Dorit Goldsher

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.

Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.

A Mutation in SNAP29, Coding for a SNARE Protein Involved in Intracellular Trafficking, Causes a Novel Neurocutaneous Syndrome Characterized by Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Palmoplantar Keratoderma

Neurocutaneous syndromes represent a vast, largely heterogeneous group of disorders characterized by neurological and dermatological manifestations, reflecting the common embryonic origin of epidermal and neural tissues. In the present report, we describe a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK syndrome). Using homozygosity mapping in two large families, we localized the disease gene to 22q11.2 and identified, in all patients, a 1-bp deletion in SNAP29, which codes for a SNARE protein involved in vesicle fusion. SNAP29 expression was decreased in the skin of the patients, resulting in abnormal maturation of lamellar granules and, as a consequence, in mislocation of epidermal lipids and proteases. These data underscore the importance of vesicle trafficking regulatory mechanisms for proper neuroectodermal differentiation.

Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields)

BackgroundThe present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial.MethodsCell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients.ResultsThe efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months.ConclusionThese results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity.

The management of metastatic spinal cord compression: A radiotherapeutic success ceiling

PURPOSE In assessing the effectiveness of the management of metastatic spinal cord or cauda equina compression, we performed a retrospective analysis of 70 patients with this complication whom we treated from 1985 to 1989. METHODS AND MATERIALS The most frequent primary diagnoses in our series were carcinomas of unknown origin and of the breast, lymphoproliferative disease, lung cancer, and prostatic carcinoma. We used the Findlay classification to group all patients according to their pre-therapeutic functional motor status as Grade I (24 patients or 34%), Grade II (27, or 39%) or Grade III (19 or 27%). Treatment consisted of 30-45 Gy of irradiation (using two different schedules) together with high-dose dexamethasone; in only five cases was there surgical intervention. RESULTS We found that a powerful predictor of response to radiotherapy was the patients neurologic status (Findlay grade) at the time of diagnosis: 66% of previously ambulatory patients remained so, whereas 30% of non-ambulatory patients and only 16% of paraplegic patients regained the ability to walk. Another important predictor of response was primary tumor histology, with the most favorable responses to radiation therapy having been observed in lymphoproliferative diseases and in breast cancer, but with some response in other radiosensitive malignancies as well. CONCLUSION The similarity of our results to those of other centers leads us to conclude that a radiotherapeutic success ceiling of 80% may have been reached for Findlay Grade I patients with metastatic spinal cord compression. In view of this, we suggest that future therapeutic endeavour would be best directed toward early diagnosis of the condition.

Posterior Cortical Atrophy Variants of Alzheimer’s Disease

Posterior cortical atrophy (PCA) was first described by Benson in 1988 and, since then, has been regarded as a variant of Alzheimer’s disease. We present 2 patients with symptoms suggestive of PCA and 2 patients with apraxia as the initial manifestation. Primary motor and sensory modalities were intact. Mild memory impairment was present early in the course of the disease and gradually worsened. Parieto-occipital atrophy was evident on brain MRI. HMPAO-SPECT demonstrated parieto-occipital hypoperfusion significantly different from the temporoparietal hypoperfusion usually described in senile dementia of the Alzheimer type. These findings suggest that HMPAO-SPECT can help in diagnosing atypical variants of Alzheimer’s disease. We suggest that PCA represents two clinically related behavioral phenotypes: PCA with predominantly apraxia manifestations and PCA with predominantly visuospatial disturbances.

Involvement of the central nervous system by ovarian carcinoma

Ovarian carcinoma rarely metastasizes to the central nervous system (CNS). Of 110 patients with epithelial ovarian carcinoma treated at the Northern Israel Oncology Center between the years 1979 and 1985, only five (4.5%) had CNS involvement. The median age of the patients was 54.5 years. All of them had treatment with cisplatin and Adriamycin (doxorubicin). The median duration from diagnosis to the development of brain involvement was 17 months. The median survival time was 28 months from diagnosis of carcinoma and 2 months from diagnosis of CNS disease. The increased incidence of this kind of metastasis in patients achieving local control of their advanced disease suggests that a change in the pattern of metastatic spread or the prolonged survival permits occult CNS metastases to become apparent. A routine computerized axial tomography (CAT) scan of the brain should therefore be performed on patients with ovarian carcinoma with prolonged survival.

CEDNIK syndrome results from loss-of-function mutations in SNAP29.

Background  CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss‐of‐function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis.

Ovarian Adrenal Rest Tumor in a Congenital Adrenal Hyperplasia Patient with Adrenocorticotropin Hypersecretion following Adrenalectomy

Objective: Ovarian adrenal rest tumors (OARTs) are rare in contrast to testicular adrenal rest tumors. We report a case of OART in a patient with congenital adrenal hyperplasia who developed Nelson’s syndrome after bilateral adrenalectomy. Methods: We describe the clinical, imaging, and laboratory findings of the patient and review the relevant literature regarding OART and the possible interaction between ACTH and brown adipose tissue. Results: An 18-year-old female with congenital adrenal hyperplasia, who had undergone bilateral adrenalectomy at the age of 10 years, presented with severe hyperpigmentation and hirsutism. Rectal ultrasonography showed a mass in the right ovary. 18F-fluorodeoxyglucose PET/CT revealed intense uptake both in this mass and in brown adipose tissue located in typical supradiaphragmatic sites. Laparoscopic removal of the ovarian mass confirmed the diagnosis of OART. A systematic review revealed 9 documented cases of OART. As in our case, all presented with elevated ACTH levels. Conclusions: Common to all documented cases of OART are sustained high ACTH levels that activate the adrenal anlagen tissue in the ovaries.

Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1.

3‐Methylglutaconic aciduria (3‐MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3‐MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3‐MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2‐6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the disease MEGDHEL syndrome.