Tumor treating fields for glioblastoma: should it or will it ever be adopted?

PURPOSE OF REVIEW: The purpose of this review is to discuss how a new treatment modality, tumor treating fields, may be incorporated into the oncologic care for patients with glioblastoma. RECENT FINDINGS: Tumor treating fields are a new treatment modality available to patients with newly diagnosed and recurrent glioblastoma. Alternating electric fields are delivered via a wearable, removable device affixed to the scalp of patients with supratentorial glioblastoma. With continuous use, the application of tumor treating fields combined with temozolomide chemotherapy has been shown to improve overall survival compared with temozolomide alone in patients with newly diagnosed glioblastoma. Adverse events attributable to the device are limited to localized skin reactions. Despite compendium guidelines in support of its use and Food and Drug Administration (FDA) approval, tumor treating fields have been slow to be adopted in the neuro-oncology community. Critics have raised concerns about the generalizability of the study data, patient quality of life, and mechanism of action of this therapy. SUMMARY: Tumor treating fields are available for the treatment of both newly diagnosed and recurrent glioblastoma and represent a new category of treatment modalities in oncologic therapy. This novel device has received FDA approval but has been slow to be adopted into clinical practice.

Pre- and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer's disease.

Amyloid imaging has identified cognitively normal older people with plaques as a group possibly at increased risk for developing Alzheimer's disease-related dementia. It is important to begin to thoroughly characterize this group so that preventative therapies might be tested. Existing cholinotropic agents are a logical choice for preventative therapy as experimental evidence suggests that they are anti-amyloidogenic and clinical trials have shown that they delay progression of mild cognitive impairment to dementia. A detailed understanding of the status of the cortical cholinergic system in preclinical AD is still lacking, however. For more than 30 years, depletion of the cortical cholinergic system has been known to be one of the characteristic features of AD. Reports to date have suggested that some cholinergic markers are altered prior to cognitive impairment while others may show changes only at later stages of dementia. These studies have generally been limited by relatively small sample sizes, long postmortem intervals and insufficient definition of control and AD subjects by the defining histopathology. We, therefore, examined pre- and post-synaptic elements of the cortical cholinergic system in frontal and parietal cortex in 87 deceased subjects, including non-demented elderly with and without amyloid plaques as well as demented persons with neuropathologically confirmed AD. Choline acetyltransferase (ChAT) activity was used as a presynaptic marker while displacement of (3)H-pirenzepine binding by oxotremorine-M in the presence and absence of GppNHp was used to assess postsynaptic M1 receptor coupling. The results indicate that cortical ChAT activity as well as M1 receptor coupling are both significantly decreased in non-demented elderly subjects with amyloid plaques and are more pronounced in subjects with AD and dementia. These findings confirm that cortical cholinergic dysfunction in AD begins at the preclinical stage of disease and suggest that cholinotropic agents currently used for AD treatment are a logical choice for preventative therapy.

Treatment Considerations for Patients with Unresectable Metastatic Melanoma Who Develop Pembrolizumab-Induced Guillain-Barré Toxicity: A Case Report.

Immunotherapy has improved outcomes in many malignancies, most notably in melanoma, lung cancer, and bladder cancer. Understanding the side effects associated with these medications is an important part of managing our patients. Although fatigue, rash, and diarrhea are commonly reported side effects, it is important to be cognizant of rarer ones, such as neuropathy. Amongst the different neurological toxicities that have been reported in the literature, Guillain-Barré-like neuropathies are quite rare. However, the occurrence of such neuropathies in a patient can be life threatening. The problem this poses in treating cancers such as melanoma is that it eliminates an effective class of medication available to the patient, which can ultimately affect their prognosis. We present a case of a 65-year-old female with unresectable metastatic melanoma who developed Guillain-Barré-like neuropathy after two doses of pembrolizumab. Her clinical course was complicated by three separate hospitalizations over 3 months due to recurring bouts of neuropathy, which resulted in a significant decline in performance status and delay in subsequent treatment of her melanoma. Her prolonged recovery eventually resulted in progression of her melanoma nearly 1 year later, while off therapy. Instead of discontinuing immunotherapy completely, she agreed to a re-challenge with ipilimumab. After one dose, her melanoma regressed and continues to show a sustained response nearly 1 year after treatment without any signs of relapse in her neuropathy. Guillain-Barré toxicity resulting from immune checkpoint inhibition poses a difficult challenge to an oncologist who is determining the next line of treatment for patients with unresectable metastatic melanoma that have progressed while off therapy and who have no targetable mutations. Our case raises the question of whether a re-challenge with a different class of immunotherapy agent is a reasonable option.

