NQO1 Triggers Neutrophil Recruitment and NET formation to Drive Lung Metastasis of Invasive Breast Cancer.

Metastasis to the lungs is a leading cause of death for breast cancer patients. Therefore, effective therapies are urgently needed to prevent and treat breast cancer lung metastasis In this study, we uncovered a mechanism by which NAD(P)H:quinone oxidoreductase 1 (NQO1) orchestrates lung metastasis. NQO1 stabilized and upregulated peptidyl-prolyl cis-trans isomerase A (PPIA), a chaperone that regulates protein conformation and activity, by preventing its oxidation at a critical cysteine residue C161. PPIA subsequently activated CD147, a membrane protein that facilitates cell invasion. Moreover, NQO1-induced secretion of PPIA modulated the immune landscape of both primary and lung metastatic sites. Secreted PPIA engaged CD147 on neutrophils and triggered the release of neutrophil extracellular traps (NET) and neutrophil elastase, which enhanced tumor progression, invasiveness and lung colonization. Pharmacological targeting of PPIA effectively inhibited NQO1-mediated breast cancer lung metastasis. These findings reveal a previously unrecognized NQO1-PPIA-CD147-NET axis that drives breast cancer lung metastasis. Inhibiting this axis is a potential therapeutic strategy to limit lung metastasis in breast cancer patients.

A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross mice.

BACKGROUND: Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. METHODS: 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice. FINDINGS: Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment. INTERPRETATION: Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC. FUNDING: The U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the "European Union Next Generation EU/PRTR," the Regional Government of Castile and León (CSI144P20), European Union.

Preoperative Ultrasonography Predicts Level II Lymph Node Metastasis in N1b Papillary Thyroid Carcinoma: Implications for Surgical Planning.

PURPOSE: To investigate whether preoperative ultrasonographic (US) features of the index cancer and metastatic lymph nodes (LNs) are associated with level II LN metastasis in N1b papillary rmfthyroid carcinoma (PTC) patients. MATERIALS AND METHODS: We enrolled 517 patients (mean age, 42 [range, 6-80] years) who underwent total thyroidectomy and lateral compartment LN dissection between January 2009 and December 2015. We reviewed the clinicopathologic and US features of the index cancer and metastatic LNs in the lateral neck. Logistic regression analysis was performed to analyze features associated with level II LN metastasis. RESULTS: Among the patients, 196 (37.9%) had level II metastasis on final pathology. In the preoperative model, larger tumor size (odds ratios [ORs], 1.031; 95% confidence interval [CI]: 1.011-1.051, p = 0.002), nonparallel tumor shape (OR, 1.963; 95% CI: 1.322-2.915, p = 0.001), multilevel LN involvement (OR, 1.906; 95% CI: 1.242-2.925, p = 0.003), and level III involvement (OR, 1.867; 95% CI: 1.223-2.850, p = 0.004), were independently associated with level II LN metastasis. In the postoperative model, non-conventional pathology remained a significant predictor for level II LN metastasis (OR, 1.951; 95% CI: 1.121-3.396; p = 0.018), alongside the presence of extrathyroidal extension (OR, 1.867; 95% CI: 1.060-3.331; p = 0.031), and higher LN ratio (OR, 1.057; 95% CI: 1.039-1.076; p < 0.001). CONCLUSIONS: Preoperative US features of the index tumor and LN may be helpful in guiding surgery in N1b PTC. These findings could enhance preoperative planning and decision-making, potentially reducing surgical morbidities by identifying those at higher risk of level II LN metastasis and tailoring surgical approaches accordingly.

A 35-gene mutation profile predicts the therapeutic outcome of patients with esophageal squamous cell carcinoma receiving neo-adjuvant chemoradiation.

