bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe case of post cholecystectomy vasculobiliary injury successfully treated by right hepatectomy with a jump graft to the remaining left hepatic lobe
Authors: Marino Carlo , Obaid Ignacio , Ochoa Gabriela , Jarufe Nicolás , Martínez Jorge A , Briceño Eduardo
Published: August 2020

Vasculobiliary injuries (VBI) caused by cholecystectomies are infrequent but extremely serious. We report a case of a severe VBI successfully treated at our center. A 22-year-old woman underwent an open cholecystectomy as treatment for acute cholecystitis and bile duct stones. She was transferred to our center on postoperative Day 4 because of progressive jaundice and encephalopathy. After a proper investigation, we found an extreme VBI with infarction of the right hepatic lobe associated with complete interruption of the portal vein and proper hepatic artery flows and full section of the common hepatic duct. Right hepatectomy with portal—Rex shunt revascularization of the left hepatic lobe and Roux-en-Y hepaticojejunostomy to the left hepatic duct was done. The patient was discharged on the 60th postoperative day.

Discussion: This case shows the successful surgical treatment of a severe cholecystectomy’s VBI, avoiding an emergency liver transplant.
Simultaneous robot-assisted surgery for rectal cancer and prostatic lesions
Authors: Kojima Yutaka , Sakamoto Kazuhiro , Horie Shigeo , Tomiki Yuichi , Kawai Masaya , Okazawa Yu , Tsuchiya Yuki , Kitamura Kosuke , China Toshiyuki
Published: August 2020

Robotic surgery has become prevalent in many departments all over the world because of its usefulness. It is used in many cases, as well as in gastrointestinal surgery, which treats the rectum as pelvic surgery, urology and gynecology. We experienced two cases of joint surgery, with urology as pelvic surgery. The patient underwent robot-assisted low anterior resection, combined prostate resection and ileostomy for prostate invasion of rectal cancer. He was discharged without any complications. Robotic surgery was considered to be useful in surgery to manipulate the same area. In addition, it was considered that smoother and safer surgical procedure could be possible by conducting preoperative meetings with the participating departments.
Appendiceal mucocele: three cases with different clinical presentation and review of literature
Authors: Cestino Luca , Festa Federico , Cavuoti Giuseppe , Bonatti Luca , Soncini Stefania , Dani Luca , Quaglino Francesco
Published: August 2020

Mucinous lesions of appendix are a rare clinical entity and may be neoplastic or non-neoplastic. The diagnosis is usual incidental during computed tomography scan or colonoscopy performed for general abdominal symptoms or occasional finding during operation for acute appendicitis. For this reason, initial treatment should be tailored to the situation, aiming at complete resection of the appendix with disease-free margins: this can be achieved by simple appendectomy or more extensive resection. The pathological examination of the specimen is the key to offer the patient a correct and complete treatment, and, if a neoplastic pathology is found, the case should be discussed in multidisciplinary group. We describe three cases with different clinical presentation leading to different surgical treatment: one elective case, in which the diagnosis was suspected preoperatively; and two urgent cases, one mimicking an intussusception and another one presenting as an acute appendicitis.
̓ΑΡΙΣΤΟΝ ΜEΝ ̔ΥΔΩΡ: Ancient Breakfasts and the Development of Eucharistic Foods
Authors: Stewart Alistair C
Published: August 2020

Although there is evidence for eucharistic celebration in the context of an evening cena in the earliest period, this celebration comes to be transferred to the morning, particularly to Sunday morning. This might bring about significant change in the celebration, part of which might lie in the foods employed, and their quantities. On the basis of an examination of the evidence for daytime eating in Graeco-Roman antiquity, the suggestion is made that eucharistic foods employed in many circles subsequently seen as deviant were standard breakfast foods, and that abstinence from wine reflects this context. Thus the use of water in the eucharist, rather than denoting an ascetic bent in some early Christian circles, simply reflects the transfer of the eucharistic meal from the evening to the morning.
The NAC transcription factor NAC019-A1 is a negative regulator of starch synthesis in wheat developing endosperm
Authors: Liu Yunchuan , Hou Jian , Wang Xiaolu , Li Tian , Majeed Uzma , Hao Chenyang , Zhang Xueyong
Published: August 2020

Starch is a major component of wheat (Triticum aestivum L.) endosperm and is an important part of the human diet. The functions of many starch synthesis genes have been elucidated. However, little is known about their regulatory mechanisms in wheat. Here, we identified a novel NAC transcription factor, TaNAC019-A1 (TraesCS3A02G077900), that negatively regulates starch synthesis in wheat and rice (Oryza sativa L.) endosperms. TaNAC019-A1 was highly expressed in the endosperm of developing grains and encoded a nucleus-localized transcriptional repressor. Overexpression of TaNAC019-A1 in rice and wheat led to significantly reduced starch content, kernel weight, and kernel width. The TaNAC019-A1-overexpression wheat lines had smaller A-type starch granules and fewer B-type starch granules than wild-type. Moreover, TaNAC019-A1 could directly bind to the ‘ACGCAG’ motif in the promoter regions of ADP-glucose pyrophosphorylase small subunit 1 (TaAGPS1-A1, TraesCS7A02G287400) and TaAGPS1-B1 (TraesCS7B02G183300) and repress their expression, thereby inhibiting starch synthesis in wheat endosperm. One haplotype of TaNAC019-B1 (TaNAC019-B1-Hap2, TraesCS3B02G092800) was positively associated with thousand-kernel weight and underwent positive selection during the Chinese wheat breeding process. Our data demonstrate that TaNAC019-A1 is a negative regulator of starch synthesis in wheat endosperm and provide novel insight into wheat yield improvement.
Self-supervised learning with physics-aware neural networks – I. Galaxy model fitting
Authors: Aragon-Calvo M A , Carvajal J C
Published: August 2020

