Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.

Joint predisposition to malignant melanoma and nervous system tumors (NSTs) is a puzzle. Several melanoma susceptibility genes have been identified, including p16, a clustered tumor suppressor. However, the molecular bases of inherited proclivity to NSTs in the absence of a recognizable genetic syndrome are unknown. We analyzed two families with joint proneness to melanoma and NSTs in view of genetic linkage and identification of the causal molecular lesions. Highly informative linkage markers were used for segregation analyses of the predisposition alleles in the two pedigrees. Characterization of the molecular lesions required hemizygosity mapping based on microsatellite markers physically mapped to contigs of the 9p21 region and a Southern blot approach using several PCR-generated probes. Both families were found to be allelic and linked to p16 markers. In the family segregating the melanoma/NST syndrome, a large germ-line deletion ablated the whole p16, p19, and p15 gene cluster (or INK4 locus), whereas a more circumscribed molecular lesion disrupting p16 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome (MIM 155755). Our results suggest that multiple cancer susceptibility in these two families ensues from contiguous tumor suppressor gene deletion. Indeed, known phenotypes associated with germ-line p16 mutations and an apparent correlation between the deletion span and tumor spectrum in the two families suggest a new model of cancer pathogenesis based on the inactivation of contiguous tumor suppressor genes, an alternative to the established pleiotropic effects of single-gene disruption.

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

Neurologic complications of hairy cell leukemia.

Involvement of the nervous system in some forms of leukemia is a common, well-recognized problem. To our knowledge, no study has investigated hairy cell leukemia (HCL) with this question in mind, so we reviewed the records of 108 patients with HCL seen during a seven-year period. Neurologic complications developed in roughly 5% of these patients. Direct infiltration of the nervous system in cases of HCL has rarely been reported in the literature, and the clinico-pathologic appearance is insufficiently documented. We found no cases of direct invasion of the nervous system and only one case of vertebral-body invasion and radicular compression, indicating that epidural spread is also rare. Infection was the most frequent cause of neurologic problems in this series of patients with HCL.

Multifocal inflammatory leukoencephalopathy associated with levamisole therapy.

Cerebral demyelinating disease developed in a patient during adjuvant therapy with levamisole for malignant melanoma. This patient had no evidence of previous neurologic disease. Levamisole was administered for 5 weeks (total dose, 1,500 mg). Over a period of 3 weeks, the patient became progressively confused and ataxic. MRI with gadolinium enhancement demonstrated prominent multifocal enhancing white matter lesions. CSF examination revealed an inflammatory profile. After discontinuation of treatment with levamisole and a short course of corticosteroid therapy, the patient's condition dramatically improved. MRI also indicated improvement. Observations in our patient suggest that the leukoencephalopathy that developed in previously reported patients who received 5-fluorouracil and levamisole may have been caused at least partly by levamisole.

Paraneoplastic encephalomyelitis and seminoma: importance of testicular ultrasonography.

We report two patients with paraneoplastic limbic and brainstem encephalitis associated with occult nonmetastatic testicular seminoma. In each patient, the neoplasm was detectable only by testicular ultrasonography. Male patients with this syndrome in whom lung cancer is not found should undergo testicular ultrasonography as part of the search for an extrapulmonary neoplasm. A normal clinical testicular examination is insufficient to exclude an occult seminoma.

The natural history of asymptomatic meningiomas in Olmsted County, Minnesota.

To define the natural history of asymptomatic meningioma found incidentally on a neuroimaging study, we performed a retrospective analysis of 35 such patients. There were 32 women and three men, with a mean age of 67 years and a mean follow-up of 74 months. Four tumors had progressed on subsequent imaging, and one patient developed symptoms related to the meningioma. Noncalcified tumors were more likely to progress than calcified tumors.

Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies.

