Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Association between systemic treatment with immune checkpoint inhibitor therapy in renal cell carcinoma and reduced risk of brain metastasis development.

OBJECTIVE: Immune checkpoint inhibitor (ICI) efficacy in the treatment of metastatic renal cell carcinoma (RCC) without brain metastases (BMs) is well established in several clinical trials; however, patients with BMs were typically excluded from these trials. Therefore, the efficacy of ICI in the treatment or prevention of BM remains unclear. The primary aim of the study was to address the efficacy of ICI in treatment of patients with RCC BMs compared with patients receiving targeted therapies. A secondary aim was to evaluate the risk of RCC BM development among patients who received ICI versus targeted therapies early in their treatment course. METHODS: A retrospective single-center review between 2011 and 2018 identified 425 patients treated for metastatic RCC. The study group included patients who received ICI and/or targeted therapies during their disease. Data analyzed included demographic information, systemic treatments, overall survival from RCC diagnosis (OSRCC) and from BM diagnosis (OSBM), and BM development. Fisher's exact test was used to evaluate the frequency of BM occurrence. Survival was assessed using Kaplan-Meier curves and log-rank tests. RESULTS: Of the 425 patients, 125 received ICI and 300 were treated with molecular targeted agents only during their clinical course. BMs occurred in 113 (9.5%) of the 425 patients. Among patients with BMs, OSRCC was improved with the use of ICI (77.2 vs 25.2 months, p < 0.001), with 1-, 2-, and 5-year survival rates of 93.9%, 81.8%, and 62.6%, respectively. The use of ICI was associated with increased OSBM (21.7 vs 8.9 months, p = 0.001). The rate of BM development was lower when patients were treated with ICI (8/100 [8.0%]) compared with targeted therapy (47/267 [17.6%]) (OR 0.41, 95% CI 0.18-0.89; p = 0.021). CONCLUSIONS: ICI was associated with improved OSRCC and OSBM in patients with BMs and decreased the probability of BM development in patients with metastatic RCC. Prospective trials are needed to further evaluate optimal use of ICI in treatment of RCC BMs.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of cytoreductive surgery in the management of progressive glioblastoma in adults.

QUESTION: In patients with previously diagnosed glioblastoma who are suspected of experiencing progression, does repeat cytoreductive surgery improve progression free survival or overall survival compared to alternative interventions? TARGET POPULATION: These recommendations apply to adults with previously diagnosed glioblastoma who are suspected of experiencing progression of the neoplastic process and are amenable to surgical resection. RECOMMENDATION: Level II: Repeat cytoreductive surgery is recommended in progressive glioblastoma patients to improve overall survival.

Genetic analysis of a malignant meningioma and associated metastases.

To identify genes altered in a highly aggressive metastatic meningioma primary as well as its metastases. Exome sequencing of a primary anaplastic meningioma and metastatic lesions in which DNA could be extracted and compared to germline DNA. Genetic analysis of the metastatic sites found 31 common mutations among the primary tumor and two metastatic sites. Additionally, genetic mutations were identified which were either infrequently (MUC3A, ALDH1A3, HOXA1) or not at all previously described in meningiomas (CASS4, CMKLR1). Exome sequencing of a metastatic meningioma and its distant metastases outside the CNS identified mutations that were not previously well described.

Neurosurgical involvement in clinical trials for CNS tumors.

INTRODUCTION: Most clinical trials in neurooncology are led by investigators primarily trained in neurology or medical oncology. While neurosurgeons are trained to be problem-solvers and innovators, research training has historically been focused on laboratory-based discovery approaches and formalized training in prospective clinical trials research is not part of routine graduate training. METHODS: We reviewed literature that demonstrates that innovation and problem-solving are integral to the practice of neurosurgery cite multiple examples of advances in technique and technology that may have had an empirical origin but that led to prospective clinical trials resulting in change in practice. RESULTS: Neurosurgeons have developed and led both traditional (clinical outcome-oriented) and translational prospective clinical trials that have evaluated the best use of currently available therapeutics or tested the ability of novel therapeutics to alter the biology and/or course of disease. CONCLUSIONS: In this review, we focus on a number of the recently developed technologies and therapeutics that were evaluated in clinical trials led or co-led by neurosurgeons. We also highlight some of the barriers that need to be addressed in order to foster neurosurgical participation and leadership in the prospective development of novel therapeutics.

Impact of cerebrospinal fluid flow study in patients undergoing intrathecal chemotherapy via ventricular catheter reservoir.

