High-risk Subtypes Research Articles

Dense phenotyping from electronic health records enables machine learning-based prediction of preterm birth

BackgroundIdentifying pregnancies at risk for preterm birth, one of the leading causes of worldwide infant mortality, has the potential to improve prenatal care. However, we lack broadly applicable methods to accurately predict preterm birth risk. The dense longitudinal information present in electronic health records (EHRs) is enabling scalable and cost-efficient risk modeling of many diseases, but EHR resources have been largely untapped in the study of pregnancy.MethodsHere, we apply machine learning to diverse data from EHRs with 35,282 deliveries to predict singleton preterm birth.ResultsWe find that machine learning models based on billing codes alone can predict preterm birth risk at various gestational ages (e.g., ROC-AUC = 0.75, PR-AUC = 0.40 at 28 weeks of gestation) and outperform comparable models trained using known risk factors (e.g., ROC-AUC = 0.65, PR-AUC = 0.25 at 28 weeks). Examining the patterns learned by the model reveals it stratifies deliveries into interpretable groups, including high-risk preterm birth subtypes enriched for distinct comorbidities. Our machine learning approach also predicts preterm birth subtypes (spontaneous vs. indicated), mode of delivery, and recurrent preterm birth. Finally, we demonstrate the portability of our approach by showing that the prediction models maintain their accuracy on a large, independent cohort (5978 deliveries) from a different healthcare system.ConclusionsBy leveraging rich phenotypic and genetic features derived from EHRs, we suggest that machine learning algorithms have great potential to improve medical care during pregnancy. However, further work is needed before these models can be applied in clinical settings.

DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer.

The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients. We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation-based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively). The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P < .001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P < .001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes. We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

Prognostic effects of clinical parameters, genetic abnormalities, and subtypes in primary gastric diffuse large B-cell lymphoma: a cohort analysis of 146 patients

This study included 146 primary gastric diffuse large B-cell lymphoma patients. Next-generation RNA sequencing and fluorescent in situ hybridization were performed on tumors from 27 and 38 patients, respectively. Five-year and 10-year overall survival (OS) rates were 77% and 57%, respectively. Lugano and TNM clinical stage were independent survival factors. Tier I mutation was found in 21 patients. The genetic subtypes were A53 (n = 3), MCD (n = 5), BN2 (n = 5), N1 (n = 5), EZB (n = 1), and NOS (n = 8). OS was significantly shorter in high-risk genetic subtypes (A53, MCD, and N1) than low-risk subtypes (BN2, EZB, and NOS). Frequencies of high-risk genetic subtypes were higher in patients with Lugano stage II/IV and TNM clinical stage III + IV than in those with Lugano stage I and TNM clinical stage I + II. Although genetic testing was performed in only a small number of cases, the results suggested that high-risk genetic subtypes were associated with advanced clinical stages and shorter survival.

Efficacy of a Coriolusversicolor-Based Vaginal Gel in Human Papillomavirus-Positive Women Older Than 40 Years: A Sub-Analysis of PALOMA Study.

In the PALOMA trial, Papilocare® demonstrated efficacy in repairing low-grade cervical lesions related to human papillomavirus (HPV). This sub-analysis aimed to evaluate its efficacy in repairing these cervical lesions and clearing HPV in women aged older than 40 years. This was a multicenter, randomized, open-label, parallel-group, controlled clinical trial. Patients with low-degree HPV-dependent cervical lesions receiving 6-month treatment with the vaginal gel were compared to those with a watchful waiting approach. Among the 41 women analyzed (aged 47.7 years), 31 presented high-risk (HR) oncogenic HPV subtypes, and 14 had 16-18-31 HPV genotypes. After 6 months, normalized cytology and concordant colposcopy were achieved by a greater percentage of treated women. The difference was significant in the total population (92.3% vs. 50.0%, p = 0.007), and HR-HPV subpopulation (90.5% vs. 33.3%, p = 0.003). In the HR HPVs-16-18-31 subpopulation, the values were 75.0% and 40.0% (p = 0.293). In the total population, 61.5% of treated patients obtained HPV clearance, compared to 50.0% in the control group. Regarding the HR-HPV subpopulation, these values were 66.7% and 44.4%, respectively. Papilocare® demonstrated significant efficacy in repairing low-degree HPV-related cervical lesions and a positive trend to clear HPV in women older than 40 years old in comparison to the watchful waiting approach.

