Phillip Hsin Kuo

Although guidelines for the use of ¹⁷⁷Lu-PSMA-617 published by various organizations are important, they do not include all the essential, practical points necessary for a complete institutional protocol. Therefore, a brief survey was performed to assess key components of the ¹⁷⁷Lu-PSMA-617 protocol before, during, and after delivery of therapy. This survey demonstrated the wide variability in many aspects of institutional protocols regarding determination of eligibility for and administration of ¹⁷⁷Lu-PSMA-617 therapy. The real-world protocol details provided here from a variety of institutions may help new and established theranostic programs.

This pilot feasibility study aimed to evaluate the effects of transcranial magnetic stimulation (TMS) on chemotherapy-related cognitive impairment (CRCI), and we report here on the first patient. Background: Deleterious cognitive changes due to chemotherapy or CRCI are commonly referred to as “chemo brain”. With the increasing survival of cancer patients, this poorly understood and inadequately treated condition will likewise have an increasing toll on individuals and society. Since there is no approved treatment for chemo brain, we have initiated a therapeutic trial using transcranial magnetic stimulation (TMS), a non-invasive brain stimulation technique approved in many countries for the treatment of neurologic and psychiatric conditions like migraine and depression. Case presentation: A 58-year-old woman, diagnosed 7 years prior with left breast cancer, underwent partial mastectomy with sentinel lymph node biopsy. She then received four cycles of adjuvant chemotherapy followed by radiation therapy. Afterwards, she was on tamoxifen for 4 years and then switched to aromatase inhibitors. The patient’s CRCI started during chemotherapy and severely impaired her quality of life for an additional two years. In the third year after chemotherapy, the CRCI partially cleared to stabilize to the level at the time of presentation for this trial. The patient continues to have memory difficulties and decreased concentration, which makes multi-tasking very difficult to impossible. She is reliant on memory aids at work and at home. The participant underwent 10 consecutive sessions of TMS during weekdays for 2 weeks. Stimulation was directed to the left dorsolateral prefrontal cortex. After TMS, the participant significantly improved in memory function on neuropsychological testing. While she reported no subjective differences in concentration or memory, she did report an improvement in her sleep. Functional magnetic resonance imaging of the brain before and after TMS showed increased resting-state functional connectivity between the stimulation site and several brain regions. Remarkably, after 6 years of chemo brain and remaining in the same position at work due to her inability to concentrate and multi-task, she applied for and received a promotion 5–6 months after her TMS treatments. Conclusions: This first patient in the phase 1 clinical trial testing of TMS for the treatment of “chemo brain” provided important lessons for feasibility and insights into mechanisms of potential benefit.

With an aging U.S. population, advancements in the treatment of Alzheimer disease (AD) and other neurodegenerative diseases are key to the maximization of health span. The recent approval of 2 antiamyloid antibodies, which decrease brain amyloid load, places us on the cusp of breakthrough therapies that target the mechanism of the disease rather than just treating the symptoms. Although the trials that led to these approvals studied patients with mild early symptoms, multiple ongoing trials have enrolled cognitively normal patients screened for AD biomarkers including risk factors for amyloid positivity, family history, and genetic markers. Thus, amyloid PET can help identify an at-risk population that can be enrolled for antiamyloid therapy to prevent AD symptoms from ever developing. In this review, we examine the paradigm of neurotheranostics and how PET biomarkers of amyloid, tau, inflammation, and neurodegeneration could characterize the pathologic stage of AD and therefore allow for personalized therapy.

