Transient abnormal myelopoiesis (TAM), also known as transient myeloproliferative disorder or transient leukemia, is a self-regressing neoplasia that afflicts infants with trisomy 21. A recent review article documented "myeloid cell thrombus (MCT)" and "fetal vascular malperfusion (FVM)" in placentas with TAM, although the characteristic TAM placental findings have not been clarified. Here, we compared the clinical and pathological placental findings between trisomy 21 patients with or without TAM. In 13 cases of trisomy 21, we identified six placentas with TAM and seven placentas without TAM. The six placentas with TAM included two stillborn cases. Microscopically, MCT was noted in all the cases, and a high incidence of FVM (50%) was observed in TAM cases. Immunohistochemically, MCT was found to be a platelet-rich thrombus. The placentas were grouped according to the presence or absence of TAM and subsequently compared. Clinically, the incidences of abnormal fetal heart rate pattern and fetal or neonatal death were significantly higher in TAM cases. Pathologically, placenta in TAM cases weighted more than those in cases without TAM, and the incidence of MCT was significantly higher in placentas with TAM. Moreover, the incidence of FVM was higher in placentas with TAM, but this difference was not statistically significant. We propose that MCT is a diagnostic feature of placentas with TAM and may be associated with poor fetal outcomes.

Keywords: Fetal vascular malperfusion; Myeloid cell thrombosis; Pathology; Placenta; Transient abnormal myelopoiesis.

Objectives: To evaluate the prognostic and locoregional metastatic features of carcinoma ex pleomorphic adenoma of submandibular gland (SMG-CXPA) and improve the understanding of this uncommon condition.

Patients and methods: We retrospectively reviewed patients who were diagnosed with SMG-CXPA. The survival data of SMG-CXPA patients were statistically analyzed using Cox regression and Kaplan-Meier method. The associations between cervical metastasis and clinicopathological parameters were evaluated using chi-squared test. Additionally, two different histological categories (histological grade and invasiveness) and their combination were evaluated with the Kaplan-Meier method and receiver operating characteristic curves.

Results: In total, 86 patients were diagnosed: 38 clinically node-negative, 31 pathologically node-negative and 17 node-positive patients. Clinical tumor stage and histological grade were two independent prognostic factors for SMG-CXPA. There were significant correlations between sex, tumor size, clinical tumor stage, clinical lymph node stage, histological grade, invasiveness, malignant components, perineural invasion and no specific criteria exist for the clinical outcome.

Conclusion: SMG-CXPA is a high-grade malignancy with an unfavorable prognosis. Elective neck dissection should be performed in SMG-CXPA patients with a risk of locoregional metastasis. Histological grade seems to be a more valuable predictor of lymph node involvement than invasiveness.

Keywords: carcinoma ex pleomorphic adenoma; locoregional metastasis; prognosis; salivary gland tumor; submandibular gland.

This past decade has seen tremendous advances in understanding the molecular pathogenesis of melanoma and the development of novel effective therapies for melanoma. Targeted therapies and immunotherapies that extend survival of patients with advanced disease have been developed; however, the vast majority of patients experience relapse and therapeutic resistance over time. Moreover, cellular plasticity has been demonstrated to be a driver of therapeutic resistance mechanisms in melanoma and other cancers, largely functioning through epigenetic mechanisms, suggesting that targeting of the cancer epigenetic landscape may prove a worthwhile endeavor to ensure durable treatment responses and cures. Here, we review the epigenetic alterations that characterize melanoma development, progression, and resistance to targeted therapies as well as epigenetic therapies currently in use and under development for melanoma and other cancers. We further assess the landscape of epigenetic therapies in clinical trials for melanoma and provide a framework for future advances in epigenetic therapies to circumvent the development of therapeutic resistance in melanoma.

Keywords: BRAFi, BRAF inhibitor; DNMT, DNA methyltransferase; DNMTi, DNA methyltransferase inhibitor; EZH2, enhancer of zeste homolog 2; EZH2i, enhancer of zeste homolog 2 inhibitor; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor; MEKi, MAPK/extracellular signal‒regulated kinase inhibitor; PTM, post-translational modification; SIRT, sirtuin; TMZ, temozolomide; dsRNA, double-stranded RNA.

