bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRLS-06. A Phase 1–2 clinical trial of EO1001 (APL-122), a novel irreversible pan-ErbB inhibitor with promising brain penetration
Authors: Frentzas Sophia , Richardson Gary , Bacha Jeffrey , Kanekal Sarath , Sankar Neil , Shen Wang , Redkar Sanjeev , Lai Chinglin , Yu Peony , Nisbet Ian , Skoff Kathy , Wheeler Helen , Pedersen Harry , Zhong Wang Zhen , Brown Dennis 
Published: August 2021

Abstract
CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive cross-talk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models.
We report on a first-in-human Phase 1–2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible.
Materials and methods Escalation: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2–6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. Expansion: EO1001 is administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study.
Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.
LMD-03. Single cell analysis reveals how therapy remodels the tumor microenvironment in melanoma CNS metastases and uncovers a novel predictor of improved survival
Authors: Smalley Inna , Chen Zhihua , Phadke Manali , Li Jiannong , Yu Xiaoqing , Wyatt Clayton , Evernden Brittany , Messina Jane , Sarnaik Amod , Sondak Vernon , Zhang Chaomei , Law Vincent , Tran Nam , Etame Arnold , Macaulay Robert , Eroglu Zaynep , Forsyth Peter , Rodriguez Paulo , Chen Ann , Smalley Keiran 
Published: August 2021

Abstract
We interrogated the microenvironment of 43 clinical samples from melanoma skin, brain (MBM) and leptomeningeal metastases (LMM) using single-cell RNA-seq analysis to determine how therapeutic intervention shaped the immune environment and affected patient survival. LMM is a poorly-characterized, devastating complication of late-stage disease, typically refractory to treatment and associated with dismal survival time. Analysis of serial specimens over the course of therapy demonstrated reductions in melanoma cells and macrophages, coupled with increased levels of T cells and dendritic cells in the CSF of a rare extraordinary responder, whereas typical poor survivors showed no improvement in T cell responses. In MBM patients, both targeted therapy and immunotherapy was associated with increased immune infiltrate. Treatment with targeted therapy was associated with an enrichment of CD8 T cells, while immunotherapy was associated with a more diverse lymphocyte landscape and higher numbers of antibody-producing cells. These findings were confirmed by multiplex-IF staining of patient specimens and using an immune-competent mouse model of MBM. Interestingly, a history of prior radiation therapy was associated with a diminished myeloid compartment. Although immune infiltrate was significantly lower in the brain compared to skin tumors, the phenotypic make-up of the lymphocyte compartment was quite similar, suggesting that the immune cells may have trafficked from the periphery to the brain post-therapy. Correlation analysis across the entire immune landscape identified the presence of a rare, novel population of dendritic cells (DC3s) to be correlated with increased overall survival, regardless of disease site/treatment. The presence of DC3s positively regulated the immune environment of both patient samples and preclinical melanoma models through modulation of activated T cells and MHC expression in the tumor. Overall, we present the first ever comprehensive single-cell atlas of the tumor microenvironment in melanoma CNS metastases in response to therapy.
LMD-11. Pure spinal cord invasion in recurrent classic Hodgkin’s Lymphoma - what is it?
Authors: Awori Violet , Cothern Jordan , Shaikh Nawal 
Published: August 2021

