Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies.

Fracture recurrence in hip fracture with menopausal hormone therapy versus risedronate: a clinical trial.

OBJECTIVES: An open-label, randomized trial was conducted to examine the effects of risedronate versus menopausal hormone therapy (MHT) in postmenopausal women with recent hip fracture. METHODS: Among 1165 eligible women, 281 were recruited and randomly assigned to receive oral risedronate (35 mg/week) or percutaneous estradiol gel (1.5 mg/day) plus oral micronized progesterone (100 mg/day) for 4 years. The primary end point was recurrent fracture and the secondary end points were mortality and bone mineral density (BMD). RESULTS: Kaplan-Meier analyses showed no significant differences in fracture recurrence and mortality between the two groups. The incidence of any new fracture per 100 person-years (PY) was 8.63 in the risedronate group and 12.86 in the MHT group (p = 0.180); that of clinical fracture was 4.75 and 6.99, respectively (p = 0.265); and that of asymptomatic vertebral fracture was 4.87 and 5.58, respectively (p = 0.764). The respective incidence of death per 100 PY was 3.58 and 4.40 (p = 0.503). BMD increased comparably at the lumbar spine in both groups. BMD at the total hip did not change in the risedronate group, but increased significantly by 2.8% in the MHT group. CONCLUSIONS: MHT might not differ from risedronate in the prevention of secondary fractures and death among postmenopausal women with recent hip fracture.

Body composition is more closely related to the development of knee osteoarthritis in women than men: a cross-sectional study using the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1, 2).

OBJECTIVE: To evaluate the association between knee osteoarthritis (OA) and body composition parameters, and to analyze the correlations of both obesity and lower extremity muscle mass with radiographic knee OA in relation to sex. METHODS: This was a cross-sectional study using data on body composition parameters measured using dual energy X-ray absorptiometry in 4246 participants in the Fifth Korea National Health and Nutrition Examination Survey. The relationships between knee OA and body composition parameters were evaluated. The associations between knee OA and the four subgroups corresponding to obesity and muscle mass percentage in both lower extremities were analyzed separately for each sex. RESULTS: The lower extremity muscle mass showed a decreasing trend, while fat parameters showed an increasing linear trend (P for trend <0.05) with increasing severity of knee OA in women. The odds ratio of each quarter percentile group (25 percentile) for fat parameters showed an increasing trend, while that of the lower extremity muscle mass showed a decreasing linear trend in relation to knee OA in women (P for trend < 0.05). In women, low percentage of lower extremity muscle mass was more associated with knee OA regardless of obesity (P < 0.05). However, there were no associations between all body composition parameters and knee OA in men. CONCLUSION: In women, high fat mass and low lower extremity muscle mass were associated with presence and severity of knee OA. Lower extremity muscle mass was more closely correlated with knee OA than obesity in women.

LAMC2 enhances the metastatic potential of lung adenocarcinoma.

Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin ß1- and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target.

Serotypes of Salmonella isolated from faeces of patients with acute diarrhoea in Gwangju Area, Korea, during 2000-2009.

The purpose of this study was to determine the changing pattern of Salmonella serotypes causing acute diarrhoea in humans in Gwangju area, Korea, during 2000-2009. A total of 596 Salmonella isolated from culture of 29,896 faecal samples of patients with acute diarrhoea were included in this study. Faecal samples were collected from local hospitals and clinics in Gwangju area during January 2000-December 2009. The mean annual frequency of isolates for the 10 years was 2.0% (range, 0.9-6.0). The isolates were serologically classified into 43 different serotypes. The 10 most common serotypes were Salmonella Enteritidis (47.9%), S. Typhimurium (20.4%), S. Braenderup (3.2%), S. Montevideo (2.9%), S. Paratyphi B (2.9%), S. London (2.3%), S. Bardo (1.7%), S. Virchow (1.7%), S. Infantis (1.5%) and S. Typhi (1.5%), accounting for 86% of all the isolates. Temporal variations were observed in the distribution of different Salmonella serotypes over the years, and only S. Enteritidis and S. Typhimurium were persistent throughout the study period. Although age specificity varied with serotypes, Salmonella was isolated most frequently from children below 5 years of age (179/596, 30.0%). A seasonal trend was apparent, and the highest rates were found in the summer months. This is the first report of the annual frequency of isolation of Salmonella serotypes, and seasonal and age-specific patterns of salmonellosis in humans in Gwangju area, Korea, over a decade-long period.

