bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural stability and microscale behaviors of the fortress wall from the sixth century Baekje Kingdom in ancient Korea
Authors: Park Jun Hyoung , Park Seok Tae , Lee Chan Hee
Published: June 2021

The Gongsanseong Fortress in Gongju, Republic of Korea, is one of the most essential remains for historical research of Baekje Kingdom, and reinforces on the fortress wall has continuously been implemented since the sixth century to present. Through visual inspections of the fortress ramparts, sections in which structural deformations have occurred, and then they were classified by morphological characteristics based on lithofacies that compose the ramparts, shape of each rock, and construction method. Also, automatic sensors that can measure behavior changes of the ramparts, and the surrounding environment were installed to monitor microscale movements of the ramparts and changes in the surrounding microclimate. As a result, damages were shown intensively on the ramparts that retain specific morphological characteristics, and it has been discovered that, even for the ramparts located in an identical environment, morphological characteristics affect damages and structural deformations of the ramparts because of behavior changes for minutes. Such changes in behavior can be classified based on reversibility and predictability, and different management schemes must be applied based on behavior change patterns. If we continuously operate and develop this monitoring system, it is expected to be meaningfully utilized in efficient maintenance of the cultural heritage of the ramparts.
Radiopharmacokinetic modelling and radiation dose assessment of 223Ra used for treatment of metastatic castration-resistant prostate cancer
Authors: Höllriegl Vera , Petoussi-Henss Nina , Hürkamp Kerstin , Ocampo Ramos Juan Camilo , Li Wei Bo
Published: June 2021

Purpose

Ra-223 dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny to show their radiopharmacokinetic behaviour. Organ absorbed doses after intravenous injection of 223Ra were estimated and compared to clinical data and data of an earlier modelling study.

Methods

The most recent systemic biokinetic model of 223Ra and its progeny, developed by the International Commission on Radiological Protection (ICRP), as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics were assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients,

$$ \overset{\sim }{a}\left({r}_S,{T}_D\right), $$

a
~

r
S

T
D

,

in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned

$$ \overset{\sim }{a}\left({r}_S,{T}_D\right) $$

a
~

r
S

T
D

values.

Results

The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinical trials of other authors. The highest absorbed dose coefficients were found for bone endosteum, liver and red marrow, followed by kidneys and colon.

Conclusion

The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values reported from clinical studies and an earlier compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.
Retraction Note to: Fungal sensing skin
Authors: Adamatzky Andrew , Gandia Antoni , Chiolerio Alessandro
Published: June 2021

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s40694-021-00114-7
Deep brain stimulation of the Cuneiform nucleus for levodopa-resistant freezing of gait in Parkinson’s disease: study protocol for a prospective, pilot trial
Authors: Chang Stephano J. , Cajigas Iahn , Guest James D. , Noga Brian R. , Widerström-Noga Eva , Haq Ihtsham , Fisher Letitia , Luca Corneliu C. , Jagid Jonathan R.
Published: June 2021

Background

Freezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson’s disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG, was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive mesencephalic locomotor region (MLR) preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation.

Methods

We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow-up.

Discussion

This paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target.

Trial registration

ClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020)
Searching for impossible subspace trails and improved impossible differential characteristics for SIMON-like block ciphers
Authors: Wang Xuzi , Wu Baofeng , Hou Lin , Lin Dongdai
Published: June 2021

In this paper, we greatly increase the number of impossible differentials for SIMON and SIMECK by eliminating the 1-bit constraint in input/output difference, which is the precondition to ameliorate the complexity of attacks. We propose an algorithm which can greatly reduce the searching complexity to find such trails efficiently since the search space exponentially expands to find impossible differentials with multiple active bits. There is another situation leading to the contradiction in impossible differentials except for miss-in-the-middle. We show how the contradiction happens and conclude the precondition of it defined as miss-from-the-middle. It makes our results more comprehensive by applying these two approach simultaneously. This paper gives for the first time impossible differential characteristics with multiple active bits for SIMON and SIMECK, leading to a great increase in the number. The results can be verified not only by covering the state-of-art, but also by the MILP model.
Bearing failure in a mobile bearing unicompartmental knee arthroplasty: an uncommon presentation of an implant-specific complication
Authors: Vajapey Sravya P. , Alvarez Paul M. , Chonko Douglas
Published: June 2021

Background

We present two cases of unicompartmental knee arthroplasty (UKA) bearing failure in this report—one case of bearing dislocation and one case of bearing fracture. The causes of failure in both cases are evaluated in depth and recommendations are provided regarding intraoperative technique to reduce risk of bearing failure in mobile bearing UKAs.

Case presentation

In the first case, intraoperative evidence of metallosis and chronic pain preceding the traumatic event may indicate that the patient had attenuation of her collateral ligaments that precipitated the instability event. In the second case, the relatively atraumatic nature of the bearing fracture-dislocation and intraoperative evidence of extensive poly wear suggest that the bearing fracture was likely due to a 3-mm bearing selection in the initial surgery.

