusion (schedule A), or cisplatin followed by docetaxel (schedule B). Docetaxel doses ranged from 55 to 100 mg/m2 and cisplatin doses from 50 to 100 mg/m2. RESULTS: Leukocytopenia and granulocytopenia were common (overall, 90%; grade 3 or 4, 87%), short-lasting, and docetaxel dose-dependent. Infections and neutropenic fever occurred in 10% and 4.5% of courses, respectively. Nonhematologic toxicities were mild to moderate and included alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity, fluid retention, and skin and nail toxicity. There were no significant differences in pharmacokinetic parameters between schedules A and B. Tumor responses included one complete response (CR) and nine partial responses (PRs). CONCLUSION: The dose levels docetaxel 100 mg/m2 plus cisplatin 75 mg/m2 and docetaxel 85 mg/m2 plus cisplatin 100 mg/m2 appeared to be manageable. At these dose levels, the median relative dose-intensity was high and 81% and 88% of all cycles, respectively, could be given at full dose. Schedule A is advocated for further treatment.

Clinical characteristics of severe peripheral neuropathy induced by docetaxel (Taxotere).

BACKGROUND: Docetaxel, a semi-synthetic taxane may cause a usually mild sensory neuropathy. We describe the clinical characteristics of five patients who developed a more severe neuropathy following treatment with docetaxel. PATIENTS AND METHODS: All patients were treated in phase II studies with 100 mg/m2 docetaxel in three weekly cycles, without steroid administration. RESULTS: The clinical picture in these patients was dominated by a sensory neuropathy, but in one case severe weakness was present. Another patient developed Lhermitte's sign. Signs and symptoms are usually reversible after discontinuation of docetaxel administration, but in three patients symptoms worsened for some time after the end of treatment before improvement occurred. CONCLUSION: Severe docetaxel neuropathy may especially occur following treatment with cumulative dosage over 600 mg/m2; in patients treated with this dosage a moderate or severe neuropathy may not be rare.

Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses.

Chemotherapy-induced peripheral neuropathy.

Peripheral neurotoxicity is an important side-effect of several chemotherapeutic agents. These agents may cause a usually axonal neuropathy, which may ultimately lead to severe and disabling symptoms and signs. We describe in this review the pathogenesis, clinical presentation, neurophysiologic findings, nerve biopsies and the relation between cumulative dosage/dosage per cycle and neuropathy for the cytostatic drugs for which neurotoxicity is an important side-effect: cisplatin, vincristine, paclitaxel, docetaxel and suramin. With the development of strategies to circumvent toxicities of other organs and with the use of combinations of neurotoxic agents such as cisplatin/paclitaxel, neurotoxicity is an important and dose-limiting side-effect of many treatment regimens. Detailed knowledge of the neurologic side-effects of these drugs is essential for the management of their neurotoxicity. The review concludes with a short discussion of neuroprotective agents. Although several nerve growth factors, gluthatione and ethiofos hold promise as possible neuroprotective factors, the clinical data on these drugs are still limited. New trials are needed to confirm the value of these drugs. If neurotoxicity could indeed be prevented or delayed, this may lead to more effective treatment regimens.

Peripheral neurotoxicity induced by docetaxel.

Docetaxel, a new semisynthetic taxoid used as an antineoplastic agent, induced a predominantly sensory neuropathy in 20 of 41 patients. We assessed neurotoxicity in all patients participating in four phase II trials conducted in our institution. The neuropathy was evaluated by a clinical sum-score for symptoms and signs and by measurement of the Vibration Perception Threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's Common Toxicity Criteria. Neuropathic symptoms were mild in most patients. However, at cumulative doses above 600 mg/m2, 3 of 15 patients developed a moderate and 1 of 15 patients a severe neuropathy. There was a significant correlation between the cumulative dose of docetaxel and the post-treatment sum-score (p = 0.002). We found no correlation between post-treatment VPT and clinical sum-score or between post-treatment VPT and the cumulative dose of docetaxel. We conclude that docetaxel produced a mild and predominantly sensory neuropathy in a high proportion of treated patients. This neurotoxicity appeared to be dose dependent and may be severe and disabling at higher dose levels. Determination of the VPT is not a reliable method to monitor docetaxel-induced neuropathy.

Non-convulsive status epilepticus as cause for focal neurological deficit.

