bluuebunny/crossref_metadata_2025_split huggingface dataset:
NVTG-06 MELANOMA BRAIN METASTASES BENEFIT FROM HIGH PRKCZ LEVELS
Authors: Schöne Lisa , Meinhardt Matthias , Mehnert Marie-Christin , Beissert Stefan , Meier Friedegund , Westphal Dana 
Published: August 2024

Abstract
Despite current therapies being proven effective against metastasized melanoma, durable responses against melanoma brain metastases remain pending. The main reasons are brain-specific resistance mechanisms, which motivate investigations into the underlying differences between intracranial and extracranial metastases. While the mutational status is mainly unaltered, epigenetic regulation is diverging. Based on methylome and transcriptome analyses of 16 matched intra- and extracranial metastases, 38 protein candidates with distinct promoter methylation and corresponding expression were identified. Eight promising candidates were validated by immunohistochemistry and had a significantly higher protein expression in intracranial metastases. (PMID: 36716920) In this study, we want to investigate the role of a likely cancer-promoting candidate, named protein kinase C zeta (PRKCz), which is upregulated in intracranial metastases. We found a wide range of PRKCz gene expression in various established as well as in-house patient-derived melanoma cell lines. Cell lines with either high or moderate PRKCz expression were chosen for further functional investigation. Using siRNA-mediated knockdown, a decreased viability was seen in PRKCz-knockdown cells in crystal violet assays. To test their role in migration, a 2D wound closure scratch assay was developed and revealed a decreased wound-closure capacity in PRKCz-knockdown cells. Further, PRKCz was found to regulate phosphorylated AKT, a component of the cancer-promoting PI3K/AKT signaling pathway, while phosphorylated ERK, a MAPK signaling component, remained unaffected. In summary, we have shown that PRKCz promotes cell viability and migration in melanoma cells. Melanoma brain metastases therefore benefit from high PRKCz levels in comparison to lower levels in extracranial metastases.
RADT-02 PRE-OPERATIVE VERSUS POST-OPERATIVE FRACTIONATED STEREOTACTIC RADIOTHERAPY: A SINGLE-INSTITUTION ANALYSIS OF 534 RESECTED METASTASES
Authors: Perlow Haley , Hennings Sarah , Bradshaw Jared , Reddy Sohil , Luu Sydney , Matsui Jennifer , Klamer Brett , Dibs Khaled , Harrell Marshall , McGregor John , Lonser Russell , Prevedello Daniel , Elder James , Wu Kyle , Prabhu Roshan , Zhu Simeng , Singh Raj , Beyer Sasha , Grecula John , Blakaj Dukagjin , Thomas Evan , Raval Raju , Palmer Joshua 
Published: August 2024