PURPOSE: Leptomeningeal carcinomatosis (LMC) is a form of CNS cancer metastasis with severe morbidity. Intrathecal chemotherapy (ITC) administration through an implanted ventricular catheter reservoir (IVCR) is often utilized. Additionally, a nuclear imaging flow study can be performed prior to ITC administration to assess cerebrospinal fluid (CSF) flow. The clinical impact of a CSF flow study is unclear. METHODS: A retrospective chart review identified 31 patients with LMC that underwent IVCR placement between 2011 and 2019. Data extracted included patient demographics, nuclear imaging flow study, surgical complications, ITC toxicities and outcomes. RESULTS: Potential drug-induced neurologic toxicities (headache, nausea/vomiting, altered mental status, etc.) were noted in (n = 4/16) 25% of patients who underwent a flow study prior to initiation of ITC, compared to (n = 1/15) 6.6% of patients who did not undergo a flow study. Median overall survival (OS) was 4.0 and 32.8 months for the patients that underwent a flow study versus patients who did not, respectively (p < 0.01). The mean interval from IVCR implantation to initiation of ITC was 15.2 ± 8.5 days and 3.3 ± 3.0 days in patients who underwent CSF flow study and patients that did not, respectively (p < 0.0001). CONCLUSIONS: A flow study can provide information regarding CSF flow dynamics prior to initiation of ITC; however this might delay initiation of ITC which may negatively impact OS. Additionally, in our study patients that underwent a flow study had more ITC induced drug toxicity events compared to those that did not. Further studies are needed to clarify the role of CSF flow study in these patients.

Intraoperative 3 T MRI is more correlative to residual disease extent than early postoperative MRI.

PURPOSE: Extent of resection of low grade glioma (LGG) is an important prognostic variable, and may influence decisions regarding adjuvant therapy in certain patient populations. Immediate postoperative magnetic resonance image (MRI) is the mainstay for assessing residual tumor. However, previous studies have suggested that early postoperative MRI fluid-attenuated inversion recovery (FLAIR) (within 48 h) may overestimate residual tumor volume in LGG. Intraoperative magnetic resonance imaging (iMRI) without subsequent resection may more accurately assess residual tumor. Consistency in MRI techniques and utilization of higher magnet strengths may further improve both comparisons between MRI studies performed at different time points as well as the specificity of MRI findings to identify residual tumor. To evaluate the utility of 3 T iMRI in the imaging of LGG, we volumetrically analyzed intraoperative, early, and late (~ 3 months after surgery) postoperative MRIs after resection of LGG. METHODS: A total of 32 patients with LGG were assessed retrospectively. Residual tumor was defined as hyperintense T2 signal on FLAIR. Volumetric assessment was performed with intraoperative, early, and late postoperative FLAIR via TeraRecon iNtuition. RESULTS: Perilesional FLAIR parenchymal abnormality volumes were significantly different comparing intraoperative and early postoperative MRI (2.17 ± 0.45 cm3 vs. 5.47 ± 1.07 cm3, respectively (p = 0.0002)). A significant difference of perilesional FLAIR parenchymal abnormality volumes was also found comparing early and late postoperative MRI (5.47 ± 1.07 cm3 vs. 3.22 ± 0.64 cm3, respectively (p = 0.0001)). There was no significant difference between intraoperative and late postoperative Perilesional FLAIR parenchymal abnormality volumes. CONCLUSIONS: Intraoperative 3 T MRI without further resection appears to better reflect the volume of residual tumor in LGG compared with early postoperative 3 T MRI. Early postoperative MRI may overestimate residual tumor. As such, intraoperative MRI performed after completion of tumor resection may be more useful for making decisions regarding adjuvant therapy.

Viral therapies for glioblastoma and high-grade gliomas in adults: a systematic review.

OBJECTIVE: High-grade gliomas (HGGs) inevitably recur and progress despite resection and standard chemotherapies and radiation. Viral therapies have emerged as a theoretically favorable adjuvant modality that might overcome intrinsic factors of HGGs that confer treatment resistance. METHODS: The authors present the results of systematic searches of the MEDLINE and ClinicalTrials.gov databases that were performed for clinical trials published or registered up to July 15, 2020. RESULTS: Fifty-one completed clinical trials were identified that made use of a virus-based therapeutic strategy to treat HGG. The two main types of viral therapies were oncolytic viruses and viral vectors for gene therapy. Among clinical trials that met inclusion criteria, 20 related to oncolytic viruses and 31 to gene therapy trials. No oncolytic viruses have progressed to phase III clinical trial testing, although there have been many promising early-phase results and no reported cases of encephalitis or death due to viral therapy. Three phase III trials in which viral gene therapy was used have been completed but have not resulted in any FDA-approved therapy. Recent efforts in this area have been focused on the delivery of suicide genes such as herpes simplex virus thymidine kinase and cytosine deaminase. CONCLUSIONS: Decades of research efforts and an improving understanding of the immunomodulatory effects of viral therapies for gliomas are informing ongoing clinical efforts aimed at improving outcomes in patients with HGG. The available clinical data reveal varied efficacy among different virus-based treatment strategies.

