Chaim B. Colen

Metabolic Remodeling of Malignant Gliomas for Enhanced Sensitization during Radiotherapy: An In Vitro Study

OBJECTIVE: To investigate a novel method to enhance radiosensitivity of gliomas via modification of metabolite flux immediately before radiotherapy. Malignant gliomas are highly glycolytic and produce copious amounts of lactic acid, which is effluxed to the tumor microenvironment via lactate transporters. We hypothesized that inhibition of lactic acid efflux would alter glioma metabolite profiles, including those that are radioprotective. 1H magnetic resonance spectroscopy (MRS) was used to quantify key metabolites, including those most effective for induction of low-dose radiation-induced cell death. METHODS: We inhibited lactate transport in U87-MG gliomas with α-cyano-4-hydroxycinnamic acid (ACCA). Flow cytometry was used to assess induction of cell death in treated cells. Cells were analyzed by MRS after ACCA treatment. Control and treated cells were subjected to low-dose irradiation, and the surviving fractions of cells were determined by clonogenic assays. RESULTS: MRS revealed changes to intracellular lactate on treatment with ACCA. Significant decreases in the metabolites taurine, glutamate, glutathione, alanine, and glycine were observed, along with inversion of the choline/phosphocholine profile. On exposure to low-dose radiation, ACCA-pretreated U-87MG cells underwent rapid morphological changes, which were followed by apoptotic cell death. CONCLUSION: Inhibition of lactate efflux in malignant gliomas results in alterations of glycolytic metabolism, including decreased levels of the antioxidants taurine and glutathione and enhanced radiosensitivity of ACCA-treated cells. Thus, in situ application of lactate transport inhibitors such as ACCA as a novel adjunctive therapeutic strategy against glial tumors may greatly enhance the level of radiation-induced cell killing during a combined radioand chemotherapeutic regimen.OBJECTIVETo investigate a novel method to enhance radiosensitivity of gliomas via modification of metabolite flux immediately before radiotherapy. Malignant gliomas are highly glycolytic and produce copious amounts of lactic acid, which is effluxed to the tumor microenvironment via lactate transporters. We hypothesized that inhibition of lactic acid efflux would alter glioma metabolite profiles, including those that are radioprotective. 1H magnetic resonance spectroscopy (MRS) was used to quantify key metabolites, including those most effective for induction of low-dose radiation-induced cell death. METHODSWe inhibited lactate transport in U87-MG gliomas with α-cyano-4-hydroxycinnamic acid (ACCA). Flow cytometry was used to assess induction of cell death in treated cells. Cells were analyzed by MRS after ACCA treatment. Control and treated cells were subjected to low-dose irradiation, and the surviving fractions of cells were determined by clonogenic assays. RESULTSMRS revealed changes to intracellular lactate on treatment with ACCA. Significant decreases in the metabolites taurine, glutamate, glutathione, alanine, and glycine were observed, along with inversion of the choline/phosphocholine profile. On exposure to low-dose radiation, ACCA-pretreated U-87MG cells underwent rapid morphological changes, which were followed by apoptotic cell death. CONCLUSIONInhibition of lactate efflux in malignant gliomas results in alterations of glycolytic metabolism, including decreased levels of the antioxidants taurine and glutathione and enhanced radiosensitivity of ACCA-treated cells. Thus, in situ application of lactate transport inhibitors such as ACCA as a novel adjunctive therapeutic strategy against glial tumors may greatly enhance the level of radiation-induced cell killing during a combined radio- and chemotherapeutic regimen.

DEVELOPMENT OF ANATOMIC SCIENCE IN THE LATE MIDDLE AGES: THE ROLES PLAYED BY MONDINO DE LIUZZI AND GUIDO DA VIGEVANO

MEDICAL HISTORIANS GENERALLY consider anatomic science, as we know it today, to have been established through the pioneering work of Vesalius during the Renaissance. Although this is largely true, detailed assessment of the scientific advances made in the late Middle Ages, though not as spectacular as those made during the Renaissance period, did pave the way and form a foundation for subsequent progress. During the two centuries of AD 1300 to 1500, several worthwhile advances occurred. Many universities, centers of learning excellence, were established throughout Europe, most notably in Italy. King Frederick II, the Holy Roman Emperor, established guidelines for medical education and practice that seem to parallel current regulations. Human cadaveric dissection was performed, after a hiatus of over 1700 years, as the foundation for the study of anatomy. Observation of human dissection became a requirement for medical students. A manual for anatomic dissection was written, printed, and published for the first time in history by Mondino de Liuzzi. His student, Guido da Vigevano, who also had an engineering background, established two “firsts” of his own: providing illustrations of anatomy and designing the first automobile in history. The authors believe that the contributions of these two key anatomists in the late Middle Ages should not be forgotten.

