Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma.

Children older than 1 year of age who have neuroblastoma with complete or partial removal of the primary tumor and positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) are a small but higher-risk subset of patients. To further evaluate the importance of identifying patients with POG stage C neuroblastoma and to assess the efficacy and toxicity of adding concurrent radiation therapy (RT) to chemotherapy (CT) in these children, a randomized study was conducted. Eligible patients received cyclophosphamide 150 mg/m2 orally days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR) every 3 weeks for five courses with or without RT to primary tumor and regional lymph nodes (24 to 30 Gy/16 to 20 fractions). Second-look surgery was advised to evaluate response and to remove residual disease. Continuation therapy alternated CYC/ADR every 3 weeks with cisplatin 90 mg/m2 day 1 followed by teniposide 100 mg/m2 day 3 (CDP/VM) for two courses each. Secondary CT with CDP/VM alone was available for patients not achieving complete response (CR) following induction treatment and second-look surgery. Of 29 eligible patients randomized to CT alone, 13 achieved CR, and nine are disease-free (NED) 1 to 52 months (median, 35 months) off therapy. Twenty-two of 33 eligible cases treated with CT/RT attained CR, and 19 are NED 1 to 77 months (median, 23 months) off therapy. Local and metastatic relapses occurred in both arms. Differences in CR, event-free survival, and survival rates were significant, P = .013, .009, and .008, respectively. Surgical compliance was excellent and complications uncommon. Therapy was tolerable in both groups but hematopoietic toxicity was more common in the CT/RT arm. We conclude that POG stage C neuroblastoma in children older than 1 year of age is a higher-risk group that should be identified, that CT/RT provides superior initial and long-term disease control compared with CT alone in this patient subset, and that the occurrence of metastatic failures in both treatment groups suggests a need for more aggressive chemotherapy.

Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) evaluated in a prospective study the hypothesis that patients who had localized, visible residual neuroblastoma without regional lymph node involvement after surgery (POG stage B) have a favorable prognosis when treated with moderate intensive chemotherapy. Eligible patients were initially treated with five courses of Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co., Evansville, IN) and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) followed by surgery (CY/AD +/- surgery). Those patients not achieving a complete remission (CR) crossed over to five courses of cisplatin and teniposide (PL/VM) +/- surgery. Radiation therapy (XRT) was given to selected patients who still were not in CR after the crossover therapy. Of the 61 eligible patients, 38 (62%) patients achieved CR after CY/AD proven by clinical (31) or surgical (seven) evaluation. One (2%) patient in clinical partial remission (PR-C) entered CR without further therapy. Nineteen (31%) patients achieved CR with the following salvage therapies: surgery (five), PL/VM +/- surgery (five) followed by XRT (three) or autologous bone marrow transplant (ABMT) (one) and further courses of CY/AD +/- PL/VM instead of courses of PL/VM (five). The overall CR rate was 95% (58 of 61). Four patients had recurrence of the disease. The probability of being disease-free at 3 years after initial or salvage therapy was estimated at 84% (SE, 5%). The overall prognosis of children older than 1 year and younger than 1 year was similar (P = .26). If, however, the three remission deaths (all younger than 1 year) were censored, there was only one other failure in 32 children younger than one versus seven of 29 children older than 1 year (P = .018). These results confirm the excellent prognosis for patients with POG stage B neuroblastoma and indicate that most patients are curable with CY/AD +/- surgery, and those not achieving CR with this therapy are curable with alternate therapy.

Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study.

A prospective study was designed to evaluate the outcome of patients with localized resectable neuroblastoma without regional lymph node involvement when no therapy beyond surgical resection was administered. One hundred one patients observed for 3 to 60 months had a 2-year disease-free survival of 89% (SE = 5%). Of the nine patients experiencing relapse, only three have died. There were no apparent distinguishing characteristics of the nine failures. Due to the favorable prognosis of the subset of neuroblastoma patients, prognostic factor analysis had very limited power and lacked clinical importance. Complete gross removal of the localized tumors is adequate therapy to ensure the survival of the majority of these patients.

Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study.