A case-control study of spontaneous patellar fractures following primary total knee replacement.

Peri-prosthetic patellar fracture following resurfacing as part of total knee replacement (TKR) is an infrequent yet challenging complication. This case-control study was performed to identify clinical, radiological and surgical factors that increase the risk of developing a spontaneous patellar fracture after TKR. Patellar fractures were identified in 74 patients (88 knees) from a series of 7866 consecutive TKRs conducted between 1998 and 2009. After excluding those with a previous history of extensor mechanism realignment or a clear traumatic event, a metal-backed patella, any uncemented component or subsequent infection, the remaining 64 fractures were compared with a matched group of TKRs with an excellent outcome defined by the Knee Society score. The mean age of patients with a fracture was 70 years (51 to 81) at the time of TKR. Patellar fractures were detected at a mean of 13.4 months (2 to 84) after surgery. The incidence of patellar fracture was found to be strongly associated with the number of previous knee operations, greater pre-operative mechanical malalignment, smaller post-operative patellar tendon length, thinner post-resection patellar thickness, and a lower post-operative Insall-Salvati ratio. An understanding of the risk factors associated with spontaneous patellar fracture following TKR provides a valuable insight into prevention of this challenging complication.

Sustained hyperphagia in adolescent rats that experienced neonatal maternal separation.

OBJECTIVE: To examine the neurobiological basis of bingeing-related eating disorders using an animal model system. DESIGN: Sprague-Dawley pups were separated from dam for 3 h daily during the first two weeks of birth (maternal separation (MS)), or left undisturbed (non-handled (NH)). Pups were subjected to repeated fasting/refeeding (RF) cycles; that is, 24 h food deprivation and 24 h RF (NH/RF or MS/RF), or had free access to food and water (NH/fed control (FC) or MS/FC) from postnatal day (PND) 28-40. MEASUREMENTS: Body weight gain and food intake were recorded. The arcuate expression of neuropeptide Y (NPY) and plasma corticosterone levels were analyzed on PND 29 and 40. RESULTS: Decrease in weight gain by repeated fasting/RF cycles was smaller in MS pups than in NH. Interestingly, weight changes responding to fasting or RF increased in MS/RF compared with NH/RF. Compensatory hyperphagia was diminished in NH/RF after the third fasting trial, but persisted in MS/RF throughout the experimental period. The arcuate expression of NPY mRNA responding to food deprivation was blunted, but elevation of plasma corticosterone exaggerated, in the MS group, compared to the NH group, on PND 29 after the first fasting session. However, both the arcuate NPY mRNA and plasma corticosterone levels were increased in MS/RF, but not in NH/RF, on PND 40 after the six sets of fasting/RF cycles, compared to the free FC groups. CONCLUSION: Experience of neonatal MS may lead to an exaggerated feeding response to repeated fasting/RF challenges at adolescence, perhaps, due to increased responsiveness of the hypothalamic-pituitary-adrenal gland axis. Additionally, the results suggested that an increased action of the hypothalamic NPY may not be necessary to induce compensatory hyperphagia following food deprivation.

Phase III trial of adjuvant 5-fluorouracil and adriamycin versus 5-fluorouracil, adriamycin, and polyadenylic-polyuridylic acid (poly A:U) for locally advanced gastric cancer after curative surgery: final results of 15-year follow-up.

