Drug-induced hyperthermia with rhabdomyolysis in CLN3 disease.

CLN3 disease (MIM# 204200), the most prevalent of the neuronal ceroid lipofuscinoses (NCL), is an autosomal recessive disorder with juvenile onset characterized by blindness, epilepsy, dementia, psychiatric manifestations, and motor deterioration. Problems related to behavior, emotions and thought are among the main features. Antidepressant and antipsychotic drugs have been employed with variable results. Neuroleptic malignant syndrome (NMS) has previously been described in two patients with NCL, one with CLN3 disease and one with adult onset NCL of unclear genetic origin. Our aims were to describe the occurrence of drug-induced hyperthermia in pediatric patients with CLN3 disease from West and South Sweden and to delineate the range of associated clinical features. Our study identified four patients presenting with seven episodes of severe drug-induced hyperthermia and either NMS-like or Serotonin syndrome (SS)-like features. Possibly provoking drugs were risperidone, clozapine, olanzapine, haloperidol, quetiapine, and sertraline. The course was atypical, frequently prolonged, associated with rhabdomyolysis and status dystonicus, and resulted in the death of three of the patients. Our study points to a vulnerability to drug-induced hyperthermia in patients with CLN3 disease which we believe could be underreported. Interestingly the proposed pathophysiological mechanisms behind NMS and SS on one hand and CLN3 on the other hand seem to converge in a common mechanism involving dysregulation of the sympathetic nervous system.

A 19-year review of paediatric patients with acute scrotum.

BACKGROUND AND AIMS: The aim of the study was to compare incidence, symptoms and signs of spermatic cord torsion to those of other conditions causing acute scrotum. MATERIAL AND METHODS: Records of 388 consecutive boys under 17 years of age treated for acute scrotum at The Hospital for Children and Adolescents in Helsinki in 1977-1995 were reviewed. During the period studied all patients with acute scrotum underwent urgent surgery to ensure accurate diagnosis and treatment. The duration and characteristics of the symptoms, clinical findings prior to operation and the age of the patients were registered. RESULTS: Scrotal explorations revealed 100 cases (26%) of spermatic cord torsion (SCT), 174 cases (45%) of torsion of the testicular appendage (AT), 38 cases (10%) of epididymitis (ED), 32 cases (8%) of incarcerated inquinal hernias and 44 (11%) other conditions. During the first year of life SCT was the most common cause of acute scrotum, another peak incidence being in adolescence. Almost half of the boys with AT were nine to 12 years of age (median 11). Except for infants, the patients' acute symptoms were pain (SCT 88%, AT 94%, ED 76%). Swelling in the hemiscrotum was found in 44% of SCT, in 39% of AT and in 88% of ED cases. Epididymitis was also accompanied by erythema (37%), but infrequently with fever (in 16%). Erythema was found also in AT (32%), but the "blue dot sign" was found positive in only 17 (10%) of the boys with AT. Three quarters of the boys who were operated on within six hours from onset of symptoms had testicle torsion. All testicles were saved when detorsion was performed within six hours, but salvage was possible in only half of the cases when symptoms had lasted more than six but less than 12 hours. CONCLUSIONS: The high probability of SCT among those admitted to an emergency department within six hours from the onset of the symptoms justifies immediate surgical exploration.

Growth patterns in young men treated for undescended testes in childhood.

Testicular maldescent may be caused by endocrinological deficiency in some cases, and, on the other hand, cryptorchidism itself may have an injurious effect on testicular development and function. The purpose was to examine whether testicular maldescent is associated with abnormal growth in various body dimensions in otherwise healthy males treated for the malformation during childhood. A total of 76 young men, 16-30 years of age, who were treated for undescended testes at an age ranging from 10 months to 13 years, were examined by measuring various body dimensions. Previously cryptorchid men were slightly taller than age-matched controls, except for those with bilateral cryptorchidism treated preoperatively with hCG. The most prominent finding was a high bihumeral to bicristal ratio. In addition, testicular volume was positively correlated to both the bicristal and bihumeral width, as well as to the sitting and total height.

Comparative genomic hybridization reveals changes in DNA-copy number in poor-risk neuroblastoma.