PURPOSE: Infants less than or equal to 1 year of age with neuroblastoma (NB) have a favorable outlook with minimal to moderate therapy. Patients with complete or partial removal of the primary tumor but positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) have a higher risk for recurrent disease. To determine the importance of distinguishing infants with POG stage C NB from those with POG stage B disease and to assess the efficacy and toxicity of treating POG stage C infants with limited, postoperative chemotherapy, a study was conducted by the POG. PATIENTS AND METHODS: Forty-four eligible POG stage C infants received cyclophosphamide 150 mg/m2 orally on days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR), every 3 weeks for five courses followed by second-look surgery. No continuation therapy was given if surgical and pathologic complete response (CR) was achieved. Secondary therapy with five courses of cisplatin 90 mg/m2 on day 1 followed by teniposide (VM-26) 100 mg/m2 on day 3 (CDP/VM) was given to infants with gross residual tumor after CYC/ADR and second-look surgery. RESULTS: Thirty-four infants achieved CR after CYC/ADR alone, three after CYC/ADR and second-look surgery, two after CYC/ADR, surgery, and maintenance therapy, and two after alternative treatment with CDP/VM (total CR rate, 42 of 44). The 3-year survival and disease-free survival are both 93%. Toxicity was nominal. CONCLUSIONS: Infants with POG stage C NB have a favorable outlook, which is similar to infants with POG stage B NB; the surgical staging procedure for distinguishing these infant subsets may not be necessary. Future studies should focus on the reduction of treatment toxicity and efficacy maintenance, and address methods to identify infants at risk for failure.

Pulmonary cytomegalovirus infection: detection by Gallium 67 imaging in the transplant patient.

Cytomegalovirus (CMV) infeciton is a frequent complication during the first few months following renal transplantation. The diagnosis is sometimes difficult but may be made by viral culture, a fourfold rise in the CMV antibody titer, or by demonstration of the CMV inclusions in the affected tissue. An increased pulmonary uptake of galliulm citrate Ga 67 has been demonstrated following renal transplantation in two patients, each of whom had a fourfold rise in CMV complement fixing antibody titer, one of whom additionally had CMV inclusion bodies in a lung biopsy specimen prior to clinical or radiological demonstration of the pulmonary involvement. Gallium imaging, therefore, appears to be a valuable noninvasive test for early diagnosis of CMV pulmonary infections.

Systematization of primary histopathologic and fine-needle aspiration cytologic features and description of unusual histopathologic features of neuroblastic tumors: a report from the Pediatric Oncology Group.

On the basis of a detailed review of the primary histopathologic features of 239 cases and the fine-needle aspiration cytologic features of seven cases, a systematized schema of differentiation, progressive maturation and organization, and biologic behavior in neuroblastic tumors (NTs) is presented. The differentiation is of the gangliocytic and schwannian lineages. Maturation occurs in differentiating neuroblasts, leading to the formation of various stages of ganglion cells and Schwann cells. Organization is characterized by nesting pattern, rosette formation, parallel arrangement of neuropil, and alignment of Schwann cells along the neurites. According to this schema the NTs can be arranged in the following order: undifferentiated, poorly differentiated, and differentiating neuroblastoma; nodular, intermixed, and borderline ganglioneuroblastoma; and ganglioneuroma. Formulation of such a schema is helpful in gaining a better understanding of the complex pathologic features and in defining the criteria for various types of NTs. Therefore, the schema also would be helpful in achieving uniformity and reproducibility of the diagnosis of various types of NTs. Previously unreported features related to shape, size, nucleus, and cytoplasm of neuroblasts; secondary changes and patterns; changes in the fibrovascular septa; and other morphologic aspects of NTs and features (such as large tumor cells, karyorrhectic cells in fine-needle aspiration biopsy, tumor giant cells, anaplasia, and nesting pattern of tumor cells that have not been sufficiently emphasized) also are described. The importance of these previously unreported and insufficiently emphasized features relates to the histologic and cytologic diagnosis of NTs. For example, some of the features, such as starry sky appearance and spindle-shaped neuroblasts, may be misleading if seen in a small biopsy specimen. Others, such as tumor giant cells resembling ganglion cells and nesting pattern, will provide clues to the correct diagnosis. Some of the features, such as sclerosing pattern, hyalinization, and dense lymphoplasmacytic infiltration, may be related to the phenomenon of regression exhibited by neuroblastomas.

Meconium-induced umbilical vascular necrosis in abortuses and fetuses: a histopathologic study for cytokines.

