Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.

OBJECTIVE: To report the presence of microscopic neoplasms of the testis in men with anti-Ma2-associated encephalitis (Ma2-encephalitis) and to discuss the clinical implications. METHODS: Orchiectomy specimens were examined using immunohistochemistry with Ma2 and Oct4 antibodies. RESULTS: Among 25 patients with Ma2-encephalitis younger than 50 years, 19 had germ-cell tumors, and 6 had no evidence of cancer. These 6 patients underwent orchiectomy because they fulfilled five criteria: 1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis, 2) life-threatening or progressive neurologic deficits, 3) age < 50 years, 4) absence of other tumors, and 5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications. All orchiectomy specimens showed intratubular-germ cell neoplasms unclassified type (IGCNU) and other abnormalities including microcalcifications, atrophy, fibrosis, inflammatory infiltrates, or hypospermatogenesis. Ma2 was expressed by neoplastic cells in three of three patients examined. Even though most patients had severe neurologic deficits at the time of orchiectomy (median progression of symptoms, 10 months), 4 had partial improvement and prolonged stabilization (8 to 84 months, median 22.5 months) and two did not improve after the procedure. CONCLUSIONS: In young men with Ma2-encephalitis, 1) the disorder should be attributed to a germ-cell neoplasm of the testis unless another Ma2-expressing tumor is found, 2) negative tumor markers, ultrasound, body CT, or PET do not exclude an intratubular germ-cell neoplasm of the testis, and 3) if no tumor is found, the presence of the five indicated criteria should prompt consideration of orchiectomy.

A pilot study of dose-intensified procarbazine, CCNU, vincristine for poor prognosis brain tumors utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with O6-methylguanine DNA methyltransferase.

Administration of chemotherapy is often limited by myelosuppression. Expression of drug-resistance genes in hematopoietic cells has been proposed as a means to decrease the toxicity of cytotoxic agents. In this pilot study, we utilized a retroviral vector expressing methylguanine DNA methyltransferase (MGMT) to transduce hematopoietic progenitors, which were subsequently used in the setting of alkylator therapy (procarbazine, CCNU, vincristine (PCV)) for poor prognosis brain tumors. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells were collected by apheresis and enriched for CD34+ expression. Nine subjects were infused with CD34+-enriched cells treated in a transduction procedure involving a 4-day exposure to cytokines with vector exposure on days 3 and 4. No major adverse event was related to the gene therapy procedure. Importantly, the engraftment kinetics of the treated product was similar to unmanipulated peripheral blood stem cells, suggesting that the ex vivo manipulation did not significantly reduce engrafting progenitor cell function. Gene-transduced cells were detected in all subjects. Although the level and duration was limited, patients receiving cells transduced using fibronectin 'preloaded' with virus supernatant appeared to show improved in vivo marking frequency. These findings demonstrate the feasibility and safety of utilizing MGMT-transduced CD34+ peripheral blood progenitor cells in the setting of chemotherapy.

Novel chemotherapeutic approaches to brain tumors.

In reviewing the numerous investigational drug trials for patients with anaplastic gliomas over the past 20 years, it would be fair to say that there have been more than a few disappointments and that the real impact of many of these therapies on patients' duration and quality of survival has been minor at best. It is also fair to state that there has been progress in developing new types of chemotherapy and other agents, in devising new treatment strategies, and in gaining a deeper understanding of the problems that must be overcome to treat patients with anaplastic gliomas successfully. The past several years have seen the realization that oligodendroglioma, primary CNS lymphoma, and medulloblastoma are sensitive to chemotherapy treatments. It is hoped that future studies will delineate better the optimal use of chemotherapy for these tumors.

Paraneoplastic neuromuscular disorders-part I.

