Spontaneous neoplasms in aged control Fischer 344 rats.

Neoplastic lesions in untreated F-344 rats (740 males and 740 females) used as controls in carcinogenicity studies were evaluated and tabulated. The incidence of spontaneous tumors was 84.3% in the males and 76.2% in the females. In males, the most common neoplasms were testicular interstitial cell tumors (79.5%) followed by mononuclear cell leukemia/lymphomas (30.5%), pituitary adenomas (20.5%), pancreatic islet cell adenomas (6.5%), thyroid c-cell adenomas (5.7%), pheochromocytomas (5.7%), skin fibromas (3.2%), keratoacanthomas (1.9%), and thyroid follicular cell adenomas (1.9%). In females, the most common neoplasms were pituitary adenomas (30.3%) followed by mononuclear cell leukemia/lymphomas (20.5%), endometrial polyps (14.1%), mammary fibroadenomas (11.1%), thyroid c-cell adenomas (5.1%), mammary adenomas (1.9%), skin fibromas (1.1%), and clitoral carcinomas (1.1%). A variety of less common neoplasms were also observed in various other organs.     

Clinical epidemiology for childhood primary central nervous system tumors

This work was conducted by the French Brain Tumor Data Bank (FBTDB) and aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. Results concerning children are presented. This study analyzes the childhood cases (0–19 years) of newly diagnosed and histologically confirmed PCNST (during the years 2004–2006) which have been recorded by the FBTDB. All French neuropathology and neurosurgery departments participated in this program. Neurosurgeons and neuropathologists completed a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault was authorized to compile the data files with personal identifiers. About 1,017 cases (533 boys and 484 girls) of newly diagnosed childhood PCNST have been recorded (gliomas: 52%, all other neuroepithelial tumors: 31%, craniopharyngioma: 5%, germ cell tumors, meningioma and neurinoma: approximately 3% each, all histological subtypes have been detailed). Tumor resections were performed in 83.3%, and biopsies in 16.7%. The distributions by histology, cryopreservation of the samples, age, sex, tumor site and surgery have been detailed. To our knowledge, this work is the first databank in Europe dedicated to PCNST that includes the collection of clinical, radiological and histological data (including cryopreservation of the specimen). The long term goals of the FBTDB are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to evaluate and harmonize the healthcare of children and adult patients affected by PCNST. Luc Bauchet, Valérie Rigau are equally contributed to this work.     

Cisplatin-based chemotherapy in primary central nervous system germ cell tumors

We report a retrospective review of our experience with cisplatin-based chemotherapy in eight patients (ages 9–44 years) with histologically confirmed primary central nervous system germ cell tumors. Five patients received chemotherapy as the primary treatment, radiation therapy being administered either at completion of chemotherapy or between chemotherapy courses. Three patients received cisplatin-based chemotherapy for recurrent disease after prior radiation therapy and/or surgery. Four of five patients treated with chemotherapy at diagnosis are in complete remission at 11–14 months from diagnosis. The remaining patient twice achieved complete remission prior to dying of progressive disease 16 months after diagnosis. Two of three patients treated with chemotherapy for recurrent disease are in complete remission at 20 and 26 months; the remaining patient deteriorated after the first cycle of chemotherapy and expired six months thereafter. Overall, of seven patients evaluable for response, five achieved complete remission with chemotherapy alone, and two with chemotherapy and radiation therapy. Our results confirm previous reports of high complete remission rates utilizing cisplatin-based chemotherapy in conjunction with radiation therapy. Prospective evaluation of cisplatin-based chemotherapy followed by radiation therapy is warranted.     

Clinical management of primary central nervous system germ cell tumors

Despite excellent long-term results for patients with germinoma treated with radiation therapy, the potential for late effects makes the treatment controversial. On the other hand, most patients with non-germinomatous tumors treated by conventional treatment with surgery and radiation therapy fail to survive longer than 3 years. After combination chemotherapy with cisplatin was confirmed to be effective in gonadal germ cell tumors, germ cell tumors of the brain became candidates for chemotherapy. The author reviews several prospective phase II studies that are being investigated to assess the effect of combination chemotherapy and radiation therapy for germ cell tumors. The aim of these studies is to reduce the volume and dose of radiation therapy for germinoma and prolong the survival of patients of non-germinomatous tumors. For germinoma, a trial with chemotherapy alone failed, with a high rate of recurrence, but Japanese and European trials with reduced-dose chemotherapy and a smaller volume of radiation therapy have resulted in high event-free survival (EFS) rates. Ongoing phase II studies with combined chemotherapy and radiation therapy for non-germinomatous tumors will result in a 5-year survival rate of greater than 50%, which is better than that achieved by radiation therapy alone.     

