Santosh Kesari | University of California, San Diego (original) (raw)

Papers by Santosh Kesari

Medical Oncology, Mar 20, 2011

Prostate cancer is rarely associated with leptomeningeal metastasis. An 87-year-old man with a hi... more Prostate cancer is rarely associated with leptomeningeal metastasis. An 87-year-old man with a history of prostate cancer presented with leptomeningeal metastasis. He received hormonal therapy with leuprolide. Subsequently, he achieved an impressive response, indicated by a constant fall in his PSA levels and by the stabilization of leptomeningeal disease and clinical improvement. Hormonal therapy may be effective in inducing remission in hormone-sensitive prostate cancer with leptomeningeal metastasis.

Springer eBooks, 2015

Neuro-oncology is a rapidly evolving, multidisciplinary field that has seen numerous exciting adv... more Neuro-oncology is a rapidly evolving, multidisciplinary field that has seen numerous exciting advances in recent years. This chapter provides background in the epidemiology and classification of brain metastasis, meningioma, and other primary brain tumors. Histopathologic and molecular classification of gliomas is reviewed. New technologies are improving the diagnostic capabilities of cerebrospinal fluid analysis including proteomics and micro-RNA analysis. Circulating tumor cell chips detect tumor cells in serum and cerebrospinal fluid with better sensitivity than conventional cytologic or cytometric analysis. The Response Assessment in Neuro-Oncology (RANO) workgroup have recently provided radiographic criteria that address progression of both enhancing and nonenhancing tumor, as well as the issue of pseudoprogression following radiation therapy. Intraoperative imaging and tumor markers have the potential to facilitate more extensive tumor resection. Angiogenesis inhibition is one of the main recent advances in malignant glioma therapeutics including the FDA approval of bevacizumab for recurrent high-grade glioma. Immunology-based therapies, viral vectors, and alternating electrical field technologies are actively being studied. These avenues of discovery and technological advancement hold promise to increase treatment options and ultimately improve clinical outcomes in this historically challenging group of diseases.

Journal of Neuro-oncology, Jan 23, 2008

We report the case of a 35 year old African American female who developed hypertrophic olivary de... more We report the case of a 35 year old African American female who developed hypertrophic olivary degeneration secondary to resection of a pontine cavernous malformation. The patient initially complained of headaches and diplopia. Unenhanced computed tomography (CT) and magnetic resonance images (MRI) of the brain revealed a left pontine cavernous malformation with scattered foci of recent and remote hemorrhage. The patient subsequently underwent surgical resection of the lesion. Follow up MRI 7 months post surgery demonstrated hypertrophy and T2 signal hyperintensity in the ipsilateral inferior olivary nucleus secondary to hypertrophic olivary degeneration. Familiarity with this diagnosis and its imaging characteristics is required of the radiologist to prevent erroneous diagnoses of other pathology.

Journal of Translational Medicine, May 13, 2014

CNS Oncology

Aim: The EMulate Therapeutics Voyager™ is a simple, wearable, home-use device that uses an altern... more Aim: The EMulate Therapeutics Voyager™ is a simple, wearable, home-use device that uses an alternating electromagnetic field to alter biologic signaling within cells. Objective: To assess the safety/feasibility of the Voyager in the treatment of recurrent glioblastoma (rGBM). Methods: In this study, patients with rGBM were treated with Voyager as monotherapy or in combination with standard chemotherapy at the Investigator's discretion. Safety was assessed by incidence of adverse events associated with the Voyager. Patients were followed until death. Results: A total of 75 patients were enrolled and treated for at least one day with the Voyager (safety population). Device-related adverse events were uncommon and generally did not result in interruption or withdrawal from treatment. There were no serious adverse events associated with Voyager. A total of 60 patients were treated for at least one month (clinical utility population). The median progression-free survival (PFS) was 17...

NEJM Journal Watch, 2008

Meningitis in cancer patients is an uncommon but serious disease with high morbidity and mortalit... more Meningitis in cancer patients is an uncommon but serious disease with high morbidity and mortality. Advances in medical and surgical treatments for

Bioelectronic medicine, Apr 10, 2024

Background Glioblastoma (GBM) presents as an aggressive brain cancer, notorious for its recurrenc... more Background Glioblastoma (GBM) presents as an aggressive brain cancer, notorious for its recurrence and resistance to conventional treatments. This study aimed to assess the efficacy of the EMulate Therapeutics Voyager ® , a noninvasive, non-thermal, non-ionizing, battery-operated, portable experimental medical device, in treating GBM. Using ultra-low radiofrequency energy (ulRFE) to modulate intracellular activity, previous preliminary results in patients have been encouraging. Now, with a focus on murine models, our investigation seeks to elucidate the device's mechanistic impacts, further optimizing its therapeutic potential and understanding its limitations. Methods The device employs a silicone over molded coil to deliver oscillating magnetic fields, which are believed to interact with and disrupt cellular targets. These fields are derived from the magnetic fluctuations of solvated molecules. Xenograft and syngeneic murine models were chosen for the study. Mice were injected with U-87 MG or GL261 glioma cells in their flanks and were subsequently treated with one of two ulRFE cognates: A1A, inspired by paclitaxel, or A2, based on murine siRNA targeting CTLA4 + PD1. A separate group of untreated mice was maintained as controls. Results Mice that underwent treatments with either A1A or A2 exhibited significantly reduced tumor sizes when compared to the untreated cohort. Conclusion The EMulate Therapeutics Voyager ® demonstrates promising potential in inhibiting glioma cells in vivo through its unique ulRFE technology and should be further studied in terms of biological effects in vitro and in vivo.