Type 1 antineuronal nuclear autoantibody (ANNA-1, also known as "anti-Hu") is a marker of neurologic autoimmunity that is highly associated with small-cell lung carcinoma (SCLC). To determine the spectrum of symptoms and signs as well as the frequency of cancer in adult patients who are seropositive for ANNA-1, we reviewed 162 sequential patients (67% female) identified as ANNA-1-positive in a comprehensive immunofluorescence screening test. In 21% of these patients, the antibody test requested by the physician was not ANNA-1. By the end of the follow-up period, cancer had been found in 142 patients (88%). Ten of these lacked evidence of SCLC (4 had prostate carcinoma, 3 breast carcinoma, 1 both prostate carcinoma and melanoma, 1 lymphoma, and 1 squamous-cell lung carcinoma). Of the 132 patients (81%) with proven SCLC, 17 had one or more coexisting malignant neoplasms (6 had renal carcinoma, 4 another lung primary carcinoma, 3 prostate carcinoma, 3 breast carcinoma, and 4 assorted neoplasms). The diagnosis of SCLC in 128 patients (97%) followed the onset of paraneoplastic symptoms. SCLC was identified in 10 patients by chest MRI after an equivocal chest radiograph or CT; in 28 by bronchoscopy, mediastinoscopy, or thoracotomy; and in 7 at autopsy. Neurologic signs in decreasing frequency were neuropathy (sensory > mixed somatic > autonomic > cranial [especially cranial nerve VIII] > motor), cerebellar ataxia, limbic encephalitis, polyradiculopathy, associated Lambert-Eaton myasthenic syndrome, myopathy, myelopathy, opsoclonus/myoclonus, motor neuronopathy, brachial plexopathy, and aphasia. Nineteen patients had a solely gastrointestinal initial presentation, including gastroparesis, pseudo-obstruction, esophageal achalasia, or other dysmotility. We conclude that seropositivity for ANNA-1 can expedite the diagnosis and treatment of otherwise occult cancer in patients, especially tobacco abusers, with varied neurologic and gastroenterologic presentations. The search for SCLC should not end on discovering a different neoplasm.

A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma.

We describe a family in which cutaneous malignant melanoma or cerebral astrocytoma, or both, developed in eight members over three generations. Other malignancies also occurred with a lesser frequency. In two patients with both malignant melanoma and astrocytoma, the brain tumor followed the diagnosis of melanoma by a period of 2 and 10 years and was the primary cause of morbidity and mortality. The findings in this family may represent a newly described genetic disorder.

Penicillamine-associated myasthenia gravis.

Electroneuromyographic studies have been reported as abnormal in only 9 of 23 cases of penicillamine-associated myasthenia gravis (MG). We report a patient with rheumatoid arthritis who developed clinical and electrodiagnostic evidence of myasthenia 7 months after beginning penicillamine therapy. Six months after discontinuing penicillamine, it was possible to discontinue anticholinesterase medications. With clinical improvement, electrodiagnostic studies (including single-fiber electrmyography) improved, serum antibody titers to human muscle acetylcholine receptor fell, and lymphocytes became more responsive to the nonspecific mitogen phytohemagglutinin. Evidence suggests that penicillamine-associated myasthenia is a distinct syndrome rather than the chance occurrence of two diseases. This syndrome is clinically and electrophysiologically distinguishable from idiopathic myasthenia only by the high remission rate after penicillamine is discontinued.

Multifocal leukoencephalopathy: occurrence during 5-fluorouracil and levamisole therapy and resolution after discontinuation of chemotherapy.

We report the fourth case of cerebral demyelinating disease associated with 5-fluorouracil and levamisole hydrochloride therapy for adenocarcinoma of the colon. The initial manifestations included subacute progressive decline in mental status, ataxia, dysarthria, and diplopia. Magnetic resonance imaging of the head demonstrated multifocal enhanced lesions in the white matter. The patient experienced improvement, without corticosteroid treatment, from 2 weeks to 4 months after cessation of chemotherapy.

Subdural hematoma in patients with systemic cancer.

We reviewed the medical records of 70 patients with systemic cancer in whom a subdural hematoma (SDH) developed. Among patients with a solid tumor, trauma and use of anticoagulants were common causes of SDH, and these patients had a relatively favourable outcome. Among patients with a hematologic cancer and in the rest of the patients with a solid tumor, coagulopathies and dural metastatic involvement were the most common causes of SDH. Recurrent SDH and death due to SDH were common in the latter group.

Herpes zoster-associated meningoencephalitis in patients with systemic cancer.

We reviewed the experience at the Mayo Clinic with neurologic complications related to herpes zoster in patients with systemic cancer. Aside from pain, the most common neurologic complication was zoster-associated meningoencephalitis, which occurred in 9 of 1,125 patients. In these nine patients, the most common underlying malignant lesions were chronic lymphocytic leukemia and lymphoma. All patients in whom meningoencephalitis developed had trigeminal zoster or disseminated zoster. The primary neurologic symptoms were headache, confusion, and somnolence. Nuchal rigidity and fever were uncommon. The response to treatment with acyclovir was generally favorable.

Subacute sensory neuronopathy associated with small cell lung carcinoma: diagnosis aided by autoimmune serology.

In two patients with subacute sensory neuronopathy associated with small cell carcinoma of the lung, the diagnosis of the paraneoplastic syndrome was aided by the finding, in highly diluted serum (1/500 and 1/2,000, respectively), of unusual and distinctive antinuclear antibodies with reactivity restricted to neuronal nuclei. Magnetic resonance imaging of the chest was instrumental in detecting both lung cancers.

Dysarthria and apraxia of speech associated with FK-506 (tacrolimus).

