Concurrent Loss Research Articles

Rapid atrophy of cardiac left ventricular mass in patients with non-small cell carcinoma of the lung.

BackgroundCancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac function, symptoms, and clinical outcomes.MethodsTreatment naïve metastatic non‐small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin‐based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function [LV ejection fraction, global longitudinal strain (GLS), diastolic function], computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival.ResultsDuring 112 ± 6 days, the median change in LVM was −8.9% [95% confidence interval (95% CI) −10.8 to −4.8, P < 0.001]. Quartiles of LVM loss were −20.1%, −12.9%, −4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle [odds ratio (OR) = 4.5, 95% CI: 1.4–14.8, P=0.01] and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7–36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9–22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C‐reactive protein (P=0.008), high sensitivity troponin T (hs‐TnT) (P=0.03), and galectin‐3 (P=0.02) increased over time, while N‐terminal pro B‐type natriuretic peptide and hs‐cTnI did not change over time. C‐reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2–46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4–153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9–22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4–35.8, P<0.001), and deterioration of performance status (OR = 4.8, 95% CI: 1.3–18.3,P=0.02). Patients with concurrent loss of LVM, skeletal muscle, and fat were more likely to deteriorate in all three symptom domains and to have reduced survival (P=0.05).ConclusionsIntense LVM atrophy is associated with non‐small cell lung cancer‐induced cachexia. Loss of LVM was associated with emerging alterations of GLS, indicating subtle changes in left ventricular function. Longer term studies are needed to assess the full scope of cardiac atrophy and its impact. LVM atrophy arises in conjunction with losses of fat and skeletal muscle and is temporally associated with meaningful declines in performance status, worsening of fatigue, and dyspnoea, as well as poorer tumour response and decreased survival. The specific contribution of LVM atrophy to these outcomes requires further study.

Abstract 2525: Comprehensive analysis of thymic epithelial tumors using an integrated bioinformatics platform reveals novel biological characteristics

Abstract Introduction:Thymic epithelial tumors (TETs) are rare malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with myasthenia gravis, followed by thymic carcinoma which is less common but more clinically aggressive. The TCGA recently published a comprehensive analysis of 117 TETs using molecular profiling by exome-seq, RNA-seq, RPPA, and methylation. Using an integrated informatics platform we re-analyzed the TCGA TET data to identify novel biological characteristics of these rare tumors. Methods: Molecular and clinical data from the TCGA TET project was downloaded from the cbioportal database and imported into the tag.bio informatics platform. Tag.bio is a commercial cloud-based analysis platform that combines data, algorithms and question-based analysis protocols. It is used to for the rapid and reproducible statistical comparison of cohorts.Statistical analysis for differential expression, methylation, RPPA and mutational enrichment was performed using the Mann-Whitney test with multiple correction testing. Pathway and upstream regulator analysis were performed using Ingenuity Pathway Analysis. Results: Differential expression analysis of myasthenia gravis (MG) patients (N=32) compared to those with no history of MG (N=85), revealed the most significant gene as PPARGC1A (overexpressed, p&amp;lt;1e-8). This gene has not been previously associated with MG. PPARGC1A is highly expressed in skeletal muscle and mediates mitochondrial biogenesis. Supporting this observation, upstream regulator analysis was performed which identifies regulators that can explain the observed gene expression changes in a dataset. The results demonstrated that PPARGC1A as the most activated transcriptional regulator in MG+ tumors and may represent a novel autoantigen for MG. TETs are relatively indolent tumors, and only a small subset metastasizes. Differential expression in a subset of Stage IV tumors (N=6) identified overexpressed FGFR3. Of note, a previous study identified two patients with activating mutations in FGFR3. A genomic hallmark of Thymic Carcinoma (TC) is Chr16q loss. Several tumor suppressors reside on 16q, including:CYLD, CBFB, CDH1, CDH11, CTCF, ZFHX3, but the exact causative candidate is unknown. Analysis of the mutational data identified 2 of 10 patients with concurrent 16q loss and deleterious mutations in CYLD, congruent with previous reports of recurrent mutations in CYLD in TC. CYLD has been previously demonstrated to regulate STAT3. Differential expression followed by upstream regulator analysis of TC vs Thymoma demonstrated activated STAT3 in TC. Conclusion:Re-analysis of the TCGA TET dataset using a novel integrated bioinformatics platform identified novel biology of TETs including: PPARGC1A association with MG; FGFR3 expression in TET metastasis; and CYLD/STAT3 axis in TC. Citation Format: Milan Radovich, Jeffrey P. Solzak, Wade Webster, Jesse Paquette. Comprehensive analysis of thymic epithelial tumors using an integrated bioinformatics platform reveals novel biological characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2525.