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

BackgroundLarotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors.MethodsPatients with TRK fusion-positive primary CNS tumors from two clinical trials ({"type":"clinical-trial","attrs":{"text":"NCT02637687","term_id":"NCT02637687"}}NCT02637687, {"type":"clinical-trial","attrs":{"text":"NCT02576431","term_id":"NCT02576431"}}NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR).ResultsAs of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. The 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45–100), 56% (95% CI: 38–74), and 85% (95% CI: 71–99), respectively. Median time to response was 1.9 months (range 1.0–3.8 months). Duration of treatment ranged from 1.2–31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3–4 in 3 patients. No new safety signals were identified.ConclusionsIn patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.     

Chemotherapy for metastatic tumors to the central nervous system

Management of patients with central nervous system metastases poses numerous challenges. This review focuses on the use of chemotherapy in these patients, addressing treatment difficulties such as drug resistance and possible solutions. The impact of the blood-brain barrier is considered less of a limitation than once thought. The advent of targeted signal transduction inhibitors is noted in this context. The current efficacy of chemotherapeutic agents and combinations is also discussed, with results from large studies highlighting a positive survival trend for chemotherapy in selected tumor histologies.     

Glioneuronal tumors of the central nervous system

Advances in the immunohistochemical detection of neuron-specific and neuronal-associated antigens have resulted in the discovery of neuronal elements in certain primary human brain tumors. The results have been not only to expand what neuropathologists commonly recognize as gangliogliomas, including the tumors now known as glioneurocytic tumor with neuropil rosettes and papillary ganglioneuroma, but also to expand the spectrum of tumor types to now include tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma. These discoveries have helped us to better understand the biology of these tumors and to refine our classification of them. Distinctions among these tumors include sites of predilection, such as the temporal lobe with the dysembryoplastic neuroepithelial tumors, and a spectrum of clinical aggressiveness that spans indolent “quasihamartomatous” lesions, such as the dysembryoplastic neuroepithelial tumor, to high-grade, highly aggressive tumors, such as the supratentorial primitive neuroectodermal tumor (World Health Organization Grade IV). Many of these tumors also commonly exhibit a glial component, as determined by both their histologic appearance and their immunoreactivity for glial fibrillary acidic protein. This review covers these recently described lesions, including the desmoplastic infantile ganglioglioma, the dysembryoplastic neuroepithelial tumor, the papillary glioneuronal tumor, the glioneuronal tumor with neuropil rosettes, and the mixed glioblastoma-cerebral neuroblastoma (supratentorial primitive neuroectodermal tumor), as well as the known tumors, ganglioglioma, medulloepithelioma, and medulloblastoma. For pathologists confronted by this growing array of tumors and subtypes, it is appropriate to focus on them and understand the differential diagnosis to be considered when confronted by them.     

Metastasis from the brain of transplanted N-ethyl-N-nitrosourea-induced central nervous system tumors in rats

Two transplantable rat central nervous system (CNS) tumors induced by N-ethyl-N-nitrosourea (ENU) were employed to study the mechanisms controlling extracranial metastasis from intracranial tumors. Cells derived from a serially passaged anaplastic astrocytoma and a malignant glioma were injected intracerebrally at doses of 10⁴, 10⁵ and 10⁶ cells per rat (Sprague-Dawley and WAG/Rij rats). As soon as neurological dysfunction appeared, animals were sacrificed and examined histologically for (1) extracerebral outgrowth of the intracerebral tumor, (2) the presence of distant metastases within the CNS and (3) remote metastases outside the CNS. In addition to histology, a bioassay procedure was performed. Metastases were found in cervical lymph nodes (74%), lung (21%) and liver (5%). For both tumor groups, rats with both distant CNS metastases and local extracerebral outgrowth developed remote metastases more frequently (P < 0.05) than animals with intracerebral growth only. The data indicate that both local extracranial spread due to surgical intervention as well as local and distant invasion of leptomeninges promote extracranial metastatic spread.     

