Histological Features Associated With Human Mpox Virus Infection in 2022 Outbreak in a Nonendemic Country.

Skin histology of papules and pustules from 5 men having sex with men with mpox infection showed viral intracytoplasmic cytopathic changes, interface dermatitis, marked inflammatory dermic infiltrate including superficial neutrophils and perivascular and periadnexal deep lymphocytes. Histologic description of mpox lesions improves our understanding about clinical presentations and may have some therapeutic implications.

Diagnostic Accuracy of GATA6 Immunostaining in Sebaceous Tumors of the Skin.

The accurate diagnosis of skin adnexal neoplasms is sometimes challenging but is necessary because medical management and follow-up may differ between tumors. GATA6 transcription factor has been identified as a new marker of the upper folliculosebaceous compartment (lower infundibulum, junctional zone and isthmus, and upper sebaceous gland) in the human skin. We aimed to determine the diagnostic accuracy of GATA6 immunostaining to diagnose sebaceous tumors compared with that to diagnose other adnexal and nonadnexal cutaneous neoplasms. We conducted a retrospective, evaluator-nonblinded study comparing the reference standard (diagnosis by an expert dermatopathologist) with GATA6 immunostaining to identify sebaceous tumors in a cohort containing 234 different tumors. The GATA6 expression score was significatively higher in sebaceous than that in nonsebaceous tumors. In addition, tumors originating from the upper hair follicle showed positive results for GATA6 staining; however, they showed lower GATA6 expression scores. Detection of sebaceous tumors using GATA6 positivity had a sensitivity of 95.7% (95% CI, 85.8-99.2), specificity of 80.8% (95% CI, 74.5-85.8), positive predictive value of 55.6% (95% CI, 44.7-65.9), and negative predictive value of 98.7% (95% CI, 95.4-99.8). GATA6 showed similar sensitivity to adipophilin, the reference marker; however, the specificity of GATA6 was higher, as observed in a cohort of 106 tumors enriched in squamous cell carcinomas with clear-cell histology. In addition, GATA6 positivity was assessed in 39 sebaceous carcinomas and compared with epithelial membrane antigen (EMA), CK7, and androgen receptor (AR) staining results. Although CK7 staining displayed lower diagnostic performances, GATA6 staining showed comparable results as EMA and AR. Finally, we found GATA6 expression in skin metastases of gastrointestinal origin, whereas GATA6 was absent in metastases originating from breast or lung cancers. Overall, our work identified GATA6 immunostaining as a new diagnostic tool for sebaceous tumors.

DHA, RvD1, RvD5, and MaR1 reduce human coronary arteries contractions induced by PGE2.

In patients with coronary artery disease (CAD), plasma levels of pro-inflammatory lipid mediators such as PGE2 and TxA2 are increased. They could increase vascular contraction while EPA and DHA could reduce it. Studies have been mostly conducted on animal vessels. Therefore, the aim of the study was to investigate if EPA, DHA, and DHA-derived metabolites: RvD1, RvD5 and MaR1 can modulate contraction of human coronary arteries (HCA) induced by PGE2 or TxA2 stable analogue (U46619). DHA and EPA relaxed HCA pre-contracted with PGE2. 18 h-incubation with DHA but not EPA reduced the PGE2-induced contractions. Pre-incubation with RvD1, RvD5 and MaR1 reduced the PGE2-induced contractions. Indomethacin did not significantly modify the PGE2 responses. L-NOARG (inhibitor of nitric oxide synthase), reduced only the PGE2-induced contractions in RvD1-treated rings. Finally, FPR2/ALX, GPR32 and LGR6 receptors are detected in HCA by immunofluorescence. Our results indicate that DHA and its metabolites could be beneficial for HCA blood flow and could be a therapeutic perspective for patients with CAD.

Recurrent FOXK1::GRHL and GPS2::GRHL fusions in trichogerminoma.

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.

Microsecretory adenocarcinoma of the skin, a novel type of sweat gland carcinoma: Report of three additional cases.

Microsecretory adenocarcinoma (MSA) is a newly described salivary gland tumor harboring a characteristic balanced chromosomal translocation resulting in MEF2C::SS18 gene fusion. Six primary cutaneous MSA cases have been recently described. We report three additional cases confirming the relevance of this recently identified entity of primary cutaneous adnexal tumor. Three patients aged 53-, 64- and 78-year-old were retrospectively diagnosed with MSA of the skin (MSAS) as consultation cases of the CARADERM (CAncers RAres DERMatologiques) national network. The clinical presentation was an indolent nodule on the upper extremities. There was no history of salivary gland tumor. Histopathologically, the tumors presented as dermal nodular proliferation with slightly infiltrative borders, composed of cribriform and microcystic structures with abundant myxoid intraluminal secretion embedded in a fibromyxoid stroma. They diffusely expressed cytokeratin 8 and SOX10, focally p63 and heterogeneously smooth muscle actin. All tumors harbored the MEF2C::SS18 gene fusion. A complete surgical excision was performed. No local recurrence or distant metastases were observed so far (follow-up: 17, 38, and 45 months). MSAS is the cutaneous homologue of MSA of the salivary gland, a low-grade adnexal neoplasm whose prognosis seems to be excellent once the complete removal of the tumor is assured.