Charles-Edouard Brown-Séquard: an eccentric genius.

BROWN-SÉQUARD IS known eponymously for the syndrome of hemisection of the spinal cord, but most clinicians are not familiar with his colorful, quixotic, and eccentric life history. His contributions to medicine and neuroscience reached much further than his discovery of the spinal hemisection syndrome. He lived in five countries on three continents and crossed the Atlantic 60 times, spending a total of almost 6 years on the sea. He contributed more than 500 papers in his lifetime, was even the editor of many prestigious journals, and spent his last years as Professeur au Collége de France, a most coveted position for a French neuroscientist. Many are not aware of his contributions to endocrinology and hormone replacement therapy, even those who consider him the father of modern endocrinology. Brown-Séquard was a skillful experimentalist. He pioneered the concept of the advancement of neuroscience through experimental physiological observation. He was devoted to science. He was not interested in monetary gains through his inventions or patient care. Although he may be criticized for arriving at some incorrect conclusions from his experiments, his visionary ideas and prescient statements have stood the test of time; he truly was an eccentric genius. This article highlights Brown-Séquards life history, specifically his time in France and North America, and his contributions to neuroscience and endocrinology.

Delayed Lateral Rectus Palsy Following Resection of a Pineal Cyst in Sitting Position: Direct or Indirect Compressive Phenomenon?

A rare case of delayed lateral rectus palsy in a patient following resection of a pineal lesion in the sitting position is presented. Postoperative pneumocephalus is common following craniospinal surgical intervention in the sitting position. The sixth cranial nerve is frequently injured because of its prolonged intracranial course. A 13-year-old girl was evaluated for unremitting headaches. No focal deficits were demonstrated on neurological examination. Magnetic resonance imaging revealed a cystlike pineal region mass with peripheral enhancement following intravenous contrast administration. A supracerebellar infratentorial craniotomy was performed in the sitting position, and complete resection of the lesion was achieved. Her postoperative course was complicated by sixth nerve palsy on the third postoperative day. Her symptoms improved with conservative management. The occurrence of sixth cranial nerve palsy secondary to pneumocephalus is a rare entity. Even rarer is the report of this anomaly following craniotomy in the sitting position. This patients symptoms manifested in a delayed fashion. Although uncommon, this complication should be considered in patients undergoing cranial or spinal surgical interventions in this position.

Periodic Alternating Nystagmus and Periodic Alternating Skew Deviation in Spinocerebellar Ataxia Type 6

The combination of periodic alternating nystagmus (PAN) and periodic alternating skew deviation (PASD) is rare. We report a case of PAN and PASD in a patient with spinocerebellar ataxia type 6 (SCA-6) and discuss the role of the cerebellum as a plausible mechanism for this combined pathologic condition.

Synchronous meningioma and anaplastic large cell lymphoma

Synchronous primary brain tumors are exceedingly rare. When they occur, most cases are associated with metastatic disease. To the best of our knowledge, we report the first case of an atypical meningioma infiltrated by a T‐cell‐primary central nervous system lymphoma (PCNSL), specifically anaplastic large cell lymphoma (ALCL). We present a novel, unifying, plausible mechanism for its origin based on theories in the current literature. A 65‐year‐old man with a history of near‐total resection of atypical meningioma presented with a complaint of progressive headaches. Imaging revealed recurrent tumor. Left frontal‐temporal craniotomy with near‐total tumor resection followed by radiation was performed. Recurrent symptomatic tumor led to repeat left frontotemporal craniotomy with tumor resection and partial anterior temporal lobectomy. Part of the specimen showed predominantly fibrotic neoplasm composed of nests and whorls of meningothelial cells, highlighted by epithelial membrane antigen (EMA) staining. The remainder of the specimen consisted of densely cellular neoplasm centered in connective tissue, including areas involved by meningioma. This tumor was composed of moderately large lymphoid cells with large nuclei, prominent nucleoli, and amphophilic cytoplasm. These cells were strongly immunoreactive for CD3 and CD30 but remained unstained with EMA, anaplastic lymphoma kinase‐1 (ALK‐1), CD15 or cytotoxic associated antigen TIA‐1. Smaller mature lymphocytes, chiefly T‐cells, were intermixed. The morphologic and immunohistochemical features were considered typical of anaplastic large T‐cell lymphoma. The pathogenesis of this association may have been due to radiation‐mediated breakdown of the blood–brain barrier with subsequent T‐cell infiltration and proliferation. We advocate aggressive resection and long‐term surveillance for individuals with metastasis, especially higher‐grade neoplasms that receive radiotherapy.

