bluuebunny/crossref_metadata_2025 huggingface dataset:
NVTG-11 EFFICACY OF TRASTUZUMAB DERUXTECAN IN HER2-POSITIVE AND HER2-LOW BREAST CANCER WITH ACTIVE BRAIN METASTASES
Authors: Burnside Georgiana , Gu Bo , Carlson-Clarke Brandon , Lalwani Kriti , Hayden-Gephart Melanie
Published: August 2024

Trastuzumab deruxtecan (T-DXd) has demonstrated strong CNS penetrance for HER2+ breast cancer with brain involvement, but further evidence is needed to support the use of T-DXd in HER2-low patients. This institutional retrospective review investigates the efficacy of T-DXd between HER2+ and HER2-low breast cancers with active brain metastases (BM). Using the Stanford Research Repository from 2020-2023, we identified 36 patients with breast cancer and active BM treated with T-DXd. Out of the 36, 7 had HER2+ breast cancer and 29 had HER2-low breast cancer. Of the 7 HER2+ patients, 6 are still living with 5 still continuing on treatment while median survival of the 29 HER2-low patients was 18 months (95%LCL 7 with indeterminate UCL based on available data) with 12 still living and 2 continuing on treatment. Using RANO-BM criteria we measured intracranial objective response rate (ORR-IC) on MRI for those with available target lesion measurements at initiation and end of treatment (EOT) windows (n=33). Of the HER2+ patients (n=7), 1/7 (14%) showed complete response, 2/7 (29%) had partial response, 3/7 (43%) had stable disease, and 1/7 (14%) had progressive disease with a notable 73.7% reduction in size of target lesions but numerous new enhancing lesions at EOT. In contrast, of the HER2-low cohort (n=26), 6/26 (23%) demonstrated partial response, 8/26 (31%) had stable disease, and 12/26 (46%) had progressive disease. Of the 12 HER2-low patients with progressive disease, 2/12 had >30% reduction in size of target lesions but numerous new lesions at EOT. Despite some intracranial responses in HER2-low patients, their median survival and high progression rates indicate limited benefits, highlighting the need for more robust prospective studies to further investigate T-DXd’s efficacy in this subgroup.
OCTS-07 TRIAL IN PROGRESS: PHASE II STUDY OF RADIATION THERAPY FOLLOWED BY INTRATHECAL TRASTUZUMAB/PERTUZUMAB IN THE MANAGEMENT OF HER2+ BREAST LEPTOMENINGEAL DISEASE
Authors: Ahmed Kamran , Kumthekar Priya , Kim Youngchul , DeJesus Michelle , Pina Yolanda , Oliver Daniel , Evernden Brittany , Arrington John , Vogelbaum Michael , Rosa Marilin , Soliman Hatem , Yu Michael , Han Hyo , Forsyth Peter
Published: August 2024

BACKGROUND

HER2+ leptomeningeal disease (LMD) has a poor prognosis with a high unmet clinical need. A previous phase I/II study revealed intrathecal (IT) trastuzumab to be well tolerated with improved overall survival (OS) compared to historical controls in HER2+ breast LMD. Radiotherapy can improve the flow of IT therapy through the cerebrospinal fluid (CSF) and provide symptomatic relief. The monoclonal antibody pertuzumab is used in conjunction with trastuzumab in the systemic management of HER2+ breast cancer. The phase I portion of the current study used a modified toxicity probability interval-2 (mTPI-2) design to determine 80 mg IT pertuzumab as the recommended phase II dose with a fixed dose of 80 mg IT trastuzumab.

METHODS

The study is designed as a prospective, single-arm, nonrandomized, open-label, phase II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. HER2+ LMD patients identified by magnetic resonance imaging (MRI) and/or CSF cytology, ≥18, with a life expectancy > 8 weeks are eligible. Treatment is initiated with radiotherapy, whole brain radiotherapy and/or focal brain/spine radiation followed by IT trastuzumab/pertuzumab. The primary objective of the phase II portion is to evaluate OS following IT trastuzumab/pertuzumab. Secondary objectives involve evaluating the response rate (leptomeningeal and parenchymal), and progression free survival (leptomeningeal and parenchymal). A single-arm two-stage trial is designed using the Restricted-Kwak-and-Jung’s Method. The primary endpoint is one-year OS. An interim analysis will be performed after 20 patients are enrolled with plans to enroll an additional 10 patients if criteria are met. This study is open with 14 patients enrolled at the time of submission. Clinical trial information: NCT04588545.
RADT-01 A COMPREHENSIVE REVIEW OF THE UTILITY OF BRACHYTHERAPY IN THE MANAGEMENT OF BRAIN METASTASIS
Authors: Leskinen Sandra , Ben-Shalom Netanel , Ellis Jason , Langer David , Boockvar John A , D’Amico Randy S , Wernicke A Gabriella
Published: August 2024

PURPOSE

This literature review investigates the current applications of brachytherapy in treating brain metastases (BMs), focusing on its advantages, limitations, and clinical outcomes.

METHODS

A comprehensive literature search was conducted using PubMed, Embase, and ClinicalTrials.gov, focusing on studies related to brachytherapy in BM treatment and adhering to PRISMA guidelines. We included studies if they reported brachytherapy techniques, isotopes, and patient outcomes.