Chemical characterization of inks in skin reactions to tattoo.

Skin reactions are well described complications of tattooing, usually provoked by red inks. Chemical characterizations of these inks are usually based on limited subjects and techniques. This study aimed to determine the organic and inorganic composition of inks using X-ray fluorescence spectroscopy (XRF), X-ray absorption spectroscopy (XANES) and Raman spectroscopy, in a cohort of patients with cutaneous hypersensitivity reactions to tattoo. A retrospective multicenter study was performed, including 15 patients diagnosed with skin reactions to tattoos. Almost half of these patients developed skin reactions on black inks. XRF identified known allergenic metals - titanium, chromium, manganese, nickel and copper - in almost all cases. XANES spectroscopy distinguished zinc and iron present in ink from these elements in endogenous biomolecules. Raman spectroscopy showed the presence of both reported (azo pigments, quinacridone) and unreported (carbon black, phtalocyanine) putative organic sensitizer compounds, and also defined the phase in which Ti was engaged. To the best of the authors' knowledge, this paper reports the largest cohort of skin hypersensitivity reactions analyzed by multiple complementary techniques. With almost half the patients presenting skin reaction on black tattoo, the study suggests that black modern inks should also be considered to provoke skin reactions, probably because of the common association of carbon black with potential allergenic metals within these inks. Analysis of more skin reactions to tattoos is needed to identify the relevant chemical compounds and help render tattoo ink composition safer.

Diagnosis and staging of cardiac masses: additional value of CMR with 18F-FDG-PET compared to CMR with CECT.

PURPOSE: Characterization of malignant cardiac masses is usually performed with cardiac magnetic resonance (CMR) and staging with whole-body contrast-enhanced computed tomography (CECT). In this study, our objective was to evaluate the role of 18Fluor-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) with CMR for both characterization and staging of cardiac masses. METHODS: Patients with cardiac masses who underwent CMR, CECT, and 18F-FDG-PET were retrospectively identified. For the characterization of cardiac masses, we calculated the respective performances of CMR alone, 18F-FDG-PET alone, and the combination of 18F-FDG-PET and CMR. For staging, we compared head-to-head the respective performances of 18F-FDG-PET and CECT. Histology served as gold standard for malignancy, and response to anticoagulation for thrombus. RESULTS: In a total of 28 patients (median age 60.5 years, 60.7% women), CMR accurately distinguished malignant from benign masses with sensitivity (Se) of 86.7%, specificity (Sp) of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 86.7%, and accuracy of 92.9%. 18F-FDG-PET demonstrated 93.3% Se, 84.6% Sp, 87.5% PPV, 91.7% NPV, and 89.3% accuracy. Combining CMR with 18F-FDG-PET allowed to benefit from the high sensitivity of 18F-FDG-PET (92.9%) and the excellent specificity of CMR (100%) for malignant diseases. For staging, 18F-FDG-PET outperformed CECT on per-patient (66.7% vs 55.6% correct diagnosis, respectively), per-organ (10 vs 7 organs, respectively), and per-lesion basis (> 29 vs > 25 lesions, respectively). CONCLUSION: Combining 18F-FDG-PET with CMR improved the characterization of cardiac masses compared to each modality alone. Additionally, the diagnostic performance of 18F-FDG-PET was better than CECT for staging. This study suggests that the combination of CMR and 18F-FDG-PET is the most effective for the characterization of cardiac masses and the staging of these lesions.

Treatment strategies and safety of rechallenge in the setting of immune checkpoint inhibitors-related myositis: a national multicentre study.

OBJECTIVES: The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyse the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICIs) rechallenge. METHODS: We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analysed in both groups. The modalities and outcomes of ICI rechallenge were reviewed. RESULTS: Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favourable evolution, including one irM-related death, and required heavy immunosuppression. ICIs were safely reintroduced in nine patients presenting a moderate (n = 6) or a severe (n = 3) irM. CONCLUSION: Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favour of a safe reintroduction of ICI following symptom resolution and creatin kinase (CK) normalization in moderate and severe forms of irM.

Truncating mutations of TP53AIP1 gene predispose to cutaneous melanoma.