Outcome of brain abscess by Clostridium perfringens

OBJECTIVEDespite the aggressive infection of soft tissue caused by Clostridium perfringens (gas gangrene-necrotizing fasciitis), a brain abscess with this bacteria treated by early surgical excision, debridement of necrotic tissue, and antibiotic coverage may be expected to have a good recovery. Long-term follow-up has not been well established in this group of patients. We report this case to show the outcome at 3 years post surgical and antibiotic treatment for C. perfringens brain abscess and stress the need for urgent intervention to achieve good outcome. We also present a literature review of Clostridial brain abscesses since the 1960s. CLINICAL PRESENTATIONA 53-year-old man was brought to the emergency room after having a witnessed seizure status postassault 3 days before admission. On presentation, he was febrile, disoriented, lethargic, and demonstrated right upper extremity weakness. A computed tomographic scan of the head showed a left frontoparietal depressed cranial fracture complicated with gas and intraparenchymal air fluid level cavity. INTERVENTIONEmergent surgery for debridement and excision of necrotic tissue was performed. Empiric intravenous antibiotic therapy was started and penicillin G was added for 6 weeks after C. perfringens was demonstrated. CONCLUSIONDespite the severe infection and effect of C. perfringens in soft tissues in the brain, it appears that emergent surgical debridement and antibiotic coverage will yield an excellent outcome for these patients.

A History of the Council of State Neurosurgical Societies

As neurological surgery evolved into its own subspecialty early in the 20th century, a need arose to create an environment for communication and education among those surgeons working in this burgeoning surgical discipline. As the socioeconomic climate in health care began to change in the United States, an unforeseen need arose that was outside the scope of the American Association of Neurological Surgeons, Congress of Neurological Surgeons, and Society of Neurological Surgeons. The capacity to understand and address the evolving socioeconomic landscape and to offer a platform for advocacy required a new entity. Grassroots efforts of neurosurgeons at the state level ultimately yielded a formal organization of state neurosurgical societies to fill this void by recognizing, understanding, and addressing socioeconomic factors affecting the practice of neurological surgery. This formal organization became the Council of State Neurosurgical Societies (CSNS). The CSNS provides a forum in which state societies can meet to identify, understand, and advocate for policies on behalf of organized neurosurgery. The purpose of this paper is to detail the history of the formation of the CSNS. By understanding this history and the need for the development of the CSNS, it is hoped that its evolving role as a voice for neurological surgeons in the modern era of health care will be made clear.

Diagnostic and therapeutic strategy for confounding radiation myelitis

We report a case of confounding radiation myelitis to demonstrate the usefulness of surgical biopsy in ensuring the correct diagnosis and to avoid unnecessary treatment. The patient was a 40-year-old man with a history of epiglottis carcinoma and sarcoidosis. Six months after radiation therapy and chemotherapy for epiglottis carcinoma, he noticed paresthesia and dysesthesia in the left arm and leg. Two months after that, he complained of severe neck pain and rapidly progressing weakness in all extremities. MRI showed an enhanced intramedullary lesion with extensive edema in the cervical spinal cord. Radiation myelitis, intramedullary spinal tumor, and neurosarcoidosis were considered as differential diagnoses. Spinal cord biopsy with laminectomy was performed and radiation myelitis was diagnosed. After the surgery, the lesion was significantly decreased in size even though corticosteroid therapy was rapidly tapered. We emphasize that a spinal cord biopsy is indicated to obtain a pathological diagnosis and to make a clear treatment strategy for patients with associated diseases causing lesions of the spinal cord.