E. Ide Smith

Age‐linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the pediatric oncology group

Histologic sections (minimum of four sections per patient) from 211 patients with neuroblastoma were reviewed. The tumors were resected before therapy, which was standardized according to age and stage. Low mitotic rate (MR) (≤ ten per ten high‐power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log‐rank tests (P < 0. 0001 and P = 0. 0065, respectively). Histologic Grades 1, 2, and 3 were defined on the basis of the presence of both, any one, or none of these two prognostic features, respectively (Grade 3 had absence of low MR, i.e., these tumors had high MR [> ten per ten high‐power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P < 0. 001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades, Age groups (≤ 1 versus > 1 year of age), which also emerged as an independent prognostic feature (P < 0. 001), were linked with the grades to define two risk groups as follows: (1) a low‐risk (LR) group consisting of patients in both age groups with Grade 1 tumors and patients 1 year of age or younger with Grade 2 tumors and (2) a high‐risk (HR) group consisting of patients older than 1 year of age with Grade 2 tumors and patients in both age groups with Grade 3 tumors. The difference in survival between LR (160 cases) and HR groups (51 cases) was statistically significant (P < 0. 001). Concordance between these LR and HR groups and the Shimada classification was observed in 84% of cases. The new histologic grading system has the following advantages: (1) use of familiar terminology and histologic features in the grading system and (2) relative ease of assessment because the degree of differentiation does not need to be determined. The grading system should be tested on a new data set with an appropriate histologic sample of similar size to confirm these results.

Thoracic neuroblastoma: A pediatric oncology group study

Ninety-six patients with thoracic neuroblastoma were studied in a prospective fashion. Median age at presentation was 0.9 years. Forty-eight percent of the patients presented with stage A disease, 20% stage B, 13% stage C, 17% stage D, and 2% stage DS. Seventy-five patients have been followed for greater than 4 years. A posterior mediastinal mass was diagnosed on incidental chest roentgenograms performed for nontumor-related symptoms in 49% of the cases. Sixteen percent of the cases presented with neurological symptoms and 14% of the patients presented with acute respiratory distress. Urinary catecholamines were elevated in 76% of the cases. Complete surgical resection was carried out in 47% of the cases, while incomplete resection or biopsy was performed in 45%. No operation was performed in 3 patients. Minor surgical complications occurred in 20% of the patients, and 3% of the patients had significant perioperative complications. One patient died as a complication of therapy. Overall actuarial survival was 88% at 4 years. This study confirms the favorable outcome in children with mediastinal neuroblastoma. The basic biology of thoracic neuroblastomas seems to differ from that of other sites in that the majority of patients present at a younger age with localized disease or regional lymph node metastases, and have an improved survival even after correcting for age and stage. While complete excision is recommended, if possible, radical surgical procedures are not indicated since an excellent prognosis is associated with combined modality therapy.

Imperforate anus: The neurologic implication of sacral abnormalities*

The association of imperforate anus with bony sacral abnormalities and neurologic deficits is well recognized. These neurologic deficits have been considered static rather than progressive. However, recent experience indicates that some patients may develop progressive neurologic problems due to spinal cord lesions that are amenable to neurosurgical correction. To investigate the frequency of such lesions, routine myelography of imperforate anus patients with sacral anomalies was undertaken. The extraordinarily high incidence of unsuspected lesions known to cause progressive bowel, bladder, and musculoskeletal dysfunction is the basis of this interim report. Thirty percent of patients with anorectal abnormalities had sacral dysplasia. Of the nine patients undergoing myelography to date, eight have been abnormal. Six children had a tethered spinal cord, one had narrowing of the bony spinal canal and dural sac stenosis, and one an anterior meningocele. Spinal cord conditions that may cause deterioration of bowel, bladder, and extremity function should be defined and corrected before irreversible damage occurs. Because of the high incidence of spinal cord lesions detected in these patients with coexisting anorectal and sacral anomalies, routine screening for spinal cord lesions is recommended.

