Aims/hypothesis This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy. Methods PubMed, EMBASE and Web of Science were searched for ...articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease ESRD) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group. Results The literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes). Conclusions/interpretation This meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.
Summary
Background
The Clinicopathological and Gene Expression Profile (CP‐GEP) model was developed to accurately identify patients with T1–T3 primary cutaneous melanoma at low risk for nodal ...metastasis.
Objectives
To validate the CP‐GEP model in an independent Dutch cohort of patients with melanoma.
Methods
Patients (aged ≥ 18 years) with primary cutaneous melanoma who underwent sentinel lymph node biopsy (SLNB) between 2007 and 2017 at the Erasmus Medical Centre Cancer Institute were eligible. The CP‐GEP model combines clinicopathological features (age and Breslow thickness) with the expression of eight target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, CXCL8 and MLANA). Using the pathology result of SLNB as the gold standard, performance measures of the CP‐GEP model were calculated, resulting in CP‐GEP high risk or low risk for nodal metastasis.
Results
In total, 210 patients were included in the study. Most patients presented with T2 (n = 94, 45%) or T3 (n = 70, 33%) melanoma. Of all patients, 27% (n = 56) had a positive SLNB, with nodal metastasis in 0%, 30%, 54% and 16% of patients with T1, T2, T3 and T4 melanoma, respectively. Overall, the CP‐GEP model had a negative predictive value (NPV) of 90·5% 95% confidence interval (CI) 77·9–96.2, with an NPV of 100% (95% CI 72·2–100) in T1, 89·3% (95% CI 72·8–96·3) in T2 and 75·0% (95% CI 30·1–95·4) in T3 melanomas. The CP‐GEP indicated high risk in all T4 melanomas.
Conclusions
The CP‐GEP model is a noninvasive and validated tool that accurately identified patients with primary cutaneous melanoma at low risk for nodal metastasis. In this validation cohort, the CP‐GEP model has shown the potential to reduce SLNB procedures in patients with melanoma.
What is already known about this topic?
The majority (70–85%) of patients with cutaneous melanoma who undergo a sentinel lymph node biopsy (SLNB) procedure have no metastasis in the SLN.
To identify patients at low risk for nodal metastasis, the Clinicopathological and Gene Expression Profile (CP‐GEP) model was developed (n = 754 patients, US cohort).
The CP‐GEP model combines age, Breslow thickness and the expression of eight target genes involved in melanoma metastasis, and has the potential to reduce SLNB procedures in patients with T1–T3 cutaneous melanoma.
What does this study add?
This is the first independent validation of the CP‐GEP model in European patients with primary cutaneous melanoma.
The CP‐GEP model can be applied to full‐excision tumour tissue and does not require macrodissection of tumour tissue.
The CP‐GEP model has a negative predictive value of 90·5% (95% confidence interval 77·9–96·2) in T1–T3 melanomas.
The CP‐GEP model is a promising tool in patient care. In this validation cohort, the CP‐GEP model has shown the potential to reduce SLNB procedures in patients with primary cutaneous melanoma.
Summary
Background
Recurrent cutaneous squamous cell carcinoma (cSCC) has been associated with an increased risk of local functional and aesthetic comorbidity, metastasis and mortality.
Objectives
To ...compare the risk of recurrence between Mohs micrographic surgery (MMS) and standard excision for cSCC of the head and neck.
Methods
This was a retrospective cohort study of all patients with a cSCC treated with MMS or standard excision at the departments of dermatology of a secondary or tertiary care hospital in the Netherlands between 2003 and 2012. To detect all recurrences, patients were linked to the Dutch pathology registry. To compare the risk of recurrence between MMS and standard excision, hazard ratios (HRs) were used adjusted for clinical tumour size > 2 cm and deep tumour invasion.
Results
A total of 579 patients with 672 cSCCs were included: 380 cSCCs were treated with MMS and 292 with standard excision. The risk of recurrence was 8% (22 of 292) after standard excision during a median follow‐up of 5·7 years interquartile range (IQR) 3·5–7·8, which was higher than the 3% (12 of 380) after MMS during a median follow‐up of 4·9 years (IQR 2·3–6·0). The cumulative incidence of recurrence was higher for standard excision than for MMS during the entire follow‐up period of 8·6 years. Carcinomas treated with MMS were at a three times lower risk of recurrence than those treated with standard excision when adjusted for tumour size and deep tumour invasion (adjusted HR 0·31, 95% confidence interval 0·12–0·66).
Conclusions
MMS might be superior to standard excision for cSCCs of the head and neck because of a lower rate of recurrence.
What's already known about this topic?
Recurrent cutaneous squamous cell carcinoma has been associated with an increased risk of local functional and aesthetic comorbidity, metastasis and mortality.
What does this study add?
Risk of recurrence was 8% after standard excision, which was higher than the 3% after Mohs micrographic surgery.
