FDA Approval Summary: Revised Indication and Dosing Regimen for Ponatinib Based on the Results of the OPTIC Trial.

On December 18, 2020, US Food and Drug Administration (FDA) approved a supplemental application for ponatinib extending the indication in patients with chronic-phase chronic myeloid leukemia (CP-CML) to patients with resistance or intolerance of at least 2 prior kinase inhibitors. Ponatinib was initially approved in December 2012 but was briefly voluntarily withdrawn due to serious safety concerns including the risk of arterial occlusive events (AOE). It returned to the market in December 2013 with an indication limited to patients with T315I mutation or for whom no other tyrosine kinase inhibitor (TKI) therapy was indicated with revised warnings and precautions. A post-marketing requirement was issued to identify the optimal safe and effective dose for CP-CML. Thus, the OPTIC trial was performed, which randomized patients to 1 of 3 doses, 45 mg, 30 mg, or 15 mg, with a dose reduction to 15 mg on achievement of MR2 (BCR-ABLIS ≤1%). Patients enrolled were treated with at least 2 prior TKIs or had a T315I mutation. Patients with a history of clinically significant, uncontrolled, or active cardiovascular disease were excluded. Efficacy was established on an interim analysis based on the rate of MR2 at 12 months in the modified intent-to-treat population of 261 patients, with 88, 86, and 87 patients in the 45, 30, and 15 mg cohorts, respectively. With a median follow-up of 28 months, the rate of achievement of MR2 at 12 months was 42%, 28%, and 24% in the respective cohorts. The safety profile was consistent with that observed in prior evaluations of ponatinib with notable adverse reactions including pancreatitis, hypertension, hyperlipidemia, liver dysfunction, and AOE. Of patients treated at the 45/15 mg dose, AOEs were seen in 13%, with a higher rate being observed in patients age 65 or older compared to younger patients. A readjudication of AOEs seen on the prior pivotal phase 2 study resulted in a rate of 26%. Overall, the results supported a modification of the recommended dose for patients with CP-CML to 45 mg until the achievement of MR2 followed by a reduction to 15 mg. The expansion of the indication to patients with exposure to 2 prior TKIs was approved given data showing that ponatinib could be successfully used for the treatment of this population with appropriate monitoring and screening for risk factors.

FDA Approval Summary: Selinexor for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Approval was based on SADAL, a multicenter trial of selinexor monotherapy in patients with DLBCL after two to five systemic regimens. Efficacy was based on independent review committee-assessed objective response rate (ORR) and duration of response using Lugano criteria. In 134 patients treated with the approved dosage (60 mg orally on days 1 and 3 of each week), the ORR was 29% (95% confidence interval, 22-38), with complete response in 13% and with 38% of responses lasting at least 6 months. Gastrointestinal toxicity developed in 80% of patients, hyponatremia in 61%, central neurological toxicity (such as dizziness and mental status changes) in 25%, and ocular toxicity in 18%. New or worsening grade 3 or 4 thrombocytopenia, lymphopenia, neutropenia, anemia, or hyponatremia developed in ≥15%. Adverse reactions led to selinexor dose interruption in 61% of patients, dose reduction in 49%, and permanent discontinuation in 17%, with thrombocytopenia being the leading cause of dose modifications. Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL. IMPLICATIONS FOR PRACTICE: Selinexor is a new potential option for adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, in the third-line setting or beyond. Toxicities are typically manageable but can be difficult to tolerate and necessitate close monitoring and supportive care.

In Situ Detection of Endogenous HIV Activation by Dynamic Nuclear Polarization NMR and Flow Cytometry.