Response to Paclitaxel, Topotecan, and Topotecan-Cyclophosphamide in Children With Untreated Disseminated Neuroblastoma Treated in an Upfront Phase II Investigational Window: A Pediatric Oncology Group Study

PURPOSE Most children older than 1 year of age with metastatic neuroblastoma (NB) die despite intensive chemotherapy and bone marrow transplantation. The Pediatric Oncology Group conducted a study of paclitaxel, topotecan, and topotecan-cyclophosphamide (topo-cyclo) in newly diagnosed children with stage IV NB. PATIENTS AND METHODS There were 102 patients enrolled between September 1993 and October 1995; two of them were later shown to be ineligible. Of the remaining 100 patients, the first cohort of 33 patients received paclitaxel 350 mg/m(2) intravenously (IV) over 24 hours every 14 to 21 days; the next 33 patients received topotecan 2 mg/m(2)/d for 5 days IV every 21 days; a third cohort of 34 patients were treated with IV cyclophosphamide 250 mg/m(2) followed by topotecan 0.75 mg/m(2) each day for 5 days every 21 days. Patients were re-evaluated after two courses and then treated with intensive induction therapy and bone marrow transplantation. RESULTS Objective responses (complete response + partial response + mixed response) were documented in 67% of children who received topotecan, 76% after topo-cyclo, and 25% after paclitaxel. Four patients had grade 3 to 4 allergic reactions to paclitaxel; most patients developed grade 3 to 4 marrow suppression after topotecan or topo-cyclo. Neither disease-free survival nor overall survival differed significantly between children who received a phase II agent and those who did not. The 6-year disease-free survival and overall survival rates for all 100 children were 18% +/- 5% and 26% +/- 5%, respectively. CONCLUSION Topotecan and topo-cyclo are active in children with NB, are well tolerated, and should be evaluated further in combination regimens.

Nonoperative management of subcapsular hematomas of the liver

The liver is the second most common organ injured in blunt abdominal trauma, and with the use of diagnostic techniques such as hepatic scanning, an increasing number of patients with intrahepatic lesions are being identified. Five patients with this type of lesion are presented. A plan of managament, including observation in an intensive care unit, repeated physical examinations, frequent reevaluation of laboratory values, bed rest, gastrointestinal tract decompression and broad spectrum antibiotics, is suggested as the treatment of choice for this type of injury. All patients in the series have done well with no abscess formation, delayed rupture of hemobilia, and all show resolution of the defect on following-up hepatic scanning.

Biological variables in thoracic neuroblastoma: A Pediatric Oncology Group study

The prognosis for patients with neuroblastoma is related to the age and stage at time of presentation, as well as to the presence or absence of biological markers such as N-myc amplification and the degree of DNA ploidy. However, previous studies have shown that neuroblastoma in the thoracic site also is a favorable prognostic indicator, in that children with mediastinal neuroblastoma have a better survival rate, regardless of age or stage at time of presentation. This study was designed to evaluate the biological differences between thoracic and nonthoracic neuroblastoma with respect to N-myc amplification, DNA index as a measure of DNA ploidy, serum lactate dehydrogenase levels, and serum ferritin levels. Patients enrolled in the Pediatric Oncology Group study protocols for neuroblastoma were evaluated retrospectively, and log-rank analysis allowed the impact of each biological variable on survival to be determined for each cohort of patients. There were 1,335 neuroblastoma patients in the data base; 227 had thoracic-site neuroblastoma. Through analysis, it was apparent that patients with thoracic neuroblastoma have better survival rates than do their nonthoracic counterparts (P < .0001), and they are less likely to have N-myc amplification (P = .001), more likely to have an LDH level of less than 1,500 (P < .0001), and usually have a DNA index of greater than 1 (P < .003). Both thoracic and nonthoracic patients have low serum ferritin levels (86% of thoracic versus 83% of nonthoracic patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric emptying in children with gastroesophageal reflux. II. The relationship to retching symptoms following antireflux surgery.

