Sunday, June 14, 2015

Third Day at 2015 American Association of Neuropathologists Meeting: Gene therapy, Amyloid Angiopathy, and the Diagnostic Slide Session

Day #3 of the annual AANP meeting commenced with a series of interesting platform sessions. Of particular note was a presentation by Dr. Michael Lawlor on results of AAV8-MTM1 gene therapy to correct muscle dysfunction in a canine model of X-linked myotubular myopathy. Dr. Lawlor showed some dramatic videos of puppies with severe muscular dysfunction who were restored to fully normal motor function after as little as one gene therapy treatment. As one audience member commented: "It's a relief, after all these years of experimentation, to see a case where gene therapy actually works!" The Korey Lecture in the morning was delivered by Dr. Matthew Frosch, who addressed cerebral amyloid angiopathy (CAA). While all neuropathologists recognize the risk of cerebral hemorrhage associated with CAA, Dr. Frosch focused on a subset of CAA patients with associated granulomatous inflammation who show cognitive decline and seizures. This subset can show dramatic improvement with immunosuppressive therapy. Among the more emotional moments of the meeting occurred today Meritorious Awards were bestowed upon two individuals who have made a significant impact on neuropathology both in scientific achievement and in service. This year's awards went to Drs. Bette K. Kleinschmidt-DeMasters and John Q. Trojanowski. Speaking of emotion, one of the aspects of coming to the AANP meeting that is not adequately acknowledged is the precious interactions we have between the formal presentations. Informal discussions which give encouragement, advice, or information are perhaps the most important part of this annual event. Our specialty is small, with many of us working in relative isolation. Chatting over a cup of coffee with a colleague brings a connectedness to like-minded individuals that renews enthusiasm for the jobs that each of us will go back to on Monday. Finally, as always, the most entertaining part of the meeting was the Diagnostic Slide Session (DSS). This year's slide session, hosted by Dr. Katerina Giannini, lived up to its long tradition of presenting great cases accompanied by insightful commentary from audience members. Among the DSS diagnoses this year were dural-based EBV-related smooth muscle tumor, Balo's concentric sclerosis, Machado-Joseph disease, and my personal favorite: copper deficiency myelopathy.
AANP 2015 Diagnostic Slide Session (Denver, CO)

Friday, June 12, 2015

Second Day at 2015 American Association of Neuropathologists Meeting: Looking Forward

The second day of the annual meeting of the American Association of Neuropathologists looked to the future -- on the scientific, professional, and clinical level. Highlighting the morning session was the annual Parisi Lecture, this year delivered by Bruce Lamb, PhD. Dr. Lamb spoke about the role of innate immunity in the development of Alzheimer Disease (AD). More specifically, Dr. Lamb discussed the special role played by the molecule Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) in the development of the plaques (and dystrophic tau neurites) associated with AD. It appears that the level of this protein on monocyte cell membranes, whether in peripheral blood  or decorating amyloid plaques in brain parenchyma, is positively associated with the development of amyloid plaques in mouse models. Strangely, there is a negative correlation between the level of this protein and the presence of hyperphosphorylated tau protein. So, whether TREM2 turns out to be a serum marker that can be used in the diagnosis of AD or as a target for the treatment of AD remains to be seen. But TREM2 does promise to play an important role in the future understanding of the molecular mechanisms underlying the development of AD. On the professional level, Dr. Ann Thor spoke to young physicians about to enter the field at a trainee luncheon in which she spoke about the future of neuropathology. She opined that -- despite predictions of gloom from some corners -- the subspecialist, including the neuropathologist, will be prized in the job market of the future. Dr. Thor's presentation was followed by short discussions by recent graduates of neuropathology fellowships who had landed positions, some with relative ease. The future of clinical practice was addressed in the afternoon with a series of platform presentations on new technologies in the characterization of brain tumors. A sampling of the platform titles which reflect the future of clinical practice included: Use of Stimulated Raman Scattering Microscopy for Quantitative Brain Tumor Imaging and Implementing 450k Methylation Array in Neuropathology: Implications for Diagnosis and Clinical Management. After a long day of looking forward toward the bright future of neuropathology, the Annual Reception was an opportunity for attendees to let their hair down and party into the evening (which, in the case of neuropathologists, of course means finishing up around 8:30 pm!)

Thursday, June 11, 2015

First Day at 2015 American Association of Neuropathologists Meeting: The Special Course

The "Special Course" which typically launches the annual AANP meeting (in Denver this year) was anything but typical this year. Rather than the usual series of research presentations which has characterized the first day of the meeting, the 2015 edition of the "Special Course" focused on need-to-know practical topics. Dr. Beatriz Lopes put together a program that offered something for everyone -- from trainee to seasoned practitioner. The morning started with a presentation by Dr. Caterina Giannini on primary CNS lymphoma, as well as its mimickers and precursors. Far from being a straightforward diagnosis, lymphoma -- particularly in the setting of corticosteroid therapy -- can be mistaken for anything from multiple sclerosis to infarct. Next, two eminent scholars from Paris, Drs. Francoise Gray and Elisabeth Tournier-Lasserve, presented a three-part lecture on the hereditary non-amyloid small vessel diseases of the brain. Then Charles Eberhart showed up from Johns Hopkins to provide a primer on ophthalmic pathology, providing a practical approach to eye specimens. For example, Dr. Eberhart discussed the significance of uveal granulomatosis in orbital exenteration specimens. The presence of this finding should be noted in the pathology report as it portends an increased risk for sympathetic ophthalmia. Dr. Arie Perry appeared next with a presentation on the molecular characterization of brain tumors using immunohistochemical surrogates -- an approach particularly appreciated by neuropathologists who work at smaller institutions which may not have the resources to perform protein sequencing and other more advanced laboratory tests. After lunch, the focus was redirected to neuropathology training. Drs. Marc Del Bigio and Suzanne Powell discussed the state of neuropathology training abroad and in the United States, respectively. Finally, a lively discussion was initiated by a panel featuring Drs. Jeff Golden, Dennis Dickson, Liz Cochran, and myself organized under the title "The Professional Market for Neuropathology Trainees". Several audience members talked about their view of the profession and how its many facets are reflected in the training we give fellows and how that training impacts the preparedness of trainees for the job market. Overall, it was engaging day which, as audience member John Donahue put it, was "well worth the price of admission!"

