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Hans Joachim Scherer (1906-1946) was a German pathologist who fled Germany to Belgium to work on glioma genesis, growth and progression. Despite being seldom cited, and due to the contributions discussed in this article, Hans Joachim Scherer, can be considered a founding father of contemporary neuropathology and glioma research. We discuss Scherer's achievements in glioma classification, glomerular structures of glioma, primary and secondary glioblastoma, glioma growth patterns, non-resectability of glioma, pseudopalisadic necrosis and the late occurrence of symptoms in glioma.

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Historically, advances in our knowledge of neuro-oncology and improvements in the survival of patients with brain tumours have been relatively scarce. One of the main turning points can be established from 2005 onwards, when the potential therapeutic role of cytostatics in these tumours was confirmed, thus changing the standard of treatment. Up until that date, only radiation therapy and surgery were considered truly effective treatments. This shift has contributed to the development of new systemic therapies and to an in-depth study of gliomagenesis. Advances in the knowledge of the basic fields of brain tumours have helped improve the design and results of new clinical trials, while clinical outcomes provide feedback and new data to further the understanding of these tumours. However, these promising advances open up new unresolved questions and offer a critical approach to the interpretation of past studies. This review mainly updates the results of trials that changed or modified the clinical practice of the treatment and management of gliomas. Commenting on relevant basic research papers that have not yet been translated into the implementation of changes in the treatment of these patients is excluded.

TITLE: Perspectiva histórica de los estudios con mayor impacto en el tratamiento de los gliomas.Históricamente, los avances en el área de conocimiento de la neurooncología y las mejoras en la supervivencia de los pacientes con tumores cerebrales han sido relativamente escasos. Uno de los principales puntos de inflexión puede establecerse a partir de 2005, cuando se constata el hasta entonces potencial papel terapéutico de los citostáticos en estos tumores, cambiando consiguientemente el estándar de tratamiento. Hasta esa fecha, sólo la radioterapia y la cirugía se consideraban tratamientos realmente eficaces. Este cambio ha contribuido al desarrollo de nuevas terapias sistémicas y a profundizar en el estudio de la gliomagénesis. Los avances en los campos básicos del conocimiento de los tumores cerebrales han ayudado a mejorar el diseño y los resultados de los nuevos ensayos clínicos, al mismo tiempo que los resultados clínicos retroalimentan y ofrecen nuevos datos para seguir avanzando en la comprensión de estos tumores. Sin embargo, estos esperanzadores avances abren nuevas cuestiones aún no resueltas y ofrecen un enfoque crítico a la interpretación de estudios pasados. La presente revisión principalmente actualiza los resultados de los ensayos que cambiaron o modificaron la práctica clínica del tratamiento y el manejo de los gliomas. Se excluyen trabajos relevantes de investigación básica que aún no han tenido traslación en la implementación de cambios en el tratamiento de estos pacientes.

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A three-page paper entitled "A case of glioma (embryonal neurocytoma) of the brain simulating pituitary tumour," written by K. G. Pandalai, Surgeon at the Madras General Hospital, and T. B. Menon, Pathologist at the Madras Medical College, was published in the Indian Medical Gazette. This paper refers to an occasional finding of a brain tumor (a glioma), presurgically diagnosed as a pituitary tumor, in 1928. This was close to the period when surgeons across the developed world believed in that cancers were by no means common among the native people of India as it was in Europe. Leopold Rogers of the Bengal Medical Service, Calcutta, in 1925 refuted this belief indicating that malignant tumors were equally common in Bengal (India) and England. Nevertheless, this report by Pandalai and Menon strikes a unique chord since the tumor was subsequently determined as a glioma - an embryonal neurocytoma -- with adequate evidences drawn from the state-of-the-art volume "A classification of the tumors of the glioma group on a histogenetic basis with a correlated study of prognosis" by Percival Bailey and Harvey Cushing published in Philadelphia in 1926. This Pandalai--Menon report impresses as pioneering and trailblazing, on a brain tumor detected in 1928, given that earliest exclusive departments of neurosurgery were established in Christian Medical College, Vellore, and Madras Medical College, Madras, by Jacob Chandy and Balasubramanian Ramamurthi, respectively, nearly two decades later.

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In the late 19th century, Dr. William B. Coley introduced the theory that infections may aid in the treatment of malignancy. With the creation of Coley's toxin, reports of remission during viral illnesses for systemic malignancies soon emerged. A few decades after this initial discovery, Austrian physicians performed intravascular injections of Clostridium to induce oncolysis in patients with glioblastoma. Since then, suggestions between improved survival and infectious processes have been reported in several patients with glioma, which ultimately marshaled the infamous use of intracerebral Enterobacter. These early observations of tumor regression and concomitant infection piloted a burgeoning field focusing on the use of pathogens in molecular oncology.

