Hypofractionation in Glioblastoma: An Overview of Palliative, Definitive, and Exploratory Uses.

Glioblastoma (GBM) is the most common primary brain malignancy in adults, and its incidence is increasing worldwide. Its prognosis remains limited despite recent imaging and therapeutic advances. The current standard of care is maximal safe resection followed by conventionally fractionated radiotherapy with concurrent and adjuvant temozolomide (TMZ), with or without tumor-treating fields (TTF). However, hypofractionated radiotherapy (HFRT) has also been utilized for a variety of reasons. It is an established treatment option in the palliative setting, where shortened treatment duration can positively impact the overall quality of life for older patients or those with additional health or socioeconomic considerations. HFRT, and in particular stereotactic radiosurgery (SRS), has also been explored in both the pre- and post-operative setting for newly diagnosed and recurrent diseases. In this review, we summarize the ways in which HFRT has been utilized in the GBM patient population and its evolving role in the experimental space. We also provide commentary on scenarios in which HFRT may be indicated, as well as guidance on dose and fractionation regimens informed by our institutional experience.

Rectal Contrast CT Scans of Limited Utility in Diagnosing Colonic Injuries in Penetrating Trauma: A Meta-Analysis.

OBJECTIVES: Using rectal contrast computed tomography (CT) to identify traumatic colorectal injuries has become commonplace; however, these injuries remain relatively infrequent findings on CTs obtained for penetrating back and flank trauma. We conducted a meta-analysis to ascertain the efficacy of rectal contrast CT in identifying such injuries in victims penetrating injuries. METHODS: PubMed and Embase were queried for relevant articles between 1974 and 2022. Review articles, case studies, and non-English manuscripts were excluded. Studies without descriptive CT and operative findings were excluded. Positive scans refer to rectal contrast extravasation. Sensitivity and specificity of rectal contrast CT scans were calculated with aggregated CT findings that were cross-referenced with laparotomy findings. RESULTS: Only 8 manuscripts representing 506 patients quantified colorectal injuries and specified patients with rectal contrast extravasation. Seven patients with true colorectal injuries had no contrast extravasation on CT. There was one true positive scan. Another scan identified contrast extravasation, but laparotomy revealed no colorectal injury. Rectal contrast had sensitivity of 12.5%, specificity 99.8%, positive predictive value (PPV) 50%, negative predictive value (NPV) 99%, and a false negative rate of 88% in identifying colonic injuries. DISCUSSION: The summation of 8 manuscripts suggest that the addition of rectal contrast in identifying colonic and rectal injuries may be of limited utility given its poor sensitivity and may be unnecessary. In its absence, subtle clues such as hematomas, extraluminal air, IV-dye extravasation, and trajectory may be additional indicators of injury. Further investigations are required to demonstrate a true benefit for the addition of rectal contrast.

Improved Progression-Free Survival for Bulky and Non-Bulky Advanced Stage Diffuse Large B-Cell Lymphoma With Consolidative Radiation Therapy: A Bi-Institutional Analysis.

Background The role of consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) is not fully established. A growing body of data suggests a role for consolidative RT in select stage III-IV DLBCL patients and emerging data from randomized studies further address the role of RT in advanced-stage patients initially presenting with bulky disease. Methods Patients with treatment-naive stage III-IV DLBCL treated at two institutions who achieved a clinically complete response to systemic therapy were included. Patients with either bulky or non-bulky disease were included, but those with the relapsed or refractory disease were excluded. Kaplan-Meier analysis was performed to determine the impact of consolidative RT. Univariate and multivariable analyses were performed using a Cox proportional hazards model. Results One hundred eighty-eight patients received systemic therapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 79%), another rituximab-based regimen (9%), or chemotherapy alone (12%). Clinical response was assessed using conventional CT or PET-CT. Sixty-eight patients (36%) received consolidative RT (median dose 30 Gy). Consolidative RT conferred a 36.7% absolute benefit in five-year progression-free survival (PFS; 85.9% vs. 49.2%, log rank p < 0.0001), a 14.5% absolute benefit in five-year overall survival (OS; 87.4% vs. 72.9%, log rank p = 0.0134), and a 37.0% absolute benefit in five-year LC (91.9% vs. 54.9%, log rank p < 0.0001). On multivariable analysis, consolidative RT was associated with improved PFS (HR 0.23, 95% CI 0.10-0.52, p < 0.001) and LC (HR 0.20, 95% CI 0.07-0.59, p = 0.003). Patients receiving consolidative RT demonstrated significantly improved PFS for tumors measuring both <5 cm (log rank p = 0.0454) and ≥5 cm (log rank p = 0.0003). Conclusions For patients with stage III-IV DLBCL who achieve clinical complete response after systemic therapy, consolidative RT improves PFS for all patients, including those with the non-bulky disease. This benefit persists in the setting of rituximab-based systemic therapy.