Abstract
Patients with large or symptomatic brain metastases and limited intracranial disease typically have surgery followed by post-operative (post-op) stereotactic radiosurgery (SRS). However, SRS can lead to elevated rates of radiation necrosis (RN), meningeal disease (MD), and local failure (LF). Fractionated treatments can deliver a higher biological effective dose and may reduce the risk of LF, and pre-operative (pre-op) treatments may reduce the risk of RN and MD through treating smaller volumes and tumor sterilization. We hypothesize that pre-op fractionated stereotactic radiation therapy (FSRT) will reduce the incidence rate of RN, MD, and LF when compared to patients who receive post-op FSRT. A retrospective analysis was performed at a single institution and included patients who had surgical resection and radiation to at least one brain metastasis. Patients with multiple metastases resected, either during the same surgery or at different times in the disease course, were eligible for inclusion. Outcomes were evaluated on a per-lesion basis. The primary outcome was a composite endpoint defined by 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. 458 patients with 534 resected brain metastases were eligible for analysis. 235 metastases received pre-op FSRT, and 299 metastases received post-op FSRT. Overall, 15% of patients had multiple brain metastases resected. Overall, 6 (2.6%) pre-op and 13 (4.3%) post-op patients experienced LF. 21 (8.9%) pre-op and 38 (12.7%) post-op patients experienced symptomatic RN. 11 (4.7%) pre-op and 29 (9.7%) post-op patients were diagnosed with MD (p=0.031). 14% and 24% of metastases that received pre-op and post-op FSRT, respectively, experienced the composite endpoint (p=0.005). In our study, pre-op FSRT compares favorably to post-op FSRT primarily due to a 50% reduction in the incidence of MD. Differences in symptomatic RN or LF were small on adjusted analyses. Prospective validation of pre-op FSRT is needed.
RADT-03 PRE-OPERATIVE SINGLE FRACTION VERSUS FRACTIONATED STEREOTACTIC RADIOTHERAPY: A SINGLE-INSTITUTION ANALYSIS OF 299 RESECTED METASTASES
Authors: Perlow Haley , Luu Sydney , Reddy Sohil , Bradshaw Jared , Hennings Sarah , Matsui Jennifer , Klamer Brett , Upadhyay Rituraj , Oliver Alexandria , McGregor John , Lonser Russell , Prevedello Daniel , Elder James , Wu Kyle , Prabhu Roshan , Zhu Simeng , Singh Raj , Beyer Sasha , Grecula John , Blakaj Dukagjin , Thomas Evan , Raval Raju , Palmer Joshua 
Published: August 2024

Abstract
The treatment standard for patients with large or symptomatic brain metastases and limited intracranial disease is surgical resection followed by post-operative (post-op) stereotactic radiosurgery (SRS). The multicenter PROPS-BM cohort showed how pre-operative (pre-op) SRS may lead to a reduced incidence of radiation necrosis (RN), local failure (LF), and meningeal disease (MD) compared to historical controls. Fractionated treatments can deliver a higher biological effective dose and may reduce the incidence of LF and MD. We hypothesize that pre-op fractionated stereotactic radiation therapy (FSRT) will reduce the incidence rate of RN, MD, and LF when compared to patients who receive pre-op SRS. Patients who had surgical resection and pre-operative radiation to at least one brain metastasis at a single institution were retrospectively analyzed. Outcomes were evaluated on a per-lesion basis. The primary outcome was a composite endpoint defined by 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. 260 patients with 299 resected brain metastases were eligible for analysis. 64 metastases received SRS and 235 metastases received FSRT. 38 patients had multiple metastases resected pre-operatively. The median gross tumor volume was 4 ccs for SRS and 10 ccs for FSRT (p&lt;0.001). Overall, 4 (6.3%) SRS and 6 (2.6%) FSRT patients experienced LF. 4 (6%) SRS and 21 (8.9%) FSRT patients experienced Grade 2 or higher RN. 3 (4.7%) SRS and 11 (4.7%) FSRT patients were diagnosed with MD. 14% of both SRS and FSRT patients experienced the composite endpoint. There were no statistically significant differences in outcome between these two treatment groups. In our study, pre-op SRS and FSRT both appear to be safe and effective options to treat resectable brain metastases. It is important to prospectively compare pre-op SRS and FSRT in matched cohorts to assess any differences in treatment efficacy and toxicity.
RMTD-01 PROGNOSTIC SIGNIFICANCE OF STABLE EXTRACRANIAL DISEASE IN PATIENTS WITH INTRACRANIAL METASTATIC DISEASE: INSIGHTS FROM A RETROSPECTIVE POPULATION-BASED STUDY
Authors: Sherman Madison , Li Alyssa Y , Das Sunit 
Published: August 2024

Abstract

BACKGROUND
Intracranial metastatic disease (IMD) is a life-limiting complication of lung cancer, breast cancer, and melanoma. Prior research suggests prolonged survival in patients with stable extracranial disease and IMD (IMD-SE), compared to patients with progressive extracranial disease (IMD-PE). A comprehensive clinical characterization of patients with IMD-SE is lacking. This study aims to investigate clinical characteristics, outcomes, and the impact of patient and treatment factors on survival in patients with IMD-SE vs. IMD-PE.