Abstract
We present the case of a 39-year-old male who initially presented in January 2017 with abdominal pain and weight loss. He was eventually diagnosed with stage IVB Classical Hodgkin’s Lymphoma. Brentuximab, Vinblastine, and Dacarbazine regimen was initiated with dose adjustments made due to cardiomyopathy and neuropathy. By cycle 5, good response was evident on systemic imaging. He was then lost to follow-up.
He represented in December 2020 with near paraplegia, preceded by months of tingling, numbness in both legs, gait imbalance and low back pain. MRI spine in January 2021 demonstrated multifocal abnormal cord signal changes with scattered areas of intramedullary cord enhancement as well as extensive enhancement of the cauda equina (Figures 1,2,3). CNS angiitis as a paraneoplastic phenomenon, mimics a similar clinical and radiographic appearance. Unfortunately none of the cord lesions were amenable to biopsy.
Full body PET CT showed florid disease concerning for recurrence. 2 lumbar punctures with limited CSF flow cytometry and cytology analyses were negative. Mediastinal lymph node biopsy revealed Classical Hodgkins Lymphoma. DHAP chemotherapy regimen was initiated, soon after. A 3rd time, high volume comprehensive CSF analysis performed later, was unremarkable. MRI spine, after 2 cycles demonstrated significant improvement(Figures 4,5,6)coinciding with systemic response and clinical improvement. This favored diagnosis of CNS Hodgkin lymphoma over secondary CNS angiitis.
CNS Hodgkin’s Lymphoma is a rare occurrence1, let alone, pure spinal intramedullary and leptomeningeal metastases. Intramedullary metastases arise from direct hematogenous spread or by, centripetal growth of tumor along spinal nerve roots with secondary invasion of spinal cord2. Systemic Hodgkin’s Lymphoma rarely affects the spine with a prevalence of 0.2% - 0.5%3,4. In an analysis of a large cohort of Hodgkin’s patients comprising 14,868 individuals, a prevalence of less than 0.02%, indicating it had been overestimated in the past5.
THER-01. Targeted therapy and intracranial metastatic disease: a population-based retrospective cohort study
Authors: Erickson Anders , Habbous Steven , Wright Frances , Lofters Aisha , Jerzak Katarzyna , Das Sunit 
Published: August 2021

Abstract

Background
Targeted therapies have been hypothesized to prolong survival in the management of patients with intracranial metastatic disease (IMD), but, paradoxically, to increase IMD incidence by improving systemic disease control and prolonging survival from the primary tumor. The real-world benefits of targeted therapy in management of patients with IMD are unclear, as clinical trials have excluded patients with IMD and lacked endpoints reporting intracranial outcomes.

Methods
This retrospective cohort study included all patients in Ontario, Canada, diagnosed with IMD from 2005 to 2018 with primary diagnoses of breast cancer, lung or bronchus cancer, or melanoma, and control patients matched by primary disease without IMD. Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient sub-cohorts divided by primary disease and stratified by targeted therapy receipt or IMD status.

Results
Post-IMD targeted therapy was associated with prolonged OS in patients with HER2-positive breast cancer (HR 0.41; 95% CI, 0.33–0.5), EGFR-positive lung cancer (HR 0.28; 95% CI, 0.23–0.34), and BRAF-positive melanoma (HR 0.2; 95% CI, 0.14–0.29), compared to those who did not receive post-IMD targeted therapy. Presence of IMD was associated with shorter OS in patients with metastatic HER2-positive breast cancer (HR 1.8; 95% CI, 1.56–2.08) and metastatic EGFR-positive lung cancer (HR 1.22; 95% CI, 1.08–1.39) but not metastatic BRAF-positive melanoma (HR 1.11; 95% CI, 0.77–1.61), compared to those without IMD.

Conclusions
Our findings show that real-world use of targeted therapies was associated with prolonged OS in patients with IMD in the setting of HER2-positive breast cancer, EGFR-positive lung cancer, and BRAF-positive melanoma. Inclusion of patients with IMD in clinical trials and use of endpoints that interrogate IMD will be critical to determine the role of targeted therapies in the management of patients with IMD.
OTHR-05. Diagnosis and Treatment of Solitary Pituitary Metastatic Cancer: A Case Series
Authors: Shan Changguo , Hong Weiping , Lai Mingyao , Wang Hui , Wen Lei , Cai Linbo 
Published: August 2021

Abstract

Objective
Metastatic pituitary carcinoma accounted for only 1% of pituitary lesions.

Methods
Patients with isolated pituitary metastatic carcinoma admitted to our hospital from 2014 to 2018 were retrospectively collected, clinical features and prognosis were analyzed.