The immunosuppressive agent FK-506 (tacrolimus) is one of the agents most commonly used to prevent rejection after liver transplantation. Neurologic toxicity related to FK-506 has been reported, including speech disorders; however, a detailed analysis of the speech disorder associated with use of FK-506 has not been presented. Herein we describe a patient who exhibited mutism, then severe apraxia of speech with a concomitant hypokinetic, spastic, and ataxic dysarthria after administration of FK-506. His residual mixed dysarthria, without radiographic evidence of a structural lesion, suggests dysfunction of one or more neurochemical systems. The pathophysiologic mechanisms underlying this intriguing entity remain obscure.

Magnetic resonance imaging in cancer-related lumbosacral plexopathy.

OBJECTIVE: To study the relative utility of computed tomography (CT) and magnetic resonance imaging (MRI) of the lumbosacral plexus in patients with systemic cancer and plexopathy. DESIGN: In a retrospective study, we identified all patients encountered at Mayo Clinic Rochester between 1987 and 1993 with a diagnosis of lumbosacral plexopathy, and we selected for analysis those with MRI scans of the plexus (an abnormal finding was not necessary for inclusion) and a clinical and electrophysiologic appearance consistent with a diagnosis of metastatic lumbosacral plexopathy. MATERIAL AND METHODS: The study group consisted of 31 patients (20 men and 11 women). The types of tumor were as follows: prostatic, 10 patients; colorectal, 7; bladder, 3; cervical, 3; and other, 8. Eighteen patients had received pelvic radiotherapy before diagnosis of lumbosacral plexopathy. All available MRI scans (in 27 patients) were reviewed blinded; the initial imaging report was used if the actual scans were unavailable (in 4). CT had been done in 22 patients, and results for 16 were available for blinded review. Original reports were available for the other six. RESULTS: Direct involvement of the lumbosacral plexus by tumor was evident on 23 MRI studies, and 6 others showed widespread metastatic disease in the region of the plexus. On 13 CT examinations, direct involvement of the lumbosacral plexus by tumor was noted. In four patients, MRI findings were abnormal and CT findings were normal. No patient had abnormal CT findings and normal MRI findings. CONCLUSION: In this retrospective review, MRI was more sensitive than CT for diagnosing cancer-induced lumbosacral plexopathy. Thus, use of MRI should be considered in the diagnostic work-up of patients with clinical and electrophysiologic evidence of plexopathy and suspected systemic cancer.

Paraneoplastic cerebellar degeneration: a clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies.

In a review of 32 patients with paraneoplastic cerebellar degeneration (PCD), 16 (all of whom were women) had Purkinje cell cytoplasmic antibodies (PCAb) and 16 (8 women) did not. Most patients (15 of 16 seropositive and 12 of 16 seronegative patients) had active cancer at the time of neurologic diagnosis. Gynecologic or breast cancers were found in 14 of 16 seropositive and in 2 of 8 seronegative female patients; lung cancer was diagnosed in 7 of 16 seronegative patients but in no seropositive patient. In seropositive patients, the onset of the syndrome was more often abrupt and abnormalities of affect, mentation, ocular motility, and cerebrospinal fluid IgG index were more common than in seronegative patients. Additional paraneoplastic neurologic syndromes were present in five seronegative patients but in no seropositive patient. Clinical impairment was equivalent in both groups; approximately 75% of patients were confined to a wheelchair or bed at last follow-up. Four of 16 seropositive patients died (4 to 18 months after onset of PCD), and 7 of 16 seronegative patients died (7 to 120 months after onset of PCD). Thus, PCAb seem to be a marker for a clinical subset of female patients with gynecologic or breast cancer. The high frequency of other autoimmune paraneoplastic syndromes in patients with seronegative PCD suggests that PCD in both seropositive and seronegative patients may have a common pathogenic basis that involves an as yet unidentified antineuronal autoimmune mechanism.

Investigation of germline PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 alterations in familial glioma.

Epidemiological studies suggest that some familial aggregations of glioma may be due to inherited predisposition. Many genes involved in familial cancers are frequently altered in the corresponding sporadic forms. We have investigated several genes known to be altered in sporadic gliomas for their potential contribution to familial glioma. Fifteen glioma patients with a family history of brain tumors were identified through the Mayo Clinic Department of Neurology (nine diffuse astrocytomas, two oligodendrogliomas, two mixed oligoastrocytomas, one pilocytic astrocytoma, and one pineal glioma). Eleven of the propositi had one or more first degree relative with a glioma. Lymphocyte DNA was derived from each of the patients and analyzed by polymerase chain reaction (PCR) and direct sequencing of the PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 genes. In addition, fluorescence in situ hybridization (FISH) was performed on EBV-transformed lymphocytes from each affected individual to detect germline copy number of the p16(INK4A)/p14(ARF) tumor suppressor region. A p53 germline point mutation was identified in one family with some findings of Li-Fraumeni syndrome, and a hemizygous germline deletion of the p16(INK4A)/p14(ARF) tumor suppressor region was demonstrated by FISH in a family with history of both astrocytoma and melanoma. Thus, whereas germ-line mutations of PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 are not common events in familial glioma, outside of familial cancer syndromes, point mutations of p53 and hemizygous deletions and other rearrangements of the p16(INK4A)/p14(ARF) tumor suppressor region may account for a subset of familial glioma cases. Collectively, these data lend genetic support to the heritable nature of some cases of glioma.

Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

We have examined a series of 135 gliomas for alterations of the p53, CDKN2A (p16) and PTEN tumor suppressor genes (TSGs) in order to evaluate the incidence of their inactivation as a function of tumor malignancy and cellular differentiation, and to examine potential associations with patient outcome. The composition of this series, classified using WHO criteria, is as follows: 27 grade 2 tumors (11 astrocytomas, 12 oligoastrocytomas, 4 oligodendrogliomas), 42 grade 3 tumors (22 astrocytomas, 16 oligoastrocytomas, 4 oligodendrogliomas), and 66 grade 4 tumors (63 astrocytomas and 3 oligoastrocytomas). Similar frequencies of p53 mutation were observed among grade 2 (37.0%), and grade 3 tumors (38.1%), as well as between astrocytomas and mixed tumors. CDKN2A and PTEN mutations were clearly associated with increasing tumor malignancy (occurring in 0% of grade 2 tumors, 14.3% and 4.8% respectively of grade 3 tumors, and 27.3% and 30.3% respectively of grade 4 tumors) and were observed at substantially higher rates among astrocytomas. For the tumor suppressor genes examined, there was no relationship between the occurrence of any two TSG inactivation events. With regard to outcome, the p53 genetic status showed no significant relationship with patient survival. The CDKN2 and PTEN alterations were negative prognostic indicators of survival when evaluated in all 135 gliomas, but failed to predict outcome when evaluated in either of the high grade (3 or 4) tumor groups.

Detection of p16, RB, CDK4, and p53 gene deletion and amplification by fluorescence in situ hybridization in 96 gliomas.

Inactivation of the p53 gene is a common early event of astrocytoma tumorigenesis. Alternatively, since the p16, retinoblastoma (RB), and CDK4 genes have been implicated in malignant progression, detection of losses or amplifications of these genes in gliomas could be diagnostically, prognostically, and therapeutically important. We obtained smear preparations from 96 diffuse gliomas and 10 nonneoplastic specimens. Dual-color fluorescence in situ hybridizations using paired probes for CEN9/p16, CEN8/RB, CEN17/p53, and CEN12/CDK4 were performed and revealed expected frequencies of abnormalities, except for p53 losses, which were low (7%). The latter supports the concept that p53 inactivation usually occurs by mitotic recombination. Detected abnormalities of the p16/RB/CDK4 pathway were highly associated with astrocytic differentiation and were univariately associated with decreased patient survival. However, only patient age and histologic classification retained statistical significance on multivariate analysis. We conclude that in diffuse gliomas, p16/RB/CDK4 abnormalities are markers of astrocytic phenotype. Thus, their detection by fluorescence in situ hybridization may have diagnostic usefulness in cases with equivocal morphologic features. Although our numbers are small, we find no additional prognostic significance to these genetic abnormalities one age, grade, and oligodendroglial histology are taken into account.

Gliosis specimens contain clonal cytogenetic abnormalities.

The relevance of sex chromosome aneusomy and trisomy 7 in neoplastic brain tissue is controversial. For better understanding of the relative importance of these anomalies, we made a conventional cytogenetic study of cells from tissue obtained from patients who underwent partial cerebral resection for a seizure disorder. Each specimen exhibited "gliosis," but none contained histologically identifiable tumor cells. Sixty-six specimens were analyzed by routine cytogenetic methods. Nonclonal abnormalities were observed in 11.6% of the cells (86% of cases) analyzed. In 11 cases, however, simple clonal karyotypes were observed. Of these cases, six involved loss of a Y chromosome and three involved loss of an X chromosome. Among the cases with loss of an X chromosome, two exhibited multiple abnormal clones. One of these cases had trisomy 7 as well as trisomy 18, and another had a supernumerary psu dic(15)(q13). The supernumerary chromosome was constitutional. One patient had possible Klinefelter syndrome. An additional case had a clonal del(10)(q23) that may have resulted from a hereditary fragile site. We conclude that although some of the apparently acquired clonal and nonclonal abnormalities may be due to a consistent in vitro artifact, it is probable that they are present in the brain tissue itself. Whatever the cause, caution should be used in interpretating cytogenetic abnormalities observed in brain tumor specimens.