Drug delivery in leptomeningeal disease: Navigating barriers and beyond.

Leptomeningeal disease (LMD) refers to the infiltration of cancer cells into the leptomeningeal compartment. Leptomeninges are the two membranous layers, called the arachnoid membrane and pia mater. The diffuse nature of LMD poses a challenge to its effective diagnosis and successful management. Furthermore, the predominant phenotype; solid masses or freely floating cells, has altering implications on the effectiveness of drug delivery systems. The standard of care is the intrathecal delivery of chemotherapy drugs but it is associated with increased instances of treatment-related complications, low patient compliance, and suboptimal drug distribution. An alternative involves administering the drugs systemically, after which they must traverse fluid barriers to arrive at their destination within the leptomeningeal space. However, this route is known to cause off-target effects as well as produce subtherapeutic drug concentrations at the target site within the central nervous system. The development of new drug delivery systems such as liposomal cytarabine has improved drug delivery in leptomeningeal metastatic disease, but much still needs to be done to effectively target this challenging condition. In this review, we discuss about the anatomy of leptomeninges relevant for drug penetration, the conventional and advanced drug delivery methods for LMD. We also discuss the future directions being set by different clinical trials.

A phase I dose-escalation study of pulsatile afatinib in patients with recurrent or progressive brain cancer.

Background: Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers. Methods: Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity. Results: A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80 mg every 4 days, 120 mg every 4 days, 180 mg every 4 days, or 280 mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280 mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%). Conclusions: Afatinib taken orally was safe and well-tolerated up to 280 mg every 7 days in brain cancer patients.

Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma.

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

Response to OKN-007 and NAC in a Patient with Unilateral Hearing Loss and Chronic Tinnitus from Vestibular Schwannoma.

BACKGROUND: Tinnitus is the perception of sound in the absence of external acoustic stimulation. Being one of the most common diseases of the ear, it has a global prevalence ranging from 4.1 to 37.2%. To date, it has been difficult to treat tinnitus as its pathophysiology is poorly understood and there are limited treatment options. OBJECTIVE: To investigate the effect of OKN-007 (also known as HPN-07), a nitrone-based investigational drug, in combination with oral N-acetylcycsteine (NAC), for the treatment of hearing loss and chronic tinnitus under an individual expanded access protocol. PATIENT CASE: We report the case of a patient who presented with left-sided ear fullness, mild tinnitus, and mild high frequency sensorineural hearing loss with 100% word recognition. A large enhancing mass seen on MRI revealed a vestibular schwannoma. He underwent subtotal resection of the tumor resulting in a moderate-to-profound sensorineural hearing loss and catastrophic tinnitus. The patient was treated with intravenous OKN-007 at 60 mg/kg dosed three times per week and oral NAC 2500 mg twice daily. RESULTS: Post-treatment audiometric testing revealed an average of 16.66 dB in hearing threshold improvement in three frequencies (125, 250 and 500 Hz) with residual hearing in the affected left ear. His tinnitus loudness matching improved from 90 dB to 19 dB post-treatment. His Tinnitus Handicap Inventory improved from 86/100 (Catastrophic) to 40/100 (Moderate). He also experienced improvements in sleep, concentration, hearing, and emotional well-being, and reported significantly decreased levels of tinnitusrelated distress. CONCLUSIONS: This case report highlights the feasibility and therapeutic potential of the combination of OKN-007 and NAC in treating hearing loss and tinnitus that warrants further investigation.

Long-term survival after salvage pemetrexed for refractory primary T-cell lymphoma of the CNS.

Primary T-cell CNS lymphoma is a rare and aggressive malignancy. High-dose methotrexate (MTX) based chemotherapy regimens are used as standard first-line treatment, followed by consolidative strategies to improve the duration of response. Although MTX-based therapy has been shown to be efficacious, treatment options for MTX-refractory disease are not well-defined. Here, we report a case of a 38-year-old man with refractory primary T-cell CNS lymphoma who demonstrated a complete response to pemetrexed treatment. He subsequently received conditioning chemotherapy consisting of thiotepa, busulfan and cyclophosphamide followed by autologous stem cell transplantation. The patient continues to remain recurrence-free to date at 9 years post-treatment.

An expanded safety/feasibility study of the EMulate Therapeutics Voyager™ System in patients with recurrent glioblastoma.

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 weeks (4.3 months) in the Voyager only group (n = 24) and 21 weeks (5.3 months) in the Voyager + concurrent therapy group (n = 36). The median overall survival (OS) was 7 months in the Voyager only group and 9 months in the Voyager + concurrent therapy group. In patients treated with Voyager + concurrent therapy, the median OS for patients enrolled with their 1st or 2nd recurrence (n = 26) was 10 months, while in patients enrolled with their 3rd or 4th recurrence (n = 10) OS was 7 months. Conclusion: The data support the safety and feasibility of the Voyager for the treatment of rGBM. Further prospective study of the device is warranted. Trial Registration Number: NCT02296580 (ClinicalTrials.gov).