Aggressive neuroblastoma remains a therapeutic challenge, and additional understanding of its biology is of paramount importance. Changes in DNA-copy number were analysed in the neuroblastoma cells of 27 patients using comparative genomic hybridization (CGH). Eighteen of the patients had a poor risk disease (16/18 stage IV) and 9 had a non-poor-risk disease (3/9 stage I-II, 2/9 stage III, and 4/9 stage IVS). Changes in DNA-copy number were detected in 72% of the poor-risk and 22% of the non-poor-risk tumors with gains of chromosomal material being more prevalent than losses. Gains were most common in chromosomes 2, 7, and 17 and losses in chromosome 11. Changes in DNA-copy number were multiple in all but one of the patients with poor-risk disease. The applicability of CGH in studies on the genomic changes in pediatric malignancies is demonstrated by our data also adding weight to the argument of multiple elements with oncogenic and/or tumor suppressor potential being involved in the aggressive phenotype of poor-risk neuroblastoma.

Effects of transcutaneous nerve stimulation on the microcirculation in chronic leg ulcers.

The purpose of this study was to find out to what extent transcutaneous electrical nerve stimulation (TENS) affects the blood flow in and around chronic lower leg ulcers, as measured with a new technique, laser Doppler imaging (LDI). Fifteen patients, mean age 73 years (range 38-85) with chronic leg ulcers of various causes participated in the study. The duration of the ulcers ranged from 3 months to 16 years. Low-frequency (2 Hz; 10-45 mA) TENS was given for 60 minutes. The changes in blood flow were measured every 5 minutes by LDI. After 60 minutes, mean blood flow had increased in the ulcer by 35%, and in the intact skin surrounding the ulcer by 15%. Even 15 minutes after the TENS had finished there was still a mean blood flow increase of 29% in the ulcer and 9% in the skin. The present results show that TENS has a stimulating effect on local blood circulation in and around chronic ulcers.

Effect of transcutaneous nerve stimulation on microcirculation in intact skin and blister wounds in healthy volunteers.

Healthy non-smoking volunteers participated in two experimental studies in which the circulatory changes induced by transcutaneous nerve stimulation (TENS) were quantified by two different methods. In experimental series 1 (intact skin), nine volunteers were given TENS on the left lower leg for 60 minutes on three occasions at different frequencies each time (2 Hz, 100 Hz, and sham). Changes in blood flow were assessed by laser Doppler imaging technique every five minutes. The mean blood flow increased by 40% during low frequency TENS and by 12% during high frequency TENS. There was no change in mean blood flow during sham stimulation. In experimental series 2 (blister wound), the circulatory changes induced by TENS were studied by intravital video microscopy and computerised image analysis in standard blister wounds on the lower leg. The microcirculatory blood flow, measured as red blood cell velocity (RBC-V) in 5-14 individual capillaries in each wound, was assessed before and during 45 minutes of TENS (2 Hz and 100 Hz). Mean RBC-V increased by 23% during low frequency TENS (n = 6) and by 17% during high frequency TENS (n = 8). The results show that: laser Doppler imaging and intravital video microscopy techniques can be used to study events at the microcirculatory level; the blister wound is an interesting new standard wound for use in clinical studies; and TENS stimulates the peripheral circulation.

Maximal preservation of renal function in patients with bilateral Wilms' tumor: therapeutic strategy of late kidney-sparing surgery and replacement of radiotherapy by high-dose melphalan and stem cell rescue.

In children with bilateral Wilms' tumor, the therapy should aim at maximal preservation of renal parenchyma and function. Local radiotherapy may give rise to second malignant neoplasms and may impair renal function. We present a therapeutic strategy without any irradiation. Three children were diagnosed with bilateral Wilms' tumor at ages from 6 months to 5 years. Each patient had a massive tumor with local stage III on one side; one had pulmonary metastases. The therapeutic strategy was first to obtain tissue for histology by percutaneous needle biopsy, to administer pre-operative chemotherapy until desired tumor shrinkage, and then to perform kidney-sparing resective surgery. After a period of conventional chemotherapy, the patients were consolidated with high-dose (HD) melphalan and ABMT. Renal parenchyma spared post-surgery (right/left) was 0%/70%, 60%/40% and 40%/60% of the original kidney volumes. The toxicity of the ABMT procedure was mild, the patients engrafted promptly, and were discharged on days +14 to +27. All patients survive disease-free, 3 years 4 months to 4 years 5 months post-transplant. Our program resulted in good preservation of renal parenchyma and normal function, and we consider the risk of this ABMT program smaller than the late consequences of local radiotherapy for children with bilateral Wilms' tumor. The therapeutic strategy described merits further evaluation.

Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult.

