bluuebunny/crossref_metadata_2025 huggingface dataset:
Surrogate model for optimizing annealing duration of self-assembled membrane-cavity structures
Authors: Jeong Mun Goung , Kim Taeyeong , Lee Bong Jae , Lee Jungchul
Published: June 2022

We propose a scheme to establish a surrogate model for optimizing the annealing duration of the self-assembled membrane-cavity structures from hole patterned silicon wafers. Although it has been reported that the design space of post-annealing shape can be extended by increasing the dimensions of hole arrays, the annealing duration for large hole arrays has not been well examined. A two-dimensional axisymmetric phase-field model in commercial FEM software is employed to establish the surrogate model with respect to three variables (i.e., radius, aspect ratio (AR), and normalized spacing). The established surrogate model based on the neural network indicates that the hole radius dominantly affects annealing duration and the temperature elevation (i.e., acceleration of diffusion speed) is necessary to achieve the practical annealing duration when the hole radius is larger than 1 μm.
A modular 3D printed microfluidic system: a potential solution for continuous cell harvesting in large-scale bioprocessing
Authors: Ding Lin , Razavi Bazaz Sajad , Asadniaye Fardjahromi Mahsa , McKinnirey Flyn , Saputro Brian , Banerjee Balarka , Vesey Graham , Ebrahimi Warkiani Majid
Published: June 2022

Microfluidic devices have shown promising applications in the bioprocessing industry. However, the lack of modularity and high cost of testing and error limit their implementation in the industry. Advances in 3D printing technologies have facilitated the conversion of microfluidic devices from research output to applicable industrial systems. Here, for the first time, we presented a 3D printed modular microfluidic system consisting of two micromixers, one spiral microfluidic separator, and one microfluidic concentrator. We showed that this system can detach and separate mesenchymal stem cells (MSCs) from microcarriers (MCs) in a short time while maintaining the cell’s viability and functionality. The system can be multiplexed and scaled up to process large volumes of the industry. Importantly, this system is a closed system with no human intervention and is promising for current good manufacturing practices.

Graphical Abstract
Platelet-rich plasma alone is unable to trigger contact osteogenesis on titanium implant surfaces
Authors: Kim Ung-Gyu , Choi Jung-You , Lee Jun-Beom , Yeo In-Sung Luke
Published: June 2022

Purpose

Osseointegration consists of bidirectional bone formation around modified implant surfaces by contact osteogenesis and distance osteogenesis. This study tested whether contact osteogenesis on the surface of a modified titanium (Ti) implant is stimulated by cytokines in the blood.

Methods

In the first two types of experiments, sandblasted, large-grit, acid-etched Ti implants and turned Ti tubes were inserted into rabbit tibiae. To exclude the influence of distance osteogenesis, the tubes were inserted into the tibiae, and implants were placed inside the tubes. In a third type of experiment, the implants and tubes were inserted into the rabbit tibiae, and platelet-rich plasma (PRP) or recombinant human bone morphogenetic protein-2 (rhBMP-2) was applied topically. Four weeks after implantation, undecalcified specimens were prepared for histomorphometry. Bone-to-implant contact (BIC) and bone area per tissue (BA) were measured, and the data were analysed using one-way ANOVA at a significance level of 0.05.

Results

When the response of bone to Ti tubes with implants was compared to that without implants (first experiment), little bone formation was found inside the tubes. The mean BIC of implant specimens inside the tubes was 21.41 ± 13.81% in a second experiment that evaluated bone responses to implants with or without Ti tubes. This mean BIC value was significantly lower than that in the implant-only group (without tubes) (47.32 ± 12.09%, P = 0.030). The third experiment showed that rhBMP-2 significantly increased contact osteogenesis on the implant surface, whereas PRP had no effect (mean BIC: 66.53 ± 14.06% vs. 16.34 ± 15.98%, P = 0.004).

Conclusions

Platelet-rich plasma alone is unable to trigger contact osteogenesis on the modified titanium implant surface.
Biocontrol of Cymbalophora rivularis (Menetries) (Lepidoptera: Erebidae) larvae by entomopathogenic bacteria and fungi
Authors: Tozlu Elif , Tozlu Göksel , Kotan Recep
Published: June 2022

Background

Sainfoin, alfalfa and clover are important forage crop plants in terms of their food value, efficiency and adaptation capabilities. Cymbalophora rivularis (Menetries, 1832) (Lepidoptera: Erebidae) causes significant damage to these plants. Chemicals are not recommended for pest control. Cultural pest control practices also remain insufficient. In this study, which was conducted to determine whether biological control can be applied in pest control, the pathogenic effects of Pseudomonas putida K-19B, Pantoea agglomerans RK-79 and RK-92, Bacillus megaterium TV-3D, P. fluorescens RK-1979, B. pumilus RK-1980 bacterial strains at a concentration of 1 × 108 CFU/ml and Beauveria bassiana (Bals.-Criv.) Vuill. (Cordycipitaceae) ET 10 fungal isolate at a concentration of 5.7 × 105 conidia/ml were tested under controlled conditions.

Results

According to the results of this study, at the end of 216 h, the tested biological control agent showed an efficacy ranged from 43.33 to 96.67% in the 1st and 2nd larval instars and 70 to 95% in the last instar larvae of C. rivularis. In the case of applications to 1st and 2nd larval instars, after 216 h, the efficacy of ET 10 fungal isolate was 96.67 and 83.33% of K-19B bacterial strain. In the last instar larvae, after 216 h, the efficacy of the strains TV-3D, K-19B and RK-1979 was 95, 90 and 90%, respectively. The efficacy of ET 10 and K-19B applications was found to be statistically not different from the efficacy of pathogenic application.