We demonstrate for the first time in-cell dynamic nuclear polarization (DNP) in conjunction with flow cytometry sorting to address the cellular heterogeneity of in-cell samples. Utilizing a green fluorescent protein (GFP) reporter of HIV reactivation, we correlate increased 15N resonance intensity with cytokine-driven HIV reactivation in a human cell line model of HIV latency. As few as 10% GFP+ cells could be detected by DNP nuclear magnetic resonance (NMR). The inclusion of flow cytometric sorting of GFP+ cells prior to analysis by DNP-NMR further boosted signal detection through increased cellular homogeneity with respect to GFP expression. As few as 3.6 million 15N-labeled GFP+ cells could be readily detected with DNP-NMR. Importantly, cell sorting allowed for the comparison of cytokine-treated GFP+ and GFP- cells in a batch-consistent way. This provides an avenue for normalizing NMR spectral contributions from background cellular processes following treatment with cellular modulators. We also demonstrate the remarkable stability of AMUPol (a nitroxide biradical) in Jurkat T cells and achieved in-cell enhancements of 46 with 10 mM AMUPol, providing an excellent model system for further in-cell DNP-NMR studies. This represents an important contribution to improving in-cell methods for the study of endogenously expressed proteins by DNP-NMR.

The Role of Leukocyte-Associated Ig-like Receptor-1 in Suppressing Collagen-Induced Arthritis.

Several observations implicate a critical role for T cell dysregulation as a central problem in rheumatoid arthritis. We investigated a mechanism for suppressing T cell activation by stimulating a natural inhibitory receptor called leukocyte-associated Ig-like receptor-1 (LAIR-1). The collagen-induced arthritis (CIA) model and DR-1 transgenic mice were used to study the importance of LAIR-1 in autoimmune arthritis. Splenocytes from wild-type or LAIR-1-/- mice were stimulated with soluble anti-CD3 Ab in the presence or absence of α1(II) and supernatants were collected for cytokine analysis. B6.DR1 mice were immunized with type II collagen/CFA to induce arthritis and were treated with either the stimulatory mAb to LAIR-1 or a hamster IgG control. Finally, B6.DR1/LAIR-1-/- and B6.DR1/LAIR-1+/+ mice were challenged for CIA and mean severity scores were recorded thrice weekly. Using splenocytes or purified CD4+ cells that were sufficient in LAIR-1, CD3-induced cytokine secretion was significantly suppressed in the presence of collagen, whereas LAIR-1-deficient splenocytes had no attenuation. Treatment with a stimulatory mAb to LAIR-1 also significantly attenuated CIA in the LAIR+/+ mice. When B6.DR1/LAIR-1-/- mice were immunized with type II collagen they developed more severe arthritis and had a greater percentage of affected limbs than the wild-type mice. These data demonstrate that collagen can suppress the T cell cytokine response through the action of LAIR-1. Treatment with stimulating LAIR-1 Abs suppresses CIA whereas B6.DR1/LAIR-1-/- mice develop more severe arthritis than wild-type controls. These data suggest that LAIR-1 may be a potential therapeutic target for suppressing rheumatoid arthritis.

Investigating the effect of endocranial volume on cranial shape in platyrrhines and the relevance of this relationship to interpretations of the fossil record.

OBJECTIVES: Fossils have been linked to Alouatta based on shared cranial morphology and small brain size. However, the relationship between endocranial volume and cranial shape is unclear; it is possible that any platyrrhine with a small brain may exhibit "Alouatta-like" features due to being "de-encephalized." We test two hypotheses: (a) there are aspects of cranial shape related to encephalization common to all platyrrhines; (b) it is these cranial traits that unite the small-brained "Alouatta-like" fossils. MATERIALS AND METHODS: Three-dimensional cranial shape and endocranial volume (ECV) were measured on 350+ extant platyrrhine crania, Cartelles, Paralouatta, and Antillothrix. Encephalization quotient (EQ) was calculated using regressions of ECV on cranial centroid size. Multivariate regressions were performed using the shape coordinates and EQ and shape changes associated with EQ were visualized. Cranial shape was predicted for a hypothetical primate with an EQ matching the fossils and this shape was compared to the Alouatta mean. RESULTS: There is a significant proportion of cranial shape variation explained by EQ in some taxa. The aspects of shape that are correlated with EQ are shared by several taxa and some have parallel regression vectors, but there is no overall pattern of shape change common to all platyrrhines. However, all taxa look more similar to Alouatta when their EQ is decreased, particularly Pithecia. DISCUSSION: Given that a decrease in encephalization can cause a more Alouatta-like cranial shape in many extant platyrrhines, it should not be automatically assumed that Alouatta-like cranial traits in a small-brained fossil are evidence of a phylogenetic link to the alouattin clade.