Objective: This study aimed to evaluate prognostic outcomes of PVL-derived oral squamous cell carcinomas (P-OSCC) based on recurrence, new primary tumour, metastasis and survival information.

Study design: Five databases and grey literature were searched electronically with the following main keywords (proliferative verrucous leukoplakia, squamous cell carcinoma and malignant transformation) to answer the following review question: 'Are survival outcomes for P-OSCC worse?' based on the PECOS principle. The Joanna Briggs Institute Critical Appraisal tool was used to identify possible biases and assess the quality of each of the primary studies.

Results: A total of 21 articles met the inclusion criteria, and the results of this systematic review suggest that P-OSCC can recur and generate new primary tumours; however, metastases are rare. Thus, most patients remain alive for an average period of 5 years.

Conclusion: Apparently, P-OSCC has better clinical prognostic characteristics than conventional OSCC. There is a lack of information on the main prognostic outcomes of P-OSCC; therefore, specific studies must be performed to achieve a better comparison between P-OSCC and conventional OSCC progression.

Keywords: malignant transformation; metastasis; new primary tumors; new primary tumours; prognosis; proliferative verrucous leukoplakia; recurrence; survival; systematic review.

Motivation: Biomarkers with prognostic ability and biological interpretability can be used to support decision-making in the survival analysis. Genes usually form functional modules to play synergistic roles, such as pathways. Predicting significant features from the functional level can effectively reduce the adverse effects of heterogeneity and obtain more reproducible and interpretable biomarkers. Personalized pathway activation inference can quantify the dysregulation of essential pathways involved in the initiation and progression of cancers, and can contribute to the development of personalized medical treatments.

Results: In this study, we propose a novel method to evaluate personalized pathway activation based on signalling entropy for survival analysis (SEPA), which is a new attempt to introduce the information-theoretic entropy in generating pathway representation for each patient. SEPA effectively integrates pathway-level information into gene expression data, converting the high-dimensional gene expression data into the low-dimensional biological pathway activation scores. SEPA shows its classification power on the prognostic pan-cancer genomic data, and the potential pathway markers identified based on SEPA have statistical significance in the discrimination of high-risk and low-risk cohorts and are likely to be associated with the initiation and progress of cancers. The results show that SEPA scores can be used as an indicator to precisely distinguish cancer patients with different clinical outcomes, and identify important pathway features with strong discriminative power and biological interpretability.

Availability: The MATLAB-package for SEPA is freely available from https://github.com/xingyili/SEPA.

Supplementary information: Supplementary data are available at Bioinformatics online.

Background: Thromboembolic events frequently complicate the course of malignancy and represent a major cause of morbidity and mortality in cancer patients. In contrast to chemotherapy and other systemic therapies, little is known about the impact of ionizing radiations on the incidence of venous thromboembolism (VTE) in cancer patients.

Methods: In the present prospective study, we aimed to investigate the incidence, management, and outcome of VTE in newly diagnosed cancer patients who received curative radiotherapy.

Results: VTE was found in 8 patients, out of 401 patients at a median time of 80 days after radiotherapy initiation. The incidence rate of VTE at 6 months post-treatment was 2% (95% CI, 0.9-3.7), with 50% of cases occurring during the radiotherapy course and 50% of cases in patients who received or were receiving chemotherapy. As none of the patients harbored a personal history of VTE, no prophylactic measure was initiated during cancer therapy. Most patients received monotherapy with low-molecular-weight heparin and were still on surveillance at the end of the study. No specific clinical risk factor was identified that might systematically indicate the need of thromboprophylaxis in the context of curative radiotherapy.

Conclusions: Although this pan-cancer descriptive study did not relate an increased risk of short-term thrombosis following ionizing radiation, it provides important insight as a basis for future studies with subcategories of cancer, in order to in fine guide further recommendations in frail patients.

Clinical trial registration number: NCT02696447.

Keywords: ionizing radiation; pan-cancer; prophylaxis; radiotherapy; venous thromboembolism.

Context-specific control mechanisms of hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha in tumors exposed to oxygen shortage remain incompletely understood. In this issue, Zhang et al (2022) identify a deubiquitinase that differentially stabilizes HIF-2alpha in stem-like glioblastoma cells, suggesting potential implications for regulation of the hypoxic response in a wide array of tissues and cancers.

