Immune expression in children with Wilms tumor: a pilot study.

BACKGROUND: Given improvements in multimodality therapy, survival among children with Wilms tumor (WT) exceeds 90%. However, 15% of children with favorable histology and 50% of children with anaplastic WT experience recurrence or progression. Of patients with advanced disease, only 50% survive to adulthood. In adult malignancies (including renal tumors), patient survival has improved with the advent of immunotherapy. However, little is known about the immune microenvironment of WT, making the potential role of immunotherapy unclear. OBJECTIVE: The objective of the study is to perform an exploratory, descriptive analysis of the immune milieu in WT. STUDY DESIGN: Between 2016 and 2017, all pediatric patients with WT, some of whom received neoadjuvant chemotherapy, underwent ex vivo wedge biopsy at the time of nephrectomy. The fresh tumor tissue and peripheral blood samples were analyzed for infiltrating immune infiltrate and effector cells using flow cytometry. Immunohistochemistry was performed for CD4, CD8, and PD-L1 expression. Matched blood samples were obtained for each patient, and circulating immune cells were analyzed by flow cytometry. RESULTS: A total of six patients were enrolled. One patient with neuroblastoma was excluded. The remaining five patients included the following: two with unilateral WT (resected before chemotherapy), two with bilateral WT (resected after neoadjuvant chemotherapy), and one with Denys-Drash syndrome, end-stage renal disease, and history of WT in the contralateral kidney. Immune analysis showed that WT were infiltrated by immune cells regardless of chemotherapy status. CD8 and CD4 T cells were present in the tumor tissue and exhibited an activated phenotype. Elevated levels of natural killer (NK) cells were observed in the tumors (Figure). Immune checkpoint PD-L1 was also found expressed in one of the tumors stained. DISCUSSION: In this pilot study, it was found that WTs were infiltrated by immune cells (CD45+) both before and after chemotherapy. Elevated levels of NK cells infiltrating the tumor specimens, which were quantitatively increased compared with levels of NK cells circulating in the blood, were noted. T cells, particularly CD4+ and CD8+ T cells, were present in tumor specimens. Tumor-infiltrating CD4 and CD8 T cells displayed an activated phenotype as defined by increased expression of human leukocyte antigen-DR isotype (HLA-DR), programmed cell death protein 1 (PD1), and CD57. Together, these findings suggest that WT microenvironment is immune engaged and may be susceptible to immunotherapy similar to other malignancies. CONCLUSIONS: These pilot data suggest an immune-engaged tumor microenvironment is present within WT. This implies that WT may be susceptible to immunotherapy similar to adult renal tumors and other adult malignancies. Follow-up studies are currently underway.

Examining the Efficacy of a Family Peer Advocate Model for Black and Hispanic Caregivers of Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects individuals across all racial and ethnic groups, yet rates of diagnosis are disproportionately higher for Black and Hispanic children. Caregivers of children with ASD experience significant stressors, which have been associated with parental strain, inadequate utilization of mental health services and lower quality of life. The family peer advocate (FPA) model has been utilized across service delivery systems to provide family-to-family support, facilitate engagement, and increase access to care. This study used a randomized controlled design to examine the efficacy of FPAs in a racially and ethnically diverse sample. Results demonstrate significantly increased knowledge of ASD and reduced levels of stress for caregivers who received the FPA intervention as compared to treatment as usual.

Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease.

OBJECTIVE: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson disease (PD). Following STN-DBS, speech intelligibility can deteriorate, limiting its beneficial effect. Here we prospectively examined the short- and long-term speech response to STN-DBS in a consecutive series of patients to identify clinical and surgical factors associated with speech change. METHODS: Thirty-two consecutive patients were assessed before surgery, then 1 month, 6 months, and 1 year after STN-DBS in 4 conditions on- and off-medication with on- and off-stimulation using established and validated speech and movement scales. Fifteen of these patients were followed up for 3 years. A control group of 12 patients with PD were followed up for 1 year. RESULTS: Within the surgical group, speech intelligibility significantly deteriorated by an average of 14.2%±20.15% off-medication and 16.9%±21.8% on-medication 1 year after STN-DBS. The medical group deteriorated by 3.6%±5.5% and 4.5%±8.8%, respectively. Seven patients showed speech amelioration after surgery. Loudness increased significantly in all tasks with stimulation. A less severe preoperative on-medication motor score was associated with a more favorable speech response to STN-DBS after 1 year. Medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. There was a strong relationship between high voltage in the left electrode and poor speech outcome at 1 year. CONCLUSION: The effect of STN-DBS on speech is variable and multifactorial, with most patients exhibiting decline of speech intelligibility. Both medical and surgical issues contribute to deterioration of speech in STN-DBS patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that STN-DBS for PD results in deterioration in speech intelligibility in all combinations of medication and stimulation states at 1 month, 6 months, and 1 year compared to baseline and to control subjects treated with best medical therapy.