Single institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases.

BACKGROUND: The management of melanoma with brain metastases (MBM) is increasingly complex, especially given recent improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a longstanding radiotherapy technique for which reported patient outcomes and experiences are limited. We sought to report our institutional outcomes for MBM patients receiving WBRT and assess whether other clinical factors impact prognosis. METHODS: A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000 to 2018 treated with WBRT, with or without other systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), distant failure-free survival (DFFS), local failure-free survival (LFFS), and progression-free survival (PFS) were assessed. Data on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits, was also captured. RESULTS: 63 patients with MBM were ultimately included in our study. 69% of patients had 5 or more brain metastases at the time of WBRT, and 68% had extracranial disease. The median dose of WBRT was 30 Gy over 10 fractions. Median follow-up was 4.0 months. Patients receiving WBRT had a median OS of 7.0 months, median PFS of 2.2 months, median DFFS of 6.1 months, and median LFFS of 4.9 months. Performance status correlated with OS on both univariate and multivariable analysis. BRAF inhibitor was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07-0.79, p = 0.019), and this effect extended to multivariable analysis as well. Post-WBRT intralesional hemorrhage decreased DFFS on both univariate and multivariable analysis. Of patients with post-treatment brain scans available, there was a 16% rate of radionecrosis, 32% rate of hemorrhage, and 19% rate of memory deficits. CONCLUSIONS: Outcomes for MBM patients receiving WBRT indicate that WBRT remains an effective treatment strategy to control intracranial disease. Treatment-related toxicities such as intralesional hemorrhage, necrosis, or neurocognitive side effects are limited. With continued innovations in WBRT technique and systemic therapy development, MBM outcomes may continue to improve. Further trials should evaluate the role of WBRT in the modern context.

Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases.

Over 90 000 people are expected to be diagnosed with melanoma in the United States this year. The development of brain metastases is particularly difficult to manage. Over the past few years, melanoma patients with multiple unresectable brain metastases for which stereotactic surgery might also not be a viable option have fortunately experienced a dramatic expansion in available management options given improvements made to targeted agents, immunotherapy, and radiotherapy. Whole-brain radiation therapy (WBRT) is a long-standing radiation technique that has become increasingly sophisticated. In this review, we summarize retrospective and prospective studies on individual advances in targeted agents, immunotherapy, and WBRT, highlighting important variables such as overall survival, intracranial progression-free survival, control and response rates, and toxicities. We also discuss the recent integration of these therapies into a multimodality approach, which has shown promise in the clinical setting although toxicities have not been insignificant. Finally, we describe ongoing prospective trials relevant to melanoma with brain metastases, and we conclude with our own thoughts on the optimal approach for these patients.

Systematic gene expression profile of hypothalamus in calorie-restricted mice implicates the involvement of mTOR signaling in neuroprotective activity.

Calorie restriction (CR) delays aging and onset of age-related diseases in a variety of organisms from yeast to mammals. However, the molecular mechanism underlying the CR effect remains to be elucidated. It is well known that the hypothalamus is an important component of the brain neuroendocrine system for the regulation of the aging process. In this report, we have systematically examined the gene expression profiles of hypothalami from 5-, 12-, 19- and 24-month-old mice fed ad libitum or subjected to CR since weaning. Our results demonstrated that CR significantly altered the expression level of 490 genes in an age-dependent manner, with the greatest impact at middle age. Classification based on functional analysis indicated that a large number of these genes were involved in brain development and neurogenesis, including genes involved in Wingless (Wnt) and Notch signaling pathways. In addition, the expression levels of numerous genes involved in the stress and inflammatory responses, as well as apoptosis, were affected by CR. Interestingly, we found that a number of genes involved in the stress response and apoptosis were down-regulated in early but up-regulated in late stage CR. The most notable finding was that CR altered the expression of genes associated with the mammalian target of the rapamycin (mTOR) nutrient sensing pathway, which has recently been shown to be involved in the regulation of energy intake and aging. By applying rapamycin, a specific pharmacological inhibitor of mTOR signaling, we found that the inhibition of mTOR could significantly prevent neuronal apoptosis induced by Paraquat. Taken together, our results provided not only a systematic expression profile of the hypothalamic response to CR, but also revealed the linkage between CR and mTOR signaling in the neuroprotection in mice.