RESULTS

Our initial search yielded 1,813 articles, of which 42 studies met inclusion criteria reporting on brachytherapy techniques, the isotopes utilized, and patient outcomes. Specifically, we identified 19 total studies assessing the use of Iodine-125 (I-125) brachytherapy, including two prospective studies, 16 retrospective studies, and one case report. There were 23 total studies assessing the use of Cesium-131 (Cs-131) brachytherapy, including five clinical trials, four prospective studies, 11 retrospective studies, and three case reports. Two retrospective studies used both Cs-131 and I-125 seeds. We identified three registered national clinical trials examining the use of Cs-131 brachytherapy for BM treatment. Although I-125 brachytherapy was found to be effective in BM treatment with local control rates and median overall survival paralleling stereotactic radiosurgery and whole brain radiotherapy, the rates of radiation necrosis were as high as 23% in one study. Conversely, Cs-131 studies described high rates of locoregional tumor control with minimal rates of radiation necrosis. One clinical trial found a statistically significant improvement in cognitive functioning and quality of life at four- and six-months following Cs-131 seed implantation.

CONCLUSION

Brachytherapy, with a particular focus on I-125 and Cs-131 isotopes, has shown promise in treating brain metastases, offering targeted radiation with minimal effects on surrounding healthy tissue. Future research, including randomized controlled trials and long-term follow-up studies, is necessary to optimize the role of brachytherapy in the treatment of brain metastases.
RADT-07 IMPACT OF KEAP1/NFE2L2 VARIANTS ON LOCAL CONTROL IN NSCLC BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Chen Mark , Carpenter David , Leng Jim , Qazi Jamiluddin , Wan Zihan , Niedzwiecki Donna , Alder Laura , Clarke Jeffrey , Kirkpatrick John , Floyd Scott , Reitman Zachary , Mullikin Trey
Published: August 2024

The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-like 2 (NFE2L2) reactive oxygen species processing pathway may be a useful biomarker of clinical radioresistance in localized non-small cell lung cancer (NSCLC). It is unknown whether KEAP1/NFE2L2 variants impact the response of brain metastases from NSCLC to radiotherapy. Here, we tested whether KEAP1/NFE2L2 variants associate with rates of local control in patients with NSCLC brain metastases undergoing stereotactic radiosurgery (SRS). We hypothesize KEAP1/NFE2L2 pathogenic variants (PV) are associated with decreased local control (LC) and increased time to intracranial progression (ICP). 541 patients undergoing SRS for NSCLC brain metastases at a single institution were retrospectively identified; n=269 underwent clinical next generation sequencing. Kaplan-Meier analyses were calculated for LC and ICP; results across variant status were compared using the log-rank test. Comparisons were performed for variant versus no mutation, and by variant type (PV and variant of unknown significance (VUS)). At 12 months, LC was 90.8% (95% CI, 79.2-96.1%) among patients with variants, compared to 90.6% (84.4-94.4%) in patients without. There was no significant difference in median time to ICP between patients with variants (5.1 months; 95% CI, 3.3-9.5 months) compared to those without (7.2 months; 95% CI, 5.7-9.5 months). 12-month LC was 92.15±5.33% in PV, 89.43±5.89% in VUS, and 90.6±2.46% in patients without mutations. LC and ICP displayed a non-significant trend for differences when KEAP1/NFE2L2 PV and VUS were compared. Overall, KEAP1/NFE2L2 variant status did not demonstrate a statistically significant difference in LC or ICP after SRS for brain metastases in this cohort. On the basis of these data, KEAP1/NFE2L2 variant status should not impact clinical management of NSCLC brain metastasis patients. Larger cohorts are needed to examine KEAP1/NFE2L2 status association with outcomes among NSCLC brain metastasis patients. Thus, the impact of KEAP1/NFE2L2 mutations may differ in the localized versus metastatic setting.
RADT-12 HIPPOCAMPAL AVOIDANCE WHOLE BRAIN RADIOTHERAPY WITH REDUCED WHOLE BRAIN DOSE ENABLES IMPROVED SPARING OF HIPPOCAMPI WITHOUT INCREASED RISK OF DISTANT BRAIN FAILURE IN NON-SMALL CELL LUNG CANCER
Authors: Khandekar Melin , Keane Florence , Soto Dan , Tansky Joanna , Oh Kevin , Willers Henning , Shih Helen
Published: August 2024

Hippocampal avoidance whole brain radiation (HA-WBRT) results in improved neurocognitive function (NCF) compared to standard WBRT, but > 50% of patients still experience NCF failure. We examined whether lower biologically effective dose (BED) of HA-WBRT enables better hippocampal sparing without impacting intracranial disease control in patients with non-small cell lung cancer (NSCLC). We conducted an IRB approved, retrospective study of patients with NSCLC receiving HA-WBRT between 2014-2022. Endpoints were distant brain failure free survival (DBFFS), local brain failure free survival (LBFFS), left and right hippocampal mean BED2 and BED21%. Kaplan-Meier survival analysis and Welch’s t-test were performed. Sixty-nine patients treated with HA-WBRT were included, with median follow up of 51.2 weeks. Thirty-six patients received standard HA-WBRT (SD) with median dose of 30 Gy in 10 fractions. Thirty-three patients received reduced BED HA-WBRT (RD), with median dose of 30 Gy in 15 fractions. All patients in the RD group had simultaneous integrated boost (SIB) to gross disease (median 37.5 Gy) while 18/36 in the SD group had an SIB (median 35 Gy). There were no significant differences between SD and RD cohorts in age, systemic therapy use, or targetable mutations. There was no difference in median DBFFS of the SD (23.1 weeks) and RD groups (40 weeks) (p=0.27). There was no difference in LBFFS of the SD (median 26.4 weeks) and RD groups (median 40 weeks), p=0.84). For the left and right hippocampi, both mean BED2 and D1% were significantly lower in the RD group (p<0.001). In this cohort, lower BED HA-WBRT improved hippocampal sparing without compromising intracranial control in patients with NSCLC. Further optimization of HA-WBRT dose and schedule may improve both intracranial control and neurocognitive outcomes. This study is limited by its retrospective nature and potential selection bias. A phase II prospective study to test these concepts is ongoing.
RADT-15 STEREOTACTIC RADIOSURGERY FOR ADENOID CYSTIC CARCINOMA BRAIN METASTASES: A SINGLE INSTITUTION RETROSPECTIVE STUDY
Authors: Kattaa Ahed , Hori Yusuke , Akhavan-Sigari Amirhossein , Persad Amit , Tayag Armine , Ustrzynski Louisa , Emrich Sara , Park David , Chang Steven
Published: August 2024