Abstract 741: Clonal evolution of non-malignant proliferative lesions into breast cancers

Abstract [Introduction] Non-malignant proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles of normal ducts, non-malignant proliferative lesions and cancers in the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from different proliferative lesions within the cancer-borne breast, including invasive cancers, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. [Results] A total of 39 samples from 6 premenopausal females carrying estrogen receptor-positive cancers were analyzed, where the samples were obtained from normal ducts (N = 5), non-malignant proliferative lesions (N = 9), and non-invasive (N = 21) and invasive (N = 4) cancers. The number of somatic mutations per sample was ranging from 1 to 311 and increased with pathological disease progression. Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining four unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7-33 mm, shared one or more driver alterations, such as an AKT1 mutation (UID: KU01), a GATA3 mutation (UID: KU03 and KU06), a CBFB mutation (UID: KU06) and concurrent 1q gain and 16q loss (UID: KU02, KU03 and KU06), while harboring private mutations/CNAs of their own. The analysis of phylogenic trees based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. [Conclusions] Early breast cancer development is thought to be shaped by a simultaneous evolution of multiple precancerous clones. It may be multi-focally initiated by a germline mutation, frequently terminated in bilateral cancers. By contrast, in unilateral cases, cancer clones might be derived from a common ancestral clone, which has acquired a driver founder mutation long before the onset of cancer, and undergo independent evolution, giving rise to multiple proliferative lesions, from which invasive cancer finally evolves. Our findings provide unique insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Kenichi Yoshida, Yukiko Kawata, Yasuhide Takeuchi, Nobuyuki Kakiuchi, Yusuke Shiozawa, Kosuke Aoki, Masahiro Hirata, Tatsuki R. Kataoka, Takaki Sakurai, Satoko Baba, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of non-malignant proliferative lesions into breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 741.

Resistance mechanisms and molecular epidemiology of carbapenem-nonsusceptible Escherichia coli in Taiwan, 2012-2015.

PurposeThis study aimed to investigate the resistance mechanisms and molecular epidemiology of carbapenem-nonsusceptible Escherichia coli (CnsEC) in Taiwan.Patients and methodsFrom 2012 to 2015, 237 E. coli isolates with minimum inhibitory concentrations of imipenem or meropenem >1 μg/mL were collected in a nationwide surveillance and subjected to polymerase chain reaction (PCR) for carbapenemase, AmpC-type β-lactamase, and extended spectrum β-lactamase (ESBL) genes. We evaluated outer membrane proteins (OmpF and OmpC) loss and conducted multilocus sequence typing and pulsed-field gel electrophoresis (PFGE). Isolates that were resistant to all carbapenems were designated as pan-carbapenem-resistant E. coli (pCREC) in this study.ResultsThe predominant resistance mechanism of CnsEC in Taiwan was the CMY-2 β-lactamase in combination with OmpF and OmpC loss. Sequence type 131 was the most prevalent type (29.2%). Among 237 CnsEC isolates, 106 (44.7%) isolates were pCREC and 18 (7.59%) produced carbapenemase. The prevalence of carbapenemases increased from 6% in 2012 to 11.36% in 2015. Various carbapenemases including KPC-2, IMP-8, NDM-1, NDM-5, VIM-1, OXA-48, and OXA-181 were identified, with NDM-1 being the most common (38.9%) carbapenemase. Comparison between pCREC and non-pCREC among the non-carbapenemase-producing CnsEC isolates revealed SHV, CMY, co-carriage of SHV and CTX-M and concurrent loss of both OmpF and OmpC were more commonly detected in the pCREC group. PFGE revealed no nationwide clonal spread of carbapenemase-producing E. coli.ConclusionNDM-1 was the most common carbapenemase and combination of CMY-2 and concurrent OmpF and OmpC porin loss was the most prevalent resistance mechanism in CnsEC in Taiwan.