Esophageal cancer is a common malignancy worldwide with a poor prognosis without radical resection. Neoadjuvant concurrent chemoradiotherapy (NACRT) followed by esophagectomy is widely used for treating locally advanced esophageal cancer in the thorax. The study aimed to assess mutation profiles and their correlation with therapeutic outcomes in patients diagnosed with locally advanced thoracic esophageal squamous cell carcinoma (ESCC). A retrospective analysis was conducted on 62 patients with ESCC who underwent NACRT. All patients received concurrent chemoradiotherapy (CCRT) utilizing intensity-modulated radiation therapy alongside concurrent chemotherapy with a cisplatin-based regimen. A 35-gene next-generation sequencing (NGS) panel detecting 402 genetic variants was used, which has been proven predictive in ESCC patients who received definitive chemoradiation. The 35-gene mutation profiles were analyzed in pre-treatment biopsies. The results reveled there were variants correlated with pathological complete remission or partial response, overall survival, and progression-free survival. A combination of p.Pro1319Ser and p.Arg2159Gly mutations in the MUC17 gene demonstrated an adverse impact on pathological response (OR [95% CI] = 7.00 (3.07-15.94), P < 0.001). Additionally, the variants located in the MUC17, MUC4, and MYH4 genes exhibited notably effects on tumor recurrence or mortality. Patients harboring either the MUC17 p.Thr2702Val or MUC4 p.Thr3355Ser mutation displayed a more than four-fold increased risk for disease recurrence or mortality. We concluded that specific mutations correlated to the pathological complete response in ESCC receiving neoadjuvant chemoradiation can be identified through the utilization of 35-gene expression profiles. Further investigation into the pathophysiological roles of MUC17 and MUC4 mutations in ESCC is warranted.

No Change in Complications Following Thyroidectomy Despite Increase in Thyroid Cancer Surgeries: A Meta-Regression Analysis.

PURPOSE: The increase in thyroid cancer incidence has inevitably led to an increase in thyroid cancer surgeries. This meta-regression analysis aimed to determine if the rate of post-thyroidectomy complications changes by year. MATERIALS AND METHODS: PubMed and Embase databases were used to perform a systematic literature search of studies published from January 1, 2005, using the keywords "thyroidectomy" and "complication." A meta-regression was performed for post-thyroidectomy hypocalcemia and bleeding. RESULTS: This meta-analysis included 25 studies involving 927751 individuals. Through the years of publications in this study, there was no significant difference in the proportion of post-thyroidectomy hypocalcemia and bleeding (p=0.9978, 0.6393). CONCLUSION: Although the number of thyroid surgeries has recently increased, the incidence of post-thyroidectomy hypocalcemia and bleeding did not significantly increase.

Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer.

The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.

Long-term, non-invasive FTIR detection of low-dose ionizing radiation exposure.

Non-invasive methods of detecting radiation exposure show promise to improve upon current approaches to biological dosimetry in ease, speed, and accuracy. Here we developed a pipeline that employs Fourier transform infrared (FTIR) spectroscopy in the mid-infrared spectrum to identify a signature of low dose ionizing radiation exposure in mouse ear pinnae over time. Mice exposed to 0.1 to 2 Gy total body irradiation were repeatedly measured by FTIR at the stratum corneum of the ear pinnae. We found significant discriminative power for all doses and time-points out to 90 days after exposure. Classification accuracy was maximized when testing 14 days after exposure (specificity > 0.9 with a sensitivity threshold of 0.9) and dropped by roughly 30% sensitivity at 90 days. Infrared frequencies point towards biological changes in DNA conformation, lipid oxidation and accumulation and shifts in protein secondary structure. Since only hundreds of samples were used to learn the highly discriminative signature, developing human-relevant diagnostic capabilities is likely feasible and this non-invasive procedure points toward rapid, non-invasive, and reagent-free biodosimetry applications at population scales.

Cabergoline as a Novel Strategy for Post-Pregnancy Breast Cancer Prevention in Mice and Human.

Post-pregnancy breast cancer often carries a poor prognosis, posing a major clinical challenge. The increasing trend of later-life pregnancies exacerbates this risk, highlighting the need for effective chemoprevention strategies. Current options, limited to selective estrogen receptor modulators, aromatase inhibitors, or surgical procedures, offer limited efficacy and considerable side effects. Here, we report that cabergoline, a dopaminergic agonist, reduces the risk of breast cancer post-pregnancy in a Brca1/P53-deficient mouse model, with implications for human breast cancer prevention. We show that a single dose of cabergoline administered post-pregnancy significantly delayed the onset and reduced the incidence of breast cancer in Brca1/P53-deficient mice. Histological analysis revealed a notable acceleration in post-lactational involution over the short term, characterized by increased apoptosis and altered gene expression related to ion transport. Over the long term, histological changes in the mammary gland included a reduction in the ductal component, decreased epithelial proliferation, and a lower presence of recombinant Brca1/P53 target cells, which are precursors of tumors. These changes serve as indicators of reduced breast cancer susceptibility. Additionally, RNA sequencing identified gene expression alterations associated with decreased proliferation and mammary gland branching. Our findings highlight a mechanism wherein cabergoline enhances the protective effect of pregnancy against breast cancer by potentiating postlactational involution. Notably, a retrospective cohort study in women demonstrated a markedly lower incidence of post-pregnancy breast cancer in those treated with cabergoline compared to a control group. Our work underscores the importance of enhancing postlactational involution as a strategy for breast cancer prevention, and identifies cabergoline as a promising, low-risk option in breast cancer chemoprevention. This strategy has the potential to revolutionize breast cancer prevention approaches, particularly for women at increased risk due to genetic factors or delayed childbirth, and has wider implications beyond hereditary breast cancer cases.

