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Medulloblastoma is the most common malignant brain tumor in children. It has WNT-driven, SHH-driven/TP53 mutant, SHH-driven/TP53 wildtype, and non-WNT/non-SHH subgroups. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encodes a mitochondrial import inner membrane translocase subunit and is responsible for the translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma. Methods: DAOY (SHH driven/tp53 mutant) and D425 (non-SHH group 3) were treated with BT9. For in vitro analysis, cell proliferation, death, migration, invasion, and metabolic activity were assessed using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. A D425 orthotopic xenograft mouse model was used to evaluate BT9 efficacy in vivo. Results: BT9 treatment resulted in a significant decrease in cell proliferation (DAOY, 24 hours IC50: 3.6 μM, 48 hours IC50: 2.3 μM, 72 hours IC50: 2.1 μM; D425 24 hours IC50: 3.4 μM, 48 hours IC50: 2.2 μM, 72 hours IC50: 2.1 μM) and a significant increase in cell death (DAOY, 24 hours p = 0.0004, 48 hours p<0.0001; D425, 24 hours p = 0.0001, 48 hours p = 0.02). In DAOY cells, 3 μM BT9 delayed migration and significantly reduced DAOY and D425 cell invasion (p < 0.0001). It also modified mitochondrial respiratory function in both medulloblastoma cell lines. Compared to control, however, BT9 administration did not improve survival in a D425 orthotopic xenograft mouse model. Conclusions: Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines, suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models. [ABSTRACT FROM AUTHOR]

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease that originates from lymphocytes and develops in the central nervous system. There is no standard consolidation/maintenance therapy for PCNSL. While there exists a variety of options, the high chance of inferior outcomes for elderly patients and the risk of neurotoxicity requires exploration of alternative options for consolidation/maintenance therapy for PCNSL in the elderly population with CNS lymphoma. We treated one 77-year-old patient with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor that crosses the blood-brain-barrier, as consolidation/maintenance therapy after induction therapy with high-dose methotrexate (HD-MTX) and rituximab plus temozolomide. This treatment resulted in good tolerance, further resolution of a small residue lymphoma, and sustained remission. The patient has completed one year of consolidation/maintenance therapy and is currently under clinical and imaging surveillance. She has survived 27 months without recurrence since diagnosis. This case shows the potential effectiveness of single agent ibrutinib as consolidation/maintenance therapy for PCNSL after induction therapy. More cases are needed to confirm the findings. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is the most common primary, malignant brain tumor in adults and has a poor prognosis. The median progression-free survival (mPFS) of newly diagnosed GBM is approximately 6 months. The recurrence rate approaches 100%, and the case-fatality ratio approaches one. Half the patients die within 8 months of recurrence, and 5-year survival is less than 10%. Advances in treatment options are urgently needed. We report on the efficacy and safety of a therapeutic vaccine (SITOIGANAP: Epitopoietic Research Corporation) administered to 21 patients with recurrent GBM (rGBM) under a Right-to-Try/Expanded Access program. SITOIGANAP is composed of both autologous and allogeneic tumor cells and lysates. Methods: Twenty-one patients with rGBM received SITOIGANAP on 28-day cycles in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), cyclophosphamide, bevacizumab, and an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody (either nivolumab or pembrolizumab). Results: The mPFS was 9.14 months, and the median overall survival (mOS) was 19.63 months from protocol entry. Currently, 14 patients (67%) are at least 6 months past their first SITOIGANAP cycle; 10 patients (48%) have received at least six cycles and have a mOS of 30.64 months and 1-year survival of 90%. The enrollment and end-of-study CD3+/CD4+ T-lymphocyte counts strongly correlate with OS. Conclusions: The addition of SITOIGANAP/GM-CSF/cyclophosphamide to bevacizumab and an anti-PD-1 monoclonal antibody resulted in a significant survival benefit compared to historic control values in rGBM with minimal toxicity compared to current therapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the role of retrograde signaling (mitochondria to nucleus) in MCF7 breast cancer cells. Therefore, in the present study, MCF7-H and MCF7-J cybrids were produced using the mitochondria from the same H and J individuals that were already used in our non-diseased retinal pigment epithelium (ARPE19) cybrids. MCF7 cybrids were treated with cisplatin and analyzed for cell viability, mitochondrial membrane potential, ROS, and expression levels of genes associated with the cGAS-STING and cancer-related pathways. Results showed that unlike the ARPE19-H and ARPE19-J cybrids, the untreated MCF7-H and MCF7-J cybrids had similar levels of ATP, lactate, and OCR: ECAR ratios. After cisplatin treatment, MCF7-H and MCF7-J cybrids showed similar (a) decreases in cell viability and ROS levels; (b) upregulation of ABCC1, BRCA1 and CDKN1A/P21; and (c) downregulation of EGFR. Cisplatin-treated ARPE19-H and ARPE19-J cybrids showed increased expression of six cGAS-STING pathway genes, while two were increased for MCF7-J cybrids. In summary, the ARPE19-H and ARPE19-J cybrids behave differentially from each other with or without cisplatin. In contrast, the MCF7-H and MCF7-J cybrids had identical metabolic/bioenergetic profiles and cisplatin responses. Our findings suggest that cancer cell nuclei might have a diminished ability to respond to the modulating signaling of the mtDNA that occurs via the cGAS-STING pathway. [ABSTRACT FROM AUTHOR]