Activity of pemetrexed in pre-clinical chordoma models and humans.

Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).

Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden.

BACKGROUND: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). OBJECTIVE: To model the relationships between handgrip strength, mobility, and MRI volumetry. METHODS: We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. RESULTS: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. CONCLUSION: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

Clinical Course of Two Patients with COVID-19 Respiratory Failure After Administration of the Anticancer Small Molecule, RRx-001.

Two critically ill COVID-19 infected patients, who had exhausted all available treatment options, were treated with the small-molecule RRx-001 with subsequent improvement. RRx-001, a first-in-class small molecule with anti-inflammatory, vascular normalizing and macrophage-repolarizing properties, has been safely administered 300+ patients in clinical trials. This is the first report of RRx-001 treatment of COVID-19.

Phase 1 First-in-Human Dose Escalation and Dose Expansion Study of KLS-1 (64Zinc Aspartate) in Patients With Cancer and Neurodegenerative Diseases.

Background KLS-1 is zinc (Zn) aspartate enriched with isotope 64Zn to 99.2% mass fraction of total zinc. KLS-1 is intended as a novel therapeutic approach for patients with a variety of diseases including but not limited to different forms of cancer and neurodegenerative diseases. The purpose of this first-in-human study was to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) in patients with medical disorders. Methods The study was designed as consisting of two consecutive parts: the dose escalation part and the dose expansion part. Adult patients with refractory glioblastoma, primary progressive aphasia/dementia, amyotrophic lateral sclerosis, Parkinson's disease (PD), and type 1 diabetes were included. KLS-1 formulated as a 10 mL water solution containing 26.42 mg/mL of 64zinc aspartate (that is equivalent to 5.184 mg/mL of 64Zn) was administered twice weekly in two-week cycles via two-hour intravenous (IV) infusion at various dose levels during the dose escalation part and twice weekly during five subsequent weeks in the dose expansion part. The study was conducted at Pan American Cancer Treatment Center (Tijuana, Mexico) in 2020 and had a duration of 10 months. Results A total of eight patients (all white/Caucasian) were enrolled in both parts of the study. A total of four patients who participated in the dose escalation part were dosed twice weekly at 1, 2, and 4 mg/kg in two-week cycles for each dose level with the dose increased to the next higher level in the subsequent cycle. Dose-limiting toxicities (DLTs) were defined at dose level 4 mg/kg due to treatment-emergent reversible adverse events that required medications for symptomatic relief. The most common drug-related toxicities that occurred in two or more patients (≥25%) were weakness (five patients), fatigue (four patients), dizziness (three patients), nausea (two patients), poor sleep (two patients), and abdominal discomfort (two patients). In the dose expansion part, a dose of 2 mg/kg administered twice weekly was investigated for five continuous weeks in four patients and was established as recommended phase 1b/2 dose. Systemic exposure to KLS-1 (area under the curve (AUC) and maximum serum concentration (Cmax)) increased from 1 to 4 mg/kg and showed a linear relationship. Conclusions Multiple doses of KLS-1 ranging from 1 to 2 mg/kg administered twice a week via intravenous infusion for up to five continuous weeks were safe and well tolerated in patients with different types of therapeutic conditions including but not limited to a few forms of cancer and Parkinson's disease, and the evaluated pharmacokinetic parameters exhibited favorable profile.

Differentiation of Subjective Cognitive Decline, Mild Cognitive Impairment, and Dementia Using qEEG/ERP-Based Cognitive Testing and Volumetric MRI in an Outpatient Specialty Memory Clinic.

BACKGROUND: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention. OBJECTIVE: We investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader® by Brainreader). METHODS: Patients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n = 161) and quantitative vMRI (n = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models. RESULTS: The qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87). CONCLUSION: This study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia.

Correction: Phase 1 First-in-Human Dose Escalation and Dose Expansion Study of KLS-1 (64Zinc Aspartate) in Patients With Cancer and Neurodegenerative Diseases.

[This corrects the article DOI: 10.7759/cureus.29921.].

Germline biomarkers predict toxicity to anti-PD1/PDL1 checkpoint therapy.