Advancing gene therapies, methods, and technologies for Parkinson's Disease and other neurological disorders.

INTRODUCTION: Vector-based intracerebral gene therapies are being used to treat specific neurodegenerative conditions such as Parkinson's Disease (PD). This review presents a basis for central nervous system (CNS) gene therapy treatments of neurodegenerative diseases such as PD, as well as the need for novel skill sets and health delivery strategies within the clinical neurosciences (neurology and neurosurgery) to meet future demand for such therapies. STATE OF THE ART: Preclinical vector-based gene therapy approaches have been translated into clinical trials for PD and other neurodegenerative conditions. Unfortunately, such trials, and parallel efforts using other therapeutics, have yet to provide a breakthrough. Image-guided convection enhanced delivery (CED) optimises the parenchymal distribution of gene therapies applied within the CNS, and may ultimately provide such a breakthrough. CLINICAL IMPLICATIONS: Currently, image-guided CED and gene therapy are not part of training programmes for most neurosurgeons and neurologists. As a result, few medical centres and hospitals have sufficiently experienced teams to participate in gene transfer clinical trials for PD or other neurological conditions. If CNS gene therapies prove to be efficacious for PD and/or other conditions, the demand for such treatments will overwhelm the available number of experienced clinical neuroscience teams and treatment centres. FUTURE DIRECTIONS: Expanded indications and demand for CNS gene therapies will require a worldwide educational effort to supplement the training of clinical neuroscience practitioners. Initially, a limited number of Centres of Excellence will need to establish relevant educational training requirements and best practice for such therapeutic approaches. Advanced technologies, including robotics and artificial intelligence, are especially germane in this regard, and will expand the treatment team's capabilities while assisting in the safe and timely care of those afflicted.

Where and when adolescents are physically active: Neighborhood environment and psychosocial correlates and their interactions.

Female adolescents are less active than male peers in certain contexts including the neighborhood. Adolescents' physical activity can be explained by interactions between environmental and psychosocial factors, but few studies have tested such interactions in relation to context-specific behaviors. This study tested interactions between neighborhood environmental and psychosocial factors in relation to adolescents' context-specific physical activity. Data were collected in 2009-11 from 910 adolescents and a parent/guardian residing in the Baltimore/Seattle regions. Measures included adolescent-reported neighborhood leisure-time physical activity (LTPA) and non-neighborhood LTPA, accelerometer-based non-school moderate-to vigorous-physical activity (MVPA), psychosocial factors, and objective and parent-perceived neighborhood environmental factors. Gender-stratified mixed effects linear models tested associations of 6 environmental and 4 psychosocial factors and their interactions in relation to each physical activity outcome. The psychosocial factors had consistent associations with the physical activity outcomes but the environmental correlates were context-specific. Decisional balance (weighing of pros and cons of physical activity) moderated the association between recreation facility density and neighborhood LTPA among females, with a negative association only among those with high decisional balance (pros outweighed cons). Decisional balance also moderated associations of neighborhood walkability with non-school MVPA among females and non-neighborhood LTPA among males, with positive associations only among those with high decisional balance. Results support context-specific ecological models of physical activity. Targeting environmental factors that may promote opportunities for physical activity in specific contexts as well as adolescent decision-making may help promote their physical activity in those contexts, potentially leading to increased overall physical activity.

Interactions between individual and perceived environmental factors on Latinas' physical activity.