Conclusions

This case report shows that late bearing in mobile bearing unicompartmental knee arthroplasty can often be a multifactorial event and treatment must address all the risk factors that led to bearing dislocation. Bearing fracture is a very rare complication associated with mobile bearing UKA and patients with thin polyethylene inserts are at risk for bearing fracture even in the absence of poly wear.
Can intraoperative ultrasound replace the frozen section in the assessment of ex vivo sentinel lymph node biopsy in early breast cancer in countries with limited resources?
Authors: Rahman Rasha Wessam Abdel , Khallaf Emad Salaheldin , Salaheldin Lamia Adel , Hafez Mohamed Nasr , Fayed Mohannad Aly , Soliman Somia Abdulatif Mahmoud
Published: June 2021

Background

Accurate staging and proper management of axillary lymph nodes (ALNs) in breast cancer patients are important for treatment. Surgical management of the axilla has evolved greatly in the last 20 years. Sentinel lymph node biopsy (SLNB), which was first investigated in the early 1990s, has replaced routine axillary lymph node dissection. This study evaluates the capability of using an ultrasound (US) as an alternative tool for the frozen section in the assessment of the ex vivo sentinel lymph node biopsy in countries with limited resources.

Results

The study is a prospective study that included 216 female patients with early breast cancer and negative axillary lymph nodes. All excised lymph nodes were examined by the intraoperative US and frozen section examinations. All the results were correlated with the final histopathological results. The number of negative nodes by US, frozen, and paraffin section examination was 58.30%, 69.40%, and 69.40%, respectively. The number of positive nodes by the US, frozen, and paraffin section examinations was 41.70%, 30.60%, and 30.60% respectively. The sensitivity, specificity, PPV, NPV, and accuracy of US in the detection of positive lymph nodes were 95.45%, 82%, 70%, 97.62%, and 86.11%, respectively, and the sensitivity, specificity, PPV, NPV, and accuracy of frozen examination in the detection of positive lymph nodes were 90.91%, 96%, 90.91%, 96%, and 94.44%, respectively.

Conclusion

Intraoperative US is a good negative test in the assessment of ex vivo SLNB, but it is not a good positive test, so it cannot replace the intraoperative frozen section in the assessment of SLNs.
Can diffusion and T2 star-weighted magnetic resonance imaging aid in the diagnosis of ectopic endometrium?
Authors: Raafat Mariam , Talaat Soha H. , Abdelghaffar Salma M. , Ali Engy A.
Published: June 2021

Background

Endometriosis is a common gynecologic disorder characterized by the implantation of the endometrial tissue ectopically outside the endometrial cavity. It affects about 10% of females at the childbearing period and is estimated to be present up to 20–50% in women complaining of infertility. While laparoscopy is considered the mainstay for diagnosis, magnetic resonance imaging (MRI) is recognized as a useful tool for definitive diagnosis, pre-surgical planning, and determining whether the patient will require multi-specialty involvement. The aim of this study is to evaluate the performance of MRI with the addition of diffusion-weighted imaging (DWI) and T2 star (T2*) to conventional MRI, for the accurate assessment of ectopic endometrium.

Results

Endometriotic lesions that showed diffusion restriction on DWI were 80.7%, and 96.1% of the endometriotic lesions had signal voids on the T2*W sequence, whereas only 65.4% of the lesions had typical signal intensities on T1WI and T2WI. Diagnostic performance of the MRI examination was improved by the use of the diffusion sequence and better improved by the T2* sequence, compared to the conventional MR protocol sensitivity (SE) = 96.12% and specificity (SP) = 85.7% in T2*-weighted images, SE = 80.7% and SP = 71.4% in DWI, and SE = 65.4% and SP = 71.4% in conventional MRI. P value for conventional MRI was 0.1, which is of no statistical significance (p < 0.05). P value for DWI was 0.016, which is statistically significant (p < 0.05). P value for T2*WI was 0.001, which is more statistically significant (p < 0.05) and could be adequately correlated with laparoscopy.

Conclusion

DWI and T2* significantly increase MRI diagnostic accuracy by allowing the detection of the hemorrhagic character of the endometriotic lesions. Studies with a large sample size are needed to confirm that they can replace invasive laparoscopy for the diagnosis of endometriosis.
Donor-derived CD7 CAR T cells for T-cell acute lymphoblastic leukemia.
Authors: Pan Jing , Pan Jing , Deng Biping , Ling Zhuojun , Song Weiliang , Xu Jinlong , Duan Jiajia , Wang Zelin , Chang Alex , Feng Xiaoming
Published: June 2021

10001

Background: Despite the success of chimeric antigen receptor T cell therapy in B cell malignances, there is currently no proved CAR T treatment for T cell neoplasms. We provide first evidence support the use of donor derived CAR T cells in T cell leukemia. Methods: In this phase 1 trial, CD7 CAR T cells were manufactured with T cells from prior SCT prior to a single infusion at doses of 5 × 105 or 1 × 106 (± 30%) cells per kilogram of body weight. donors, or from new donors who were HLA-matched or haploidentical, via leukopheresis and transduced with a lentiviral vector which carries a CD7 CAR construct. The primary endpoint was safety. Short-term efficacy was also assessed. Results: Results of 20 enrolled patients who received infusion are reported. Of 20 patients, 12 received previous HSCT-donor derived CAR T cells and 8 received fresh haplo-identical donor derived CAR T cells and plan to received transplantation as consolidation after remission.Adverse events included grade 3-4 hematologic toxicity in all (100%), grade 3-4 and grade 1-2 cytokine release syndrome in 2 (10%) and in 18 (90%), grade 1 neurotoxicity in 3 (15%), grade 1-2 graft-versus-host disease in 12 (60%), and grade 1 viral activation in 3 (15%) patients. Nineteen (95%) patients had a response, including 18 (90%) with complete remission and 1 (5%) with partial remission. Of 19 responders, 7 were bridged to SCT and remained minimal residual disease (MRD)-negative until last visit; 12 were followed up at a medium of 4.4 months, among whom 9 remained MRD-negative, 1 had a relapse, 1 discontinued for other treatment, and 1 died of pulmonary fungal infection at 5.5 months. CAR cells mostly persisted beyond 3 months. Patient CD7-positive healthy T cells were depleted, while CD7-negative T cells increased. Conclusions: We report the initial toxicity profile and anti-leukemia activity of a donor-derived CD7-targeted cellular immunotherapy for patients with relapsed or refractory T-ALL. (Funded by the National Key R&D program; ChiCTR.org number, ChiCTR2000034762). Clinical trial information: ChiCTR2000034762. [Table: see text]
Pilot study of nivolumab in pediatric patients with hypermutant cancers.
Authors: Morgenstern Daniel A. , Collins Natalie Bucheimer , Deyell Rebecca , Dvir Rina , Edwards Melissa , Faure-Conter Cecile , Hassall Timothy E. , Sambira Lauren , Taylor Emily L. , Tabori Uri , Bouffet Eric
Published: June 2021