Results
A total of 5 patients (4 males and 1 female) with a median age of 48 years (21 to 66 years) were included, all with single intracranial pituitary nodules as the initial clinical presentation. The related symptoms were visual impairment (5/5 cases), hypopituitarism (5/5 cases), visual field defect (5/5 cases), headache (4/5 cases), hypothyroidism (4/5 cases), diabetes insipidus (2/5 cases). All the 5 patients received surgical resection (total or partial resection) of tumors in the sellar region via nasal sphenoidal approach. Postoperative pathology confirmed that 4 cases were metastatic adenocarcinoma and 1 case was metastatic squamous carcinoma. Further imaging examinations, such as CT or whole-body PET/CT, confirmed that the primary lesions of all the 5 patients were from the lung. Gene testing indicated that 3 of the 4 adenocarcinoma patients were EGFR mutation positive and 1 of the 4 adenocarcinoma patients was ROS1 mutation positive. Patients received radiotherapy (5/5 cases), targeted therapy (4/5 cases), or chemotherapy (1/5 cases) after surgery. Survival follow-up to May 2019 showed that 4 patients had died, with a survival of 2, August, 28, and 30 months, respectively, and 1 patient was still alive with a survival of 4 months.

Conclusion
The first clinical manifestation of isolated pituitary metastatic carcinoma is nervous system related symptoms, which is easily misdiagnosed. The most of the primary lesions are from lung, especially lung adenocarcinoma with positive driver gene. Surgery, radiotherapy combined with targeted therapy or chemotherapy can provide survival benefits for patients with pituitary metastatic carcinoma.
RADI-06. Gamma knife surgery for brain stem metastases
Authors: Tan Choo Heng , Karlsson Bengt , Wang Shilin , Zhang John J Y , Ang Yvonne , Vellayappan Balamurugan , Teo Kejia , Nga Vincent D W , Lwin Sein , Yeo Tseng Tsai 
Published: August 2021

Abstract

Introduction
Gamma Knife Surgery (GKS) is widely used for treatment of brainstem metastases (BSMs) with or without whole bran radiation therapy (WBRT). We hypothesized that BSMs treated with GKS using lower doses and omitting WBRT result in acceptable tumor control rates and low complication rates.

Methods
A retrospective single center study was performed to investigate the outcome following GKS of BSMs. All 33 patients with follow-up information treated with GKS for 39 metastases located in the cerebral peduncle, midbrain, pons or medulla oblongata were included in the study. The median treatment dose, defined as the lowest dose to 95% of the tumor volume, was 18 Gy. The tumor control rate as well as the survival time were related to a number of patients, tumor and treatment parameters.

Results
The local tumor control rate was 100% at one year and 89% at five years, and the overall median survival was 17 months. A good performance status and a treatable extracranial disease were favorably related to survival time. Two complications were observed, one lethal hemorrhage at the day of the treatment and one transient complication three months following GKS, resulting in a 6% complication rate at five years. Four of the 10 patient with symptomatic BSM improved clinically after GKS, while six remained unchanged.

Conclusions
High local control and a low complication rates can be achieved using GKS for BSMs using lower doses as compared to brain metastases in other locations.
RADI-22. Toxicity and local control outcomes for brain metastases managed with resection and aggressive reirradiation after initial radiosurgery failure
Authors: Bhatia Rohini , Siu Catherine , Baker Brock , Redmond Kristin , Jackson Christopher , Bettegowda Chetan , Lim Michael , Kleinberg Lawrence 
Published: August 2021

Abstract

Objectives
To describe toxicity and tumor outcome after resection and aggressive re-irradiation (stereotactic radiosurgery(SRS) or brachytherapy) of brain metastasis that have pathologically confirmed recurrence after prior radiosurgery.

Methods
A retrospective chart review identified 40 lesions in 35 patients that were initially treated with SRS, then demonstrated evidence of recurrence with pathologic confirmation and underwent re-irradiation either with radiosurgery (n=28, 70%) or intracavitary brachytherapy with Cesium-131 seeds (n=12, 30%). Toxicity was measured by: steroids initiated or increased within 3 months, imaging evidence of treatment effect vs disease progression at any time point, further intervention for local recurrence or necrosis, and any grade 3/4 neurologic events. Local control (with failure defined by sustained progression on imaging or pathologic confirmation of tumor) was measured from time of retreatment.