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Epigenetics now refers to the study or research field related to DNA methylation and histone modifications. Historically, global DNA hypomethylation was first revealed in 1983, and, after a decade, silencing of a tumor suppressor gene by regional DNA hypermethylation was reported. After the proposal of the histone code in the 2000s, alterations of histone methylation were also identified in cancers. Now, it is established that aberrant epigenetic alterations are involved in cancer development and progression, along with mutations and chromosomal losses. Recent cancer genome analyses have revealed a large number of mutations of epigenetic modifiers, supporting their important roles in cancer pathogenesis. Taking advantage of the reversibility of epigenetic alterations, drugs targeting epigenetic regulators and readers have been developed for restoration of normal pattern of the epigenome, and some have already demonstrated clinical benefits. In addition, DNA methylation of specific marker genes can be used as a biomarker for cancer diagnosis, including risk diagnosis, detection of cancers, and pathophysiological diagnosis. In this paper, we will summarize the major concepts of cancer epigenetics, placing emphasis on history.

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During his lifetime and a career spanning 42 years, James Watson Kernohan made numerous contributions to neuropathology, neurology, and neurosurgery. One of these, the phenomenon of ipsilateral, false localizing signs caused by compression of the contralateral cerebral peduncle against the tentorial edge, has widely become known as "Kernohan's notch" and continues to bear his name. The other is a grading system for gliomas from a neurosurgical viewpoint that continues to be relevant for grading of glial tumors 60 years after its introduction. In this paper, the authors analyze these two major contributions in detail within the context of Kernohan's career and explore how they contributed to the development of neurosurgical procedures.

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George Gershwin, the famous American composer, died in 1937 of a temporal lobe glioma. An emergency surgery was performed by R. Nafziger and W. E. Dandy. The case of George Gershwin indicates the beginning of a new era in music history as well as in the history of neurosurgery.

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OBJECT: The early 20th century posed several challenges in the diagnosis and surgical treatment of intracranial tumors. However, this was a time in which more information was becoming more readily available based on pathological examination and surgical case reports. Such early work was crucial in shaping the current understanding of the nervous system and in developing modern treatment strategies. An early historical overview of the diagnosis and surgical interventions in pediatric patients with brainstem gliomas has not been described. Furthermore, Dr. Harvey Cushing's contributions to this field have not been reported. METHODS: Following institutional review board approval, and through the courtesy of the Alan Mason Chesney Archives, the authors reviewed the Johns Hopkins Hospital surgical files dating from 1896 to 1912. RESULTS: The authors describe Cushing's early experience with a pediatric brainstem glioma during his time as a young attending physician at the Johns Hopkins Hospital. The case, presented in 1909, described the clinical events in a 15-year-old schoolgirl who presented with signs of a cerebellopontine lesion. A suboccipital exploration was performed by Cushing; his findings and surgical approach are described. CONCLUSIONS: Harvey Cushing's early contributions to the field of pediatric neurosurgery, and to the operative treatment of pediatric brainstem gliomas have remained largely unknown. The case presented here represents the early work of the American "Father of Neurosurgery."

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PURPOSE: Diagnosing and operating pediatric patients with intracranial lesions posed a greater diagnostic challenge for physicians during the early twentieth century. At the time, an intracranial neoplasm was indistinctively diagnosed as a glioma, encompassing a broad category of brain tumor pathologies. The treatment and surgical interventions followed for children diagnosed with gliomas is not well-described in the literature from this time. METHODS: Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896-1912. Patients 18 years or younger, who underwent surgical intervention by Cushing for suspected intracranial tumors, were selected. RESULTS: Of the eight pediatric cases diagnosed with gliomas by Cushing, four cases were later diagnosed as medulloblastomas by Dr. Cushing in 1925. Of the remaining four pediatric cases, one was diagnosed as a brainstem glioma and another as a ventricular glioma. We describe the remaining two cases. CONCLUSION: These examples illustrate Cushing's approach to treating brain tumors diagnosed as gliomas in pediatric patients, focusing on an initial decompression and followed by a thorough surgical exploration for tumor. Furthermore, these cases demonstrate Cushing's early attempts to manage such lesions in children and highlight the challenges faced in diagnosing and localizing intracranial lesions within this group of patients.