Conclusion

Environmentally friendly P. putida and B. megaterium bacterial strains and B. bassiana fungal isolate were determined and can be successfully used in the biological control of this pest.
Withdrawal seizures vs on-medication seizures: an intracranial EEG recording case report
Authors: Khateb Mohamed , Grinfeld Anat , Weiler-Sagie Michal , Herskovitz Moshe
Published: June 2022

Background

It has long been an interesting question of whether withdrawal seizures in epileptic patients differ from habitual seizures in terms of semiology and electrophysiology.

Case presentation

Here, we addressed this issue in a 40 year-old woman with drug-resistant focal epilepsy monitored by presurgical intracranial EEG. As a part of this routine pre-operative investigation, anti-seizure medications (ASMs) were halted; as a result, multiple withdrawal seizures were recorded before ASM readministration. During 4 days of invasive monitoring, we noticed three different phases in seizure organization: Acute withdrawal seizure (AWS): The first recorded seizure 10h after the implantation; the stabilized withdrawal seizures (SWS): seven habitual seizures recorded from 24h post implantation to readministration of ASMs; and the Non-withdrawal seizures (NWS): ten seizures recorded 24h after readministration of ASMs. AWS and SWS had the same semiology and same epileptic network, but the propagation time from the temporal pole to the para-hippocampal gyrus (PHG) and hippocampus ranged from no latency in AWS to up to 50 s in SWS. NWS were electrographic seizures, without any apparent clinical manifestation. Seizure onset in this type of seizure, as in the first two types, was in the temporal pole. However, NWS could last up to 3 min without involving the PHG or hippocampus.

Conclusions

We concluded that in acute withdrawal seizures the propagation time of epileptic activity is significantly reduced without affecting ictal organization network or semiology. Furthermore, ASM in this case had a remarkable influence on propagation rather than initiation of epileptic activity.
The frequency of pulmonary hypertension in chronic obstructive pulmonary disease of geriatric patients: a narrative literature review
Authors: Luca Ecaterina , Bodrug Nicolae
Published: June 2022

Background

Pulmonary hypertension (PH) is a serious complication with complex pathogenesis in the natural history of chronic obstructive pulmonary disease COPD, with a progressively increasing frequency with a meanwhile decreasing in functional capacity.

Purpose

Assessment of the incidence, pathogenesis, peculiarities, and complications of PH in COPD in geriatric population worldwide.

Methods

We performed an analysis of randomized, retrospective, and prospective clinical, case-control and observational studies, published at the international level, according to the subject studied and target population. Four hundred ninety-seven full articles were identified after the search through engine Google Search and databases PubMed, Hinari, SpringerLink, and Scopus (Elsevier) according to the keywords and subsequent filters.

Results

Depending on various factors, like the population examined, the definition used for mPAP (mPAP> 20 mm Hg or ≥25 mm Hg), the severity of the lung disease, and the method of measuring PAP, a varied incidence of COPD patients with PH complication was discovered, namely 10–91%. PH prevalence increases with the COPD severity. The presence of PH is associated with acute exacerbations of COPD, reduced survival, and increasing expenses for healthcare programs. Mild to moderate levels of PH (mPAP 25–34 mm Hg) are relatively common in COPD and usually are associated with severe airflow obstruction or parenchymal destruction. Only a minority of patients (1–5%) have severe PH (mPAP ≥35 mm Hg).

Conclusions

Diagnosis of PH in COPD is difficult, especially in a mild form, and requires a clinical approach associated with a comprehensive set of investigations for confirming the etiology, evaluation of the functional and hemodynamical impairment severity, and important factors in the appropriate treatment election.
Quantitative analysis of paleoenvironment of Qingshankou Formation in northern Songliao Basin, Northeastern China
Authors: Fu Xiuli , Meng Qi’an , Bai Yue , Su Yangxin , Jin Mingyu , Huo Zhengwang , Li Hongxia , Cui Kunning , Xu Qingxia , Zhu Zhengmao , Cao Weifu , Jia Qiong
Published: June 2022

The Qingshankou Formation in the Songliao Basin of northeastern China is an important layer for unconventional oil exploration. To solve the problem of the main controlling factors of shale oil enrichment, to quantitatively analyze the paleosalinity, paleoclimate, paleoredox environment, provenance, and lake productivity, and to clarify the relationship between sedimentary environment and total organic carbon, we have analyzed quantitative reconstruction of the sedimentary environment by using comprehensive analysis of multiple indicators with major and trace elements, fossils, and biomarkers. The results are as follows: the paleosalinity index w(Sr)/ w(Ba) ratio is 0.4–4, the w(B)/ w(Ga) value is 0.7–8.5, and the w(Pr)/ w(Ph) value is 0.8–2.8, which mainly stand for fresh brackish to saline water. The paleoclimate CIW′ (Chemical index of weathering, CIW = [A12O3/(AI203 + CaO+Na20)] × 100 [molecular proportions]) value is 90–100, indicating a warm and humid climate. The redox index w(V)/ w((V + Ni)) value is 0.54–0.89, which mainly belongs to the dysoxic environment. The provenance input of terrigenous debris index w(Ti)/ w(Al) value is 0.026–0.034, mainly standing for low terrigenous debris input. The production index CAL (enrichment degree of Cu) value is 1–3, belonging to high production. We conclude that the humid climate, the fresh brackish to saline and dysoxic water, and the high lake production provide favorable geologic conditions for biological reproduction and then provide a foundation for the formation, enrichment, and preservation of organic matter. The quantitative reconstruction of the paleoenvironment of the Qingshankou Formation has theoretical significance for Gulong shale oil exploration and development.
Minimal residual disease comparison between Ig/TCR PCR versus NGS assays in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: A report from the COG AALL1631 study.
Authors: Tran Thai Hoa , Reshmi Shalini , Kirsch Ilan Richard , Kairalla John A. , Tasian Sarah K , Schultz Kirk R. , Raetz Elizabeth A. , Shago Mary , Carroll Andrew J. , Devidas Meenakshi , Hunger Stephen , Loh Mignon L. , Silverman Lewis B.
Published: June 2022