BACKGROUND: This phase III trial was to compare 5-fluorouracil (5-FU), adriamycin, and polyadenylic-polyuridylic acid (poly A:U) against 5-fluorouracil plus adriamycin (FA) for operable gastric cancer. PATIENTS AND METHODS: From 1984 to 1989, patients who had D(2-3) curative resection were randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consisted of 12 mg/kg 5-FU every week for 18 months and 40 mg/m2 adriamycin every 3 weeks for 12 cycles. Chemoimmunotherapy consisted of FA plus 100 mg of poly A:U weekly for six cycles and was followed 6 months later by six weekly 50-mg booster injections. RESULTS: A total of 292 patients were enrolled. After excluding 12 ineligible patients, 142 and 138 patients were allocated to each treatment. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation, degree of tumor invasion (T2-T4a), and lymph node status (N0-N2). During the 15-year follow-up, chemoimmunotherapy significantly prolonged overall (P = 0.013) and recurrence-free (P = 0.005) survivals compared with chemotherapy alone. The survival benefits were prominent in the subset of patients with T3/T4a, N2, or stage III. Treatments were generally well tolerated in both arms. CONCLUSIONS: These results indicate a survival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resected gastric adenocarcinoma.

Morphological adaptation of the bone graft and fused bodies after non-instrumented anterior interbody fusion of the lower cervical spine.

PURPOSE: To assess the remodelling process of the bone graft and fused bodies after non-instrumented anterior interbody fusion with autogenous iliac graft in patients with spondylosis, infections, fractures, or disorders of the cervical spine. METHODS: 68 patients aged 18 to 58 years who underwent non-plated anterior lower cervical interbody fusion with an iliac graft were retrospectively studied. Diagnoses of the patients were degenerative disc diseases (n=32), disc herniation (n=15), fractures (n=13), and tuberculosis (n=8). The Robinson and Smith technique was used to treat degenerative disc diseases and protruded disc, and the Bailey and Badgley procedure for fractures or tuberculosis of the cervical spine. 34, 25, and 9 patients underwent one-, 2-, and 3-segment fusions, respectively. 18 of the 25 patients underwent two-segment fusion with a single large bone block, and 7 with 2 separate bone blocks for each segment. Four of the 9 patients underwent three-segment fusion with a single large bone block, and 5 used separate grafts for each segment independently. Plain and stress radiography was primarily used to assess the fusion. Computed tomography and magnetic resonance imaging were also used in some patients. Some anterior graft extrusion (amounting to less than 10% of corresponding anteroposterior body width) was used to observe the remodelling during graft-take and thereafter. Postoperative cervical traction for 2 to 4 weeks, then cervical collar immobilisation for 4 to 12 weeks were strictly followed according to the numbers of fused segments. A halo vest was applied in 4 patients with fracture undergoing 3-segment fusion as they could not tolerate the prolonged bed rest or rigid cervical brace. RESULTS: The mean time for the graft to fuse was 8.6 (range, 7-14) weeks in patients who underwent each segment fusion with independent free grafts, and 10 and 14 weeks in those who underwent 2- and 3-segment single large graft fusion, respectively. The final loss of disc height and joint angle were negligible, regardless of the extent of fusion. Bony absorption of the anteriorly protruded part of the graft began at postoperative week 10 (range, 6-28), which coincided with the time of graft-take and initiation of remodelling. CONCLUSION: The earliest sign of bony absorption of the anteriorly protruded part of the graft indicated the initiation of the graft-take and the graft remodelling. The inwaisting sign of the surgically fused block of vertebral bodies was a morphological adaptation. Despite the altered biomechanics of the spine in the fused area, the inwaisting sign indicated maintenance of normal function at the parafusion motion segments.