Mohs micrographic surgery might be superior to standard excision for squamous cell carcinomas of the head and neck because of a lower rate of recurrence.
Linked Editorial: Motley and Arron. Br J Dermatol 2019; 181:233–234.
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Abstract Background Uterine serous carcinoma (USC) shows greater morphological, clinical and molecular similarities to high-grade ovarian tubal serous carcinoma than to other types of endometrial ...cancer. As high-grade ovarian tubal serous carcinoma is known to be associated with BRCA1/ 2 pathogenic germline mutations (PMs), we aimed to explore whether USC is also a constituent of hereditary breast and ovarian cancer syndrome. Methods Pubmed, EMBASE and Web of Science were searched in July 2016 for articles assessing the association between USC and germline BRCA1/2 -PMs. Pooled analysis and comparisons were performed using a random effects logistic model, stratifying for ethnicity (Ashkenazi versus non-Ashkenazi). In addition, tumour tissue from an USC case with a hereditary BRCA1 -PM was analysed for loss of heterozygosity at the BRCA1 locus and was functionally analysed for homologous recombination proficiency. Results The search yielded 1893 citations, 10 studies were included describing 345 USC patients. For Ashkenazi Jews, the pooled odds ratio of having a germline BRCA1/2 -PM was increased in USC patients compared with the general Ashkenazi population: odds ratio 5.4 (95%confidence interval: 2.2–13.1). In the patient with USC, we identified the known germline BRCA1 -PM in the tumour DNA. Furthermore, we showed both loss of heterozygosity of the wild-type allele and a deficiency of homologous recombination. Conclusion This study suggests that USC may be an overlooked component of BRCA1/2 -associated hereditary breast and ovarian cancer syndrome. Screening for germline BRCA1/2 -PMs should be considered in patients diagnosed with USC, especially in cases with a positive first-degree family history for breast and/or ovarian cancer.
BACKGROUND Pre-eclampsia has a clear familial component, suggesting that the condition may be partly attributable to genetic susceptibility. The search for susceptibility genes has led to a drastic ...increase in the number of published studies associating genetic factors with pre-eclampsia. However, attempts to replicate these findings have yielded inconsistent results. This meta-analysis assessed the pooled effect of each genetic variant that is reproducibly associated with pre-eclampsia. METHODS Studies that assessed the association between genes and pre-eclampsia were searched in PubMed, Embase and Web of Science. We selected all genetic variants that were significantly associated with pre-eclampsia in an initial study and were subsequently independently reproduced in at least one additional study. All studies that assessed these reproduced variants were then included. The association between genetic variants and pre-eclampsia was calculated at the allele level, and the main measure of effect was a pooled odds ratio in a random-effects model. RESULTS The literature search yielded 2965 articles, of which 542 investigated genetic associations in pre-eclampsia. We identified 22 replicated genetic variants, of which 7 remained significantly associated with pre-eclampsia following meta-analysis. These variants were in or near the following genes: ACE, CTLA4, F2, FV, LPL and SERPINE1. CONCLUSIONS This meta-analysis identified seven genetic variants associated with pre-eclampsia. Importantly, many of these variants are also risk factors for developing cardiovascular disease, revealing that pre-eclampsia and cardiovascular disease have shared genetic risk factors. The contribution of the identified genetic variants in the pathogenesis of pre-eclampsia should be the focus of future studies.
Background
Lentigo maligna (LM) based on biopsy material might be lentigo maligna melanoma (LMM) after excision.
Objectives
Investigate whether clinical and dermoscopic mapping increases the ...detection rate of LMM when investigating staged excision specimens of biopsy proven LM.
Methods
Patients with biopsy‐proven LM planned for staged excision were included. Using clinical inspection and dermoscopy, spots suspicious for LMM were marked. After the excision, needles were placed at the marked spots. Histological examination using vertical sections was done at the needles followed by the standard amount of vertical sections.
Results
In 28 of the 58 biopsy‐proven LM, there was clinical suspicion of LMM, only 3 of these 28 cases were upgraded into LMM. These three cases showed LMM in other sections, whereas only 1 case showed LMM around the needle. Within the group without clinical suspicion of LMM, 2 cases were LMM. Biopsy‐proven LM were in fact LMM in 8.6% of the cases and were found without the clinical guidance of the dermatologist.
Conclusions
8.6% of the biopsy‐proven LM were LMM after complete histological examination. In this study, the dermatologist was not able to increase the detection rate of LMM by using clinical and dermoscopic mapping.
Purpose
Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell ...percentage and high-quality RNA. As a consequence, a certain amount of samples drop out. If tumor characteristics are different between samples included and excluded from GE profiling, this can lead to bias. Therefore, we assessed whether patient and tumor characteristics differ between tumors suitable or unsuitable for generating GE profiles in breast cancer.