Abstract 3172: Prognostic and therapeutic implication of programmed death ligand 1 (PD-L1), microsatellite instability, and PIK3CA gene in lipoarcoma

Abstract Background: With the promising efficacies with personalized approach, we tested clinically relevant molecular target programmed death ligand 1 (PD-L1), microsatellite Instability (MSI), and PIK3CA molecules in liposarcoma to provide practical guide. Methods: A consecutive series of 74 liposarcoma patients who underwent curative resection between 2005 and 2016 were assessed using immuno-molecular panels: PD-L1 (22C3 pharmDx assay) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry (IHC), MSI using PCR, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. Results: For all the cases, PD-L1 was positive only in tumor infiltrating lymphocytes (TILs), while no PD-L1 expression was found on tumor cell and 23% were tumors with PD-L1+ TILs. PD-L1+ TILs was significantly predominant in abdominal site (P=0.004) and had significantly longer overall survival than PD-L1- TILs (5 year OS 84.4% vs 60.8%, P=0.007). Regarding the MSI status, 2 well differentiated liposarcoma showed MSI [MSI-H (n=1) and MSI-L (n=1)]. For concordance with mismatch repair protein using IHC, only 1 out of 8 with concurrent loss of MLH1, MSH6, and PMS2 showed MSI-H (D2S123, D17S250). Activating PIK3CA mutation was detected in 7 patients [9.5%, exon 9 (n=4) and exon 20 (n=3) mutation] and 6 cases were PD-L1-TIL group. PIK3CA copy number gain were detected in 18 (24.3%) cases and significantly associated with PD-L1+TIL tumors (P=0.045). Conclusions: With our comprehensive immuno-moleuclar panel, liposarcoma need to be categorized based on the molecular genomic subtype and this may facilitate the development of successful future clinical trials using molecular agents. Citation Format: Hyo Song Kim, Hyae Min Jeon, Jae Seok Lee, Soo Hee Kim, Young Han Lee, Hyuk Hur, Sung Hoon Kim, Seung Hyun Kim, Hei-Cheul Jeung. Prognostic and therapeutic implication of programmed death ligand 1 (PD-L1), microsatellite instability, and PIK3CA gene in lipoarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3172.

Abstract 2049: LKB1 regulates BH3-mimetics vulnerability of KRAS mutant non-small cell lung cancer by alternating mitochondrial apoptotic protein interactions