10011

Background: Responses to immune checkpoint inhibitors (ICI) in unselected pediatric solid tumors have been disappointing. We hypothesized that pediatric cancers with an increased tumor mutation burden (TMB) and/or replication repair deficiency (RRD) may be uniquely susceptible to ICI therapy. Methods: OZM-075 (NCT2992964) is a multicenter pilot study in patients (pts) aged 1-25 yrs with relapsed/refractory cancers (including CNS tumors). Pts were eligible only if tumor showed evidence of RRD (based on immunohistochemistry showing loss of expression of relevant RR protein) or elevated TMB > 5mut/Mb determined by gene panel DNA sequencing. Pts with measurable or evaluable disease were eligible. Enrolment began in May 2017 and was completed in Nov 2020. Pts received programmed death-1 (PD-1) inhibitor nivolumab (NIVO) at a fixed dose of 3mg/kg every 2 weeks. Primary objective was objective response rate (ORR) by iRECIST or iRANO for those with measurable disease. Tumor tissue and serial blood samples were collected for analysis of biomarkers of response and survival. Results: As of 26Jan2021, 6 male and 5 female patients aged 9-18 yrs received treatment with NIVO (5 glioblastoma (GBM), 2 anaplastic astrocytoma (AA), 2 neuroblastoma, 1 colorectal adenocarcinoma (CRC), 1 adrenocortical carcinoma). 3pts had TMB 5-10mut/Mb, 5pts had TMB > 10mut/Mb (range 14-837, median 64), 3 pts enrolled on basis of RRD. Time on treatment ranged from 0-21 months and 2 pts remain on therapy. Best OR was partial response (PR) in 2 pts (both GBM), with an additional patient with CRC achieving pathological CR. Remarkably one of the pts with PR showed early evidence of progression on imaging and elected to discontinue NIVO. Without further therapy, subsequent imaging 7 months later showed PR. Best response of stable disease was demonstrated in 5 further pts, lasting ≥5 months in 3 pts. Median overall survival (OS) not reached. Of 7 patients with relapsed GBM/AA, 5 were alive for ≥12 months following start of NIVO including 4 pts with confirmed TMB > 10mut/Mb. Conclusions: This pilot study showed evidence of impressive clinical benefit particularly for relapsed GBM/AA patients for whom median survival is typically ̃6 months (JCO 1995 13(1):112-). These data contrast previous pediatric data and suggest that in the context of RRD and hypermutation ICI therapy may provide profound long-term response and survival for these children. Analysis of other correlative biomarkers is ongoing. Clinical trial information: 2992964.
Naxitamab and GM-CSF for consolidation of high-risk neuroblastoma (HR-NB) patients in complete remission.
Authors: Mora Jaume , Castañeda Alicia , Perez-Jaume Sara , Gorostegui Maite , Santa-María Vicente , Muñoz Juan Pablo , Varo Amalia , Mañe Salvador
Published: June 2021

