Rimas V. Lukas

Epidermal Growth Factor Receptor–Mediated Signal Transduction in the Development and Therapy of Gliomas

The epidermal growth factor receptor (EGFR) and its ligands figure prominently in the biology of gliomas, the most common tumors of the central nervous system (CNS). Although their histologic classification seems to be straightforward, these tumors constitute a heterogeneous class of related neoplasms. They are associated with a variety of molecular abnormalities affecting signal transduction, transcription factors, apoptosis, angiogensesis, and the extracellular matrix. Under normal conditions, these same interacting factors drive CNS growth and development. We are now recognizing the diverse molecular genetic heterogeneity that underlies tumors classified histologically into three distinct grades. This recognition is leading to new therapeutic strategies targeted directly at specific molecular subtypes. In this article, we will review the role of EGFR and related molecular pathways in the genesis of the normal CNS and their relationship to glial tumorigenesis. We will discuss barriers to effective treatment as they relate to anatomic specialization of the CNS. We will also consider the ways in which specific EGFR alterations common to glioma reflect outcomes following treatment with targeted therapies, all with an eye towards applying this understanding to improved patient outcomes.

Molecular Heterogeneity in Glioblastoma: Therapeutic Opportunities and Challenges

Glioblastoma (GBM) has been recognized as a clinical and pathologic entity for more than a century. Throughout its history, its cells of origin have been in question. Its behavior is aggressive and despite decades of effort, median survival is just beginning to improve. Surgical techniques and radiotherapy schemas continue to be refined, but the most recent progress has been achieved through improved medical therapies. These are the result of both pharmacological advances and a deeper understanding of the biological characteristics of GBM. Due to a combination of its complex phenotype and organ-specific clinical manifestations, efforts to refine GBM treatment with targeted therapies largely have been frustrated. In this review, we discuss recent attempts to exploit new molecular insights, consider the reasons for slow progress in developing better treatments, and examine future therapeutic options.

Anti- N -methyl-D-aspartate-receptor encephalitis: diagnosis, optimal management, and challenges

Objective Anti-N-methyl-D-aspartate-receptor (NMDA-R) encephalitis is a new autoimmune disorder, often paraneoplastic in nature, presenting with complex neuropsychiatric symptoms. Diagnosed serologically, this disorder is often responsive to immunosuppressant treatment. The objective of this review is to educate clinicians on the challenges of diagnosis and management of this disorder. Materials and methods A review of the relevant literature on clinical presentation, pathophysiology, and recommended management was conducted using a PubMed search. Examination of the results identified articles published between 2007 and 2014. Results The literature highlights the importance of recognizing early common signs and symptoms, which include hallucinations, seizures, altered mental status, and movement disorders, often in the absence of fever. Although the presence of blood and/or cerebrospinal fluid autoantibodies confirms diagnosis, approximately 15% of patients have only positive cerebrospinal fluid titers. Antibody detection should prompt a search for an underlying teratoma or other underlying neoplasm and the initiation of first-line immunosuppressant therapy: intravenous methylprednisolone, intravenous immunoglobulin, or plasmapheresis, or a combination thereof. Second-line treatment with rituximab or cyclophosphamide should be implemented if no improvement is noted after 10 days. Complications can include behavioral problems (eg, aggression and insomnia), hypoventilation, catatonia, and autonomic instability. Those patients who can be managed outside an intensive care unit and whose tumors are identified and removed typically have better rates of remission and functional outcomes. Conclusion There is an increasing need for clinicians of different specialties, including psychiatrists, neurologists, oncologists, neurooncologists, immunologists, and intensivists to become familiar with this disorder and its potential complications. Remission can be optimized with prompt detection and aggressive, collaborative treatment within a multidisciplinary team.

Structure of neuroscience clerkships in medical schools and matching in neuromedicine.