Abstract Over 30% of lung adenocarcinomas harbor KRAS mutation. Despite progress in targeted therapies for specific genetic subsets of lung cancer (e.g. EGFR or ALK), there are no clinically effective targeted therapies for KRAS non-small cell lung cancer (NSCLC). Interpatient heterogeneity of KRAS mutant lung cancers, with large variability in co-occurring mutations, may contribute to its refractory phenotype. Specifically, KRAS mutant lung cancers with concurrent loss of the tumor suppressor LKB1 (KRAS-LKB1) have increased metastatic frequency and resistance to chemotherapy in pre-clinical models, and these patients have poor responses to immune checkpoint inhibitor. Thus, there is a critical need to develop novel therapeutic approaches for this subset of NSCLC. Intrinsic resistance to apoptosis limits the efficacy of therapies targeting KRAS signaling. Previous studies reported BCL-2/BCL-XL + MEK inhibition can increase apoptotic responses of some KRAS mutant cancers. Recently, potent and selective inhibitors of MCL-1 have been developed, creating additional possibilities for targeting apoptotic machinery for cancers that dependent upon MCL-1 for survival. We recently reported that novel MCL-1 inhibitor AMG-176 combined with MEK inhibitor trametinib can induce tumor regression in subsets of KRAS mutant NSCLC pre-clinical tumor models. In addition to commercially available cell lines, we established 20 patient-derived cell line/xenograft mouse model and showed that KRAS-LKB1 cell lines are particularly sensitive to MEK + MCL1 inhibition with high synergy score. Moreover, restoring LKB1 expression in LKB1-/- cell lines hampers the synergy and blocks mitochondrial depolarization and apoptosis. BH3-profiling reveals high dependency on MCL-1 in KRAS-LKB1 cell lines. We reported that trametinib increase intercellular Bim (pro-apoptotic protein) and subsequent loading of Bim onto pro-survival proteins BCL-XL and/or MCL1. MCL1 inhibitor releases Bim from MCL1 and initiates the apoptotic cascade. Interestingly, trametinib induces preferential sequestration of Bim by MCL-1 in KRAS-LKB1 models. Restoration of LKB1 in LKB1-/- cell lines reduces the trametinib-induced Bim:MCL-1 protein-protein interactions. Combined inhibition of MEK + MCL1 caused dramatic tumor regression in LKB1-deficient xenograft mouse models compared to LKB1-restored models. Our results reveal fundamental insights into a novel role for LKB1 in the regulation of mitochondrial apoptosis and will lay a solid pre-clinical foundation for the clinical investigation of the MEK + MCL-1 inhibitor combination. Our data may also support using LKB1 as a genetic biomarker for guiding the selection of BH3 mimetics in targeting KRAS mutant NSCLC. Citation Format: Chendi Li, Audris Oh, Varuna Nangia, Aaron N. Hata. LKB1 regulates BH3-mimetics vulnerability of KRAS mutant non-small cell lung cancer by alternating mitochondrial apoptotic protein interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2049.

Conditional Deletion of Eaf1 Induces Murine Prostatic Intraepithelial Neoplasia in Mice

ELL-associated factor 1 is a transcription elongation factor that shares significant homology and functional similarity to the androgen-responsive prostate tumor suppressor ELL-associated factor 2. EAF2 is frequently down-regulated in advanced prostate cancer and Eaf2 deletion in the mouse induced the development of murine prostatic intraepithelial neoplasia. Here we show that similar to EAF2, EAF1 is frequently down-regulated in advanced prostate cancer. Co-downregulation of EAF1 and EAF2 occurred in 40% of clinical specimens with Gleason score >7. We developed and characterized a murine model of prostate-epithelial specific deletion of Eaf1 in the prostate and crossed it with our previously generated mouse with conventional deletion of Eaf2. The prostates of Eaf1 deletion mice displayed murine prostatic intraepithelial neoplasia lesions with increased proliferation and inflammation. Combined deletion of Eaf1 and Eaf2 in the murine model induced an increased incidence in mPIN lesions characterized by increased proliferation and CD3+ T cells and CD19+ B cells infiltration compared to individual deletion of either Eaf1 or Eaf2 in the murine prostate. These results suggest that EAF1 may play a tumor suppressive role in the prostate. Cooperation between EAF1 and EAF2 may be important for prostate maintaining prostate epithelial homeostasis, and concurrent loss of these two tumor suppressors may promote prostate tumorigenesis and progression.

TP53 structural variants in metastatic prostatic carcinoma.

Sequencing data have been instrumental in identifying oncogenic drivers in prostatic carcinoma and highlighting biomarkers that define aggressive disease. A review of a series of 30 primary and metastatic prostatic carcinomas clinically sequenced at our cancer genomics laboratory utilizing a targeted gene panel identified recurrent structural variants in the TP53 gene. These structural variants were found in 27% of all sequenced cases and represented 36% of the cases with metastatic disease. TP53 structural rearrangements have been previously reported in a significant subset of osteosarcomas, where they result in loss of p53 protein expression by immunohistochemistry. Similarly, in our prostate cases with TP53 structural rearrangements for which tissue was available for testing, we find loss of p53 protein expression by immunohistochemistry. In the eight TP53-rearranged cases, concurrent PTEN loss was identified in 4 cases, TMPRSS2-ERG fusion in 5 cases, and AR and FOXA1 amplification in 1 case each. Our results from this small case series suggest that TP53 rearrangements with loss of expression represent a frequent alternative mechanism of inactivation of this key tumor suppressor gene with potential utility as a marker of aggressive disease. Recognition of this TP53 rearrangement pathway is essential to accurately identify prostatic carcinomas with loss of TP53 function.