Background: Latinas have disproportionately low levels of physical activity (PA) and the ecological correlates of their PA remain unclear. This study aims to test interactions between individual and environmental factors on Latinas' PA. Methods: We analyzed baseline data from 436 Latinas participating in a PA randomized controlled trial in San Diego, CA [Fe en Acción/Faith in Action]. Measures included demographics, perceived environment, PA and anthropometrics. Mixed effects models examined interactions between individual and environmental factors on self-reported leisure-time and transportation, and accelerometer-assessed PA. Results: Significant positive associations were found between neighborhood aesthetics and leisure-time moderate-to-vigorous PA (MVPA) and between having destinations within walking distance from home and transportation PA (P < 0.05). We found significant interactions of income with aesthetics and sidewalk maintenance as well as between weight status and safety from crime. Favorable aesthetics was related to more leisure-time MVPA only among lower income women (odds ratio (OR) = 1.57; 95% confidence interval (CI): 1.18, 2.08); however, higher income women reporting better sidewalk maintenance reported more leisure-time MVPA (OR = 1.51; 95% CI: 1.06, 2.15). Higher perceived safety from crime was positively related to transportation PA only among overweight/obese women. Conclusions: Subgroup differences should be considered when developing interventions targeting the neighborhood environment to promote Latinas' PA.

Promoting cancer screening among churchgoing Latinas: Fe en Acción/faith in action.

Cancer screening rates among Latinas are generally low, reducing the likelihood of early cancer detection in this population. This article examines the effects of a community intervention (Fe en Acción/Faith in Action) led by community health workers (promotoras) on promoting breast, cervical and colorectal cancer screening among churchgoing Latinas. Sixteen churches were randomly assigned to a cancer screening or a physical activity intervention. We examined cancer knowledge, barriers to screening and self-reported mammography, clinical breast exam, Pap test, fecal occult blood test and sigmoidoscopy or colonoscopy at baseline and 12 months follow-up. Participants were 436 adult Latinas, with 16 promotoras conducting a cancer screening intervention at 8 out of 16 churches. The cancer screening intervention had a significant positive impact on self-reported mammography (OR = 4.64, 95% CI: 2.00-10.75) and breast exams in the last year (OR= 2.82, 95% CI: 1.41-5.57) and corresponding reductions in perceived (87.6%) barriers to breast cancer screening (P < .008). Cervical and colorectal cancer screening did not improve with the intervention. These findings suggest Fe en Acción church-based promotoras had a significant impact on promoting breast cancer screening among Latinas. Colon cancer screening promotion, however, remains a challenge.

The corticomotor projection to liminally-contractable forearm muscles in chronic spinal cord injury: a transcranial magnetic stimulation study.

STUDY DESIGN: A cross-sectional study in chronic spinal cord injury with cervical lesions (cSCI). OBJECTIVE: To determine the corticomotor projection and motor cortex organization of paralyzed forearm muscles that presented only liminal voluntary activation. SETTING: Burke Medical Research Institute, White Plains, NY, USA. METHODS: We identified ten people with chronic SCI who had a wrist flexor or extensor muscle with a motor power (MP) of 1 over 5. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) over the primary motor cortex of the hemisphere contralateral to the target muscle. We measured resting motor threshold (RMT), corticomotor latency (LTY), MEP amplitude (AMP) and performed cortical motor mapping to determine the optimal site (OPT) and map area (AREA). Results were compared with the data from 18 controls. RESULTS: A MEP in the target muscle was observed for all cSCI cases. LTY was normal, while corticomotor excitability (as determined by RMT and AMP) was reduced in about half of the group. The OPT site of the motor maps was within control range for all cSCI cases, while AREA was reduced in three cases. CONCLUSIONS: Corticomotor conduction and cortical topography were appreciably normal despite only liminal activation of the target muscle with voluntary effort. Muscles with these characteristics may benefit from a targeted rehabilitation program even in the chronic phase after SCI.

Trends in central nervous system tumor incidence relative to other common cancers in adults, adolescents, and children in the United States, 2000 to 2010.

BACKGROUND: Time trends in cancer incidence rates (IR) are important to measure the changing burden of cancer on a population over time. The overall IR of cancer in the United States is declining. Although central nervous system tumors (CNST) are rare, they contribute disproportionately to mortality and morbidity. In this analysis, the authors examined trends in the incidence of the most common cancers and CNST between 2000 and 2010. METHODS: The current analysis used data from the United States Cancer Statistics publication and the Central Brain Tumor Registry of the United States. Age-adjusted IR per 100,000 population with 95% confidence intervals and the annual percent change (APC) with 95% confidence intervals were calculated for selected common cancers and CNST overall and by age, sex, race/ethnicity, selected histologies, and malignancy status. RESULTS: In adults, there were significant decreases in colon (2000-2010: APC, -3.1), breast (2000-2010: APC, -0.8), lung (2000-2010: APC, -1.1), and prostate (2000-2010: APC, -2.4) cancer as well as malignant CNST (2008-2010: APC, -3.1), but a significant increase was noted in nonmalignant CNST (2004-2010: APC, 2.7). In adolescents, there were significant increases in malignant CNST (2000-2008: APC, 1.0) and nonmalignant CNST (2004-2010: APC, 3.9). In children, there were significant increases in acute lymphocytic leukemia (2000-2010: APC, 1.0), non-Hodgkin lymphoma (2000-2010: APC, 0.6), and malignant CNST (2000-2010: APC, 0.6). CONCLUSIONS: Surveillance of IR trends is an important way to measure the changing public health and economic burden of cancer. In the current study, there were significant decreases noted in the incidence of adult cancer, whereas adolescent and childhood cancer IR were either stable or increasing.