BACKGROUND

Adenoid cystic carcinoma (ACC) is a malignant neoplasm arising from the minor and major salivary glands that tends to spread by perivascular and perineural routes. Brain metastases (BM) secondary to ACC are very rare, and the standard management strategy has not been well reported due to the rarity. Especially, only a few case reports described the use of stereotactic radiosurgery (SRS) for BM from ACC.

METHODS

We retrospectively reviewed cases of BM from ACC treated with SRS at our institute between 1998 and 2023. A total of 40 lesions from 5 patients were included, and the patient and lesion background variables were collected. Tumor control was defined based on radiological response to SRS as a complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) per RECIST guidelines.

RESULTS

The median overall survival was 12.0 months (interquartile range (IQR): 6.5–33.5 months). The mean age at treatment was 51.2 years (standard deviation (SD): 7.8 years) and 60% were male patients. The mean maximum diameter of the lesions was 11.1 mm (SD: 10.9 mm). The median dose delivered was 24 Gy (IQR: 22– 24Gy). The MRIs at 3 and 6 months demonstrated reductions in mean maximum diameters at 5.5 mm and 3.3 mm, respectively. The treatment responses at the first follow-up were; CR/PR/SD/PD: 10/19/11/0. At the last follow-up, 5 lesions had local progression, with one lesion at 39 months, and 4 lesions at 11 months after CK SRS, while 16 lesions remained CR. The cumulative 3-months, 6-months, and 12-months local control rates were 100%, 100%, and 87.5%, respectively.

CONCLUSION

To date, this is the largest study examining the efficacy of SRS for ACC BM. Our results showed the sufficient local control following the treatment. Further studies are required to confirm our results.
RMTD-08 RADIATION ABSORBED DOSE TO SPINAL CORD: THERAPY OF LEPTOMENINGEAL METASTASES USING BETA-EMISSION RADIOPHARMACEUTICALS
Authors: Bao Ande , Zhao Xia , Phillips William , Brenner Andrew , Youssef Michael , Kumthekar Priya , Yang Jonathan , Zheng Yiran , Spratt Daniel E , Moore Melissa , Hedrick Marc , LaFrance Norman , Juverdianu Leonardo , Blouw Barbara
Published: August 2024

BACKGROUND

Over 100,000 cancer patients develop leptomeningeal metastases (LM) annually in the US. LM prognosis is poor with limited treatment options. Beta-emission radiopharmaceuticals, for example, 186Re-nanoliposomes (Rhenium (186Re) Obisbemeda, 186RNL), are a promising new therapeutic approach to deliver high doses of ionizing radiation to the disease without significant normal tissue exposure. However, the dose and possible toxicity to the spinal cord may be a concern. Herein, we report radiation dosimetry to understand the radiation absorbed dose to spinal cord for this novel treatment approach.

METHODS

The T2-weighted MRI of the cervical spine from a patient with LM was segmented into volumes of the cerebrospinal fluid (CSF) and spinal cord. The radiation absorbed dose distribution in CSF and spinal cord were calculated using dose voxel kernel and 3D convolution. The beta-emission radionuclides with different beta-energies (177Lu, 131I, 186Re, 188Re, and 90Y) were calculated. The dose distribution in CSF and spinal cord were summarized and evaluated.

RESULTS

It was found that the radiation absorbed doses to spinal cord are associated with the beta-energy of radionuclides. The mean doses to the spinal cord in the calculated volume were 2.75%, 7.25%, 10.89%, 29.69%, and 37.66% of mean doses in CSF for 177Lu, 131I, 186Re, 188Re, and 90Y, respectively. The radionuclides with lower beta-energy can largely spare the spinal cord with significantly lower radiation doses. The radionuclides with higher beta-energy provide larger doses to spinal cord, while the dose to CSF were more heterogeneous.

CONCLUSION

This radiation dosimetry study demonstrates that beta-emission radiopharmaceuticals with lower beta-energies are optimal for the treatment of LM to maximize the therapeutic ratio given the proximity of the spinal cord. This study provides the guidance for the possible doses to be applied for the safe treatment of LM, including the treatment of patients with previous external beam radiation therapy.
SPCM-04 SURGICAL EXCISION OF SPINAL INTRADURAL METASTASES: A 10 YEAR INSTITUTIONAL EXPERIENCE
Authors: Ambati Vardhaan , Patel Arati , Tawil Michael , Krishnan Nishanth , Bernabei John , Zammar Samer , Ames Christopher , Clark Aaron , Chin Cynthia , Alan Nima , Chou Dean , Mummaneni Praveen
Published: August 2024

INTRODUCTION)

Spinal intradural metastases are rare and are usually managed non-operatively given poor prognosis of widespread metastatic disease. Surgical resection is considered in cases of rapid, progressive neurological decline. We describe our single-center, 10-year experience of surgical resection of spinal intradural metastases.

METHODS)

Adults who underwent surgical resection of spinal intradural metastatic (excluding neurogenic) tumors at a single quaternary care institution over 10 years were reviewed. Clinical, surgical, and postoperative outcomes were summarized.