The prognostic significance of weight loss in chronic obstructive pulmonary disease-related cachexia: a prospective cohort study.

BackgroundCachexia is an important extra‐pulmonary manifestation of chronic obstructive pulmonary disease (COPD) presenting as unintentional weight loss and altered body composition. Previous studies have focused on the relative importance of body composition compared with body mass rather than the relative importance of dynamic compared with static measures. We aimed to determine the prevalence of cachexia and pre‐cachexia phenotypes in COPD and examine the associations between cachexia and its component features with all‐cause mortality.MethodsWe enrolled 1755 consecutive outpatients with stable COPD from two London centres between 2012 and 2017, stratified according to European Respiratory Society Task Force defined cachexia [unintentional weight loss >5% and low fat‐free mass index (FFMI)], pre‐cachexia (weight loss >5% but preserved FFMI), or no cachexia. The primary outcome was all‐cause mortality. We calculated hazard ratios (HRs) using Cox proportional hazards regression for cachexia classifications (cachexia, pre‐cachexia, and no cachexia) and component features (weight loss and FFMI) and mortality, adjusting for age, sex, body mass index, and disease‐specific prognostic markers.ResultsThe prevalence of cachexia was 4.6% [95% confidence interval (CI): 3.6–5.6] and pre‐cachexia 1.6% (95% CI: 1.0–2.2). Prevalence was similar across sexes but increased with worsening Global Initiative for Chronic Obstructive Pulmonary Disease spirometric stage and Medical Research Council dyspnoea score (all P < 0.001). There were 313 (17.8%) deaths over a median (interquartile range) follow‐up duration 1089 (547–1704) days. Both cachexia [HR 1.98 (95% CI: 1.31–2.99), P = 0.002] and pre‐cachexia [HR 2.79 (95% CI: 1.48–5.29), P = 0.001] were associated with increased mortality. In multivariable analysis, the unintentional weight loss feature of cachexia was independently associated with mortality [HR 2.16 (95% CI: 1.31–3.08), P < 0.001], whereas low FFMI was not [HR 0.88 (95% CI: 0.64–1.20), P = 0.402]. Sensitivity analyses using body mass index‐specific, age‐specific, and gender‐specific low FFMI values found consistent findings.ConclusionsDespite the low prevalence of cachexia and pre‐cachexia, both confer increased mortality risk in COPD, driven by the unintentional weight loss component. Our data suggest that low FFMI without concurrent weight loss may not confer the poor prognosis as previously reported for this group. Weight loss should be regularly monitored in practice and may represent an important target in COPD management. We propose the incorporation of weight monitoring into national and international COPD guidance.

Electron Doping BaZrO3 via Topochemical Reduction.

We report the topochemical reduction of epitaxial thin films of the cubic perovskite BaZrO3. Reduction with calcium hydride yields n-type conductivity in the films, despite the wide band gap and low electron affinity of the parent material. X-ray diffraction studies show concurrent loss of out-of-plane texture with stronger reducing conditions. Temperature-dependent transport studies on reduced films show insulating behavior (decreasing resistivity with increasing temperature) with a combination of thermally activated and variable-range hopping transport mechanisms. Time-dependent conductivity studies show that the films are stable over short periods, with chemical changes over the course of weeks leading to an increase in electrical resistance. Neutron reflectivity and secondary ion mass spectrometry indicate that the source of the carriers is most likely hydrogen incorporated from the reducing agent occupying oxygen vacancies and/or interstitial sites. Our studies introduce topochemical reduction as a viable pathway to electron-dope and meta-stabilize low electron affinity and work function materials.