Pyroptosis: a novel signature to predict prognosis and immunotherapy response in gliomas.

Gliomas are the most common primary brain tumors and are highly malignant with a poor prognosis. Pyroptosis, an inflammatory form of programmed cell death, promotes the inflammatory cell death of cancer. Studies have demonstrated that pyroptosis can promote the inflammatory cell death (ICD) of cancer, thus affecting the prognosis of cancer patients. Therefore, genes that control pyroptosis could be a promising candidate bio-indicator in tumor therapy. The function of pyroptosis-related genes (PRGs) in gliomas was investigated based on the Chinese Glioma Genome Atlas (CGGA), the Cancer Genome Atlas (TCGA) and the Repository of Molecular Brain Neoplasia Data (Rembrandt) databases. In this study, using the non-negative matrix factorization (NMF) clustering method, 26 PRGs from the RNA sequencing data were divided into two subgroups. The LASSO and Cox regression was used to develop a 4-gene (BAX, Caspase-4, Caspase-8, PLCG1) risk signature, and all glioma patients in the CGGA, TCGA and Rembrandt cohorts were divided into low- and high-risk groups. The results demonstrate that the gene risk signature related to clinical features can be used as an independent prognostic indicator in glioma patients. Moreover, the high-risk subtype had rich immune infiltration and high expression of immune checkpoint genes in the tumor immune microenvironment (TIME). The analysis of the Submap algorithm shows that patients in the high-risk group could benefit more from anti-PD1 treatment. The risk characteristics associated with pyroptosis proposed in this study play an essential role in TIME and can potentially predict the prognosis and immunotherapeutic response of glioma patients.

Prevalence of high-risk HPV among marginalized urban women in India and its implications on vaccination: A cross sectional study.

To discover the prevalence and distribution of high-risk human papilloma virus (HPV) subtypes in urban slums and their implications. A cross-sectional study was performed to discover prevalence and distribution of high-risk HPV subtypes. We screened 956 women. Data were analyzed using SPSS v.25. Inclusion criterion was married women between 30 and 45 years of age. Exclusion criteria were women with known cervical cancer at the time of the survey or those who had undergone hysterectomy. Of the women, 32.47% were HPV positive and of these, about 84.50% were positive for high-risk HPV. HPV type 6 (HPV 6) and HPV 11 were not seen in the population. After HPV 16 and HPV 18, type 58 was the most common variant seen in our study. Currently-used vaccines in India do not cover HPV 58. Knowing and understanding the distribution of high-risk HPV are necessary for an effective strategy to eliminate cervical cancer from India. Deoxyribonucleic acid-based HPV screening is a useful method along with vaccination to prevent cervical cancer.

Prognostic factors and outcomes of infant acute lymphoblastic leukemia (ALL), hypodiploid ALL, and mixed-phenotype acute leukemia (MPAL) in Canada: a report from CYP-C

The epidemiology of infant acute lymphoblastic leukemia (ALL), hypodiploid ALL, and mixed-phenotype acute leukemia (MPAL) in Canada is unknown. The main objective was to describe the prevalence, prognostic factors, and outcomes of three rare and high-risk ALL subtypes in Canada. This is a retrospective study using the Cancer in Young People-Canada (CYP-C) database. Event-free survival (EFS) and overall survival (OS) were described by the Kaplan–Meier method and compared using the log-rank test. Among 2626 children aged 0–14 years diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) between 2001 and 2018, 227 (8.6%) patients were identified to be infant ALL (n = 139), hypodiploid ALL (n = 43), or MPAL (n = 45). The 5-year EFS/OS was significantly worse in the infant ALL subgroup compared to that of hypodiploid ALL and MPAL. For the entire cohort, presenting White blood cells (WBCs) ≥50 × 109/L was independently associated with worse EFS/OS.

Allogeneic hematopoietic stem cell transplantation overcome the poor prognosis of patients with IKZF1plus CD20-a very high-risk subtype in B-cell acute lymphoblastic leukemia.