In a four-and-a-half year period, 19 patients with focal neurological deficits accompanied by a focal electrographic status epilepticus were encountered. Sixteen of these patients showed clouding of consciousness or confusion. Computed tomography of the brain revealed focal lesions in 15 patients. In 7 patients the lesions were the result of a recent cerebral event and in 8 patients they were long-standing. All patients were treated with anti-epileptic drugs. Ten of the 12 patients without an acute lesion showed a complete recovery in a few days. In these patients the symptoms may have been caused by the continuous seizure activity, classifying them as cases of non-convulsive focal status epilepticus. Only 2 of the 7 patients with an acute lesion had a full recovery. In patients with an acute lesion the part played by the electrographic status epilepticus in the acquired deficits is unclear. Continuous or frequent intermittent focal epileptic discharges on the EEG may warrant treatment with anti-epileptic drugs in patients with focal neurological deficits, even when one of the hallmarks of epilepsy, clonic movements, is absent.

Effect of an ACTH(4-9) analogue on cisplatin neuropathy of longstanding duration: a phase II study.

The efficacy of Org 2766, an ACTH(4-9) analogue, on the recovery of cisplatin neuropathy of longstanding duration was investigated in a phase II study. Twenty-two patients were treated with Org 2766 during a period of 4 months and vibration perception threshold (VPT) and sum scores for neuropathic symptoms and signs were compared with pre-treatment values. No change in VPT could be detected. Although there was a small improvement of clinical measures for neuropathy, no clear evidence for repair could be obtained. These results indicate no beneficial effect of Org 2766 on recovery of a longstanding cisplatin neuropathy.

Normal pressure hydrocephalus associated with rheumatoid arthritis responding to prednisone.

We describe 2 patients with longstanding rheumatoid arthritis (RA) complicated by normal pressure hydrocephalus. After treatment with prednisone, both patients improved remarkably with respect to mental status, urinary control, and gait. We suggest that normal pressure hydrocephalus may occur as an extraarticular manifestation of RA, and studies are warranted to confirm a beneficial response to prednisone.

Neurotoxicity is not enhanced by increased dose intensities of cisplatin administration.

It is uncertain whether intensive dosing schedules of cisplatin, intended to attain a higher anti-tumour efficacy, alter the severity of cisplatin-induced neuropathy. We assessed the development of neuropathy in three groups of patients treated with cisplatin in different dosing schedules. The severity of neuropathy was determined by measurement of the vibration perception threshold (VPT) before treatment and during follow-up for 2-12 months after the last cycle. 66 patients were treated with an intensive weekly regimen of doses varying from 70 to 85 mg/m2 in 1 day (trial A), 21 patients with a 3-weekly combination chemotherapy containing cisplatin 75 mg/m2 in 1 day (trial B) and 20 patients with a 3-weekly regimen containing cisplatin 20 mg/m2 for 5 consecutive days (trial C). The mean dose intensity achieved was 59 mg/m2/week in trial A, 21 mg/m2/week in trial B and 33 mg/m2/week in trial C. The maximum post-treatment VPT correlated significantly with pretreatment VPT (P < 0.001) and with the cumulative dose of cisplatin (P < 0.001). Following correction for these two variables, the maximum posttreatment VPT did not show a statistically significant association with dose intensity. These results suggest that neuropathy is not related to dose intensity of cisplatin. This implies that treatment with more intensive dosing schedules, employing equal cumulative doses of cisplatin, does not result in a concomitant increase in neurotoxicity within a cumulative dose range of 280-675 mg/m2.

Clinical course and risk factors of neurotoxicity following cisplatin in an intensive dosing schedule.

An intensive weekly regimen of cisplatin was administered to 66 patients with solid cancer in doses varying from 70 to 85 mg/m(2) . The occurrence of sensory neuropathy was prospectively examined by assessment of neuropathic signs and symptoms and measurement of vibration perception threshold (VPT). Evaluation was performed before initiation of therapy and during follow-up until 3-12 months after the last cycle of cisplatin. A mild or moderate neuropathy developed in 47% of patients at 2 weeks after treatment This neuropathy continued to deteriorate until approximately 3 months after cessation of chemotherapy leading to a mild or moderate neuropathy in 71% of patients and a severe neuropathy in 9% of patients. Thereafter we observed a gradual but incomplete recovery. The high incidence of neuropathy we found may be explained by the prolonged observation period compared with earlier reports. The only factor correlated with severity of neuropathy was the cumulative dose of cisplatin, while there was no association with either pre-treatment VPT, age, sex, tumor type or co-treatment with etoposide. The progressing course up to approximately 3 months after the end of treatment underscores the need for prolonged follow-up in future studies on cisplatin neuropathy.-