10021

Background: Naxitamab was recently approved in the US in combination with GM-CSF for the treatment of patients (pts) with relapse/refractory HR-NB in the bone/bone marrow who have demonstrated a partial response (PR), minor response (MR), or stable disease (SD) to prior therapy. Here we describe the use of 5 cycles of naxitamab and GM-CSF through compassionate use for consolidation of HR-NB pts in first or subsequent complete remission (CR). Methods: HR-NB pts in CR (first or subsequent) after initial multimodal induction treatment were eligible. Disease status was assessed at study entry by histology of BM biopsies/aspirates obtained from bilateral posterior and bilateral anterior iliac crests, I-MIBG SPECT scan, and whole body MRI. FDG-PET was used for MIBG non-avid cases at diagnosis. Quantitative reverse transcription-polymerase chain reaction was used to assess MRD in pooled heparinized BM aspirates. Disease response was defined according to the revised INRC. Four BM aspirates and 123I-MIBG SPECT scan or FDG-PET scans were performed after cycles 2 and 5 and every 3 months thereafter for one year in all pts to assess response. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3.0 mg/kg/infusion (9.0 mg/kg/cycle) in combination with GM-CSF at 250 ug/m2/day on Days -4 to 0 and at 500 ug/m2/day on days 1 to 5. Treatment cycles were repeated every 4 weeks. Survival curves were built from the time of naxitamab treatment initiation by Kaplan-Meier methods and compared using the log-rank test. Results: From June 2017 to November 30 2020, 73 pts were treated: 55 (75%) in first CR and 18 (25%) in second or more CR. Majority of pts were MYCN non-amplified (n=56, 77%), all stage 4, median age at treatment initiation 4.5 years. 61 (84%) pts had received >5 cycles of induction chemotherapy; 22 (30%) high-dose chemotherapy and autologous stem cell transplant (ASCT); and 36 (49%) radiotherapy before receiving naxitamab. 58 (79.5%) pts completed naxitamab therapy, 53 (73%) in continued CR. 10 (14%) pts relapsed during treatment and 5 (7%) had grade 4 toxicities: 2 apnea related to naxitamab; and 2 non-related: 1 opioid related chest rigidity syndrome and 1 stroke. 3-y event-free-survival (EFS) for all pts is 58% [95% CI, 43.5; 78.4], 74% for first CR and 19% for second or more CR (p=0.0029). 3-y OS for the whole group is 82% [95% CI, 66.8; 100.0], 92% for first CR and 66% for second or more CR pts (p=0.18). Univariate Cox models for CR group, MYCN status, number of chemotherapies, ASCT, radiotherapy, MRD, and age showed significant p value only for prior relapse as predictor of EFS (p=0.047). Conclusions: Naxitamab for HR-NB pts in CR provided excellent 3-y OS rates regardless of previous management. The only predictor for relapse is prior history of recurrence.
Trastuzumab plus endocrine therapy or chemotherapy as first-line treatment for metastatic breast cancer with hormone receptor-positive and HER2-positive: The sysucc-002 randomized clinical trial.
Authors: Yuan Zhongyu , Huang Jia-Jia , Hua Xin , Zhao Jian-Li , Lin Ying , Zhang Yuan-Qi , Wu Zhiyong , Zhang Lehong , Bi XiWen , Xia Wen , Zhong Yong-yi , Wang Shu-Sen , Xu Fei , Hong Ruoxi , Jiang Kuikui , Shi Yanxia , Xue Cong , An Xin
Published: June 2021

1003

Background: For metastatic breast cancer with hormone receptor-positive and HER2-positive, no evidence showed that which first-line regimens were preferred, either anti-HER2 therapy plus endocrine therapy or anti-HER2 therapy plus chemotherapy. This study aimed to determine whether trastuzumab plus endocrine therapy is as efficacious as trastuzumab plus chemotherapy and with decreased toxic effects. Methods: We conducted an open-label, non-inferiority, phase 3, randomized, controlled trial at nine hospitals in China. Patients with hormone receptor-positive and HER2-positive histologically confirmed advanced breast cancer were randomly assigned (1:1) to receive trastuzumab plus chemotherapy (CT group) or endocrine therapy (ET group). The primary endpoint was progression-free survival with a non-inferiority upper margin of 1.35 for the hazard ratio (HR). This trial is registered with ClinicalTrials.gov, number NCT01950182. Results: Between Sep 16, 2013, and Dec 28, 2019, 392 patients were enrolled and randomly assigned to receive trastuzumab plus endocrine therapy (n = 196) or trastuzumab plus chemotherapy (n = 196). In the intention-to-treat population, the median PFS was 14.8 months (95% CI 12.8-16.8) in the CT group and 19.2 months (95% CI 16.7-21.7) in the ET group (HR 0.88, 95% CI 0.71-1.09; Pnon-inferiority < 0.0001). Significantly higher frequency of toxicities were observed in CT group compared with ET group, including: leucopenia (98 [50%] vs 13 [6.6%]), nausea (93 [47%] vs 24 [12%]), fatigue (47 [24%] vs 31 [16%]), vomiting (45 [23%] vs 12 [6%]), headache (65 [33%] vs 24 [12%]) and alopecia (125 [64%] vs 8 [4%]). No patients died from treatment-related causes. Conclusions: Trastuzumab plus endocrine therapy was non-inferior to and had decreased toxicities to trastuzumab plus chemotherapy in patients with metastatic breast cancer with hormone receptor-positive and HER2-positive. Trastuzumab plus endocrine therapy could provide more convenient treatment and allow better treatment tolerance. Clinical trial information: NCT01950182 .
Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer.
Authors: Tiu-lim Justin Wayne Wong , Yin Jun , Xiu Joanne , Korn Wolfgang Michael , Lenz Heinz-Josef , In Gino Kim , Roussos Torres Evanthia T. , Lu Janice M. , Spicer Darcy V. , Xia Bing , Hoon Dave S. B. , Krill-Jackson Elisa , Heeke Arielle Lutterman , Sammons Sarah , Isaacs Claudine , Ademuyiwa Foluso Olabisi , Ma Cynthia X. , Tan Antoinette R. , Kang Irene
Published: June 2021