Friday, June 5, 2015

The Tumor Biomarker Series: 1p/19q co-deletion

Allelic losses on chromosomes 1p and 19q are associated with oligodendroglial phenotype. Most studies have indicated that combined loss of 1p and 19q are specific to oligodendrogliomas, with only a few astrocytomas and a small subset of oligoastrocytomas harboring these alterations. Those oligodendrogliomas with 1p/19q loss show enhanced response to chemotherapy and are associated with prolonged survival. Solitary losses of 1p or 19q are also occasionally noted within an infiltrating glioma, but are not as strongly linked to the oligodendroglioma histologic phenotype and are not predictive of enhanced response to therapy or prolonged survival. Co-deletion of 1p/19q is highly associated with the IDH1 mutation, with over 80% of 1p/19q co-deleted oligodendrogliomas also carrying the IDH1 mutation.

Monday, June 1, 2015

The Tumor Biomarker Series: IDH

Mutations in two isoforms of isocitrate dehydrogenase (IDH1 and IDH2) are relevant to clinical practice. Mutations in IDH1 are frequent (70-80%) in WHO grade II & III astrocytomas, oligodendrogliomas, oligoastrocytomas, as well as secondary glioblastomas. Mutations in IDH2 have also been detected in these tumor types, but far less frequently. The finding of an IDH mutation in an infiltrating glioma is associated with a substantially improved prognosis, grade for grade. Indeed, IDH-mutant GBMs are associated with longer survival time than IDH wild-type anaplastic astrocytomas! More than 90% of IDH1 mutations involve a base exchange of guanine to adenine within codon 132, resulting in an amino acid change from arginine to histidine (R132H). The resulting protein alteration can be detected immunohistochemically. Of course, other mutations in IDH1 and mutations in IDH2 cannot be detected in this manner, but protein sequencing can be used to pick up these less common mutations if necessary.

Tuesday, May 26, 2015

The Tumor Biomarker Series: EGFR

Epidermal growth factor receptor (EGFR) is the most frequently amplified oncogene in astrocytic tumors (>40% or GBMs and 5-10% of anaplastic astrocytomas). EGFR is far more often amplified in de novo GBMs as compared to secondary GBMs. About one-half of those GBMs with EGFR amplification also have specific EGFR mutations (the vIII mutant), which produce a truncated receptor with constitutive activity. Both EGFR amplification and EGFRvIII mutant are mutually exclusive with IDH mutations. So, what is the utility of EGFR testing? First, astrocytomas with EGFR amplification tend to be of higher grade. So if, for example, the diagnostician is vacillating between a WHO grade II and a WHO grade III tumor, positive EGFR amplification status would favor the latter. Secondly, EGFR amplification can also help distinguish between a small cell GBM (which would potentially harbor the amplification) from anaplastic oligodendrogliomas (which do not exhibit the amplification).

Wednesday, May 20, 2015

"Bad Ass" CrossFitter and Neuropathologist Greg Fuller set to compete in kettlebell competition for brain cancer research

Elite Neuropathologist
Elite Athlete
It's no secret that Dr. Greg Fuller (pictured) is the fittest neuropathologist in the world. What his colleagues might not know is that he is the 67th fittest man in the world for his age class (60+). Greg's wife, Tina, describes him as a "bad ass CrossFitter". As a former owner of a CrossFit "box" myself, I know what it takes to achieve Greg's level in the Sport of Fitness. It requires true grit. There are many of us who would also consider Greg a "bad-ass neuropathologist" -- in the very best sense of that phrase. He's bringing together his love of fitness with his commitment to the study of CNS malignancies by participating in the Kettlebells For Brain Cells competition in Boerne, Texas on June 13. (So, he has a legitimate reason for not showing up at the concurrent AANP annual meeting. in Denver.) All proceeds from the competition will be going to the American Brain Tumor Association. The event is being organized by a brain tumor patient at MD Anderson Cancer Center, where Greg is Chief Neuropathologist. This is a shining example of a neuropathologist reaching out to a patient in a very personal way. Best of luck in the competition, Greg. Crush it!

Monday, May 11, 2015

The Tumor Biomarker Series: Ki-67

An immunohistochemical marker of cellular proliferation, the nuclear antigen Ki-67 is positive in cells that are actively engaged in cell cycle (i.e., not in G0). Results are expressed as a percent index of positively staining cells. Several studies have shows a correlation between Ki-67 indices in various astrocytomas, oligodendrogliomas, and mixed gliomas. Among grade II and grade III diffuse gliomas, the Ki-67 index provides prognostic value. However, investigations have consistently shown that Ki-67 proliferation indices have no prognostic value on patient outcomes for GBM. So, if you have an unmistakable GBM under your microscope, you are not practicing evidence-based parsimonious medicine by ordering Ki-67 immunohistochemistry on that tumor.  On the other hand, if you are debating between diagnosing a grade III or a grade IV astrocytoma, Ki-67 can be helpful in swaying your decision. The Ki-67 index is not used in the WHO grading system because of the high degree of technical variability between laboratories, making standardization difficult.