Predictors of sense of coherence in typically developing adolescent siblings of individuals with autism spectrum disorder.

BACKGROUND: Children with autism spectrum disorder (ASD) may be a stressor for family members yet there is little published research on the impact of having a child with ASD on their typically developing (TD) adolescent siblings. According to Antonovsky's salutogenic model, a strong sense of coherence leads to the view that the stressor is a manageable challenge rather than a burden and promotes healthier adaptation. This study examines the relationship between stress, TD sibling resources and the sense of coherence in TD siblings. METHOD: This quantitative mail-based study uses a survey methodology, analysing the responses of TD adolescent siblings (n = 96) of individuals with autism, Asperger's syndrome, or pervasive developmental disorder - not otherwise specified to several rating scales. Adolescent siblings, ages 11 to 18 years, completed the Adolescent Coping Orientation for Problem Experience (ACOPE), Network of Relationship Inventory - Social Provision Version (NRI-SPV), Youth Self Report (YSR), and Sense of Coherence (SOC) instruments; parents completed the Child Autism Rating Scale - 2nd Edition (CARS-2). RESULTS: The salutogenesis model was used to guide and inform this research. Findings suggested the following: (a) the stress of ASD severity and resource of adjustment are related in TD adolescent siblings; (b) TD sibling adjustment has a strong relationship with sense of coherence levels; and (c) a greater number of positive coping strategies buffer TD sibling coherence levels when ASD severity scores are high. CONCLUSIONS: ASD severity and TD adolescent sibling resources influence sense of coherence in adolescent TD siblings of individuals with ASD.

The Cost Effectiveness of Polyetheretheketone (PEEK) Cages for Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Cost-effectiveness analysis using a Markov model with inputs from published literature. OBJECTIVE: To learn which graft or hardware option used in a single-level anterior cervical discectomy and fusion (ACDF) is most beneficial in terms of cost, quality of life, and overall cost effectiveness. Options studied were autograft, allograft, and polyetheretherketone (PEEK) cages for cervical fusion. SUMMARY OF BACKGROUND DATA: ACDF is commonly used to treat cervical myelopathy and/or radiculopathy. No study has compared the cost effectiveness of autograft, allograft, and PEEK in 1-level ACDF. MATERIALS AND METHODS: A literature review provided inputs into a Markov decision model to determine the most effective graft or hardware option for 1-level ACDF. Data regarding rate of complications, quality-adjusted life years (QALYs) gained, and cost for each procedure type was collected. The Markov model was first run in a base case, using all currently available data. The model was then tested using 1-way and 2-way sensitivity analyses to determine the validity of the model's conclusions if specific aspects of model were changed. This model was run for 10 years postoperatively. RESULTS: The cost per QALY for each option in the base case analysis was $3328/QALY for PEEK, $2492/QALY for autograft, and $2492/QALY for allograft. All graft/hardware options are cost effective ways to improve outcomes for patients living with chronic neck pain. For graft/hardware options the most cost-effective option was allograft. The incremental cost-effectiveness ratio for PEEK compared with autograft or allograft was >$100,000/QALY. CONCLUSIONS: Allograft is the most cost-effective graft/hardware option for ACDF. Compared with living with cervical myelopathy and/or radiculopathy, ACDF using any graft or hardware option is a cost-effective method of improving the quality of life of patients. PEEK is not a cost-effective option compared with allograft or autograft for use in ACDF.

Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome).

BACKGROUND: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. RESULTS: All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. CONCLUSION: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

Intrinsic growth rate and evolution of the Premnotrypes Vorax population using fuzzy information.

