Long Term Survivals in Aggressive Primary Brain Malignancies Treated With an Adjuvant Ketogenic Diet.

Aggressive primary brain tumors (APBT) glioblastoma multiforme and grade IV astrocytoma are treated with multimodality treatments that include surgery to remove as much tumor as possible without sacrificing neurological function followed by radiation therapy and chemotherapy usually temozolomide. Survivals in adults are in the range of 8-16 months. The addition of a ketogenic diet (KD) to rodents with transplanted brain tumors increased survival in nine of 11 animals to over 299 days compared to survival in untreated controls of 33 days and radiation only controls of 38 days. We treated humans with APBT with standard of care neurosurgery immediately followed by 6 weeks of an adjuvant ketogenic diet concurrent with radiation therapy and temozolomide. Twice daily measurements of blood ketones and glucose were recorded and the patients' diet was modified toward the goal of maintaining blood ketone levels approaching 3 mM. Of the nine patients who completed the protocol three younger patients age 32, 28, and 22 at enrollment are alive and employed with clinically stable disease and brain images 74, 58, and 52 months since diagnosis. All the six older patients mean age 55 have died with disease progression detected on average 8 months after Dx. In conclusion: 1. It is possible to implement and maintain dietary induced ketosis in patients with APBT; 2. The longer survivals observed in younger patients treated with KD need to be confirmed in larger studies that should be focused on younger patients possibly under age 40.

Intracranial angiomatoid fibrous histiocytoma with rhabdoid features: a mimic of rhabdoid meningioma.

Angiomatoid fibrous histiocytoma (AFH) is an uncommon soft-tissue neoplasm that arises mostly in the extremities of young people and generally carries a good prognosis. Intracranial location is unusual and frequently associated with myxoid change. EWSR1 gene fusions with members of the CREB family (CREB1, ATF1, and CREM) are well-established events in AFH. These fusions have also been described in other neoplasms including intracranial myxoid mesenchymal tumor, and it is still uncertain whether the latter is a distinct entity or if it represents a myxoid variant of AFH. Here, we describe a rare falcine AFH presenting in a 50-year-old woman. The most striking feature of this tumor was its diffuse rhabdoid morphology with focal high mitotic activity, raising the consideration of rhabdoid meningioma (WHO grade III). The tumor cells were moderately positive for EMA and negative for progesterone receptor and SSTR2 prompting additional studies. Desmin was strongly positive and CD99 showed membranous immunoreactivity. BAP1, INI-1, and BRG1 expressions were retained. Next-generation sequencing analysis demonstrated an EWSR1-ATF1 gene fusion, supporting the diagnosis of an unusual rhabdoid variant of AFH. After gross total resection of this tumor, the patient remains free of disease 5 months after the surgery without additional treatment.

Statin-induced necrotizing autoimmune myopathy: An uncommon complication of a commonly used medication.

A well-known side effect of statin therapy is myopathy. We report a case of statin induced necrotizing autoimmune myopathy, a rare variant of statin-induced myopathy. A 64-year-old gentleman on atorvastatin presented with muscle weakness. Initial laboratory results showed elevated liver function tests, a creatine phosphokinase (CPK) of 8200 IU/L, and positive urine myoglobin. Despite discontinuing atorvastatin, his CPK remained persistently elevated. Muscle biopsy was consistent with necrotizing myopathy. Anti-HMG CoA reductase antibody was strongly positive. Steroids followed by intravenous immunoglobulin were given. The patient's muscle weakness, CPK, and liver functions gradually improved, and he was eventually discharged on oral steroids. Statin induced necrotizing autoimmune myopathy should be considered when discontinuing statin does not lead to muscle recovery and improvement in CPK. Diagnosis is confirmed by positive anti-HMG-CoA reductase autoantibody.

Hemorrhagic colloid cyst in a 9-year-old girl.

Colloid cysts of the third ventricle are benign intracranial tumors that usually become symptomatic in adults, rather than in children. Rare hemorrhages in these cysts can cause acute obstructive hydrocephalus and sudden death. We report a novel pediatric case of hemorrhagic colloid cyst in a 9-year-old girl who presented with headaches, nausea, and had sudden deterioration of her mental status. The patient underwent emergent ventriculostomy and then craniotomy to resect the colloid cyst; she had an excellent recovery.

Intracranial and scalp metastasis of endometrial carcinoma.

BACKGROUND: Endometrial adenocarcinoma is one of the most common gynecological tumors in postmenopausal women. The distant metastasis mostly involves liver, lung and bone. Scalp metastases from endometrial adenocarcinoma are very rare. CASE REPORT: A 63-year-old female with history of irregular vaginal bleeding presented with progressive headaches and a rapidly enlarging mass on the left forehead. There were no other associated symptoms including any motor or sensory deficits. MRI of the head showed a large 8 cm tumor extending from the left frontal subcutaneous tissue through the skull into the epidural space. CT scan of the abdomen, pelvis and thorax revealed a uterine mass and showed multiple signal abnormalities in the ribs and vertebra indicative of metastasis. The patient underwent craniotomy and also had an endometrial biopsy. Both craniotomy and endometrial biopsies revealed endometrioid adenocarcinoma. CONCLUSIONS: This case illustrates that although scalp or intracranial metastases from endometrial adenocarcinoma are very rare, it must remain in the differential diagnosis in an elderly woman with dysfunctional uterine bleeding and a scalp tumor.