METHODS
This retrospective cohort study included patients diagnosed with primary lung cancer, breast cancer, or melanoma, and IMD in Ontario, Canada between April 1, 2010, and August 31, 2019. IMD-SE criteria included no extracranial metastases within 2 months of primary cancer diagnosis and ≥2 rounds of systemic therapy, documented in provincial records. Analyses, including Cox regression, Kaplan-Meier, and logistic regression, assessed overall survival (OS) and associations with IMD-SE. Data analysis occurred between September and December 2023.

RESULTS
In our analysis of 15,577 patients, 16.0% had IMD-SE, comprising 50.6% lung cancer, 40.0% breast cancer, and 9.3% melanoma. IMD-SE patients showed longer median OS from primary cancer diagnosis (27.72 months vs. 6.54 months in IMD-PE; p&lt;0.0001) and from IMD diagnosis (4.60 months vs. 1.91 months in IMD-PE; p&lt;0.0001). Receipt of systemic therapy and brain surgery decreased the risk of death in IMD-SE patients (HR &lt;0.8), while lung cancer and cranial radiotherapy increased the risk. IMD-SE status was least associated with lung cancer and most associated with age &lt;65 years, systemic therapy, primary radiation, and ≥2 rounds of cranial radiotherapy.

CONCLUSION AND RELEVANCE
This study provides insights into IMD prognosis, emphasizing the importance of considering extracranial disease progression for survival predictions. Our findings enhance understanding of IMD-SE, guiding refined prognostic assessments and innovative treatments. Future studies should explore additional variables for a comprehensive understanding of factors influencing IMD-SE.
RMTD-04 EXAMINING THE REAL-WORLD CUMULATIVE INCIDENCE OF BRAIN METASTASES IN US MEDICARE ALK+ METASTATIC NON-SMALL CELL LUNG CANCER (MNSCLC) PATIENT POPULATIONS THAT ARE UNDERREPRESENTED IN RANDOMIZED CLINICAL TRIALS
Authors: Abrahami Devin , Sang Angela , Davis Matthew , Marcum Zachary , Rifi Nada , Li Benjamin , Duncan Kirsten , Kelton John , Uprety Dipesh , Bazhenova Lyudmila 
Published: August 2024

Abstract
Brain metastases (BM) are a serious outcome for patients with ALK+ mNSCLC and may occur at diagnosis (baseline) or during disease progression (incident). Gaps in understanding the impact of BM remain, especially in populations that are underrepresented in randomized clinical trials (RCTs). Using a 100% sample of Medicare fee-for-service and Medicare Advantage beneficiaries from 2017-2022, patients &gt;65 years with ALK + mNSCLC (index date = first-line alectinib/brigatinib initiation) were identified. Patient characteristics were compared to pivotal RCTs. BM were assessed as occurring at diagnosis if there was a record in the year prior to the index date (baseline), while BM during progression were observed from the index date forward among those without baseline BM. The incidence of BM by age and racial/ethnic group was estimated using a cumulative incidence function accounting for the competing risk of death within strata of the population. In the study cohort, 988 (95%) and 53 (5%) of patients were initiated on alectinib and brigatinib, respectively, and 290/1041 (28%) and 126/751 (17%) had baseline or incident BM, respectively. In contrast to published RCTs, the median age in this study was 74 years, with 10% of the patients ≥85 years at baseline, and 32% of patients were non-White (Black: 8%, Asian/Pacific Islander: 12%, Hispanic: 8%). After 4 years from the index date, the cumulative incidence of BM was highest in patients ≥85 years (25%), compared to 19% and 18% in patients &lt;75 and 75-84 years, respectively. The cumulative incidence of BM was higher in non-White patients (23%) compared to White patients (17%). This study demonstrated a higher cumulative incidence of BM among US Medicare populations in the real-world setting that are underrepresented in RCTs. More work is needed to ensure adequate representation of patients in RCTs to further inform safety and efficacy data in broader populations.
RMTD-06 TREATMENT PATTERNS AND OUTCOMES OF HR+/HER2- BREAST CANCER WITH BRAIN METASTASES: A SINGLE-CENTER RETROSPECTIVE STUDY
Authors: Wei Zhu Jie , Moravan Veronika , Jerzak Katarzyna 
Published: August 2024