10023

Background: Minimal residual disease (MRD) assessment by immunoglobulin/T-cell receptor (Ig/TCR) polymerase chain reaction (PCR) is currently being used in the international pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) trial EsPhALL2017/AALL1631 for risk stratification. MRD concordance has previously been demonstrated between Ig/TCR PCR and flow cytometry in Ph+ALL. We sought to assess concordance of MRD assessment between conventional Ig/TCR PCR and next-generation sequencing (NGS) assays. Methods: MRD was assessed in all pts on AALL1631 by Ig/TCR PCR at end-induction IB; those with MRD <5x10-4 were classified as standard-risk (SR) and randomized to treatment with imatinib and one of two chemotherapy regimens without hematopoietic stem cell transplant (HSCT), whereas pts with end-induction 1B MRD ≥ 5x10-4 were considered high-risk (HR) and assigned to HSCT after consolidation chemotherapy. Residual diagnostic and end-induction IB samples from consenting pts were assessed for NGS MRD by the clonoSEQ assay (Adaptive Biotechnologies) in blinded fashion and subsequently compared to Ig/TCR MRD to determine concordance as related to MRD-based HSCT recommendations ( ie, MRD ≥ 5x10-4 consistent with HR group assignment). MRD values were calculated using the kappa statistic for agreement above chance. Results: Sixty-seven pts had matched samples available for MRD assessment at end-induction 1B by both Ig/TCR PCR and NGS (Table). NGS MRD was evaluable for all 67 pts and stratified as 62 SR (<5x10-4) and 5 HR (≥5x10-4). In contrast, Ig/TCR PCR results were inevaluable for 3 pts (unsatisfactory sample quality) and indeterminate (positive, but not quantifiable) in 4 pts. Of the remaining 60 pts, 55 met SR and 5 HR criteria using Ig/TCR PCR. There was only 1 discordant case between the two methods for MRD-based HSCT recommendation among these 60 pts with a kappa statistic for agreement above chance of 0.88. Conclusions: NGS and Ig/TCR PCR assays were highly concordant in MRD assessment for risk stratification at a threshold of 5x10-4 in pediatric pts with Ph+ALL enrolled on AALL1631. Of note, the NGS assay yielded MRD results amenable for risk stratification in 100% pts compared to 89.6% for the Ig/TCR PCR methodology. These data support the use of NGS MRD testing for risk stratification in pediatric Ph+ALL.[Table: see text]
Combined IL-6 and IL-8 inhibition to overcome mesenchymal stem cell (MSC)-induced resistance to antimetastatic drugs in osteosarcoma.
Authors: Baglio S. Rubina , De Schrijver Celine , Massaro Crescenzo , Lagerweij Tonny , Gomez Martin Cristina , Giorgio Cristina , Brandolini Laura , Gavioli Elizabeth Marie , Allegretti Marcello , Pegtel D. Michiel
Published: June 2022

10037

Background: Mesenchymal stem cells (MSCs) play a key role in the progression of osteosarcoma (OS). In response to tumor-associated signals, including tumor-secreted extracellular vesicles (EVs), MSCs increase the expression of inflammatory cytokines promoting tumor cell aggressiveness. Previous data has demonstrated that IL-6 and IL-8 signaling mediate metastasis in OS. The aim of this study was to evaluate tumor EV-induced alterations of MSCs and identify combination therapies that can counteract MSC-induced resistance to antimetastatic drugs. Methods: Tumor EV-induced alterations of the MSC transcriptome were analyzed by RNA-seq. Gene set enrichment analysis (GSEA) was applied to discriminate TGFβ-dependent and independent pathways. EV RNA-induced expression changes were identified by transfecting purified EV-RNA in MSCs and by using a selective dsRNA antagonist. We selected candidate targets to block MSC-induced drug resistance and evaluated their effect in an orthotopic xenograft model of OS. Ladarixin (an allosteric inhibitor of the CXCL8/IL-8 receptors CXCR1 and CXCR2; 30 mg/kg 6x per week i.p.) and tocilizumab (anti-IL6 receptor antibody; 100 µg/mouse every other day i.p.) were administered starting from day one until the experimental endpoint. Metastasis were quantified by histological examination. This study was funded by the Dutch Cancer Society (KWF), POR FESR Campania 2014‐2020 and Dompé Farmaceutici SpA. Results: EVs from aggressive cancer cell lines induced an inflammatory MSC (iMSC) phenotype, characterized by increased expression of chemokines, including IL-8 as the most upregulated. Apart from IL-6, these alterations were mostly independent from TGFβ signaling and related to pattern recognition receptor (PRR) activation. We demonstrated that tumor EV-associated non-coding RNAs trigger TLR3 signaling in MSCs activating an innate immune response leading to high induction of IL-8 and other chemokines. Ladarixin and tocilizumab combination significantly reduced metastasis formation in a spontaneous metastasis model and overcame iMSC-induced resistance observed with single antimetastatic treatments. No effect was observed on primary tumor growth. Conclusions: EV-associated TGFβ together with EV-RNA induce iMSCs development in OS. Ladarixin in combination with tocilizumab reduced metastasis formation in a xenograft mouse model of OS, and, importantly, may prevent the occurrence of iMSC-induced tumor resistance to antimetastatic drugs.
Long-term medical and functional outcomes of ependymoma survivors: A population-based, matched cohort study.
Authors: Coltin Hallie , Pequeno Priscila , Liu Ning , Tsang Derek S. , Taylor Michael D. , Bouffet Eric , Ramaswamy Vijay , Nathan Paul C.
Published: June 2022