Following antireflux surgery, children with persistent retching symptoms are presumably more likely to have delayed gastric emptying. We report 66 children between 2 weeks and 16 years of age who had an operation to control gastroesophageal reflux (GER). All patients had GER confirmed by 18- to 24-hour esophageal pH monitoring. Preoperative gastric emptying studies were performed in each patient with 99m-Tc sulfur colloid in apple juice. In addition to the percent gastric emptying (%GE), an effective gastric emptying was estimated by correcting the %GE for postcibal reflux (corrected %GE). Repeat 18- to 24-hour esophageal pH monitoring was performed postoperatively in all patients, and a repeat gastric emptying study was performed in 32 patients. After an average postoperative follow up of 6 months (range of 1 to 18 months), persistent retching was present in 12 (18%) patients. The retching was associated with dumping symptoms in six patients. Retching was seen in patients with a preoperative increase in effective gastric emptying (10/34, 29%, P less than .05) or a decrease in effective gastric emptying (2/15, 13%, NS), and not in patients with an effective gastric emptying within the control range (0/17, 0%). Postoperatively, retching with dumping symptoms was associated with an increased effective gastric emptying, and retching without dumping symptoms with a decreased effective gastric emptying. In conclusion, persistent retching followed anti-reflux surgery in children is related to extremes in effective gastric emptying. The preoperative measurement of corrected %GE identifies children at increased risk for this postoperative problem.

Correlation between Morphologic and Other Prognostic Markers of Neuroblastoma A Study of Histologic Grade, DNA Index, N-myc Gene Copy Number, and Lactic Dehydrogenase in Patients in the Pediatric Oncology Group

Background. Histologic grades (HG), N‐myc (NM) gene copy number, DNA index (DI), and serum lactic dehydrogenase (LDH) have been shown to be related to prognosis in neuroblastoma. The relationship between HG and nonmorphologic prognostic markers has not been investigated previously.

Postoperative small bowel obstruction in infants and children: A problem following nissen fundoplication

A serious consequence of antireflux surgery is postoperative small bowel obstruction in an infant who cannot speak and has been rendered unable to vomit. We reviewed the operative rate for small bowel obstruction following all antireflux operations (210 Nissen fundoplications, 16 Hill fundoplications, 12 modified Thal fundoplications, and 3 Boerema anterior gastropexies) performed on children at our institution between January 1977 and July 1984. Eighteen patients (17 Nissen fundoplications, one Hill fundoplication) were operated upon for small bowel obstruction within two years after the primary operation. The most consistent clinical findings in these children were abdominal distention and a decreased frequency of bowel movements. For operations performed between January 1982 and July 1984, reoperation for small bowel obstruction was needed in 6.1% (6/99) of children following Nissen fundoplication as compared to 0.9% (6/649), P less than 0.001) of children following other major laparotomies. A combination of our experience with that reported by others suggests an estimated incidence of postoperative adhesive small bowel obstruction of 5.5% (24/436) for Nissen fundoplication, 0.9% (3/347) for modified Thal fundoplication, and 0.8% (1/126) for Boerema anterior gastropexy. The performance of a Nissen fundoplication has led to a significant rate of reoperation for small bowel obstruction compared with other major laparotomies and antireflux operations performed in children.

The accuracy of abbreviated esophageal pH monitoring in children.

Extended (18 to 24 hour) esophageal pH monitoring establishes the diagnosis of gastroesophageal reflux (GER) utilizing a pH score, and relates respiratory symptoms to GER when the mean duration of sleep reflux (ZMD) is prolonged. A disadvantage of this method is the expense of overnight hospitalization. We performed extended esophageal pH recordings in 66 consecutive children (1 week to 15 years old) being evaluated for GER. Six portions of the 18- to 24-hour esophageal pH recording were compared to the complete record in an attempt to define the relative accuracy of abbreviated monitoring periods. The abbreviated monitoring periods included the 30 minutes after apple juice feedings (30 minutes AJ), the 2 hours after apple juice feedings (2 hours PC AJ), the 2 hours after milk-formula feedings (2 hours PC MF), the 8 hours with two feedings of apple juice (8 hours AJ), the 8 hours with two feedings of milk formula (8 hours MF), and the first 12 hours of recording (1st 12 hours). The accuracy relative to the 18- to 24-hour recording was poor for 30 minutes AJ, 2 hours PC AJ, and 2 hours PC MF periods (30% to 58%). An improved accuracy occurred during 8-hour AJ periods (29/31, 94%) in children without respiratory symptoms. Although the accuracy in patients with respiratory symptoms was best during 8-hour MF (31/35, 89%) and 1st 12-hour (33/35, 94%) periods, a high false-negative rate for the ZMD (31% to 41%) during abbreviated pH monitoring indicates that many patients with reflux-induced respiratory symptoms will be unrecognized.(ABSTRACT TRUNCATED AT 250 WORDS)