Investigating the Ketogenic Diet As Treatment for Primary Aggressive Brain Cancer: Challenges and Lessons Learned.

Survival of glioblastoma multiforme (GBM) with the current recommended treatment is poor. Reported median survivals are approximately 8-15 months. Based on recent publications from animal models, combining cancer drugs, radiation, and diet-metabolic treatments may be a new route to better survivals. To investigate this possibility, we have begun a clinical trial that has enrolled 15 subjects using a ketogenic diet (KD) as an addition to current standard treatments that include surgery, radiation therapy, and chemotherapy. Of the 15 enrolled, 10 completed the protocol. This perspective describes the challenges and lessons learned during this clinical trial and discusses the critical elements that are essential for investigating treatment with a KD. We also reviewed and compared various types of KDs. We believe that the diet selected should be standardized within individual clinical trials, and more importantly, the patients' blood should be monitored for glucose and ketones twice daily so that the supervising dietitian can work with the patient and their caregivers to make appropriate changes in the diet. Compliance with the diet is best in highly motivated patients who have excellent home support from a family member or a friend who can help to overcome administrative, physical, and cognition deficiencies associated with the disease. Treatment of GBM using a KD represents a reasonable investigative approach. This perspective summarizes the challenges and lessons learned implementing and continuing KD therapy while the patients are concurrently being treated with radiation and chemotherapy.

Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.

NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation.

Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature.

BACKGROUND: Based on the hypothesis that cancer cells may not be able to metabolize ketones as efficiently as normal brain cells, the ketogenic diet (KD) has been proposed as a complementary or alternative therapy for treatment of malignant gliomas. CASE PRESENTATION: We report here our experience in treating two glioma patients with an IRB-approved energy-restricted ketogenic diet (ERKD) protocol as monotherapy and review the literature on KD therapy for human glioma patients. An ERKD protocol was used in this pilot clinical study. In addition to the two patients who enrolled in this study, we also reviewed findings from 30 other patients, including 5 patients from case reports, 19 patients from a clinical trial reported by Rieger and 6 patients described by Champ. A total of 32 glioma patients have been treated using several different KD protocols as adjunctive/complementary therapy. The two patients who enrolled in our ERKD pilot study were monitored with twice daily measurements of blood glucose and ketones and daily weights. However, both patients showed tumor progression while on the ERKD therapy. Immunohistochemistry reactions showed that their tumors had tissue expression of at least one of the two critical mitochondrial ketolytic enzymes (succinyl CoA: 3-oxoacid CoA transferase, beta-3-hydroxybutyrate dehydrogenase 1). The other 30 glioma patients in the literature were treated with several different KD protocols with varying responses. Prolonged remissions ranging from more than 5 years to 4 months were reported in the case reports. Only one of these patients was treated using KD as monotherapy. The best responses reported in the more recent patient series were stable disease for approximately 6 weeks. No major side effects due to KD have been reported in any of these patients. CONCLUSIONS: We conclude that 1. KD is safe and without major side effects; 2. ketosis can be induced using customary foods; 3. treatment with KD may be effective in controlling the progression of some gliomas; and 4. further studies are needed to determine factors that influence the effectiveness of KD, whether as a monotherapy, or as adjunctive or supplemental therapy in treating glioma patients. TRIAL REGISTRATION: ClinicalTrials.gov# NCT01535911.

An uncommon cause of transient neurological dysfunction.

Transient neurological dysfunction may be associated with uncommon disorders and should prompt consideration of a broad differential diagnosis when assessing patients with episodic symptoms. The most common causes of transient neurological dysfunction include transient ischemic attack (TIA), seizure disorder, and migraine and its variants. However, underlying unusual pathophysiological processes such as brain tumors can also cause transient neurological dysfunction. Here we present a case of a 68-year-old male with oligodendroglial gliomatosis cerebri (OGC) who presented with TIA-like symptoms. Brain magnetic resonance imaging revealed multiple diffuse T2 hyperintensities within the white and gray matter. Magnetic resonance spectroscopy was suggestive of gliomatosis cerebri and was particularly helpful in this case. The diagnosis of OGC was confirmed by histopathology and molecular genetic studies on brain biopsy tissue. In this report, we discuss the clinical and radiological characteristics of OGC and highlight the unusual presentation of this case.

Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy.