Cryptorchidism results in impaired fertility. Reduced numbers of testicular germ cells can be shown histologically during the first years of life. The process causing germ cell loss in cryptorchid prepubertal boys is unknown, but it could be the result of a form of programmed cell death known as apoptosis. 25 adult men with a history of surgically treated cryptorchidism were studied, 15 of whom had received an unsuccessful human chorionic gonadotropin (hCG) therapy before orchidopexy. Apoptotic DNA fragmentation was assayed in testis biopsies taken during orchidopexy by end-labeling, both in extracted DNA and histochemically in situ. Only a few scattered apoptotic spermatogonias were seen by end-labeling of biopsies from patients not treated with hCG, whereas more extensive labeling of spermatogonia was seen after hCG treatment. As estimated by gel electrophoresis, the amount of low molecular weight DNA was 4.3-fold higher in the hCG-treated group when compared with the level in scrotal testis of non-hCG-treated patients (P < 0.001). About 20 yr after the biopsy, the low molecular weight DNA fragmentation correlated negatively with the testis volume (r = -0.84; P < 0.001) and positively with serum FSH levels (r = 0.73; P < 0.001). Findings in the semen analysis were similar between the groups. Apoptotic loss of spermatogonia after hCG treatment of cryptorchidism warrants reevaluation of the safety of this treatment.

Effect of age at operation, location of testis and preoperative hormonal treatment on testicular growth after cryptorchidism.

PURPOSE: We evaluated the effect of patient age, primary location of the gonad and preoperative human chorionic gonadotropin administration on future testicular growth in patients treated for cryptorchidism. MATERIALS AND METHODS: Testicular volume was measured in 75 adults treated for cryptorchidism when they were 10 months to 13 years old. RESULTS: The mean volume of the cryptorchid testes plus or minus standard deviation, whether unilateral or bilateral, was 11 +/- 6 ml. compared to 20 +/- 7 ml. for the spontaneously descended testes in patients with unilateral cryptorchidism. The results showed no significant correlation between patient age at treatment or original testicular location and final testicular volume, although the 22 testes of 18 patients undergoing surgery after age 5 years were somewhat smaller (9 +/- 5 ml.) than the 66 testes of 55 younger patients (12 +/- 6 ml.). However, 26 patients who had received human chorionic gonadotropin treatment had a significantly smaller testis (9 +/- 5 ml.) than did 57 treated with surgery alone (12 +/- 6 ml., p < 0.05). CONCLUSIONS: Early orchiopexy at age younger than 2 years is not necessarily essential. Adult testicular volume is slightly greater in patients with cryptorchidism if treated at ages up to 5 years. Preoperative location of the testis in otherwise healthy boys exerts no definite effect on final testicular volume. Preoperative human chorionic gonadotropin administration may have an adverse effect on future testicular growth.

In vivo purging of bone marrow in children with poor-risk neuroblastoma for marrow collection and autologous bone marrow transplantation.

PURPOSE: To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used. PATIENTS AND METHODS: Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT. RESULTS: Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease. CONCLUSION: In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.

Surgical results in the International Reflux Study in Children (Europe).

In the European part of the International Reflux Study in Children (7 participating centers) 151 infants and children were randomly allocated to surgical treatment of primary grades III and IV vesicoureteral reflux. Reimplantation was performed unilaterally in 65 patients and bilaterally in 86, for a total of 237 ureters reimplanted. The patients were followed at regular intervals for 5 years. Reflux was absent in 231 of the reimplanted ureters (97.5%) at the end of 5 years. No patient underwent reoperation for reflux. In 10 ureters (4.2%, 10 patients) obstruction developed postoperatively and 7 needed reoperation. All reoperations were performed on the left side. Of the obstructed kidneys new scars developed in 6 during the 5-year followup. Including these cases, the number of new renal scars was equal in the surgical and medical groups (20 each). The number of pyelonephritic episodes during followup was significantly less in the surgical group (without chemoprophylaxis) than in the medical group (on chemoprophylaxis). No kidneys were lost and no child became hypertensive. If voiding cystourethrography and excretory urography were normal 6 months postoperatively, the reflux had been permanently eradicated and postoperative obstruction could be ruled out. In this study the patients who underwent reimplantation had a 74% (112 of 151) chance of an uncomplicated postoperative course (no persisting reflux, obstruction, pyelonephritis or severe renal damage).

Percutaneous needle biopsy preceding preoperative chemotherapy in the management of massive renal tumors in children.