Carcinogenicity of aflatoxicol in Fischer 344 rats

Aflatoxicol (AFL), a metabolite of aflatoxin B1 (AFB1), is formed in vitro by liver preparations from several species including humans. A positive correlation appears to exist between the sensitivity of a species to AFB1 and the species ability to metabolize AFB1 to AFL. Conversion of AFB1 to AFL is, therefore, a questionable detoxification step. The carcinogenicity of a diastereoisomeric mixture of AFL, prepared chemically from AFB1, was compared to AFB1 by tumor incidences being determined in 4 groups of 20 weanling male F344 rats fed either a negative control diet with no aflatoxin, a positive 50-ppb AFB1 control diet, a 50-ppb AFL diet, or a 200-ppb AFL diet for 1 year and then killed at the end of the 2d year. The respective hepatocellular carcinoma incidences were 0, 40, 20, and 70%, demonstrating that AFL is carcinogenic in the rat. The data show that a diastereoisomeric mixture of AFL is one-half as carcinogenic as AFB1, and the dose response appeared nearly linear in that a fourfold increase in dose produced a 3.5-fold increase in tumor incidence. The data did not establish unequivocally that AFL is a proximate carcinogen, but metabolism of AFB1 to AFL should not be considered an efficient detoxification reaction.     

Immunology of tumors of the central nervous system

Central nervous system (CNS) tumours possess special immunological features resulting from their development in an organ having a privileged immunological status. The following review gives a summary of actual data concerning their tumour-associated antigens, the immunological responses of their hosts and the mechanisms permitting them to escape from these responses. There is presently no proof of the existence of tumour-specific antigens on spontaneous glial tumours. Much progress has been made in this area with the development of monoclonal antibodies technology which mainly disclosed the profound antigenic heterogeneity of brain tumours. This heterogeneity could favour the escape of brain tumours from immunosurveillance; furthermore, it represents a major limitation to the use of monoclonal antibodies for diagnosis or therapy. Regarding the immunological responses of brain tumour patients, the main feature is a profound depression of cellular immunity creating an anergic state toward a large number of antigens. In vitro, it concerns specifically T4 helper lymphocytes: their mitogenic responses and secretion of interleukin-2 after antigenic stimuli are drastically reduced. Three phenomena have also been incriminated to explain the defect of immunosurveillance in brain tumour patients: 1) the synthesis by tumour cells of a protective mucopolysaccharidic coat, 2) the secretion by these cells of specific immunosuppressive factors related to cytokines, 3) the isolation of CNS maintained by the blood-brain barrier which regulates the circulation of immunocompetent cells between the intra- and extracerebral compartments. Currents efforts are focused on the individualization of therapy based on these biologic principles.     

Unrecognized visual field deficits in children with primary central nervous system brain tumors

Visual field deficits can be a consequence of brain tumor location or treatment. The prevalence of unrecognized visual field deficits in children diagnosed with brain tumors is not known. All children at a single tertiary care pediatric children’s hospital diagnosed with a primary brain tumor were tested for visual field deficits by a child neurologist and neuro-ophthalmologist over 16 months. Children with reproducible visual field deficits on two separate occasions were included in the analysis. Patients with optic glioma, craniopharyngioma, or previously known visual field deficits were excluded. Fourteen of 92 (15.2%) children (average 8.9 years, 8 girls) had undiagnosed visual field deficits. Average time between diagnosis of tumor and unrecognized visual field deficit was 3.7 years (range 0–13 years). Unrecognized visual field deficits were not associated with age (P = 0.27) or gender (P = 0.38). Visual field deficits were attributed to direct tumor infiltration (n = 8), postoperative complications (n = 5) and post-radiation edema (n = 1). Deficits included bitemporal hemianopsia (n = 2), homonymous hemianopsia (n = 9), quadrantanopsia (n = 2), and concentric visual field loss (n = 1.) Tumor location included temporal lobe (n = 9), parietal lobe (n = 2), posterior fossa (n = 2), hypothalamic-chiasmatic (n = 2) and multifocal areas (n = 4). Children with temporal lobe tumors were more likely to have unrecognized visual field deficits (P = 0.004). In all 14 patients, visual field deficits were determined by examination only and were not reported by either the patient or caregiver regardless of age. The prevalence of unrecognized visual field deficits in children with brain tumors can be surprisingly high. Serial neuro-ophthalmologic evaluation of children with brain tumors is often required to diagnose a visual field deficit since patient or caregiver reporting may be limited.     