BACKGROUND: Recent studies in animal models, based on the hypothesis that malignant glioma cells are more dependent on glycolysis for energy generation, have shown promising results using ketogenic diet (KD) therapy as an alternative treatment strategy for malignant glioma, effectively starving glioma cells while providing ketone bodies as an energy source for normal neurons and glial cells. In order to test this treatment strategy in humans, we investigated the relative expression of several key enzymes involved in ketolytic and glycolytic metabolism in human anaplastic glioma (WHO grade III) and glioblastoma (GBM, WHO grade IV). METHODS: Immunohistochemistry was performed on formalin fixed paraffin embedded sections from 22 brain biopsies (17 GBM, 3 anaplastic astrocytoma and 2 anaplastic oligoastrocytoma) using antibodies raised against glycolytic and ketolytic enzymes. The glycolytic enzymes included hexokinase-II (HK2) and pyruvate kinase M2 isoform (PKM2). The ketone body metabolic enzymes included: succinyl CoA: 3-oxoacid CoA transferase (OXCT1), 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and BDH2), and acetyl-CoA acetyltransferase 1 (ACAT1). The immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: POS (>20%), LOW (5-20%), and very low (VLOW) (<5%). Focal non-neoplastic "normal" brain tissue within the biopsy specimens served as internal controls. RESULTS: The rate limiting mitochondrial ketolytic enzymes (OXCT1 and BDH1) were either LOW or VLOW, concordantly in 14 of the 17 GBMs and in 1 of 5 anaplastic gliomas, whereas at least one of the glycolytic enzymes was POS in 13 of these 17 GBMs and all 5 anaplastic gliomas. Cytosolic BDH2 and mitochondrial ACTAT1 were, surprisingly, POS in most of these tumors. CONCLUSION: Our results showing that malignant gliomas have differential expression of ketolytic and glycolytic enzymes are consistent with previous studies that have shown that these are genetically heterogeneous tumors. It seems reasonable to hypothesize that patients with low or very low expression of key ketolytic enzymes in their malignant gliomas may respond better to the KD therapy than those patients with positive expression of these enzymes. Further studies in animal models and/or a large-scale clinical trial would be needed to test this hypothesis.

6-year-old girl with hydrocephalus.

With rare exceptions, pediatric tectal gliomas have been generally reported as low-grade tumors with relatively good prognosis. The patients are usually treated conservatively to manage the signs and symptoms of obstructive hydrocephalus. We report a case of a tectal glioma in a 6-years-old girl with histological features of anaplastic mixed oligoastrocytoma that continues to progress despite chemotherapy and radiation therapy.

Lymphomatoid granulomatosis masquerading as interstitial pneumonia in a 66-year-old man: a case report and review of literature.

Lymphomatoid granulomatosis (LG) is a rare, Epstein-Barr virus (EBV)-associated systemic angiodestructive lymphoproliferative disorder that may progress to a diffuse large B cell lymphoma. Pulmonary involvement may mimic other more common lung pathologies including pneumonias. Therapeutic standards have not been established for LG, but rituximab, interferon-alpha2b (INF-alpha2b), and chemotherapy have shown to improve symptoms and long term prognosis.We report a case of rapid respiratory deterioration in a 66-year-old man with clinical presentation, chest radiography, pulmonary function testing and high resolution computed tomography (HRCT) findings consistent with idiopathic interstitial pneumonia, but very poor response to antibiotics and low dose steroids. Lung biopsy showed histopathology consistent with LG that was confirmed by a positive in situ hybridization for Epstein - Barr virus encoded RNA (EBER). The patient was treated with rituximab and combination chemotherapy and showed significant initial clinical improvement with gradual resolution of abnormal findings on imaging. However, the patient developed pancytopenia as a complication of chemotherapy and died secondary to septic shock and renal failure that were refractory to medical management. Autopsy showed diffuse alveolar damage but no evidence of any residual LG within the lungs.This case demonstrates that an open lung biopsy or video-assisted thoracoscopic surgical (VATS) biopsy is often necessary to rule out the presence of LG in order to determine the appropriate therapeutic strategy early in the course of illness to improve prognosis.

Pediatric cerebellar pleomorphic xanthoastrocytoma with anaplastic features: a case of long-term survival after multimodality therapy.

CASE REPORT: A 4-year-old girl had a large midline cerebellar solid and cystic mass partially attached to the meninges. The original diagnosis was glioblastoma multiforme and she was treated by a gross-total surgical resection followed by chemotherapy and radiation therapy to the posterior fossa during the ensuing 14 months. She has received no further therapy and appears to be doing well 12 years later. This unusual favorable clinical outcome prompted our review of this case. METHODS: Additional special stains and immunocytochemistry were performed on the paraffin embedded tumor sections. RESULTS: We have confirmed the original histopathological observations of hypercellularity and focal nuclear pleomorphism, atypical mitoses, vascular hyperplasia, as well as focal necrosis. However, the additional stains revealed that the tumor is a relatively well-circumscribed meningeal-based astrocytic tumor (positive for GFAP) with extensive reticulin deposit and focal neuronal differentiation (positive for synaptophysin). A Ki67 labeling index is generally very low, but is positive in up to 5-10% of tumor cells focally. In the light of the favorable clinical outcome and the overall histological features, this tumor may be best reclassified as a rare example of cerebellar pleomorphic xanthoastrocytoma with foci of anaplasia.