Background: Computer-based cognitive rehabilitation programs may help adolescent and young adult (AYA) patients with cancer-related cognitive impairment. This pilot study investigated the feasibility of cognitive rehabilitation as a preventive intervention for AYA patients receiving chemotherapy. Explorative objectives included the correlation of cognitive performance with serum brain-derived neurotrophic factor (BDNF). Methods: This pilot prospective study included English-speaking patients 12–25 years of age with a fist diagnosis of cancer requiring chemotherapy. Participants enrolled in the intervention arm participated in a computer-based neurocognitive training program for 20–30 minutes daily for 16 weeks. Outcome measures, including engagement with and completion of computerized neurocognitive testing and serum BDNF levels, were obtained within the first month following diagnosis, ∼16 and 24 weeks from enrollment. Results: Fourteen of 18 eligible patients provided consent, with 7 patients assigned to each the intervention arm and nonintervention arm. Seventy-one percent of the patients in the intervention arm completed at least 80% of the required activities. Compared to baseline, patients in the nonintervention arm demonstrated higher prevalence of impairment in four of the six cognitive domains (processing speed, visual attention, attention/working memory, and executive function) at the end of the study period. There was a nonstatistically significant reduction of serum BDNF levels over time, which was observed in both intervention and nonintervention arms. Conclusion: This pilot study provides some evidence that it is feasible for AYAs with new cancer diagnoses to receive standardized cognitive rehabilitation. Patients receiving cognitive activities experienced less impairment in numerous cognitive domains. [ABSTRACT FROM AUTHOR]

The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID‐19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID‐19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full‐scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre‐pandemic cancer care delivery. [ABSTRACT FROM AUTHOR]

Background: The rapid spread of coronavirus disease 2019 (COVID-19) revealed significant constraints in critical care capacity. In anticipation of subsequent waves, reliable prediction of disease severity is essential for critical care capacity management and may enable earlier targeted interventions to improve patient outcomes. The purpose of this study is to develop and externally validate a prognostic model/clinical tool for predicting COVID-19 critical disease at presentation to medical care. Methods: This is a retrospective study of a prognostic model for the prediction of COVID-19 critical disease where critical disease was defined as ICU admission, ventilation, and/or death. The derivation cohort was used to develop a multivariable logistic regression model. Covariates included patient comorbidities, presenting vital signs, and laboratory values. Model performance was assessed on the validation cohort by concordance statistics. The model was developed with consecutive patients with COVID-19 who presented to University of California Irvine Medical Center in Orange County, California. External validation was performed with a random sample of patients with COVID-19 at Emory Healthcare in Atlanta, Georgia. Results: Of a total 3208 patients tested in the derivation cohort, 9% (299/3028) were positive for COVID-19. Clinical data including past medical history and presenting laboratory values were available for 29% (87/299) of patients (median age, 48 years [range, 21–88 years]; 64% [36/55] male). The most common comorbidities included obesity (37%, 31/87), hypertension (37%, 32/87), and diabetes (24%, 24/87). Critical disease was present in 24% (21/87). After backward stepwise selection, the following factors were associated with greatest increased risk of critical disease: number of comorbidities, body mass index, respiratory rate, white blood cell count, % lymphocytes, serum creatinine, lactate dehydrogenase, high sensitivity troponin I, ferritin, procalcitonin, and C-reactive protein. Of a total of 40 patients in the validation cohort (median age, 60 years [range, 27–88 years]; 55% [22/40] male), critical disease was present in 65% (26/40). Model discrimination in the validation cohort was high (concordance statistic: 0.94, 95% confidence interval 0.87–1.01). A web-based tool was developed to enable clinicians to input patient data and view likelihood of critical disease. Conclusions and relevance: We present a model which accurately predicted COVID-19 critical disease risk using comorbidities and presenting vital signs and laboratory values, on derivation and validation cohorts from two different institutions. If further validated on additional cohorts of patients, this model/clinical tool may provide useful prognostication of critical care needs. [ABSTRACT FROM AUTHOR]