Paraneoplastic disorders ace uncommon but clinically important complications of a large number of neoplasms. Most paraneoplastic syndromes are thought to have an autoimmune etiology, although the weight of evidence supporting autoimmunity vanes among syndromes. Prompt diagnosis of a paraneoplastic disorder can increase the likelihood of a favorable neurologic and oncologic outcome. This article reviews the; clinical features, autoimmune aspects, diagnostic approach, and treatment options for patients with paraneoplastic disorders affecting the spinal cord, motor neurons, neuromuscular junction, and muscle. Part 2 of this review, to be published in the next issue, will discuss the paraneoplastic neuropathies.

Paraneoplastic neuromuscular disorders-part 2.

Paraneoplastic neuropathies are a clinically diverse group of disorders associated with a variety of neoplasms. This article reviews the clinical features, autoimmune aspects, diagnostic approach, and treatment options for patients with paraneoplastic neuropathies.

Dose-intensification of procarbazine, CCNU (lomustine), vincristine (PCV) with peripheral blood stem cell support in young patients with gliomas.

BACKGROUND: The regimen of procarbazine, CCNU, and vincristine is active against gliomas. Previous attempts at dose-intensification have been unsuccessful because of delayed and cumulative myelosuppression. We sought to determine whether peripheral blood stem cell (PBSC) infusions would allow dose-escalation and time compression. PROCEDURE: Eleven patients, age 2.8-35.9 years, with newly diagnosed (n = 10) or recurrent (n = 1) gliomas underwent PBSC harvesting after mobilization with G-CSF. Chemotherapy consisted of CCNU 130 mg/m2 on day 0, vincristine 1.5 mg/m2 on days 0 and 7, and procarbazine 150 mg/m2 on days 1-7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered 28 days apart or when counts recovered. Involved field radiation was administered to newly diagnosed high-grade glioma patients following recovery from chemotherapy. RESULTS: Compared to the standard PCV regimen given every 6 weeks, dose intensity received was 1.7- and 1.8-fold greater for CCNU and procarbazine. Chemotherapy was delivered on time in 33/41 (80.5%) courses. Four courses (9.8%) were complicated by absolute neutrophil counts < 200/microL; platelet nadirs < 50,000/microL occurred in two courses (4.9%). Fever with neutropenia complicated three courses. Eight of 9 patients with measurable disease had an objective decrease in tumor size and/or decreased enhancement. Median survival for patients with high-grade gliomas (n = 6) was 13 months. CONCLUSIONS: Dose-intensification of PCV is possible using PBSCs.

Phase II study of intracarotid or selective intracerebral infusion of cisplatin for treatment of recurrent anaplastic gliomas.

PURPOSE: To assess the response of patients with recurrent malignant gliomas to intra-arterial (IA) cisplatin. METHODS: Eligibility criteria included patients with recurrent supratentorial malignant gliomas and measurable, unilateral contrast-enhancing tumor located within the territory of one or two major cerebral arteries. Patients received 75 mg/m2 IA cisplatin every four weeks. Depending on individual patients' tumor topography, cisplatin was infused either into the cervical internal carotid artery (ICA) (15 patients), or into one or two major cerebral arteries (26 patients), most often the M1 segment of the middle cerebral artery. RESULTS: Of 40 patients evaluable for tumor response, four patients (10%) were responders and nine patients (22%) had disease stabilization. The median time to tumor progression among the 13 patients with tumor response or stable disease was 23.7 weeks. The response rate did not significantly differ between patients receiving ICA versus selective intracerebral infusion, although the latter group contained a higher proportion of glioblastoma. Tumor progression occurred solely as local failure in 33 patients (82%), with all enhancing tumor still located within the vascular territory infused with IA cisplatin. Ipsilateral vision loss occurred in two patients after ICA cisplatin but in none of the selective infusion patients. Seizures and/or transient or permanent neurologic deterioration occurred in four patients (27%) after ICA cisplatin and in 11 patients (44%) after selective intracerebral infusion. CONCLUSIONS: Although this was not a randomized comparison, selective intracerebral artery cisplatin infusion in this group of patients reduced the risk of eye toxicity, but did not produce a better tumor response rate, and carried a higher risk of neurotoxicity relative to ICA infusion.