Cancer Cell International, Mar 20, 2014

Background: Primary and secondary brain cancers are highly treatment resistant, and their marked ... more Background: Primary and secondary brain cancers are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. Recent observations reveal that the microvascular endothelium of primary high-grade gliomas expresses prostate specific membrane antigen (PSMA). Breast cancers express PSMA and they frequently form secondary brain tumors. Hence we report here our pilot study addressing the feasibility of PSMA targeting in brain and metastatic breast tumors, by examining PSMA levels in all glioma grades (19 patients) and in breast cancer brain metastases (5 patients). Methods: Tumor specimens were acquired from archival material and normal brain tissues from autopsies. Tissue were stained and probed for PSMA, and the expression levels imaged and quantified using automated hardware and software. PSMA staining intensities of glioma subtypes, breast tumors, and breast tumor brain metastases were compared statistically versus normals. Results: Normal brain microvessels (4 autopsies) did not stain for PSMA, while a small proportion (<5%) of healthy neurons stained, and were surrounded by an intact blood brain barrier. Tumor microvessels of the highly angiogenic grade IV gliomas showed intense PSMA staining which varied between patients and was significantly higher (p < 0.05) than normal brain. Grade I gliomas showed moderate vessel staining, while grade II and III gliomas had no vessel staining, but a few (<2%) of the tumor cells stained. Both primary breast cancer tissues and the associated brain metastases exhibited vascular PSMA staining, although the intensity of staining was generally less for the metastatic lesions. Conclusions: Our results align with and extend previous data showing PSMA expression in blood vessels of gliomas and breast cancer brain metastases. These results provide a rationale for more comprehensive studies to explore PSMA targeted agents for treating secondary brain tumors with PSMA expressing vasculature. Moreover, given that PSMA participates in angiogenesis, cell signaling, tumor survival, and invasion, characterizing its expression may help guide later investigations of the poorly understood process of low grade glioma progression to glioblastoma.

Translational Neuroscience, 2016

The acknowledgment of active stem cells within the adult CNS and the subsequent association of ca... more The acknowledgment of active stem cells within the adult CNS and the subsequent association of cancer etiology have brought about an entirely new field of study. Cancer stem cells (CSCs) have gained significant traction in oncology research with the discovery of a treatment-resistant, highly tumorigenic subpopulation of tumor cells. Multiple theories exist as to the cellular origins of CSCs and their abilities to differentiate from precursor cells to solid tissue malignancies. Each of these theories and the following stem cell hypotheses relating to the differentiation and cellular distribution capabilities of stem cells will be discussed. In gliomas, the search for the glioma stem cell (GSC) has brought about numerous researchers looking to identify external markers for GSC classification. To date, there has been no successful identification of a GSC within any patient or immortalized cell line by external marker. Here, we will also discuss the research done in search of a GSC marker and the consequent possible treatment options for cells that have been identified as highly tumorigenic, treatment resistant, and metastatic.

Metabolites

We developed a machine-learning system for the selective diagnostics of adenocarcinoma (AD), squa... more We developed a machine-learning system for the selective diagnostics of adenocarcinoma (AD), squamous cell carcinoma (SQ), and small-cell carcinoma lung (SC) cancers based on their metabolomic profiles. The system is organized as two-stage binary classifiers. The best accuracy for classification is 92%. We used the biomarkers sets that contain mostly metabolites related to cancer development. Compared to traditional methods, which exclude hierarchical classification, our method splits a challenging multiclass task into smaller tasks. This allows a two-stage classifier, which is more accurate in the scenario of lung cancer classification. Compared to traditional methods, such a “divide and conquer strategy” gives much more accurate and explainable results. Such methods, including our algorithm, allow for the systematic tracking of each computational step.

Neuro-Oncology, 2019

BACKGROUND The EMulate Therapeutics Hælo system is an investigational non-sterile, non-invasive, ... more BACKGROUND The EMulate Therapeutics Hælo system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE®) cognate for the treatment of pediatric brain tumors. METHODS Sixteen patients with brain tumors consisting of diffuse midline glioma/diffuse intrinsic pontine glioma (DMG/DIPG, n=14), recurrent medulloblastoma (n=1), or anaplastic astrocytoma (n=1) – were treated with the Hælo under FDA’s single-patient compassionate use pathway, as protocol deviations in a glioblastoma trial, or under TGA’s Special Access Scheme. Baseline information and on-treatment safety and exposure data were collected. RESULTS Patients ranged in age from 4 to 28 years (median = 8 years) and were diagnosed 91 – 1399 days (median = 397 days) prior to treatment with the Hælo system. Patients were treated for 2 – 52 weeks (median = 15 weeks), with 4 patients still alive (all with a diag...