RESULTS)

Twelve patients (5 female) with mean age 58.3 (range 32.5-77.6) years underwent resection of spinal intradural metastases (5 intramedullary, 7 extramedullary). Cases included metastatic adenocarcinoma (2 breast, 1 parotid, 1 uterine), melanoma (3), renal cell carcinoma (2), follicular thyroid carcinoma (1), adenoid cystic carcinoma (1), and prostate cancer (1). Tumors were located at thoracolumbar junction (6), cervicothoracic junction (3), lumbar (2), and cervical spine (1). Patients presented with mean 9.4 weeks (range 1-day to 1-year) of symptoms. At presentation, 9 were found to have leptomeningeal disease; 6 had brain metastases. All patients underwent laminectomy (median 3; range 2-5 levels). Gross total resection of symptom-causing tumors was achieved in 5 of 12 patients. Postoperatively, 11 patients demonstrated stable/improving neurological exams from preoperative baseline. Ninety-day readmission rate was 50%, and two patients required reoperation for pseudomeningocele. Eleven patients were treated with neoadjuvant/adjuvant therapy (TKIs, hormonal, immunotherapy). Six underwent radiation therapy. Mean follow-up was 1.2 years, at which point, 3 patients died (mean survival 2-years, range 1month-4.9years). Mean cohort Karnofsky Performance Scale (KPS) improved from 44% preoperatively (range 30-70%) to 53% (range 0% [deceased]-90%); mean KPS improves to 64% if deceased patients are excluded.

CONCLUSION)

This represents one of the largest series of surgically treated intradural nonneurogenic metastases. Even in patients with widespread metastatic burden, intradural tumor resection in patients with neurological decline may improve postoperative function and survival.
QSPC-06 TIME-SERIES SINGLE-CELL ANALYSES REVEAL INCESSANT REWIRING OF MICROGLIA AFTER OF CRANIAL IRRADIATION
Authors: Osman Ahmed , Romero Alejandro Lastra , Preka Efthalia , Pizzirusso Giusy , Arroyo-Garcia Luis Enrique , Zisiadis Georgios Alkis , Oliva-Vilarnau Nuria , Seitz Thea , Zhou Kai , Isla Arturo Gonzalez , Sun Ying , Zhu Changlian , Rodrigues Carlos , Fisahn André , Fragkopoulou Adamantia , Lauschke Volker , Betsholtz Christer , Blomgren Klas
Published: August 2024

Cranial irradiation (IR) is one of the pillars of treatment of brain tumors and metastases, but it causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is believed to contribute to this, but its dynamics and consequences on brain function remain poorly understood. Here, we performed longitudinal molecular and cellular profiling of the irradiated mouse hippocampus, a key brain structure for cognitive tasks, using single cell transcriptomics and computational analyses, proteomics and histology, covering multiple time points, from 6 hours to 1 year after IR. We found that IR induced biphasic inflammatory waves, and microglia were the key orchestrating cells. The first wave occurred within the first 24 hours after IR, triggered by the death of neural progenitors in the dentate gyrus. The second, delayed wave occurred 2 weeks after IR, coupling interferon signaling to mitotic progression, and a subsequent induction of temporally regulated subtypes. Trajectory analysis uncovered that this subset of microglia drives microglial mitotic progression, cell death, or a senescent-like phenotype predominantly observed 6 weeks after IR. At this timepoint, the levels of cytokines known to have negative effects on cognition, like tumor necrosis factor and interleukin-6, were increased, coinciding with neuronal asynchrony of the hippocampal circuitry. We also found that IR caused progressive microglial loss and that they fail to repopulate the empty territories by self-renewal, leading to infiltration of peripheral macrophages to repopulate the hippocampus and differentiate into microglia-like cells by 6 months after IR. After 1 year, microglial alterations were largely related to neuronal and synaptic plasticity, and again coinciding with neuronal asynchrony. Thus, the inflammation profile in the hippocampus after IR is dynamic, and therapies targeting inflammation should be tailored accordingly.
SRGD-03 PRESENTATION AND POST-OPERATIVE OUTCOMES IN DIVERSE PATIENTS RECEIVING LASER ABLATION FOR CENTRAL NERVOUS SYSTEM METASTASES
Authors: Haskell-Mendoza Aden , Gonzalez Ariel , Reason Ellery , Jackson Joshua , Seas Andreas , Zaidi Saif , Mohan Aditya , Lerner Emily , Srinivasan Ethan , Bradbury Claire , Herndon James , Goodwin C Rory , Fecci Peter
Published: August 2024

OBJECTIVE

Laser interstitial thermal therapy (LITT) is a minimally invasive option for the management of intracranial pathologies, including radiographically progressive tumors following stereotactic radiosurgery. Although LITT has been increasingly accepted in recent years, little is known regarding presentation and outcomes of patients with diverse backgrounds, particularly for centers specializing in central nervous system (CNS) metastases.

METHODS

All patients receiving their index LITT for brain metastasis at a single center from 2015 – 2023 were retrospectively reviewed. Patient demographics and geospatial data was used to compare differences in receipt of LITT by race/ethnicity, survival outcomes, and clinical trial enrollment.

RESULTS

From 2015-2023, 137 patients presented for LITT to 146 intracranial lesions. One hundred and six patients (77.3%) were non-Hispanic White (NHW), 25 (18.2%) were Black or African American, 5 (3.6%) were Asian American/Pacific Islander, and 1 (0.7%) was Hispanic or Latino (Hispanic or non-White, HNW). Among HNW patients, women more frequently received LITT (P = 0.022), with skin cancers being a more frequent indication among NHW patients (P = 0.019). NHW patients traveled a median of 62.0 (6.2 – 1045.9) miles to receive LITT vs 25.9 (1.31 – 238.3) miles for HNW patients (p = 0.001). In multivariate analyses, post-LITT overall survival was predicted by pre-LITT KPS (P = 0.0007) and recurrent tumor on biopsy (P = 0.0002), while probability of clinical trial enrollment was lower among those of female sex (P = 0.049), HNW race/ethnicity (P = 0.041), or external referral status (P = 0.035).