[ ⁶⁸Ga]Ga-PSMA-11 ( ⁶⁸Ga-PSMA-11) is used to identify prostate-specific membrane antigen (PSMA)–positive tumors on PET scans. In the VISION study, ⁶⁸Ga-PSMA-11 was used to determine the eligibility of patients with metastatic castration-resistant prostate cancer for treatment with [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617), based on predefined read criteria. This substudy aimed to investigate the interreader variability and intrareader reproducibility of visual assessments of ⁶⁸Ga-PSMA-11 PET/CT scans using the VISION read criteria and evaluate the agreement between read results for this and the VISION study. Methods: In VISION, ⁶⁸Ga-PSMA-11 PET/CT scans were centrally read as inclusion cases if they had at least 1 PSMA-positive lesion and no PSMA-negative lesions that fulfilled the exclusion criteria. In this substudy, 125 PET/CT scans (75 inclusion and 50 exclusion cases) were randomly selected from VISION and retrospectively assessed by 3 independent central readers. A random subset of 20 cases (12 inclusion and 8 exclusion cases) was recoded for assessment of intrareader reproducibility. Classification of cases as inclusion or exclusion cases was based on the VISION read criteria. Overall interreader variability was assessed by Fleiss κ-statistics, and pairwise variability and intrareader reproducibility were assessed by Cohen κ-statistics. Results: For interreader variability, the readers agreed on 77% of cases (overall average agreement rate, 0.85; Fleiss κ, 0.60 [95% CI, 0.50–0.70]). The pairwise agreement rate was 0.82, 0.88, and 0.84, and the corresponding Cohen κ was 0.54 (95% CI, 0.38–0.71), 0.67 (95% CI, 0.52–0.83), and 0.59 (95% CI, 0.43–0.75), respectively. For intrareader reproducibility, the agreement rate was 0.90, 0.90, and 0.95, and the corresponding Cohen κ was 0.78 (95% CI, 0.49–0.99), 0.76 (95% CI, 0.46–0.99), and 0.89 (95% CI, 0.67–0.99), respectively. The number of actual VISION inclusion cases out of the total number of cases scored as inclusion in this substudy was 71 of 93 (agreement rate, 0.76; 95% CI, 0.66–0.85) for reader 1, 70 of 88 (0.80; 0.70–0.87) for reader 2, and 73 of 96 (0.76; 0.66–0.84) for reader 3. All readers agreed on 66 of 75 VISION inclusion cases. Conclusion: Moderate-to-substantial interreader agreement and substantial-to-almost perfect intrareader reproducibility for ⁶⁸Ga-PSMA-11 PET/CT scan assessment using the VISION read criteria were observed. The read rules applied in VISION can be readily learned and demonstrate good reproducibility. Visual Abstract

Mentoring success is derived from active and respectful listening and the willingness to learn and accept opportunities for personal growth. Mentoring shapes every trainee and their career path in science, technology, engineering, and mathematics (STEM). Productive mentoring relationships cultivate rapport, stimulate moments of introspection, and provide constructive feedback. Effective mentoring in STEM allows trainees, especially underrepresented minorities (URMs), to flourish in welcoming and supportive environments. However, URM trainees often experience inadequate mentoring due to their mentor’s inexperience with URM groups, poor mentorship training, or a lack of understanding of their mentee’s journey. To promote diversity, equity, and inclusion in STEM education and research, it is essential for mentors and mentees to work together with creativity, authenticity, and networking. In this workshop, we will focus on mentees’ perspective on how mentors can enhance their training, professional and career development, and improve their focus. We analyzed data on feedback obtained from students interested in pursuing graduate education who attended a recent workshop. Our results show that despite low initial expectations for the workshop, many students were satisfied with the knowledge they learned. The future of increasing the URM representation in STEM lies in providing adequate community support and mentorship throughout the careers of URM professionals.

Background: Parkinsonian syndrome (PS) is a broad category of neurodegenerative movement disorders that includes Parkinson disease, multiple system atrophy (MSA), progressive supranuclear palsy, and corticobasal degeneration. Parkinson disease (PD) is the second most common neurodegenerative disorder with loss of dopaminergic neurons of the substantia nigra and, thus, dysfunction of the nigrostriatal pathway. In addition to the motor symptoms of bradykinesia, rigidity, tremors, and postural instability, nonmotor symptoms such as autonomic dysregulation (AutD) can also occur. Heart rate variability (HRV) has been used as a measure of AutD and has shown to be prognostic in diseases such as diabetes mellitus and cirrhosis, as well as PD. I-123 ioflupane, a gamma ray-emitting radiopharmaceutical used in single-photon emission computed tomography (SPECT), is used to measure the loss of dopaminergic neurons in PD. Through the combination of SPECT and HRV, we tested the hypothesis that asymmetrically worse left-sided neuronal loss would cause greater AutD. Methods: 51 patients were enrolled on the day of their standard of care I-123 ioflupane scan for the work-up of possible Parkinsonian syndrome. Demographic information, medical and medication history, and ECG data were collected. HRV metrics were extracted from the ECG data. I-123 ioflupane scans were interpreted by a board-certified nuclear radiologist and quantified by automated software to generate striatal binding ratios (SBRs). Statistical analyses were performed to find correlations between the HRV and SPECT parameters. Results: 32 patients were excluded from the final analysis because of normal scans, prior strokes, cardiac disorders and procedures, or cancer. Abnormal I-123 ioflupane scans were clustered using T-SNE, and one-way ANOVA was performed to compare HRV and SBR parameters. The analysis was repeated after the exclusion of patients taking angiotensin-converting enzyme inhibitors, given the known mechanism on autonomic function. Subsequent analysis showed a significant difference between the high-frequency domains of heart rate variability, asymmetry of the caudate SBR, and putamen-to-caudate SBR. Conclusion: Our results support the hypothesis that more imbalanced (specifically worse left-sided) neuronal loss results in greater AutD.