Purpose: This study identified factors predicting malignant upgrade for atypical ductal hyperplasia (ADH) diagnosed on core-needle biopsy (CNB) and developed a nomogram to facilitate evidence-based decision making.

Methods: This retrospective analysis included women diagnosed with ADH at the National Cancer Centre Singapore (NCCS) in 2010-2015. Cox proportional hazards regression was used to identify clinical, radiological, and histological factors associated with malignant upgrade. A nomogram was constructed using variables with the strongest associations in multivariate analysis. Multivariable logistic regression coefficients were used to estimate the predicted probability of upgrade for each factor combination.

Results: Between 2010 and 2015, 238,122 women underwent mammographic screening under the National Breast Cancer Screening Program. Among 29,564 women recalled, 5,971 CNBs were performed. Of these, 2,876 underwent CNBs at NCCS, with 88 patients (90 lesions) diagnosed with ADH and 26 lesions upgraded to breast malignancy on excision biopsy. In univariate analysis, factors associated with malignant upgrade were the presence of a mass on ultrasound (p = 0.018) or mammography (p = 0.026), microcalcifications (p = 0.047), diffuse microcalcification distribution (p = 0.034), mammographic parenchymal density (p = 0.008). and ≥ 3 separate ADH foci found on biopsy (p = 0.024). Mammographic parenchymal density (hazard ratio [HR], 0.04; 95% confidence interval [CI], 0.005-0.35; p = 0.014), presence of a mass on ultrasound (HR, 10.50; 95% CI, 9.21-25.2; p = 0.010), and number of ADH foci (HR, 1.877; 95% CI, 1.831-1.920; p = 0.002) remained significant in multivariate analysis and were included in the nomogram.

Conclusion: Our model provided good discrimination of breast cancer risk prediction (C-statistic of 0.81; 95% CI, 0.74-0.88) and selected for a subset of women at low risk (2.1%) of malignant upgrade, who may avoid surgical excision following a CNB diagnosis of ADH.

Keywords: Breast; Carcinoma in Situ; Carcinoma, Intraductal, Noninfiltrating; Nomograms; Prognosis.

Background: Identifying branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance.

Objective: We aimed to externally validate the previously developed Dutch-American Risk stratification Tool (DART-1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high-risk stigmata (HRS).

Methods: Three prospective cohorts of individuals under surveillance for BD-IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART-1, a multivariable Cox-proportional logistic regression model with five predictors for the development of WFs or HRS.

Results: Of 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART-1's discriminative ability (C-statistic 0.68) was similar to that in the development cohort (0.64-0.72) and showed moderate calibration. DART-1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3-year risk was 0%-0% versus 0%-3.7% for Q1; 0.3%-0.4% versus 3%-11% for Q2; and 2.6%-3% versus 2.4%-9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%).

Conclusions: The performance of DART-1 to predict the development of WFs or HRS in BD-IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD-IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.

Keywords: intraductal papillary mucinous neoplasm; pancreatic cyst; prediction; prognosis; screening; surveillance.

The global survival rates for childhood cancers are high: approximately 80% of affected children will survive. Nevertheless, the burden of treatment for survivors is also high as three-quarters experience late effects of varying severity following cancer treatment. The aims of this study were to evaluate the treatment-related late effects of patients with childhood solid tumour in northern Finland and to report their survival rates. Our study included 104 patients treated for malignant solid tumours, excluding central nervous system tumours and lymphomas, between 1990 and 2015. Information regarding the type of late effects as well as other clinical data were obtained from the patients' medical records. Late effects were observed in 65 (63%) patients, and almost half (40%) of the patients displayed more than one late effect. The most common late effect was hearing loss (n = 20). The 5-year survival rate in our study was 75%. Conclusion: Our results highlight the importance of long-term follow-up for childhood cancer survivors. As survivors age and survival rates improve, late effects and their impact on patient health as well as the value of surveillance must be considered. What is Known: • Up to three-quarters of childhood cancer survivors experience treatment-related late effects. What is New: • The 5-year survival rate and the prevalence of late effects amongst childhood solid tumour patients treated in northern Finland are in line with findings from previous studies.

Keywords: Childhood; Late effects; Solid tumours; Survival.