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Although recent efforts to advance the treatment of gliomas through radiotherapy and chemotherapy may seem to be a relatively new area of growth and development, these efforts have been in progress since the therapeutic potential of radiation therapy was discovered in the late 19th century. Cushing's use of brachytherapy has been mentioned several times in the literature without receiving an appropriate in-depth analysis. The reasoning behind Cushing's initial use of brachytherapy was not fully examined, and a close analysis of the outcomes of this therapy was not made. In addition, Cushing's use of his "radium bomb" occurred more commonly than the 3 cases previously documented. The authors reviewed all the patient records available at the Cushing Brain Tumor Registry--which represents the most complete series of patient records from the Cushing era--and selected those patients who underwent treatment with Cushing's "radium bomb." The authors place these early attempts to optimize interstitial radiation of brain tumors in their historical perspective.

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BACKGROUND/AIMS: The combination of inadequate technology and incomplete nomenclature systems created challenges for early neurosurgeons, and contributed to the dismal prognosis for brain tumors, particularly within the pediatric population. METHODS: Following IRB approval, and by the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896 to 1912. A single case of a pediatric patient with an intraventricular glioma was selected for further review. RESULTS: Here we report the case of a 10-year-old girl who presented to the Johns Hopkins Hospital in 1907, with a 7-year history of subtle symptoms of increased intracranial pressure, secondary to a tumor. Dr. Harvey Cushing operated upon her, and during surgical intervention resected a large parenchymal and intraventricular glioma. CONCLUSIONS: High-grade gliomas are rare occurrences in pediatric patients, with intraventricular gliomas described in only a handful of cases. Although advances in neuroimaging, hemostasis and understanding of the cerebrospinal fluid system have allowed neurosurgeons to resect intraventricular gliomas more safely, the surgical approaches in use today are still fraught with challenges. Here we describe a case of attempted resection of an intraventricular glioma in a pediatric patient, which predates the earliest published report of intraventricular gliomas by 30 years.

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On December 14, 1883, William Osler, then pathologist at the Montreal General Hospital, presented the specimen of a brain with an almond-sized glioma beneath the right motor cortex to the Montreal Medico-Chirurgical Society. The brain specimen was from a young woman who had suffered from intermittent Jacksonian seizures for 14 years and had eventually died in status epilepticus. Aware of the pioneering removal of a tumor from the cortex reported on in 1885 by Bennett and Godlee, Osler wrote of his case, "this was an instance in which operation would have been justifiable and possibly have been the means of saving life." In 1953, a young man with Jacksonian attacks that began in his foot underwent removal of a Grade I glioma from the central fissure. The operation was performed in an awake craniotomy during which cortical mapping was used to define the motor and sensory cortices. Treatment with focal radiation followed, and afterward the patient became seizure-free, stopped taking anticonvulsant medication, and has led an active life over the past 50 years. Reference is made to the experiences of Sherrington, Cushing, and Penfield with cortical stimulation in the awake patient under regional anesthesia as an effective aid to surgery for epileptogenic lesions, tumors, and vascular malformations. Their technique allows for maximal resection with minimal neurological deficits. Over the past 20 years, this approach has been adopted effectively in many neurosurgical centers.

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Pediatric high grade gliomas represent a heterogeneous group of tumors with poor prognoses despite the use of multimodal treatment. Very little progress has been made over the past decades in identifying efficacious therapeutic modalities against both high grade gliomas and diffuse brainstem gliomas in children. The degree of surgical resection is the most important clinical prognostic factor for children with high grade gliomas, and a complete resection should be attempted whenever feasible. The role of radiation therapy in the treatment of older children with high grade gliomas and diffuse brain stem gliomas is undisputed; however the benefit of using radiation for patients less than 6 years of age (with high grade gliomas) might be questionable. Despite the absence of solid evidence to support its use, chemotherapy is routinely used against these tumors. Currently temozolomide is being investigated due to its activity in adult trials and based on preliminary data regarding recurrent disease. A small subgroup of patients can be successfully treated with high dose chemotherapy followed by autologous stem cell rescue. Early trials using this modality in the past had been associated with high morbidity and mortality. High dose chemotherapy with autologous stem cell rescue in selected patients with minimal residual disease, angiogenesis inhibitors, radiosensitizers and other biological modifiers are being currently investigated in phase I/II trials.

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Throughout his illustrious career, Percival Bailey made numerous contributions to the fields of neurology, neuroanatomy, psychiatry, neuropathology, and, of course, neurosurgery. His expertise, his curiosity about the nervous system, and his desire to examine it from all angles were unique. With the exception of Harvey Cushing, Dr. Bailey made some of the greatest contributions in the area of neuro-oncology at the turn of the last century. In this essay the authors summarize the key episodes of Bailey's life and discuss his impact on the classification and treatment of human brain tumors.

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