CONCLUSION

Patient sex, systemic disease histology, and distance from a treating center may differentially influence presentation for LITT according to underlying racial/ethnic identity. However, patients successfully treated in multidisciplinary CNS metastasis centers experience excellent post-procedural outcomes. Such centers should enact measures to ensure equitable clinical trial enrollment.
TRSC-05 TUMOR REACTIVE T CELLS FROM THE CEREBROSPINAL FLUID IN MELANOMA LEPTOMENINGEAL DISEASE
Authors: Pina Yolanda , Carter Michael , Hall Maclean , Rodriguez Madeline , Beatty Matthew , Forsyth Peter , Pilon-Thomas Shari
Published: August 2024

BACKGROUND

Leptomeningeal disease (LMD) is a devastating complication from cancer, with a median survival of 6-8 weeks. The incidence of LMD is highest in melanoma (5-25%) carrying the worst prognosis. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) showed complete and durable responses in patients with advanced metastatic melanoma. CSF-derived T cell populations in LMD shift to more exhausted phenotypes compared to extracranial and brain metastases. Adoptive T cell transfer can be a novel therapeutic approach to treat melanoma LMD (M-LMD). Our goal is to optimize CSF-derived tumor reactive T cell expansion in M-LMD and assess their anti-tumoral response.

METHODS

Cells from CSF from M-LMD patients (n=6) were plated following established TIL culture protocols to determine optimal expansion conditions i.e.: 1) 6000 IU/mL IL-2, 2) IL-2+OKT3, 3) IL-2+anti-4-1BB agonistic antibody, 4) IL-2+IL-7+IL-15+IL-21, 5) IL-2+anti-CD3/CD28 human dynabeads, & 6) IL-2+anti-CD3/CD28/CD137 human dynabeads. After 4 weeks, T cells were propagated via REP and phenotyped. T cells were co-cultured with HLA-matched melanoma cell lines and IFN-y levels evaluated. TCR beta seq was done at different times point of expansion and peripheral T cells.

RESULTS

After initial culture in IL-2, 61.9% of samples showed increased cell yield with an average 101.68-fold expansion (range 2.35-1054). PreREP T cells were predominantly CD4+ (45.7%). REP was 100% success rate (mean 187.47-fold expansion). Post-REP flow cytometry revealed similar results. M-LMD T cells were highly functional, producing substantial levels of IFN-y in response to HLA-matched cells. Anti-CD3/CD28 produced a larger expansion of T cells with higher levels of IFN-y. TCR beta sequencing results are pending.

CONCLUSIONS

Therapies for LMD patients are desperately needed. Results demonstrate successful expansion of T cells ex vivo from CSF in M-LMD. Results raise potential to use autologous CSF-derived T cells as therapeutic strategy for patients with LMD.
Radiation protection adherence and associated factors among radiology personnel
Authors: Fathabadi Amirhossein , Oloomi Shabnam
Published: August 2024

The aim of the study was to investigate radiation protection adherence among radiology personnel and associated factors. In light of the increasing integration of ionizing radiation in medical diagnostics and treatment—specifically in areas such as computed tomography, fluoroscopy, and therapeutic radiology—it is vital for radiology personnel to consistently uphold rigorous radiation protection standards. This cross-sectional study employed a self-administered questionnaire to collect demographic data and assess various aspects of radiation protection adherence among radiology personnel. The gathered data were entered into SPSS 16 for statistical analysis. Among the 119 participants, 72 (60.5%) worked in the radiology department, and 88 (77.9%) were married. Significant associations were observed between adherence levels and marital status, age groups, years of experience, and department type. Study findings showed a significant association between several demographic factors and radiation protection adherence. Furthermore, our results highlight the value of implementing radiation protection courses to enhance adherence among personnel.
A Qualitative Analysis of Workers Perceptions on the Role of Management in Promoting Health Behavior, Informed by the COM-B Model
Authors: Gradidge Philippe Jean-Luc , Alsop Tahlia , Palmeira António , Gordon Neil F. , Gomersall Sjaan
Published: August 2024

Background

The primary objective of this study was to explore the viewpoints held by employees at a pharmaceutical manufacturing workplace in a middle-income country regarding management's role in promoting health behaviors in the workplace.

Methods

This study used transcripts of focus group discussion from an original study that investigated employee perceptions of factors associated with healthy behaviors among South African pharmaceutical manufacturing factory workers.

Results

Participants felt that workplace managers could improve capability through health promotion strategies, supportive leadership, and promoting a culture of health. They could provide opportunity through employee engagement programs and resources, and physical activity opportunities were specifically identified.

Conclusions

This study demonstrates that managers in a middle-income country have the potential to contribute to workplace health in a range of ways that include addressing capability, opportunity, and motivation of their workers.
Effect of Deep Learning Image Reconstruction Algorithms on Radiomic Features of Pulmonary Nodules in Ultra-Low-Dose CT
Authors: Zheng Zhijuan , Liang Yuying , Wu Zhehao , Han Qijia , Ai Zhu , Ma Kun , Xiang Zhiming
Published: August 2024

Objective

The purpose of this study is to explore the impact of deep learning image reconstruction (DLIR) algorithm on the quantification of radiomic features in ultra-low-dose computed tomography (ULD-CT) compared with adaptive statistical iterative reconstruction-Veo (ASIR-V).