1034

Background: The Ras-MAPK pathway is a known driver of tumorigenesis and therapeutic target in a variety of cancers. Alterations in this pathway have been linked to decreased tumor immunogenicity. However, molecular alterations in the Ras-MAPK are rare in breast cancer (BC) and their clinical implications remain unclear. As mutational status does not accurately correlate with transcriptional activity, a MAPK pathway activity score (MPAS, Wagle et al., 2018, npj Precision Medicine) is indicative of MAPK activation and correlates with response to MEK (MEKi) or BRAF inhibition (BRAFi). Our goal was to determine the frequency of molecular alterations in the Ras-MAPK and correlate to MAPK pathway activation in MBC. Methods: A total of 6464 BC samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq; whole exome sequencing, NovaSEQ), RNA (NovaSeq, whole transcriptome sequencing, WTS) and IHC. MPAS and immune cell fraction (ICF, Quantiseq) were assessed by mRNA analysis. Wilcoxon, Fisher’s exact, or Dunnett’s test was used. All results shown were statistically significant (p < 0.05). Results: The predominant alteration of RAS genes was mutation followed by amplification, no fusions were detected (Table). Only 0.17% of all tumors harbor KRAS G12c mutations. The highest MPAS scores were found in KRAS mutants (mut), HRAS mut (Q61, G1213), BRAF V600 (class 1) mut and NRAS Q61 mut (Table) and therefore used to define Genomic MAPK Activated Tumors (GMAT). GMAT compared to wild type (WT) had significantly higher PD-L1 expression, TMB and MSI/dMMR. GMAT had less B cells (3.4% vs 4.4%), more M1 Macrophages (4.4% vs 3.4%) and neutrophils (5.5% vs 2.7%) regardless of HR status but less NK cells (2.3% s 3.0%), MSDCs (0.9% vs 3.0%) only in HR- tumors with respect to WT. GMAT tumors showed more frequent mutation rate (mr) of PIK3CA (HR+: 57.3% vs 40%; HR-: 41.9% vs 17.9%). HR+ tumors had a higher mr of MSH3 (11.8% vs 0.6%) while HR- tumors had higher mr of PIK3R1 (9.6% vs 3.8%), RhoA (5.3% vs 0.5%), DNA repair genes (TERT, 18.2% vs 1.0%; ARID1A, 18.2% vs 5.9%; PRKDC, 3.9% vs 0) and lower TP53 mr (54.5% vs 85.8%) compared to WT. Conclusions: Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi. GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.[Table: see text]
Pyrotinib plus capecitabine for HER2-positive metastatic breast cancer patients with brain metastases (PERMEATE): A multicenter, single-arm phase II study.
Authors: Yan Min , Ouyang Quchang , Sun Tao , Niu Limin , Yang Jin , Li Li , Song Yuhua , Hao Chunfang , Chen Zhanhong
Published: June 2021

1037

Background: HER2-positive metastatic breast cancer (BC) has a high risk of brain metastases (BM), leading to poor survival. Small molecule tyrosine kinase inhibitor (TKI) with enhanced penetrability to the blood brain barrier combined with capecitabine have demonstrated promising clinical outcomes in HER2-positive metastatic BC patients with untreated (such as lapatinib) or previously treated (such as neratinib) BM. The randomized phase III PHOEBE trial has proved better efficacy of pyrotinib, an irreversible pan-HER receptor TKI, versus lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic BC. This study was conducted to investigate the efficacy and safety of pyrotinib plus capecitabine in HER2-positive metastatic BC patients with BM. Methods: In this multicenter phase II trial (NCT03691051), eligible patients received pyrotinib 400 mg orally once daily without breaks and capecitabine 1000 mg/m2 orally twice daily for 14 days followed by 7 days off. Treatment was continued until disease progression or intolerable toxicity. Prior HER2 TKIs were not allowed. Cohort A included patients with radiotherapy-naive BM, and cohort B included those with progressive BM after whole brain radiotherapy or stereotactic conformal radiotherapy. The primary endpoint was confirmed central nervous system (CNS) objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. Results: Between January 2018 and July 2020, a total of 78 female patients were included (Table). For cohort A (n = 59), the CNS ORR was 74.6% (95%CI: 61.6%-85.0%). For cohort B (n = 19), the CNS ORR was 42.1% (95%CI: 20.3%-66.5%). By the cutoff date on 25 January 2021, the median progression-free survival was 12.1 months (95%CI: 9.0-14.7) in cohort A and 5.6 months (95%CI: 3.4-10.7) in cohort B. The most common grade ≥3 adverse events were diarrhea (23.1% [18/78]), neutrophil count decreased (12.8% [10/78]), white blood cell count decreased (12.8% [10/78]), anemia (9.0% [7/78]), hand-foot syndrome (7.7% [6/78]), hypertriglyceridemia (6.4% [5/78]), and hypokalemia (5.1% [4/78]). Conclusions: Pyrotinib plus capecitabine resulted as an effective and safe treatment for HER2-positive BC patients with radiotherapy-naive BM, but the efficacy was modest in those with radiotherapy-treated BM. Clinical trial information: NCT03691051 .[Table: see text]
Mismatch repair gene alteration subtypes impact age of onset of mismatch repair-deficient cancers.
Authors: Wang Aifen , Hu Weidong , Feng Ninghan , Yin Yong , Pei Zhe
Published: June 2021

10521

Background: This study investigated whether mismatch repair (MMR) gene alterations and alteration subtypes impacted age at onset of MMR-deficient cancers. Methods: A retrospective study of association of MMR-deficient alterations and age of onset of MMR-deficient lung, breast, prostate, bladder, colorectal, endometrial, and/or ovarian cancers was conducted by using cBIPORTAL dataset. Results: A total of 815 participants with MMR-deficient alterations were enrolled, 346 males and 469 females (median age 63 years; age range, 20-90 years). Males were diagnosed as colorectal and bladder cancer at later ages than females. When stratified by alteration type, individuals with MSH6 or PMS2 missense alterations had later ages of onset of colorectal cancer than those with no missense alterations. Participants with MSH2 AMP alterations were older at the diagnosis of endometrial cancer than those without MSH2 AMP alterations. Females with MLH1 missense alterations had later ages of onset of ovarian cancer than those with no missense alterations. Individuals with PMS2 AMP alterations were confirmed with lung cancer at later ages than those with no PMS2 AMP alterations. Carriers with MSH6or PMS2 missense alterations were older at the time of diagnosis of prostate cancer than those with no missense alterations. Conclusions: Gene alterations and subtype of alterations could stratify carriers with MMR-deficiency in bespoke surveillance. The mechanism of the association of MMR-deficient alterations and alteration subtypes and age at the diagnosis of MMR-deficient cancers needs to be further study.[Table: see text]
Germline alterations among Hispanic men with prostate cancer.
Authors: Shaya Justin , Nielsen Sarah M. , Hatchell Kathryn E. , Esplin Edward D. , Nussbaum Robert Luke , Weise Nicole , Madlensky Lisa , Murphy James Don , Martinez Elena , McKay Rana R.
Published: June 2021