Expert Review of Neurotherapeutics, 2016

Glioma classification and grading has been historically based in morphologic appearance of tumor ... more Glioma classification and grading has been historically based in morphologic appearance of tumor cells: astrocytomas, oligodendrogliomas, oligoastrocytomas and ependymomas. Recent molecular advances have transformed the field of neuro-oncology, as some molecular markers harbor diagnostic, prognostic and therapeutic implications. In this paper we will review the major molecular changes associated with gliomas and their implications in diagnosis, prognosis, and opportunities in therapeutics. Expert commentary: Based on current understanding, adult diffuse infiltrating gliomas can be molecularly divided into three to five major subgroups with different clinical outcomes. Pediatric gliomas harbor mutations for H3F3A, ATRX and DAXX but not IDH. Circumscribed low-grade gliomas tend to have BRAF alterations. Clinical behavior of ependymomas correlates more with location than WHO grading. Posterior fossa ependymomas tend to behave worse than their cerebral or spinal cord counterparts. However, with the posterior fossa ependymomas, two distinct subtypes have emerged molecularly.

Brain pathology (Zurich, Switzerland), May 1, 2016

Science Translational Medicine, 2016

Toca 511 and Toca FC show promising results in treating recurrent high-grade glioma, and a specif... more Toca 511 and Toca FC show promising results in treating recurrent high-grade glioma, and a specific molecular signature correlates with treatment-related survival.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 16, 2016

There is growing interest in using circulating tumor DNA (ctDNA) testing in patients with cancer.... more There is growing interest in using circulating tumor DNA (ctDNA) testing in patients with cancer. 168 patients with diverse cancers were analyzed. Patients had digital next-generation sequencing (54 cancer-related gene panel including amplifications in ERBB2, EGFR, and MET) performed on their plasma. Type of genomic alterations, potential actionability, concordance with tissue testing, and patient outcome were examined. Fifty-eight percent of patients (98/168) had {greater than or equal to}1 ctDNA alteration(s). Of the 98 patients with alterations, 71.4% had {greater than or equal to} 1 alteration potentially actionable by an FDA-approved drug. The median time interval between the tissue biopsy and the blood draw was 2.7 months for patients with {greater than or equal to} 1 alteration in common compared to 14.4 months (P=0.006) for the patients in whom no common alterations were identified in the tissue and plasma. Overall concordance rates for tissue and ctDNA were 70.3% for TP53 a...

Oncotarget, 2016

Analysis of cell-free DNA using next-generation sequencing (NGS) is a powerful tool for the detec... more Analysis of cell-free DNA using next-generation sequencing (NGS) is a powerful tool for the detection/monitoring of alterations present in circulating tumor DNA (ctDNA). Plasma extracted from 171 patients with a variety of cancers was analyzed for ctDNA (54 genes and copy number variants (CNVs) in three genes (EGFR, ERBB2 and MET)). The most represented cancers were lung (23%), breast (23%), and glioblastoma (19%). Ninety-nine patients (58%) had at least one detectable alteration. The most frequent alterations were TP53 (29.8%), followed by EGFR (17.5%), MET (10.5%), PIK3CA (7%), and NOTCH1 (5.8%). In contrast, of 222 healthy volunteers, only one had an aberration (TP53). Ninety patients with non-brain tumors had a discernible aberration (65% of 138 patients; in 70% of non-brain tumor patients with an alteration, the anomaly was potentially actionable). Interestingly, nine of 33 patients (27%) with glioblastoma had an alteration (6/33 (18%) potentially actionable). Overall, sixty-ni...

Molecular cancer therapeutics, Apr 12, 2016

By profiling their patients' tumors, oncologists now have the option to use molecular results... more By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a "matched" versus "unmatched" therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a "matched" therapy; 93 (26.8%) with an "unmatched" therapy. More patients in the matched group achieved [SD≥6 months/PR/CR] (34.5% versus 16.1%, (P≤0.020 multivariable or propensity score methods). Matched patients had a longer median PFS (4.0 versus 3.0 months, P=0.039 in Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P=0.009); however, this shor...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 29, 2015

Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing a... more Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing anti-apoptotic proteins, have been shown to inhibit the growth of various human cancer cells in culture and xenograft models. Here, we evaluated the antitumor efficacy of a novel gossypol derivative and BH3 mimetic ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone) in colon cancer models. Several innovative combination strategies were also explored and elaborated. Ch282-5 was synthesized by modifying the active aldehyde groups and R groups of gossypol according to a computer-aided drug design program. The stability of ch282-5 was examined by HPLC and cytotoxic effects of ch282-5 on colon cancer cells were assessed by MTS assay. Activation of mitochondrial apoptotic pathway by ch282-5 was evidenced with a series of molecular biology techniques. In vivo antitumor activity of ch282-5 and its combination with chloroquine, rapamycin, oxaliplatin and ABT-263 was also evaluated in colon can...