Neurologic paraneoplastic syndromes.

Several neurologic paraneoplastic disorders are believed to be caused by an autoimmune reaction against antigen(s) co-expressed by tumour cells and neurons. Of the paraneoplastic syndromes, the evidence for an autoimmune etiology is strongest for the Lambert-Eaton myasthenic syndrome, in which autoantibodies downregulate voltage-gated calcium channels at the presynaptic nerve terminal. For other syndromes, including cerebellar degeneration, multifocal encephalomyelitis, sensory neuronopathy, limbic encephalitis, opsoclonus-myoclonus, stiff person syndrome, and retinal degeneration, the autoimmune theory is supported by the presence of specific antineuronal antibodies. These antibodies serve as a useful diagnostic tool, but their actual role in causing neuronal injury and clinical disease remains unclear. Further understanding of immunopathogenesis awaits successful experimental models. Among different syndromes, a varied proportion of patients shows neurologic improvement with immunosuppressive treatments; it is likely that many patients have already suffered irreversible neuronal injury at the time of diagnosis.

Anti-Hu-associated paraneoplastic sensory neuropathy responding to early aggressive immunotherapy: report of two cases and review of literature.

Anti-Hu-associated paraneoplastic sensory neuropathy (PSN) has been reported to be nonresponsive to immunotherapy or cancer therapy. We report 2 patients with anti-Hu-associated PSN who achieved sustained clinical improvement with early and aggressive immunotherapy 10-15 months before the diagnosis of small-cell lung carcinoma. Both had chronic "sensory neuronopathy plus"; in addition to sensory neuronopathy, case 1 had a motor-autonomic dysfunction with encephalopathy, and case 2 had a motor-autonomic dysfunction with swallowing difficulty. These two cases were unusual in that sustained clinical improvement was achieved with early aggressive immunotherapy before the detection of cancer and without any concomitant anticancer therapy or lowering of anti-Hu antibody titer. We believe that early and aggressive immunotherapy should be tried in any patient with anti-Hu-associated PSN, as it may induce sustained clinical improvement.

The prognostic impact of prior low grade histology in patients with anaplastic gliomas: a case-control study.

At the time of recurrence, the majority of low-grade cerebral gliomas transform to a higher grade of histologic malignancy. The purpose of this study was to determine the survival outcome for patients whose anaplastic gliomas began as low-grade tumors compared with patients with de novo high-grade gliomas. Seventy-seven (11.5%) of 667 patients with anaplastic gliomas consecutively treated at the University of Alabama at Birmingham had histologically proven prior low-grade tumors. As a group, the patients with prior low-grade tumors would be expected to have a relatively favorable outcome, as they were younger and had a lower proportion of glioblastoma multiforme than the patients with de novo anaplastic gliomas. The provide a valid comparison, we performed a matched case-control study. We matched 68 patients from the prior low-grade group one-to-one with patients from de novo group for tumor histology, age, Karnofsky performance scores, and type of surgery, without knowledge of outcome. The two groups received comparable radiotherapy and chemotherapy. For the 68 patients with prior low-grade tumor, median actuarial survival from the time of diagnosis of malignant degeneration was 19.7 months and the 5-year survival rate was 22%, compared with 22.0 months and 28% for the 68 matched de novo patients. Kaplan-Meier survival curves for the two group did not significantly differ (p = 0.24 by logrank test). There were no significant survival differences between the patient subsets of prior low-grade versus de novo with glioblastoma, anaplastic astrocytoma, or anaplastic oligodendroglioma/mixed anaplastic glioma. The data indicate that the currently available treatment options, the survival outlook for patients with anaplastic gliomas, whose tumors arose from transformation of low-grade gliomas, is equivalent to the prognosis for patients with de novo anaplastic gliomas.