Evaluation of Parkinsonian Syndromes (PS) with Ioflupane iodine-123 dopamine transporter single photon emission computed tomography (DaT-SPECT), in conjunction with history and clinical examination, aids in diagnosis. FDA-approved, semi-quantitative software, DaTQUANT^TM (GE Healthcare, Chicago, IL, USA) is available to assist in interpretation. This study aims to evaluate the optimal variables and thresholds of DaTQUANT to yield the optimal diagnostic accuracy. It is a retrospective review with three different patient populations. DaT-SPECT images from all three study groups were evaluated using DaTQUANT^TM software, and both single and multi-variable logistic regression were used to model PS status. The optimal models were chosen via accuracy, sensitivity, and specificity, then evaluated on the other study groups. Among single variable models, the posterior putamen yielded the highest accuracy (84% to 95%), while balancing sensitivity and specificity. Multi-variable models did not substantially improve the accuracy. When the optimal single variable models for each group were used to evaluate the remaining two groups, comparable results were achieved. In typical utilization of DaT-SPECT for differentiation between nigrostriatal degenerative disease (NSDD) and non-NSDD, the posterior putamen was the single variable that yielded the highest accuracy across three different patient populations. The posterior putamen’s recommended thresholds for DaTQUANT are SBR ≤ 1.0, z-score of ≤−1.8 and percent deviation ≤ −0.34.

The number of patients surviving repair of complex congenital heart disease (CCHD) has increased due to improved surgical techniques, post operative management and outpatient care. Likewise, this growing patient population has demonstrated an increasing number and complexity of complications involving the lymphatic system. To evaluate the peripheral and central lymphatic system, whole-body lymphangioscintigraphy (LAS) is considered as the initial imaging evaluation of choice. To date, very few publications exist on the value of lymphatic imaging techniques in infants and small children with lymphatic complications following surgery for congenital heart disease. A retrospective review of medical records from 2008 to 2018 was performed for pediatric patients referred for lymphatic complications after CCHD surgery at an academic medical center. LAS and SPECT/CT was performed using intradermal bipedal injections of Tc 99m labeled filtered sulfur colloid, and in some patients also bilateral hand injections, followed by dynamic imaging and whole- body planar imaging typically up to 180 minutes post injection. Clinical decision making and outcomes were recorded. LAS and SPECT/CT were performed without complication in pediatric patients with prior surgery for CCHD. LAS successfully localized various lymphatic abnormalities such as lymphatic obstruction, reflux, and leaks, which were further delineated by SPECT/CT. LAS findings directed further evaluation with more definitive studies, management and prognosis. Five of the ten patients had follow up outcome data – 2 years and up to 10 years. LAS and SPECT/CT are safe and effective techniques for the initial evaluation of lymphatic abnormalities in pediatric patients with CCHD. LAS, particularly with further 3D localization by SPECT/CT, provides functional imaging of peripheral and central lymphatic flow and thus provides guidance for medical therapy, non operative interventional management, and surgical therapy for these diverse, debilitating, and often life threatening disorders.

The recent report of the existence of meningeal lymphatic vessels (MLVs) in human and nonhuman primates used both histology and magnetic resonance imaging (MRI). Many questions about the physiology and function of these lymphatic vessels remain unanswered. Through the combination of appropriately positioned saturation bands and time-of-flight angiography sequences, MRI can resolve direction of flow within vessels without the use of exogenous contrast agent. Six healthy volunteers underwent high-resolution MRI of the MLVs running alongside the superior sagittal sinus to determine the direction of the lymphatic flow. In all subjects, the lymphatic flow was posterior to anterior, countercurrent to the direction of venous flow in the superior sagittal sinus and alongside the superior sagittal sinus. This flow strongly supports that a large proportion of the CNS lymphatic flow in humans is directed to the cribriform plate. The countercurrent direction of flow in the MLVs relative to venous flow in the superior sagittal sinus has implications for modeling flow of fluid and solutes across the various compartments of the CNS. A hypothetical compartmental model incorporating countercurrent flow is presented here.