Neoadjuvant chemotherapy with infusional 5-fluorouracil, adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer: an early response predicts good prognosis.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy with infusional 5-fluorouracil (5-FU), adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer (LABC). PATIENTS AND METHODS: Eighty-two LABC patients were treated with neoadjuvant iFAC chemotherapy including infusional 5-FU (1000 mg/m2, continuous intravenous infusion, days 1-3), adriamycin (40 mg/m2, intravenous bolus, day 1) and cyclophosphamide (600 mg/m2, intravenous bolus, day 1) every 3 weeks until maximum tumor response. Patients subsequently received surgery, adjuvant chemotherapy, radiotherapy and hormonal therapy as appropriate. RESULTS: Downstaging occurred in 71 of the 82 patients (86.6%). Seventy-two patients (67 patients with downstaging and five patients without downstaging) were resectable (resectability rate, 87.8%). The clinical response rate was 84.2%, with a complete response (CR) rate of 17.1% and a pathological CR rate of 7.8%. During 891 cycles of chemotherapy, the most common grade 3/4 hematological toxicity was leukopenia (36.0%). There were no treatment-related deaths. The median follow-up period was 51 months, with a median overall survival (OS) of 66 months, and a 5 year OS rate of 50.9% for all patients. The 5 year OS and disease-free survival (DFS) rates of the 64 patients who underwent surgery were 55.8% and 44.7%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy with iFAC had a comparable response rate and DFS to the conventional bolus FAC regimen, with an acceptable toxicity in LABC using the AJCC 2002 staging system. An early response to neoadjuvant iFAC was a favorable prognostic factor.

Stabilisation of fractured thoracic and lumbar spine with Cotrel-Dubousset instrument.

OBJECTIVE: To evaluate the effectiveness of 2 different types of Cotrel-Dubousset instrument systems in stabilising thoracolumbar and lumbar spine fractures. METHODS: Between January 1989 and December 1993, 45 fractures in 42 patients with unstable fracture or fracture dislocation of the thoracolumbar and lumbar spines were randomly assigned to 2 surgical treatments with Cotrel-Dubousset instrumentation-using either a long segment (Group 1) or a short segment (Group 2)-and short posterolateral fusion. RESULTS: Consolidation of the fractured vertebral body and posterolateral fusion were achieved at a mean time of 4.5 months; fusion rates were 75% in Group 1 and 83% in Group 2. The average collapses of anterior vertebral body height in Group 1, in the immediate postoperative period and at the final follow-up, were 15% and 17%, respectively; and in Group 2, the figures were 16% and 24%, respectively. The correction of vertebral height and kyphosis at the last follow-up were lost more in Group 2 (5.7 degrees ) than in Group 1 (4.4 degrees ). There were neurological recoveries in 6 of the 9 cases of incomplete paraplegics, including complete recovery in 5, and one-Frankel grade increase in one. There were 15 instrument failures in 12 patients, including screw breakage in 3 Group 1 cases and 6 Group 2 cases. The plug dislodged in 3 Group 1 cases, and the hook dislodged in 3 Group 2 cases. In other words, instrument failures were more common in Group 2. CONCLUSION: Cotrel-Dubousset stabilisation of the fractured spine achieves fracture consolidation, but does not maintain the restored height and sagittal curve completely until fusion. The long rod and short fusion construct was more effective for all fracture types than was the short rod and fusion construct, although it leads to wider immobilisation of normal segments.

Brooks' posterior stabilisation surgery for atlantoaxial instability: review of 54 cases.

