A Cys-loop mutation in the Caenorhabditis elegans nicotinic receptor subunit UNC-63 impairs but does not abolish channel function.

The nematode Caenorhabditis elegans is an established model organism for studying neurobiology. UNC-63 is a C. elegans nicotinic acetylcholine receptor (nAChR) α-subunit. It is an essential component of the levamisole-sensitive muscle nAChR (L-nAChR) and therefore plays an important role in cholinergic transmission at the nematode neuromuscular junction. Here, we show that worms with the unc-63(x26) allele, with its αC151Y mutation disrupting the Cys-loop, have deficient muscle function reflected by impaired swimming (thrashing). Single-channel recordings from cultured muscle cells from the mutant strain showed a 100-fold reduced frequency of opening events and shorter channel openings of L-nAChRs compared with those of wild-type worms. Anti-UNC-63 antibody staining in both cultured adult muscle and embryonic cells showed that L-nAChRs were expressed at similar levels in the mutant and wild-type cells, suggesting that the functional changes in the receptor, rather than changes in expression, are the predominant effect of the mutation. The kinetic changes mimic those reported in patients with fast-channel congenital myasthenic syndromes. We show that pyridostigmine bromide and 3,4-diaminopyridine, which are drugs used to treat fast-channel congenital myasthenic syndromes, partially rescued the motility defect seen in unc-63(x26). The C. elegans unc-63(x26) mutant may therefore offer a useful model to assist in the development of therapies for syndromes produced by altered function of human nAChRs.

A wandering fish bone.

A unique case is described of an ingested fish bone migrating into the common hepatic duct, without perforation. Most foreign bodies are known to pass through the gastrointestinal tract uneventfully. Sharper objects such as fish bones have been known to cause perforation. This is more common, in countries where fish consumption is considerably higher, such as, south east Asia. However, even in these regions there have been no reports of such a proximal migration.

Acute toxicities associated with radiation in the second National Wilms' Tumor Study.

Twenty-three of 303 patients (7.6%) entered into National Wilms' Tumor Study Number 2 (NWTS-2) with groups II, III, and IV disease experienced 26 toxic events thought to be related to radiotherapy (RT). The randomization between vincristine (VCR) plus dactinomycin (AMD) and the same two drugs plus doxorubicin (ADR) had a minimal effect on RT toxicity. Five (1.6%) fatalities were recorded and the surviving 18 patients recovered without discernible residua. Sixteen patients had hepatic, four had pulmonary, and three had cardiac toxicity. Hepatic toxicity was significantly more common when the right side of the abdomen or the whole abdomen was irradiated than when the left side was treated (P = .01). We conclude that acute RT-related toxicity in NWTS-2 was very similar to that in NWTS-1, in which 26 (7.2%) of 359 randomized patients developed RT-related toxicity and three died. This acceptable rate was maintained despite more intensive chemotherapy (CT) in NWTS-2.

Abdominal relapses in irradiated second National Wilms' Tumor Study patients.

Ten of 259 (3.8%) irradiated patients with group 2 and 3 tumors in the second National Wilms' Tumor Study experienced initial clinical relapse either in the operative site or elsewhere in the abdomen, excluding the liver and opposite kidney. Analysis of factors associated with abdominal recurrences has shown the independent significance of unfavorable histology, field size of the radiotherapy portals, and a postoperative delay of ten or more days before starting irradiation.

Treatment of children with stages II to IV anaplastic Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of the combination of vincristine, dactinomycin, and doxorubicin with (regimen J) or without (regimen DD-RT) cyclophosphamide on the relapse-free survival of children with stages II to IV Wilms' tumor and focal or diffuse anaplasia. PATIENTS AND METHODS: We reviewed the clinical courses of all randomized patients from National Wilms' Tumor Study (NWTS)-3 and NWTS-4 with stages II to IV anaplastic Wilms' tumor, and determined the 4-year relapse-free survival rate separately for those with focal or diffuse anaplasia. Anaplasia was evaluated using newly developed topographic definitions for focal and diffuse anaplasia. RESULTS: The 4-year relapse-free survival rate for five children with focal anaplasia who received regimen DD-RT was 80.0%, compared with 100.0% for eight children who received regimen J (P = .68). The 4-year relapse-free survival rate for 29 children with diffuse anaplasia treated with regimen DD-RT was 27.2%, compared with 54.8% for 30 children treated with regimen J (P = .02). CONCLUSION: We conclude that children with focal anaplasia have an excellent prognosis when treated with vincristine, doxorubicin, and dactinomycin. The addition of cyclophosphamide to the three-drug treatment regimen improved the 4-year relapse-free survival rate of children with stage II to IV diffuse anaplasia. This result suggests that further intensification of the treatment regimen for children with diffuse anaplasia may result in an additional improvement in prognosis.

Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study.

PURPOSE: The purpose of this study was to test the hypothesis that survivors of medulloblastoma who were younger at diagnosis and those who received standard-dose cranial irradiation (SRT) of 36 Gy would have a lower performance on standardized tests of cognitive function and achievement than children who were older and those treated with reduced-dose cranial irradiation (RRT) of 23.4 Gy. PATIENTS AND METHODS: Eligible patients had been treated on Pediatric Oncology Group (POG) study 8631 for low-risk medulloblastoma that randomized patients to receive RRT or SRT after surgical resection. Those who were alive and free of progressive disease 6.1 to 9.9 years from completion of treatment were eligible for this study. Of the 35 eligible patients, 22 patients (13 SRT, nine RRT) participated in a battery of tests that included intellectual and academic development as well as ratings of health-related quality of life. RESULTS: Patients were stratified by treatment group (SRT v RRT) and into younger (Y) and older (O) groups by the median age at diagnosis (8.85 years), which resulted in four groups that we hypothesized would show neuropsychologic test scores in the following order: Y/SRT less than Y/RRT less than O/SRT less than O/RRT. Evidence to support the hypothesized ordering of groups in terms of neuropsychologic toxicity was obtained with regard to Performance Intelligence Quotient (IQ), Full Scale IQ, Attention, Reading, and Arithmetic. CONCLUSION: Children treated for medulloblastoma experienced less severe neuropsychologic toxicity when treated with 23.4 Gy instead of 36 Gy cranial irradiation. Older children experienced less toxicity than children who were younger at the time of irradiation.

Ewing's sarcoma in bones of the hands and feet: a clinicopathologic study and review of the literature.

Review of current data from the Intergroup Ewing's Sarcoma Study (IESS) shows that Ewing's sarcoma (ES) is rare in bones of the hands and feet. Only 12 of 377 evaluable patients in the first two IESS studies had a primary tumor in these small, distal bones. The age distribution was typical for that seen in patients with ES at other sites. Males were affected twice as often as females, and tumors in the bones of the feet were much more common than those in the hands. All signs and symptoms were local in distribution. As in other sites, the dominant histologic pattern was categorized as diffuse. With the exception of those patients with lesions in the calcaneus, the prognosis for disease-free survival was excellent. A literature review of cases of ES reported in bones of the hands and feet showed generally comparable results.

Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of the administration of different regimens for the treatment of Wilms' tumor (WT). PATIENTS AND METHODS: Between August 6, 1986 and September 1, 1994, 905 previously untreated children aged younger than 16 years with stage II favorable histology (FH) WT (low-risk [LR]), stages III to IV FH WT, or stages I to IV clear-cell sarcoma of the kidney (high-risk[HR]) were randomized after the completion of 6 months of chemotherapy to discontinue (short) or continue for 9 additional months (long) treatment with chemotherapy regimens that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either divided-dose (STD) courses (3 days) or single-dose (PI) treatment with doxorubicin. RESULTS: The 4-year relapse-free survival (RFS) rates after the second randomization for LR patients were 83.7% for the 190 patients treated with short and 88.2% for the 187 patients treated with long chemotherapy (P = .11). The 4-year RFS rates after the second randomization for HR FH patients were 89.7% for the 256 patients treated with short and 88.8% for the 246 patients treated with long chemotherapy (P = .87). The charge for treatment with the short PI treatment regimens for all children with stages I through IV FH WT was approximately one half of that with the long STD treatment regimens. CONCLUSION: The short administration schedule for the treatment of children with WT is no less effective than the long administration schedule and can be administered at a substantially lower total treatment cost.

Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: The National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of administration of different regimens for the treatment of Wilms' tumor (WT). PATIENTS AND METHODS: Between August 6, 1986 and September 1, 1994, 1,687 previously untreated children less than 16 years of age with stages I to II/favorable histology (FH) or stage I/anaplastic histology WT (low-risk [LR] group) or stages III to IV/FH WT or stages I to IV/clear cell sarcoma of the kidney (high-risk [HR] group) were randomized to treatment that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either STD courses (3 days) or PI treatment with doxorubicin. RESULTS: The 2-year relapse-free survival (RFS) rates for LR patients were 91.3% for 544 randomized to treatment with PI and 91.4% for 556 randomized to treatment with STD chemotherapy (P = .988). The 2-year RFS rates for HR patients were 87.3% for 299 randomized to treatment with PI and 90.0% for 288 randomized to treatment with STD chemotherapy (P = .865). CONCLUSION: We conclude that patients treated with PI combination chemotherapy for LR or HR WT or clear cell sarcoma of the kidney have equivalent 2-year RFS to those treated with STD regimens. PI drug administration is recommended as the new standard based on demonstrated efficacy, greater administered dose-intensity, less severe hematologic toxicity, and the requirement for fewer physician and hospital encounters.

Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: Children younger than 24 months with small (< 550 g), favorable histology (FH) Wilms tumors (WTs) were shown in a pilot study to have an excellent prognosis when treated with nephrectomy only. PATIENTS AND METHODS: A study of nephrectomy only for the treatment of selected children with FH WT was undertaken. Stringent stopping rules were designed to insure closure of the study if the true 2-year relapse-free survival rate was 90% or lower. RESULTS: Seventy-five previously untreated children younger than 24 months with stage I/FH WTs for which the surgical specimen weighed less than 550 g were treated with nephrectomy only. Three patients developed metachronous, contralateral WT 1.1, 1.4, and 2.3 years after nephrectomy, and eight patients relapsed 0.3 to 1.05 years after diagnosis (median, 0.4 years; mean, 0.51 years). The sites of relapse were lung (n = 5) and operative bed (n = 3). The 2-year disease-free (relapse and metachronous contralateral WT) survival rate was 86.5%. The 2-year survival rate is 100% with a median follow-up of 2.84 years. The 2-year disease-free survival rate (excluding metachronous contralateral WT) was 89.2%, and the 2-year cumulative risk of metachronous contralateral WT was 3.1%. CONCLUSION: Children younger than 24 months treated with nephrectomy only for a stage I/FH WT that weighed less than 550 g had a risk of relapse, including the development of metachronous contralateral WT, of 13.5% 2 years after diagnosis. All patients who experienced relapse on this trial are alive at this time. This approach will be re-evaluated in a clinical trial using a less conservative stopping rule.

Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation.

PURPOSE: To evaluate prospectively the effects on survival, relapse-free survival, and patterns of relapse of reduced-dose (23.4 Gy in 13 fractions) compared with standard-dose (36 Gy in 20 fractions) neuraxis irradiation in patients 3 to 21 years of age with low-stage medulloblastoma, minimal postoperative residual disease, and no evidence of neuraxis disease. PATIENTS AND METHODS: The Pediatric Oncology Group and Children's Cancer Group randomized 126 patients to the study. All patients received posterior fossa irradiation to a total dose of 54 Gy in addition to the neuraxis treatment. Patients were staged postoperatively with contrast-enhanced cranial computed tomography, myelography, and CSF cytology. Of the registered patients, 38 were ineligible. RESULTS: The planned interim analysis that resulted in closure of the protocol showed that patients randomized to the reduced neuraxis treatment had increased frequency of relapse. In the final analysis, eligible patients receiving standard-dose neuraxis irradiation had 67% event-free survival (EFS) at 5 years (SE = 7.4%), whereas eligible patients receiving reduced-dose neuraxis irradiation had 52% event-free survival at 5 years (SE = 7.7%) (P =.080). At 8 years, the respective EFS proportions were also 67% (SE = 8.8%) and 52% (SE = 11%) (P =.141). These data confirm the original one-sided conclusions but suggest that differences are less marked with time. CONCLUSION: Reduced-dose neuraxis irradiation (23.4 Gy) is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year EFS and overall survival than standard irradiation (36 Gy). The 5-year EFS for patients receiving standard-dose irradiation is suboptimal, and improved techniques and/or therapies are needed to improve ultimate outcome. Chemotherapy may contribute to this improvement.

Comparison of digital nerve sensory recovery after repair using loupe or operating microscope magnification.

UNLABELLED: Our purpose was to determine whether there was a significant difference in sensory recovery after digital nerve repair using loupe magnification or an operating microscope. We identified patients aged 21-75 who had primary proper digital nerve repairs at least 24 months before our study. A total of 12 patients with 13 digital nerve injuries repaired with loupe magnification and nine patients with 12 digital nerve injuries repaired using the operating microscope, agreed to return for assessment by a therapist blinded to treatment. We found no significant difference in sensory recovery between the two groups as measured by static two-point discrimination, moving two-point discrimination, and Semmes-Weinstein monofilament. There were also no significant differences in average Disabilities of the Arm Shoulder and Hand or visual analogue pain scores. LEVEL OF EVIDENCE: IV.