MRI-guided STN DBS in Parkinson's disease without microelectrode recording: efficacy and safety.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a commonly employed therapeutic procedure for patients with Parkinson's disease uncontrolled by medical therapies. This series describes the outcomes of 79 consecutive patients that underwent bilateral STN DBS at the National Hospital for Neurology and Neurosurgery between November 2002 and November 2008 using an MRI-guided surgical technique without microelectrode recording. Patients underwent immediate postoperative stereotactic MR imaging. The mean (SD) error in electrode placement was 1.3 (0.6) mm. There were no haemorrhagic complications. At a median follow-up period of 12 months, there was a mean improvement in the off-medication motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III) of 27.7 points (SD 13.8) equivalent to a mean improvement of 52% (p<0.0001). In addition, there were significant improvements in dyskinesia duration, disability and pain, with a mean reduction in on-medication dyskinesia severity (sum of dyskinesia duration, disability and pain from UPDRS IV) from 3.15 (SD 2.33) pre-operatively, to 1.56 (SD 1.92) post-operatively (p=0.0001). Quality of life improved by a mean of 5.5 points (median 7.9 points, SD 17.3) on the Parkinson's disease Questionnaire 39 summary index. This series confirms that image-guided STN DBS without microelectrode recording can lead to substantial improvements in motor disability of well-selected PD patients with accompanying improvements in quality of life and most importantly, with very low morbidity.

Staged gamma knife radiosurgery for large critically located benign meningiomas: evaluation of a series comprising 20 patients.

OBJECTIVES: This study investigated the efficacy of staged radiosurgical treatment for intracranial meningiomas exceeding 3 cm in diameter. METHODS: Between April 1992 and May 2008, staged gamma knife radiosurgery was performed in 20 patients with large benign meningiomas. 14 patients had undergone surgery at least once. The patients' ages ranged between 26 and 73 years (median 60.5). Tumour volumes measured between 13.6 and 79.8 cm(3) (median 33.3) and treatment volumes between 5.4 and 42.9 cm(3) (median 19.0). Of 41 treatments, the prescription dose at the tumour margin was 12 Gy for 33 treatments, 10 Gy for one treatment, 14 Gy for four treatments, 15 Gy for one treatment and 25 Gy for a further two treatments (median 12 Gy to a marginal isodose of 45%). Median follow-up was 7.5 years. RESULTS: Tumour control was achieved in 90% of our series (25% tumour regression, 65% stable size). Two patients (10%) experienced tumour progression outlying the planning target volumes treated by an additional radiosurgical procedure. Thereafter tumour volume decreased in one patient and remained stable in the second one. Clinically, nine patients (45%) improved within the time of follow-up and 11 (55%) remained unchanged. CONCLUSION: As a result of excellent tumour control at a low concomitant morbidity, staged radiosurgical treatment for meningiomas represents a safe treatment modality that can be recommended for meningiomas in critical locations either after incomplete surgery or as primary treatment for patients with significant comorbidity.

Recurrent trigeminal neuralgia: long term outcome of repeat gamma knife radiosurgery.

OBJECTIVE: To date, the efficacy and safety of repeat radiosurgery (RS) for trigeminal neuralgia (TN) is based mainly on short term results. METHODS: Between 1994 and 2006, 93 patients were treated by RS for TN at the Department of Neurosurgery, Graz, Austria. 22 patients underwent repeat gamma knife radiosurgery (GKRS) a mean of 18.8 months after the initial treatment. The mean dose for repeat treatment was 74.3 Gy. Pain outcome was rated using the Barrow Neurological Institute (BNI) Pain Intensity Scale and facial numbness according to the BNI Facial Numbness Scale. RESULTS: Mean follow-up after repeat RS was 5.4 years. Pain relief was noted in 72.7% (16/22) of patients; six patients had a second pain recurrence after a mean of 9.3 months and underwent medical, alternative and/or further RS. One patient was lost to follow-up. BNI pain scale evaluation for 21 patients indicated improvement in 76.2% (16/21) of cases without medication (BNI I and II). Facial numbness was recorded in 73.7% (14/19) but in only one was it classified as bothersome. CONCLUSIONS: Long term observation of repeat GKRS for TN showed good pain relief in more than two-thirds of patients. Despite a high percentage of facial numbness, most likely attributable to the higher delivered dose, repeat RS can still be regarded as safe. However, further studies are needed to determine an optimised treatment protocol.