PURPOSE: To assess the effectiveness of Brooks' posterior stabilisation and fusion for the unstable atlantoaxial joint due to congenital dysplastic dens and trauma. METHODS: We retrospectively studied records of 54 patients (36 males and 18 females; age range, 3-58 years) who underwent Brooks' posterior stabilisation procedure between March 1975 and December 1999, at the Catholic University of Korea Medical Center and Dong-Shin General Hospital, Seoul. A single-stranded Kirschner wire was used to stabilise the first 19 cases (thin wires in 12 cases and thick wires in 7), and double-stranded wires were used in the next 35 cases (thin wires in 4 cases and thick wires in 31). After surgery, patients were immobilised in bed with light Halter traction of the head, followed by cervical bracing. RESULTS: Fusion was observed by X-ray postoperatively at 15 weeks in 48 patients. Reduction was achieved in 3 luxation cases (including the single case of rotatory fixation). Brooks' fusion failed in 4 patients with dens fractures and 2 with dens anomaly. Four dens fractures in cases of successful Brooks' fusion in Brooks' fusion did not unite. Wire failure occurred in 4 cases of thin single-stranded wire fixation, namely, 2 cases of dens fractures and 2 of dens anomaly. CONCLUSION: Brooks' procedure is safe and has a high fusion rate when double-stranded strong wire fixation of the atlantoaxial joint is combined with meticulous bone grafting and subsequent cervical bracing.

Traumatic spondylolisthesis of the axis: 42 cases.

Fourty-two patients (34 males and 8 female) with traumatic spondylolisthesis of the axis were studied in a retrospective review There were 20 stable and 22 unstable fractures. The 22 unstable fractures were treated surgically: 16 anterior interbody fusion (10 non-plated and 6 plated), 4 pedicle screw fixation for osteosynthesis of the fractured pedicles, and 2 posterior wire fixation for flexion and axial load injury. For all non-surgical cases, head halter tractions for 1 to 8 weeks was prescribed and a cervical orthosis was worn for an additional 6 to 18 weeks. The surgical cases underwent 5 to 7 days of preoperative and 1 to 4 weeks of post-operative head halter traction. In all cases pedicle fractures united after 13 weeks on average in group treated conservatively, 12 weeks (11 to 13 weeks) in the posterior wiring group, 8 weeks (7 to 9 weeks) in the group in which pedicle screws were used, and 11 weeks (9 to 15 weeks) in the anterior fusion group (13 weeks in non-plated, and 8 weeks in plated). There were no differences in patterns of anterior fusion between those in the non-plated and plated groups. There were no non-unions of fractured pedicles and there was no late instability of the C2-C3 or neurological complications. In 2 cases in the posterior surgery group, there was mild nuchal discomfort and some rigidity for a short while postoperatively. Final outcomes were good in all cases.

Missense mutation of the MET gene detected in human glioma.

Multiple mechanisms, such as gene mutations, amplifications, and rearrangements, as well as perturbed mitogen and receptor function, are likely to contribute to glioma formation. The MET (also known as c-met proto-oncogene located at 7q31-34 has been shown to be amplified in human gliomas, and activating mutations within the tyrosine kinase domain of MET have been causally related to tumorigenesis in hereditary papillary renal cell carcinoma. To elucidate the role of MET gene in glioma formation, sporadic gliomas from 11 patients were examined for MET gene mutations and allelic duplications or deletions by polymerase chain reaction-single strand conformational polymorphism analysis and fluorescence in situ hybridization. Three of 11 sporadic gliomas showed a deletion of one copy of the MET gene, and a specific METgene missense mutation in the remaining gene copy was detected in one of those tumors. The corresponding sequence in non-tumor DNA was normal in all cases. Three of 11 sporadic gliomas showed duplication of one copy of the MET gene, but none of them contained mutations. One tumor showed METamplification without mutation. Three showed neither allelic change nor mutation. These data suggest that somatic MET gene mutation may play a role in the development of a subgroup of sporadic gliomas. However, MET mutations appear to be absent in the majority of sporadic gliomas.

Cellular distribution of isozymes of protein kinase C in septal olfactory epithelium of mice.