Cranial and endocranial diversity in extant and fossil atelids (Platyrrhini: Atelidae): A geometric morphometric study.

OBJECTIVES: Platyrrhines constitute a diverse clade, with the modern Atelidae exhibiting the most variation in cranial and endocast morphology. The processes responsible for this diversification are not well understood. Here, we present a geometric morphometric study describing variation in cranial and endocranial shape of 14 species of Alouatta, Ateles, Brachyteles, and Lagothrix and two extinct taxa, Cartelles and Caipora. METHODS: We examined cranial and endocranial shape variation among species using images reconstructed from CT scans and geometric morphometric techniques based on three-dimensional landmarks and semilandmarks. Principal components analyses were used to explore variation, including the Procrustes shape coordinates, summing the logarithm of the Centroid Size, the common allometric component, and residual shape components. RESULTS: Differences in endocranial shape are related to a relative increase or decrease in the volume of the neocortex region with respect to brainstem and cerebellum regions. The relative position of the brainstem varies from a posterior position in Alouatta to a more ventral position in Ateles. The shape of both the cranium and endocast of Caipora is within the observed variation of Brachyteles. Cartelles occupies the most differentiated position relative to the extant taxa, especially in regards to its endocranial shape. CONCLUSIONS: The pattern of variation in the extant species in endocranial shape is similar to the variation observed in previous cranial studies, with Alouatta as an outlier. The similarities between Caipora and Brachyteles were unexpected and intriguing given the frugivorous adaptations inferred from the fossil's dentition. Our study shows the importance of considering both extant and fossil species when studying diversification of complex traits.

Status epilepticus triggers long-lasting activation of complement C1q-C3 signaling in the hippocampus that correlates with seizure frequency in experimental epilepsy.

Status epilepticus (SE) triggers a myriad of neurological alterations that include unprovoked seizures, temporal lobe epilepsy (TLE), and cognitive deficits. Although SE-induced loss of hippocampal dendritic structures and synaptic remodeling are often associated with this pathophysiology, the underlying mechanisms remain elusive. Recent evidence points to the classical complement pathway as a potential mechanism. Signaling through the complement protein C1q to C3, which is cleaved into smaller biologically active fragments including C3b and iC3b, contributes to the elimination of synaptic structures in the normal developing brain and in models of neurodegenerative disorders. We recently found increased protein levels of C1q and iC3b fragments in human drug-resistant epilepsy. Thus, to identify a potential role for C1q-C3 in SE-induced epilepsy, we performed a temporal analysis of C1q protein levels and C3 cleavage in the hippocampus along with their association to seizures and hippocampal-dependent cognitive functions in a rat model of SE and acquired TLE. We found significant increases in the levels of C1q, C3, and iC3b in the hippocampus at 2-, 3- and 5-weeks after SE relative to controls (p<0.05). In the SE group, greater iC3b levels were significantly correlated with higher seizure frequency (p<0.05). Together, these data support that hyperactivation of the classical complement pathway after SE parallels the progression of epilepsy. Future studies will determine whether C1q-C3 signaling contributes to epileptogenic synaptic remodeling in the hippocampus.

Effect of thyroid hormone on cardiac function following orthotopic heart transplantation in piglets.

Studies in adult HT have demonstrated improved cardiac function in the recipient following administration of T3 to the donor. The purpose of this experiment was to assess the effects of T3 on the function of the immature donor heart following HT in a piglet model. A total of 32 piglets were divided into 16 donors and 16 recipients. Following creation of brain death, half of the donor piglets were randomized to receive three doses of T3 (0.2 µg/kg) along with hydrocortisone (1 mg/kg). The donor hearts were then transplanted into the recipient piglets on CPB. Duration of survival off CPB, inotrope score, and EF of heart following CPB were evaluated. There were no differences between the two groups in age, weight, pre-brain death EF, T3 levels, and CPB times. Post-CPB survival times were inversely related to the ischemic times in both groups (Pearson r=-0.80, P<.001), and this relationship was not influenced by T3. There was no difference in inotrope score, EF, or biochemical assessment between the two groups. Administration of T3 in combination with hydrocortisone to the brain-dead donor confers no beneficial effect on myocardial function or survival following HT in a piglet model.