10054

Background: Ependymoma is the third most common pediatric central nervous system tumour. Treatment approaches are intensive and may include surgery, radiation, and chemotherapy. There are no longitudinal population-based cohort studies evaluating the long-term medical and functional outcomes of survivors of childhood ependymoma. Methods: Using a provincial pediatric cancer registry, all 5+ year ependymoma survivors diagnosed between 1987-2015 in Ontario, Canada were identified and matched to cancer-free population controls based on age, sex, and geographical location. Cases were followed from the index date (5 years from latest of diagnosis, or relapse/subsequent malignancy prior to age 18 years) until December 31, 2020 or censorship (death, or relapse/ new cancer after age 18 years). Clinical data were linked to administrative health databases to estimate the cumulative incidences and cause-specific hazard ratios (HR) of mortality, hospitalizations, strokes, hearing loss requiring a hearing aid, receipt of homecare services, and subsequent malignant neoplasms (SMNs) between cohorts, accounting for matching and competing risks. Results: Of 166 ependymoma diagnoses in the study period, 70 (42.2%) were excluded, most commonly due to early death prior to the index date. Ninety-six cases were matched to 480 controls (Table). The 10-year survival probability after the index date was 92.8% in cases and 99.6% in controls (HR 9.3, 95% CI 2.3-45.2, p=0.002). Compared to controls, cases were at higher risk of hospitalization (HR 3.2, 95% CI 2.2-4.6, p<0.0001), stroke (HR 33.3, 95% CI 5.7-629.1, p<0.0001), and receiving homecare services (HR 4.1, 95% CI 2.5-6.5, p<0.0001). Cases were at high risk of hospitalizations, strokes, hearing loss, and SMNs, with cumulative incidences of 64.7% (95% CI 46.6-78.0), 9.7% (95% CI 3.4-19.9), 13.5% (95% CI 5.3-25.5), and 12.8% (95% CI 4.7-24.9) at 20-years post index date, respectively. Conclusions: As survival of pediatric ependymoma improves, establishing the burden of late morbidity is critical. Dedicated screening programs for late sensory and neurovascular sequelae are warranted, as are interventions during and following treatment to mitigate the risk of developing such complications. [Table: see text]
Targetable genomic mutations in young women with advanced breast cancer.
Authors: Ansari Norin , Gao Lucy , Sokol Ethan , Sivakumar Smruthy , Huang Richard S.P. , Pelletier Maureen , Levy Mia Alyce , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S. , Lustberg Maryam B. , Rozenblit Mariya
Published: June 2022

1027

Background: Advanced breast cancer in women < 40 years is more aggressive, with worse prognosis and disease-free survival, compared to older women with the disease. With increasing availability of targeted and immune therapies, we aimed to compare genomic alterations (GA) using comprehensive genomic profiling (CGP) of tumor tissue. Methods: We analyzed 2,049 breast cancers submitted to Foundation Medicine for CGP. Hybrid-capture based CGP was performed to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on at least 0.8 Mbp of sequenced DNA and microsatellite instability was determined on at least 95 loci. Tumor cell PD-L1 expression (defined as tumor proportion score >/= 1) was determined by IHC (Dako 22C3). We identified 28 (1.37%) patients <30 years, 159 (7.76%) between 30-39 years, and 1862 (90.87%) >/= 40 years. Breast tissue was used for CGP in 69.5% of cases and remainder of specimens were lymph node, metastatic, or unspecified. Results: Breast tumors were less likely to be estrogen receptor positive in younger women (54% of those <30 years, 60% of those 30-39 years, 69.4% of those >/= 40 years) and more likely to be triple negative (43%, 33%, 26.1% in the same respective groups). There was no clear pattern in HER2+ status by age (0%, 15.1%, 7.2%). Younger women had higher rates of BRCA1 (17.9%, 10.1%, 2.6%), BRCA2 mutations (7.10%, 5.70%, 4.1%), and RB1 mutations (14.3%, 9.4%, 6.1%), and lower rates of CDH1 (7.1%, 5%, 15.4%) and PIK3CA mutations (17.9%, 17.6%, 40.0%). Younger women were more likely to have PD-L1 expression (55.6%, 54.4%, 51.5%) but had lower frequencies of TMB >10 (0.0%, 5.0%, 8.7%). Differences are statistically significant in BRCA1, CDH1, and PIK3CA. Conclusions: These findings confirm that young women with breast cancer have actionable GA. Different mutational profiles may support differential use of targeted and immune therapies. Statistically and clinically significant differences include higher BRCA1 mutations which may lend to PARP inhibitor use and lower PIK3CA mutations which may reduce alpelisib use. Higher RB1 mutations and immunotherapy biomarker differences were not statistically significant. However, these may clinically translate into CDK4/6 resistance and reduced immunotherapy options, respectively. [Table: see text]
Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial.
Authors: Jhaveri Komal L. , Goldman Jonathan W. , Hurvitz Sara A. , Guerrero-Zotano Angel , Unni Nisha , Brufsky Adam , Park Haeseong , Waisman James Ross , Yang Eddy Shih-Hsin , Spanggaard Iben , Reid Sonya A. , Burkard Mark E. , Prat Aleix , Loi Sherene , Crown John , Hanker Ariella , Ma Cynthia X. , Bose Ron , Eli Lisa DeFazio , Wildiers Hans
Published: June 2022