Estimating the parameters of a model describing a set of observations using a neural network is, in general, solved in a supervised way. In cases when we do not have access to the model’s true parameters, this approach can not be applied. Standard unsupervised learning techniques, on the other hand, do not produce meaningful or semantic representations that can be associated with the model’s parameters. Here we introduce a novel self-supervised hybrid network architecture that combines traditional neural network elements with analytic or numerical models, which represent a physical process to be learned by the system. Self-supervised learning is achieved by generating an internal representation equivalent to the parameters of the physical model. This semantic representation is used to evaluate the model and compare it to the input data during training. The semantic autoencoder architecture described here shares the robustness of neural networks while including an explicit model of the data, learns in an unsupervised way, and estimates, by construction, parameters with direct physical interpretation. As an illustrative application, we perform unsupervised learning for 2D model fitting of exponential light profiles and evaluate the performance of the network as a function of network size and noise.
Rotating convective core excites non-radial pulsations to cause rotational modulations in early-type stars
Authors: Lee Umin , Saio Hideyuki
Published: August 2020

We discuss low-frequency g modes excited by resonant couplings with weakly unstable oscillatory convective modes in the rotating convective core in early-type main-sequence stars. Our non-adiabatic pulsation analyses including the effect of Coriolis force for $2\, \mathrm{ M}_\odot$ main-sequence models show that if the convective core rotates slightly faster than the surrounding radiative layers, g modes in the radiative envelope are excited by a resonance coupling. The frequency of the excited g mode in the inertial frame is close to |mΩc| with m and Ωc being the azimuthal order of the g mode and the rotation frequency of the convective core, respectively. These g-mode frequencies are consistent with those of photometric rotational modulations and harmonics observed in many early-type main-sequence stars. In other words, these g modes provide a non-magnetic explanation for the rotational light modulations detected in many early-type main-sequence stars.
04. ASSESSMENT OF EFFICACY AND SAFETY OF OSIMERTINIB FOR PATIENTS WITH INTRACRANIAL METASTATIC DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Erickson Anders , Brastianos Priscilla , Das Sunit
Published: August 2020

INTRODUCTION

Intracranial metastatic disease (IMD) is a serious and life-altering complication for many patients with cancer. Targeted therapy may address limitations of current treatments as an additional agent to achieve intracranial disease control in some patients with IMD. Osimertinib is a mutant epidermal growth factor receptor (EGFR) inhibitor that can penetrate the blood-brain barrier and inhibit tumor cell survival and proliferation in patients with non-small cell lung cancer (NSCLC) with specific EGFR mutations. The purpose of this study is to assess the efficacy and safety of osimertinib in the management of IMD.

METHODS

Studies reporting intracranial outcomes for patients with EGFR-mutant NSCLC and IMD treated with osimertinib were included. Among 271 records identified in MEDLINE and EMBASE, 15 studies fulfilled eligibility criteria. Outcomes were pooled using a random-effects model. Risk of bias was assessed using the Cochrane Risk of Bias tool and modified Newcastle-Ottawa scale. Information extracted included study characteristics, intracranial efficacy measures, and safety measures. Meta-analyses were conducted to pool applicable outcomes.

RESULTS

15 studies reporting on 324 patients were included in the analysis. Combined CNS ORR and CNS DCR were calculated to be 64% (95% CI, 53–76%; n = 195), and 90% (95% CI, 85–93%; n = 246). Risk ratios for CNS ORR and CNS DCR were calculated to be 1.44 (95% CI, 1.06–1.96; n = 52) and 1.13 (95% CI, 0.96–1.33; n = 52). Included studies reported complete intracranial response rates of 7–23%, median best decrease in intracranial lesion size of 40–64%, and grade 3+ adverse event rates of 19–39%.

CONCLUSIONS

Findings reported here support a potential role for osimertinib for patients with EGFR-mutant NSCLC and IMD. Clinical decision-makers would benefit from the inclusion of patients with IMD in future trials to identify factors that predict responses to targeted therapy.
17. MELANOMA BRAIN METASTASIS: PRESENTATION, TREATMENT AND OUTCOMES IN THE AGE OF TARGETED- AND IMMUNO-THERAPIES
Authors: Bander Evan D , Yuan Melissa , Carnevale Joseph A , Reiner Anne S , Panageas Katherine S , Postow Michael A , Tabar Viviane , Moss Nelson S
Published: August 2020

BACKGROUND

Melanoma brain metastasis (MBM) prognosis has historically been dismal. However, breakthroughs in targeted and immunotherapies have improved long-term survival in advanced melanoma. As such, MBM presentation, prognosis and multimodality CNS-directed treatment use were reassessed in this contemporary age of treatment.

METHODS

This retrospective study evaluated patients treated at Memorial Sloan Kettering Cancer Center between 2010–2019 with a diagnosis of melanoma brain metastases (MBM). Kaplan-Meier methodology was used to describe overall survival (OS). Recursive partitioning analysis (RPA) and time-dependent multivariable Cox modeling were used to assess prognostic variables and associate CNS-directed treatments with OS.