NCAPH drives breast cancer progression and identifies a gene signature that predicts luminal a tumour recurrence.

BACKGROUND: Luminal A tumours generally have a favourable prognosis but possess the highest 10-year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post-diagnosis. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers might require more aggressive treatment. METHODS: We conducted a study to explore non-structural chromosome maintenance condensin I complex subunit H's (NCAPH) role in luminal A breast cancer pathogenesis, both in vitro and in vivo, aiming to identify an intratumoural gene expression signature, with a focus on elevated NCAPH levels, as a potential marker for unfavourable progression. Our analysis included transgenic mouse models overexpressing NCAPH and a genetically diverse mouse cohort generated by backcrossing. A least absolute shrinkage and selection operator (LASSO) multivariate regression analysis was performed on transcripts associated with elevated intratumoural NCAPH levels. RESULTS: We found that NCAPH contributes to adverse luminal A breast cancer progression. The intratumoural gene expression signature associated with elevated NCAPH levels emerged as a potential risk identifier. Transgenic mice overexpressing NCAPH developed breast tumours with extended latency, and in Mouse Mammary Tumor Virus (MMTV)-NCAPHErbB2 double-transgenic mice, luminal tumours showed increased aggressiveness. High intratumoural Ncaph levels correlated with worse breast cancer outcome and subpar chemotherapy response. A 10-gene risk score, termed Gene Signature for Luminal A 10 (GSLA10), was derived from the LASSO analysis, correlating with adverse luminal A breast cancer progression. CONCLUSIONS: The GSLA10 signature outperformed the Oncotype DX signature in discerning tumours with unfavourable outcomes, previously categorised as luminal A by Prediction Analysis of Microarray 50 (PAM50) across three independent human cohorts. This new signature holds promise for identifying luminal A tumour patients with adverse prognosis, aiding in the development of personalised treatment strategies to significantly improve patient outcomes.

Robotic parathyroidectomy is a feasible technique for primary hyperparathyroidism.

PURPOSE: Focused parathyroidectomy is the gold standard treatment modality for primary hyperparathyroidism, which allows accurate preoperative localization. Robotic parathyroidectomy has emerged as a feasible procedure for focused parathyroidectomy. This study aimed to report the experiences of gasless robotic transaxillary parathyroidectomy for primary hyperparathyroidism in a single center. METHODS: We assessed the data obtained from patients who underwent gasless robotic parathyroidectomy with the transaxillary approach between December 2013 and August 2022 and were diagnosed with primary hyperparathyroidism at our institute. The data included clinical, biochemical, and pathological features and operation time. RESULTS: Of the 12 patients, 11 were women and one was a man. The median age of the patients was 44.5 years (range: 15-65 years). The median preoperative maximum mass diameters on ultrasonography and neck computed tomography were 1.2 ± 0.5 and 1.1 ± 0.6 cm, respectively. The median size of the postoperative maximum mass diameter in gross pathology was 1.3 ± 0.4 cm. The location of the enlarged parathyroid was left superior in five patients, right inferior in four, left inferior in three, and no right superior in one. In the final pathological examination, all cases were parathyroid adenomas. Only one case experienced a postoperative bleeding complication. At six months from surgery, average of an axillary scar length was 5.85 cm, and an average width was 0.21 cm. The mean operative time was 113 ± 48 min. The mean robot docking and console times were 9 ± 5 and 47 ± 52 min, respectively. CONCLUSIONS: Robotic transaxillary parathyroidectomy is a feasible technique in select patients with primary hyperparathyroidism and preoperatively localized disease. The gasless robotic transaxillary approach provides procedural safety as well as superior cosmetic results without a neck scar.