Analysis of age, tumor-sidedness, and mismatch repair (MMR) genes with response to immune checkpoint inhibitors (ICIs) in MMR-deficient (dMMR) colorectal cancer (CRC) patients (pts): A multi-institutional study.

e15029 Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age &lt; 50 and 50-65 years old had better ORRs compared to pts with age &gt;65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts &gt; 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]

Associations of Changes in Weight and Waist Circumference with Cardiovascular Disease and Mortality in Chinese Adults

Background: The associations of age-related changes in body weight and waist circumferences with cardiovascular disease (CVD) and mortality remain unclear. Methods: We assessed changes in weight and waist circumference from baseline survey and resurvey among 27 964 participants in the China Kadoorie Biobank (CKB, 2004-2008) and Dongfeng-Tongji Cohort (DF-TJ, 2008-2013). We used Cox proportional hazards models to evaluate the associations between adiposity changes and the subsequent risks of incident CVD, CVD mortality and all-cause mortality. Findings: On average, during a median of 3·4 years from baseline to resurvey, participants experienced a weight loss of 0·6 kg, accompanied by a 2·1 cm increase in waist circumference. We identified 3589 incident CVD cases, 485 CVD deaths, and 1283 all-cause deaths during the follow-up in the CKB (2008-2016) and DF-TJ (2013-2016). Weight loss and waist gain were associated with increased risks of those outcomes in the two cohorts. In particular, compared with participants who had stable waist (waist change -2·0 to 7·0 cm) and weight (weight change -2·5 to 2·5 kg), those who gained waist but lost weight (waist circumference change >7·0 cm, weight change ≤ -2·5 kg) had the highest risk of incident CVD, CVD mortality and all-cause mortality, with the pooled multivariate hazard ratios (HRs) of 1·41 (95% CI, 1·13 to 1·75), 2·48 (1·40 to 4·37), and 1·71 (1·16 to 2·51), respectively. Among the weight-stable participants, waist circumference was linearly associated with CVD risk, with 17% higher risk (HR 1·17, 1·04 to 1·32) for those gained waist while 13% lower risk (HR 0·87, 0·77 to 0·99) for those lost waist compared to waist-stable participants. Interpretation: Increased waist circumference with concurrent weight loss is significantly associated with increased risks of CVD morbidity, CVD mortality, and all-cause mortality among Chinese middle-aged and elderly adults. Funding Statement: This work was partly supported by grants from the Foundation of National Key Programs of Research and Development of China (2016YFC0900800, 2016YFC0900500, 2017YFC0907501 and 2017YFC0907504), the National Natural Science Foundation of China (91643202 and 81390540), the 111 Project and the Program for Changjiang Scholars and Innovative Research Team in University. The China Kadoorie Biobank baseline survey and the first resurvey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by the UK Wellcome Trust (grants 088158/Z/09/Z, 104085/Z/14/Z), and the Chinese Ministry of Science and Technology (2011BAI09B01). The British Heart Foundation, UK Medical Research Council, and Cancer Research provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The CKB study was approved by the ethics committees or institutional review boards at the University of Oxford, the Chinese Center for Disease Control and Prevention (China CDC), the Chinese Academy of Medical Sciences. The DF-TJ cohort was approved by the ethics committees of Tongji Medical College and the Sinopharm Dongfeng General Hospital. All participants provided written informed consents.

Roles of RAD51 and RTEL1 in telomere and rDNA stability in Physcomitrella patens.

Telomeres and ribosomal RNA genes (rDNA) are essential for cell survival and particularly sensitive to factors affecting genome stability. Here, we examine the role of RAD51 and its antagonist, RTEL1, in the moss Physcomitrella patens. In corresponding mutants, we analyse their sensitivity to DNA damage, the maintenance of telomeres and rDNA, and repair of double-stranded breaks (DSBs) induced by genotoxins with various modes of action. While the loss of RTEL1 results in rapid telomere shortening, concurrent loss of both RAD51 genes has no effect on telomere lengths. We further demonstrate here the linked arrangement of 5S and 45S rRNA genes in P.patens. The spacer between 5S and 18S rRNA genes, especially the region downstream from the transcription start site, shows conspicuous clustering of sites with a high propensity to form quadruplex (G4) structures. Copy numbers of 5S and 18S rDNA are reduced moderately in the pprtel1 mutant, and significantly in the double pprad51-1-2 mutant, with no progression during subsequent cultivation. While reductions in 45S rDNA copy numbers observed in pprtel1 and pprad51-1-2 plants apply also to 5S rDNA, changes in transcript levels are different for 45S and 5S rRNA, indicating their independent transcription by RNA polymerase I and III, respectively. The loss of SOL (Sog One-Like), a transcription factor regulating numerous genes involved in DSB repair, increases the rate of DSB repair in dividing as well as differentiated tissue, and through deactivation of G2/M cell-cycle checkpoint allows the cell-cycle progression manifested as a phenotype resistant to bleomycin.