Mild Cognitive Impairment and Exposure to General Anesthesia for Surgeries and Procedures: A Population-Based Case-Control Study.

BACKGROUND: To examine whether exposure to general anesthesia for procedures at age ≥40 years is associated with prevalent mild cognitive impairment (MCI) in the elderly. METHODS: A case-control study nested within a population-based cohort. Olmsted County, Minnesota, residents, aged 70-91 years, underwent baseline evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychologic testing. Individuals identified with MCI (cases) at enrollment were matched 1:2 on age, sex, education, and apolipoprotein genotype with participants who were cognitively normal at the time of the index visit. Medical records from age 40 years until the index visit were reviewed to determine exposures to general anesthesia. Conditional logistic regression, taking into account the matched set study design and adjusting for MCI risk factors, was used to assess whether exposure to anesthesia after the age of 40 years was associated with prevalent MCI. RESULTS: A total of 387 Mayo Clinic Study of Aging participants (219 males, 168 females) were diagnosed with MCI at enrollment with mean age of 81 ± 5 years. Exposure to general anesthesia after the age of 40 years was not significantly associated with prevalent MCI when analyzed as a dichotomous variable (any versus none, adjusted odds ratio, 0.97 [95% confidence interval, 0.68-1.40]) or the number of exposures (odds ratio, 1.13 [0.74-1.72], 0.81 [0.53-1.22], and 1.03 [0.67-1.58] for 1, 2-3, and ≥4 exposures, respectively, with no exposure as the reference). Similar results were obtained for exposure to anesthesia after the age of 60 years and during 5, 10, and 20 years before the first visit. CONCLUSIONS: Exposure to general anesthesia for procedures at age ≥40 years was not associated with prevalent MCI in the elderly.

Stereoselective Metabolism of Bupropion to OH-bupropion, Threohydrobupropion, Erythrohydrobupropion, and 4'-OH-bupropion in vitro.

Bupropion is a widely used antidepressant, smoking cessation aid, and weight-loss therapy. It is administered as a racemic mixture, but the pharmacokinetics and activity of bupropion are stereoselective. The activity and side effects of bupropion are attributed to bupropion and its metabolites S,S- and R,R-OH-bupropion, threohydrobupropion, and erythrohydrobupropion. Yet the stereoselective metabolism in vitro and the enzymes contributing to the stereoselective disposition of bupropion have not been characterized. In humans, the fraction of bupropion metabolized (fm) to the CYP2B6 probe metabolite OH-bupropion is 5-16%, but ticlopidine increases bupropion exposure by 61%, suggesting a 40% CYP2B6 and/or CYP2C19 fm for bupropion. Yet, the CYP2C19 contribution to bupropion clearance has not been defined, and the enzymes contributing to overall bupropion metabolite formation have not been fully characterized. The aim of this study was to characterize the stereoselective metabolism of bupropion in vitro to explain the stereoselective pharmacokinetics and the effect of drug-drug interactions (DDIs) and CYP2C19 pharmacogenetics on bupropion exposure. The data predict that threohydrobupropion accounts for 50 and 82%, OH-bupropion for 34 and 12%, erythrohydrobupropion for 8 and 4%, and 4'-OH-bupropion for 8 and 2% of overall R- and S-bupropion clearance, respectively. The fm,CYP2B6 was predicted to be 21%, and the fm,CYP2C19, 6% for racemic bupropion. Importantly, ticlopidine was found to inhibit all metabolic pathways of bupropion in vitro, including threohydrobupropion, erythrohydrobupropion, and 4'OH-bupropion formation, explaining the in vivo DDI. The stereoselective pharmacokinetics of bupropion were quantitatively explained by the in vitro metabolic clearances and in vivo interconversion between bupropion stereoisomers.

The Veterans Affairs's Corporate Data Warehouse: Uses and Implications for Nursing Research and Practice.