To determine the presence of protein kinase C (PKC) isozymes in the septal olfactory epithelium of mice (mSOE), western blotting and immunohistochemistry were performed using antibodies against PKC isozymes. With the exception of PKC-betaI, all of the PKC isozymes were detected in the whole lysate of septal tissue layer and apparent molecular weights for each isoform were found. PKC-alpha, PKC-gamma and PKC-epsilon were detected in the olfactory glandular cells of the lamina propria, and PKC-betaI and PKC-betaII were located in the microvillar cells. Neither novel PKC nor atypical PKC was detected in olfactory glandular cells or microvillar cells, except for PKC-epsilon. PKC-lambda was localized in the mucous layer of the mSOE. Meanwhile, PKC-delta and PKC-xi were distributed in the receptor cells in the mSOE. These data demonstrate the isoform-specific expression of PKC in mSOE and suggest a role for the novel and atypical types of PKC in olfactory transduction.

Limitations on the quantitative determination of telomerase activity by the electrophoretic and ELISA based TRAP assays.

Telomerase is a promising new tumor marker and can be detected using the TRAP (Telomeric Repeat Amplification Protocol) method. To address factors affecting its quantitative determination, we evaluated two commercial TRAP assays, an electrophoretic and an ELISA assay formats, using cultured cells and human tumor samples. We found that both TRAP assays had a limited linearity from 250 to 5000 tumor cells, with a similar intra-assay variation. The quantification of TRAP products was affected by high cell number in sample, the presence of non-tumor cells, and interfering substances in patient specimens. Because both assays have different limitations, determination of telomerase by a combined use of the two may provide more accurate information on the telomerase activity in a specimen. Extracts of specimens should also be tested at several concentrations to insure that the result is not being falsely decreased by an inhibitor. The quantitative results for telomerase activity by the TRAP assays, however, should be interpreted cautiously.

Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the development of endocrine tumors of the parathyroid and pituitary glands, pancreas, and duodenum. Less frequently occurring tumors associated with MEN1 include non-endocrine tumors such as lipomas and angiofibromas. An increased incidence of thyroid neoplasms, leiomyomas, adrenal cortical hyperplasia, hepatic focal nodular hyperplasia, and renal angiomyolipoma has been noted in the MEN1 population. The pathogenesis of non-neuroendocrine tumors in MEN1 is unknown. We report a complex clinical course and a detailed morphologic and genetic analysis of a series of tumors that developed in a patient with MEN1. All tumors were microdissected and analyzed for loss of heterozygosity of the MEN1 gene. A germline mutation of the MEN1 gene was detected, and deletions of the MEN1 gene were consistently detected in multiple neuroendocrine tumors involving the parathyroid glands and the pancreas and a hepatic neuroendocrine tumor metastasis, as predicted by Knudson's "two hit" hypothesis. Two hits of the MEN1 gene were also detected in esophageal leiomyoma tissue, suggesting that tumorigenesis was directly related to the patient's underlying MEN1. In contrast, follicular thyroid adenoma, papillary thyroid carcinoma, hepatic focal nodular hyperplasia, and adrenal cortical hyperplasia consistently showed retained heterozygosity of the MEN1 gene with flanking markers and an intragenic marker. Therefore, these tumors appear to develop along pathogenetic pathways that are different from classical MEN1-associated tumors.

Deletion analysis of the adenomatous polyposis coli and PTCH gene loci in patients with sporadic and nevoid basal cell carcinoma syndrome-associated medulloblastoma.