Methods
In a consecutive cohort of 738 breast cancer patients who received neoadjuvant chemotherapy at the Netherlands Cancer Institute, GE profiling was performed. We compared tumor characteristics and treatment outcome between patients included and excluded from GE profiling. Results were validated in an independent cohort of 812 patients treated with primary surgery.
Results
GE analysis could be performed in 53% of the samples. Patients with tumor GE profiles more often had high-grade tumors odds ratio 2.57 (95%CI 1.77–3.72),
p
< 0.001 and were more often lymph node positive odds ratio 1.50 (95%CI 1.03–2.19),
p
= 0.035 compared to the group for which GE profiling was not possible. In the validation cohort, tumors suitable for gene expression analysis were more often high grade.
Conclusions
In our gene expression studies, tumors suitable for GE profiling had more often an unfavorable prognostic profile. Due to selection of samples with a high tumor percentage, we automatically select for tumors with specific features, i.e., tumors with a higher grade and lymph node involvement. It is important to be aware of this phenomenon when performing gene expression analysis in a research or clinical context.
Background
Mastocytosis is characterized by the accumulation of mast cells (MCs) in the skin or other organs, and can manifest at any age. A significant number of paediatric mastocytosis cases ...persist after puberty. In particular, monomorphic maculopapular cutaneous mastocytosis (mMPCM) is often persistent and associated with systemic mastocytosis. However, clinical differentiation of MPCM from polymorphic (p)MPCM can be difficult.
Aim
To identify histopathological features that can help to distinguish mMPCM from other subtypes of paediatric mastocytosis.
Methods
This was a retrospective study using skin biopsies from patients with any subtype of mastocytosis. The localization and density of the MC infiltrate, MC morphology and expression of aberrant markers were evaluated and correlated with clinical characteristics.
Results
In total, 33 biopsies were available for evaluation from 26 children (10 with mMPCM, 5 with mastocytoma, 3 with diffuse cutaneous mastocytosis (DCM), 8 with pMPCM) and 7 adults with MPCM. The MC number was increased in all patients, but was higher in children than adults (P < 0.01). The presence of mMPCM was associated with sparing of the papillary dermis from MC infiltration, whereas MC density in the papillary dermis was highest in pMPCM and DCM (P < 0.01). The positive predictive value of the presence of a reticular MC infiltrate for mMPCM was 72.7% (95% CI 51.4–87.0), and the negative predictive value was 83.3% (95% CI 42.2–97.2). There were no relevant differences in the expression of CD2, CD25 or CD30 between the different subtypes.
Conclusion
Skin histopathology might enhance the phenotypical differentiation of mMPCM from other subtypes in children, thereby increasing the accuracy of one's prognosis.
In this study, we found that paediatric monomorphic maculopapular cutaneous mastocytosis (mMPCM) was associated with a specific histopathological pattern compared with other paediatric subtypes of mastocytosis such as polymorphic (p)MPCM. Paediatric mMPCM was characterized by a predominantly reticular situated MC infiltrate with sparing of the papillary dermis. This was similar to the pattern seen in adult‐onset MPCM; however, total MC counts in lesional skin were significantly higher in children compared with adults. Histopathology might be a useful addition to the clinical phenotype and laboratory parameters to distinguish mMPCM from pMPCM in children.
Summary
Cutaneous squamous cell carcinoma (cSCC) is a serious complication after organ transplantation and patients benefit from an early risk assessment. We hypothesized that functional differences ...in circulating T cells may represent risk factors for post‐transplant cSCC development. Here, we analysed genome‐wide DNA methylation of circulating T cells of kidney transplant recipients before the clinical onset of cSCC, to identify differences associated with post‐transplant cSCC development. This analysis identified higher DNA methylation of SERPINB9, which is an intracellular inhibitor of granzyme B, a protein that induces apoptosis in target cells. High DNA methylation of SERPINB9 in circulating T cells was confirmed in a second patient cohort during recurrent cSCC, indicating that high SERPINB9 methylation represents a persistent risk factor for cSCC development. At the functional level, the inverse correlation between DNA methylation and messenger RNA expression present in non‐cSCC patients was absent in the cSCC patients. Also, a significant difference in serpinB9 protein expression between cSCC patients and non‐cSCC patients was observed. It was concluded that disturbed regulation of serpinB9 in circulating T cells represents a novel risk factor for post‐transplant cSCC in kidney transplant recipients.
Figure 2 Cutaneous squamous cell carcinoma (cSCC) is a very common complication after kidney transplantation. We identified a higher methylated region in SERPINB9 in circulating T cells of patients with post‐transplant cSCC, both before and after they developed a de novo post‐transplant cSCC. In addition, we also demonstrated a disturbed transcriptional regulation of SERPINB9 and a lower protein expression of serpinB9 in cSCC patients.
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