The effect of systemic human interferon-alpha administration to patients with glioblastoma multiforme

Summary This report presents the results of a phase I trial of the value of human leucocyte inferon-alpha in the treatment of glioblastoma. Twelve patients entered the trial. In one case we believe that the patient benefitted from the interferon treatment. CT scans of patients on interferon did not reveal the true extent of the tumorous tissue.     

Scalp metastases of glioblastoma multiforme: case report

Glioblastoma multiforme is an aggressive neoplasm of the central nervous system and skin metastases are extremely rare. In this article, a patient who had rapidly developing scalp masses after surgery for glioblastoma multiforme is presented. The metastatic masses with ulceration were disturbing for the patient and his family, so he was operated on for palliative resection of the tumor. The resulting extensive defect was reconstructed with a free latissimus dorsi flap. Healing phase was uneventful and he was discharged from the hospital on the ninth postoperative day. A palliative surgery, even if it may necessitate a complex reconstruction, can be recommended in specific cases to improve quality of life and to ease patient care.     

Influence of type and extent of surgery on early results and survival time in glioblastoma multiforme

Summary We studied the influence of the type of surgery (microsurgery or macrosurgery) and extent (complete resection with lobectomy, complete resection alone, partial resection with lobectomy or partial esection alone) on early postoperative results and survival time in 118 consecutive patients who underwent surgery for glioblastoma multiforme. Early results were assessed by the Karnofsky score at 4 weeks postoperatively. Survival was compared using Kaplan-Meier curves and Mantel statistics. The median survival time (MST) after microsurgery (12.1 months) was significantly longer than that after macrosurgery (7.3 months). The longer survial after microsurgery was, however, largely attributable to better early results and a consequently higher proportion of patients who could undergo radio-Theraphy. Complete resection was superior to partial resection. Additional lobectomy did not appreciably influence the early results and the MST in completely resected tumours. So the MST after complete resection in the microsurgical group without lobectomy was 12.6 months, with lobectomy 12.9 months. In the macrosurgical group the respective values were 7.4 months without and 8.2 months with lobectomy. In incompletely resected tumours lobectomy worsened the early results compared to incomplete resection alone and led to a shorter MST.     

Comparative genomic hybridization shows complex genomic changes of plasmacytoid urothelial carcinoma

ObjectivesTo describe genomic imbalances in plasmacytoid urothelial carcinoma (PUC), which is a rare and aggressive variant of urothelial carcinoma (UC).Methods and materialsIn total, 25 formalin-fixed paraffin-embedded PUCs were analyzed by metaphase comparative genomic hybridization. Genomic imbalances were considered to be characteristic if they were detected in≥20% of the cases. Chromosome regions deviating by≥3 standard deviations from the average chromosome profile were scored as chromosomal gains or losses. Copy-number variations (CNVs) of CDH1 (16q 22.1), SNAI1 (20q 13.1), CCND1 (11q13.3), ERBB2 (17q12), and FOXO3 (6q21) were validated using quantitative polymerase chain reaction.ResultsChromosomal aberrations were detected in every PUC analyzed, and the average number of aberrations was 10.24 (ranging from 1–15). Characteristic aberrations were gains on 1q (48%), 3p (20%), 6p (32%), 11q (72%), 15q (36%), 16q (44%), 17p (76%), 17q (88%), and 20q (88%) and losses on 2q (24%) 4p (36%), 4q (84%), 5q (44%), 6q (68%), 13q (20%), and Xq (52%). polymerase chain reaction-based analysis of CNV for CCND1 (11q13) showed a deletion in 73% of the cases. CDH1 (16q22) was deleted in 72% and amplified in 5%. ERBB2 (17q12) displayed remarkably few copy-number alterations, with only 14% showing an amplification. SNAI1 (20q13) showed reduced gene copy numbers in 59.1% of the cases, whereas no copy-number gains were detected. FOXO3 (6q21) exhibited the lowest number of copy-number alterations, with 9% of all cases showing an amplification.ConclusionsIn PUCs, the frequency of aneuploidy and the complexity of genomic changes per tumor are greater than those described in conventional UC. The aberrations described in PUC involve the same regions that are associated with aggressive biological behavior in conventional UC. Gains on 11q, 17q, 17p, and 20q and losses on 4q and 6q affect most PUCs and seem to harbor important chromosomal regions for PUC carcinogenesis. Large-scale deletions on chromosome 9 were not detected. CNV analysis indicates heterozygous deletion of CDH1 as one underlying mechanism of loss of membranous E-cadherin in PUC. Loss of CCND1 and SNAI1 is a common molecular feature and could contribute to the aggressive biological behavior of PUC.     