Results
Median follow-up from time of re-irradiation was 11.8 months (range 1 – 89.7 months). Dose for repeat radiosurgery was 18–25 Gy in 1–5 fractions, and brachytherapy dose was 55–65 Gy at 5 mm depth. Twelve lesions subsequently had imaging evidence of radionecrosis vs. progression. Of these, eight underwent repeat resection with pathology demonstrating radiation necrosis in five patients (n=4 with SRS, n=1 with brachy) and tumor recurrence in 3 (n=2 with brachy, and n=1 with SRS). Toxicities included: Steroids, 14(35%); imaging progression/necrosis 12(30%); grade 3/4 event, 3(20%); and surgically confirmed radionecrosis 5(12.5%). Local control of retreated lesions at 6 months is 85.5%, and at 12 months is 79.3%, OS at 1 year is 52.5% and at 2 years 46.6%. Local control at one year for repeat stereotactic treatment was 82.9% and for Cs131 brachytherapy was 80.8%

Conclusions
Aggressive re-irradiation after resection for pathologic confirmation appears to be appropriately safe and effective for the majority of patients after local failure of initial radiosurgery.
SURG-06. Metastases in the pineal region: a systematic review of clinical features, treatment strategies and survival outcomes
Authors: Palmisciano Paolo , Haider Ali S , Ogasawara Christian , Nwagwu Chibueze D , Wahood Waseem , Sagoo Navraj S , El Ahmadieh Tarek Y 
Published: August 2021

Abstract

Background
Pineal region metastases are rare but often lead to severe neurological deficits. Surgical resection may play a therapeutic role.

Methods
We searched PubMed, EMBASE, Scopus, and Cochrane according to PRISMA guidelines. Studies reporting clinical outcomes data of patients with pineal region metastases were included. Clinical characteristics, management strategies, and survival data were reviewed.

Results
We included 30 studies comprising 46 patients. The median age at diagnosis was 58 years (range 27–82). Lung cancer (30.4%) and carcinomas of unknown origin (15.2%) were the most frequent primary tumors. In 50% of patients, symptomatic pineal metastases preceded primary tumor diagnosis. Headache (66.7%) and confusion (45.2%) were the most common presenting symptoms. Parinaud’s syndrome (47.6%) and hydrocephalus (87%) were commonly noted. Biopsy (67.4%) was preferred over surgical resection (32.6%). The most common CSF diversion protocols were endoscopic third ventriculostomy (45%) and ventriculoperitoneal shunting (27.5%). Eleven patients received adjuvant chemotherapy and 31 underwent radiotherapy. At post-treatment follow-up, symptomatic improvement (55.2%) and hydrocephalus reduction (80%) were described. Post-treatment performance status scores were statistically superior that pre-treatment scores for patients undergoing biopsy (P&lt;0.001) and tumor resection (P=0.007) coupled with adjuvant chemo/radiotherapy. Mean follow-up was 8 months, and median overall survival was 3 months. Only two cases (4.8%) of pineal metastases recurrence were reported, and median progression-free survival was 3 months. In patients receiving adjuvant chemo/radiotherapy, no survival differences were reported between surgery and biopsy (P=0.912), nor between gross-total and subtotal resection (P=0.220). Overall survival was neither correlated with surgical approach (P=0.157), nor with CSF diversion protocol (P=0.822).

Conclusion
Pineal region metastases can severely impair clinical status. Biopsy or surgical resection may significantly improve symptoms and baseline performance status when combined with adjuvant chemo/radiotherapy and CSF diversion.
SURG-11. Surgery for control of brain metastases after prior checkpoint inhibitor immunotherapy: a single-center series
Authors: Morshed Ramin , Chung Jason , Sudhakar Vivek , Cummins Daniel , Young Jacob , Hervey-Jumper Shawn , Theodosopoulos Philip , Aghi Manish 
Published: August 2021

Abstract

Background
Despite the promising results for treating metastatic cancer with checkpoint inhibitor immunotherapies, there are limited data on surgical outcomes for brain metastases (BMs) that have progressed after prior checkpoint inhibitor treatment. The objective of this study was to identify factors associated with local progression, leptomeningeal disease, and survival for patients undergoing surgical resection of a BM in patients previously treated with checkpoint inhibitor immunotherapy.