OBJECTIVE: To show that meconium causes fetal morbidity and death at earlier gestations than reported previously. METHODS: We searched for specimens from 1997 and 1998 with pathologic diagnosis of meconium-induced umbilical vascular necrosis in placentas of nonmalformed fetuses and newborns. Because intra-amniotic infection is known to activate cytokines, and blood pigment is often microscopically indistinguishable from meconium, we removed those confounding considerations by excluding placentas with chorioamnionitis and signs of intra-amniotic bleeding. Light microscopic identification of vacuolar amniotic epithelial degeneration was used to select specimens with meconium because blood does not cause that histopathologic abnormality. We used histochemical procedures to show absence of hemosiderin and presence of bilirubin, and immunocytochemical labeling with interleukin-1beta to show cytokine. RESULTS: Four cases had meconium-induced umbilical vascular necrosis. The gestational ages were 16, 19, 29, and 38 weeks. Two cases were abortuses, the third was stillborn, and the fourth was a small-for-gestational-age liveborn, delivered by cesarean because of repetitive variable decelerations. Luna-Ishak staining showed bilirubin in macrophages between umbilical vascular myocytes and in the Wharton's jelly. Immunocytochemical methods showed interleukin-1beta in those same macrophages. CONCLUSION: Cytokines and other meconium-associated factors may contribute to the pathogenesis of fetal death. Survivors may suffer intraventricular hemorrhage, periventricular leukomalacia, and other morbidity.

Amniotic bans syndrome in an immature fetus.

A case of a 14-week fetus with congenital malformation due to amniotic bands is reported, including a description of the placenta. The literature is briefly reviewed, and attention is drawn to the occurrence of this syndrome in the immature human fetus.

Antenatal infection: adequate protection against hyaline membrane disease?

It has been argued that fetal and placental infections decrease the incidence of hyaline membrane disease (HMD). However, others contend that this is not so. We performed a rigidly controlled clinicopathologic investigation of one group of infants with evidence of severe antenatal infection compared with another group free of infection. This study shows that placental infection correlated positively with neonatal sepsis and that in this series of patients neither infection nor prolonged rupture of membranes is associated with a decrease of HMD. Our data do not support the proposal that antenatal infections protect the neonate against later development of HMD.

The epidemiology of placental features: associations with gestational age and neonatal outcome.

OBJECTIVE: To investigate the epidemiologic and pathogenetic significance of placental features and neonatal outcome in a high-risk population. METHODS: One pathologist examined 1252 placentas from clinically selected at-risk singleton pregnancies. Placental pathology features were analyzed relative to gestational age and status of the newborn, including fetal growth restriction (FGR), low 1-minute Apgar score, infection, liver disorder, anomalies, and death in the immediate postnatal period. RESULTS: The most frequent placental pathologic features were ischemic change, meconium staining, and chorioamnionitis. Only 8% of placentas were considered normal. The number of features per placenta increased with gestational age. Among preterm infants, chorioamnionitis occurred most frequently with low 1-minute Apgar score (40%), clinically apparent infection (43%), liver disorder (43%), and anomalies (42%), compared with healthy newborns (15%). Chorioamnionitis at term was most frequent among infants with low 1-minute Apgar score (26%), infection (30%), and liver disorder (23%), compared with healthy newborns (16%). Meconium and ischemic changes were most frequent in placentas from healthy newborns, compared with affected newborns, regardless of gestational age. Multivariable analyses revealed an independent association between chorioamnionitis and low 1-minute Apgar score (P < .05), and both chorioamnionitis and villitis were associated with newborn infection (P < .05). CONCLUSION: The frequency of many major pathologic placental features, especially ischemic changes and meconium, in the absence of immediately detectable abnormality is relatively high. Thus, continued follow-up is needed to determine their long-term clinical significance. In addition, associations of ischemic changes and infarction with FGR in term infants suggest that need for comprehensive investigations of the effects of histopathologically apparent low placental blood flow.

Meconium-induced umbilical cord vascular necrosis and ulceration: a potential link between the placenta and poor pregnancy outcome.

The literature lacks epidemiologic study of pregnancy outcome with light-microscopic meconium-related lesions. We recently described previously unreported meconium-induced necrosis of placental and umbilical cord vessels and hypothesized that the lesions represent preceding vasocontraction and fetal hypoperfusion. Preliminary experiments then confirmed that meconium produces vasocontraction in isolated umbilical venous tissue. In the present study, we examined whether clinically meaningful abnormalities occur with these vascular signs of remote fetal meconium discharge. In a light-microscopic review of 1100 meconium-stained placentas, we found ten with meconium-induced vascular necrosis. In six of these ten cases, fetal distress necessitated cesarean delivery. Seven newborns had Apgar scores of 3 or less at 1 minute, and each of the seven cases tested had umbilical arterial pH less than 7.19. Because seven of the ten infants were born after December 1, 1989, clinical follow-up was limited. One died, another has neurodevelopmental deficiency, and a third has experienced enlargement of head circumference from the 50th percentile at birth to the 95th percentile at 10 months of age. Two placentas had umbilical cord ulceration, a lesion that has rarely been reported in the literature. We conclude that meconium-induced vascular necrosis seems to be a meaningful, detrimental lesion.