原发性中枢神经系统淋巴瘤的治疗进展

原发性中枢神经系统淋巴瘤（PCNSL）是一种少见疾病,至今尚无标准治疗方案。单纯放疗复发率高,生存期短。放疗宜在化疗结束后进行。化疗联合标准放疗明显降低了复发率,并延长了生存期,但神经毒性发生率高。老年患者易出现神经毒性,不建议放疗,应首选单纯化疗;年轻患者可将放疗作为难治复发时的二线治疗。目前,以大剂量甲氨蝶呤为主的化疗已成为PCNSL的一线治疗,大剂量阿糖胞苷为最常联合的药物。年轻患者可选用包含一些新药如甲基苄肼、替莫唑胺的化疗方案。替莫唑胺为老年患者一种有前途的新药。预防性鞘内化疗的必要性尚未达成共识。自体造血干细胞支持下的大剂量化疗对年轻的初发及复发PCNSL患者均有效。手术通常用于PCNSL诊断。糖皮质激素不宜在取得病理组织前使用。      

Rejection of tumors and metastases in Fischer 344 rats following intratumor administration of killed Corynebacterium parvum

Killed Corynebacterium parvum vaccine was infiltrated into growing subcutaneous tumors (two antigenically different types) syngeneic to the Fischer 344 rats. In all these animals decrease in tumor size was followed by total and lasting disappearance. The protective response conferred as a result of intratumor C. parvum appeared to prevent progressive growth of potentially lethal pulmonary and visceral metastases. Animals which rejected their tumors showed an increased protection that was tumorspecific. Histological examination of tumors from rats exhibiting C. parvum-mediated rejection revealed an intense non-specific infiltration consisting mainly of macrophages with some lymphocytes. Of the groups of rats treated with surgical removal of the growing tumor, 30-60% died with growing tumors and metastases. Suppressed rates of tumor growth and prolonged survival were observed in the group of rats treated with killed C. parvum subcutaneously 1 cm around and away from the growing tumors.     

Primary central nervous system tumors in stillborns and infants

Summary An epidemiologic investigation of true neoplasms of the central nervous system in fetuses and infants in the German Democratic Republic (GDR) was undertaken. Since all fetal deaths and all deaths in the first year of life are subject to a full postmortem examination and since all cancer cases or deaths are reported to a central registry, the prerequisites for a valid assessment of the incidence of these tumors are present. During the years 1960–1979, 55 histopathologically verified tumors of the central nervous system were identified in the GDR, a frequency of approximately 1.1 per 100 000 births. Unexpectedly, medulloblastoma (13 cases) was the most frequent tumor type.     

Spontaneous basophilic foci of hepatocellular alteration in Fischer 344 female rats do not exclude iron.

Iron exclusion has been used to identify foci of hepatocellular alteration (FHA) in rats exposed to known carcinogens. This study investigates whether basophilic FHA occurring spontaneously in aged female Fischer 344 rats also exclude iron. Female rats 514-544 days of age were given supplemental iron by injection for 2 weeks prior to being killed. Serial sections of the liver stained with hematoxylin and eosin or Gomori's stain were examined. Seventy-five basophilic FHA were identified; none excluded iron. It may be possible to differentiate spontaneous basophilic FHA from carcinogen-induced, iron-excluding FHA by the use of this staining method.     

Calmodulin content in human central nervous system tumors

Summary Benign and malignant brain tumors and normal cerebral cortex were assayed for calmodulin content by enzymatic and radioimmunoassay techniques. Normal cerebral cortex contained more (8.31 ± 1.27 vs 3.30 ± 0.42 µg/mg protein) calmodulin than the brain tumors. The contents of calmodulin in the malignant glioblastomas were significantly higher than the meningiomas (5.41 ± 0.31 vs 2.97 ± 0.16 µg/mg protein). These differences were independent of tumor location and persisted when calmodulin content was normalized for DNA rather than protein content. This data supports differences in the tissue calmodulin contents with normal cortex> primary malignant tumors> benign tumors> metastatic tumor tissue.     

Insulin-like growth factors in central nervous system tumors

Insulin-like growth factors (IGFs) appear to play arole in the development of tumors in generaland brain tumors in particular. Specific receptors forIGFs have been identified in normal human andrat brain, and evidence suggests that components ofthe IGF signal transduction system may play arole in the transformation process. Secretion of IGFsby a variety of human brain tumors hasbeen confirmed, and these growth factors appear tohave an autocrine stimulatory effect on these tumors.IGFs circulate in the blood stream bound toat least six distinct binding proteins which maymodulate the effects of these growth factors ontarget tissues. Sex steroids may also regulate thebehavior of certain brain tumors such as meningiomasat least in part through their effects onthe expression of IGFs and their binding proteins.Recently, antisense gene technology against certain IGFs ortheir receptors have resulted in potent antitumor effectsin the case of several gliomas, although themechanism for this remains unclear.