10534

Background: With the growing indications for germline testing in prostate cancer (PCa), there is accumulating evidence that African American and Hispanic men with PCa are significantly under-tested compared to non-Hispanic white (NHW) men. Given this, little is known about the pathogenic germline variant landscape in Hispanic men with PCa. Methods: This was a retrospective cohort analysis of 17,256 men with PCa who underwent diagnostic germline testing through a commercial laboratory (Invitae) from 2015-2020. Self-identified Hispanic and NHW men were selected for comparative analysis. The primary endpoint was the rate of pathogenic/likely pathogenic (PLP) germline alterations in Hispanic men among 25 genes associated with PCa. Secondary endpoints included comparison of PLP rates in Hispanic vs NHW men, the rate of specific PLP alterations, and the rate of variants of uncertain significance (VUS). Fisher’s exact test was used to compare germline alteration rates for significance. Results: We identified 508 Hispanic and 12,542 NHW men with PCa who underwent testing during the study period. Median age at the time of testing was 69 vs 67 years in Hispanic vs NHW cohorts. A family history of PCa was reported in 21.1% (N=108) vs 27.3% (N=3428) in the Hispanic vs NHW cohorts, respectively (p=0.002). The PLP alteration rate was 7.1% in the Hispanic cohort and this rate was numerically lower but not significantly different when compared to the NHW cohort (9.7%) (p=0.058). A significantly higher rate of VUS was seen in the Hispanic cohort (Table). The four most frequently detected genes with PLP alterations in both cohorts were ATM, BRCA1, BRCA2, and CHEK2. Only the rate of CHEK2 alterations was significantly different between cohorts among all 25 genes analyzed (Table). Conclusions: In this analysis, the PLP alteration rate among Hispanic men was 7.1%, a much higher rate than has been previously reported, and the germline genomic landscape was similar to that of NHW men. The VUS rate was significantly higher among Hispanic men, a known consequence of under-testing among minority populations.These data support germline testing in Hispanic men with prostate cancer and emphasize the importance of improving testing rates.[Table: see text]
Impact of the sessile serrated polyp pathway on predicted colorectal cancer outcomes in the CRC-AIM model.
Authors: Kisiel John B. , Itzkowitz Steven H. , Ozbay A. Burak , Saoud Leila , Parton Marcus , Lieberman David A. , Limburg Paul J.
Published: June 2021

10545

Background: Approximately 20–30% of colorectal cancers (CRC) arise from the serrated polyp pathway. The multitarget stool DNA (mt-sDNA) test has greater sensitivity to detect sessile serrated polyps (SSPs) than a leading fecal immunochemical test (FIT). However, most modeling analyses do not account for the contribution of the SSP pathway to risk of CRC. We used the CRC-AIM model to assess the impact of the SSP pathway on predicted CRC outcomes with mt-sDNA or FIT screening. Methods: A simulated cohort of average-risk US patients underwent triennial mt-sDNA or annual FIT screening from ages 50–75. The percentage of CRCs arising from the SSP pathway were modeled at 0% (base case), 20%, and 30%, with stool screening adherence based on theoretical (100%) or previously reported (mt-sDNA 71%; FIT 43%) rates. Published SSP sensitivities for mt-sDNA and FIT were used. All other model inputs were identical to CISNET models. Sensitivity analyses used screening adherence rates of 40–70%. Key outcomes were life-years gained (LYG), CRC incidence and CRC mortality per 1000 patients. Results: Including SSPs in the model demonstrated a greater loss of LYG with FIT than mt-sDNA (Table). At 100% adherence, compared with base case, modeling 20% or 30% SSP pathway CRCs resulted in a decrease of 9–15 LYG with FIT and 2–4 LYG with mt-sDNA, a decrease in CRC incidence reduction of 3.9–6.1% with FIT and 0.7–1.1% with mt-sDNA, and a decrease in CRC mortality reduction of 2.6–4.0% with FIT and 0.4–0.8% with mt-sDNA. Using previously reported adherence, compared with base case, modeling 20% or 30% SSP pathway CRCs resulted in a decrease of 13–20 LYG with FIT and 2–5 LYG with mt-sDNA, a decrease in CRC incidence reduction of 4.4–6.9% with FIT and 0.6–1.1% with mt-sDNA, and a decrease in CRC mortality reduction of 3.5–5.4% with FIT and 0.4–0.9% with mt-sDNA. Assuming reported adherence and 30% SSP pathway CRCs, mt-sDNA had 48 more LYG, 14.6% greater CRC incidence reduction, and 12.4% greater CRC mortality reduction than FIT. Assuming 30% SSP pathway CRCs, outcomes favored mt-sDNA vs FIT even after modeling equivalent adherence rates ranging from 40–70%. Conclusions: After incorporating the SSP pathway into the model, outcomes with mt-sDNA neared those of FIT at 100% screening adherence rates and surpassed FIT at more realistic reported screening adherence rates.[Table: see text]
AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).
Authors: Chandarlapaty Sarat , Linden Hannah M. , Neven Patrick , Petrakova Katarina , Bardia Aditya , Kabos Peter , Braga Sofia A. D. S. , Boni Valentina , Gosselin Alice , Cartot-Cotton Sylvaine , Doroumian Séverine , Celanovic Marina , Cohen Patrick , Paux Gautier , Campone Mario
Published: June 2021