A model of bacterially induced umbilical vein spasm, relevant to fetal hypoperfusion.

From experience with placental pathology and autopsies, we hypothesize that infected amniotic fluid may produce umbilical cord and placental surface vasospasm, reduced fetal perfusion, and perinatal asphyxia, morbidity, and mortality. We tested the hypothesis by a preliminary investigation with group B beta-hemolytic streptococcus, a common cause of perinatal morbidity and mortality. Our methods included suspension of isolated human umbilical vein segments in a 30-mL organ bath with modified Krebs solution, pH 7.3-7.4, under continuous aeration by 95% O2 and 5% CO2 at 37C. The vessels were attached to an isometric transducer which was connected to a polygraph. We tested Krebs solution, sterile culture medium, group B streptococcus spent medium, and washed whole group B streptococcus bacteria. Contractility was compared with results produced by 10(-5) M serotonin. The average contraction produced by 30 microL/mL group B streptococcus spent medium was 40.8% of that produced by serotonin. Whole washed bacteria produced 8.6% of the serotonin contraction. Krebs solution and sterile culture medium did not stimulate vascular contraction. Intraperitoneal injection of group B streptococcus spent medium in mice at four times the maximal experimental dose had little effect. Boiling group B streptococcus spent medium failed to affect its vasoactive stimulatory properties. We conclude that in vitro, group B streptococcus synthesizes a heat-stable, non-protein exotoxin that causes human umbilical vein contraction.

The ovarian dysgenesis of trisomy 18.

Ovarian abnormalities have been reported as a rare feature of the trisomy 18 syndrome. Gross and histological examination of autopsy material from 13 female infants with this syndrome revealed that ovarian dysgenesis, in varying degrees of severity, is more common than is indicated by the literature. The characteristic changes are reduction in germ cells due to necrobiosis, and the presence of mesothelial clefts and abnormal masses of stromal cells.

Contact cooling of the skin.

Skin precooling can be used to reduce epidermal thermal damage in laser procedures (such as hair removal) where the target structures are located up to several millimetres below the skin surface. We have developed and experimentally verified a computational model that describes contact precooling of a multilayered skin structure prior to laser irradiation. The skin surface is assumed to be brought into thermal contact with a cold plate made of material with a high thermal conductivity. The approximate analytical solution for the skin temperature is obtained by considering the plate as a local heat sink. The time evolution of temperature (in both the skin and the plate) is simulated numerically to yield the optimal cooling parameters. To experimentally verify the numerical results of the model, we performed direct measurements of skin temperature for contact cooling with a sapphire plate held at several different temperatures in the range +10 to -30 degrees C.

Some placental considerations related to neurodevelopmental and other disorders.

Many newborns who appear normal at birth later manifest substantial neurologic and other disease. Pathologists are able to explain some of that sad enigma. Placental pathology frequently reveals the pathogenesis of cerebral palsy, mental retardation, and other neurodevelopmental disorders. This requires recognition of gross placental abnormalities and insightful light microscopic examination. Chorioamnionitis is now proven to be the major cause of premature onset of labor and prematurity. There is important need for investigation of pathogenetic processes associated with ascending intrauterine infection. Major complications therein include bacterially mediated fetal hypoperfusion resulting from placental and umbilical vasocontraction. Placentas of 10% of newborns have villitis of unknown etiology. The importance of villitis is incompletely known. The fetus may discharge meconium on more than one occasion, particularly so when the fetus is postmature. Clinicians may not recognize that fetal discharge has occurred if the event occurred 4 days or more prior to delivery. Intra-amniotic meconium associated with oligohydramnios probably causes placental and umbilical vasocontraction. Meconium probably thus contributes to the pathogenesis of pulmonary vasoconstriction, persistent fetal circulation, necrotizing enterocolitis, and damage of the fetal brain, liver, and kidneys. Fetal hypoxia and asphyxia may be acutely or chronically acquired. Major placental lesions associated with neonatal asphyxia include chronic ischemic change, nucleated red blood cells, intravillous hemorrhages, intimal vascular fibrin cushions, meconium staining, and intervillous fibrin.

