Introduction  Pituitary neuroendocrine tumors (PitNETs) are rare skull base tumors which can impart significant disability owing to their locally invasive potential. To date, the gamut of PitNET subtypes remains ill-understood at the ligand-receptor (LR) interactome level, potentially limiting therapeutic options. Here, we present findings from in silico analysis of LR complexes formed by PitNETs with clinical presentations of acromegaly, Cushing\'s disease, high prolactin production, and without symptoms of hormone hypersecretion. Methods  Previously published PitNET gene expression data was acquired from ArrayExpress. These data represented all secretion types. LR interactions were analyzed via a crosstalk score approach. Results  Cortisol (CORT) ligand was significantly involved in tumor-to-tumor signaling across all PitNET subtypes but prolactinomas, which evidenced active CORT depletion. Likewise, CCL25 ligand was implicated in 20% of the top LR complex interactions along the tumor-to-stroma signaling axis, but silent PitNETs reported unique depletion of the CCL25 ligand. Along the stroma-to-tumor signaling axis, all clinical PitNET subtypes enriched stromal vasoactive intestinal polypeptide ligand interactions with tumor secretin receptor. All clinical PitNET subtypes enriched stromal DEFB103B (human β-defensin 103B) ligand interactions with stromal chemokine receptors along the stroma-to-stroma signaling axis. In PitNETs causing Cushing\'s disease, immune checkpoint ligand CD274 reported high stromal expression, and prolactinomas reported low stromal expression. Moreover, prolactinomas evidenced distinctly high stromal expression of immune-exhausted T cell response marker IL10RA compared with other clinical subtypes. Conclusion  Relative crosstalk score analysis revealed a great diversity of LR complex interactions across clinical PitNET subtypes and between solid tumor compartments. More data are needed to validate these findings and exact clinical importance.

BACKGROUND: The progression of tumors from less aggressive subtypes to more aggressive states during metastasis poses challenges for treatment strategies. Previous studies have revealed the molecular subtype conversion between primary and metastatic tumors in breast cancer (BC). However, the subtype conversion during lymph node metastasis (LNM) and the underlying mechanism remains unclear.
METHODS: We compared clinical subtypes in paired primary tumors and positive lymph nodes (PLNs) in BC patients and further validated them in the mouse model. Bioinformatics analysis and macrophage-conditioned medium treatment were performed to investigate the role of macrophages in subtype conversion.
RESULTS: During LNM, hormone receptors (HRs) were down-regulated, while HER2 was up-regulated, leading to the transformation of luminal A tumors towards luminal B tumors and from luminal B subtype towards HER2-enriched (HER2-E) subtype. The mouse model demonstrated the elevated levels of HER2 in PLN while retaining luminal characteristics. Among the various cells in the tumor microenvironment (TME), macrophages were the most clinically relevant in terms of prognosis. The treatment of a macrophage-conditioned medium further confirmed the downregulation of HR expression and upregulation of HER2 expression, inducing tamoxifen resistance. Through bioinformatics analysis, MNX1 was identified as a potential transcription factor governing the expression of HR and HER2.
CONCLUSIONS: Our study revealed the HER2-E subtype conversion during LNM in BC. Macrophages were the crucial cell type in TME, inducing the downregulation of HR and upregulation of HER2, probably via MNX1. Targeting macrophages or MNX1 may provide new avenues for endocrine therapy and targeted treatment of BC patients with LNM.