1058

Background: AMEERA-1 (NCT03284957) investigates amcenestrant, an oral SERD, as monotherapy and combined with targeted therapies in ER+/HER2– mBC. Here we report data from dose escalation (Part C) and dose expansion (Part D) of amcenestrant + palbo. Methods: Patients (pts) were postmenopausal women with ER+/HER2– mBC and ≥ 6 mos prior advanced endocrine therapy (ET) or adjuvant (adj) ET resistance (relapse on adj ET started ≥ 24 mos ago or < 12 mos after completing adj ET). Prior chemotherapy (≤ 1) for advanced disease was allowed; targeted therapies were not except ≤ 1 CDK4/6i in Part C. Part C assessed dose-limiting toxicities (DLTs) and aimed to establish the recommended phase 2 dose (RP2D) for amcenestrant (200 or 400 mg once daily [QD], in 28-day cycles) in combination with palbo (125 mg QD for 21 days on/ 7 days off). Safety (treatment-emergent adverse events [TEAEs] and lab abnormalities per CTCAE v4.03) and pharmacokinetics (PK) were evaluated. Antitumor activity at the RP2D for amcenestrant + palbo was evaluated in a subset of Part C pts and Part D, according to RECIST v1.1, determined locally by investigators. Results: Feb 8, 2021 data cutoff. In Part C (n = 15; 200 mg: 9; 400 mg: 6), no DLTs occurred and amcenestrant 200 mg QD was selected as the RP2D with palbo, based on PK and safety data. In the pooled safety population at the RP2D (n = 39; Part C: 9; Part D: 30), median (range) age was 59 y (33–86) with ECOG PS 0 (74.4%) or 1 (25.6%) and 2 (1–6) organs involved. Immediate prior therapy was neo/adj (41.0%, all ET resistant) or advanced (59.0%, range 1–4 lines). Median (range) exposure was 32 wks (1–66) with 59.0% pts on ongoing therapy. No amcenestrant dose reductions occurred; 25.6% had ≥ 1 palbo dose reduction. Most common non-hematological TEAEs related to amcenestrant were Grade 1–2 nausea and fatigue (17.9% each), asthenia and hot flush (10.3% each); to palbo were fatigue (30.8%), nausea (25.6%), asthenia and dysgeusia (10.3% each). Two pts discontinued due to AEs. The majority (94.9%) had neutrophil count decrease (53.8% Grade ≥ 3). Preliminary antitumor activity after at least 6 cycles of therapy (unless early treatment discontinuation) is reported in the table below. Conclusions: In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). Clinical trial information: NCT03284957 .[Table: see text]
Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after treatment with endocrine therapy and CDK 4/6 inhibitors within randomized clinical trials.
Authors: Munzone Elisabetta , Pagan Eleonora , Bagnardi Vincenzo , Montagna Emilia , Cancello Giuseppe , Dellapasqua Silvia , Iorfida Monica , Mazza Manuelita , Colleoni Marco
Published: June 2021

1059

Background: CDK4/6 inhibitors combined with endocrine therapy (ET) deeply transformed the treatment landscape of HR+/HER2− advanced breast cancer. After progression with the combination, there are no established guidelines for an optimal sequencing of the various therapeutic options. Data from randomized clinical trials (RCT) suggest that subsequent progression free survival (PFS2) was not compromised by the use of these drugs and time to subsequent chemotherapy (TTC) may be delayed. Therefore, we performed a meta-analysis to evaluate the benefit of such treatments on PFS2 and on delaying the TTC. Methods: We conducted a systematic literature search using PubMed to select all available randomized clinical trials of CDK4/6-inhibitors and ET reporting PFS2 or TTC data in first- or second-line therapy of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC with 95% confidence intervals (CI) using fixed-effects models. The pooled HRs for PFS and OS were also calculated. I2 was used to quantify heterogeneity between studies’ results. Results: Seven studies (PALOMA 1-2-3, MONALEESA 3-7, MONARCH 2-3) were included in our analyses (n = 3912 patients). A clear PFS2 benefit was observed in patients who received CDK 4/6 inhibitors + ET (pooled HR = 0.67, 95% CI = 0.61 to 0.74, I2 = 0.0%) and also a delay in subsequent TTC (pooled HR = 0.63, 95% CI = 0.58 to 0.70, I2 = 0.0%). As previously reported, the benefit in terms of PFS (pooled HR = 0.54, 95% CI = 0.50 to 0.59, I2= 0%) and OS (pooled HR = 0.77, 95% CI = 0.68 to 0.86, I2= 0%) was also confirmed. Conclusions: CDK4/6-inhibitors plus ET compared with ET alone improve PFS2, and TTC. The delay of chemotherapy can spare the patients toxicities, potentially improving the quality of life. Thus, the observed benefit in PFS2 may postpone the onset of endocrine resistance and may offer an additional therapeutic advantage in this setting.
Circulating tumor DNA (ctDNA) as a tool to help guide germline testing in patients with solid malignancies.
Authors: Patel Nikita Pankaj , Shah Ami N. , Davis Andrew A. , Gerattana Lorenzo , Jacob Saya , Katam Neelima , Wehbe Firas Hazem , Behdad Amir , Sciaraffa Theresa , Cristofanilli Massimo
Published: June 2021

