In breast cancer (BC), axillary lymph node (ALN) involvement is one of the strongest adverse prognostic factors. However, it is unclear whether loco-regional lymph node deposits are effectively the ...root of secondary metastases or only an indicator of competence of the primary tumour to spread to distant organs.
Here, we investigated the evolutionary trajectories of primary tumour, ALN and distant metastasis samples from 16 estrogen-receptor (ER)-positive lymph node-positive BC patients. Low-pass whole genome sequencing was performed to infer somatic copy number aberrations and the phylogenetic profiles for all patients were obtained.
We show that lymph nodes and distant metastases shared a common origin in only 25% of the cases highlighting that the predominant route of metastatic dissemination is the direct seeding of tumour cells from the primary tumour to distant organs, independently of lymph node metastasis. Noticeably, patients sharing a common origin significantly have worse prognosis.
Our results shed light on the routes on which tumour cells metastasize and their role in disease progression in ER-positive BC.
This work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF), the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS) and from a grant of the Région Wallonne.
Late distant recurrence is a challenge for the treatment of invasive lobular carcinoma (ILC) of the breast. Despite in-depth characterisation of primary ILC, the molecular landscape of metastatic ILC ...is still only partially understood.
We retrospectively identified 38 ILC patients from the tissue banks of six European institutions. DNA extracted from patient matched primary and metastatic FFPE tissue blocks was whole genome sequenced to compute somatic copy number aberrations. This, in turn, was used to infer the evolutionary history of these patients.
The data show different metastatic seeding patterns, with both an early and late divergence of the metastatic lineage observed in ILC. Additionally, cascading dissemination from a metastatic precursor was a dominant rule. Alterations in key cancer driver genes, such as TP53 or CCND1, were acquired early while additional aberrations were present only in the metastatic branch. In about 30% of the patients, the metastatic lineage harboured less aberrations than the primary tumour suggesting a period of tumour dormancy or prolonged adaptation at the distant site. This phenomenon was mostly observed in tumours from de novo metastatic patients.
Our results provide insights into ILC evolution and offer potential paths for optimised ILC care.
This work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF) and the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS).
Abstract Background High levels of tumor-infiltrating lymphocytes (TILs) in primary triple negative and HER2-positive breast cancer (BC) have been associated with an improved patients' outcome. The ...role of TILs in Luminal (hormone receptor positive and HER2 negative) tumors remains to be elucidated. Moreover, the association between TILs and prognosis in the metastatic setting is still unknown. Patients and methods We evaluated the relationship between TILs and time to progression (TTP) in metastatic BC patients enrolled in a prospective phase II trial of metronomic chemotherapy, that used cyclophosphamide 50 mg daily, capecitabine 500 mg thrice daily and vinorelbine 40 mg orally three times a week (VEX combination). Results Of the 108 ER + BC patients enrolled in the VEX trial, 92 (85%) had sufficient tumor tissue and were assessed for TILs in H&E stained slides. TILs were evaluated in 38 primary BC samples and 54 metastatic sites. High (≥10%) TILs levels were significantly correlated with high Ki-67 labeling index. At multivariable analysis, each 10% increase in TILs strongly predicted a worse TTP (HR: 1.27, p = 0.008). VEX trial patients, categorized by a 3 tiers system (0–4%, 5–9% and >10% TILs) showed significantly different progression free survival curves (p = 0.011). Conclusions High TILs levels are significantly associated with a worse TTP in Luminal metastatic BC patients treated by metronomic chemotherapy. Our data confirm the reliability of TILs as a biomarker in the BC metastatic setting. The putative unfavorable prognostic role of TILs in Luminal BC patients might have clinical utility if validated by further studies.