UNASSIGNED: Extreme temperatures are associated with the risk of preterm birth (PTB), but evidence on the effects of different clinical subtypes and across different regions is limited. We aimed to evaluate the effects of maternal exposure to extreme temperature on PTB and its clinical subtypes in China, and to identify effect modification of regional factors in dimensions of population, economy, medical resources and environmental factors.
UNASSIGNED: This was a prospective population-based cohort of 210,798 singleton live births from 16 counties in eight provinces across China during 2014-2018. We used an extended Cox regression with time-varying variables to evaluate the effects of extreme heat and cold on PTB and its subtypes in the entire pregnancy, each trimester, the last gestational month and week. Meta-analysis and meta-regression were conducted to estimate the pooled effects of each city and effect modification by regional characteristics.
UNASSIGNED: Exposure to heat and cold during the entire pregnancy significantly increased the risk of PTB. The effects varied with subtypes, for medically indicated and spontaneous PTB, hazard ratios were 1·84 (95% CI: 1·29, 2·61) and 1·50 (95% CI: 1·11, 2·02) for heat, 2·18 (95% CI: 1·83, 2·60) and 2·15 (95% CI: 1·92, 2·41) for cold. The associations were stronger for PTB less than 35 weeks than those during weeks 35-36. The effects varied across locations, and GDP per capita (β=-0·16) and hospital beds per 1000 persons (β=-0·25) were protective factors for the effects.
UNASSIGNED: Extreme temperature can increase the risk of medically indicated and spontaneous PTB, and higher regional socio-economic status may moderate such effects. In the context of climate change, such findings may have important implications for protecting the health of vulnerable groups, especially newborns.
UNASSIGNED: National Key R&D Program of China (2018YFA0606200), National Natural Science Foundation of China (42175183), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA20030302), National Natural Science Foundation of China (42071377).

Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of patients with ATL diagnosed in the 1980s. This article highlighted the classification and prognosis of ATL based on different surveys and focused on the comparison of data derived from the available surveys. The 11th nationwide hospital-based survey was conducted in patients with ATL diagnosed in 2010-2011 using the same method as that used in the 1980s survey. The median age of disease onset was 68 years, which was increased compared with previous surveys. While median survival of patients with the acute and lymphoma types had not improved much since the 1980s, the 4-year survival rate was higher. Little improvement in the prognosis was observed for the chronic and smoldering types. The 12th nationwide survey of patients with ATL diagnosed in 2012-2013 also showed an increase in age at onset. Further epidemiological research that includes more cases is needed to deepen our understanding of the actual state of treatment and prognosis of this disease.

Adult T-cell leukemia-lymphoma (ATL) is a rare disease, and the nationwide surveys conducted in Japan have played an important role in improving our understanding of the clinical features and prognosis of this disease. The diagnostic criteria of clinical subtypes have been proposed based on the surveys conducted on patients with ATL who were diagnosed in the 1980s; the current treatment guideline in Japan is based on this classification of ATL subtypes. In the survey for patients diagnosed between 2000 and 2009, the usefulness of the clinical subtypes was confirmed, and soluble interleukin-2 receptor was identified as a new prognostic factor for chronic- and smoldering-type ATL. We conducted another survey for patients who were diagnosed in 2010 and 2011. The age at diagnosis was higher than that reported in previous trials, and the median patient age at diagnosis was 68 years in the study. The 4-year survival rate was better than that in previous studies on acute- and lymphoma-type disease; however, the prognosis has not improved in chronic- and smoldering-type disease. Further nationwide surveys are expected to improve the treatment strategies for ATL.

Cranial nerve palsy is occasionally present in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), but its prevalence, characteristics and relations with the CIDP subtypes have rarely been investigated. The aim of this study was to systematically assess cranial nerve involvement in typical and atypical CIDP.
Clinical data were reviewed in 132 consecutive patients with CIDP, including typical CIDP (n = 89), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (n = 31), distal acquired demyelinating symmetric (DADS) (n = 9) and others (n = 3).
The frequency of cranial nerve palsy was 11% in typical CIDP, 48% in MADSAM and 11% in DADS. Facial and bulbar palsy was most frequently present (9%), followed by ocular motor nerve palsy (5%). Bilateral involvement was seen in all typical CIDP and DADS patients, whereas 80% of MADSAM patients had unilateral palsy. The presence of cranial nerve involvement was associated with more severe limb muscle weakness in typical CIDP, but not in MADSAM. Cranial nerve palsy fully recovered in 90% of typical CIDP and in 67% of MADSAM patients.
Amongst the CIDP subtypes, cranial palsy is frequent and unilateral in MADSAM, and less frequent and bilateral in typical CIDP and DADS. In typical CIDP, facial and bulbar palsy reflects more severe and extensive inflammation.