Methods

One hundred eighty-three patients with pulmonary nodules underwent standard-dose computed tomography (SDCT) (4.30 ± 0.36 mSv) and ULD-CT (UL-A, 0.57 ± 0.09 mSv or UL-B, 0.33 ± 0.04 mSv). SDCT was the reference standard using (ASIR-V) at 50% strength (50%ASIR-V). ULD-CT was reconstructed with 50%ASIR-V, DLIR at medium and high strength (DLIR-M, DLIR-H). Radiomics analysis extracted 102 features, and the intraclass correlation coefficient (ICC) quantified reproducibility between ULD-CT and SDCT reconstructed by 50%ASIR-V, DLIR-M, and DLIR-H for each feature.

Results

Among 102 radiomic features, the percentages of reproducibility of 50%ASIR-V, DLIR-M, and DLIR-H were 48.04% (49/102), 49.02% (50/102), and 52.94% (54/102), respectively. Shape and first order features demonstrated high reproducibility across different reconstruction algorithms and radiation doses, with mean ICC values exceeding 0.75. In texture features, DLIR-M and DLIR-H showed improved mean ICC values for pure ground glass nodules (pGGNs) from 0.69 ± 0.23 to 0.75 ± 0.18 and 0.81 ± 0.12, respectively, compared with 50%ASIR-V. Similarly, the mean ICC values for solid nodules (SNs) increased from 0.60 ± 0.19 to 0.66 ± 0.14 and 0.69 ± 0.13, respectively. Additionally, the mean ICC values of texture features for pGGNs and SNs in both ULD-CT groups decreased with reduced radiation dose.

Conclusions

DLIR can improve the reproducibility of radiomic features at ultra-low doses compared with ASIR-V. In addition, pGGNs showed better reproducibility at ultra-low doses than SNs.
Impact on Image Quality and Diagnostic Performance of Dual-Layer Detector Spectral CT for Pulmonary Subsolid Nodules: Comparison With Hybrid and Model-Based Iterative Reconstruction
Authors: Ding Li , Li Xiaomei , Lin Jie , Deng Shuting , Chen Mingwang , Deng Weiwei , Xu Yikai , Chen Zhao , Yan Chenggong
Published: August 2024

Objective

To evaluate the image quality and diagnostic performance of pulmonary subsolid nodules on conventional iterative algorithms, virtual monoenergetic images (VMIs), and electron density mapping (EDM) using a dual-layer detector spectral CT (DLSCT).

Methods

This retrospective study recruited 270 patients who underwent DLSCT scan for lung nodule screening or follow-up. All CT examinations with subsolid nodules (pure ground-glass nodules [GGNs] or part-solid nodules) were reconstructed with hybrid and model-based iterative reconstruction, VMI at 40, 70, 100, and 130 keV levels, and EDM. The CT number, objective image noise, signal-to-noise ratio, contrast-to-noise ratio, diameter, and volume of subsolid nodules were measured for quantitative analysis. The overall image quality, image noise, visualization of nodules, artifact, and sharpness were subjectively rated by 2 thoracic radiologists on a 5-point scale (1 = unacceptable, 5 = excellent) in consensus. The objective image quality measurements, diameter, and volume were compared among the 7 groups with a repeated 1-way analysis of variance. The subjective scores were compared with Kruskal-Wallis test.

Results

A total of 198 subsolid nodules, including 179 pure GGNs, and 19 part-solid nodules were identified. Based on the objective analysis, EDM had the highest signal-to-noise ratio (164.71 ± 133.60; P < 0.001) and contrast-to-noise ratio (227.97 ± 161.96; P < 0.001) among all image sets. Furthermore, EDM had a superior mean subjective rating score (4.80 ± 0.42) for visualization of GGNs compared to other reconstructed images (all P < 0.001), although the model-based iterative reconstruction had superior subjective scores of overall image quality. For pure GGNs, the measured diameter and volume did not significantly differ among different reconstructions (both P > 0.05).

Conclusions

EDM derived from DLSCT enabled improved image quality and lesion conspicuity for the evaluation of lung subsolid nodules compared to conventional iterative reconstruction algorithms and VMIs.
Usefulness of Picture Archiving and Communication System–Based Quantitative Ultrasound Measurements in Evaluation of Allograft Dysfunction in Patients With Liver Transplantation
Authors: Erdem Toslak Iclal , Joyce Cara , Yacoub Joseph H.
Published: August 2024

Objective

The aim of this study was to assess the usefulness of picture archiving and communication system (PACS)–based quantitative grayscale ultrasonography (US) measurements in detecting allograft dysfunction in posttransplant patients.

Methods

In this retrospective study, 116 patients with liver transplantation who underwent biopsy for allograft evaluation were recruited from the database. All participants had US images prior to procedure. Normal, acute cellular rejection (ACR), recurrent hepatitis (Hep), or combined (ACR/Hep) groups were generated based on pathology results. Region of interests were drawn for liver and rectus abdominus muscle to perform quantitative US analysis. The liver/muscle mean ratio (L/M) and heterogeneity index (HI; liver standard deviation/liver mean) were obtained. The ratios of groups were compared, and receiver-operating-characteristic analysis was performed.

Results

There was a significant difference between normal (n = 16) and each of other groups (ACR, 39; Hep, 36; combined, 25) for L/M and HI (P < 0.05). No significant difference was detected between ACR, Hep, and combined groups. The areas under the curve for L/M and HI were 0.755 (moderate) and 0.817 (good), respectively. To differentiate abnormal (ACR, Hep, and combined) from normal allografts sensitivity, specificity, PPV, and NPV were 50.0%, 87.5%, 96.2%, and 21.9% for cut point of L/M ≥1 and 84.0%, 68.8%, 94.4%, and 40.7% for cut point of HI ≥0.2 with odds ratios of 7.52 (for L/M ≥1) and 13.10 (for HI ≥0.2), respectively (P < 0.01).