The Department of Veterans Affairs Veterans Healthcare Administration (VHA) is supported by one of the largest integrated health care information systems in the United States. The VHA's Corporate Data Warehouse (CDW) was developed in 2006 to accommodate the massive amounts of data being generated from more than 20 years of use and to streamline the process of knowledge discovery to application. This article describes the developments in research associated with the VHA's transition into the world of Big Data analytics through CDW utilization. The majority of studies utilizing the CDW also use at least one other data source. The most commonly occurring topics are pharmacy/medications, systems issues, and weight management/obesity. Despite the potential benefit of data mining techniques to improve patient care and services, the CDW and alternative analytical approaches are underutilized by researchers and clinicians.

Cortico-limbic responses to masked affective faces across ptsd, panic disorder, and specific phobia.

BACKGROUND: Exaggerated amygdala and reduced ventromedial prefrontal cortex (vmPFC) responsiveness during emotional processing have been reported in studies examining individual anxiety disorders. Studies are needed, however, which directly compare activation of amygdalo-cortical circuitry across multiple anxiety disorders within the same study. Here we compared cortico-limbic neurocircuitry across three different anxiety disorders using a well-validated emotional probe task. METHODS: Sixty-five adult volunteers, including 22 healthy controls (HC) and participants meeting DSM-IV criteria for either posttraumatic stress disorder (14 PTSD), panic disorder (14 PD), or specific animal phobia (15 SP), underwent functional magnetic resonance imaging (fMRI) at 3 T while passively viewing backward-masked images of faces expressing fear, happy, and neutral emotions. RESULTS: A group comprising all three anxiety disorders showed greater activation within the left amygdala and reduced activation within the vmPFC compared to the HC group during the masked fear versus neutral condition. Pairwise group comparisons showed that amygdala activation only reached significance for the PTSD versus HCs, whereas decreased vmPFC was only evident for SP and PD groups versus the HC group. Furthermore, activation did not differ among the anxiety groups when contrasted directly with one another. A similar pattern was observed for masked happy versus neutral faces. CONCLUSIONS: Exclusive of specific diagnostic category, anxiety disorders were generally associated with increased activation of the amygdala and reduced activation within vmPFC. Categorical distinctions were generally weak or not observed and suggest that functional differences may reflect the magnitude of responses within a common neurocircuitry across disorders rather than activation of distinct systems.

State Mindfulness and Misinformation Susceptibility.

Two experiments examined whether brief mindful meditation exercises and belief in task utility impacted memory in the misinformation paradigm. Participants watched a fictionalized crime video, received post-event misinformation about the video, and completed a cued recall memory test. They were randomly assigned to complete either a brief mindfulness exercise or unrelated task prior to encoding the video (E1) or prior to the final cued recall test (E2). Further, half of the participants in each group were informed that their assigned task was beneficial to memory performance. In Experiment 1, information about task benefits reduced misinformation reports on the final recall test, regardless of the task. The brief mindfulness exercise increased self-reported mindfulness scores in both experiments. While no group differences in memory were found, correlational analyses across the two experiments suggest that individuals who achieve more intense states of mindfulness may have lower susceptibility to misinformation and better event memory when meditation occurs prior to encoding. The results suggest that brief mindfulness exercises can reliably increase state experiences of mindfulness and have potential for use as experimental manipulations. However, the intensity of a self-guided mindfulness experience can vary across individuals, so it is important to consider individual differences when considering the application of the exercises.

Cryogenic-compatible spherical rotors and stators for magic angle spinning dynamic nuclear polarization.

Cryogenic magic angle spinning (MAS) is a standard technique utilized for dynamic nuclear polarization (DNP) in solid-state nuclear magnetic resonance (NMR). Here we describe the optimization and implementation of a stator for cryogenic MAS with 9.5 mm diameter spherical rotors, allowing for DNP experiments on large sample volumes. Designs of the stator and rotor for cryogenic MAS build on recent advancements of MAS spheres and take a step further to incorporate sample insert and eject and a temperature-independent spinning stability of ±1 Hz. At a field of 7 T and spinning at 2.0 kHz with a sample temperature of 105-107 K, DNP enhancements of 256 and 200 were observed for 124 and 223 µL sample volumes, respectively, each consisting of 4 M 13C, 15N-labeled urea and 20 mM AMUPol in a glycerol-water glassy matrix.