Background: Meningiomas are the most common adult primary intracranial tumors in the United States. Despite high recurrence rate of atypical and malignant subtypes, there is no approved drug indicated specifically for meningioma. Since the majority of meningiomas exhibit high density of somatostatin receptors subtypes, somatostatin analogs have been under close investigation. The aim of this study was to evaluate efficacy and safety of Sandostatin LAR (octreotide) in patients with progressive, and/or recurrent meningioma, and identify subset of patients who were more likely to benefit from this treatment. Methods: A total of 43 patients ≥ 18 years old were included in the retrospective chart review. The patients underwent treatment with Sandostatin LAR (octreotide) from 01.01.2010 to 06.01.2017 at the University of California, Irvine after confirmation of the diagnosis. Six months progression free survival (PFS6) was defined as a primary endpoint, and the overall survival (OS), safety, and toxicity were identified as secondary endpoints. Results: The OS for 6 months, 1, and 3 years for all WHO grades was 94.8, 88.1, and 67.0%, respectively. The PFS6 for WHO I, II, III, and all was 89.4, 89, 33.3, and 80% respectively. For patients with no prior surgeries, chemotherapy or radiation, the PFS6 was 88.9, 84.8, and 94.8%, respectively. Interestingly, the PFS6 was 90.5% for skull-based and 80% for 3–6 cm tumors. Patients with tumors in parasagittal location had PFS6 of 83.3% compared to PFS6 of 50.0% for patients with convexity tumors. Evaluation of PFS6 based on the effect of estrogen and progesterone on meningioma identified that ER-PR+ tumors had PFS6 of 87.8% while patients with ER-PR- meningiomas had PFS6 of 62.5%. Median TTP for WHO grade I, II, and III was 3.1, 2.40, and 0.26 years, respectively. Subgroup analysis showed that median TTP was 3.1 years for <3 cm tumors, 3.22 years for skull-based tumors, 2.37 years for patients with prior surgeries and 3.10 years for patients with no history of chemotherapy. History of radiation had no effect on median TTP. Sandostatin LAR (octreotide) was well-tolerated. Conclusions: This is one of the largest retrospective analysis of meningioma patients treated with Sandostatin LAR (octreotide) suggesting that this treatment has minimal to no adverse events and could prolong overall survival, and progression free survival especially for patients with ER-PR+ tumors who underwent surgeries for small skull-based tumors. [ABSTRACT FROM AUTHOR]

Background Optimum management of low-grade gliomas remains controversial, and widespread practice variation exists. This evidence-based meta-analysis evaluates the association of extent of resection, radiation, and chemotherapy with mortality and progression-free survival at 2, 5, and 10 years in patients with low-grade glioma. Methods A quantitative systematic review was performed. Inclusion criteria included controlled trials of newly diagnosed low-grade (World Health Organization Grades I and II) gliomas in adults. Eligible studies were identified, assigned a level of evidence for every endpoint considered, and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality and of progression at 2, 5, and 10 years was calculated for patients undergoing resection (gross total, subtotal, or biopsy), radiation, or chemotherapy. Results Gross total resection was significantly associated with decreased mortality and likelihood of progression at all time points compared to subtotal resection. Early radiation was not associated with decreased mortality; however, progression-free survival was better at 5 years compared to patients receiving delayed or no radiation. Chemotherapy was associated with decreased mortality at 5 and 10 years in the high-quality literature. Progression-free survival was better at 5 and 10 years compared to patients who did not receive chemotherapy. In patients with isocitrate dehydrogenase 1 gene (IDH1) R132H mutations receiving chemotherapy, progression-free survival was better at 2 and 5 years than in patients with IDH1 wild-type gliomas. Conclusions Results from this review, the first to quantify differences in outcome associated with surgery, radiation, and chemotherapy in patients with low-grade gliomas, can be used to inform evidence-based management and future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Cisplatin, a powerful antitumor agent, causes formation of DNA adducts, and activation of apoptotic pathways. Presently, cisplatin resistance develops in up to 70% of patients but the underlying molecular mechanism(s) are unclear and there are no markers to determine which patients will become resistant. Mitochondria play a significant role not only in energy metabolism but also retrograde signaling (mitochondria to nucleus) that modulates inflammation, complement, and apoptosis pathways. Maternally inherited mitochondrial (mt) DNA can be classified into haplogroups representing different ethnic populations that have diverse susceptibilities to diseases and medications. Methods: Transmitochondrial cybrids, where all cell lines possess identical nuclear genomes but either the H (Southern European) or J (Northern European) mtDNA haplogroups, were treated with cisplatin and analyzed for differential responses related to viability, oxidative stress, and expression levels of genes associated with cancer, cisplatin-induced nephrotoxicity and resistance, apoptosis and signaling pathways. Results: The cisplatin-treated-J cybrids showed greater loss of cell viability along with lower levels of reactive oxygen species and mitochondrial membrane potential compared to cisplatin-treated-H cybrids. After cisplatin treatment, J cybrids showed increased gene expression of BAX, CASP3 , and CYP51A , but lower levels of SFRP1 compared to untreated-J cybrids. The cisplatin-treated-H cybrids had elevated expression of CDKN1A/P21 , which has a role in cisplatin toxicity, compared to untreated-H cybrids. The cisplatin-treated H had higher transcription levels of ABCC1, DHRS2/HEP27 , and EFEMP1 compared to cisplatin-treated-J cybrids. Conclusions: Cybrid cell lines that contain identical nuclei but either H mtDNA mitochondria or J mtDNA mitochondria respond differently to cisplatin treatments suggesting involvement of the retrograde signaling (from mitochondria to nucleus) in the drug-induced cell death. Varying toxicities and transcription levels of the H vs. J cybrids after cisplatin treatment support the hypothesis that mtDNA variants play a role in the expression of genes affecting resistance and side effects of cisplatin. [ABSTRACT FROM AUTHOR]