RESULTS

Four hundred and twenty-five patients with 2,488 MBM were included. Median OS from MBM diagnosis was 8.9 months (95%CI: 7.9–11.3). RPA demonstrated significantly longer survival in patients diagnosed with MBM between 2015–2019 versus 2010–2014 (13.0 months [95%CI: 10.47–17.06] versus 7.0 months [95%CI: 6.1–8.3]; p=0.0003) and patients with <5 BM versus ≥5 BM (12.49 months [95%CI: 10.52–16.03] versus 5.48 months [95%CI: 4.2–6.8]; p<0.0001). Prognostic multivariable modeling significantly associated shortened OS independently with leptomeningeal dissemination (p<0.0001), >5 BM at diagnosis (p<0.0001), MBM diagnosis year 2010–2014 (p=0.0007), immunotherapy treatment prior to BM diagnosis (p=0.02), and extracranial disease presence (p=0.03). CNS-directed treatment modalities associated with BM number, dominant BM size, presenting symptoms, diagnosis year, and extracranial disease presence. Multivariable analysis demonstrated improved survival for patients that underwent craniotomy (p=0.01).

CONCLUSIONS

MBM prognosis has improved in the period following targeted and immunotherapy introduction, and even within the last 5 years of this study. Improving survival reflects and may influence the willingness to use aggressive multimodality treatment for MBM.
19. PLEKHA5 REGULATES TUMOR GROWTH IN METASTATIC MELANOMA
Authors: Oria Victor , Zhang Hongyi , Zhu Huifang , Deng Gang , Zito Christopher , Rane Chetan , Zhang Shenqi , Weiss Sarah , Tran Thuy , Adeniran Adebowale , Zhang Fanfan , Zhou Jiangbing , Kluger Yuval , Bosenberg Marcus , Kluger Harriet , Jilaveanu Lucia
Published: August 2020

Understanding the mechanisms behind melanoma brain metastasis, a disease that continues to portend a poor prognosis, will lead to the identification and development of novel drug targets. We previously identified PLEKHA5, a gene involved in brain development, as a novel molecule implicated in melanoma brain metastasis. Our aim was to further characterize the function of this protein in brain-tropic melanoma. We established stable loss- and gain-of-function cell lines to explore the underlying mechanisms of PLEKHA5-mediated tumor growth. The effect of PLEKHA5 expression silencing on proliferation and tumor growth was assessed using both in vitro systems and xenograft models of brain-tropic melanomas, respectively. The clinical relevance of PLEKHA5 dysregulation in brain metastasis was also investigated in two unique cohorts of melanoma patients with cerebrotropic disease and included analysis of matched cranial and extra-cranial specimens. Knock-down of PLEKHA5 in brain-tropic melanoma cells negatively regulated cell proliferation by inhibiting G1 to S cell cycle transition. This coincided with up-regulation of PDCD4, p21, and p27, as well as the downregulation of pRb protein, involved in the regulation of cell cycle. Conversely, the ectopic re-expression of PLEKHA5 had an inverse effect. Subcutaneous and direct cranial injections of PLEKHA5 knock-down cells in nude mice significantly inhibited tumor growth, while its overexpression upregulated the growth of tumors. This reduction in tumor growth in vivo might be attributed to decreased phosphorylation of Akt (S473) and mTOR (S2448), key mediators for tumor growth and survival. Our results demonstrate the role of PLEKHA5 as a mediator of melanoma brain metastasis. Our findings highlight the significance of PLEKHA5 as a possible regulator of cell cycle transition via crosstalk with the ubiquitin-proteasome and PI3K/AKT/mTOR signaling pathways, driving the proliferation and growth of brain-tropic melanomas. Our studies suggest that PLEKHA5 targeting should be further investigated for melanoma brain metastasis patient population.
21. A PHASE II TRIAL OF COMPREHENSIVE TREATMENT BASED ON RADIOTHERAPY IN LEPTOMENINGEAL METASTASIS
Authors: Yang Siran , Liu Qingfeng , Xiao Jianping , Zhang Hongmei , Bi Nan , Zhang Ye , Ma Yuchao , Wang Kai , Chen Xuesong , Zhao Ruizhi , Wu Xi , Li Junling , Yi Junlin , Wang Shulian , Wang Yexiong
Published: August 2020

OBJECTIVES

To investigate the efficacy and security prospectively for patients with leptomeningeal metastases (LM) of comprehensive treatment based on radiotherapy.

METHODS

From 2014 to 2017, 93 patients diagnosed with LM admitted to our hospital who underwent whole brain radiotherapy (WBRT) or craniospinal irradiation (CSI) with or without simultaneously boost were enrolled. The dynamic changes of enhanced magnetic resonance imaging, clinical signs and symptoms, cerebrospinal fluid cytology and liquid biopsy detection were recorded. The primary endpoint was overall survival (OS), the secondary endpoints were local control (LC), intracranial progress-free survival (IPFS), brain metastasis specific survival (BMSS) and toxicity.

RESULTS

The major primary diagnosis was non-small cell lung cancer. Subjects received WBRT with boost (40 Gy in 20 fractions (f) for WBRT and 60Gy in 20 f for boost), focal radiation to LM, WBRT and CSI (40 Gy in 20 f or 50Gy in 25 f for WBRT and 36 Gy in 20 f for CSI). 20 patients were found tumor cells and were administrated intrathecal chemotherapy. 63 patients used target therapy. The median follow-up time was 33.8 months. OS/LC/IPFS at 1 year were 62.4%/77.2% and 52.6%, respectively. The median survival time was 15.9 months, and the median brain metastasis-specific survival was 42.2 months. Treatment-related grade 3–4 adverse events were rare and included eight grade 3 hematological toxicity.