BACKGROUND: Medulloblastomas can occur sporadically or may be associated with hereditary tumor syndromes including familial adenomatous polyposis (FAP) and nevoid basal cell carcinoma syndrome (NBCCS). METHODS: The authors performed a retrospective analysis for allelic deletion of the adenomatous polyposis coli (APC) and PTCH gene loci using paraffin embedded medulloblastoma specimens from patients who were admitted to Children's National Medical Center in Washington, DC, between 1982 and 1997. Thirty-five cases from which tumor and normal tissue could be procured were analyzed. Two of the analyzed cases had a positive family and personal history for NBCCS; in both cases the histology of the medulloblastoma revealed a desmoplastic phenotype. Thirty-three cases were not known to be associated with hereditary disease; 2 of those cases revealed desmoplastic and 31 cases revealed nondesmoplastic "classic" medulloblastoma histology. RESULTS: Although medulloblastoma tumorigenesis has been associated strongly with FAP associated with APC germline mutation, none of the 22 informative sporadic cases revealed loss of heterozygosity of the APC gene locus. PTCH gene deletion was detected in the tumors of both patients with NBCCS. In contrast, only 1 of 33 sporadic medulloblastomas revealed PTCH gene deletion. The sporadic case with PTCH gene deletion did not demonstrate the desmoplastic phenotype. CONCLUSIONS: In conjunction with previous studies, the data from the current study confirm that allelic deletion occurs in NBCCS-associated medulloblastomas, consistent with the role of PTCH as a tumor suppressor gene. However, in sporadic medulloblastomas, allelic deletion of PTCH is an infrequent event. Morphologic examination in conjunction with genetic analysis of PTCH gene deletion in medulloblastoma tissue may prove to be a quick and efficient test with which to screen for NBCCS in patients with medulloblastomas. Although medulloblastoma is a component of Turcot syndrome with demonstrated APC mutations, APC gene deletions appear to be absent or very uncommon in patients with sporadic and NBCCS-associated medulloblastomas.

Telomerase activity in microdissected human gliomas.

Future improvements in the diagnosis and treatment of human gliomas might rely on obtaining more specific information concerning the biologic characteristics of individual tumor cells. Telomerase, a ribonucleoprotein that synthesizes telomeres, has been reported to be expressed in a majority of human tumors, including several subtypes of brain tumor. We hypothesized that a quantitative assay for telomerase activity, combined with selective microdissection of tumor or normal brain cells, might reveal telomerase gain-of-function to be important in the pathogenesis of gliomas and that telomerase levels might have prognostic significance. We used tissue microdissection for selective analysis of tumor cells obtained from eight patients with glioma, one with a meningioma, and one with a primary B-cell lymphoma of the central nervous system. Normal brain tissue microdissected from another patient was used as a control. Telomerase activity was screened by an electrophoretic method and then assayed by a quantitative ELISA method. All of the eight gliomas had positive telomerase activity, as did the lymphoma. The meningioma and normal brain were negative. Quantitative analysis of telomerase activity did not correlate with tumor grade nor predict outcome. Selective tissue microdissection, combined with qualitative and quantitative telomerase assays, permits rapid and reliable detection of telomerase activity in diverse brain tumor tissues. These preliminary findings suggest that telomerase reactivation is a frequent event in glioma tumorigenesis that can be sensitively and specifically detected in gliomas of all histologic grades. Furthermore, specific detection of telomerase reactivation represents another mechanism by which tumor formation and progression might become the target of novel therapeutics.

Mutation of the uracil DNA glycosylase gene detected in glioblastoma.

Despite extensive characterization of genetic changes in gliomas, the underlying etiology of these tumors remains largely unknown. Spontaneous DNA damage due to hydrolysis, methylation, and oxidation is a frequent event in the brain. Failure of DNA repair following this damage may contribute to tumorigenesis of gliomas. Uracil DNA glycosylase (UDG), an enzyme which excises uracil from DNA, is an important component of the base excision repair pathway. The sequence of a human homologue of uracil DNA glycosylase gene (UNG) has been recently identified. We performed PCR-based SSCP mutational analysis of UNG in 11 sporadic gliomas (six glioblastomas, two anaplastic astrocytomas, and three oligodendrogliomas) and eight glioblastoma cell lines. One out of six sporadic glioblastomas had a point mutation in exon 3, which resulted in a missense mutation in codon 143. None of the eight glioblastoma cell lines or the five non-glioblastoma sporadic gliomas showed a mutation. Genetic alterations of UNG may play a role in the development of a subset of primary glioblastomas.