Meconium-induced vasocontraction: a potential cause of cerebral and other fetal hypoperfusion and of poor pregnancy outcome.

Chronically meconium-stained fetuses may ultimately suffer cerebral palsy and other devastation. The mechanism is unknown. Innocuous pregnancy complications may cause some fetuses to discharge meconium, which may become hazardous, independently of aspiration. We herein report previously undescribed, meconium-induced umbilical and placental vascular necrosis. To investigate whether meconium causes vasocontraction, we tested umbilical vein tissue with an isometric transducer connected to a polygraph. The specimens were suspended in a 30-mL organ bath with Krebs solution (pH, 7.4; temperature, 37 degrees C; under aeration with 95% O2 and 5% CO2). We exposed the tissue to meconium and compared meconium-induced vasocontraction with that induced by Krebs solution and 10(-5) molar serotonin. Meconium maximally produced 62.9% of serotonin-induced vasocontraction. Krebs solution and boiled meconium did not produce vasocontraction. We hypothesize that meconium may cause placental and umbilical cord vasocontraction, cerebral and other fetal hypoperfusion, and major poor outcome.

Placental insights into neurodevelopmental and other childhood diseases.

Deficient information regarding placental pathology has compromised epidemiological investigations of cerebral palsy, mental retardation, and other diseases. This article reviews light microscopic signs of low placental blood flow, fetal nucleated red blood cells, villitis (villous inflammatory lesions), chorangiosis (placental villous capillary hypervascularity), meconium staining, and chorioamnionitis. These findings can be used with data of birth weight, head circumference, and length to document the duration of fetal disease. The article includes pathophysiological considerations; for example, chorioamnionitis and fetal meconium discharge may cause autacoids to produce fetal hypoperfusion of the fetal brain and other vital organs.

Serum lactate dehydrogenase in childhood neuroblastoma. A Pediatric Oncology Group recursive partitioning study.

On the basis of an extensive recursive partitioning analysis of 668 patients with newly diagnosed neuroblastoma registered on Pediatric Oncology Group (POG) studies between October 1981 and May 1987, four major subsets of patients were created. Important prognostic factors included the patient's stage of disease, age, and level of serum lactate dehydrogenase (LDH). After adjusting for these factors, no other clinical prognostic factors were significant. The implications for protocol design are that (a) fine tuning of current therapy should be sought for the two favorable disease patient subsets, while (b) novel aggressive therapies are needed for the two unfavorable disease patient subsets where the overwhelming majority are dying. This article may serve as a model for others investigating prognostic factors. The data were divided into two subsets: one was used for an exploratory analysis; the other was used to confirm the exploratory findings. Despite spite the large number of statistical tests performed, the likelihood that the findings can be attributed to chance can be dismissed as virtually zero.

Placenta within the medicolegal imperative.

Bad pregnancy outcome includes abortion, stillbirth, neonatal death, morbidity, malformation, cerebral palsy, and mental retardation. These afflictions cause devastating personal impact. In the United States, almost 10% of all school-aged children are handicapped. Neurologic and communicative disorders affect 42 million people and cost $114 billion each year. The cause of cerebral palsy is known in less than 10% of these cases. Enormous litigations have threatened clinicians, paramedical personnel, hospitals, and insurance carriers. The placenta is an important potential means of establishing that fetal damage causes bad pregnancy outcome independently of clinical care. All pathologists serve an important role in the documentation of gross placental features and in the procurement of appropriate light microscopic slides. Pathologic placentas are common. Only an expert can determine whether an abnormal placenta represents the probable cause of bad pregnancy outcome.

Chorangiosis. An important placental sign of neonatal morbidity and mortality.

Chorangiosis is a placental change that has not been studied, to my knowledge, by investigators who publish in English. It occurs rarely in normal pregnancies. Each year, however, more than 30,000 neonates in the United States die within the first 28 days of life. Of 1,350 singleton newborns hospitalized in a regional neonatal intensive care unit, 74 (5%) had chorangiosis. One hundred thirty-four informational items of clinical, placental, and autopsy data were evaluated with a computer program written in Microsoft Basic. Depending on the gestational age of the population studied and the severity of the chorangiosis, the incidences of neonatal death and major congenital malformations were as high as 39% and 42%, respectively. Detailed findings introduce question of etiologic association with gestational diabetes, toxemia of pregnancy, and placental infection.