1028

Background: N is an oral, irreversible pan-HER TKI with activity against HER2 mutations. Genomic analyses from the SUMMIT MBC cohort following N±F suggest that resistance to N may occur via mutant allele amplification or secondary HER2 mutations. Adding T to N+F in SUMMIT showed encouraging durable responses in patients (pts) with HR+, HER2-mutant MBC and prior CDK4/6 inhibitors (CDK4/6i). Methods: SUMMIT (NCT01953926) enrolled pts with HR+, HER2-negative MBC with activating HER2 mutation(s) and prior CDK4/6i. Pts received N+F+T (oral N 240 mg/d with loperamide prophylaxis, im F 500 mg d1&15 of cycle 1 then q4w, iv T 8 mg/kg initially then 6 mg/kg q3w). During the small, randomized portion of the trial, pts received N+F+T, F+T or F (1:1:1 ratio). Pts randomized to F+T or F could crossover to N+F+T at progression. Efficacy endpoints: investigator-assessed ORR and CBR (RECIST v1.1); DOR; best overall response. Pre-treatment tumor tissue was centrally assessed retrospectively by next-generation sequencing. ctDNA from patient samples was assessed by NGS. Results: SUMMIT has completed enrolment; we report efficacy from 45 pts in the N+F+T cohort, plus 10 pts who progressed on F (n=6) or F+T (n=4) and crossed over to N+F+T (Table). HER2 allelic variants in the 45 N+F+T pts and ORR (%) (pts may have >1 mutation) were: V777L (n=6, 50%), L755S/P (n=15, 40%), S310F (n=4, 50%), exon 20 insertion (n=11, 36%), other KD missense (n=6, 33%), TMD missense (n=2, 0%), exon 19 deletion (n=1, 0%). Conclusions: N+F+T is a promising combination for HR+, HER2-mutated MBC with prior exposure to CDK4/6i, across a range of activating HER2 mutations. Results from the upcoming Apr 2022 data cut, including biomarkers, safety, mechanisms of acquired resistance, and preclinical mechanism of N+T, will be presented. Clinical trial information: NCT01953926. [Table: see text]
HER2-targeted immunoconjugates for breast cancer: Ancestry and dose adjustment for thrombocytopenia.
Authors: Rainone Michael , Behrendt Carolyn E. , Kasparian Saro , Nguyen Tina , Mortimer Joanne E. , Yuan Yuan , Waisman James Ross , Stewart Daphne B. , Lavasani Sayeh Moazami , Sedrak Mina S. , Patel Niki , Pullarkat Vinod A.
Published: June 2022

1048

Background: Thrombocytopenia (TCP) is a common toxicity of HER2-targeted agents, trastuzumab emtansine (TDM1) and trastuzumab deruxtecan (TDXd). A high incidence of this toxicity was observed in pivotal trials that led to approval of these agents. We investigated whether Asian ancestry increases risk of dose adjustment for TCP on TDM1/TDXd and its impact on dosing in the real-world setting. Methods: Females with HER2+ breast cancer who initiated TDM1/TDXd between 1/16/17-10/26/21 were identified by retrospective review. Primary endpoint was number of chemotherapy cycles until adjustment of TDM1/TDXd dose for TCP; competing endpoints included discontinuation for other toxicity, disease progression, and completion of treatment. Individuals who were switched from TDM1 to TDXd contributed an additional observation post-switch. Recurrent events analysis evaluated Asian ancestry (p<0.05) using a proportional means model, with robust sandwich estimate recognizing correlation between repeated observations per individual. Covariates (age, metastatic disease, drug, prior adjustment) were retained if they improved the model. Results: The study excluded individuals who declined to self-identify (n=23), self-identified as other than Asian or White (n=28), and/or dissented to research (n=24). The study included n=181 individuals (mean age 55.1+12.8 years), of whom n=48 (26.5%) identified as Asian and n=124 (68.5%) had metastatic disease. Overall, 33 individuals received TDXd exclusively, leaving 148 (81.8%) individuals who received TDM1, including 45 individuals who later switched to TDXd after development of TCP while on TDM1 (n=9) or other toxicity (n=36) on TDM1. For n=226 observations (total 2551 cycles), the endpoint was dose adjustment for TCP (n=32), discontinuation for other toxicity or disease progression (n=112), completion of treatment (n=27), or censoring (n=55). Taking into account history of switching drug for TCP, Asian ancestry was associated with increased risk of dose adjustment for TCP (Table). Neither age, metastatic disease, nor specific drug improved the model (data not shown). Conclusions: Among individuals taking TDM1 and/or TDXd for HER2+ breast cancer, we observed that those with Asian ancestry are at greater risk of dose reduction for TCP than their non-Asian counterparts. Upon confirmation in additional individuals with HER2+ cancers of the breast and other sites, this heightened susceptibility to TCP among Asian individuals should be further investigated to elucidate the underlying mechanism and optimize clinical guidelines for prevention and management. [Table: see text]
Trends in stage I lung cancer.
Authors: Singareddy Aashray , Flanagan Mary Ellen , Samson Pamela Parker , Waqar Saiama Naheed , Devarakonda Siddhartha , Ward Jeffrey P. , Herzog Brett , Rohatgi Anjali , Robinson Clifford Grant , Govindan Ramaswamy , Puri Varun , Morgensztern Daniel
Published: June 2022