Genetic architecture of the acute and persistent immune cell response after radiation exposure.

Hematologic toxicity is a common side effect of multimodal cancer therapy. Nearly all animal studies investigating the causes of radiotherapy-induced hematologic toxicity use inbred strains with limited genetic diversity and do not reflect the diverse responses observed in humans. We used the population-based Collaborative Cross (CC) mouse resource to investigate the genetic architecture of the acute and persistent immune response after radiation exposure by measuring 22 immune parameters in 1,720 CC mice representing 35 strains. We determined relative acute and persistent radiation resistance scores at the individual strain level considering contributions from all immune parameters. Genome-wide association analysis identified quantitative trait loci associated with baseline and radiation responses. A cross-species radiation resistance score predicted recurrence-free survival in medulloblastoma patients. We present a community resource of immune parameters and genome-wide association analyses before and after radiation exposure for future investigations of the contributions of host genetics on radiosensitivity.

NCAPH Drives Breast Cancer Progression and Identifies a Gene Signature that Predicts Luminal A Tumor Recurrence.

Despite their generally favorable prognosis, luminal A tumors paradoxically pose the highest ten-year recurrence risk among breast cancers. From those that relapse, a quarter of them do it within five years after diagnosis. Identifying such patients is crucial, as long-term relapsers could benefit from extended hormone therapy, whereas early relapsers may require aggressive treatment. In this study, we demonstrate that NCAPH plays a role in the pathogenesis of luminal A breast cancer, contributing to its adverse progression in vitro and in vivo. Furthermore, we reveal that a signature of intratumoral gene expression, associated with elevated levels of NCAPH, serves as a potential marker to identify patients facing unfavorable progression of luminal A breast cancer. Indeed, transgenic mice overexpressing NCAPH generated breast tumors with long latency, and in MMTV-NCAPH/ErbB2+ double-transgenic mice, the luminal tumors formed were more aggressive. In addition, high intratumoral levels of Ncaph were associated with worse breast cancer evolution and poor response to chemotherapy in a cohort of genetically heterogeneous transgenic mice generated by backcrossing. In this cohort of mice, we identified a series of transcripts associated with elevated intratumoral levels of NCAPH, which were linked to adverse progression of breast cancer in both mice and humans. Utilizing the Least Absolute Shrinkage and Selection Operator (LASSO) multivariate regression analysis on this series of transcripts, we derived a ten-gene risk score. This score is defined by a gene signature (termed Gene Signature for Luminal A 10 or GSLA10) that correlates with unfavorable progression of luminal A breast cancer. The GSLA10 signature surpassed the Oncotype DX signature in discerning tumors with unfavorable outcomes (previously categorized as Luminal A by PAM50) across three independent human cohorts. This GSLA10 signature aids in identifying patients with Luminal A tumors displaying adverse prognosis, who could potentially benefit from personalized treatment strategies.

Analysis of Risk Factors to Predict Occurrence and Prognosis of Postsurgical Hypertrophic Scar Development: A Review of 4238 Cases.

PURPOSE: This study aimed to identify the risk factors associated with the occurrence and prognosis of hypertrophic scarring following thyroidectomy. MATERIALS AND METHODS: A total of 4238 patients who underwent thyroidectomy were included in this study. A multivariable logistic regression model was developed to identify the risk factors for hypertrophic scar development and its prognosis. RESULTS: Our analysis revealed that hypertrophic scar development was associated with younger age [odds ratio (OR)=0.949, p<0.0001], male sex (OR=0.562, p<0.0001), higher body mass index (OR=1.137, p<0.0001), prominent sternocleidomastoid muscles (OR=2.522, p<0.0001), scarring located within 1 cm of the sternal notch (OR=4.345, p<0.0001), and a history of keloid development (OR=2.789, p=0.0031). Additionally, scar location within 1 cm of the sternal notch (beta=4.326, p=0.0429) and a history of keloid development (beta=23.082, p<0.0001) were found to be associated with the prognosis of hypertrophic scarring. CONCLUSION: The findings of this study provide valuable insights into the risk factors associated with hypertrophic scarring following thyroidectomy. Clinicians can use this information to predict the occurrence of hypertrophic scarring and its prognosis, and take preventative measures accordingly.

Comparison of delayed bleeding to immediate bleeding following thyroidectomy.