Abstract

BACKGROUND
Approximately 14% of patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) develop BrM during their lifetime, which is associated with a poor prognosis. We sought to assess the treatment patterns and outcomes of patients with HR+/HER2- breast cancer brain metastases (BCBrM).

METHODS
We conducted a single-centre retrospective cohort study of 204 patients (≥18 years of age) diagnosed with HR+/HER- mBC who were treated for BrM at the Sunnybrook Odette Cancer Centre between 2008 and 2018. We used descriptive statistics to summarize patient and treatment characteristics and Kaplan-Meier analyses for survival outcomes. The log-rank test was used to compare outcomes of patients with endocrine sensitive versus endocrine resistant disease.

RESULTS
Among 204 patients with HR+/HER2- BCBrM, the median age at BrM diagnosis was 56 years (range 31 – 93) and the median time between diagnosis of mBC to development of BrM was 15 months (interquartile range [IQR] 3 – 36 months). 135 (66.2%) patients had endocrine resistant disease, 53 (26%) patients had endocrine sensitive disease; endocrine sensitivity was not available for 16 patients (7.8%). The first line of systemic treatment following BrM diagnosis was chemotherapy for 46.1% of patients and endocrine therapy for 28.9% of patients. The median brain-specific (bs) progression-free survival (PFS) was 7 months (95% CI: 5.2 – 9) and median overall survival (OS) was 10 months (95% CI: 8.5 – 13.4). In subgroup analyses, bsPFS (5 months versus 11 months, p&lt;0.001) and OS (7.3 versus 20.7 months, p&lt;0.001) were significantly shorter among patients with endocrine resistant breast cancer than those with endocrine sensitive disease.

CONCLUSIONS
Patients with HR+/HER2- BCBrM have poor outcomes. A substantial proportion of patients with endocrine resistant disease have particularly short bsPFS and OS, highlighting the need for novel systemic treatment approaches with efficacy in the brain.
TRSC-01 STEM CELL THERAPY HAS EFFICACY FOR LEPTOMENINGEAL DISSEMINATION OF DIVERSE TYPES OF SOLID CANCERS
Authors: Kitamura Yohei , Kanaya Nobuhiko , Moleirinho Susana , Tamura Ryota , Ueda Ryo , Sasaki Hikaru , Toda Masahiro , Shah Khalid 
Published: August 2024

Abstract
Leptomeningeal dissemination (LMD), known as carcinomatous meningitis, occurs in approximately 5% of all cancer patients. LMD presents an extremely poor prognosis, with an average life expectancy of 4-6 weeks. While treatments such as whole brain/spinal cord irradiation and intrathecal injection of anticancer drugs are sometimes performed, their effects are limited, which urgently necessitates new therapeutic strategies for LMD. We evaluated the efficacy of a stem cell (SC)-based therapeutic strategy for LMD in various solid cancers based on two primary advantages: (1) LMD is a condition where cancer cells spread within a single closed space without separation, and SCs with cancer tropism and chemotaxis can easily reach these cells; (2) Repeated intrathecal injections of drugs are invasive and risky, but SCs can continuously secrete therapeutic agents into the cerebrospinal cavity after a few injections, increasing local concentrations of these substances. Our findings suggest that treatment using engineered SCs may be an effective option against LMD from breast, lung, and malignant melanoma, which are types of cancer that tend to metastasize to the central nervous system. Specifically, we found that engineered allogeneic SCs simultaneously targeting epidermal growth factor receptor (EGFR) and death receptor (DR) have efficacy for LMD of triple negative breast cancer and non-small cell lung cancer. In addition, twin SCs releasing oncolytic herpes virus, granulocyte-macrophage colony-stimulating factor (GM-CSF), and single-chain variable region fragments (scFv) against programmed death receptor-1 (PD-1) show encouraging results in managing LMD in cases of malignant melanoma. We believe that SC therapy has the potential to become a new therapeutic option for LMD in the future.
TRSC-02 RESPONSE TO PARP INHIBITORS IN PATIENTS WITH BREAST CANCER METASTATIC TO THE CENTRAL NERVOUS SYSTEM
Authors: Grinda Thomas , Lee Seoho , Bansal Rani , Hughes Melissa , Swearingen Amanda Van , Moore Heather , Kamson David , Sahebjam Solmaz , Kirkner Greg , Gorfinkel Anna , Sammons Sarah , Lin Nancy , Anders Carey , Santa-Maria Cesar 
Published: August 2024