10508

Background: The American Cancer Society has recently reported an increase in the percentage of patients with localized lung cancer from 2004 to 2018 with a corresponding improvement in survival for all patients combined. We analyzed the recent trends in stage distribution for lung cancer including tumor and demographic factors. Methods: We selected patients with lung cancer from the National Cancer Database (NCDB) public benchmark report diagnosed between 2010 and 2017. Patients with unknown stage were excluded. Stage distribution using the AJCC 7th edition of the TNM system was evaluated according to year of diagnosis, histology, age, gender, race, insurance and income. Results: Among the 1,447,470 patients from 1,384 hospitals identified in the database, 56,382 (3.9%) were excluded due to unknown stage or incorrect histology, leaving 1,391,088 patients eligible. The percentage of patients with stage I progressively increased from 23.5% in 2010 to 29.1% in 2017 while stage IV decreased from 45.5% to 43.1% during the same period (Table). The increased in percentages of stage I from 2010 to 2017 were 25.9% to 31.8% in non-small cell lung cancer (NSCLC) and 5.0% to 5.4% in small cell lung cancer (SCLC). Although the increased percentage of stage I lung cancer was observed in all subsets of patients, there were significant imbalances according to demographic and socio-economic factors. In the year 2017, the major gaps in stage I included insurance (31.4% for Medicare, 26.4% for private insurance, and 12.9% for uninsured), income (32.4% for the highest annual income and 25.4% for the lowest) and race (29.9% in whites and 24.3% in blacks). Conclusions: There has been a significant increase in the percentage of stage I lung cancer at diagnosis from 2010 to 2017 which occurred mostly in NSCLC. Disparities in diagnosis and access to treatment may account for the differences in the percentage of patients with stage I among selected demographic populations. The staging trends and recent treatment improvements may lead to better survival for lung cancer. [Table: see text]
Ancestry-specific risk of triple-negative breast cancer (TNBC) associated with germline pathogenic variants (PV) in hereditary cancer (CA) predisposition genes.
Authors: Hall Michael J. , Hughes Elisha , Kucera Matthew , Kidd John , Bernhisel Ryan , Hullinger B , Slavin Thomas Paul , Kurian Allison W.
Published: June 2022

10517

Background: TNBC represents ̃15% of invasive BC. Ancestry-specific variabilities in TNBC risk are well-described, with African American (AA) women experiencing higher incidence and mortality from TNBC than women of other races/ethnicities. Increased risk of TNBC has been associated with both rarer (e.g. RAD51C/D, BARD1) and more commonly detected (e.g. BRCA1/2, PALB2) germline PV in hereditary CA predisposition genes, but less is known about ancestry-specific TNBC risks for PV carriers. Methods: We examined clinical and genetic records from women referred for multigene CA panel testing (9/2013-5/2020). Multivariable logistic regression was used to test associations of PV in 13 genes with risk of TNBC after accounting for age, ancestry, and personal/family CA history. We analyzed each gene in the full cohort, and in subcohorts defined by self-reported ancestry. Effect sizes are expressed as odds ratios with 95% confidence intervals. Seven genes are not reported in ancestry-stratified analyses due to small numbers of PV carriers with TNBC. Results: From 627,219 individuals referred for multigene panel testing, 115,337 (18.4%) women with personal history of BC were identified, of whom 17,951 (15.6%) reported TNBC. Personal history of TNBC was reported more frequently in women of African ancestry (26.9%) than in women of European (13.9%) or Asian (11.7%) or Latinx ancestry (14.9%). Ancestry-stratified risks of TNBC associated with germline PVs are seen in the Table. Conclusions: While small samples sizes limit some gene-specific analyses, comparable ancestry-specific risks of TNBC were seen across the racial/ethnic groups examined here. [Table: see text]
Comparison of characteristics and outcomes of young onset versus average onset pancreatobiliary adenocarcinoma.
Authors: Jayakrishnan Thejus , Kamath Suneel Deepak , Nair Kanika G. , Wei Wei , Estfan Bassam N. , Krishnamurthi Smitha S. , Khorana Alok A.
Published: June 2022

10522

Background: Young-onset gastrointestinal malignancies appear to be increasing in incidence but most investigations have focused on colorectal cancer and there are limited data on young-onset pancreatobiliary cancers (YO-PBA). We evaluated trends and characteristics of YO-PBA in comparison to average-onset disease (AO-PBA). Methods: The study cohort comprised patients with PBA (pancreatic adenocarcinoma, intra- and extra-hepatic cholangiocarcinoma) diagnosed between 2004 and 2017 from the National Cancer Database. YO-PBA was defined as diagnosis at age < 50 years and AO-PBA as >50 years. Logistic regression was used to assess factors associated with YO-PBA status, and cox proportional hazards modeling was performed to associate demographic and clinical factors with overall survival. Results: Of 360,764 patients analyzed, 20,822 (5.8%) were YO-PBA with a median age at diagnosis of 45 years (IQR 42 – 48) vs 70 (62-78) years for AO-PBA. The number of patients with YO-PBA increased by 33.3% during the study period compared to 111.8% for AO-PBA. Characteristics associated with YO-PBA were (p-values<0.001 for all): male sex (6.3% YO-male out of all male patients vs 5.2% YO-female out of all female patients, OR 1.2), Black race (7.9% YO-Black vs 5.0% YO-White, OR 1.4), lower income (6.4% YO-lowest household income based category vs 5.5% highest, OR 1.3), and lower education (6.9% YO-lowest educational status category vs. 4.9% highest, OR 1.4). YO-PBA were more likely to present with stage-IV disease (6.4% YO-Stage IV of all stage IV vs 5.4% YO-Stage I-III, OR 1.2, p-value<0.0001), but more likely to undergo surgery (7.4% YO-surgery patients vs 5.4% YO no-surgery patients). Median OS was YO 11.0 (95% CI 10.8 – 11.3) vs. AO 7.1 months (95% CI 7.0 – 7.1). Effects of patients’ characteristics on OS differed significantly between YO and AO-PBA cohorts (interaction p-values < 0.001), and were analyzed separately (table). Notably, Black patients experienced worse outcomes in both age groups. Conclusions: Young-onset pancreatobiliary cancers (YO-PBA) reported in NCDB have increased over the years. YO-PBA is associated with better survival compared to AO-PBA. Socioeconomic disparities significantly impact incidence and outcomes. More work is needed to help address these health disparities, especially for those with young-onset cancer. [Table: see text]
Renal cell carcinoma in renal transplant recipients: Is there a role for screening?
Authors: Yohannan Binoy , Sridhar Arthi , Kaur Harmanpreet , De Golovine Aleksandra , Maithel Neha
Published: June 2022