It is important to identify risk factors for post-thyroidectomy bleeding requiring airway intervention or reoperation. Therefore, we aimed to compare the characteristics of patients with postoperative bleeding after thyroid surgery according to the period until reoperation. We conducted a retrospective study analyzing data between April 2009 and July 2022 and included 126 patients who had postoperative bleeding. The patients were grouped according to the period between thyroidectomy and reoperation due to bleeding (0 day, 1-7 days, > 7 days). We performed among-group comparisons of patient characteristics and surgical aspects, including the extent of surgery. The ratios of male-female and lateral neck dissection were higher in the post-operative bleeding group than in the group without bleeding. In the analysis of patients with postoperative bleeding, grouped according to period between thyroidectomy and reoperation, there was a significant among-group difference in the male-female ratio. The male sex was positively correlated with the reoperation period. Further, the reoperation period was also positively correlated with total thyroidectomy and lateral neck dissection and the operation time showed a significant among-group difference. Our results indicate that the male sex and lateral neck dissection are risk factors for postoperative bleeding after thyroidectomy. Furthermore, male sex, total thyroidectomy, and lateral neck dissection are risk factors for delayed bleeding. Therefore, clinicians should consider these factors for interventions against immediate or delayed bleeding after thyroidectomy.

Evaluation of public's perception of scar cosmesis after thyroidectomy: results of a survey of Turkish versus South Korean individuals.

Purpose: Visible scars on the neck caused by thyroid surgery give rise to significant aesthetic, functional, and psychosocial problems. The objective of this study is to comparatively investigate the public perception of neck scar cosmesis in Turkish and South Korean populations. Methods: This survey was prepared to collect participants' demographic and socioeconomic data and determine their perception of scar cosmesis on the neck and consisted of 15 questions. One thousand thirty-nine individuals who did not undergo thyroid surgery completed the survey. The P-values of <0.05 were deemed to indicate statistical significance. Results: There were 1,039 respondents, of whom 525 (50.5%) were Turkish and 514 (49.5%) were South Korean. South Korean respondents stated that they would be significantly more uncomfortable with the thought of having a scar due to thyroid surgery, compared to the Turkish respondents (P < 0.001). The South Korean respondents stated that they would be significantly more concerned about the scar's length, thickness, and darkening color, compared to the Turkish respondents (P < 0.001 for all cases). Conclusion: Patients' expectations, which are affected by various sociodemographic factors and cultural characteristics, are as important as the medical condition when deciding on the type of thyroid surgery. The study findings clearly indicated that the South Korean population would be significantly more uncomfortable with having a scar on the neck, compared to the Turkish population. Therefore, in selected cases, a scarless thyroidectomy approach, such as transoral endoscopic thyroidectomy, vestibular approach may be preferable for societies like South Korea.

AI-empowered cellular morphometric risk score improves prognostic stratification of cutaneous squamous cell carcinoma.

INTRODUCTION: Risk stratification of cutaneous squamous cell carcinoma (CSCC) is essential for managing patients. Artificial intelligence and machine learning might help stratify patients with CSCC by risk using more than solely clinical and histopathological factors. METHODS: A retrospective cohort of 104 CSCCs excised with clear margins was retrieved. Clinical and histopathological risk factors were evaluated. Hematoxylin and eosin-stained slides were scanned and analyzed by an algorithm based on the stacked predictive sparse decomposition technique. Cellular morphometric biomarkers (CMBs) were identified via machine learning and used to derive a cellular morphometric risk score (CMRS) that classified CSCC into clusters of differential prognosis. Concordance analysis, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated and compared with results obtained with the Brigham and Women's Hospital (BWH) staging system. The performance of the combination of the BWH staging system and the CMBs was also analyzed. RESULTS: There were no differences among CMRS groups in terms of clinical and histopathological risk factors and T-stage assignment, but there were significant differences in prognosis. Combining the CMRS with BWH staging systems increased distinctiveness and improved prognostic performance. C-indices were 0.92 for local recurrence and 0.91 for nodal metastasis when combining the two approaches. The NPV was 94.41% and 96.00%, the PPV was 36.36% and 41.67%, and accuracy reached 86.75% and 89.16% with the combined approach. CONCLUSION: CMRS is helpful for CSCC risk stratification beyond classic clinical and histopathological risk features. Combining the information from the CMRS and the BWH staging system offers outstanding prognostic performance for high-risk CSCC patients.