CONCLUSION

Reasonable comprehensive treatment including precise radiotherapy, intrathecal chemotherapy and targeted agents were well tolerated and could extend the survival time of LM patients compared with historical controls.
24. LOCAL TUMOR PROGRESSION IS A RISK FACTOR FOR POSTOPERATIVE SEIZURES IN PATIENTS WITH BRAIN METASTASIS
Authors: Grossenbacher Bettina , Moors Selina , Lareida Anna , Roth Patrick , Imbach Lukas , Le Rhun Emilie , Weller Michael , Wolpert Fabian
Published: August 2020

PURPOSE

Brain tumor-related epilepsy (BTRE) occurs in 20–35% of patients with brain metastases (BM) and influences morbidity, mortality as well as quality of life. Several factors associated with seizure risk have been identified, including incomplete resection and supratentorial localization of BM. In primary brain tumors like lower grade glioma, tumor growth is associated with seizures. However, it remains to be elucidated whether this holds also true for patients with BM. METHOD: We identified 295 patients who had been diagnosed with BM between 2004 and 2014 by review of our electronic chart system. Occurrence of new onset of postoperative seizures dependent on BM progression was tested during the clinical course as well as pattern of progression and previously described predictors of postoperative seizures. Chi-square test was used for univariate analysis, a Cox-regression model for multivariate testing.

RESULTS

Postoperative seizures were observed in 49 of 295 patients (16.6%). Supratentorial localization (p=0.043, OR 4.45, 95% CI 1.1–19.3) and incomplete resection (p=0.018, OR 3.68, 95% CI 1.4–10.9), along with intracranial (p=0.038, OR 1.4, 95% CI 1.4–5.8) but not extracranial progression (p=0.729, OR 0.90, 95% CI 0.4–1.7) were confirmed as factors independently associated with postoperative seizures. Furthermore, there was a significantly higher rate of postoperatives seizures in patients with local progression (18 of 84 patients, 21.4 %) compared to those with distant brain progression (12 of 93 patients, 12.9%, p=0.042, Chi-square test).

CONCLUSION

Here we define tumor progression as a risk factor for the development of postoperative seizures in a well defined cohort of BM patients. Extracranial tumor recurrence seems to be not significant for seizure risk. Subgroup analysis indicates that patients with local progression of BM are more prone to seizures than those with new, distant BM lesions. Patients with local tumor recurrence might thus be candidates for primary prophylaxis with antiepileptic drugs.
25. EFFECT OF STEREOTACTIC RADIOSURGERY COMPARED TO WHOLE-BRAIN RADIOTHERAPY FOR LIMITED BRAIN METASTASIS ON LONG TERM COGNITION AND QUALITY OF LIFE: A POOLED ANALYSIS OF NCCTG N107C/CEC.3 AND N0574 (ALLIANCE) RANDOMIZED CLINICAL TRIALS
Authors: Palmer Joshua , Klamer Brett , Ballman Karla , Brown Paul , Cerhan Jane , Anderson Keith , Whitton Anthony , Greenspoon Jeffrey , Chung Caroline , Burri Stuart , Parney Ian , Stieber Volker , Pollock Bruce , Laack Nadia , Ashman Jonathon , Bahary Jean-Paul , Barker Fred , Galanis Evanthia , Asher Anthony , Roberge David
Published: August 2020

PURPOSE

We investigated the long term impact of SRS and WBRT in two large prospective phase III trials.

METHODS

Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of >1 standard deviation from baseline in >2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences in trend over time between groups and the effect of >2 cognitive scores with >2 SD change from baseline were assessed.

RESULTS

88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in >1 and >2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in >3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in >1 CM at every time point. SRS had fewer patients with a 2 SD decline at >2 and >3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p<0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p<0.001).

CONCLUSIONS

We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.
35. EVALUATING CSF CIRCULATING TUMOR DNA IN INTRAPARENCHYMAL BRAIN METASTASIS
Authors: Cheok Stephanie , Narayan Azeet , Arnal-Estape Anna , Patel Abhijit , Nguyen Don , Chiang Veronica
Published: August 2020

INTRODUCTION

Discordant response between brain and systemic metastases occur in patients receiving targeted therapies and repeat tumor profiling of the progressing site could guide further therapy. We propose that circulating tumor DNA (ctDNA) might be detectable in the cerebrospinal fluid (CSF) and reflective of the genetic profile of intraparenchymal brain metastases.

METHODS

Patients with brain metastases undergoing a craniotomy or lumbar puncture were enrolled between July 2018 to April 2019 under an IRB-approved protocol. CSF and blood were collected simultaneously. Cell-free DNA (cfDNA) were extracted and ctDNA were identified and quantified using an Error-Suppressed Deep Sequencing method previously published by our group. Forty-three mutation-prone regions of 24 cancer-associated genes were assayed, and the allelic fractions were calculated against wild-type sequence counts.

RESULTS

Sixteen patients were enrolled in this study - 12 patients with intraparenchymal brain metastases, two patients with CSF cytology-positive leptomeningeal disease (LMD) and 2 patients with normal pressure hydrocephalus (NPH) as controls. Primary cancer types were lung (n=10), melanoma (n=2), renal cell (n=1) and colorectal (n=1) cancers. cfDNA was found in all sixteen samples of CSF. CSF ctDNA were found in eight patients (67%) and plasma ctDNA were only found in five patients (42%) with intraparenchymal tumors. In six patients with additional time-matched brain metastasis tissue, four were found to have congruent mutations in the CSF, while only one harbored such mutation in the plasma.