10528

Background: Renal transplant (RT) recipients are at an increased risk of developing renal cell carcinoma (RCC), mainly due to iatrogenic immunosuppression and changes in immune surveillance. Most RCCs in RT recipients arises from the native kidney, but rarely may arise from the allograft. RCC post-RT can adversely affect allograft function and long-term survival. Screening for RCC in RT recipients is controversial and is not routinely done. Methods: We performed a retrospective chart review of RT recipients who underwent transplantation between January 1, 1999, and December 31, 2019. The following data were collected: Baseline demographic variables, cause of end-stage renal disease (ESRD), duration of dialysis prior to RT, type of RT (cadaveric vs. living donor), immunosuppressive regimen, site of RCC (native kidney vs transplanted kidney), time from RT to diagnosis of RCC, stage and Fuhrman grade, tumor histology, RCC treatment, and RCC-related mortality. RCC stage at diagnosis and survival were compared between patients who were screened versus those who were not. Results: Among 1998 RT recipients who underwent transplantation at Memorial Hermann Hospital (MHH) Texas Medical Center (TMC); 16 patients (0.8%) developed RCC. An additional 4 patients with RCC who underwent RT elsewhere but received follow up at MHH TMC were also included. Therefore, a total of 20 patients with post-RT RCC were identified, of whom 75% were men. Subject races included White (20%), Black (50%), Hispanic (20%), and Asian (10%). The median age was 56 years. Median duration of dialysis prior to RT was 36 months (range, 1–120). Median time to RCC diagnosis post-RT was 96 months (range, 16–312). Histologies included clear cell (75%), papillary (20%), and chromophobe (5%) RCC. RCC developed in the native kidney in 60% and in the allograft in 40% of the patients. Post-RT RCC patients were divided into those who underwent regular screening (n = 12) and no screening (n = 8). The regular screening group (n = 12) underwent ultrasound or computerized tomography annually or every 2 years. All of these patients had early-stage disease at presentation: stage I (n = 11) or II (n = 1). All patients who had RCC detected by screening were cured by nephrectomy (n = 10) or cryotherapy (n = 2). In patients who had no screening post RT, 37.5% had stage I, 25% had stage III, and 37.5% had stage IV RCC. Two patients with stage IV RCC died from metastatic disease. The RCC-related mortality was 0% in patients who were screened, compared to 25% in patients who had no screening. Conclusions: All RT recipients who had RCC diagnosed based on screening had an early diagnosis and no RCC-related mortality. Screening for RCC in RT recipients is an effective tool for early diagnosis and to reduce RCC-related mortality. Further research into the cost-effectiveness of screening is imperative.
Comparison of simulated outcomes between stool- and blood-based colorectal cancer screening tests.
Authors: Fendrick A. , Vahdat Vahab , Chen Jing Voon , Lieberman David A. , Karlitz Jordan J. , Limburg Paul J. , Ozbay A. Burak , Kisiel John B.
Published: June 2022

10529

Background: The Centers for Medicare & Medicaid Services (CMS) recommends covering blood-based biomarker tests with proposed minimum performance thresholds for colorectal cancer (CRC) screening test every 3 years for average-risk, asymptomatic Medicare beneficiaries ages 50–85 years. A blood-based test is a non-invasive screening method to detect CRC but is limited by low sensitivity to detect adenomas. Using the CRC-AIM microsimulation model, predicted life-years gained (LYG) and CRC incidence and mortality reduction were compared between a blood-based test meeting the CMS minimum thresholds and stool-based screening tests (fecal immunochemical test [FIT], fecal occult blood test [FOBT], and multitarget stool DNA [mt-sDNA]). Methods: Outcomes of blood- and stool-based tests were simulated for average-risk individuals free of diagnosed CRC at age 40 and screened between ages 45–75 years per USPSTF recommendations. Per CMS proposed criteria, CRC sensitivity and specificity for a blood-based test were set at 74% and 90%, respectively, and adenoma sensitivity was set at 10%. Published adenoma and CRC sensitivity and specificity were used for each stool test. For the primary analysis, adherence was assumed to be 100%. For secondary analysis, adherence was set at 30–70%, in 10% increments. Outcomes were per 1000 individuals. Results: At 100% adherence, LYG was 229 for a blood test and ≥305 for stool tests, corresponding to at least 25% lower LYG for a blood test relative to all stool tests (Table). Absolute CRC incidence and mortality reductions were at least 19% and 18% lower, respectively, for a blood test vs all stool tests. Secondary analysis indicates that at identical adherence rates that are less than 100%, a blood test had lower LYG vs all stool tests (Table). When the adherence of any test was 50%–70%, a blood test resulted in at least 20% lower LYG vs any stool test, and absolute reductions in CRC incidence and mortality were at least 9% and 10% lower, respectively, vs any stool test. Conclusions: This model suggests that if blood-based CRC screening tests do not sufficiently detect advanced adenomas, clinical outcomes will be inferior to stool-based testing due to lack of cancer prevention. Further discovery efforts to identify blood-based markers associated with both invasive and preinvasive neoplasia are needed to address this deficiency. [Table: see text]
Phase I study combining pembrolizumab and aromatase inhibitor in patients with metastatic hormone receptor–positive breast cancer.
Authors: Ge Xuan , Yost Susan Elaine , Lee Jin Sun , Frankel Paul Henry , Ruel Christopher , Cui Yujie , Murga Mireya , Tang Aileen , Martinez Norma , Chung Samuel , Yeon Christina Haeyoung , Stewart Daphne B. , Li Daneng , Rajurkar Swapnil Padmakar , Somlo George , Mortimer Joanne E. , Waisman James Ross , Yuan Yuan
Published: June 2022