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors with an extremely poor prognosis. Based on the several biological features related to glutamine metabolism in ATC, we hypothesized glutaminolysis inhibition induces cell death in ATC cells. However, glutamine metabolism inhibition triggered cell growth arrest independent of cell death in ATC, suggesting that other signaling pathways avoid glutamine metabolism inhibition-induced stress exist. To investigate the functional mechanism against glutamine metabolism inhibition, we conducted mRNA and ATAC-Sequencing data analysis and found that glutamine deprivation increased ATF4-mediated one-carbon metabolism. When we inhibited PHGDH, the first rate-limiting enzyme for one-carbon metabolism, cell growth arrest was promoted upon glutamine metabolism inhibition by accumulating intracellular ROS. We next observed that the co-inhibition of glutamine and one-carbon metabolism could augment the anticancer effects of drugs used in patients with ATC. Finally, single-cell RNA sequencing analysis revealed that one-carbon metabolism was strengthened through the evolutionary process from PTC to ATC. Collectively, our data demonstrate that one-carbon metabolism has a potential role of modulation of cell fate in metabolic stress and can be a therapeutic target for enhancing antitumor effects in ATC.

Lateral neck dissection for the treatment of synchronous and metachronous lateral neck metastasis of N1b papillary thyroid cancer.

Introduction: Metachronous lateral neck recurrence after thyroidectomy for N1b papillary thyroid cancer is accompanied by high morbidity and increased difficulty of reoperation. From the perspective of recurrence, the objective of this study was to compare patients who underwent metachronous lateral neck dissection (mLND) despite initial thyroidectomy and patients who underwent synchronous lateral neck dissection (sLND) for papillary thyroid cancer and analyze the risk factors for recurrence after mLND. Method: This retrospective study involved 1,760 patients who underwent lateral neck dissection for papillary thyroid cancer at the Gangnam Severance Hospital, a tertiary medical center in Korea, from June 2005 to December 2016. The primary outcome was structural recurrence, and secondary outcome measures were risk factors of recurrence in the mLND group. Result: A total of 1,613 patients underwent thyroidectomy and sLND at diagnosis. In 147 patients, thyroidectomy alone was performed at the time of diagnosis, and mLND was performed when recurrence to the lateral neck lymph node was confirmed. During a median follow-up of 102.1 months, 110 (6.3%) patients experienced a recurrence. There was no significant difference in the recurrence between the sLND and mLND groups (6.1% vs 8.2%, P=.32). The period from lateral neck dissection to recurrence was longer in the mLND group than in the sLND group (113.6 ± 39.4 months vs 87.0 ± 33.8 months, respectively, P<.001). Age ≥50 years (adjusted HR=5.209, 95% CI=1.359-19.964; P=.02), tumor size >1.45 cm (adjusted HR=4.022, 95% CI=1.036-15.611; P=.04), and lymph node ratio in the lateral compartment (adjusted HR=4.043, 95% CI=1.079-15.148; P=.04) were independent variables predictive of recurrence after mLND. Conclusion: mLND is suitable for treating lateral neck recurrence in patients with N1b papillary thyroid cancer who previously underwent thyroidectomy. Lateral neck recurrence after treatment in patients who underwent mLND was predicted by age, tumor size, and lymph node ratio in the lateral compartment.

Pan-cancer evaluation of clinical value of mitotic network activity index (MNAI) and its predictive value for immunotherapy.

Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types, 10,061 patients) and validation on other publicly available cohorts (23 tumor types, 9,209 patients) confirmed the significant association of MNAI with overall survival, progression-free survival, and other prognostic endpoints in multiple cancer types, including lower-grade gliomas (LGG), breast invasive carcinoma (BRCA), as well as many others. We also showed significant association between MNAI and genetic instability, which provides a biological explanation of its prognostic impact at pan-cancer landscape. Our association analysis revealed that patients with high MNAI benefitted more from anti-PD-1 and Anti-CTLA-4 treatment. In addition, we demonstrated that multimodal integration of MNAI and the AI-empowered Cellular Morphometric Subtypes (CMS) significantly improved the predictive power of prognosis compared to using MNAI and CMS alone. Our results suggest that MNAI can be used as a potential prognostic biomarker for different tumor types toward different clinical endpoints, and multimodal integration of MNAI and CMS exceeds individual biomarker for precision prognosis.