Radiotherapy for carcinoma of the pancreas.

Many carcinomas of the pancreas are locally unresectable but have no gross evidence of metastases at diagnosis. Initial experience showed the disease to be relatively unresponsive to radiotherapy. However, results from Duke University and the Mayo Clinic led to the study of the disease by the Gastrointestinal Tumor Study Group (GITSG). The GITSG studies showed that radiotherapy and 5-fluorouracil chemotherapy in a relatively nonaggressive regimen prolonged the survival following apparent curative resection of carcinoma of the pancreas. In addition, for locally unresectable disease, GITSG showed that both chemotherapy and radiotherapy were necessary for the best results. However, even with optimal therapy the median survival in this group of patients is no more than 1 year. Many studies of specialized radiation techniques have also been evaluated. These included preoperative radiotherapy and chemotherapy, use of radiosensitizers, particle irradiation, interstitial irradiation, intraoperative irradiation, and hyperthermia. Results of these studies have not shown major improvement over the GITSG experience. In general, patients with pancreatic cancer who are irradiated appear to do better than those who are not. No other single modality has been more effective. It is therefore hoped that successful chemotherapeutic agents or other modalities can be developed and combined with the limited efficacy of radiotherapy.

Response of growing bone to irradiation: a proposed late effects scoring system.

The effect of radiation on epiphyseal bone growth is one of the most important dose-limiting factors in the radiotherapeutic management of children with malignant neoplasms. Clinical and laboratory evidence suggest that many factors may influence the severity of radiation-induced growth arrest. However, the absence of a consistent scoring system for late effects has hampered efforts to analyze the influence of various therapeutic maneuvers or to compare and collate results from different reported series. In this review, laboratory and clinical studies of radiation effects on growing bone are summarized, and a late effects scoring system is proposed.

Late effects of treatment for Wilms' tumor.

Twenty-six out of a total of 49 patients who were treated for Wilms' tumor at the Mallinckrodt Institute of Radiology between January 1960 and December 1975 have survived at least five years. The median follow-up time is 153 months (12 years, 9 months). One girl, who received pelvic irradiation, has not reached puberty at age 14, but the other 25 patients are currently in good health and have no major complaints or functional impairments at present. Twenty-one patients have, however, developed some complication at some time since treatment. Serious side-effects requiring hospitalization included one case of pericarditis and one of esophageal varices secondary to portal hypertension. Both these patients, however, had advanced tumors requiring aggressive treatment and their complications should be seen in perspective. There has also been one case of temporary low grade renal failure and one of transient hypertension. More common complications were 14 instances of scoliosis (only three have had any symptoms, however), five of osseous hypoplasia, three of soft tissue hypoplasia, three of liver damage and three of lung damage. There was one case of osteochondroma within a radiotherapy field. The factors pertaining to these complications and the anticancer therapy which preceded them are discussed in detail. We conclude that, whereas structural changes following modern radiotherapy for Wilms' tumor are very common, severe dysfunctions are infrequent. Even more extended periods of observation will be required before the total number of abnormalities is ascertained. However, the striking observation from this study is the lack of late functional effects.

Multivariate analysis of prognostic factors in pediatric and adult thalamic and brainstem tumors.

A multivariate analysis of prognostic variables was performed on a retrospective review of 136 patients with presumed or histologically proven primary lesions of the thalamus and brainstem treated by combined surgery and post-operative irradiation or by irradiation alone from January 1950 through December 1983. Overall survival for all patients at 5 and 10 years was 34.4 and 27.8%, respectively. Follow-up of 33 living patients ranged from 3 to 22 years. Prognostic variables analyzed by univariate analysis and found to be of significance (p less than 0.05) were race, duration of symptoms, extent of surgery (i.e. subtotal excision), and dose of irradiation. Further evaluation by Cox regression analysis revealed these same factors to be of prognostic significance (p less than 0.05). It is of importance to note that age and tumor site were not significant prognostic variables in the multivariate analysis but were significant by univariate analysis. The 5-year overall survival for patients with thalamic tumors was 59.5 and 20.9% for children and adults, respectively (p = 0.006). The 5-year overall survival for patients with pontine lesions was 46.6 and 16.0% for adults and children, respectively (p = 0.01). Only one patient was known to have expired due to a complication of therapy. Neurologic deficits and functional ability was normal or mild in 57.6% of the surviving patients.

Radiation therapy for gliomas of the optic nerve and chiasm.