Effects of enriched environment on gene expression and signal pathways in cortex of hippocampal CA1 specific NMDAR1 knockout mice.

N-methyl-D-aspartate glutamate receptor 1 (NMDAR1) plays a pivotal role in different forms of memory. Indeed, hippocampal CA1 region specific knockout (KO) of NMDAR1 in mice showed memory impairment. Recently, it has been reported that environmental enrichment enhanced memory and rescued the memory deficits of the NMDAR1-KO mice. It is well known that cortex has synaptic connections with hippocampus and is the storage region of the brain for long-term memory. To understand the molecular mechanisms of the memory impairments in the NMDAR1-KO mice, we have examined gene expression profiles in cortex from the receptor KO mice compared to wild type mice. Furthermore, since memory deficits were rescued after exposure of the NMDAR1-KO mice to enriched environment, we also analyzed the gene expression in the cortex of the KO mice after 3 hours, 2 days and 2 weeks enrichment. We found that the expression levels of 104 genes were altered in the cortex of NMDAR1-KO mice. Environmental enrichment for 3 hours, 2 days and 2 weeks affected the expression of 45, 34 and 56 genes, respectively. Genes involved in multiple signal pathways were regulated in the NMDAR1-KO mice, such as neurotransmission, structure, transcription, protein synthesis and protein processing. It is not surprising that since enriched environment rescued the memory decline in the NMDAR1-KO mice, the expression changes of a number of genes involved in these signal pathways were recovered or even reversed after enrichment. Our results further demonstrated that reelin and Notch signal pathways could be involved in the enrichment effects on memory improvement in the KO mice.

Distinct gene expression profiles in hippocampus and amygdala after fear conditioning.

It is well known that the hippocampus and amygdala are involved in the formations of fear conditioning memories, and both contextual and cued fear memory requires activation of the NMDA receptors. However, the global molecular responses in the hippocampus and amygdala have not been investigated. By applying high-density microarrays containing 11,000 genes and expressed sequence tags, we examined fear conditioning-induced gene expression profiles in these two brain regions at 0.5, 6, and 24 h. We found that 222 genes in the amygdala and 145 genes in the hippocampus showed dynamic changes in their expression levels. Surprisingly, the overall patterns of gene expression as well as the individual genes for the amygdala and hippocampus were drastically different and only small number of genes exhibited the similar regulation in both brain regions. Based on expression kinetics, the genes from the amygdala can be further grouped into eight unique clusters, whereas the genes from the hippocampus were placed into six clusters. Therefore, our study suggests that different genomic responses are initiated in the hippocampus and amygdala which are known to play distinct roles in fear memory formation.

Generation of a bioactive neuropeptide in a cell-free system.

We have developed an in vitro assay for pre-pro-neuropeptide synthesis and processing. Mouse proopiomelanocortin (POMC) cDNA was cloned into a vector containing T7 promoter. In vitro transcription and translation were carried out to produce the proopiomelanocortin peptide. The pro-peptide was processed by incubating with cell extract of mouse and rat pituitary cell lines. The activity of processed mature peptide was tested in a cell line expressing human melanocortin 4 receptor (MC4R). Using this approach, we produced biologically active alpha-melanocyte-stimulating hormone (alpha-MSH). Furthermore, we developed a universal functional assay for G-protein-coupled receptors (GPCRs) using a reporter gene assay. More than 20 different GPCRs were examined using this functional assay. Our results demonstrated that the activity of all GPCRs could be measured by the functional assay. It should be possible to identify novel bioactive peptides for orphan GPCRs by the combination of in vitro processing and GPCR functional assays.