Genetic deletions of IKZF1 (IKZF1del) and IKZF1del plus other mutations (IKZF1plus) have been identified in B-cell acute lymphoblastic leukemia (B-ALL) with a poor prognosis. Herein, we investigated the combination of IKZF1del and CD20 immunotypes in adult patients with B-ALL in the PDT-ALL-2016 cohort. This study cohort consisted of 161 patients with B-ALL with detailed information on IKZF1del and CD20 expression. The independent cohort included 196 patients from the TARGET dataset. IKZF1del was detected in 36.0% of patients with 3-year event-free survival (EFS) of 37.1 ± 6.7% and overall survival (OS) of 51.5 ± 7.3%, compared to IKZF1 wild-type (IKZF1wt) with an EFS 55.3 ± 5.1% (P = 0.011) and OS 74.4 ± 4.5% (P = 0.013), respectively. CD20-positive (CD20+) was associated with inferior EFS compared to the CD20-negative (CD20-) group (P = 0.020). Furthermore, IKZF1del coupled with CD20+, IKZF1del/CD20+, comprised 12.4% of patients with a 3-year EFS of 25.0 ± 9.7%, compared with IKZF1wt/CD20- (P ≤ 0.001) and IKZF1del/CD20- (P = 0.047) groups. Multivariable analyses demonstrated the independence of IKZF1del/CD20+, with the highest predicted hazard ratio for EFS and OS. Furthermore, the prognostic panel of IKZF1del/CD20+ was confirmed in the TARGET cohort. Notably, neither the IKZF1del, CD20+, or IKZF1del/CD20+ groups were identified to have poor outcomes in the cohort of allogeneic hematopoietic stem cell transplantation (n = 81).Collectively, our data define IKZF1del/CD20+ as a very high-risk subtype in B-ALL, and allo-HSCT could abrogate the poor outcome of both IKZF1del and IKZF1del/CD20+ subsets.

A signature based on chromatin regulation and tumor microenvironment infiltration in clear cell renal cell carcinoma.

Aims: This research aimed to construct a signature based on chromatin regulation in localized clear cell renal cell carcinoma (ccRCC). Materials & methods: Non-negative matrix factorization clustering was performed on 438localized ccRCC cases. The immune infiltration was generated by the single-sample gene set enrichment analysis algorithm. Survival analyses were performed using the Kaplan-Meier method, and the significance of the differences was determined using the log-rank test. The risk score was constructed based on the expression of chromatin regulators to quantify chromatin modification. Results: A score system based on chromatin modification was established. The high-risk subtype was characterized by increased tumor mutation burden, whereas a low-risk score was characterized by an increase in chromatin regulator expression and better overall survival. Conclusion: This research has constructed a signature based on chromatin regulation in localized ccRCC.

35334 Clinical usage data demonstrates appropriate use of the prognostic 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma with one or more risk factors

Although the overall metastatic rate for cutaneous squamous cell carcinoma (cSCC) is low, because the incidence exceeds a million cases per year, deaths from this disease are estimated to surpass those from melanoma. The risk of poor outcomes guides patient management decisions, therefore accurate risk assessment is critical. Risk assessment occurs through weighting of clinicopathologic risk factors by physician judgement and/or through staging systems (e.g. AJCC staging). The 40-gene expression profile (40-GEP) test was developed and validated to accurately classify risk for regional/distant metastasis as low (Class1), moderate (Class2A), or high (Class2B) in patients with primary cSCC with one or more risk factors. The objective of this study was to report on clinicopathologic conditions leading to clinical usage of the 40-GEP. Summary metrics on the first 2000 clinical cases received that met testing criteria were generated by a review of the clinical requisition form. Risk factors included location on the H or M area, ≥2cm diameter, poorly defined borders, patient immunosuppression, rapidly growing tumor, site of prior radiation or chronic inflammation, high-risk subtype, invasion beyond the subcutaneous fat, poor differentiation, lymphovascular invasion, and perineural invasion. In this clinically tested cohort, the technical reliability of the test was 96.8%. Lesions submitted for testing had 1-2 (50.3%), 3-6 (47.3%), or 7+ (2.4%) risk factors (average of 2.8). The intended use population aligns with cases submitted for clinical testing suggesting that physicians understand appropriate use of molecular prognostic testing. Incorporating 40-GEP test results may support risk-appropriate surveillance and treatment decisions.