Due to the scientific advances of the last decades, cancer patient's survival has greatly improved, and 70% of the patients now survive more than five years. However, many of the cancer survivors are affected by a constellation of chronic conditions induced by the powerful cancer treatments required to achieve cancer control. The effects of chemotherapy and radiation therapy on the brain are multifactorial and involve acute and sustained insult to neuronal structures essential for normal cognitive processes, as well as for emotional modulation. As a result, the cognitive and emotional deficits associated with cancer treatments are pervasive. The brain-derived neurotrophic factor (BDNF) is an important neuromediator that plays a significant role in developing cancer-related central nervous system complications. Multiple pharmacological strategies have been proven beneficial in raising BDNF levels. Equally important, there are safe and easy to implement dietary and life-style modifications which physicians can recommend, and which can potentially stimulate BDNF synthesis and improve the cancer patient's cognitive and emotional function and quality of life. [ABSTRACT FROM AUTHOR]

Adaptive homeostasis is defined as the transient expansion or contraction of the homeostatic range following exposure to subtoxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events (Mol. Aspects Med. (2016) 49, 1-7). Adaptive homeostasis allows us to transiently adapt (and then de-adapt) to fluctuating levels of internal and external stressors. The ability to cope with transient changes in internal and external environmental stress, however, diminishes with age. Declining adaptive homeostasismay make older peoplemore susceptible to many diseases. Chronic oxidative stress and defective protein homeostasis (proteostasis) are two major factors associated with the etiology of age-related disorders. In the present paper, we review the contribution of impaired responses to oxidative stress and defective adaptive homeostasis in the development of age-associated diseases. [ABSTRACT FROM AUTHOR]

The article discusses the cognitive outcomes specific to adolescent and young adult (AYA)-onset survivors of non-central nervous system (CNS) cancers who may be at particular risk for chemotherapy-associated cognitive impairment (CACI).

Objectives: Glioblastoma multiforme (GBM) is a highly aggressive tumor, which recurs despite resection, focal beam radiation, and temozolomide chemotherapy. At recurrence, the only second-line treatment approved by the US Food and Drug Administration is bevacizumab (Avastin). To date, no single agent has shown to extend the life of patients with progressive malignant gliomas after bevacizumab failure. Once the tumor recurs during bevacizumab therapy, it is universally fatal, with death occurring within a few weeks. ERC-1671 is an experimental treatment strategy, which uses the patient's own immune system to attack the tumor cells. We report preliminary data on the first human administration of ERC-1671 vaccination, under a single-patient, compassionate-use protocol, to a patient with progressive, bevacizumab-resistant GBM. Methods: Treatment involved sequential administration to the patient of GBM tumor cells and cell lysates combined from three different donors with GBM, followed by the patient's own tumor cells and lysates. Results: The patient survived for ten months after the vaccine administration without any other adjuvant therapy and died of complications related to his previous chemotherapies. The tissues collected after two vaccination cycles and at the time of death showed a robust immune response and no viable tumor. Conclusion: These preliminary data strongly indicate that ERC-1671 could be effective in the treatment of progressive malignant gliomas. On the basis of these preliminary data, we are planning a larger study to assess the efficacy of ERC-1671 in the treatment of patients with recurrent GBM. [ABSTRACT FROM AUTHOR]