DISCUSSION

Analysis of CSF can be a viable alternative to obtaining brain metastasis tissue for DNA profiling in the detection of novel and resistance mutations. The presence CSF ctDNA is not restricted to LMD and were isolated from two-thirds of patients with intraparenchymal disease in our cohort. Furthermore, CSF remains a better source than plasma for the detection of ctDNA across multiple brain metastases tumor subtypes.
36. A PROSPECTIVE TRIAL OF RESECTION PLUS SURGICALLY TARGETED RADIATION THERAPY FOR BRAIN METASTASIS
Authors: Brachman David , Nakaji Peter , Smith Kris , Youssef Emad , Thomas Theresa , Pinnaduwage Dilini , Rogers C Leland
Published: August 2020

INTRODUCTION

Achieving durable local control for larger brain metastases remains problematic. Resection (R) alone is typically insufficient. Even with the addition of stereotactic radiation the 12-month recurrence rate for larger lesions (i.e., >2.5–3 cm) is 20% or more in many series. To improve outcomes we designed and prospectively evaluated a permanently implanted radiation device consisting of Cs-131 seeds positioned within a collagen tile (GammaTile, GT Medical Technologies, Tempe AZ). We combined maximum safe resection and collagen tile brachytherapy (CTBT) with the hypothesis that immediate radiation initiation and/or dose intensification could improve outcomes.

MATERIALS/METHODS

From 2013–2018 patients undergoing resection with either previously untreated or recurrent brain metastasis were enrolled on a single arm, multi-histology study (ClinicalTrials.gov, NCT#03088579). At resection completion the tumor bed was lined with collagen tiles imbedded with Cs-131, delivering 60–80 Gy at 5 mm depth. The device was designed to prevent direct source-to-brain contact and to maintain inter-source spacing after closure. No additional local therapy was given unless progression occurred.

RESULTS

16 metastases (12 recurrent/4 previously untreated) in 11 patients were treated. Median diameter 3.1 cm, range 1.9–5.1. Histology was 7 breast, 6 lung, and 3 sarcoma. Median age 60 years; 7 females/4 males. Average time for implantation was 5 minutes. At median radiographic follow-up of 9.5 months (range 0.1–25.2) treatment site progression occurred 1/16 (6%) at 10.9 months. Median treatment site time-to-progression (TTP) has not been reached (95% CI, >10.9 months). Median overall survival (OS) 9.3 months. No surgical adverse events occurred. One patient (6.2%) experienced radiation brain changes and was treated medically.

CONCLUSION

R+CTBT demonstrated excellent safety and local control outcomes in this single-arm pre-commercial study. The device recently received FDA clearance for use in newly diagnosed and recurrent brain metastasis. Randomized clinical trials vs standard of care treatments are expected to open in 2020.
37. IN VIVO FUNCTIONAL GENOMIC SCREEN TO IDENTIFY NOVEL DRIVERS OF LUNG-TO-BRAIN METASTASIS
Authors: Aghaei Nikoo , Lam Fred , Venugopal Chitra , Singh Sheila
Published: August 2020

Brain metastasis, the most common tumour of the central nervous system, occurs in 20–36% of primary cancers. In particular, 40% of patients with non-small cell lung cancer (NSCLC) develop brain metastases, with a dismal survival of approximately 4–11 weeks without treatment, and 16 months with treatment. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). Genomic interrogation of LBM using CRISPR technology can inform preventative therapies targeting genetic vulnerabilities in both primary and metastatic tumours. Loss-of-function studies present limitations in metastasis research, as knocking out genes essential for survival in the primary tumour cells can thwart the metastatic cascade prematurely. However, gene overexpression using CRISPR activation (CRISPRa) has the potential for overcoming dependencies of gene essentiality. We theorize that an in vivo genome-wide CRISPRa screen will identify novel genes that, when overexpressed, drive LBM. We have developed a patient-derived orthotopic murine xenograft model of LBM using primary patient-derived NSCLC cell lines (termed LTX cells) from the Swanton Lab TRACERx study. We are now poised to transduce LTX cells with a human genome-wide CRISPRa single guide RNA (sgRNA) library, and to subsequently inject the cells into the lungs of immunocompromised mice. We will then track the process of LBM using bioluminescent and MRI imaging until mice reach endpoint. Sequencing of primary lung tumours and subsequent brain metastases promises to uncover enriched sgRNAs, which may represent novel drivers of primary lung tumour formation and LBM. To the best of our knowledge, this study is the first in vivo genome-wide CRISPRa screen focused on identifying novel drivers of LBM, and can inform future preventative therapies to improve survival outcomes for NSCLC patients.
40. AN UPDATE ON THE DEVELOPMENT OF A NEW TOOL TO ASSESS RESPONSE IN LEPTOMENINGEAL METASTASIS
Authors: Weller Michael , Le Rhun Emilie
Published: August 2020