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition.

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of SMARCB1 for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor SMARCB1 loss, which also require expression of the E2 ubiquitin-conjugating enzyme, UBE2C. Our studies identify a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.

Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma.

The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16−/− mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso−/− mice was equivalent to wild type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16−/−. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16−/− samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.

Stakeholder Perspectives on the Biopsychosocial and Spiritual Realities of Living With ALS: Implications for Palliative Care Teams.

Amyotrophic lateral sclerosis (ALS) is an all-encompassing, life-limiting disease, resulting in the eventual paralysis of all voluntary muscles and concurrent loss of independence. As the disease advances, both patients and their family caregivers develop complex biological, psychological, and social needs, leading to increasing calls for the involvement of palliative care teams in the management of ALS. The purpose of this study was to generate a rich description of the realities of living with ALS, equipping palliative care teams with an in-depth understanding of the experiences and needs of patients with ALS and their family caregivers. This study employed a mixed-methods design, with quantitative data supplementing a larger body of qualitative data. Semi-structured interviews with 42 key stakeholders, including patients, family caregivers, and health-care providers, were analyzed for themes essential for effective understanding of ALS. Identified themes were organized into 2 broad categories: (1) biopsychosocial needs of patients with ALS and family caregivers and (2) the impact of ALS on spiritual and emotional well-being. Quantitative data supported the recognized themes, particularly with regard to challenges associated with preserving independence, securing sufficient social support, and managing the emotional complexities of the disease. Study findings illustrate the intricacies of living with ALS and the importance of eliciting individualized values when caring for patients with ALS and their families. The complex biopsychosocial needs experienced by patients and family caregivers suggest numerous opportunities for meaningful palliative care involvement.

Abstract P3-06-04: Clonal evolution of non-malignant proliferative lesions into breast cancers

Abstract [Introduction] Non-malignant proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles (with and without pathogenic germline mutations) of normal mammary ducts, non-malignant proliferative lesions, and cancer tissues from the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from different proliferative lesions within the cancer-borne breast, including invasive cancers, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. [Results] We analyzed a total of 34 samples from 5 premenopausal females carrying estrogen receptor-positive cancers, where the samples were obtained from normal ducts (N = 6), non-atypical (N = 1) and atypical (N = 8) proliferative lesions, and non-invasive (N = 16) and invasive (N = 3) cancers. The number of somatic mutations per sample ranged from 1 to 276 and increased with disease progression, regardless of the germline mutation status. Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 or TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining three unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7-25 mm, shared one or more driver alterations, such as an AKT1 mutation (UID: KU01), concurrent 1q gain and 16q loss (der(1;16)) (UID: KU02), and a GATA3 mutation and der(1;16) (UID: KU03), while harboring private mutations and/or CNAs of their own. The phylogenetic analysis based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. [Conclusions] Our results suggest that early breast cancer development is shaped by the evolution of multiple precancerous clones. These clones are originated from a common ancestor that acquired a founder mutation long before the onset of cancer, followed by branching evolution of multiple clones that acquired additional driver mutations of their own, from which an invasive cancer ultimately develops. In hereditary cases, this process is thought to be substantially promoted multi-focally from within the entire breasts by a germline mutation shared by all mammary cells, frequently resulting in bilateral and/or multifocal breast cancers. Our findings provide unique insight into the early development of breast cancer. Citation Format: Nishimura T, Yoshida K, Kawata Y, Takeuchi Y, Kakiuchi N, Shiozawa Y, Aoki K, Hirata M, Kataoka TR, Sakurai T, Baba S, Shiraishi Y, Chiba K, Takeuchi K, Haga H, Miyano S, Toi M, Ogawa S. Clonal evolution of non-malignant proliferative lesions into breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-04.