Calvarium mass as the first presentation of glioblastoma multiforme: A very rare manifestation of high-grade glioma

Glioblastoma multiforme (GBM) is a high grade glial tumor, primarily located in cerebral hemispheres. The most common clinical presentations are slowly progressive neurological deficit such as motor weakness, seizure, and headaches that last less than three months. Calvarium and extra-axial invasion are very rare and generally occur after a brain biopsy or surgery, or secondary to radiotherapy of primary intra-axial glial tumors. We report a case of GBM with calvarium involvement in a 60-year-old man who presented with a frontal bump and left-sided clumsiness. Imaging studies revealed a tumoral lesion that destroyed the frontal bone with white matter involvement of the frontal lobe and extension into the corpus callosum. Histopathological examination of intra-axial and extra-axial lesions revealed pleomorphic high-grade tumor with large areas of necrosis and hemorrhage. Immunohistochemical (IHC) studies confirmed GBM that spread directly into the dura, galea, and calvarium (positive reaction for GFAP, S-100, CD68, OLIG2, and p53). The patient was treated with radiotherapy (60 Gy/30 fractions) and concomitant temozolomide. Unfortunately, the patient died seven months after the initial diagnosis.     

Fatal outcome related to carmustine implants in glioblastoma multiforme

Following the resection of newly diagnosed or recurrent glioblastomas, local implantation of carmustine-impregnated biodegradable wafers (Gliadel) in the resection cavity constitutes an adjuvant therapy that can improve the possibilities of survival. However, some precautions should be taken regarding Gliadel implantation. We report three cases in whom patients with glioblastoma multiforme were implanted with fibrin glue-secured Gliadel after the lateral ventricles had been opened, and who later developed severe hydrocephalus leading to death. Although Gliadel may be an important adjunct to treatment, opening of the ventricles during surgery as part of its application should be considered a contra-indication.     

Head and Neck Squamous Cell Carcinoma in the Young: A Spectrum or a Distinct Group? Part 2

While most head and neck squamous carcinoma (HNSCC) occurs in older people, an increasing number of young patients are being affected worldwide, with up to 5.5% <40. These are predominantly oral and oropharyngeal cancers. Some patients have heavy exposure to the usual risk factors, but an increasing number do not. Part of this trend appears to be due to rising numbers of HPV associated tonsil carcinoma, particularly in males (smokers and non-smokers). A subset of young patients, however, is non-smoking females usually with tongue cancers, not related to HPV, the aetiology of which is unclear. Various mechanisms may be at work here: the variation in ability to detoxify the products of smoke and alcohol varies in individuals, which may explain why environmental exposure to smoke seems to play a role in some non-smokers with HNSCC. The role of marijuana remains possible but uncertain, and it may be that anaemia is a co-factor. There is an increased risk of HNSCC in first degree relatives of HNSCC patients, and while inherited syndromes associated with HNSCC are rare, elucidation of their genetics may help to develop our understanding the disease in these young patients without recognised risk factors.     