In 2016, a standardized scorecard to aid in the evaluation of MRI findings during the course of disease was proposed by the RANO leptomeningeal metastasis (LM) subcommittee. In this scorecard, LM main features and the different CNS metastases types were to be reported as present or absent, dimensions of measurable nodules were to be noted, and changes from the previous MRI were to be scored from -3 to +3. A feasibility and validation study of this scorecard was performed by asking 19 experts to evaluate response in 22 patients diagnosed with and treated for LM. The outcome was disappointing in that the scorecard appeared to be too complicated (Le Rhun et al. Neuro-Oncology 2019;21:648–658). Specific challenges were (i) to understand that the form should be used to rate the current MRI and to compare it with the previous one, (ii) to use the proposed rating with “minus” or “plus” options to assess the change and (iii) to derive a sum score that does not take into consideration (per instruction) changes for the items “hydrocephalus”, “brain metastases” and “parenchymal medullary metastases”. In addition to the apparent challenges for experienced raters to use the LANO scorecard instructions without further instructions, we identified additional weaknesses. These include to eliminate epidural metastases from response assessment, to include the definition of a nodule, the distinction of leptomeningeal versus parenchymal brain disease, and to include parallel, but clearly separate criteria to document brain parenchymal disease. The revised, published proposal for a new scorecard has been used to rate another series of LM cases by experienced neuro-oncologists from March to May 2020. First analyses of this novel feasibility and validation study will be available in August.
42. IDENTIFICATION OF BRAIN METASTASIS VULNERABILITIES USING METPLATFORM
Authors: Zhu Lucía , Yebra Natalia , Retana Diana , Blanco-Aparicio Carmen , Martínez Sonia , Soffietti Riccardo , Bertero Luca , Cassoni Paola , Weiss Tobias , Muñoz Javier , Manuel Sepúlveda Juan , Pérez-Núñez Ángel , Hernández-Laín Aurelio , Toldos Óscar , Caleiras Eduardo , Nör Carolina , Taylor Michael D , Weller Michael , Pastor Joaquín , Valiente Manuel
Published: August 2020

The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. In this study, we report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures). We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. Debio-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from melanoma, lung and breast adenocarcinoma with distinct oncogenomic profiles at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, we have also used METPlatform to perform unbiased proteomics of brain metastases in situ. By applying this analysis to brain metastases treated with the chaperone inhibitor, we uncovered non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.
51. BRAIN METASTASES FROM ENDOMETRIAL CARCINOMA: TUMOR GENETIC ALTERATIONS IN A CASE SERIES AND META-ANALYSIS
Authors: Chapman Emily K , Tsankova Nadejda , Sebra Robert , Germano Isabelle M
Published: August 2020

INTRODUCTION

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the world. While most patients (80%) can be cured with a hysterectomy, the remaining 20% patients who are diagnosed with advanced or recurrent disease have worse survival rates and limited adjuvant treatment options. Discovery of novel target(s)/pathway(s) is needed for better understanding of the pathogenesis and treatment development for this disease. The aim of this study is to review clinical characteristics and genetic signatures of histologically proven EC brain metastasis (BM).

METHODS

For the period 2000–2019 the medical records of patients with histological diagnosis of EC BM at our Institution were reviewed. Data were collected and analyzed for age, time interval between EC and EC BM diagnoses, tumor molecular and genetic signatures, and outcome. Immunohistochemistry and sequencing performed as published. A meta-analysis was also performed for the same time period. Data presented as mean+SD and analyzed by t-test and Chi square.

RESULTS

There were 6 BM from 5 patients meeting our cohort entry criteria and a total 123 cases reported in the literature. The mean age was 57.6 + 11.7 (range 39–69) consistent with reported data. The time interval between EC and EC BM diagnoses was 145.7 + 119.7 (range 33.1–275.7), significantly longer than reported (19.4 + 27.8; range 0–156; p<0.05). All BM in our cohort were metachronous, while only 59% were in the literature. Whereas all FIGO grades are reported in the literature (I=20%; II=6%; III=42%; IV=32%), only I and III were found in our cohort (I=60%, III=40%). Tumor microsatellite instability genes MSH2 and MSH6 were intact, whereas MLH1 and PMS2 showed mutations. PD-L1 expression was low. EC BM genomic reports were not found in the literature.

CONCLUSIONS

Our study provides insight into the genomic alteration burden on EC BM. Information-driven genomic testing will continue to lead patient-centered therapeutic approaches.
53. TUCATINIB VS PLACEBO ADDED TO TRASTUZUMAB AND CAPECITABINE FOR PATIENTS WITH PREVIOUSLY TREATED HER2+ METASTATIC BREAST CANCER (MBC) WITH BRAIN METASTASES (BM) (HER2CLIMB)
Authors: Lin Nancy , Murthy Rashmi , Anders Carey , Borges Virginia , Hurvitz Sara , Loi Sherene , Abramson Vandana , Bedard Philippe , Oliveira Mafalda , Zelnack Amelia , DiGiovanna Michael , Bachelot Thomas , Chien A Jo , O’Regan Ruth , Wardley Andrew , Mueller Volkmar , Carey Lisa , McGoldrick Suzanne , An Xuebei , Winer Eric
Published: August 2020

BACKGROUND

HER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 2019). We report results of exploratory efficacy analyses in pts with brain metastases (BM).

METHODS

All HER2+ MBC pts enrolled had a baseline brain MRI. Pts with BM were eligible and randomized 2:1 to receive tucatinib (TUC) or placebo, in combination with trastuzumab and capecitabine. Efficacy analyses were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR-IC and DOR-IC were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy until second progression, and time from randomization to second progression or death was evaluated.