Conclusions

L/M has moderate and HI has good discrimination of normal from abnormal allograft in liver transplant patients. PACS-based quantitative US measurements is an objective, easy to use, noninvasive auxiliary tool to discriminate hepatic allograft dysfunction.
The Feasibility of a Model-Based Iterative Reconstruction Technique Tuned for the Myocardium on Myocardial Computed Tomography Late Enhancement
Authors: Toritani Hidetaka , Yoshida Kazuki , Hosokawa Takaaki , Tanabe Yuki , Yamamoto Yuta , Nishiyama Hikaru , Kido Tomoyuki , Kawaguchi Naoto , Matsuda Megumi , Nakano Shota , Miyazaki Shigehiro , Uetani Teruyoshi , Inaba Shinji , Yamaguchi Osamu , Kido Teruhito
Published: August 2024

Objectives

This study evaluated the feasibility of a model-based iterative reconstruction technique (MBIR) tuned for the myocardium on myocardial computed tomography late enhancement (CT-LE).

Methods

Twenty-eight patients who underwent myocardial CT-LE and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) within 1 year were retrospectively enrolled. Myocardial CT-LE was performed using a 320-row CT with low tube voltage (80 kVp). Myocardial CT-LE images were scanned 7 min after CT angiography (CTA) without additional contrast medium. All myocardial CT-LE images were reconstructed with hybrid iterative reconstruction (HIR), conventional MBIR (MBIR_cardiac), and new MBIR tuned for the myocardium (MBIR_myo). Qualitative (5-grade scale) scores and quantitative parameters (signal-to-noise ratio [SNR] and contrast-to-noise ratio [CNR]) were assessed as image quality. The sensitivity, specificity, and accuracy of myocardial CT-LE were evaluated at the segment level using an American Heart Association (AHA) 16-segment model, with LGE-MRI as a reference standard. These results were compared among the different CT image reconstructions.

Results

In 28 patients with 448 segments, 160 segments were diagnosed with positive by LGE-MRI. In the qualitative assessment of myocardial CT-LE, the mean image quality scores were 2.9 ± 1.2 for HIR, 3.0 ± 1.1 for MBIR_cardiac, and 4.0 ± 1.0 for MBIR_myo. MBIR_myo showed a significantly higher score than HIR (P < 0.001) and MBIR_cardiac (P = 0.018). In the quantitative image quality assessment of myocardial CT-LE, the median image SNR was 10.3 (9.1–11.1) for HIR, 10.8 (9.8–12.1) for MBIR_cardiac, and 16.8 (15.7–18.4) for MBIR_myo. The median image CNR was 3.7 (3.0–4.6) for HIR, 3.8 (3.2–5.1) for MBIR_cardiac, and 6.4 (5.0–7.7) for MBIR_myo. MBIR_myo significantly improved the SNR and CNR of CT-LE compared to HIR and MBIR_cardiac (P < 0.001). The sensitivity, specificity, and accuracy for the detection of myocardial CT-LE were 70%, 92%, and 84% for HIR; 71%, 92%, and 85% for MBIR_cardiac; and 84%, 92%, and 89% for MBIR_myo, respectively. MBIR_myo showed significantly higher image quality, sensitivity, and accuracy than the others (P < 0.05).

Conclusions

MBIR tuned for myocardium improved image quality and diagnostic performance for myocardial CT-LE assessment.
Optogenetic hedonic hotspots in orbitofrontal cortex and insula: causing enhancement of sweetness ‘liking’
Authors: Morales Ileana , Berridge Kent C.
Published: August 2024

Hedonic hotspots are brain subregions that causally amplify the hedonic impact of palatable tastes, measured as increases in affective orofacial ‘liking’ reactions to sweetness. Previously, two cortical hedonic hotspots in orbitofrontal cortex and insula were identified by neurochemical stimulation using opioid or orexin microinjections. Here we used optogenetic stimulation in rats as an independent neurobiological technique for activating cortical hedonic hotspots to identify hedonic functions and map boundaries. We report that channelrhodopsin stimulations within rostral orbitofrontal and caudal insula hotspots doubled the number of hedonic ‘liking’ reactions elicited by sucrose taste. This independently confirms their robust functional identity as causal amplifiers of hedonic ‘liking’ and confirms their anatomical boundaries. Additionally, we confirmed an intervening suppressive hedonic coldstrip, to stretching from caudal orbitofrontal cortex to rostral insula. By contrast to localized hedonic hotspots for ‘liking’ enhancement, motivational ‘wanting’ for reward, measured as laser self-stimulation, was mediated by more widely distributed anatomical sites.
Distinct neuromodulatory effects of endogenous orexin and dynorphin corelease on projection-defined ventral tegmental dopamine neurons
Authors: Mohammadkhani Aida , Qiao Min , Borgland Stephanie L.
Published: August 2024

Abstract

Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues and circuit-specific signaling drives different aspects of motivated behavior. Orexins (ox; also known as hypocretin) and dynorphin (dyn) are co-expressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADAneurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors, respectively. Given that Ox1R activation increases VTADAfiring, and KOR decreases firing, it is unclear how the co-released peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LH neuromodulates VTADAneuronal activity via peptide release and if the effects of optically driven LHox/dynrelease segregates based on VTADAprojection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch clamp electrophysiology in male and female orexincremice we showed a diverse response of LH optical stimulation on VTADAneuronal firing, that are not mediated by fast transmitter release and are blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyninputs in the VTA inhibited firing of the majority of BLA projecting VTADAneurons, optical stimulation of LH inputs in the VTA bidirectionally affects firing of either lAcbSh or mAchSh projecting VTADAneurons. These findings indicate that LHox/dyncorelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.