The accumulation of adipose tissue in the body occurs because the energy introduced with food and drink exceeds that expense, but to understand why this imbalance is established and why it is ...maintained over time, it is important to consider the main causes and risk factors of excess weight. In this review, we will refer to the main factors linked to obesity, starting from oxidative stress to hormonal factors including the role of obesity in breast cancer. Among the many hypotheses formulated on the etiopathology of obesity, a key role can be attributed to the relationship between stress oxidative and intestinal microbiota. Multiple evidences tend to show that genetic, epigenetic, and lifestyle factors contribute to determine in the obese an imbalance of the redox balance correlated with the alteration of the intestinal microbial flora. Obesity acts negatively on the wound healing, in fact several studies indicate morbid obesity significantly increased the risk of a post-operative wound complication and infection. Currently, in the treatment of obesity, medical interventions are aimed not only at modifying caloric intake, but also to modulate and improve the composition of diet with the aim of rebalancing the microbiota-redox state axis.
Increasing evidence relate anti-SARS-CoV-2 vaccinations to orofacial adverse reactions, therefore, the present systematic review aimed to evaluate primary oral lesions diagnosed in adult subjects, ...following the WHO Emergency Use Listing approved and EMA authorized vaccines, also in relation to cases’ age, gender, comorbidities, and history of COVID-19, and in relation to vaccine type and doses. The study protocol, registered on PROSPERO (CRD42022339032) and compliant with the PRISMA statement, included an electronic search across Scopus, MEDLINE/PubMed, BioMed Central databases, and PROSPERO, ended on 18 June 2022 and succeeded by a manual search, an independent data extraction, and arisk of bias evaluation through ROBINS-I tool. Qualitatively synthesized data from the 13studies included showed an overall low prevalence (16 cases), though higher in females (68.8%), of oral lesions, mainly erosions and ulcers (34.5%). Nine cases were diagnosed following Pfizer-BioNTech, two Moderna, and one AstraZeneca, Serum Institute of India, Sinopharm, and Johnson&Johnson vaccines, respectively; specifically, eight after the first dose and seven after the second. In one case, vaccine type and dose were not specified. Considering newly developing vaccines, presented findings may be updated and further studies needed to highlight factors affecting oral lesion occurrence and specific macro-microscopic phenotypes in relation to cases’ and vaccines’ characteristics.
Background
In patients with end stage renal disease and atrial fibrillation (AF), undergoing chronic dialysis, direct oral agents are contraindicated and warfarin does not fully prevent embolic ...events while increasing the bleeding risk. The high hemorrhagic risk represents the main problem in this population. Aim of the study was to estimate the safety and efficacy for thromboembolic prevention of left atrial appendage (LAA) occlusion in a cohort of dialysis patients with AF and high hemorrhagic risk.
Methods
Ninety-two dialysis patients with AF who underwent LAA occlusion were recruited. For comparative purposes, two cohorts of dialysis patients with AF, one taking warfarin (oral anticoagulant therapy, OAT cohort, n = 114) and the other not taking any OAT (no-therapy cohort, n = 148) were included in the study. Primary endpoints were (1) incidence of peri-procedural complications, (2) incidence of 2-year thromboembolic and hemorrhagic events, (3) mortality at 2 years. In order to evaluate the effect of the LAA occlusion on the endpoints with respect to the OAT and No-therapy cohorts, a multivariable Cox regression model was applied adjusted for possible confounding factors.
Results
The device was successfully implanted in 100% of cases. Two major peri-procedural complications were reported. No thromboembolic events occurred at 2-year follow-up. The adjusted multivariable Cox regression model showed no difference in bleeding risk in the OAT compared to the LAA occlusion cohort in the first 3 months of follow-up HR 1.65 (95% CI 0.43–6.33), when most of patients were taking two antiplatelet drugs. In the following 21 months the bleeding incidence became higher in OAT patients HR 6.48 (95% CI 1.32–31.72). Overall mortality was greater in both the OAT HR 2.76 (95% CI 1.31–5.86) and No-Therapy HR 3.09 (95% CI 1.59–5.98) cohorts compared to LAA occlusion patients.
Conclusions
The study could open the way to a non-pharmacological option for thromboembolic protection in dialysis patients with AF and high bleeding risk.