10602

Background: As the use of circulating tumor DNA (ctDNA) is more widely implemented, incidental identification of pathogenic variants reflecting germline alterations in cancer predisposition genes will occur more frequently. Such mutations are expected to have a high mutant allele frequency (MAF) or occur in genes typically associated with inherited syndromes. When a similar analysis was conducted by our group, we found that MAF of about 30% or greater in BRCA1/ 2 was associated with confirmed putative germline mutations in patients with breast cancer (Jacob et al & Davis et al, SABCS 2020). In this study, we extended this analysis to non-breast malignancies. Methods: Patients with non-breast solid malignancies and ctDNA testing between 2015-2020 were retrospectively identified from Northwestern Medicine. All ctDNA was analyzed using Guardant 360 (Guardant Health, Inc. Redwood City, Ca). Patients with ctDNA samples with mutations at high MAF (>30%) and those with BRCA1/2 mutations at any MAF were identified. We reviewed these charts for referral to genetic counselors and/or CLIA-approved germline testing. Descriptive analysis was reported for these findings. Genetic alterations were classified as pathogenic or of unknown significance based on OncoKB (Chakravarty et al, JCO PO 2017). Results: We identified ctDNA samples of 548 patients with non-breast solid malignancies, of whom 56 had gene mutations occurring at high MAF (>30%). Predominant cancer subtypes were lung (48%), colorectal (21%), pancreatic (7%), ovarian (3.5%), prostate (3.5%), and gastroesophageal (3.5%). The most common gene mutations identified were TP53 (46%), BRCA1/2 (18%), EGFR (18%), APC (13%), and KRAS (9%). 87.5% were pathogenic and 12.5% were of unknown significance. 11 patients (19.6%) had germline testing of whom 6 tested positive. These germline mutations were in BRCA2 (n = 3), EGFR, APC, and TP53. In addition to the 10 patients with BRCA1/2 mutations at high MAF (>30%), we identified 70 patients with BRCA1/2 mutations at low MAF ( < 30%). 54% were pathogenic and 46% were of unknown significance. 11 patients (14%) had germline testing of whom 3 tested positive for BRCA2, all at high MAF. 1 patient with a BRCA2 mutation at low MAF of 1.4% tested positive for a different germline BRCA2 variant. Conclusions: In patients with advanced cancers, ctDNA analysis can reveal variants with MAF >30% that are reflective of a germline mutation. Unfortunately the rate of genetic testing in these patients was low (20%). Future studies with germline testing in patients with high MAF variants would help understand the prevalence of germline variants. This can facilitate developing a more standardized approach for genetic counselor referral to identify families that may benefit from interventions for early detection or prevention of future cancers.
Endocrine therapy-based strategies with different endocrine sensitivity statuses for hormone receptor positive/HER2 negative metastatic breast cancer: A network meta-analysis.
Authors: Wang Jiani , Han Yiqun , Wang Jiayu , Xu Binghe
Published: June 2021

1062

Background: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Since the absence of direct head-to-head comparisons for all regimens, decision-making guidelines are urgently needed for different endocrine sensitivity statuses. This study is to evaluate the efficacy of ET-based regimens in patients with HR+/HER2- MBC and to assess the heterogeneity among different compounds with a particular focus on their ability to improve survival outcomes. Methods: This network meta-analysis of phase II/III randomized controlled trials (RCTs) with at least one ET in HR+/HER2- MBC were enrolled. Based on the endocrine responses, participants were stratified into endocrine therapy sensitivity (ETS) and endocrine therapy resistance (ETR) groups. Primary endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed by bayesian algorithms and primarily measured as surface under the cumulative ranking curve (SUCRA). Results: A total of 42 trials (22917 patients) were included. Regarding PFS, cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) +fulvestrant 500mg (F500) was recommended for the ETS group (SUCRA = 76.92%), while chemotherapy was considered as the most effective option for the ETR group (SUCRA = 73.47%). For visceral metastases, CDK4/6i +aromatase inhibitors (AIs) could provide the extreme efficacy for the ETS group (SUCRA = 63.27%) while the CDK4/6i +F500 (SUCRA = 76.17%) as the prior regimen for the ETR group. For bone-only disease, CDK4/6i+F500 was preferred for both the ETS (SUCRA = 67.04%) and the ETR (SUCRA = 70.24%) group. Concerning OS, CDK4/6i+tamoxifen was estimated as the first-rank regimen for the ETS subgroup (SUCRA = 67.04%) and chemotherapy for the ETR subgroup (SUCRA = 60.02%). Regarding resistance category, abemaciclib +F500 was likely the best option with PFS, for both primary (SUCRA = 69.19%) and secondary ETR (SUCRA = 69.09%) settings, as well as primary ETR associated with OS improvement (SUCRA = 67.67%). Pictilisib +F500 could be the optimal treatment with OS for secondary ETR (SUCRA = 60.50%)group. Conclusions: The results showed that CDK4/6i + F500 was probably the most promising option in ETS, visceral ETR and bone-only disease settings in terms of PFS. OS subgroup analysis showed that different endocrine sensitivity statuses required various optimal treatment strategies.