Objective: Due to the burden of neurologic disease, there is high demand for neurologists, child neurologists, and neurosurgeons. Only 2.6% of graduating medical students matched in neuromedicine residencies in 2014. This number will not likely meet the needs of the population or the projected shortfall. To compensate for this, the medical education system has an obligation to ensure competence in neuromedicine for all trainees and mentorship for students pursuing training in the field. We aim to evaluate the state of the neurology clerkship in US medical schools and how this impacts graduates entering the field. Methods: Publicly available curricula of 158 US medical schools were reviewed. Presence of a required neurology clerkship, its duration, and the year offered were tabulated, as were the availability of child neurology and neurosurgery electives and affiliated neuromedicine residencies. The total graduating students from each medical school matching into neuromedicine residencies for 2011–2014 were recorded. Repeated-measure analysis of variance was used to assess the relationship of these variables to number of students matching into the collective neuromedicine. Results: All but 4 schools (97%) published clerkship information. Neurology was a required clerkship at 56% of reporting institutions. Residency match data were not published from 53 schools (35%) and these were excluded from the analysis. In the remaining schools, all variables showed a relationship to students matching in neuromedicine residencies. Conclusions: The presence of a required neurology clerkship and opportunities for students to explore neuromedicine during medical school correlates with students matching into neuromedicine residencies.

The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy

We hypothesized that peripheral tryptophan (Trp) and/or kynurenine (Kyn) levels would provide prognostic value for physicians planning to enroll glioblastoma multiforme (GBM) patients in immunotherapy. GBM is the most common form of malignant glioma in adults. Despite aggressive surgical resection, irradiation and chemotherapy, patients with GBM have a median survival of only 14.6 months after diagnosis. This poor outcome has led to the search for more effective treatments, including immunotherapy. However, the identification of parameters that proactively stratify GBM patients who have the potential for therapeutic benefit has been challenging. Given recent observations demonstrating high indoleamine 2,3 dioxygenase 1 (IDO1) expression in GBM, the immunosuppressive impact of IDO1-mediated Trp catabolism, as well as active transport of Trp and the IDO1-downstream Trp catabolite, Kyn, across the blood brain barrier, we hypothesized that peripheral blood analysis of this pathway would provide diagnostic utility. When comparing individuals without tumors to GBM patients prior to surgical resection, or at the 48 hour (48 h) and ⩾10 week (10 w+) postoperative time points, Trp levels were significantly decreased (p<0.0002). Similarly, Kyn levels were decreased in the pre- and 48 h postoperative GBM patients (p<0.0001), while there was no difference between individuals without tumors and 10 w+ GBM patients. Interestingly, those 10 w+ patients with a high Kyn/Trp ratio (⩾9.5) had a mean overall survival (OS) of 23.6 ± a standard error of 6.8 months, compared to an OS of 38.7 ± 4.9 months for patients with lower Kyn/Trp values. Since the 10 w+ blood draw and analyses occurred prior to patient enrollment in the heat shock protein peptide complex-96 clinical trial, these novel data suggest that the late Kyn/Trp index may be a relevant clinical benchmark, providing prognostic value for GBM patients who are enrolled in immunotherapeutic regimens.

Treatment of leptomeningeal carcinomatosis: current challenges and future opportunities.

Leptomeningeal metastasis (LM) in breast cancer patients confers a uniformly poor prognosis and decreased quality of life. Treatment options are limited and often ineffective, due in large part to limitations imposed by the blood-brain barrier and the very aggressive nature of this disease. The majority of studies investigating the treatment of LM are not specific to site of origin. Conducting randomized, disease-specific clinical trials in LM is challenging, and much clinical outcomes data are based on case reports or retrospective case series. Multiple studies have suggested that chemo-radiotherapy is superior to either chemotherapy or radiation therapy alone. Attempts to overcome current obstacles in the treatment of breast cancer LM hold promise for the future. We review the epidemiology, diagnosis, and prognosis of LM in breast cancer, and discuss the treatment options currently available as well as those under investigation.