A plethora of systemic manifestations of COVID-19 and adverse reactions to COVID-19 vaccines have been described in pediatric subjects. Therefore, the present systematic review primarily aimed to ...assess the prevalence and macro-microscopic features of oral lesions following SARS-CoV-2 infection, grading primary oral lesions based on COVID-19 forms, in pediatric subjects. The secondary aim was to evaluate the epidemiology, clinical appearance, and histopathology of oral lesions following the WHO Emergency Use Listing approved and EMA authorized vaccines, in relation to cases and vaccine characteristics. The study protocol was compliant with the PRISMA statement and registered on PROSPERO (CRD42022351821). Case reports, case series, and observational studies were electronically searched till 27 July 2022, on MEDLINE/PubMed, Scopus, and Cochrane library databases, and the PROSPERO register. Data from nine studies describing oral lesions following viral infection and two records reporting oral lesions following vaccine administration, evaluated through the ROBINS-I tool for quality, were independently extracted and qualitatively synthesized, resulting in scarce, jeopardized, and incomplete findings. Since most of the rare lesions recorded were a part of broad-spectrum systemic disorders and syndromes and, thus. undetailed or nonspecific, further studies should assess oral lesions following SARS-CoV-2 infection and vaccination in pediatric subjects, considering novel viral variants and newly developing vaccines.
In recent years, an increasing prevalence of obesity in inflammatory bowel disease (IBD) has been observed. Obesity, moreover, has been directly correlated with a more severe clinical course and loss ...of response to treatment.
To assess the prevalence and associated factors of obesity in IBD.
We collected data about IBD disease pattern and activity, drugs and laboratory investigations in our center. Anthropometric measures were retrieved and obesity defined as a body mass index (BMI) > 30. Then, we compared characteristics of obese
non obese patients, and Chi-squared test and Student's t test were used for discrete and continuous variables, respectively, at univariate analysis. For multivariate analysis, we used binomial logistic regression and estimated odd ratios (OR) and 95% confidence intervals (CI) to ascertain factors associated with obesity.
We enrolled 807 patients with IBD, either ulcerative colitis (UC) or Crohn's disease (CD). Four hundred seventy-four patients were male (58.7%); the average age was 46.2 ± 13.2 years; 438 (54.2%) patients had CD and 369 (45.8%) UC. We enrolled 378 controls, who were comparable to IBD group for age, sex, BMI, obesity, diabetes and abdominal circumference, while more smokers and more subjects with hypertension were observed among controls. The prevalence of obesity was 6.9% in IBD and 7.9% in controls (not statistically different;
= 0.38). In the comparison of obese IBD patients and obese controls, we did not find any difference regarding diabetes and hypertension prevalence, nor in sex or smoking habits. Obese IBD patients were younger than obese controls (51.2 ± 14.9 years
60.7 ± 12.1 years,
= 0.03). At univariate analysis, obese IBD were older than normal weight ones (51.2 ± 14.9
44.5 ± 15.8,
= 0.002). IBD onset age was earlier in obese population (44.8 ± 13.6
35.6 ± 15.6,
= 0.004). We did not detect any difference in disease extension. Obese subjects had consumed more frequently long course of systemic steroids (66.6%
12.5%,
= 0.02) as well as antibiotics such as metronidazole or ciprofloxacin (71.4%
54.7%,
= 0.05). No difference about other drugs (biologics, mesalazine or thiopurines) was observed. Disease activity was similar between obese and non obese subjects both for UC and CD. Obese IBD patients suffered more frequently from arterial hypertension, type 2 diabetes, non-alcoholic fatty liver disease. Regarding laboratory investigations, obese IBD patients had higher levels of triglyceridemia, fasting blood glucose, gamma-glutamyl-transpeptidase. On multivariate analysis, however, the only factor that appeared to be independently linked to obesity in IBD was the high abdominal circumference (OR = 16.3, 95%CI: 1.03-250,
= 0.04).
Obese IBD patients seem to have features similar to general obese population, and there is no disease-specific factor (disease activity, extension or therapy) that may foster obesity in IBD.
Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) ...gene have been characterized. Biallelic variants in
cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in
in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including
,
and
. The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted
sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic.
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