High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways and predicts poor patient outcomes

Triple-negative breast cancer (TNBC) is a particularly aggressive and heterogeneous disease with few effective targeted therapies and precision therapeutic options over a long period. It is generally considered that TNBC is an estrogen-independent breast cancer, while a new estrogen receptor, namely G protein-coupled estrogen receptor (GPER), is demonstrated to mediate estrogenic actions in TNBC. Based on our transcriptomic analysis, expression of GPER was correlated with clinicopathological variables and survival of 360 TNBC patients. GPER expression at mRNA level was significantly correlated with immunohistochemistry scoring in 12 randomly chosen samples. According to the cutoff value, 26.4% (95/360) of patients showed high GPER expression and significant correlation with the mRNA subtype of TNBC (P = 0.001), total metastatic events (P = 0.019) and liver metastasis (P = 0.011). In quantitative comparison, GPER abundance is correlated with the high-risk subtype of TNBC. At a median follow-up interval of 67.1 months, a significant trend towards reduced distant metastasis-free survival (DMFS) (P = 0.014) was found by Kaplan–Meier analysis in patients with high GPER expression. Furthermore, univariate analysis confirmed that GPER was a significant prognostic factor for DMFS in TNBC patients. Besides, high GPER expression was significantly linked to the worse survival in patients with lymph node metastasis, TNM stage III as well as nuclear grade G3 tumors. Transcriptome-based bioinformatics analysis revealed that GPER was linked to pro-metastatic pathways in our cohort. These results may supply new insights into GPER-mediated estrogen carcinogenesis in TNBC, thus providing a potential strategy for endocrine therapy of TNBC.

Increased histologic inflammation is an independent risk factor for nonconventional dysplasia in ulcerative colitis

Several types of nonconventional dysplasia have been described in inflammatory bowel disease. Hypermucinous, goblet cell-deficient, and crypt cell dysplasias are considered high-risk subtypes, as they often have molecular features of advanced neoplasia (e.g. aneuploidy) and are more frequently associated with advanced neoplasia than conventional dysplasia. This study investigated if increased colonic inflammation is a risk factor for nonconventional dysplasia. A cohort of 125 patients with ulcerative colitis (UC)-associated dysplasia were analyzed and compared with 50 control UC patients without a history of neoplasia. For each patient, all biopsies prior to the initial detection of dysplasia were scored using a 4-point inflammatory activity score. Both mean and maximum scores from all biopsies taken during each colonoscopy were derived. Inflammation burden was calculated by multiplying the average maximum score between each pair of surveillance episodes by length of surveillance interval in years. The average scores of all colonoscopies were used to calculate overall mean, maximum, and inflammation burden scores. In multivariate analyses, higher maximum (odds ratio [OR] 3.4) and inflammation burden (OR 4.2) scores were significantly associated with the detection of dysplasia (P < 0.05). Similarly, higher mean and maximum scores increased the odds of nonconventional dysplasia by 2.7 and 4.9, respectively (P < 0.05). There was a stronger association between these two scores and high-risk subtypes (ORs 4.0 and 7.5, respectively, P < 0.05). The risk of nonconventional dysplasia is significantly associated with increased colonic inflammation, which may contribute to its higher rates of aneuploidy and malignancy.

Coinfection of HPV18 with some high-risk less frequent HPV subtypes

Coinfection of HPV18 with some high-risk less frequent HPV subtypes

Construction and validation of a novel prognostic model using the cellular senescence-associated long non-coding RNA in gastric cancer: a biological analysis