RESULTS

Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; P<0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of overall death was reduced by 42% in the TUC arm (OS HR: 0.58; P=0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%) vs the control arm (20.0%). Median DOR-IC was 6.8 mo vs 3.0 mo. In pts with isolated brain progression who continued study therapy after local treatment (n=30), risk of second progression or death was reduced by 71% (HR: 0.29), and median time from randomization to second progression or death was 15.9 mo vs 9.7 mo, favoring the TUC arm.

CONCLUSIONS

In pts with previously treated HER2+ MBC with BM, TUC in combination with trastuzumab and capecitabine doubled the ORR-IC, reduced risk of IC progression or death by two-thirds and reduced risk of death by nearly half.
54. tGLI1 IS AN ACTIONABLE THERAPEUTIC TARGET IN BREAST CANCER BRAIN METASTASES
Authors: Doheny Daniel , Sirkisoon Sherona , Rimkus Tadas , Zhu Dongqin , Aguayo Noah , Anguelov Marlyn , Manore Sara , Regua Angelina , Thomas Alexandra , Henson-Masters Adrianna , Strowd Roy , Lo Hui-Wen
Published: August 2020

Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive an average of 6–18 months following diagnosis. Cancer stem cells are thought to be one of the driving forces behind distant metastasis, treatment resistance, and late-stage recurrence. The hedgehog-smoothened pathway has been identified as an important mediator of breast cancer stem cells (BCSC); however, FDA-approved therapies targeting smoothened have demonstrated limited clinical efficacy in breast cancer. Despite advances made in understanding BCSC, it is still challenging to effectively target BCSC underscoring the need to identify and inhibit novel mediators of BCSC for treating BCBM patients. Our laboratory recently reported that truncated glioma-associated oncogene homolog 1 (tGLI1) promotes preferential metastasis to the brain in breast cancer by activating BCSC and astrocytes in the tumor microenvironment (Oncogene 39:64–78, 2020). tGLI1 was discovered in our laboratory as an alternatively spliced GLI1 that functions as a tumor-specific gain-of-function transcription factor and terminal effector of the hedgehog pathway. We found that tGLI1 knockdown abrogated BCBM, providing the rationale to therapeutically target tGLI1. Cell-based chemical screens followed by validations demonstrated that ketoconazole, an FDA-approved azole antifungal, specifically inhibits tGLI1 leading to suppression of BCSC in vitro and BCBM in vivo. Based on these data, we opened a window-of-opportunity study in patients with BCBM to determine if ketoconazole penetrates the blood-brain barrier (BBB) and alters tGLI1 signaling in humans (NCT03796273). Preliminary sample analysis has confirmed tGLI1 expression in collected BCBM samples. To help identify more effective tGLI1 inhibitors, we screened 63 azole compounds for tGLI1-selectivity and identified four additional compounds as potential tGLI1 inhibitors. Animal studies were performed to compare the efficacy of these four compounds with ketoconazole in suppressing BCBM. Collectively, these data establish tGLI1 as an actionable target for BCBM.
56. TUMOR-HOMING STEM CELL THERAPY INHIBITS THE PROGRESSION OF BREAST CANCER LEPTOMENINGEAL CARCINOMATOSIS
Authors: Jiang Wulin , Valdivia Alain , Mercer-Smith Alison , Anders Carey , Hingtgen Shawn
Published: August 2020

INTRODUCTION

Leptomeningeal carcinomatosis remains one of the most lethal forms of central nervous system metastasis, with a median survival of only 4 months. Effective new therapies are urgently needed to treat this highly aggressive cancer. In this study, we used models of both prophylactic and established leptomeningeal disease to investigate the efficacy of engineered tumor-homing neural stem cells (NSCs) therapy for breast cancer leptomeningeal carcinomatosis.

METHODS

Personalized NSC carriers were created using Sox2 overexpression to transdifferentiate human fibroblasts into induced NSCs (iNSCs) that home to cancer cells and carry therapeutic agents to induce tumor kill. Leptomeningeal models were created by engineering MDA-MB231-Br human breast cancer cells with fluorescent and bioluminescent reporters, then using intracisternal injection to inoculate Nude mice with the tumor cells. iNSC therapy was evaluated by infusing iNSCs releasing the pro-apoptotic agent TRAIL into the lateral ventricle of mice either 1 week prior to or 3 days after tumor inoculation for prophylactic or established tumor treatment respectively. Tumor progression in the brain and spinal cord was monitored by serial bioluminescence imaging (BLI).

RESULTS

Serial BLI showed that intracerebroventricular (ICV) iNSC-TRAIL therapy reduced the volume of metastatic tumor burden 99.49% in the brain and 99.80% in the spine within 2 weeks post-infusion and extended survival from 24 to 42 days. Additionally, prophylactic iNSC-TRAIL therapy delivered ICV markedly delayed tumor development, with tumors in the brain remaining >1000-fold smaller than control through 1-month post-treatment, below the limit of detection in the spinal cord through 1 month, and eliminating mortality through 50 days post-therapy.

CONCLUSION

These data suggest that iNSC therapy could be a promising treatment option for breast cancer patients with leptomeningeal carcinomatosis.
66. CLINICAL CHARACTERISTICS AND RESULTS OF PEDIATRIC SOLID TUMORS WITH BRAIN METASTASES: EXPERIENCE FROM A SINGLE REFERRAL CANCER CENTER
Authors: Aguilar Clarissa , Toro Víctor , Medina Rina
Published: August 2020

BACKGROUND

80% of childhood cancer are located in low- and middle-income countries (LMIC). The most common form of presentation is disseminated or metastatic disease. The rate of survival has not been equitable across the world, since in these countries only 1 of 5 children are cured.