Thirty-three patients with optic glioma seen over a 30-year period were reviewed. Five patients (15%) had tumor confined to the optic nerve, 8 patients (24%) had optic nerve and chiasmal involvement, and the remaining 20 patients (61%) had invasion of contiguous structures as well as chiasmal involvement. Eleven patients (33%) had a history of neurofibromatosis. Two-thirds of the patients had either a biopsy or a partial resection of the tumor, with the remaining one-third being clinically diagnosed. All patients received irradiation to local fields. The median dose was 5040 cGy in 160 cGy fractions. Of patients alive at last follow-up, the median time of follow-up was 12.3 years. The 5-, 10-, and 15-year overall actuarial survivals were 94, 81, and 74%, respectively. Univariate and multivariate analysis were performed on the following clinical variables: extent of primary tumor, extent of surgery, dose of radiation, gender, race, age, and presence or absence of neurofibromatosis. Extension of the primary lesion to the optic chiasm and age less than or equal to 15 years were the only two variables to have statistically significantly inferior 15-year progression free survivals by multivariate analysis. Eighteen (55%) patients had treatment related complications with most involving the pituitary gland. We conclude that postoperative radiotherapy is beneficial in patients with chiasmal involvement and those with incomplete resections. A minimum tumor dose of 4000 cGy is recommended.

Perineal effects of postoperative treatment for adenocarcinoma of the rectum.

Nine (4%) first recurrences that involved the perineum were identified in a randomized study of 202 patients treated by no further therapy, chemotherapy only, radiotherapy only, combined radiotherapy and chemotherapy, following complete surgical excision of adenocarcinoma of the rectum. Six of these were in unirradiated patients and in two of the three irradiated patients the perineum was included in the treatment volume. Eight of the nine patients were male and all nine had received abdominoperineal resection (APR). Our quality assurance procedures identified 22 of 96 irradiated patients in whom the perineum was grossly outside the fields. Sixteen of these had undergone APR. As only one of these 16 relapsed in the perineum no definite effect of the surgical procedure on the likelihood of perineal recurrence could be demonstrated. Examination of the pathology reports revealed that 28 patients undergoing APR had tumors within 2 cm of the anorectal junction (pectinate line). Five (17.8%) developed perineal recurrence compared with 4 (3.6%) of 110 patients whose tumors were more than 2 cm from the anus (p less than 0.02-Fisher exact test). No survival differences could be demonstrated between those receiving perineal irradiation and those not but perineal irradiation was associated with toxicity with at least nine (12.2%) out of 74 developing severe complications directly related to the perineum. The routine inclusion of the perineum in postoperative pelvic irradiation fields for all cases of adenocarcinoma of the rectum is questioned. Our current policy following APR includes optional coverage of the perineum for those tumors more than 5 cm from the anorectal junction.

Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience.

The Gastrointestinal Tumor Study Group (GITSG) protocol GI-7175 randomized 227 patients between 1975 and 1980 following complete surgical resection of stages B2 and C rectal adenocarcinoma to four treatment arms: (1) no adjuvant therapy, (2) chemotherapy only, (3) radiotherapy only, and (4) radiotherapy and chemotherapy (combined modality). The results of the study showed an advantage for combined modality treatment over no adjuvant therapy for time to recurrence (p = 0.005) and for survival (p = 0.01). Severe acute toxicity was frequent in the combined modality arm (61%) but late effects, including radiation enteritis, have been infrequent. We conclude that postoperative adjuvant therapy is indicated in certain stages of rectal carcinoma and that the present state of knowledge suggests combined modality therapy.

The treatment of Wilms tumor. Results of the National Wilms Tumor Studies.

The study of Wilms tumor has provided a model for the evaluation of the histopathology, prognostic factors, and multimodality therapy regimens in children and adults with rare malignant tumors. The NWTS Group has provided the scientific and administrative framework for the assessment of various treatment schemes in children with renal tumors, a research goal that could not have been realized using the resources available to either a single or a small group of institutions. These studies have yielded higher survival rates while demonstrating that therapy can be individualized according to well-defined risk factors most accurately identified in non-pretreated tumors. Thus, it has been found that treatments associated with significant acute and/or long-term morbidity are not necessary for patients with stage I or II, favorable histology Wilms tumor. Future studies may allow more accurate identification of those patients with stage III and IV/favorable histology Wilms tumor for whom treatment with an anthracycline is not necessary. If successful, this would decrease the size of the group of survivors at risk for cardiac dysfunction, which can follow the administration of even modest cumulative dosages of these agents.