Abstract

BACKGROUND
Central nervous system (CNS) metastasis from breast cancer can be challenging to treat due to the limited blood brain barrier penetration of many systemic therapies. The goal of our study is to describe the clinical benefit of PARP inhibitors (PARPi) in patients with breast cancer CNS metastasis.

METHODS
This retrospective case series was conducted at three academic cancer centers (Johns Hopkins, Dana-Farber, and Duke) and included patients with the following criteria: age≥18 years with a breast cancer diagnosis (any subtype); diagnosis of parenchymal brain metastasis or leptomeningeal disease (LMD); and received PARPi for CNS metastasis. Descriptive statistics, Kruskal-Wallis rank sum tests, and Kaplan-Meier analyses were performed.

RESULTS
Although this analysis includes one center’s experience, we will present a combined dataset (N = 45) at the main conference. 11 patients were identified at Johns Hopkins. 4 (36.4%) were Black and 6 (54.5%) were White; 6 (54.5%) had ER+HER2- disease and 5 (45.5%) had TNBC; 5 (45.5%) had BRCA1 mutations and 5 (45.5%) had BRCA2 mutations. Median lines of therapy prior to PARPi was 6 [1 - 11]. On average, patients remained on PARPi for 5 months [0.5 - 66], and overall survival (OS) time from PARPi to death was 16 months [2 - 66]. Duration of PARPi and OS did not differ significantly between ER+HER2- and TNBC (p=0.74 and 0.69) or BRCA 1 and 2 (p=0.78 and 0.72). Black patients had significantly shorter PARPi duration and survival than White patients (PARPi 2 vs. 8 months, p=0.028 and OS 4 vs 18 months, p=0.028). Prior CNS radiation was significantly associated with longer PARPi duration and survival (PARPi 5 vs 1 month, p=0.02 and OS 17 vs. 3 months, p=0.032).

CONCLUSIONS
PARPi are associated with significant clinical benefit in patients with breast cancer CNS metastasis. Larger data series will help confirm these observations.
Tracing Lower Crustal Contamination in Continental Arc Magmas Using Sr–Nd–Hf Isotopes: A Combined In Situ and Bulk Rock Approach Applied to the Adamello Batholith
Authors: Pimenta Silva Manuel , Giuliani Andrea , Schaltegger Urs , Chiaradia Massimo , Nowak Alexandra , Schoene Blair , Ulmer Peter , Müntener Othmar 
Published: August 2024