1053

Background: Aromatase inhibitor (AI) is standard of care for patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The current phase I trial was designed to test the safety and efficacy of AI and the immune checkpoint inhibitor pembrolizumab (NCT 02648477). Methods: Key eligibility criteria were HR+ HER2- MBC per ASCO/CAP; RECIST 1.1 measurable disease; adequate organ function; and ECOG 0-1. Eligible patients received 200 mg pembrolizumab IV every 3 weeks plus AI until progression or unacceptable toxicity. Primary objectives were to evaluate the safety and efficacy of this combination. This study employed a 3-at-risk design with a lead-in at the standard dosing of both AI and pembrolizumab with a targeted accrual of 20 patients. Results: A total of 20 patients were accrued between March 2016 and April 2017. Median age was 62 (range 34-79), with 75% white, 15% Asian and 10% unknown. Median lines of therapy were 3 (0, 9). All but one patient received aromatase inhibitor and/or fulvestrant prior to enrollment. The combination was well tolerated, and the most common adverse events were grade 2 fatigue (35%), rash (15%), and hot flashes (10%). Grade 3 adverse events were elevated AST/ALT (5%), rash (5%), and lymphopenia (5%). Responses were 10% partial response and 15% stable disease, resulting in a clinical benefit rate (CBR) of 20% at 6 months. Median follow-up time was 40.1 months (range 31.3 – 46.8 months). Median progression free survival was 1.8 months (95% CI 1.6, 2.6) and median overall survival was 17.2 months (95% CI 9.4, NA). 14 tumor specimens had programmed death ligand 1–positive (PD-L1) by 22C3 testing, including 3 PD-L1-positive and 11 PD-L1 negative. No association between PD-L1 and response was found. Conclusions: The combination of pembrolizumab and AI is well tolerated in patients with HR+ HER2- MBC who were not pre-selected for PD-L1. There was minimal overall clinical activity observed beyond what was to be expected with AI alone in this group of patients. Clinical trial information: NCT 02648477.
Project BRA: Breast cancer risk assessment.
Authors: Nye Lauren Elizabeth , Smith Sharla , Knight Catherine J , Klemp Jennifer R.
Published: June 2022

10549

Background: In Kansas, breast cancer (BC) incidence is similar in Black and white women, yet Black women are 42% more likely to die from the disease. In models where screening is equal, there is no difference in survival from early-stage BC. Barriers to BC early detection in Black women include provider lack of knowledge in cancer risk, performing risk assessments and providing culturally sensitive education to patients. Our team developed a didactic and case-based learning intervention using Project ECHO (Extension for Community Health Outcomes) to improve provider knowledge on performing BC risk assessment and enhance risk stratified screening in Community Health Clinics (CHCs). A Community Advisory Board (CAB) was established to address barriers to early detection. Methods: CHCs participated in five 1-hour ECHO sessions June thru August 2021. Session topics focused on calculating BC risk, community resources, and cultural sensitivity and were led by experts in breast oncology, risk, genetics, screening, and health care equity. Pre/post surveys administered to participants assessed knowledge and satisfaction and continuing education credits were offered. A CAB member survey gained insight into organizational characteristics and community reach. Asset mapping identified barriers, resources, and opportunities to promote BC screening. Descriptive statistical analyses and the RE-AIM framework were used to assess reach and scalability of the ECHO. Results: Seventy-seven individuals from 16 CHCs registered to participate with a mean of 26 attendees at each session and 34% attending two or more. Participants were physicians (19%), advanced practice providers (18%), nurses (29%), and allied health professionals (34%). Sixty-three (82%) completed the baseline survey and 10 (13%) completed the post-ECHO survey. At baseline, 32% of participants reported lack of training and time as barriers to performing risk assessment. While post-ECHO survey responses were low, 60% reported their knowledge greatly or moderately improved across all topics. Participants reported clinical practice change in assessing personal history of cancer and collecting family history beyond first degree relatives. CAB members reported a broad range of expertise in community engagement and development (44%), direct patient care (15%), healthcare access (15%) and patient advocacy (26%). CAB education and collaboration led to support for tomosynthesis for women screened in our state funded BC screening program, Early Detection Works (EDW). Ongoing asset mapping identified gaps in access for Black women to the EDW program. Conclusions: Project BRA demonstrated successful participation in a limited series Project ECHO and achieved perceived changes in knowledge on performing BC risk assessment. Next steps include incorporating CAB informed opportunities to expand risk-based screening across Kansas and advocate for improved access to risk stratified screening.