Significance Statement

The mesolimbic dopamine (DA) system is known to play a crucial role in motivation and reward-learning and receives neuromodulatory input from the lateral hypothalamus (LH). We show that optical stimulation of the orexin-containing LH input in the VTA releases both orexin and dynorphin to bidirectionally alter VTADAfiring. Furthermore, orexin and dynorphin differentially modulate firing of DA inputs to the basolateral amygdala, whereby dynorphin predominates, or to the nucleus accumbens which is sensitive to both neuromodulators. Our findings contribute to a more comprehensive understanding of the neuromodulatory effects of coreleased LH orexin and dynorphin on the VTADAsystem.
Biased estimates of phylogenetic branch lengths resulting from the discretised Gamma model of site rate heterogeneity
Authors: Ferretti Luca , Golubchik Tanya , Di Lauro Francesco , Ghafari Mahan , Villabona-Arenas Julian , Atkins Katherine E. , Fraser Christophe , Hall Matthew
Published: August 2024

A standard procedure in phylogenetic reconstruction to represent variation in substitution rates between sites in the genome is the discrete Gamma model (DGM). Relative rates are assumed to be distributed according to a discretised Gamma distribution, where the probabilities that a site is included in each discrete class are equal. Here, we identify a serious bias in the branch lengths of reconstructed phylogenies when the DGM is used, whereby branch lengths are usually, and often substantially, overestimated, and the magnitude of this effect increases with the number of sequences in the alignment. We show that the alternative “FreeRate” model, which assumes no parametric distribution and allows the class probabilities to vary, is not subject to the issue. We further establish that reason for the behaviour is the equal class probabilities, not the discretisation itself. We recommend that the DGM be retired from general use. We note that FreeRate is an immediately available replacement, but that it is highly parameterised and known to be difficult to fit, and thus there is scope for innovation in rate heterogeneity models. In a mathematical appendix, we explore the reasons for the phenomenon in more detail. We give an expression for the likelihood of a star tree with uniform branch lengths according to some simplifying assumptions, and use this to estimate the magnitude of the phenomenon for different values of that branch length and alignment size. We show that the effect occurs when the amount of mutation (in substitutions per site) in the sites of the observed alignment differs from that in the unobserved “true” phylogeny, and further that the magnitude of the effect is determined by the mean relative rate of evolution amongst the observed sites. Finally, by investigating the case where the true underlying rate heterogeneity distribution is FreeRate with variable class probabilities but the reconstruction insists on equal probabilities, we show that branches lengths will be overestimated where there is a long-tail of fast-evolving sites in the true rate distribution, the usual situation in real datasets. We finish by giving an example of how to explicitly calculate the magnitude of the effect for a simple case where the true underlying continuous Gamma distribution is an exponential distribution and the reconstruction method uses two equal probability classes.
A modified dual preparatory method for improved isolation of nucleic acids from laser microdissected fresh-frozen human cancer tissue specimens
Authors: Kimble Danielle C. , Litzi Tracy J. , Snyder Gabrielle , Olowu Victoria , TaQee Sakiyah , Conrads Kelly A. , Loffredo Jeremy , Bateman Nicholas W. , Alba Camille , Rice Elizabeth , Shriver Craig D. , Maxwell George L. , Dalgard Clifton , Conrads Thomas P.
Published: August 2024

A central theme in cancer research is to increase our understanding of the cancer tissue microenvironment (TME), which is comprised of a complex and spatially heterogeneous ecosystem of malignant and non-malignant cells, both of which actively contribute to an intervening extracellular matrix. Laser microdissection (LMD) enables histology selective harvest of cellular subpopulations from the tissue microenvironment for their independent molecular investigation, such as by high-throughput DNA and RNA sequencing. Although enabling, LMD often requires a labor-intensive investment to harvest enough cells to achieve the necessary DNA and/or RNA input requirements for conventional next generation sequencing workflows. To increase efficiencies, we sought to use a commonplace dual preparatory (DP) procedure to isolate DNA and RNA from the same LMD harvested tissue samples. While the yield of DNA from the DP protocol was satisfactory, the RNA yield from the LMD harvested tissue samples was significantly poorer compared to a dedicated RNA preparation procedure. We identified that this low yield of RNA was due to incomplete partitioning of RNA in this widely used DP protocol. Here we describe a modified DP protocol that effectively partitions nucleic acids and results in significantly improved RNA yields from LMD harvested cells.
Destination image change through the course of a visit: a longitudinal study
Authors: Tasci Asli D.A. , Moreno-Gil Sergio
Published: August 2024

Purpose

Image change through visit experience with a destination is a common assumption, yet with rare empirical support to date. Thus, this study treats destination image as an interactive system of cognitive and affective components that are dynamic and changing through the course of an experience with a destination.

Design/methodology/approach

This longitudinal study tracks the change in images of 162 European visitors to the Gran Canaria Island one month before a two-week trip, on the last day of the trip, one month after the trip, and one year after the trip. A one-way repeated-measures analysis of variance with Bonferroni post hoc tests was conducted to evaluate the change in visitors’ cognitive, affective, or holistic images of Gran Canaria Island.

Findings

The Gran Canaria Island’s one-month post-visit image was more positive than the pre-visit image reflecting an improvement because of visitation. However, this improvement did not last long since the one-year post-visit image was not as positive as the one-month post-visit image. Surprisingly though, principle component analysis revealed more factors with more image items in the pre-visit image, whereas post-visit image factors were fewer in numbers and more generic, reflecting a reduction of details in the image after the visit.

Originality/value

This study is one of the very few efforts that contribute empirical evidence for the role of visitation in destination image evolution. It focuses on the pre and post-visit changes in the cognitive image and pre-, during, and post-visit changes in affective and overall images of a tourist destination in Europe.