Abstract
The incremental construction of plutons characterises magmatic activity in arc settings, where new continental crust is produced. This polyphasic growth entails interactions with one or more crustal components, which modulate the geochemical and isotopic compositions of the newly formed crust. However, the early stages of magmatism are not always preserved due to obliteration by later magmatic pulses. Spatial migration of magmatism during the construction of the Adamello batholith (Northern Italy) enables the examination of the early pulses of pluton formation, thus allowing a time-integrated study of the relative importance of crystallisation-differentiation and contamination in a continental arc setting. We conducted a detailed textural, major and trace element and Sr isotopic study of plagioclase from the first intrusive pulses of the Adamello batholith, combined with new major, trace element and Sr–Nd isotopic analyses of bulk rock samples across the entire Adamello batholith. We selected well-characterised samples with published CA-ID-TIMS 206Pb-238U ages and Hf isotopic composition for zircons. Strontium isotopes in plagioclase from the same samples were determined by laser ablation multi-collector ICP-MS. The tonalitic samples in the early magmatic stages show elevated but constant Sr isotopic compositions despite large variations in anorthite contents (An90 to An13), indicating that crustal contamination occurred before significant differentiation. Invariant bulk-rock 87Sr/86Sr with variable SiO2 in all superunits of the Adamello batholith further supports contamination preceding significant melt differentiation. Contamination by lower crustal basement lithologies is due to the increasing thermal anomaly triggered by consecutive magmatic injections coupled with the heterogeneous and less restitic nature of the basement in the early stage of the magmatic system (i.e., before consumption of fusible components). In addition, we observe significant variability in crustal contamination proxies (e.g., 87Sr/86Srplag, 87Sr/86Srbulk, εNdbulk, εHfzircon) during the initial phases of magmatism. This variability likely reflects the uneven distribution of positive thermal anomalies in the lower crust during early magmatic stages as well as the diverse lithological and isotopic makeup of the lower crust. The processes identified in our case study are pertinent to continental arc magmatism, particularly where magmas interact with a metapelitic lower crust.
The Telecommunications Act, 2023: Solidarity Between Democracy and Totalitarianism
Authors: Mehla Akshra , Mehla Lakshay 
Published: August 2024

ABSTRACT
With the coming of a surveillance culture, even minute aspects of human life are being observed, collected, analyzed, and stored by institutions in charge of surveillance. On the other hand, the same does not apply to the institutions which are surveillant of the lives of individuals. Such phenomenon can be observed via various technologies of power prevalent in societies. One such technology of power is legislation passed by the State to access, control, analyze, disseminate, or store the personal information of citizens. This article analyses the Telecommunications Act, 2023 which has been hailed as a move towards decolonization by repealing the former colonial laws over telecom services. The article discusses various attributes of the 2023 Act to analyze the means through which the usage of biometric systems of identification leads to violation of the fundamental right to privacy, as envisaged by the apex court of India in the landmark judgment of Justice K S Puttaswamy (Retd) v Union of India and other judgments before and after. The article also argues how the works of Giorgio Agamben and Didier Bigo on a permanent state of emergency being materialized through surveillance of minute aspects of human life and consequently marks a shift towards totalitarian tendencies of governance.
Investigating Blood Lead Levels and Its Health Effects on Employees of a Petroleum Industry and the Surrounding Residents
Authors: Mohammad Luay M. , Karami Manoochehr , Mehrabi Yadollah , Hashemi Nazari Seyed Saeed , Farhang Dehghan Somayeh , Baiee Hasan A. , Rafiee Mohammed 
Published: August 2024

Objective
This study has been aimed to investigate factors associated with elevated blood lead levels (BLLs) across different percentiles in individuals employed in the petroleum industry and residents of Kirkuk City . In addition, to provide evidence-based approaches to mitigate exposure risks and safeguard vulnerable populations.

Methods
The study involved 357 participants and utilized quantile regression to examine BLL in petroleum industry workers and Kirkuk residents.

Results
Median BLLs were higher among workers (17.5 μg/dL) compared to residents in the city (9.9 μg/dL) and suburbs (7.4 μg/dL). Factors such as smoking, outdoor work, and lower education were associated with elevated BLLs, as confirmed by quantile regression.

Conclusions
This study found higher BLLs in petroleum workers compared to Kirkuk residents, associated with smoking, outdoor work, and lower education. The results emphasize the need for targeted interventions and policies to mitigate lead exposure risks in this industrial region.