Antiamphiphysin antibodies with small-cell lung carcinoma and paraneoplastic encephalomyelitis.

Paraneoplastic encephalomyelitis developed as the presenting feature of small-cell lung carcinoma in 3 patients. Two patients with paraneoplastic encephalomyelitis manifested predominantly as subacute sensory neuronopathy did not improve after prednisone treatment and chemotherapy. The third patient had severe axial and limb rigidity and myoclonus, which partially improved after chemotherapy and treatment with intravenous immunoglobulin and prednisone. Serum from each patient immunocytochemically stained the neuropil and to a lesser degree the neuronal cytoplasm in human cerebral and cerebellar cortex. On immunoblots of human neuronal extracts, each patient's serum contained high-titer IgG antibodies reacting with a protein band of apparent molecular mass 125 kd. This autoantibody pattern is indistinguishable from antibodies recently identified in several women with breast carcinoma and stiff-man syndrome. Screening of a human brain complementary DNA expression library with patient serum yielded clones whose sequence is identical to that of the synaptic vesicle-related protein amphiphysin. Reverse transcriptase-polymerase chain reaction demonstrated expression of amphiphysin in 8 of 10 small-cell lung carcinomas and in 5 of 14 breast carcinomas. These observations highlight the clinical and serological heterogeneity of paraneoplastic central nervous system disorders: Patients with a given clinical syndrome may have different antineuronal antibodies, and patients with a given autoantibody specificity have differing clinical presentations.

Expression of Hel-N1 and Hel-N2 in small-cell lung carcinoma.

Hel-N1 and HuD are neuron-specific RNA-binding proteins that are antigenic targets of anti-Hu antibodies. Although expression of Hu antigens is most commonly seen in small-cell lung carcinoma, their exact identity (e.g., Hel-NI, Hel-N2, HuD, and HuC cannot be distinguished by immunological methods. Analysis of messenger RNA expression is needed for this distinction. Here we demonstrate that Hel-NI and Hel-N2 are expressed in small-cell lung carcinoma using reverse transcription-polymerase chain reaction.

A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium.

PURPOSE: This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%. METHODS AND MATERIALS: In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). CONCLUSIONS: (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

Autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options.

The presence of specific antineuronal antibodies in some patients with paraneoplastic central nervous system (CNS) disorders supports the theory that these syndromes have an autoimmune etiology. The anti-Purkinje cell antibodies (APCAs) in some patients with paraneoplastic cerebellar degeneration and ovarian or breast carcinomas stain the cytoplasm of Purkinje cells. APCAs react with several distinct neuronal protein autoantigens, including proteins featuring a "leucine zipper" sequence motif, which suggests that they function in regulating DNA transcription. Type 1 anti-neuronal nuclear antibodies (ANNA-1) associated with paraneoplastic encephalomyelitis and small-cell lung carcinoma stain the nucleus and cytoplasm of all neurons, and react with a group of 35- to 40-kd proteins in neuronal immunoblots. The protein targets of ANNA-1 belong to a family of RNA-binding proteins that probably regulate posttranscriptional processing of RNA. Type 2 anti-neuronal nuclear antibodies (ANNA-2) associated with paraneoplastic opsoclonus-ataxia and breast carcinoma also produce a panneuronal immunocytochemical staining pattern, but react with a group of higher-molecular-mass proteins (53-61 kd and 79-84 kd); these autoantigens probably also function as RNA-binding proteins. Several patients with paraneoplastic stiff-man syndrome have antibodies against a 128-kd synaptic protein. These antineuronal antibodies are highly specific (but not infallible) diagnostic markers for the presence of a neoplasm in patients who present with neurological dysfunction. The actual role of these autoantibodies in the pathogenesis of neuronal damage and clinical disease remains to be determined. Current management options for patients with CNS neurological paraneoplastic syndromes are very limited. Only a small minority of patients with paraneoplastic cerebellar degeneration or encephalomyelitis show significant neurological improvement after successful tumor treatment and/or immunosuppressive treatments, while patients with paraneoplastic opsoclonus or stiff-man syndrome have a somewhat better outlook.

Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To examine the rate and duration of response of anaplastic oligodendrogliomas to a dose-escalated combination chemotherapy regimen consisting of procarbazine, lomustine (CCNU), and vincristine (PCV) and to evaluate the side effects of this treatment. METHODS: In this single-arm multicentered phase II study, patients with measurable, newly diagnosed or recurrent, contrast-enhancing anaplastic oligodendrogliomas were treated with up to six cycles of PCV. Central pathology and radiology review were mandatory, and rigorous response criteria based on imaging were used. RESULTS: Thirty-three patients entered the trial; nine were excluded subsequently, seven due to ineligible pathology. Eighteen of 24 eligible patients (75%) responded, nine completely (38%), four had stable disease (SD), and two progressed during the first cycle of PCV. Responses were observed in nine of 10 patients (90%) with a preexisting low-grade oligodendroglioma and 10 of 15 (67%) with necrotic tumors, called glioblastoma multiforme by some. Previously irradiated patients were as likely to respond to PCV as those newly diagnosed (11 of 15 [73%] v seven of nine [78%]). The median time to progression will be at least 25.2 months for complete responders, and was 14.2 months for partial responders and 6.8 months for stable patients. Four ineligible patients also responded to PCV; all had gliomas with oligodendroglial differentiation. All responders, eligible or ineligible, were stable or improved neurologically, but nine of 22 (41%) experienced a decline in Eastern Cooperative Oncology Group (ECOG) performance status of one grade while on PCV. Adverse events on treatment included a death from Pneumocystis pneumonia, a severe reversible encephalopathy due to procarbazine, an intratumoral hemorrhage, and a subdural hematoma. All other acute toxicities were anticipated and manageable. CONCLUSION: Anaplastic oligodendrogliomas are chemosensitive brain cancers. Patients with these tumors respond predictably, durably, and often completely to PCV, and many tolerate a dose-escalated formulation. Cooperative group and randomized trials will be necessary to explore fully the role of chemotherapy in the treatment of aggressive oligodendrogliomas.

Autoantibodies against the Hel-N1 RNA-binding protein among patients with lung carcinoma: an association with type I anti-neuronal nuclear antibodies.

Hel-N1 is a novel human complementary DNA encoding a neuronal RNA-binding protein which shares considerable sequence homology with the HuD protein, a target of type I anti-neuronal nuclear antibodies in patients with paraneoplastic encephalomyelitis. The aim of the present study was to determine the prevalence of antibodies against the Hel-N1 protein among patients with lung carcinoma, including those with paraneoplastic disorders. Sera from 45 patients with lung cancer (42 with small-cell carcinoma) and from 28 control patients with other neurological diseases were studied by enzyme-linked immunosorbent assay (ELISA) and by immunoblotting with recombinant Hel-N1 protein. Sixteen of the 45 lung cancer patients (14 with small-cell and 2 with undifferentiated carcinoma) had paraneoplastic encephalomyelitis and high-titer type I anti-neuronal nuclear antibodies; sera from each of these 16 patients also showed strong reactivity with Hel-N1 protein. The other 29 lung cancer patients, all of whom had neurological dysfunction and 24 of whom had known or suspected paraneoplastic disorders, lacked the type I antibody by standard testing. The mean anti-Hel-N1 titer (by ELISA) of sera from patients negative for type I anti-neuronal nuclear antibody was significantly less than that of the patients positive for the type I antibody, but exceeded that of the control patients with other neurological diseases (p < 0.001). Fifteen (52%) of the 29 type I antibody-negative patients had positive serum anti-Hel-N1 titers which did not overlap the high anti-Hel-N1 titers of the 16 type I antibody-positive patients.(ABSTRACT TRUNCATED AT 250 WORDS)