BACKGROUND: There is great interest in finding ways to identify patients who will develop toxicity to cancer therapies. This has become especially pressing in the era of immune therapy, where toxicity can be long-lasting and life-altering, and primarily comes in the form of immune-related adverse effects (irAEs). Treatment with the first drugs in this class, anti-programmed death 1 (anti-PD1)/programmed death-ligand 1 (PDL1) checkpoint therapies, results in grade 2 or higher irAEs in up to 25%-30% of patients, which occur most commonly within the first 6 months of treatment and can include arthralgias, rash, pruritus, pneumonitis, diarrhea and/or colitis, hepatitis, and endocrinopathies. We tested the hypothesis that germline microRNA pathway functional variants, known to predict altered systemic stress responses to cancer therapies, would predict irAEs in patients across cancer types. METHODS: MicroRNA pathway variants were evaluated for an association with grade 2 or higher toxicity using four classifiers on 62 patients with melanoma, and then the panel's performance was validated on 99 patients with other cancer types. Trained classifiers included classification trees, LASSO-regularized logistic regression, boosted trees, and random forests. Final performance measures were reported on the training set using leave-one-out cross validation and validated on held-out samples. The predicted probability of toxicity was evaluated for its association, if any, with response categories to anti-PD1/PDL1 therapy in the melanoma cohort. RESULTS: A biomarker panel was identified that predicts toxicity with 80% accuracy (F1=0.76, area under the curve (AUC)=0.82) in the melanoma training cohort and 77.6% accuracy (F1=0.621, AUC=0.778) in the pan-cancer validation cohort. In the melanoma cohort, the predictive probability of toxicity was not associated with response categories to anti-PD1/PDL1 therapy (p=0.70). In the same cohort, the most significant biomarker of toxicity in RAC1, predicting a greater than ninefold increased risk of toxicity (p<0.001), was also not associated with response to anti-PD1/PDL1 therapy (p=0.151). CONCLUSIONS: A germline microRNA-based biomarker signature predicts grade 2 and higher irAEs to anti-PD1/PDL1 therapy, regardless of tumor type, in a pan-cancer manner. These findings represent an important step toward personalizing checkpoint therapy, the use of which is growing rapidly.

Correction to: Mesenchymal stem cells in the treatment of severe COVID-19.

[This corrects the article DOI: 10.1186/s41231-021-00095-0.].

Molecularly targeted treatment of recurrent anaplastic astrocytoma - a case report.

High-grade astrocytomas are malignant and aggressive, with limited treatment options. Treatment is geared not only toward increasing patient's overall survival but also in delaying or preventing neurological disability, a cause of significant morbidity. Increasingly, targeted and customized treatment approaches, especially for recurrent disease, are being explored. Here we present a successful outcome in a young patient with rapidly progressive disease who responded to targeted treatment based on genetic sequencing and circulating tumor DNA markers, given the inaccessibility of the tissue to biopsy. Molecular testing on tissue, serum or CSF may be helpful in identifying unique targets in these complex patients.

Terminal Bleeding in Angiosarcoma.

Introduction: Terminal bleeding, a distressing symptom experience for patients, caregivers, and health professionals, occurs in a subset of patients in the palliative care setting. Terminal bleeding is often thought of as a large-volume catastrophically fatal event, but it can also occur for a longer period of time and still be the precipitating event for a patient's death. Case Report: We present the case of terminal bleeding in an 87-year-old patient with angiosarcoma, a rare aggressive vascular neoplasm that can occur anywhere in the body but tend to occur more frequently in the head and neck. Discussion: The patient's advanced age and aggressive disease presented challenges in managing the symptoms and precluded many of the conventional recommended interventions to manage bleeding. Conclusion: This case report speaks to the need for multidisciplinary planning that takes prognosis, performance status, previous therapies, and patient preferences into account when caring for patients with advanced cancer.

Analysis of cell-free circulating tumor DNA in 419 patients with glioblastoma and other primary brain tumors.

Aim: Genomically matched trials in primary brain tumors (PBTs) require recent tumor sequencing. We evaluated whether circulating tumor DNA (ctDNA) could facilitate genomic interrogation in these patients. Methods: Data from 419 PBT patients tested clinically with a ctDNA NGS panel at a CLIA-certified laboratory were analyzed. Results: A total of 211 patients (50%) had ≥1 somatic alteration detected. Detection was highest in meningioma (59%) and gliobastoma (55%). Single nucleotide variants were detected in 61 genes, with amplifications detected in ERBB2, MET, EGFR and others. Conclusion: Contrary to previous studies with very low yields, we found half of PBT patients had detectable ctDNA with genomically targetable off-label or clinical trial options for almost 50%. For those PBT patients with detectable ctDNA, plasma cfDNA genomic analysis is a clinically viable option for identifying genomically driven therapy options.

Venous Flare Reactions: A Case Report of Reactions Following Etoposide Infusion.

Venous flare reaction, a localized allergic response associated with the administration of an irritant, is one of the most common chemotherapy infusion-related reactions. Etoposide, a drug commonly used in patients with lung cancer, has been reported to be an irritant with vesicant properties depending on the volume administered. This article presents the case of a patient who has a venous flare reaction immediately following the administration of etoposide for the treatment of diffuse large B-cell lymphoma. Managing such complications is crucial to maintaining patient safety. Proper training and education should be incorporated into nursing practice when identifying, preventing, and managing such reactions.