FDA Approval Summary: Selpercatinib for the Treatment of Advanced RET Fusion-Positive Solid Tumors.

On September 21, 2022, the FDA granted accelerated approval to selpercatinib (Retevmo, Eli Lilly and Company) for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval was based on data from Study LOXO-RET-17001 (LIBRETTO-001; NCT03157128), an international, non-randomized, multi-cohort clinical trial that included patients with advanced solid tumors harboring RET alterations. The overall response rate in 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than non-small cell lung cancer (NSCLC) or thyroid cancer was 44% [95% confidence interval (CI), 28%-60%], with median duration of response 24.5 months (95% CI, 9.2-not evaluable). Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses, including patients with the following tumors: pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft-tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The recommendation for approval was supported by results from LIBRETTO-001 in patients with RET fusion-positive NSCLC and thyroid cancer, which formed the basis of prior approvals in these tumor types. The most common adverse reactions (>25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. This is the first tissue-agnostic approval of a RET-directed targeted therapy.

Lessons Learned in a Large-Scale Mass Casualty Simulation.

BACKGROUND: Traditional Nursing Programs are required to provide student instruction regarding disaster care. The Brigham Young University College of Nursing, in conjunction with campus emergency medical services (EMS), holds two large-scale mass casualty simulations each year. Nursing students work alongside EMS to provide initial care to the victims. METHOD: After the mass casualty simulation, nursing students completed an anonymous survey evaluating their preparation and experience during the simulation. Students were also prompted to reflect on future implications of the exercise and give suggestions for simulation improvement. RESULTS: Nursing students felt the triage and communication skills they learned during this simulation will help them as future registered nurses. Interdisciplinary communication between nursing and EMS students presented a barrier to effective disaster response. CONCLUSION: Data gathered from this postsimulation survey will be used to improve future nursing student preparation and simulation participation. [J Nurs Educ. 2022;61(1):50-52.].

Neural correlates of anxiety sensitivity during masked presentation of affective faces.

BACKGROUND: Anxiety Sensitivity (AS), the tendency to fear the thoughts, symptoms, and social consequences associated with the experience of anxiety, is associated with increased risk for developing anxiety disorders. Some evidence suggests that higher scores on the Anxiety Sensitivity Index (ASI), a measure of the AS construct, are associated with activation of the anterior insular cortex during overt emotion perception. Although the ASI provides subscale scores measuring Physical, Mental Incapacitation, and Social Concerns of AS, no study has examined the relationship between these factors and regional brain activation during affect processing. We hypothesized that insular responses to fear-related stimuli would be primarily related to the Physical Concerns subscale of the ASI, particularly for a sample of subjects with specific phobias. METHODS: Adult healthy controls (HC; n = 22) and individuals with specific phobia, small animal subtype (SAP; n = 17), completed the ASI and underwent functional magnetic resonance imaging while engaged in a backward-masked affect perception task that presents emotional facial stimuli below the threshold of conscious perception. RESULTS: Groups did not differ in ASI, state or trait anxiety scores, or insula activation. Total ASI scores were positively correlated with activation in the right middle/anterior insula for the combined sample and for the HC and SAP groups separately. Multiple regression analysis revealed that the relationship between AS and insular activation was primarily accounted for by Physical Concerns only. CONCLUSIONS: Findings support the hypothesized role of the right anterior insula in the visceral/interoceptive aspects of AS, even in response to masked affective stimuli.

Minibeam radiation therapy enhanced tumor delivery of PEGylated liposomal doxorubicin in a triple-negative breast cancer mouse model.