Concomitant bone marrow metastasis of a glioblastoma multiforme revealed at the diagnosis

Summary The rare occurrence of extra-neural metastases in patients having a tumour of the central nervous system (CNS) could mean that the symptoms of a metastatic lesion are confused with a second pathology. We recently treated a patient with a glioblastoma multiforme who was developing a pancytopaenia at the initial diagnosis. The frequent red cell and platelet transfusions were transitorily active. An extensive radiological investigation and a unilateral iliac bone marrow aspirate and biopsy were performed. Cells immunoreactive to glial fibrillary acidic protein were detected in a specimen obtained from the iliac bone. Post-mortem examination confirmed metastasis to extra-cranial bone and revealed other metastases in lung, mediastinal lymph node and spleen. Therefore, in patients with malignant glioma tumours, bone marrow metastasis, though not common, should be investigated when bone pain or cytopaenia occur.     

Complete remission of recurrent glioblastoma multiforme following local infusions of lymphokine activated killer cells

Summary We report the case of a 26-year-old man in whom glioblastoma multiforme had recurred six months following a subtotal resection. Despite radiotherapy and a course of interferon beta and ACNU, the tumour increased in size (to 3 cm) and there was neurological deterioration. Treatment was then initiated with LAK cells, together with ACNU and interferon beta. After three courses of LAK cells, tumour size was markedly reduced, and at about six months the tumour had nearly disappeared on computed tomographic (CT) scans. At one year, and after nine courses of LAK cell therapy (total dose of 2.7×10⁹ cells) infused via an Ommaya reservoir and supplemented by ACNU and interferon beta, the tumour has disappeared and the patient is considered to be in complete remission since 6 months. This marked response is thought to be due chiefly to LAK cell therapy. The relatively low dose administered was well-tolerated.     

Cell death induction by betulinic acid,ceramide and TRAIL in primary glioblastoma multiforme cells

Summary Background. Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. Method. Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and -irradiation). Findings. At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death 75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of -irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. Conclusion. Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM.     

比较基因组杂交研究瘢痕疙瘩遗传变异

目的 了解瘢痕疙瘩遗传学改变的特征。方法 应用比较基因组杂交技术研究6例瘢痕疙瘩基因组的不平衡即遗传物质的丢失或扩增情况。结果 瘢痕疙瘩出现高频率的DNA拷贝数缺失的染色体是1p(66．7％)、16号染色体(83．3％)、20号染色体(83．3％)、22号染色体(83．3％)，其最小重叠区分别为1pter-32．2、16p13．2-p11．1、20q11．1-q13．2、16p13．2-p11．1，未发现特异区域的DNA拷贝数的高频率扩增。结论 1p、16号染色体、20号染色体、22号染色体极可能存在相关的瘢痕疙瘩抑制基因，这些基因的丢失可能参与了瘢痕疙瘩的发生、发展。     

Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) in the diagnosis of hepatocellular carcinoma

Background: The histomorphological diagnosis of well differentiated hepatocellular carcinoma (HCC) may be a challenging task, because regenerative nodules and adenomas share similar microscopic features. Moreover, the differentiation of intrahepatic metastatic spread from multicentric growth in multinodular HCC is frequently not possible by histological criteria alone. Whether molecular cytogenetic analysis can contribute to the differential diagnosis of HCC was recently investigated by our group. Methods: We applied comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) to 12 cases of hepatocellular adenoma (HCA) and 28 cases of well differentiated HCC. Results: CGH revealed aberrations in 2/6 HCAs, affecting 7p in 1 sample each and 17q and 20 in the second case. In 4/4 well differentiated HCCs, aberrations occurred, with a mean of eight aberrations per case, focused on 1q, 4q, 8p, 8q, 16p, and 17p. In all HCC samples, at least two of these sites were affected. In 2 multinodular HCCs, six and four different tumor nodes, respectively, were analyzed. In the first case, aberration patterns of chromosomes 1, 4, 5, 9, 13, and 17 were almost identical in all six nodes, indicating metastatic spread. In the second case, three of the nodes showed very similar patterns of chromosome aberrations, including those of chromosomes 1, 4, 5, 7, 8, 10, 12, 14, 17, and 18. Aberrations of chromosomes 4, 5, 8, 10, 12, and 15 were shown in the fourth node, findings conclusive for both the metastatic spread and the multicentric origin of the HCC. Based on the CGH results, five probes, for chromosomes 1, 6, 7, 8, and X, were selected for FISH. Using this panel, we found no aberrations in 14 HCAs. By contrast, 13/14 HCCs demonstrated aberrations for two to five chromosomes in the FISH analysis. Conclusions: We conclude that CGH and FISH are helpful diagnostic tools for the histopathological differential diagnosis of HCC. Received: April 8, 2001 / Accepted: May 11, 2001     