The white potato worm (Premnotrypes Vorax (Hustache)) is one of the pests that causes the greatest damage to the potato crop and the greatest economic losses to the grower; therefore, knowing its life cycle and estimating its intrinsic growth rate is crucial for selecting an appropriate chemical control method, in order to reduce the environmental impact and ensure a profitable production suitable for consumption. In this article, we present a fuzzy Malthusian model describing the evolution of the white potato worm in the crop, considering that the intrinsic growth rate and the reported initial data on the problem are of fuzzy nature. The main contributions and novelty of this paper are summarized in the following two aspects: first, the estimation of the intrinsic growth rate of the white potato worm, in function of the temperature, by using a Takagi-Sugeno-Kang type fuzzy rule-based model; and second, since in practice the initial white potato worm population in a crop is subjective, imprecise and vague, knowing the intrinsic growth rate, we propose and solve a fuzzy initial value problem to determine the evolution in time of the white potato worm population. In conclusion, given a weekly average temperature, it is possible to know the white potato worm population per unit area oscillating in an interval whose length depends on the degree of inaccuracy of the initial population and the intrinsic growth rate. This study can be relevant for grower decision making in terms of the type and frequency of pest control on his crop.

Preoperative prescription opioid use as an independent predictor of 90-day mortality and adverse events in craniotomy and craniectomy patients.

OBJECTIVE: A growing body of literature suggests that preoperative opioid exposure is an independent predictor of poor outcomes in surgical patients. No outcomes data exist on preoperative opioid use and craniotomies/craniectomies. The objective of this study was to determine the impact of preoperative opioid use on 90-day adverse events after craniotomy or craniectomy. METHODS: A single-center retrospective cohort study of 2445 patients undergoing a craniotomy/craniectomy between January 1, 2013, and October 1, 2018, was conducted. Baseline demographics, pre- and postoperative opioid use (morphine milligram equivalents [MMEs]), and surgical metrics were recorded. Patients were categorized based on whether they took prescription opioids preoperatively, defined as within 1 month of surgery, or were opioid naive. The outcomes were mortality and adverse events 90 days after craniotomy/craniectomy. RESULTS: Overall, 26.6% of patients composed the preoperative opioid group. The median daily MME intake among this group was 34.6 (IQR 14.1-90) MMEs. Lower employment rates (p < 0.001), uninsured status (p = 0.016), and intravenous drug use (p = 0.006) were associated with preoperative opioid use. Preoperative opioid use was associated with increased venous thromboembolism (p = 0.001), acute kidney injury (p = 0.002), acute respiratory failure (p < 0.001), myocardial infarction (p = 0.002), delirium (p < 0.001), and infection (p < 0.001). Preoperative opioid use was an independent predictor of overall 90-day adverse events (OR 1.643, 95% CI 1.289-2.095; p < 0.001) and 90-day mortality (OR 1.690, 95% CI 1.254-2.277; p < 0.001). CONCLUSIONS: Preoperative opioid use was independently associated with 90-day postoperative adverse events and mortality. Opioid use increases vulnerability in craniotomy/craniectomy patients and necessitates close monitoring to improve outcomes.

Unsupervised machine learning models reveal predictive clinical markers of glioblastoma patient survival using white blood cell counts prior to initiating chemoradiation.

Background: Glioblastoma is a malignant brain tumor requiring careful clinical monitoring even after primary management. Personalized medicine has suggested the use of various molecular biomarkers as predictors of patient prognosis or factors utilized for clinical decision-making. However, the accessibility of such molecular testing poses a constraint for various institutes requiring identification of low-cost predictive biomarkers to ensure equitable care. Methods: We collected retrospective data from patients seen at Ohio State University, University of Mississippi, Barretos Cancer Hospital (Brazil), and FLENI (Argentina) who were managed for glioblastoma-amounting to 581 patient records documented using REDCap. Patients were evaluated using an unsupervised machine learning approach comprised of dimensionality reduction and eigenvector analysis to visualize the inter-relationship of collected clinical features. Results: We discovered that the serum white blood cell (WBC) count of a patient during baseline planning for treatment was predictive of overall survival with an over 6-month median survival difference between the upper and lower quartiles of WBC count. By utilizing an objective PD-L1 immunohistochemistry quantification algorithm, we were further able to identify an increase in PD-L1 expression in glioblastoma patients with high serum WBC counts. Conclusions: These findings suggest that in a subset of glioblastoma patients the incorporation of WBC count and PD-L1 expression in the brain tumor biopsy as simple biomarkers predicting glioblastoma patient survival. Moreover, machine learning models allow the distillation of complex clinical data sets to uncover novel and meaningful clinical relationships.