OBJECTIVE

To evaluate the clinical and histopathological features of patients with metastatic pediatric solid tumors, in a single referral cancer center in Honduras.

METHODS

We conducted a retrospective review of patients diagnosed with pediatric solid tumors from January 2010 to April 2020. Among the 260 patients through a collection form, we obtained: sociodemographic characteristics, clinical presentation at diagnosis, common histological subtypes, sites of metastasis, treatment and outcome at the time of follow-up.

RESULTS

During the last 10 years, 260 cases of childhood cancer were referred to our center for treatment. 127 patients (48.8%), have a solid tumor, patients ranged in age from 1 to 18 years and distribution for sex were 38% for males and 62% females. At the time of initial diagnosis 40/127 (31%) have advanced disease (stages III and IV). We found brain metastases in 22/40 cases (55%), the primary cancer was localized at CNS in 13/22 (59%) and the most common extracranial tumors causing brain metastases were neuroblastoma (4/22), rhabdomyosarcoma (3/22), retinoblastoma (2/22). Currently in the follow-up there were 18/22 (82%) died and 4/22 (18%) are in treatment with palliative intent.

CONCLUSION

There is a lack of information about the epidemiology of brain metastases among children with solid tumors in the low/middle income countries (LMIC) where the prognosis of metastatic disease is very poor, despite efforts, multimodal therapy and multidisciplinary management, in absence of other options like bone marrow transplantation, and reliable access to high-quality medicines. For our countries, timely diagnosis is still the main determining factor for cure.
74. EFFICACY OF HER2-TARGETED THERAPY IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES: A NATIONAL ANALYSIS
Authors: Hulsbergen Alexander , Broekman Marike , Smith Timothy , Iorgulescu Bryan
Published: August 2020

BACKGROUND

Breast cancer brain metastases (BCBM) commonly develop in human epidermal growth factor 2-positive (HER2+) breast cancer, but BCBM patients are underrepresented in clinical trials, leading to a lack of knowledge on the efficacy of HER2-targeted therapy in this population.

METHODS

We analyzed clinical characteristics and outcomes of HER2+ BCBM patients from the National Cancer Database 2010–2016, comprising 70% of newly-diagnosed cancers in the U.S, to assess overall survival (OS) associated with HER2-targeted monoclonal antibody therapy (HER2-mab; i.e. trastuzumab, pertuzumab, and trastuzumab emtansine; encoded as of 2013). Survival was estimated with Kaplan-Meier techniques and compared with landmark analysis and Cox regression. The landmark timepoint was selected at which 75% of HER2-mab patients received HER2-mab, which was within 58 days of diagnosis.

RESULTS

1,059 HER2+ BCBM patients were identified, 717 (67.7%) patients were estrogen receptor negative (ER-) and 342 (32.3%) were ER+. Median follow-up was 12.0 months, at the end of which 73.8% of patients were deceased. Median OS was 12.2 and 22.1 months for ER- and ER+ patients, respectively. HER2-mab usage for BCBM patients rose from 53.6% in 2013 to 71.7% in 2016. 420 BCBM patients had complete data for landmark analyses: 70.0% (n=294) received HER2-mab and 30.0% (n=126) did not, in which HER2-mab was associated with significantly improved OS in both ER- (median 22.2 months, 95%CI: 18.2–25.4; vs. 9.5 mos, 95%CI: 6.3–10.7; p=0.0001) and ER+ (median 25.7 months, 95%CI: 21.4-not reached; vs. 19.6 months, 95%CI: 11.1–35.2; p=0.02) patients. In multivariable Cox landmark analysis adjusted for ER status, age at diagnosis, extracranial disease, chemotherapy, radiotherapy, and metastasectomy; HER2-mab demonstrated significantly improved OS (hazard ratio 0.59 vs. no HER2-mab, 95%CI: 0.44–0.77; p<0.001).

CONCLUSIONS

In this large, national study, HER2-mab was associated with substantially improved overall survival in BCBM patients.
Effects of dietary macronutrients and body composition on glucose homeostasis in mice
Authors: Hu Sumei , Togo Jacques , Wang Lu , Wu Yingga , Yang Dengbao , Xu Yanchao , Li Li , Li Baoguo , Li Min , Li Jianbo , Wang Guanlin , Zhang Xueying , Niu Chaoqun , Mazidi Mohsen , Douglas Alex , Speakman John R
Published: August 2020

As a major health issue, obesity is linked with elevated risk of type 2 diabetes. However, whether disrupted glucose homeostasis is due to altered body composition alone, or whether dietary macronutrients play an additional role, independent of their impact on body composition, remains unclear. We investigated the associations between macronutrients, body composition, blood hormones and glucose homeostasis. We fed C57BL/6N mice 29 different diets with variable macronutrients for 12 weeks. After 10 weeks, intraperitoneal glucose tolerance tests were performed. Generalized linear models were generated to evaluate the impacts of macronutrients, body composition and blood hormones on glucose homeostasis. The area under the glucose curve (AUC) was strongly associated with body fat mass, but not dietary macronutrients. AUC was significantly associated with fasting insulin levels. Six genes from transcriptomic analysis of epididymal white adipose tissue and subcutaneous white adipose tissue were significantly associated with AUC. These genes may encode secreted proteins that play important previously unanticipated roles in glucose homeostasis.