Angiosarcoma (AS) is a rare sarcoma of endothelial origin, arising spontaneously (primary AS) or after external damage such as radiation therapy or UV exposure (secondary AS). To date, reliable assessment of prognostic factors has proven difficult, due to disease rarity and heterogeneity of study cohorts. Although large registries provide relatively large AS patient series, these cases often lack histological confirmation. This study aimed to analyze AS prognostic factors in a large nationwide cohort of histologically confirmed cases, established through linkage of clinical data from the Netherlands Cancer Registry and pathology data from the Dutch pathology registry (PALGA). All cases were reviewed by an expert pathologist, showing a 16% discordance rate. Multivariable Cox regression survival analysis among 479 confirmed AS patients revealed remarkably poorer overall survival (OS) for primary AS compared to secondary AS (7 vs 21 months, Hazard ratio (HR) = 1.5; 95% confidence interval (CI) = 1.2-1.9). Age above 65 years, male gender, and no surgical treatment also significantly correlated to worse OS. Overall, OS was relatively poor, with a median of 13 months (95% CI = 10-16 months) and 22% five-year survival rate. With this study, we illustrate AS heterogeneity in clinical behavior and show for the first time better survival for secondary AS compared to primary AS.

Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples.
A total of 57 paired primary and metastatic tumours from GEICAM/2009-03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion.
CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3-29) and 9 (range, 1-38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptor-positive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006).
Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution.

BACKGROUND: Tinea capitis is a scalp infection caused by different fungi. Etiological diagnosis is based on suggestive clinical findings and confirmation depends on the fungus growth in culture. However, it is not always possible to perform this test due to lack of availability. The association of clinical and dermatoscopic findings in suspected cases of tinea capitis may help the identification of the etiological agent, facilitating precocious, specific treatment.
METHODS: We report a prospective descriptive analytical study of 34 children with tinea capitis. We performed a trichoscopic examination of all patients; only six children were able to have the mycological culture.
RESULTS: Trichoscopy was abnormal in all 34 patients; it showed hair shaft abnormalities and, in some cases, scalp disorders too. We found that the comma and corkscrew appearance was found in microsporic tinea capitis, V-shaped hair was mainly seen in inflammatory tinea capitis, scales and follicular keratosis in non-inflammatory tinea capitis, and crusts and follicular pustules in inflammatory tinea capitis. Finally, erythema was seen in trichophytic and inflammatory tinea capitis.
CONCLUSIONS: We propose a classification of trichoscopic signs of tinea capitis. This classification will enable rapid diagnosis and prediction of the type of fungus before mycological culture, thus a faster and more adapted management. Our study shows the importance of trichoscopy in the diagnosis and monitoring of tinea capitis. We suggest further prospective studies with a larger number of patients with tinea capitis, having performed mycological culture, to confirm this classification.

Age and tumor subtype are prognostic factors for breast cancer survival, but it is unclear which matters the most. We used population-based data to address this question. We identified 21,384 women diagnosed with breast cancer at ages 20-89 between 2005 and 2015 in the Cancer Registry of Norway. Subtype was defined using estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status as luminal A-like (ER+PR+HER2-), luminal B-like HER2-negative (ER+PR-HER2-), luminal B-like HER2-positive (ER+PR+/-HER2+), HER2-positive (ER-PR-HER2+) and triple-negative (TNBC) (ER-PR-HER2-). Cox regression estimated hazard ratios (HR) for breast cancer-specific 7-year survival by age and subtype, while adjusting for year, grade, TNM stage and treatment. Young women more often had HER2-positive and TNBC tumors, while elderly women (70-89) more often had luminal A-like tumors. Compared to age 50-59, young women had doubled breast cancer-specific mortality rate (HR = 2.26, 95% CI 1.81-2.82), while elderly had two to five times higher mortality rate (70-79: HR = 2.25, 1.87-2.71; 80-89: HR = 5.19, 4.21-6.41). After adjustments, the association was non-significant among young women but remained high among elderly. Young age was associated with increased breast cancer-specific mortality among luminal A-like subtype, while old age was associated with increased mortality in all subtypes. Age and subtype were strong independent prognostic factors. The elderly always did worse, also after adjustment for subtype. Tumor-associated factors (subtype, grade and stage) largely explained the higher breast cancer-specific mortality among young. Future studies should address why luminal A-like subtype is associated with a higher mortality rate in young women.