Effect of human atrial natriuretic peptide on blood glucose concentrations and hormone stimulation during insulin-induced hypoglycaemia in healthy man.

A double-blind placebo-controlled study using the double-dummy technique has been done to examine whether the responses of pituitary and adrenal hormones to insulin-induced hypoglycaemia were impaired by a pharmacological dose of human atrial natriuretic peptide (human ANF-(99-126),hANP). After an overnight fast eight male healthy volunteers (aged 23-40 years) received in random order i.v. bolus injections of insulin 0.125 U.kg-1 + placebo,hANP 100 micrograms + placebo,insulin + hANP, or both placebo preparations. In the insulin-only experiment, human growth hormone, adrenocorticotrophic hormone, cortisol, aldosterone, plasma renin activity, adrenaline, and noradrenaline were all stimulated by hypoglycaemia. In the hANP-only experiment there were no hormonal changes other than decreases in plasma renin activity and aldosterone concentration. In the insulin + hANP experiment the nadir of blood glucose was decreased to 1.3 from the 2.0 mmol.1-1 found in the insulin-only experiment. The exaggerated hypoglycaemia resulted in increased stimulation of human growth hormone, adrenocorticotrophic hormone and adrenaline when compared to the insulin-only experiment. The rise in the cortisol and aldosterone concentrations was only slightly increased, and the stimulation of plasma renin activity was blunted. Unexpectedly, hANP was found to enhance the hypoglycaemic action of insulin, most probably by inhibiting insulin degradation within the liver. There was no evidence of an inhibitory effect of hANP on the stimulation of pituitary or adrenal hormones during insulin-induced hypoglycaemia. The reduction in renin may indicate an inhibitory action of hANP on catecholaminergic effects within the kidney.

[What pathophysiologic significance does increased plasma levels of human atrial natriuretic peptide have in patients with diabetes mellitus?]. / Welchen pathophysiologischen Stellenwert haben erhöhte Plasmaspiegel des humanen atrialen atriuretischen Peptids bei Patienten mit Diabetes mellitus?

Hypertension is more frequently found in patients with diabetes mellitus than in subjects with normal glucose tolerance. On the other hand, concomitant hypertension accelerates the progression of diabetic nephropathy. To examine whether human atrial natriuretic peptide (human ANF-[99-126], hANP) is involved into the pathogenesis of hypertension and nephropathy of diabetic patients and to find out whether the detection of increased hANP levels can serve as an early marker, helping to identify diabetic patients at increased risk of developing these diabetes complications, we studied 107 randomly selected patients with Type 1 or Type 2 diabetes mellitus (53 women, 54 men). There were no differences between patients with normal hANP levels and patients with hANP levels above normal range regarding age, diabetes duration, metabolic control, kidney function (creatinine clearance and proteinuria), electrolytes, and in plasma renin activity, aldosterone, epinephrine and norepinephrine levels in plasma. However, higher blood pressure was measured and antihypertensive therapy was found more frequently in patients with increased hANP levels (p less than 0.05). This was confirmed by analyzing the subgroup of patients with normal blood pressure without antihypertensive therapy: Again, diastolic blood pressure was found to be higher (p less than 0.05) in patients with elevated hANP than in patients with normal hANP levels. In this subgroup, increased creatinine clearance tended to be found more frequently among patients with increased hANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

On the differential affinities of two anticancer analogues to their target.

The aim of the present study was to compare the pharmacokinetics of 5-fluorouracil (FU) and 5-fluoro-2-deoxyuridine (FUDR) during intra-arterial infusion. For this purpose 10 patients with widespread metastatic disease of the liver received implantable hepatic arterial catheters through the gastroduodenal artery. The patients were given FU (7.5 mg/kg) and FUDR (0.75 mg/kg) respectively via the hepatic catheter; drugs were administered for 30 min at a constant infusion rate. Blood samples were drawn from the hepatic vein after the end of the intra-arterial infusion. An established HPLC method was used to determine drug plasma levels. The patients who were on the FU infusion protocol during the first week showed mean FU plasma levels of 10 micrograms/ml, whereas FUDR plasma levels in the same patients, treated in the second week, were about 1 microgram/ml. Apparently hepatic removal was equally effective, with 97% of FU and with 96% of FUDR being extracted from the plasma. Kinetic consideration of the these data, however, suggested significantly differing affinities--on analogy with enzyme kinetics--of active facilitated transport mechanisms towards FUDR (KD = 4.2 X 10(-2)) and towards FU (KD = 64.2 X 10(-2)).