Emerging therapies for malignant glioma

The current standard of care for malignant gliomas consists of surgery, radiotherapy and conventional (DNA-damaging) chemotherapies. These treatments are relatively nonspecific and may be applied to all glioma subtypes. Developments in cancer medicine, however, now offer the opportunity to direct therapies to specific molecular pathways involved in tumorigenesis. This offers the potential to tailor treatments to tumor subtypes – perhaps with greater efficacy and less toxicity. Many of the so-called targeted therapies are under investigation in the treatment of malignant glioma. In this review, we will focus on the use of agents that affect signal transduction. In particular, we will review the potential role for inhibitors of: tyrosine kinases, targets of rapamycin, farnesyl transferase and histone deacetylase. Inhibitors of angiogenesis will also be discussed. Some ‘targeted’ therapies are less specific than others,working on more than one pathway or receptor, thus complex interactions are possible.

Treatment of Brain Metastases

Brain metastases are associated with substantial morbidity and mortality. Key prognostic classification systems for brain metastases are reviewed. The role of surgery, particularly for single brain metastases, is discussed. This is followed by an overview of radiation, both whole brain and focal, in the treatment of brain metastases. Finally, we review examples of important concepts regarding the role of systemic therapy in the treatment of brain metastases.

Education Research: Case logs in the assessment of medical students in the neurology outpatient clinic

Objective: Using outpatient neurology clinic case logs completed by medical students on neurology clerkships, we examined the impact of outpatient clinical encounter volume per student on outcomes of knowledge assessed by the National Board of Medical Examiners (NBME) Clinical Neurology Subject Examination and clinical skills assessed by the Objective Structured Clinical Examination (OSCE). Methods: Data from 394 medical students from July 2008 to June 2012, representing 9,791 patient encounters, were analyzed retrospectively. Pearson correlations were calculated examining the relationship between numbers of cases logged per student and performance on the NBME examination. Similarly, correlations between cases logged and performance on the OSCE, as well as on components of the OSCE (history, physical examination, clinical formulation), were evaluated. Results: There was a correlation between the total number of cases logged per student and NBME examination scores (r = 0.142; p = 0.005) and OSCE scores (r = 0.136; p = 0.007). Total number of cases correlated with the clinical formulation component of the OSCE (r = 0.172; p = 0.001) but not the performance on history or physical examination components. Conclusion: The volume of cases logged by individual students in the outpatient clinic correlates with performance on measures of knowledge and clinical skill. In measurement of clinical skill, seeing a greater volume of patients in the outpatient clinic is related to improved clinical formulation on the OSCE. These findings may affect methods employed in assessment of medical students, residents, and fellows.

Why neurology? Factors which influence career choice in neurology.

Objective: To evaluate the factors which influence the decision to pursue a career in neurology. Methods: An anonymous survey was developed using a Likert scale to rate responses. The survey was sent to adult and child neurology faculty, residents and fellows, as well as medical students applying for neurology. Descriptive statistics were used to analyse the factors of influence. Respondents were subsequently categorized into pre-neurology trainees, neurology trainees, child neurologists and adult neurologists, and differences between the groups were analysed using Pearson’s chi-square test. Results: One hundred and thirty-three anonymous responses were received. The respondents were neurologists across all levels of training and practice. Across all respondents, the most common factor of high importance was intellectual content of specialty, challenging diagnostic problems, type of patient encountered and interest in helping people. Responses were similar across the groups; however, the earliest trainees cited interest in helping people as most important, while those in neurology training and beyond cite intellectual content of the specialty as most important. Discussion: As trainees transition from their earliest levels of clinical experience into working as residents and faculty, there is a shift in the cited important factors. Lifestyle and financial factors seem to be the least motivating across all groups. Encouragement from peers, mentors, faculty and practicing physicians is considered high influences in a smaller number of neurologists. This may present an opportunity for practicing neurologists to make connections with medical students early in their education in an effort to encourage and mentor candidates.