Genetic predisposition to cutaneous malignant melanoma (CMM) involves highly penetrant predisposing genes and low and intermediate penetrant predisposing alleles. However, the missing heritability in (CMM) is still high. For such and in order to identify new genetic factors for CMM, we conducted an exome sequencing study in high-risk CMM patients. Two rounds of exome sequencing were successively performed in 33 and 27 high-risk patients. We focused on genes carrying rare nonsense, frameshift, and splice variants (allelic frequency <1%) that were present in both series of exomes. An extension study was then conducted in a large cohort (1 079 CMM patients and 1 230 Caucasian ethnically matched healthy controls), and the inactivating variants frequency was compared between groups using two-sided Fisher exact test. Two TP53AIP1 truncating mutations were identified in four patients: a frameshift c.63_64insG, p.Q22Afs*81 in two patients from the same family and in the proband of a second family; and a nonsense mutation c.95 C > A, p.Ser32Stop in a patient with multiple CMMs. In all patients, TP53AIP1 truncating variants were strongly associated with CMM risk (two-sided Fisher exact test = 0.004, OR = 3.3[1.3-8.5]). Additionally, we showed that TP53AIP1 mRNA was strongly down-regulated throughout different phases of melanoma progression. TP53AIP1 gene is a TP53 target which plays a key role by inducting apoptosis in response to UV-induced DNA damage. Constitutional mutations of TP53AIP1 had previously been involved in susceptibility to prostate cancer. Our results show that constitutional truncating TP53AIP1 mutations predispose to CMM in the French population. Replication studies in other populations should be performed.

Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype.

We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of α5/ß1/αv/ß3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma.

Imbalanced Angiogenesis in Peripartum Cardiomyopathy　- Diagnostic Value of Placenta Growth Factor.

BACKGROUND: Concentrations of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) are altered in peripartum cardiomyopathy (PPCM). In this study we investigated changes in the angiogenesis balance in PPCM.Methods and Results:Plasma concentrations of sFlt-1 and the pro-angiogenic placenta growth factor (PlGF) were determined in patients with PPCM during the post-partum phase (n=83), in healthy women at delivery (n=30), and in patients with acute heart failure (AHF; n=65). Women with cardiac failure prepartum or associated with any form of hypertension, including pre-eclampsia, were excluded. Compared with non-pregnant women, in women with AHF and PPCM, median PlGF concentrations were greater (19 [IQR 16-22] and 98 [IQR 78-126] ng/mL, respectively; P<0.001) and the sFlt-1/PlGF ratio was lower (9.8 [6.6-11.3] and 1.2 [0.9-2.8], respectively; P<0.001). The sFlt-1/PlGF ratio was lower in PPCM than in normal deliveries (1.2 [0.9-2.8] vs. 94.8 [68.8-194.1], respectively; P<0.0001). The area under the curve for PlGF (cut-off value: 50ng/mL) and/or the sFlt-1/PlGF ratio (cut-off value: 4) to distinguish PPCM from either normal delivery or AHF was >0.94. Median plasma concentrations of the anti-angiogenic factor relaxin-2 were lower in PPCM and AHF (0.3 [IQR 0.3-1.7] and 0.3 [IQR 0.3-1] ng/mL, respectively) compared with normal deliveries (1,807 [IQR 1,101-4,050] ng/mL; P<0.001). CONCLUSIONS: Plasma of PPCM patients shows imbalanced angiogenesis. High PlGF and/or low sFlt-1/PlGF may be used to diagnose PPCM.

MRI characteristics of carotid bulb atypical fibromuscular dysplasia in black stroke patients.

BACKGROUND AND PURPOSE: In black stroke patients, a particular form of fibromuscular dysplasia (FMD), called atypical FMD (aFMD), is involved in stroke mechanism. The high rate of stroke recurrence under medical treatment leads to propose surgery in such patients. Regarding its location level on the carotid bulb, aFMD is often confused with atherosclerosis or free-floating thrombus. Nowadays, only histology can confirm the diagnosis. MRI of aFMD has never been assessed. MATERIALS AND METHODS: The constitution of a black patient's cohort with aFMD-related ischemic stroke is currently in progress in the French West Indies, Martinique. In patients scheduled for surgery, MRI of the carotid bifurcation was analyzed preoperatively, with subsequent histological examination of the excised specimen. The first four black stroke patients with MRI and histological findings are described. RESULTS: On imaging, aFMD lesion was homogeneous with isosignal on T2-weighted sequences and slight hypersignal on T1-weighted sequences with mild gadolinium enhancement of the inner layer. Histological findings confirmed the aFMD mainly located in the intima. CONCLUSIONS: aFMD generates a particular MRI pattern in our four patients, which could increase the diagnosis accuracy. Carotid bulb lesion in black stroke patients should suggest aFMD and MRI analysis may contribute to rule out differential diagnoses.

Sézary syndrome without erythroderma.

BACKGROUND: Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement. OBJECTIVE: We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma. METHODS: Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied. RESULTS: Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred. LIMITATIONS: Retrospective design and small sample size are limitations. CONCLUSION: Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.