While the National Wilms' Tumor Study (NWTS) Group in the United States puts an emphasis on accurate staging and histology before any therapy is given for Wilms' tumor, the International Society of Pediatric Oncology (SIOP) in Europe focuses on preoperative therapy and safer surgery. Our current approach combines the benefits of both policies in the management of massive renal tumors in children. In seven consecutive patients we first obtained a percutaneous posterior needle biopsy to obtain adequate tissue for histology, and proceeded with preoperative chemotherapy with vincristine and dactinomycin until tumor shrinkage was sufficient. Tumor removals were feasible and uneventful. At the time of operation, two tumors were found to be totally or almost totally necrotic. In the others, which still included viable tumor, the histology corresponded well to the needle biopsy findings. One case with unfavorable histology and one with rhabdoid sarcoma would have been missed and given suboptimal therapy without the primary needle biopsy. As possible biopsy-related complications, subcapsular intratumoral bleeding was recognized in two patients. We conclude that percutaneous posterior needle biopsy is safe and yields definite, detailed histology in massive renal tumors in children. Preoperative chemotherapy facilitates surgery in these patients.

Localized amyloidosis of the urinary bladder.

Localized amyloidosis of the urinary bladder is a rare condition. Five patients, 1 with localized secondary amyloidosis, are described. The symptoms, macroscopic hematuria and tumor-like appearance in cystoscopy, may mimic bladder cancer. Diagnosis is based on histopathological examinations with Congo red staining. In most instances, the treatment of choice is transurethral resection and electrocoagulation. Because of the risk of recurrences, a close follow-up is recommended.

Transanal resectoscopic excision of rectal adenoma. Case report.

In three cases of rectal adenoma a Storch 27 Fr urologic resectoscope was used for transanal excision of the tumour. The lesions were of different sizes and situated in different parts of the rectum. The cases are presented and the advantages and limitations of the method are discussed.

Improved prognosis for children with stage IV neuroblastoma: high-dose melphalan and autologous unpurged marrow transplantation after aggressive surgery and short chemotherapy with cisplatinum and etoposide.

A new therapeutic approach was adopted for 13 consecutive patients with stage IV neuroblastoma over 1 year of age admitted to the Children's Hospital, University of Helsinki, between October 1981 and August 1985. Treatment was based on induction, with aggressive, repeated early surgery and a relatively short course of chemotherapy with cisplatinum and etoposide, and on consolidation, with 140-180 mg/m2 of melphalan followed by autologous unpurged bone marrow. Induction therapy failed in only 2 of the 13 patients. One of the two was never autografted. So a total of 12 children underwent autologous marrow transplantations, 10 in primary and 1 in secondary remission, and one with residual disease. One patient died in septicemia during postmelphalan pancytopenia, and four patients relapsed 0.3-2.9 years after transplantation. Seven of the original 13 patients (54%) are well and living in continuous remission 2.3-4.1 (median 2.8) years after diagnosis.

Bilateral Wilms' tumor and secondary malignancies.

A series of six patients with bilateral Wilms' tumor (nephroblastoma) is presented. Multimodal therapy yielded a survival rate of 83% at 2 yr of follow-up. However, at the end of a later follow-up period only two patients (33%) were alive. of the 4 patients who died. Only 1 died of Wilms' tumor. One died of complications of aggressive chemotherapy and two patients died after 12 and 16 yr following treatment of secondary malignant tumors arising in the irradiated region. Patients with bilateral tumor should be followed at regular intervals for the duration of life for the occurrence of secondary malignant tumors.

Heme compounds in the plasma in small bowel ischemia in the rat.

The early diagnosis of acute mesenteric occlusion presents a difficult problem in abdominal surgery. In a study on rats the relation between graded small bowel ischemia and the concentration of heme compounds in the plasma was investigated. The ischemia was produced by ligation of terminal vessels at the mesenteric margin of the intestine (mesenteric end arcades) or the superior mesenteric artery. Heme compounds were assayed by a benzidine method developed by Crossby et al. The concentration of heme compounds in the plasma was higher in animals with various grades of intestinal ischemia than in animals subjected to laparotomy alone. This increase was noted as early as 4 hours after induction of moderate and severe grade of ischemia. The results indicate that an increase in plasma concentration of heme compounds takes place at an early stage of moderate and severe small bowel ischemia following mesenteric vascular occlusion but not until after 48 hours in mild ischemia. The clinical value of this method has to be tested in a clinical study.