Methods
A retrospective, single-center cohort study was conducted with inclusion of adult patients undergoing surgical resection of a BM in the setting of progression after prior checkpoint inhibitor treatment. Univariate and multivariate analyses were performed to identify factors associated with outcomes of interest.

Results
Over an 8-year period, 26 patients who underwent resection of 30 BMs met inclusion criteria. Median patient age at surgery was 63.9 years, and median clinical follow-up was 6.9 months (range 0.1 – 52.9). Extracranial disease was present at the time of surgery in 73.3% of cases. There were 6 postoperative complication events (20% of cases) by 30-days. By last follow-up, 65.4% of the cohort had died with a median censored survival of 7.6 months from surgery. Eight patients (30.8%) died within 3 months of surgery. On multivariate analysis, postoperative complications were associated with worse survival (HR 5.33, 95%CI 1.15–24.77, p=0.03). Four BMs had local progression (13.3%), and 60% of procedures were associated with distant progression within a median time of 3.6 months. Leptomeningeal disease developed in 32% of cases. On multivariate analysis, increased time from BM diagnosis to surgery was associated with a greater risk of leptomeningeal disease (OR 1.2, 95%CI 1.00–1.43, p=0.021).

Conclusion
Patients who require BM resection after prior checkpoint inhibitor treatment have an overall poor prognosis. Although local control rates are acceptable, these patients are at high risk for developing leptomeningeal disease postoperatively.
Macrolide Resistance, Clinical Features, and Cytokine Profiles in Taiwanese Children With Mycoplasma pneumoniae Infection
Authors: Wu Tsung-Hua , Wang Nancy M , Liu Fang-Ching , Pan Hui-Hsien , Huang Fang-Liang , Fang Yu-Ping , Chiang Ting-Wei , Yang Yu-Ying , Song Chiah-Sing , Wu Hsiang-Chin , Lee Chun-Yi 
Published: August 2021

Abstract

Background
The factors that predict the progression of Mycoplasma pneumoniae infection remain inconclusive. Therefore, we investigated macrolide resistance prevalence, M pneumoniae genotype, and clinical characteristics of childhood M pneumoniae respiratory tract infections in Taiwan.

Methods
A total of 295 children hospitalized with respiratory tract infections with positive serological M pneumoniae immunoglobulin M test results were enrolled in this 3-year prospective study. Oropharyngeal swabs were obtained for M pneumoniae cultures and polymerase chain reaction tests. All M pneumoniae specimens were further characterized by P1 typing, multilocus variable-number tandem-repeat analysis (MLVA), and macrolide resistance genotyping. The clinical characteristics and blood cytokine profiles were analyzed accordingly.

Results
Of 138 M pneumoniae specimens, type I P1 was the predominant (136 of 138, 98.6%). The MLVA type P (4-4-5-7-2) was the leading strain (42 of 138, 30.4%), followed by type J, U, A, and X. The overall macrolide-resistant rate was 38.4% (53 of 138); the resistance rate increased dramatically yearly: 10.6% in 2017, 47.5% in 2018, and 62.5% in 2019 (P &lt; .001). All macrolide-resistant M pneumoniae (MRMP) harbored the A2063G mutation and were MLVA type 4-5-7-2 (49 of 53, 92.5%), especially type U and X. No significant differences in clinical symptoms, duration of hospital stay, and radiographic findings were identified among patients between MRMP and macrolide-sensitive M pneumoniae (MSMP) groups. Patients with MRMP infection had more febrile days before and during hospitalization and higher interleukin (IL)-13 and IL-33 levels than patients with MSMP infection (P &lt; .05).

Conclusions
Macrolide-resistant M pneumoniae surged in Taiwan throughout the study period, but macrolide resistance was not a determinant factor of clinical severity.