Extremely rare glioblastoma multiforme of the conus medullaris with holocord and brain stem metastases, leading to cranial nerve deficit and respiratory failure: a case report and review of the literature

BACKGROUND: Spinal glioblastoma multiforme (GBM) is an uncommon entity and metastases are extremely rare. Glioblastoma multiforme of the conus medullaris is a rare and highly aggressive entity that can quickly progress to a dismal state. Proper diagnosis via histopathologic and immunochemical staining with close clinical and radiological follow-up is important for the management of this very aggressive tumor. CASE DESCRIPTION: The authors report the clinical features, histopathologic and immunochemical staining characteristics, as well as the radiographic evidence of a case of primary GBM of the conus medullaris with metastases to the whole spinal cord and brain in a 20-year-old man who presented with low back pain and bilateral lower extremity weakness and numbness. Review of the pathology slides using histopathologic and immunochemical staining showed GBM. Serial magnetic resonance scans, performed after the initial surgery, demonstrated enlargement of the primary GBM in the conus medullaris with metastases to the thoracic and cervical spinal cord as well as to the brain. CONCLUSIONS: Glioblastoma multiforme of the conus medullaris with such clinical findings is extremely rare. We analyze similar cases in the literature and discuss the importance of monitoring the progression of such an entity as well as the need for aggressive management of the different complications as they arise to maintain a good quality of life.     

比较基因组杂交检测散发性结直肠癌染色体变异的临床意义

目的了解散发性结直肠癌（SCRC）的染色体变异及其与SCRC临床病理特征的关系。方法采用比较基因组杂交（CGH）技术检测40例SCRC的染色体变异情况,分析其与临床病理特征的关系。结果40例SCRC患者CGH检测结果显示．所有病例均有不同程度的染色体臂发生扩增或丢失,平均每例变异数为7．55,扩增数为4．73,丢失数为2．83。染色体扩增区域有20q、12q、13q、7P、7q和16q;缺失区域有18q、5q、4q、8P和17P。结直肠癌TNM分期中Ⅲ、Ⅳ期患者的染色体总变异数和扩增数、缺失数均高于Ⅰ、Ⅱ期患者。本组患者染色体总变异数、扩增数和丢失数在不同的肿瘤部位、组织学类型和分化程度间比较．差异均无统计学意义。20q的扩增与TNM分期有关。结论染色体变异在SCRC中普遍存在,SCRC的染色体变异数及20q的扩增与TNM分期有关。     

Prognosis factors of survival time in patients with glioblastoma multiforme: a multivariate analysis of 340 patients

Summary Background. The prognosis of glioblastoma multiforme remains poor despite recent therapeutic advances. Several clinical and therapeutic factors as well as tumour characteristics have been reported as significant to survival. A more efficient determination of the prognostic factors is required to optimize individual therapeutic management. The aim of our study was to evaluate by univariate then multivariate analysis the factors that influence prognosis and particularly survival. Methods. Data of 340 patients with newly-diagnosed GBM were retrospectively analyzed. Univariate analysis of prognosis factors of survival time was performed. Factors that seemed determinant were evaluated by Kaplan–Meier survival curves. Finally, the significant factors found in univariate analysis were tested in multivariate analysis using the COX regression method. Findings. Using multivariate analysis, the following factors were found to influence survival: radiotherapy was the predominant factor followed by radical surgery, tumour location, age and chemotherapy. Patients treated with temozolomide had a markedly better survival rate than patients treated with other chemotherapies (Log-rank test P < 0.005). The values of GBM type (de novo or secondary), as well as repeated surgery and partial surgery (vs. simple biopsy) were suggested by univariate analysis but not confirmed by the COX regression method. After radical surgery, progression-free survival was correlated to overall survival (r = 0.87, P < 10e-5). Conclusions. The influence of radiotherapy on survival was greater than the influence of age, an argument supporting the proposition of radiotherapy for patients until at least age 70. In the case of recurrence, the correlation between overall survival and progression-free survival is an important factor when considering the therapeutic options. Initial radical surgery and repeated procedures dramatically influence survival. The benefit of partial surgery remains difficult to evaluate. Partial surgery could be used to decrease intracranial pressure and to minimize residual tumours in order to enable treatment by chemotherapy and radiotherapy. The value of temozolomide treatment was confirmed.     