Neurohistiocytosis of the Cerebellum: A Rare Cause of Ataxia.

Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis that affects multiple body organs, notably the skeletal system. We examined a 58-year-old man who presented with ataxia and T2 hyperintensity of the middle cerebellar peduncles and dentate nuclei without contrast enhancement on MRI brain. Workup for malignancy revealed "hairy kidneys" on CT scan of the abdomen, and excisional biopsy of the retroperitoneal mass for concerns of lymphoma revealed foamy histiocytes that tested positive for CD68 and negative for CD1a, confirming the diagnosis of ECD. Further genetic testing on excised tissue revealed BRAF (V600E) gene mutation that is present in 50% of ECD patients. Treatment was initiated with targeted therapy using the BRAF inhibitor Dabrafenib. X-ray of the lower extremities did not reveal sclerosis of the long bones, and bone scan with technetium 99 was negative except for a nonspecific tracer uptake in left calvarial bone with no corresponding CT changes or T1/T2 signal changes on MRI. His MRI brain revealed classic cerebellar involvement in ECD without other central nervous system (CNS) involvement. It has been postulated that bone involvement is almost universal in ECD; however, our patient with ECD had ataxia and cerebellar involvement without significant bone involvement, as evidenced by bone scan. This is a rare presentation of ECD affecting the CNS and sparing the skeletal system. It confirms the wide spectrum of presentation this multisystem disease can have.

Thiorphan-induced neprilysin inhibition raises amyloid beta levels in rabbit cortex and cerebrospinal fluid.

Studies on the pathogenesis of Alzheimer's disease (AD) suggest overproduction of amyloid beta (Abeta) may not be the only pathogenic route to AD. Decreased degradation of Abeta is another possible disease mechanism. Neprilysin is a neutral endopeptidase that has been proposed to be the major enzyme responsible for Abeta degradation. Studies have reported correlations between Abeta deposition and neprilysin activity in the human brain. This study shows that intracerebroventricular infusion of thiorphan, a neprilysin inhibitor, raises cortical and cerebrospinal fluid (CSF) Abeta concentrations in rabbits. Rabbits treated with thiorphan for 5 days had levels of CSF and cortical Abeta40 that were 147 and 142% of the control group, respectively. Results for Abeta42 showed a similar trend. The results indicate that age-related decreases of neprilysin could lead to increased brain concentrations of Abeta, plaque formation, and AD.

Anti-N-methyl-D-aspartate receptor encephalitis: a patient with refractory illness after 25 months of intensive immunotherapy.

IMPORTANCE: N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is an autoimmune encephalitis that can be paraneoplastic and usually responds to treatment. It is quickly becoming the most common paraneoplastic encephalitis. OBSERVATIONS: We present a case of a woman in her late 30s who developed psychiatric symptoms that progressed to encephalopathy, seizures, autonomic instability, and hyperkinetic movements. The patient was found to have an ovarian teratoma and serum and cerebrospinal fluid NMDAR antibodies. Despite resection of the teratoma and treatment with immunosuppressive therapy, the patient progressed to a minimally conscious state. She was supported medically in our institution for 25 months. During her hospitalization, she was treated with multiple immunosuppressive agents. With each treatment, we analyzed the serum and cerebrospinal fluid for NMDAR antibodies. While there was some initial reduction in the serum antibodies, the spinal fluid antibodies remained persistently elevated. The patient did not have any clinical improvement and eventually died after the family decided to withdraw care. CONCLUSIONS AND RELEVANCE: As far as we know, this case represents the longest active treatment without improvement of a patient with anti-NMDAR encephalitis. The patient had persistently high cerebrospinal fluid and serum antibody titers, which may be of prognostic significance.