BACKGROUND: Minibeam radiation therapy is an experimental radiation therapy utilizing an array of parallel submillimeter planar X-ray beams. In preclinical studies, minibeam radiation therapy has been shown to eradicate tumors and cause significantly less damage to normal tissue compared to equivalent radiation doses delivered by conventional broadbeam radiation therapy, where radiation dose is uniformly distributed. METHODS: Expanding on prior studies that suggested minibeam radiation therapy increased perfusion in tumors, we compared a single fraction of minibeam radiation therapy (peak dose:valley dose of 28 Gy:2.1 Gy and 100 Gy:7.5 Gy) and broadbeam radiation therapy (7 Gy) in their ability to enhance tumor delivery of PEGylated liposomal doxorubicin and alter the tumor microenvironment in a murine tumor model. Plasma and tumor pharmacokinetic studies of PEGylated liposomal doxorubicin and tumor microenvironment profiling were performed in a genetically engineered mouse model of claudin-low triple-negative breast cancer (T11). RESULTS: Minibeam radiation therapy (28 Gy) and broadbeam radiation therapy (7 Gy) increased PEGylated liposomal doxorubicin tumor delivery by 7.1-fold and 2.7-fold, respectively, compared to PEGylated liposomal doxorubicin alone, without altering the plasma disposition. The enhanced tumor delivery of PEGylated liposomal doxorubicin by minibeam radiation therapy is consistent after repeated dosing, is associated with changes in tumor macrophages but not collagen or angiogenesis, and nontoxic to local tissues. Our study indicated that the minibeam radiation therapy's ability to enhance the drug delivery decreases from 28 to 100 Gy peak dose. DISCUSSION: Our studies suggest that low-dose minibeam radiation therapy is a safe and effective method to significantly enhance the tumor delivery of nanoparticle agents.

Vaccine-induced ErbB (EGFR/HER2)-specific immunity in spontaneous canine cancer.

Epidermal Growth Factor Receptor (EGFR) is overexpressed on a number of human cancers, and often is indicative of a poor outcome. Treatment of EGFR/HER2 overexpressing cancers includes monoclonal antibody therapy (cetuximab/trastuzumab) either alone or in conjunction with other standard cancer therapies. While monoclonal antibody therapy has been proven to be efficacious in the treatment of EGFR/HER2 overexpressing tumors, drawbacks include the lack of long-lasting immunity and acquired resistance to monoclonal therapy. An alternative approach is to induce a polyclonal anti-EGFR/HER2 tumor antigen response by vaccine therapy. In this phase I/II open-label study, we examined anti-tumor immunity in companion dogs with spontaneous EGFR expressing tumors. Canine cancers represent an outbred population in which the initiation, progression of disease, mutations and growth factors closely resemble that of human cancers. Dogs with EGFR expressing tumors were immunized with a short peptide of the EGFR extracellular domain with sequence homology to HER2. Serial serum analyses demonstrated high titers of EGFR/HER2 binding antibodies with biological activity similar to that of cetuximab and trastuzumab. Canine antibodies bound both canine and human EGFR on tumor cell lines and tumor tissue. CD8 T cells and IgG deposition were evident in tumors from immunized dogs. The antibodies inhibited EGFR intracellular signaling and inhibited tumor growth in vitro. Additionally, we illustrate objective responses in reducing tumors at metastatic sites in host animals. The data support the approach of amplifying anti-tumor immunity that may be relevant in combination with other immune modifying therapies such as checkpoint inhibitors.

FDA Approval Summary: Selpercatinib for the Treatment of Lung and Thyroid Cancers with RET Gene Mutations or Fusions.

On May 8, 2020, the FDA granted accelerated approval to selpercatinib for (i) adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was granted on the basis of the clinically important effects on the overall response rate (ORR) with prolonged duration of responses observed in a multicenter, open-label, multicohort clinical trial (LIBRETTO-001, NCT03157128) in patients whose tumors had RET alterations. ORRs within the approved patient populations ranged from 64% [95% confidence interval (CI), 54-73] in prior platinum-treated RET fusion-positive NSCLC to 100% (95% CI, 63-100) in systemic therapy-naïve RET fusion-positive thyroid cancer, with the majority of responders across indications demonstrating responses of at least 6 months. The product label includes warnings and precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity. This is the first approval of a drug specifically for patients with RET alterations globally.