The Role of KRAS in Endometrial Cancer: A Mini-Review.

Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from oestrogen-related proliferative endometrium (type I, endometrioid), or from atrophic endometrium (type II, non-endometrioid). Each type of EC is characterized by different molecular profile alterations. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a signalling protein which moderates response to various extracellular signals via down-regulation of the mitogen-activated protein kinase (MAPK) or phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT) pathways. This article reviews the role of KRAS in predicting transition from hyperplastic endometrium to early-stage well-differentiated EC, as well as further invasive proliferation of the tumour to advanced-stage disease. KRAS seems to be directly associated with type I EC, and most studies support its early involvement in carcinogenesis. Current evidence correlates KRAS mutations with increased cell proliferation and apoptosis, as well as up-regulation of endometrial cell oestrogen receptors. Tumours positive for KRAS mutation can harbour hypermethylation-related changes in genome expression, and this can be the cause of concurrent loss of DNA repair proteins. Despite some evidence that KRAS mutation status affects cancer progression, a consensus is yet to be reached. Based on the available evidence, we suggest that screening for KRAS mutations in patients with hyperplastic endometrium or early-stage type I EC, may provide important information for prognosis stratification, and further provision of personalised treatment options.

Thermal activation and aging of a V2O5/WO3-TiO2 catalyst for the selective catalytic reduction of NO with NH3

Real-world vanadium-based catalysts for the selective catalytic reduction (SCR) of NO with NH3 are occasionally exposed to high temperatures, which can induce catalyst aging. In this work, a 2.0 wt% V2O5/WO3-TiO2 catalyst based on commercial WO3-TiO2 was lab aged in dry and wet feed at different time lengths and temperatures. Aging carried out in static atmosphere or in flow only marginally influenced its performance, while e.g. temperature and water in the feed heavily affected the SCR activity. The low temperature NOx conversion (≤300 °C) increased after aging up to 600 °C for 16 h and was more pronounced after hydrothermal aging compared to thermal aging, which was associated with the increased surface coverage of the SCR-active vanadyl groups. Measurements of vanadium volatility in the temperature range selected for the aging temperatures revealed the high mobility of V species induced by the (hydro-)thermal treatments. The onset of catalyst deactivation, observed at lower aging temperature for the hydrothermally aged catalyst compared to the thermally treated one, is possibly due to a larger amount of mobile V and W species and the concurrent loss of specific surface area. The set of catalytic and characterization data showed that water is an essential component in aging protocols because it heavily affects the structure and the resulting catalytic activity of the SCR catalyst. Removal of residual sulfate groups, which are present on the commercial support, also contributed to catalyst activation at 550°C aging temperature as a result of structural changes evidenced by surface area measurements and by IR and Raman spectroscopy, including rearrangement of V species and apparent increase of Lewis acidity.

Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function.

53BP1 is a chromatin-associated protein that regulates the DNA damage response. In this study, we identify the TPX2/Aurora A heterodimer, nominally considered a mitotic kinase complex, as a novel binding partner of 53BP1. We find that TPX2/Aurora A plays a previously unrecognized role in DNA damage repair and replication fork stability by counteracting 53BP1 function. Loss of TPX2 or Aurora A compromises DNA end resection, BRCA1 and Rad51 recruitment, and homologous recombination. Furthermore, loss of TPX2 or Aurora A causes deprotection of stalled replication forks upon replication stress induction. This fork protection pathway counteracts MRE11 nuclease activity but functions in parallel to BRCA1. Strikingly, concurrent loss of 53BP1 rescues not only BRCA1/Rad51 recruitment but also the fork instability induced upon TPX2 loss. Our work suggests the presence of a feedback mechanism by which 53BP1 is regulated by a novel binding partner and uncovers a unique role for 53BP1 in replication fork stability.