BackgroundThe onset and progression of many cancers, including gastric cancer (GC), are strongly influenced by cell senescence. Numerous studies have demonstrated that long non-coding RNA (lncRNA) impacts cell senescence, thus affecting cancer progression. However, it is not possible to develop a relevant predictive model for GC owing to the absence of a cell senescence-linked lncRNA. Since lncRNAs are linked to cellular senescence, the goal of this work was to create a prognostic signature for stomach adenocarcinoma (STAD) patients utilizing these lncRNAs.MethodsThrough the Pearson correlation, variance, and univariate Cox regression analyses, the cellular senescence lncRNAs that were related to the disease prognosis could be successfully identified. Using the least absolute shrinkage and selection operator (LASSO) regression algorithm, a predictive model that utilized the 11 cellular senescence-linked lncRNAs was constructed. Kaplan-Meier (KM) survival and the receiver operating characteristic (ROC) curve analyses, were employed for assessing the prognostic performance of the proposed model. In addition, ESTIMATE analysis of the low- and high-risk subtypes for the infiltration of various immune cells was carried out. Additionally, the CIBERSORT algorithm was utilized for investigating the infiltration status of numerous immune cells in both groups, while the expression of the immune checkpoint genes in the two groups, was also determined.ResultsIn this study, a new prognostic model was constructed using 11 cellular senescence-related lncRNAs. The findings revealed that the OS status of the patients in the low-risk group (category) was significantly higher compared to the high-risk category (P<0.001). The 1-year ROC-area under the curve (AUC) values for the risk score in the training group was 0.714, while the AUC value for the test and comprehensive groups were recorded to be 0.666 and 0.695, respectively, which were obviously due to stage, grade, age, etc. And based on univariate [hazard ratio (HR): 1.435; P<0.001; 95% confidence interval (CI): 1.295–1.589] and multivariate analyses (P<0.001; 95% CI: HR: 1.387; 1.247–1.543), it was noted that risk scores were effectively employed as a patient-independent prognostic factor.ConclusionsTaken together, these results suggest that cellular senescence-related lncRNAs are likely to be valuable prognostic markers for GC. They also reflect the situation of the STAD immune microenvironment and may provide direction for future GC treatment.

Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: Case report and literature review.

Introduction and importanceHPV-related carcinoma with adenoid cystic carcinoma-like features currently known as HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a rare distinct head and neck high-risk HPV-related carcinoma. The high-risk HPV subtypes implicated are particularly type 33,35 and 56. So far this is the first reported rare case of a variant of sinonasal carcinoma in Tanzania.Case presentationWe present a 59-year old female who presented with a history of right-sided nasal obstruction and intermittent epistaxis for about one year and later on had ipsilateral proptosis. A provisional diagnosis of advanced right-sided malignant sinonasal tumor was made. Trans nasal biopsy revealed HMSC.Clinical discussionThe patient had a right sided fixed neck mass that measured about 7.5 × 8.2 cm. Magnetic resonance imaging (MRI) of the paranasal sinuses revealed a T1 weighted contrasted images that showed a huge extensive enhancing mass (estimated to measure 4.5 × 4.4) involving the nasal cavity, bilateral ethmoid sinuses, frontal and sphenoid sinuses and also the tumor exhibit intracranial extension (anterior cranial fossa) and tend to compress medial walls of both orbits though more marked on the right side. Histopathology and immunohistochemistry confirmed HPV-related multiphenotypic sinonasal carcinoma. The disease was staged to be T4bN3aM0 and the patient was referred for palliative chemoradiation.ConclusionAlthough HMSC presents at advanced stage in close to half of cases and has a high-grade histological appearance it paradoxically exhibits a relatively indolent manner with frequent local recurrences. Prompt histopathological diagnosis is important to prevent metastases and HMSC-related deaths.

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia

AbstractThe fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.

The value of HPV genotypes combined with clinical indicators in the classification of cervical squamous cell carcinoma and adenocarcinoma

BackgroundTo investigate the differences in HPV genotypes and clinical indicators between cervical squamous cell carcinoma and adenocarcinoma and to identify independent predictors for differentiating cervical squamous cell carcinoma and adenocarcinoma.MethodsA total of 319 patients with cervical cancer, including 238 patients with squamous cell carcinoma and 81 patients with adenocarcinoma, were retrospectively analysed. The clinical characteristics and laboratory indicators, including HPV genotypes, SCCAg, CA125, CA19-9, CYFRA 21–1 and parity, were analysed by univariate and multivariate analyses, and a classification model for cervical squamous cell carcinoma and adenocarcinoma was established. The model was validated in 96 patients with cervical cancer.ResultsThere were significant differences in SCCAg, CA125, CA19-9, CYFRA 21–1, HPV genotypes and clinical symptoms between cervical squamous cell carcinoma and adenocarcinoma (P < 0.05). Logistic regression analysis showed that SCCAg and HPV genotypes (high risk) were independent predictors for differentiating cervical squamous cell carcinoma from adenocarcinoma. The AUC value of the established classification model was 0.854 (95% CI: 0.804–0.904). The accuracy, sensitivity and specificity of the model were 0.846, 0.691 and 0.899, respectively. The classification accuracy was 0.823 when the model was verified.ConclusionThe histological type of cervical cancer patients with persistent infection of high-risk HPV subtypes and low serum SCCAg levels was more prone to being adenocarcinoma. When the above independent predictors occur, the occurrence and development of cervical adenocarcinoma should be anticipated, and early active intervention treatment should be used to improve the prognosis and survival of patients.

Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism.

Metabolic features of the tumor microenvironment (TME) antagonize anti-tumor immunity. We hypothesized that T cell infiltrated tumors with a known antigen should exhibit superior clinical outcomes, though some fare worse given unfavorable metabolic features leveraging T cell-infiltrated (Thi), human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to test this hypothesis. Expression of 2,520 metabolic genes were analyzed among Thi HPV+ HNSCs stratified by high-risk molecular subtype. RNAseq data from The Cancer Genome Atlas (TCGA; 10 cancer types), single cell RNAseq data, and an immunotherapy-treated melanoma cohort were used to test the association between metabolic gene expression and clinical outcomes and contribution of tumor versus stromal cells to metabolic gene expression. Polyamine (PA) metabolism genes were overexpressed in high-risk, Thi HPV+ HNSCs. Genes involved in PA biosynthesis and transport were associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA biogenesis gene sets were associated with tumor intrinsic features while myeloid cells in HPV+ HNSCs were enriched in PA catabolism, regulatory, transport, putrescine, and spermidine gene set expression. PA gene set expression also correlated with IFNγ or cytotoxic T cell ssGSEA scores across TCGA tumor types. PA transport ssGSEA scores were associated with poor survival whereas putrescine ssGSEA scores portended better survival for several tumor types. Thi melanomas enriched in PA synthesis or combined gene set expression exhibited worse anti-PD-1 responses. These data address hurdles to anti-tumor immunity warranting further investigation of divergent polyamine metabolism in the TME.

JAK2 Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 (JAK2) correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating JAK2 point mutations and JAK2 fusion genes in ALL, was a breakthrough for potential targeted therapies. However, the molecular mechanisms by which these alterations activate JAK2 and promote downstream signaling is poorly understood. Furthermore, as clinical data regarding the limitations of approved JAK inhibitors in myeloproliferative disorders matures, there is a growing awareness of the need for alternative precision medicine approaches for specific JAK2 lesions. This review focuses on the molecular mechanisms behind ALL-associated JAK2 mutations and JAK2 fusion genes, known and potential causes of JAK-inhibitor resistance, and how JAK2 alterations could be targeted using alternative and novel rationally designed therapies to guide precision medicine approaches for these high-risk subtypes of ALL.

Periocular basal cell carcinoma recurrence following surgical treatment: Safe surveillance time.

To report the rate of primary periocular BCC recurrence following surgical excision in low-risk and high-risk BCCs, and to propose long term follow up guidelines. Retrospective case series of primary BCC treated with surgical excision (Mohs micrographic surgery [MMS], wide local excision [WLE] or fast paraffin excision) who have histologically-confirmed BCC subtype and histologically-measured tumour clearance margins. 77 patients (78 eyelids) were included. Mean age was 72.0 ± 12.8 years with a female predominance (42, 54.5%). Most common histological BCC subtype was nodular (39, 50.0%). 44 (56.47.1%) patients underwent MMS. Tumour clearance was achieved in 59 (75.6%) eyelids after one surgery. 9 had further surgery to achieve tumour clearance while 10 were monitored. There was no statistical significance between recurrence rates in patients who had tumour clearance compared with patients with incomplete tumour clearance after initial surgery (p = 0.15). In patients with incomplete tumour clearance, there was no statistical significance between recurrence rates in those who underwent further surgery versus those monitored (p = 0.47). Average follow-up duration was 37.9 ± 17.2 months. Three (3.9%) cases had recurrent BCC. All three cases had high-risk BCC features (infiltrative subtypes and/or incomplete tumour excision after initial surgery). There was no evidence of recurrence of completely excised, low-risk BCCs at three years, regardless of type of surgical excision. We recommend patients with completely excised, primary BCCs without high-risk features be monitored for one year. Patients with any high-risk BCC features, such as incompletely excised tumours or high-risk histological subtypes, should be monitored for five years.