Occurrence of glioblastoma multiforme in three closely related patients

Three cases of glioblastoma multiforme are presented. These cases have in common the fact that all three patients were relatives but not blood relatives. There had been prolonged intimate contact between them before the development of the neoplastic lesion.     

A very rare case report of long-term survival: A patient operated on in 1994 of glioblastoma multiforme and currently in perfect health

IntroductionGlioblastoma multiforme is the most aggressive type of primary brain tumors, but there is a small percentage of patients who have a long-term survival and some exceptional cases who survive decades after surgical removal of tumor.Presentation of caseIn 1994, a 44 year-old man, suffering from intense headache and loss of strength of the left arm, was operated for a glioblastoma multiforme in the posterior part of the right frontal lobe. After the operation the patient underwent whole-brain radiotherapy and chemotherapy. 22 years after surgery the patient has no recurrence of the tumor.DiscussionA very small percentage of glioblastoma cases showed >3 years survival. There have been exceptional cases of long-survival spanning 10 years or more, without tumor recurrence, so as to deem those affected ‘cured’. The long-survival for glioblastoma multiforme is linked to young age, to aggressive and complete surgical excision, a good Karnofsky index score before surgery, the application of radiotherapy after surgery and to the molecular make-up of a specific glioma.ConclusionThe fact that there are extremely rare cases of long-term survival and even zero recurrence of the glioblastoma should serve as a stimulus to continue the research effort and not give up the fight against this tumor on a day-to-day basis.     

比较基因组杂交研究原发性胃癌的遗传学变异

目的研究原发性胃癌发生、发展过程中遗传学变异情况。方法采用比较基因组杂交分析23例原发性胃癌基因组DNA拷贝数变化情况。结果原发性胃癌患者平均每例肿瘤染色体臂变化数为7.52,扩增数要明显多于丢失数(5.38∶2.14)。DNA拷贝数扩增常见于8q(9/21,42.9%)、20q(9/21,42.9%)、17q(8/21,38.1%)、3q(7/21,33.3%)、7q(7/21,33.3%)、11q(6/21,28.6%)、13q(6/21,28.6%)、1q(5/21,23.8%)、20p(5/21,23.8%);DNA拷贝数缺失常见于17p(7/21,33.3%)、18q(6/21,28.6%)、5q(5/21,23.8%)、8p(5/21,23.8%)、9p(5/21,23.8%)。结论原发性胃癌中存在多条染色体拷贝数的变化,由此引起相应癌基因的扩增和抑癌基因的丢失可能参与了胃癌的发生和发展。     

Molecular characteristics and pathways of Avastin for the treatment of glioblastoma multiforme

This article provides historical background and current research involving the use of bevacizumab for the treatment of recurrent glioblastoma. Although bevacizumab, approved by the Food and Drug Administration, prolongs glioblastoma progression free survivial, decreases tumor vascularization, and reduces permeability of vessels, it does not seem to prolong overall survival. Despite slowed primary tumor progression, bevacizumab treatment may facilitate transformation to a more invasive phenotype. Adaptive responses, which make glioblastoma particularly resistant to various treatment modalities have been described. Conferred benefits, adverse effects, mechanisms of resistance, and potential areas for future research are discussed.